gmp
TRANSCRIPT
Email|Print| Share
Del.icio.us Digg Reddit Facebook
|Save|LicenseManufacturing Considerations for Sourcing GMP Fermentation Services
The authors describe the critical aspects of an ideal fermentation services provider.
Sep 1, 2008By: Sheryl Henderson, Steven McWethy, Keith DixonPharmaceutical Technology
The need for good manufacturing practices (GMP) fermentation is likely to increase during the next several years—at a time when many pharmaceutical businesses are rationalizing and sometimes downsizing their core manufacturing operations, resulting in what many believe will be a growing need to identify outsourced fermentation sources to augment their own supply chains. Seeking additional outsourcing strategies while working to ensure quality for their end products, manufacturers are increasingly challenged when
sourcing such specialized functions as large-scale fermentation.
GMP fermentation today is a complex process that requires a large investment in expertise, equipment, process, and quality control, and very few companies in the industry currently have or choose to invest in developing those resources in-house. A deep understanding of quality systems, strain development, process development, scale-up, isolation, and purification can help ensure pharmaceutical firms make the right decisions in large-scale fermentation outsourcing and help companies make the right choices for their supply-chain requirements.
Make or buy?
The fermentation of microorganisms is the basis for the production of a wide range of products such as antibiotics, hormones, and specialized proteins, thereby making fermentation an important process for related commercial products. Fermentation is frequently the preferred production method, particularly with therapeutic proteins or chemical compounds requiring a multistep synthetic process offering the optimal economic route and allowing firms to shorten their production process and time to
PFIZER, INC.
market. Because of the importance of fermentation in the industry, it figures prominently in a company's overall decision regarding which processes and functions it must outsource.
With GMP fermentation, quality is built into the entire process, as opposed to simply testing for product quality at the end of the process. Fermentation achieved in this manner is expensive to implement—a key factor to consider. A pharmaceutical business or its fermentation services provider must maintain the facilities, procedures, and controls needed to ensure that the manufacturing, packaging, and handling of the product is conducted in a way that meets the requirements of regulatory agencies regarding safety, product identity, quality, and purity characteristics. Essentially, for a specialized function such as GMP fermentation, the "make" decision is simply not an option for most companies, and they must outsource this key process.
Fortunately, selecting an outside provider offloads a number of procedures and controls related to the fermentation process, including raw material qualification, master and batch production records, change control procedures, deviation investigations, fermentation sterilization validation, downstream process validation, cleaning validation, equipment qualification, expiration testing, and stability testing.
Perhaps the biggest factor that drives pharmaceutical manufacturers toward the "buy" decision for fermentation is cost. The capital investment for a properly equipped current good manufacturing practices (CGMP) fermentation facility, including manufacturing equipment and utilities, is significant and often runs into the high tens of millions of dollars. In addition, the provision and training of a technical staff (manufacturing, technical support, quality assurance and quality control, engineering, maintenance and utilities, etc.) further adds to the investment required. By outsourcing to a company that already has the staff and facilities in place, customers can significantly accelerate their timeline and minimize overall investment. Quite often, outsourcing to a specialized provider of custom fermentation services is the lower cost option, a key driver in swaying executive management in a time of tight cost controls.
Once the outsourcing path is chosen, the supplier selection process requires a series of key considerations for making the right contracting decisions regarding large-scale fermentation.
Fermentation process experience
Although it sounds like an obvious factor, GMP fermentation experience is extremely important but easy to overlook. Several factors should be taken into consideration to determine whether a prospective supplier is equipped to handle fermentation services.
Figure 1 (ALL IMAGES ARE COURTESY OF PFIZER INC.)
Fermentation process development begins with strain selection and optimization, media development, process development, and scale-up to maximize productivity. Downstream processing can use various technologies for extracting, concentrating, and purifying the product from a dilute fermentation broth. Any provider of custom fermentation services must be proficient in these aspects.
Flexibility in the types of microbial systems with which a contract manufacturer can work is important because it ensures a broad base of staff knowledge and expertise across a wider spectrum of microorganisms. When looking
through product literature or otherwise evaluating contract capabilities, the following capabilities are typical: microbial cells (bacterial and fungal), microbial enzymes, recombinant organisms, enzymatic bioconversions, and secondary metabolites.
A company should also rate a prospective partner on fermentation downstream processing. A well-rounded capabilities portfolio includes various technologies for extraction and purification. A fermentation services provider should be able to easily handle soluble and insoluble products in the fermentation broth using technologies such as centrifugation, ion exchange, large-scale distillation, nanofiltration, large-scale crystallization, filtration, and drying.
Process development and ongoing production support are additional tools a contractor should have at its customers' disposal. Troubleshooting and process optimization (to reduce costs and improve processes) are two important examples. Operating a biological process such as fermentation is a great deal more complex than operating a chemical synthesis process, largely because there are many more variables to consider and control. For example, the media components used in fermentation are essentially agricultural products like soy, corn flour, natural cereals, fats, and oils, and other materials that can literally vary from crop to crop, harvest to harvest, and year to year. The fermentation services contract manufacturer must manage these natural changes on a day-to-day basis, taking them fully in stride and adjusting its process accordingly.
Beyond initial outlays for any specialized equipment required, a contractor should sustain an aggressive maintenance program that includes annual or periodic calibrations of sensitive instruments. When evaluating a provider, ask to see its maintenance schedule or other proof that equipment is adequately cared for and updated as required.
The team running all this technology is equally as important. Initial and ongoing training in all aspects of fermentation is essential and includes operator, laboratory analyst, and specialized support-staff training. All personnel should have required curricula for their fermentation-related assignments. Training is not limited to providers of fermentation services, it is an integral part of GMP, and the complexity of fermentation processes underscores its importance when potential partners are evaluated.
Figure 2 (ALL IMAGES ARE COURTESY OF PFIZER INC.)
Another important contract manufacturing criterion, and is by no means restricted to fermentation services, is technical development and regulatory support. A potential provider should understand its customer's drug products, markets, and business needs. Ideally, the provider will maintain an experienced team of professionals that provides a continuous surveillance of global regulatory and CGMP requirements, and writes and maintains worldwide registration documents. Typically, such a customer support team will handle the technical package, quality agreements, customer audits and inquiries, technical facilitation, investigation support and supply team feedback, among other responsibilities. If the fermentation provider can't point to a standing team capable of helping manage these details, think twice before engaging with them. Fermentation operations are complex and can easily consume the customer's time if a contractor isn't willing or able to offer such a range of technical and regulatory value-added services.
Quality systems
Systems for quality control remain one of the most important and effective bulwarks for protecting the supply chain and ensuring patient health and safety. This is true especially in biologically based production. As such, quality must be very high on the list of the criteria for selecting a provider of fermentation services.
When searching for a contract manufacturer, don't expect the company to have identical standards. However, it must have a comparable and compatible set of standards that ensures high-quality products using fully compliant operations. Today, no manufacturer can take the chance of using contract suppliers that do not have the quality and compliance systems already in place or whose track record meets only the minimal levels of performance. The service provider must clearly demonstrate quality and compliance in its fermentation offering. One question to ask is whether the supplier's quality and compliance records in fermentation services are among the best in the industry. If not, don't consider engaging with them; the downside potential for the supply chain is simply not worth the risk.
When evaluating quality systems, look carefully at the laboratory facilities and trained quality analysts and quality assurance personnel. Do these elements operate under CGMP conditions, ensuring that even routine updates are made on an ongoing basis for quality reasons?
A company should also know whether a service provider has a standing quality assurance group that is responsible for ensuring written procedures are followed so that all components, product containers, closures, in-process materials, and finished materials conform to appropriate standards of identity, strength, quality, and purity. Request to see samples of written procedures that cover sampling, identification, storage, handling, testing, and documentation of test results. Auxiliary or support activities such as training, calibration, maintenance, stability evaluations, and audits must also be described in written procedures.
Trained personnel (according to a formalized certification program) should be the ones performing all laboratory testing, which is conducted according to current written, validated, and approved procedures. The use of validated analytical procedures ensures the accuracy, precision, specificity, sensitivity, ruggedness, and reproducibility of test results. The GMP computer systems in the supplier's laboratory operations should be validated. Record checking systems provide the necessary verification that the appropriate tests, procedures, and calculations are used and performed correctly and that the transcription of data is performed accurately. In a service provider's quality assurance process, every item essential to the analysis of the material or product must be checked; look for such assurances when conducting a supplier capabilities evaluation.
Technology transfer and scale-up
Typically when a company has made a decision to outsource a large-scale fermentation process, it has developed the process at the laboratory- or pilot-scale, and the contract manufacturer works with the company during the technology transfer stage to first transfer the process at the same scale and then optimize the process in the contract manufacturer's facility. Sometimes, however, the relationship starts at the preclinical or early clinical materials stage. In such cases, it's worth identifying a contract supplier that can offer extensive pilot-scale facilities and commercial-scale facilities.
Once underway, the technology transfer experience becomes one of the most important in the relationship, so vetting a contract manufacturer on this point in advance is recommended. A supplier must have the technical resources in place to receive technology from a customer and implement successful scale-up and commercial supply in a timely manner. Evaluate its track record and its ability to demonstrate success in this key area. Technology transfer includes a number of challenging steps, including transferring process knowledge, analytical methods, raw material specifications, equipment requirements, and so forth. So a pharmaceutical firm should look for a strong technical team that can successfully implement every step. A contract manufacturer's staff should be able to quickly learn how to operate the process themselves.
There is a great deal that can go wrong when lab- or pilot-scale quantities of material are scaled-up. Scale-up can include various hurdles, and key alterations may need to be made in the process. A contract manufacturer must demonstrate clearly the capabilities of its project management approach. Without experienced support resources on-hand during this difficult period, successful technology transfer, scale-up, and implementation will not be possible.
Ensuring the "supply" in supply chain
A final point to consider: none of the above points, from process expertise to scale-up, means anything without the assurance of supply. A successful fermentation services provider must prove it has the capacity and robust business systems (e.g., raw material supply, production planning) to provide reliable supply for a customer, both in terms of quantity of material and timing of deliveries.
Important questions to ask well in advance are: Does the supplier have the available capacity for the fermentation requirements for the foreseeable future? Are its packaging, shipping, logistics, and customer service infrastructure and procedures adequate to guarantee your supply requirements on a regional, national, or global basis?
Conclusion
Large-scale GMP fermentation is a complicated undertaking and requires more than just a token commitment by a contract manufacturer. It requires a commitment to excellence at each stage of the manufacturing and supply process, a substantial investment in fermentation expertise and infrastructure, and a series of best practices across the broad spectrum of contract manufacturing support services.
The investment in expertise, equipment, process, and quality control can be daunting; certainly enough so that many companies are driven to seek outside supply for fermentation. By carefully defining project requirements, evaluating prospective suppliers on objective criteria for fermentation specifically and contract manufacturing overall, and being willing to walk away if there isn't a fit, a pharmaceutical company can rest assured it is taking the most rigorous steps possible to identify an important partner in its product supply chain.
Sheryl Henderson is the director of Plant Network Strategy Implementation at Pfizer Inc., tel. 269.833.5667, fax 269.833.9106, [email protected] McWethy is the senior manager of the fermentation plant at Pfizer's Kalamazoo, Michigan, site. Keith Dixon is the director of bioprocess development at Pfizer.
U.S. Food and Drug Administration • Center for Drug Evaluation and Research
Guidance Document
Guidance for IndustryQ7A Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients
[PDF version of this document]
U.S. Department of Health and Human ServicesFood and Drug Administration
Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)
August 2001ICH
Additional copies are available from:
Office of Training and CommunicationsDivision of Communications Management
Drug Information Branch, HFD-2105600 Fishers Lane
Rockville, MD 20857(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training andManufacturers Assistance, HFM-40
Center for Biologics Evaluation and ResearchFood and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448Internet: http://www.fda.gov/cber/guidelines.htm
Fax: 1-888-CBERFAX or 301-827-3844Mail: the Voice Information System at 800-835-4709 or 301-827-1800
August 2001
ICH
Table Of Contents
I. INTRODUCTION (1)
A. Objective (1.1)B. Regulatory Applicability (1.2)C. Scope (1.3)
II. QUALITY MANAGEMENT (2)
A. Principles (2.1)B. Responsibilities of the Quality Unit(s) (2.2)C. Responsibility for Production Activities (2.3)D. Internal Audits (Self Inspection) (2.4)E. Product Quality Review (2.5)
III. PERSONNEL (3) 8
A. Personnel Qualifications (3.1)B. Personnel Hygiene (3.2)C. Consultants (3.3)
IV. BUILDINGS AND FACILITIES (4)
A. Design and Construction (4.1)B. Utilities (4.2)C. Water (4.3)D. Containment (4.4)E. Lighting (4.5)F. Sewage and Refuse (4.6)G. Sanitation and Maintenance (4.7)
V. PROCESS EQUIPMENT (5)
A. Design and Construction (5.1)B. Equipment Maintenance and Cleaning (5.2)C. Calibration (5.3)D. Computerized Systems (5.4)
VI. DOCUMENTATION AND RECORDS (6)
A. Documentation System and Specifications (6.1)B. Equipment Cleaning and Use Record (6.2)C. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials (6.3)D. Master Production Instructions (Master Production and Control Records) (6.4)E. Batch Production Records (Batch Production and Control Records) (6.5)F. Laboratory Control Records (6.6)
G. Batch Production Record Review (6.7)
VII. MATERIALS MANAGEMENT (7)
A. General Controls (7.1)B. Receipt and Quarantine (7.2)C. Sampling and Testing of Incoming Production Materials (7.3)D. Storage (7.4)E. Re-evaluation (7.5)
VIII. PRODUCTION AND IN-PROCESS CONTROLS (8)
A. Production Operations (8.1)B. Time Limits (8.2)C. In-process Sampling and Controls (8.3)D. Blending Batches of Intermediates or APIs (8.4)E. Contamination Control (8.5)
IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES (9)
A. General (9.1)B. Packaging Materials (9.2)C. Label Issuance and Control (9.3)D. Packaging and Labeling Operations (9.4)
X. STORAGE AND DISTRIBUTION (10)
A. Warehousing Procedures (10.1)B. Distribution Procedures (10.2)
XI. LABORATORY CONTROLS (11)
A. General Controls (11.1)B. Testing of Intermediates and APIs (11.2)C. Validation of Analytical Procedures - See Section 12. (11.3) D. Certificates of Analysis (11.4)E. Stability Monitoring of APIs (11.5)F. Expiry and Retest Dating (11.6)G. Reserve/Retention Samples (11.7)
XII. VALIDATION (12)
A. Validation Policy (12.1)B. Validation Documentation (12.2)
C. Qualification (12.3)D. Approaches to Process Validation (12.4)E. Process Validation Program (12.5)F. Periodic Review of Validated Systems (12.6)G. Cleaning Validation (12.7)H. Validation of Analytical Methods (12.8)
XIII. CHANGE CONTROL (13)
XIV. REJECTION AND RE-USE OF MATERIALS (14)
A. Rejection (14.1)B. Reprocessing (14.2)C. Reworking (14.3)D. Recovery of Materials and Solvents (14.4)E. Returns (14.5)
XV. COMPLAINTS AND RECALLS (15)
XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) (16)
XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS (17)
A. Applicability (17.1)B. Traceability of Distributed APIs and Intermediates (17.2)C. Quality Management (17.3)D. Repackaging, Relabeling, and Holding of APIs and Intermediates (17.4)E. Stability (17.5)F. Transfer of Information (17.6)G. Handling of Complaints and Recalls (17.7)H. Handling of Returns (17.8)
XVIII. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION (18)
A. General (18.1)B. Cell Bank Maintenance and Record Keeping (18.2)C. Cell Culture/Fermentation (18.3)D. Harvesting, Isolation and Purification (18.4)E. Viral Removal/Inactivation steps (18.5)
XIX. APIs FOR USE IN CLINICAL TRIALS (19)
A. General (19.1)
B. Quality (19.2)C. Equipment and Facilities (19.3)D. Control of Raw Materials (19.4)E. Production (19.5)F. Validation (19.6)G. Changes (19.7)H. Laboratory Controls (19.8)I. Documentation (19.9)
GLOSSARY (20)
Guidance for Industry1
Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
I. INTRODUCTION (1)
A. Objective (1.1)
This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.
In this guidance, the term manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.
The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related to protecting the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws.
This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met.
B. Regulatory Applicability (1.2)
Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.
C. Scope (1.3)
This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities.
This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section XVIII (18).
This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or plasma as raw materials. Note that cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk-packaged drug (medicinal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals.
Section XIX (19) contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products).
An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.
The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are
entered into the process. For other processes (e.g., fermentation, extraction, purification), this rationale should be established on a case-by-case basis. Table 1 gives guidance on the point at which the API starting material is normally introduced into the process.
From this point on, appropriate GMP as defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a company chooses to validate a process step does not necessarily define that step as critical.
The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not need to be completed. The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification, and packaging. Physical processing of APIs, such as granulation, coating or physical manipulation of particle size (e.g., milling, micronizing) should be conducted according to this guidance.
This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.
Table 1: Application of this Guidance to API Manufacturing
Type of Manufacturing
Application of this guidance to steps (shown in gray) used in this type of manufacturing
Chemical Manufacturing
Production of the API starting material
Introduction of the API starting material into process
Production of Intermediate(s)
Isolation and purification
Physical processing, and packaging
API derived from animal sources
Collection of organ, fluid, or tissue
Cutting, mixing, and/or initial processing
Introduction of the API starting material into process
Isolation and purification
Physical processing, and packaging
API extracted from plant sources
Collection of plant
Cutting and initial extraction(s)
Introduction of the API starting material into process
Isolation and purification
Physical processing, and packaging
Herbal extracts used as API
Collection of plants
Cutting and initial extraction
Further extraction
Physical processing, and packaging
API consisting of comminuted or powdered herbs
Collection of plants and/or cultivation and harvesting
Cutting/ comminuting
Physical processing, and packaging
Biotechnology:
fermentation/
cell culture
Establishment of master cell bank and working cell bank
Maintenance of working cell bank
Cell culture and/or fermentation
Isolation and purification
Physical processing, and packaging
"Classical" Fermentation to produce an API
Establish-ment of cell bank
Maintenance of the cell bank
Introduction of the cells into fermentation
Isolation and purification
Physical processing, and packaging
II. QUALITY MANAGEMENT (2)
A. Principles (2.1)
Quality should be the responsibility of all persons involved in manufacturing.
Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented.
There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
The persons authorized to release intermediates and APIs should be specified.
All quality-related activities should be recorded at the time they are performed.
Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.
No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine as described in Section X (10) or the use of raw materials or intermediates pending completion of evaluation).
Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).
B. Responsibilities of the Quality Unit(s) (2.2)
The quality unit(s) should be involved in all quality-related matters.
The quality unit(s) should review and approve all appropriate quality-related documents.
The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to:
1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company
2. Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials
3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution
4. Making sure that critical deviations are investigated and resolved
5. Approving all specifications and master production instructions
6. Approving all procedures affecting the quality of intermediates or APIs
7. Making sure that internal audits (self-inspections) are performed
8. Approving intermediate and API contract manufacturers
9. Approving changes that potentially affect intermediate or API quality
10. Reviewing and approving validation protocols and reports
11. Making sure that quality-related complaints are investigated and resolved
12. Making sure that effective systems are used for maintaining and calibrating critical equipment
13. Making sure that materials are appropriately tested and the results are reported
14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate
15. Performing product quality reviews (as defined in Section 2.5)
C. Responsibility for Production Activities (2.3)
The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:
1. Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures
2. Producing APIs and, when appropriate, intermediates according to pre-approved instructions
3. Reviewing all production batch records and ensuring that these are completed and signed
4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded
5. Making sure that production facilities are clean and, when appropriate, disinfected
6. Making sure that the necessary calibrations are performed and records kept
7. Making sure that the premises and equipment are maintained and records kept
8. Making sure that validation protocols and reports are reviewed and approved
9. Evaluating proposed changes in product, process or equipment
10. Making sure that new and, when appropriate, modified facilities and equipment are qualified
D. Internal Audits (Self Inspection) (2.4)
To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.
E. Product Quality Review (2.5)
Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:
· A review of critical in-process control and critical API test results
· A review of all batches that failed to meet established specification(s)
· A review of all critical deviations or nonconformances and related investigations
· A review of any changes carried out to the processes or analytical methods;
· A review of results of the stability monitoring program
· A review of all quality-related returns, complaints and recalls
· A review of adequacy of corrective actions
The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.
III. PERSONNEL (3)
A. Personnel Qualifications (3.1)
There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.
The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should
be specified in writing.
Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed.
B. Personnel Hygiene (3.2)
Personnel should practice good sanitation and health habits.
Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination.
Personnel should avoid direct contact with intermediates or APIs.
Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.
Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.
C. Consultants (3.3)
Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.
Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.
IV. BUILDINGS AND FACILITIES (4)
A. Design and Construction (4.1)
Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or
API, facilities should also be designed to limit exposure to objectionable microbiological contaminants, as appropriate.
Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.
Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.
The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups or contamination.
There should be defined areas or other control systems for the following activities:
· Receipt, identification, sampling, and quarantine of incoming materials, pending release or rejection
· Quarantine before release or rejection of intermediates and APIs
· Sampling of intermediates and APIs
· Holding rejected materials before further disposition (e.g., return, reprocessing or destruction)
· Storage of released materials
· Production operations
· Packaging and labeling operations
· Laboratory operations
Adequate and clean washing and toilet facilities should be provided for personnel. These facilities should be equipped with hot and cold water, as appropriate, soap or detergent, air dryers, or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.
Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process, intermediate, or API.
B. Utilities (4.2)
All utilities that could affect product quality (e.g., steam, gas, compressed air, heating, ventilation, and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.
Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimize risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment.
If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.
Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems, or alternative means. Pipework should be located to avoid risks of contamination of the intermediate or API.
Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate.
C. Water (4.3)
Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.
Unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (potable) water quality.
If drinking (potable) water is insufficient to ensure API quality and tighter chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms, and/or endotoxins should be established.
Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.
Where the manufacturer of a nonsterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.
D. Containment (4.4)
Dedicated production areas, which can include facilities, air handling equipment and/or process
equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins.
The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.
Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another.
Any production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials, such as herbicides and pesticides, should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic nonpharmaceutical materials should be separate from APIs.
E. Lighting (4.5)
Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.
F. Sewage and Refuse (4.6)
Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.
G. Sanitation and Maintenance (4.7)
Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.
Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.
When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labeling materials, intermediates, and APIs.
V. PROCESS EQUIPMENT (5)
A. Design and Construction (5.1)
Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation (where appropriate), and maintenance.
Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.
Production equipment should only be used within its qualified operating range.
Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.
Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter the quality of APIs or intermediates beyond the official or other established specifications. Any deviations from this practice should be evaluated to ensure that there are no detrimental effects on the material's fitness for use. Wherever possible, food grade lubricants and oils should be used.
Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.
A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems).
B. Equipment Maintenance and Cleaning (5.2)
Schedules and procedures (including assignment of responsibility) should be established for the preventative maintenance of equipment.
Written procedures should be established for cleaning equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:
· Assignment of responsibility for cleaning of equipment
· Cleaning schedules, including, where appropriate, sanitizing schedules
· A complete description of the methods and materials, including dilution of cleaning agents used to clean equipment
· When appropriate, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning
· Instructions for the removal or obliteration of previous batch identification
· Instructions for the protection of clean equipment from contamination prior to use
· Inspection of equipment for cleanliness immediately before use, if practical
· Establishing the maximum time that may elapse between the completion of processing and equipment cleaning, when appropriate
Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.
Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g., degradants or objectionable levels of microorganisms).
Nondedicated equipment should be cleaned between production of different materials to prevent cross-contamination.
Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.
Equipment should be identified as to its contents and its cleanliness status by appropriate means.
C. Calibration (5.3)
Control, weighing, measuring, monitoring, and testing equipment critical for ensuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.
Equipment calibrations should be performed using standards traceable to certified standards, if they exist.
Records of these calibrations should be maintained.
The current calibration status of critical equipment should be known and verifiable.
Instruments that do not meet calibration criteria should not be used.
Deviations from approved standards of calibration on critical instruments should be investigated to
determine if these could have had an effect on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration.
D. Computerized Systems (5.4)
GMP-related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity, and criticality of the computerized application.
Appropriate installation and operational qualifications should demonstrate the suitability of computer hardware and software to perform assigned tasks.
Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.
Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g., system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made.
Written procedures should be available for the operation and maintenance of computerized systems.
Where critical data are being entered manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself.
Incidents related to computerized systems that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.
Changes to computerized systems should be made according to a change procedure and should be formally authorized, documented, and tested. Records should be kept of all changes, including modifications and enhancements made to the hardware, software, and any other critical component of the system. These records should demonstrate that the system is maintained in a validated state.
If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized systems.
Data can be recorded by a second means in addition to the computer system.
VI. DOCUMENTATION AND RECORDS (6)
A. Documentation System and Specifications (6.1)
All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures. Such documents can be in paper or
electronic form.
The issuance, revision, superseding, and withdrawal of all documents should be controlled by maintaining revision histories.
A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.
All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.
When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still legible.
During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.
Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.
Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically affect quality. Acceptance criteria should be established and documented for in-process controls.
If electronic signatures are used on documents, they should be authenticated and secure.
B. Equipment Cleaning and Use Record (6.2)
Records of major equipment use, cleaning, sanitation, and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment and the person who performed the cleaning and maintenance.
If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the
batch record or maintained separately.
C. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials (6.3)
Records should be maintained including:
· The name of the manufacturer, identity, and quantity of each shipment of each batch of raw materials, intermediates, or labeling and packaging materials for API's; the name of the supplier; the supplier's control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt
· The results of any test or examination performed and the conclusions derived from this
· Records tracing the use of materials
· Documentation of the examination and review of API labeling and packaging materials for conformity with established specifications
· The final decision regarding rejected raw materials, intermediates, or API labeling and packaging materials
Master (approved) labels should be maintained for comparison to issued labels.
D. Master Production Instructions (Master Production and Control Records) (6.4)
To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).
Master production instructions should include:
· The name of the intermediate or API being manufactured and an identifying document reference code, if applicable
· A complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics
· An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production should be included. Variations to quantities should be included where they are justified
· The production location and major production equipment to be used
· Detailed production instructions, including the:
- sequences to be followed
- ranges of process parameters to be used
- sampling instructions and in-process controls with their acceptance criteria, where appropriate
- time limits for completion of individual processing steps and/or the total process, where appropriate
- expected yield ranges at appropriate phases of processing or time
· Where appropriate, special notations and precautions to be followed, or cross-references to these
· The instructions for storage of the intermediate or API to ensure its suitability for use, including the labelling and packaging materials and special storage conditions with time limits, where appropriate.
E. Batch Production Records (Batch Production and Control Records) (6.5)
Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.
These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the product code together with the date and time can serve as the unique identifier until the final number is allocated.
Documentation of completion of each significant step in the batch production records (batch production and control records) should include:
· Dates and, when appropriate, times
· Identity of major equipment (e.g., reactors, driers, mills, etc.) used
· Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing
· Actual results recorded for critical process parameters
· Any sampling performed
· Signatures of the persons performing and directly supervising or checking each critical step in the operation
· In-process and laboratory test results
· Actual yield at appropriate phases or times
· Description of packaging and label for intermediate or API
· Representative label of API or intermediate if made commercially available
· Any deviation noted, its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored separately
· Results of release testing
Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.
F. Laboratory Control Records (6.6)
Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:
· A description of samples received for testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing
· A statement of or reference to each test method used
· A statement of the weight or measure of sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions
· A complete record of all raw data generated during each test, in addition to graphs, charts and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested
· A record of all calculations performed in connection with the test, including, for example,
units of measure, conversion factors, and equivalency factors
· A statement of the test results and how they compare with established acceptance criteria
· The signature of the person who performed each test and the date(s) the tests were performed
· The date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards
Complete records should also be maintained for:
· Any modifications to an established analytical method
· Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices
· All stability testing performed on APIs
· Out-of-specification (OOS) investigations
G. Batch Production Record Review (6.7)
Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labeling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.
Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of noncritical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).
All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.
The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.
VII. MATERIALS MANAGEMENT (7)
A. General Controls (7.1)
There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.
Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.
Materials should be purchased against an agreed specification, from a supplier, or suppliers, approved by the quality unit(s).
If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.
Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.
B. Receipt and Quarantine (7.2)
Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labeling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined, or tested, as appropriate, and released for use.
Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.
If bulk deliveries are made in nondedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following:
· certificate of cleaning
· testing for trace impurities
· audit of the supplier
Large storage containers and their attendant manifolds, filling, and discharge lines should be appropriately identified.
Each container or grouping of containers (batches) of materials should be assigned and identified with a distinctive code, batch, or receipt number. This number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch.
C. Sampling and Testing of Incoming Production Materials (7.3)
At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below. A supplier's certificate of analysis can be used in place
of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers.
Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Complete analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis. Reliability of certificates of analysis should be checked at regular intervals.
Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company's control do not need to be tested if the manufacturer's certificate of analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.
Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quantity needed for analysis.
Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.
Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.
D. Storage (7.4)
Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.
Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.
Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.
Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.
Rejected materials should be identified and controlled under a quarantine system designed to
prevent their unauthorized use in manufacturing.
E. Re-evaluation (7.5)
Materials should be re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).
VIII. PRODUCTION AND IN-PROCESS CONTROLS (8)
A. Production Operations (8.1)
Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.
If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:
· Material name and/or item code
· Receiving or control number
· Weight or measure of material in the new container
· Re-evaluation or retest date if appropriate
Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.
Other critical activities should be witnessed or subjected to an equivalent control.
Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.
Any deviation should be documented and explained. Any critical deviation should be investigated.
The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.
Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized
use.
B. Time Limits (8.2)
If time limits are specified in the master production instruction (see 6.40), these time limits should be met to ensure the quality of intermediates and APIs. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.
Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.
C. In-process Sampling and Controls (8.3)
Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the developmental stage or from historical data.
The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product's quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).
Critical in-process controls (and critical process monitoring), including control points and methods, should be stated in writing and approved by the quality unit(s).
In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All tests and results should be fully documented as part of the batch record.
Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.
In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.
Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.
D. Blending Batches of Intermediates or APIs (8.4)
For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.
Out-of-specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.
Acceptable blending operations include, but are not limited to:
· Blending of small batches to increase batch size
· Blending of tailings (i.e., relatively small quantities of isolated material) from batches of the same intermediate or API to form a single batch
Blending processes should be adequately controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate.
The batch record of the blending process should allow traceability back to the individual batches that make up the blend.
Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process.
If the blending could adversely affect stability, stability testing of the final blended batches should be performed.
The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend.
E. Contamination Control (8.5)
Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual
layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.
Production operations should be conducted in a manner that prevents contamination of intermediates or APIs by other materials.
Precautions to avoid contamination should be taken when APIs are handled after purification.
IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES (9)
A. General (9.1)
There should be written procedures describing the receipt, identification, quarantine, sampling, examination, and/or testing, release, and handling of packaging and labeling materials.
Packaging and labeling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.
Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.
B. Packaging Materials (9.2)
Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.
Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.
If containers are reused, they should be cleaned in accordance with documented procedures, and all previous labels should be removed or defaced.
C. Label Issuance and Control (9.3)
Access to the label storage areas should be limited to authorized personnel.
Procedures should be established to reconcile the quantities of labels issued, used, and returned and
to evaluate discrepancies found between the number of containers labeled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).
All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.
Obsolete and out-dated labels should be destroyed.
Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record.
Printed labels issued for a batch should be carefully examined for proper identity and conformity to specifications in the master production record. The results of this examination should be documented.
A printed label representative of those used should be included in the batch production record.
D. Packaging and Labeling Operations (9.4)
There should be documented procedures designed to ensure that correct packaging materials and labels are used.
Labeling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.
Labels used on containers of intermediates or APIs should indicate the name or identifying code, batch number, and storage conditions when such information is critical to ensure the quality of intermediate or API.
If the intermediate or API is intended to be transferred outside the control of the manufacturer's material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be included on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.
Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation system.
Packaged and labeled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label. This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control
records.
Intermediate or API containers that are transported outside of the manufacturer's control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.
X. STORAGE AND DISTRIBUTION (10)
A. Warehousing Procedures (10.1)
Facilities should be available for the storage of all materials under appropriate conditions (e.g., controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.
Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.
B. Distribution Procedures (10.2)
APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company's control when authorized by the quality unit(s) and if appropriate controls and documentation are in place.
APIs and intermediates should be transported in a manner that does not adversely affect their quality.
Special transport or storage conditions for an API or intermediate should be stated on the label.
The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.
A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.
XI. LABORATORY CONTROLS (11)
A. General Controls (11.1)
The independent quality unit(s) should have at its disposal adequate laboratory facilities.
There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in
accordance with Section 6.6.
All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).
Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g., organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.
Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.
Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.
Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.
Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard's storage and use in accordance with the supplier's recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier's recommendations.
Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.
Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.
B. Testing of Intermediates and APIs (11.2)
For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.
An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.
The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.
Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.
C. Validation of Analytical Procedures - See Section 12. (11.3)
D. Certificates of Analysis (11.4)
Authentic certificates of analysis should be issued for each batch of intermediate or API on request.
Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.
The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).
Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original manufacturer.
If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original
manufacturer and to the original batch certificate, a copy of which should be attached.
E. Stability Monitoring of APIs (11.5)
A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.
The test procedures used in stability testing should be validated and be stability indicating.
Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.
Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.
Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.
For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first 3 months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.
Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.
F. Expiry and Retest Dating (11.6)
When an intermediate is intended to be transferred outside the control of the manufacturer's material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).
An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.
Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and (2) the quality of the API represents the material to be made
on a commercial scale.
A representative sample should be taken for the purpose of performing a retest.
G. Reserve/Retention Samples (11.7)
The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.
Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.
The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.
XII. VALIDATION (12)
A. Validation Policy (12.1)
The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.
The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include:
· Defining the API in terms of its critical product attributes
· Identifying process parameters that could affect the critical quality attributes of the API
· Determining the range for each critical process parameter expected to be used during routine manufacturing and process control
Validation should extend to those operations determined to be critical to the quality and purity of the API.
B. Validation Documentation (12.2)
A written validation protocol should be established that specifies how validation of a particular
process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.
The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs.
A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.
Any variations from the validation protocol should be documented with appropriate justification.
C. Qualification (12.3)
Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:
· Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose
· Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer's recommendations and/or user requirements
· Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges
· Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications
D. Approaches to Process Validation (12.4)
Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.
Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation of an API process should be completed before the commercial distribution of
the final drug product manufactured from that API.
Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.
An exception can be made for retrospective validation of well-established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:
1. Critical quality attributes and critical process parameters have been identified
2. Appropriate in-process acceptance criteria and controls have been established
3. There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability
4. Impurity profiles have been established for the existing API
Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
E. Process Validation Program (12.5)
The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.
Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.
Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.
F. Periodic Review of Validated Systems (12.6)
Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
G. Cleaning Validation (12.7)
Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.
Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.
The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.
Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).
Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method's attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.
Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).
Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.
H. Validation of Analytical Methods (12.8)
Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.
Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.
Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.
Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.
XIII. CHANGE CONTROL (13)
A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API.
Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.
Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s).
The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a validated process.
When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.
After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.
The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.
Current dosage form manufacturers should be notified of changes from established production and process control procedures that can affect the quality of the API.
XIV. REJECTION AND RE-USE OF MATERIALS (14)
A. Rejection (14.1)
Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.
B. Reprocessing (14.2)
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.
Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.
Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely affected due to the potential formation of by-products and over-reacted materials.
C. Reworking (14.3)
Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for nonconformance should be performed.
Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality
to that produced by the original process. Concurrent validation is often the appropriate validation approach for rework procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable.
Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.
D. Recovery of Materials and Solvents (14.4)
Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.
Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or commingling with other approved materials.
Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.
The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.
E. Returns (14.5)
Returned intermediates or APIs should be identified as such and quarantined.
If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.
Records of returned intermediates or APIs should be maintained. For each return, documentation should include:
· Name and address of the consignee
· Intermediate or API, batch number, and quantity returned
· Reason for return
· Use or disposal of the returned intermediate or API
XV. COMPLAINTS AND RECALLS (15)
All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.
Complaint records should include:
· Name and address of complainant
· Name (and, where appropriate, title) and phone number of person submitting the complaint
· Complaint nature (including name and batch number of the API)
· Date complaint is received
· Action initially taken (including dates and identity of person taking the action);
· Any follow-up action taken
· Response provided to the originator of complaint (including date response sent)
· Final decision on intermediate or API batch or lot
Records of complaints should be retained to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.
There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.
The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.
In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.
XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) (16)
All contract manufacturers (including laboratories) should comply with the GMP defined in this guidance. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.
Companies should evaluate any contractors (including laboratories) to ensure GMP compliance of the specific operations occurring at the contractor sites.
There should be a written and approved contract or formal agreement between a company and its contractors that defines in detail the GMP responsibilities, including the quality measures, of each party.
A contract should permit a company to audit its contractor's facilities for compliance with GMP.
Where subcontracting is allowed, a contractor should not pass to a third party any of the work entrusted to it under the contract without the company's prior evaluation and approval of the arrangements.
Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.
Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes.
XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS (17)
A. Applicability (17.1)
This section applies to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute, or store an API or intermediate.
All agents, brokers, traders, distributors, repackers, and relabelers should comply with GMP as defined in this guidance.
B. Traceability of Distributed APIs and Intermediates (17.2)
Agents, brokers, traders, distributors, repackers, or relabelers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include:
· Identity of original manufacturer
· Address of original manufacturer
· Purchase orders
· Bills of lading (transportation documentation)
· Receipt documents
· Name or designation of API or intermediate
· Manufacturer's batch number
· Transportation and distribution records
· All authentic Certificates of Analysis, including those of the original manufacturer
· Retest or expiry date
C. Quality Management (17.3)
Agents, brokers, traders, distributors, repackers, or relabelers should establish, document and implement an effective system of managing quality, as specified in Section 2.
D. Repackaging, Relabeling, and Holding of APIs and Intermediates (17.4)
Repackaging, relabeling, and holding APIs and intermediates should be performed under appropriate GMP controls, as stipulated in this guidance, to avoid mix-ups and loss of API or intermediate identity or purity.
Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.
E. Stability (17.5)
Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.
F. Transfer of Information (17.6)
Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.
The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or intermediate to the customer should provide the name of the original API or intermediate manufacturer and the batch number(s) supplied.
The agent should also provide the identity of the original API or intermediate manufacturer to regulatory authorities upon request. The original manufacturer can respond to the regulatory authority directly or through its authorized agents, depending on the legal relationship between the authorized agents and the original API or intermediate manufacturer. (In this context authorized refers to authorized by the manufacturer.)
The specific guidance for certificate of analysis included in Section 11.4 should be met.
G. Handling of Complaints and Recalls (17.7)
Agents, brokers, traders, distributors, repackers, or relabelers should maintain records of complaints and recalls, as specified in Section 15, for all complaints and recalls that come to their attention.
If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabelers should review the complaint with the original API or intermediate manufacturer to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party.
Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabelers should include any response received from the original API or intermediate manufacturer (including date and information provided).
H. Handling of Returns (17.8)
Returns should be handled as specified in Section 14.5. The agents, brokers, traders, distributors, repackers, or relabelers should maintain documentation of returned APIs and intermediates.
XVIII. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION (18)
A. General (18.1)
Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for classical processes for production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.
The term biotechnological process (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma, or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and
carbohydrates, can also be produced by recombinant DNA technology. The level of control for these types of APIs is similar to that employed for classical fermentation.
The term classical fermentation refers to processes that use microorganisms existing in nature and/or modified by conventional methods (e.g., irradiation or chemical mutagenesis) to produce APIs. APIs produced by classical fermentation are normally low molecular weight products such as antibiotics, amino acids, vitamins, and carbohydrates.
Production of APIs or intermediates from cell culture or fermentation involves biological processes such as cultivation of cells or extraction and purification of material from living organisms. Note that there may be additional process steps, such as physicochemical modification, that are part of the manufacturing process. The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary.
Appropriate controls should be established at all stages of manufacturing to ensure intermediate and/or API quality. While this guidance starts at the cell culture/fermentation step, prior steps (e.g., cell banking) should be performed under appropriate process controls. This guidance covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.
Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for determining environmental quality and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).
In general, process controls should take into account:
· Maintenance of the working cell bank (where appropriate)
· Proper inoculation and expansion of the culture
· Control of the critical operating parameters during fermentation/cell culture
· Monitoring of the process for cell growth, viability (for most cell culture processes) and productivity, where appropriate
· Harvest and purification procedures that remove cells, cellular debris and media components while protecting the intermediate or API from contamination (particularly of a microbiological nature) and from loss of quality
· Monitoring of bioburden and, where needed, endotoxin levels at appropriate stages of
production
· Viral safety concerns as described in ICH guidance Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin
Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities and contaminants should be demonstrated.
B. Cell Bank Maintenance and Record Keeping (18.2)
Access to cell banks should be limited to authorized personnel.
Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.
Records of the use of the vials from the cell banks and storage conditions should be maintained.
Where appropriate, cell banks should be periodically monitored to determine suitability for use.
See ICH guidance Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.
C. Cell Culture/Fermentation (18.3)
Where cell substrates, media, buffers, and gases are to be added under aseptic conditions, closed or contained systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there should be controls and procedures in place to minimize the risk of contamination.
Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.
Personnel should be appropriately gowned and take special precautions handling the cultures.
Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.
Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation
equipment should be cleaned, sanitized, or sterilized.
Culture media should be sterilized before use, when necessary, to protect the quality of the API.
Appropriate procedures should be in place to detect contamination and determine the course of action to be taken. Procedures should be available to determine the impact of the contamination on the product and to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified, as appropriate, and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.
Records of contamination events should be maintained.
Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.
D. Harvesting, Isolation and Purification (18.4)
Harvesting steps, either to remove cells or cellular components or to collect cellular components after disruption should be performed in equipment and areas designed to minimize the risk of contamination.
Harvest and purification procedures that remove or inactivate the producing organism, cellular debris and media components (while minimizing degradation, contamination, and loss of quality) should be adequate to ensure that the intermediate or API is recovered with consistent quality.
All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.
If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.
Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.
E. Viral Removal/Inactivation steps (18.5)
See ICH guidance Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.
Viral removal and viral inactivation steps are critical processing steps for some processes and
should be performed within their validated parameters.
Appropriate precautions should be taken to prevent potential viral contamination from previral to postviral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.
The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g., through equipment or environment) from previous steps.
XIX. APIs FOR USE IN CLINICAL TRIALS (19)
A. General (19.1)
Not all the controls in the previous sections of this guidance are appropriate for the manufacture of a new API for investigational use during its development. Section XIX (19) provides specific guidance unique to these circumstances.
The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.
B. Quality (19.2)
Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism for approval of each batch.
A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.
Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.
Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.
Process and quality problems should be evaluated.
Labeling for APIs intended for use in clinical trials should be appropriately controlled and should
identify the material as being for investigational use.
C. Equipment and Facilities (19.3)
During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean, and suitable for its intended use.
Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.
D. Control of Raw Materials (19.4)
Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier's analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.
In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone.
E. Production (19.5)
The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.
Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.
F. Validation (19.6)
Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification ensures API quality during this development phase.
Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.
G. Changes (19.7)
Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded.
H. Laboratory Controls (19.8)
While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.
A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.
Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.
I. Documentation (19.9)
A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.
The development and implementation of the analytical methods used to support the release of a batch of API for use in clinical trials should be appropriately documented.
A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.
GLOSSARY (20)
Acceptance Criteria: Numerical limits, ranges, or other suitable measures for acceptance of test results.
Active Pharmaceutical Ingredient (API) (or Drug Substance): Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
API Starting Material: A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials are normally of defined chemical properties and structure.
Batch (or Lot): A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either
by a fixed quantity or by the amount produced in a fixed time interval.
Batch Number (or Lot Number): A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.
Bioburden: The level and type (e.g., objectionable or not) of microorganisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.
Calibration: The demonstration that a particular instrument or device produces results within specified limits by comparison with results produced by a reference or traceable standard over an appropriate range of measurements.
Computer System: A group of hardware components and associated software designed and assembled to perform a specific function or group of functions.
Computerized System: A process or operation integrated with a computer system.
Contamination: The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging, or repackaging, storage or transport.
Contract Manufacturer: A manufacturer who performs some aspect of manufacturing on behalf of the original manufacturer.
Critical: Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.
Cross-Contamination: Contamination of a material or product with another material or product.
Deviation: Departure from an approved instruction or established standard.
Drug (Medicinal) Product: The dosage form in the final immediate packaging intended for marketing. (Reference Q1A)
Drug Substance: See Active Pharmaceutical Ingredient.
Expiry Date (or Expiration Date): The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions and after which it should not be used.
Impurity: Any component present in the intermediate or API that is not the desired entity.
Impurity Profile: A description of the identified and unidentified impurities present in an API.
In-Process Control (or Process Control): Checks performed during production to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.
Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (Note: this guidance only addresses those intermediates produced after the point that a company has defined as the point at which the production of the API begins.)
Lot: See Batch
Lot Number: See Batch Number
Manufacture: All operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage, and distribution of APIs and related controls.
Material: A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs, and packaging and labeling materials.
Mother Liquor: The residual liquid that remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API, and/or impurities. It can be used for further processing.
Packaging Material: Any material intended to protect an intermediate or API during storage and transport.
Procedure: A documented description of the operations to be performed, the precautions to be taken, and measures to be applied directly or indirectly related to the manufacture of an intermediate or API.
Process Aids: Materials, excluding solvents, used as an aid in the manufacture of an intermediate or API that do not themselves participate in a chemical or biological reaction (e.g., filter aid, activated carbon).
Process Control: See In-Process Control.
Production: All operations involved in the preparation of an API from receipt of materials through processing and packaging of the API.
Qualification: Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.
Quality Assurance (QA): The sum total of the organized arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.
Quality Control (QC): Checking or testing that specifications are met.
Quality Unit(s): An organizational unit independent of production that fulfills both quality assurance and quality control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
Quarantine: The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.
Raw Material: A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.
Reference Standard, Primary: A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognized source, (2) prepared by independent synthesis, (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material.
Reference Standard, Secondary: A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.
Reprocessing: Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete, is considered to be part of the normal process, and is not reprocessing.
Retest Date: The date when a material should be re-examined to ensure that it is still suitable for use.
Reworking: Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).
Signature (signed): See definition for signed.
Signed (signature): The record of the individual who performed a particular action or review. This record can be initials, full handwritten signature, personal seal, or authenticated and secure
electronic signature.
Solvent: An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or API.
Specification: A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Conformance to specification means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.
Validation: A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria.
Validation Protocol: A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters and/or operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results.
Yield, Expected: The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data.
Yield, Theoretical: The quantity that would be produced at any appropriate phase of production based upon the quantity of material to be used, in the absence of any loss or error in actual production.
1 This guidance was developed within the Expert Working Group (Q7A) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.
Arabic numbers in subheadings reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000.
Back to Top Parent
FDA/Center for Drug Evaluation and Research
Last Updated: September 24, 2001Originator: OTCOM/DLISHTML by PKS
World Health OrganizationGeneva1997GLOBAL PROGRAMME FOR VACCINES AND IMMUNIZATIONVACCINE SUPPLY AND QUALITYGLOBAL TRAINING NETWORK
A WHO guide to goodmanufacturing practice(GMP) requirementsPart 1: Standard operating procedures andmaster formulaeWritten by:Gillian Chaloner-Larsson, Ph.D, GCL Bioconsult, OttawaRoger Anderson, Ph.D, Director of Quality Operations, Massachusetts Public Health Biologic LabsAnik Egan, BSc.,GCL Bioconsult, OttawaIn collaboration with:Manoel Antonio da Fonseca Costa Filho, M.Sc., Consultant in Quality Assurance, Biomanguinhos/FIOCRUZ, BrazilDr Jorge F. Gomez Herrera, Director of Quality Assurance, Gerencia General de Biologicos yReactivos, Secretaria De Salud, MexicoWHO/VSQ/97.01
ENGLISH ONLYDISTR.: LIMITEDPB Good manufacturing requirements -- Part 1: SOPs and master formulaePrinted: January 1997© World Health Organization 1997This document is not issued to the general public, and all rights are reserved by the World Health Organization(WHO). The document may not be reviewed, abstracted, quoted, reproduced or translated, inpart or in whole, without the prior written permission of WHO. No part of this document may bestored in a retrieval system or transmitted in any form or by any means – electronic, mechanical or other– without the prior written permission of WHO.The views expressed in documents by named authors are solely the responsibility of those authors.The Vaccine Supply and Quality Unit of the Global Programme for Vaccines andImmunization thanks the following donors whose financial support has made theproduction of this document possible: the World Bank, USAID, JICA, the RockefellerFoundation and the Governments of Australia, China, Republic of Korea, Denmark,Ireland, Japan, Netherlands, Norway, Sweden, and the United Kingdom of GreatBritain and Northern Ireland.Copies may be requested from:World Health OrganizationGlobal Programme for Vaccines and ImmunizationCH-1211 Geneva 27, SwitzerlandTelephone: +22 791 4373/4421 • Fax: +22 791 4193/4192 • E-mail: [email protected] Global Training Network is designed for staff of National Control Authoritiesand selected vaccine manufacturers meeting specific entrance criteria. Thisdocument is designed for use by participants in the Global Training Network,specifically for those participating in curricula related to Good ManufacturingPractices.Curricula and curricula material for the Global Training Network have been overseenby Expert Review Panels convened at the request of WHO and comprised ofexperts internationally known for their proficiency in the particular field. TheVaccine Supply and Quality Unit would like to particularly thank the experts whoreviewed this document and served on the Expert Review Panel: Dr Ian Sykes,Pharmaceutical Consultancy Service, Haastrecht, Netherlands, Dr Chung K Lee,Salk Institute, Swiftwater, Pennsylvania, USA, and Ms Carolyn Woodruff, TherapeuticGoods Administration, Melbourne, Victoria, Australia. The Global TrainingNetwork is financed in part through funds donated by the World Bank.WHO/VSQ/97.01 3
ContentsAbbreviations ....................................................................................................... iv1. Introductionand purpose of the guide ............................................................ 12. Good manufacturing practices (GMP) ........................................................... 23. Quality management ........................................................................................ 34. Documentation ................................................................................................. 54.1. Standard operating procedures, specifications and master formulae .... 54.2 Forms for recording data ............................................................................... 54.3 Identification numbers ................................................................................... 54.4 Labels ................................................................................................................. 65. Range of requirements for written procedures .............................................. 76. Standard operating procedures (SOPs) ........................................................... 87. Format for standard operating procedures (SOPs) ..................................... 108. Forms for recording data ............................................................................... 13
9. Examples of SOPs ........................................................................................... 159.1 Samples of SOPs prepared in the proposed format. ............................... 159.2 Content requirements for SOPs for several types of procedures ......... 4710. Master formulae ............................................................................................ 6811. Priorities for the preparation of SOPs and master formulae .................... 79Appendix 1: List of document requirements ................................................... 81Appendix 2: List of SOP titles from three vaccine manufacturers ................. 83Appendix 3: List of reference articles and publications .................................. 96Appendix 4: Glossary ......................................................................................... 99Appendix 5: SOPs contributed by vaccine manufacturers ........................... 106Appendix 6: Sample master formula for a hypothetical biological product 173PB Good manufacturing requirements -- Part 1: SOPs and master formulae
AbbreviationsEP: European PharmacopoeiaGMP: Good Manufacturing PracticesMF: Master FormulaeQA: Quality AssuranceQC: Quality ControlQO: Quality OperationsSOP: Standard Operating ProcedureTRS: Technical Report Series (publication of the World Health Organization)USP: United States PharmacopoeiaWHO: World Health OrganizationWHO/VSQ/97.01 5
1. Introductionand purpose of the guideThis guidance document has been prepared to provide a framework to aid vaccinemanufacturers to assess their planned or existing documents describing the methodsused to produce and test, and administratively control the manufacture of a vaccine.The framework is based on the World Health Organization (WHO) requirements forGood Manufacturing Practices (GMP), but in addition, other GMP Regulations/Guidelinesand publications were consulted during preparation of the Guide. These referencesare listed in Appendix 3. The terms used, including the glossary (Appendix 4),and the overall direction of this guide follows the WHO GMP requirements.The Guide provides a summary of the range of “written procedures” which are identifiedin the WHO’s documents on GMP (ref. 21, 27), a presentation of a format for aStandard Operating Procedure (SOP) and accompanying data recording form, severalsample SOPs, and summaries of the expected contents of several types of SOPs. Italso provides information on the preparation of Master Formulae and batch processingrecords which are the written instructions and recording form for the productionand control process.In addition to the examples, the three vaccine manufacturers who collaborated in thepreparation of this guide have contributed a full list of the titles of their SOPs, andcopies of several SOPs from their facilities. These lists and examples are presented toaid manufacturers in developing the full range of SOPs required with suitably detailed
instructions for performance and recording data. Altogether, 24 SOPs have been presentedin this Guide providing examples of the range of documents needed. These canbe used by manufacturers as examples or reference for preparing or revising their ownStandard Operating Procedures.This guide for SOPs and Master Formulae is Part 1 of 2: Part 2 is a guide to Validation.PB Good manufacturing requirements -- Part 1: SOPs and master formulae
2. Good manufacturingpractices (GMP)WHO defines Good Manufacturing Practices (GMP) as “that part of quality assurancewhich ensures that products are consistently produced and controlled to the qualitystandards appropriate to their intended use and as required by the marketing authorization”(ref 27). GMP covers all aspects of the manufacturing process: defined manufacturingprocess; validated critical manufacturing steps; suitable premises, storage,transport; qualified and trained production and quality control personnel; adequatelaboratory facilities; approved written procedures and instructions; records to showall steps of defined procedures taken; full traceability of a product through batch processingrecords and distribution records; and systems for recall and investigation ofcomplaints.The guiding principle of GMP is that quality is built into a product, and not just testedinto a finished product. Therefore, the assurance is that the product not only meetsthe final specifications, but that it has been made by the same procedures under thesame conditions each and every time it is made. There are many ways this is controlled- controlling the quality of the facility and its systems, controlling the qualityof the starting materials, controlling the quality of production at all stages, controllingthe quality of the testing of the product, controlling the identity of materials by adequatelabelling and segregation, controlling the quality of materials and product byadequate storage, etc. All of these controls must follow prescribed, formal, approvedprocedures, written as protocols, SOPs, or Master Formulae, describing all the taskscarried out in an entire manufacturing and control process.WHO/VSQ/97.01 7
3. Quality managementQuality management in the drug industry is discussed in the WHO GMP for PharmaceuticalProducts (ref 27). In this document the following are presented:• The basic elements of quality management are:- an appropriate infrastructure or “quality system”, encompassing theorganizational structure, procedures, processes, and resources; and- systematic actions necessary to ensure adequate confidence that a product(or service) will satisfy given requirements for quality. The totality of theseactions is termed “quality assurance”.• The concepts of quality assurance, GMP, and quality control are interrelatedaspects of quality management. They are of “fundamental importance to theproduction and control of pharmaceutical products”.QA encompasses all of the arrangements made to ensure that pharmaceutical productsmeet the quality required for their intended use. Although QA is not specified in allGMP documents, the WHO GMP guidelines (ref 27) present the principles of QA areto ensure that GMP and other regulatory codes (GLP - Good Laboratory Practice,
and GCP - Good Clinical Practice) are respected; that responsibilities are clearly specified;all testing, controls, calibrations, validations, etc are performed as specified; thatproducts are not sold before the correct authorizations have been obtained; that productsare appropriately handled throughout their shelf-life; and that there is a procedurefor self inspections (quality audit).All GMP Regulations or Guidelines agree that the independence of quality controlfrom production is fundamental. QC specifically involves sampling, determining specifications,and testing and approving of starting materials, intermediate and final product;maintaining records of all sampling, inspecting, testing; ensuring that deviationsare recorded and investigated; retaining sufficient samples to permit future examination;and to ensure that no product is released without the certification required bythe marketing authorization (product licence, registration certificate).Depending on the size of a pharmaceutical manufacturer, the number of productsmanufactured, the complexity of the operations, and the requirements of the localregulatory authorities, the system of “quality management” will differ. A companycan range from: i) a small single product facility with a production and QC departmentand a quality assurance programme which performs quality audits with a teamcomprised of staff from the two departments; to: ii) a large multi-product companywith production, quality control, quality assurance, engineering, and regulatory affairsdepartments. Provided that the quality assurance system, incorporating GMPPB Good manufacturing requirements -- Part 1: SOPs and master formulae
and quality control, is well planned, with all functions specified and appropriatelyimplemented, and the regulatory requirements taken into account, the allocation ofspecific duties to QA and QC may vary .When writing SOPs, the section identifying the responsibilities for approvals or authorizationswill reflect the quality management structure of the company. Each SOPexample given in this guide presents one of many possibilities for assigning authorizationresponsibilities to QA and QC, and in several cases either QA or QC has beenindicated.WHO/VSQ/97.01 9
4. DocumentationDocumentation is the key to operating a pharmaceutical company in compliance withGMP requirements. The system of documentation devised or adopted should have asits main objective to establish, monitor, and record "quality" for all aspects of theproduction and quality control. Several types of documents are needed to accomplishthis.4.1 Standard operating procedures, specifications and master formulaeDescriptive documents give instructions on how to perform a procedure or a study, orgive a description of specifications. The instruction type documents are: standardoperating procedures (SOP); protocols (for validation studies, stability studies, safetystudies); and master formulae (manufacturing instructions). Each of these gives instructionon how to perform specific procedures. Specifications describe the requiredcharacteristics or composition of a product or material or test. These kinds of documentsprovide the specific details defining the quality of incoming materials, the qualityof the production environment, the quality of the production and control process,and the quality of the final product.4.2 Forms for recording dataAnother type of documentation is the form used for recording data as it is taken duringthe performance of tasks, tests, or events. These are forms (datasheets, or data
record forms), reports, batch processing records, and equipment log books. Thesedocuments provide the evidence that the raw materials, facility environment, the productionprocess, and the final product consistently meet the established quality requirements.4.3 Identification numbersThere are also the identification systems or codes devised to number and track bothinformation and documents. These are SOP numbers, equipment numbers, form numbers,receiving codes, and batch/lot numbers. These numbering systems should bedesigned so that procedures, processes and materials can be traced throughout the datarecords.PB Good manufacturing requirements -- Part 1: SOPs and master formulae
4.4 LabelsLabelling systems are used to identify the status of the equipment or facility, restrictedareas, and warning labels. These include raw material tags, quarantine labels, releaselabels, reject labels, labels to identify specific storage areas, biohazard or radioactivelabels, restricted access labels, equipment "cleaned" or "waiting for cleaning" labels,process intermediate labels, and the final product labels. These permit the identificationand tracking of materials, of the progress of a production process, and assuranceof the proper functioning of equipment.The WHO guidelines for Good Manufacturing Practices (ref. 21, 27) and all othernational and international GMP Guidelines and Regulations (ref. 3, 5, 7, 11, 18, 19)emphasize the requirement for complete documentation. A well-structured documentationsystem, including SOPs for the regular document review and revision, providesthe structure for recording the evidence for the quality of the product.All documentation must be organized into files which must be maintained for specifiedperiods of time after the expiry date of the product.A well-designed documentation system is useful only if it is well used. The systemmust include quality assurance procedures to ensure that instructions are followed,that labels and numbering systems are properly used and recorded, and that data recordforms and batch processing records are assembled and reviewed. Control and assessmentof the documentation system itself is a significant management tool that permitsan ongoing assessment of the changes and revisions necessary to remain in compliance,to delete what is unnecessary or redundant and to improve procedures or processes.WHO/VSQ/97.01 11
5. Range of requirements forwritten proceduresThroughout the WHO GMP Guidelines, in addition to sections on document requirements,many references are made to the need for written procedures for specificaspects of the manufacturing process. There is a broad range of SOPs needed for apharmaceutical manufacturing establishment. GMP Guidelines and Regulations forpharmaceuticals, sterile products, and biologicals from WHO, the EU and severalother countries make reference to ‘written procedures” throughout the documents.In Appendix 2 of this Guide, a list of the titles of the SOPs from three vaccine manufacturersis presented to give an idea of the SOPs needed by a manufacturer.A review of WHO’s GMP Requirements for reference to "written procedures" resultedin a long list of operations and activities which must follow written approvedprocedures. The list covered the requirements for all aspects of the control of quality:raw materials and packaging materials, the premises, the equipment, the test procedures,the production, personnel performance, and quality assurance.
Appendix 1 of this Guide lists a range of the types of procedures which should beprepared in written format. Others may be required depending on the products manufactured,on the size of operations, and on the management structure of the company.PB Good manufacturing requirements -- Part 1: SOPs and master formulae
6. Standard operatingprocedures (SOPs)Standard operating procedures (SOPs) are the detailed written instructions that specifyhow a test or administrative procedure is to be performed, or how a piece of equipmentis operated, maintained and calibrated. SOPs describe the "standard" approvedprocedures that are routinely carried out in a GMP facility. They indicate exactly howthings are done, and are kept current by review and approved revision on a predeterminedschedule (usually annual), or when planned changes are made to the procedureor equipment and reagents used in the procedure. The original of a current version ofan SOPs is maintained in a central file, and copies are distributed to the locationswhere the procedure is performed. The procedure for describing the writing, revisingand approving of SOPs and the control of distribution of SOPs is one of the importantquality assurance procedures. The term “change control” has recently been introducedto the vocabulary of pharmaceutical manufacturing and control. Although thisis primarily a term for validation procedures, it may also apply to the control of thereview and revision of SOPs for routine procedures. Any SOP describing the distributionand control of documents must clearly indicate the mechanisms by which SOPscan be modified or changed: from assessment and rationale for the need for a change,to the evaluation of other SOPs that might be changed as a result, to the final approvalof changes and the implementation of the changed procedure. SOPs are used as areference by the persons responsible for the performance, and are also used for trainingnew operators in the performance of the procedure. Quality assurance proceduresshould be in place to ensure that SOPs are enforced and properly used.SOPs follow a scientific format, and are written with the view that they will be usedby persons trained in the procedure. They should be specific instructions for each stepin sequential order including the preparatory work which must be done before startingthe main procedure, as well as instructions for recording and reporting the results.There is little need for excess text on theory and background - what is required is clearconcise instructions for carrying out a procedure which has been approved.Usually the initial draft of an SOP is written by the person performing the procedureor by someone who knows the procedure well and must be written including thedetails and the time course of the tasks. Supervisors review the SOPs for completenessand content and QC or QA staff approve for regulatory compliance.When appropriate, a formal data sheet or data record form is prepared for an SOP.This form is a parallel summary document with checklists, checkboxes, and blanks forall data to be recorded during the performance of the procedure. It also has spaces forsignatures of the operator and other technicians who verify and countersign certaincritical operations during the procedure. Finally, there is the space for the signature ofthe department supervisor who reviewed the completed data record form. Such blanksWHO/VSQ/97.01 13
and checklists ensure that the required data are collected, that nothing is overlookedand also provide the evidence that the procedure was performed according to the SOP.The datasheets also provide instructions for recording deviations to the procedure, forcalculations or reporting requirements, for comparison of results with predetermined
specifications, and the criteria for repeating procedures in cases where unacceptableresults were obtained.PB Good manufacturing requirements -- Part 1: SOPs and master formulae
7. Format for standardoperating procedures (SOPs)This section of the guide presents a basic format for an SOP with instructions on whatinformation should be provided. It also gives information for the design of data recordforms. Several specific SOPs have been presented in this format, and instructions andexamples have been presented indicating the type of information which should beincluded for other types of SOPs.The formats and sample SOPs can be used, modified, or redesigned by each manufactureraccording to their organizational structure, and by the complexity of their manufacturingoperations.The information in the format is essentially an SOP describing "How to Write anSOP".WHO/VSQ/97.01 15
Format for a standard operating procedure (SOP)Name of facility ________________________________________________page .......... of ..........SOP Number ________ Title _________________________________________________Revision number ________Written by ______________________________ Edited by __________________________Authorization signature ________________________ Department _______ Date ___________Effective date ____________________________________ Replaces ____________________Purpose:WHY:Why is this procedure written.Why is it being performed.ScopeWHEN:Indicate when this procedure needs to be performed.WHERE:Indicate where this procedure applies.ResponsibilityWHO:Who performs the procedure, who is responsible to see it is performed correctly.Materials and equipmentWHAT: What is needed to perform the test. The list should be complete and specific.16 Good manufacturing requirementsSOP Number: .......... Rev...........Name of facility ........................................... page .......... of ..........Short title: ..................................................................................................ProcedureHOW:Clear concise, step by step instructions on how to perform the procedure.This should be written as instructions for the operator to follow, without a lot of theoreticalbackground. A section on fundamental principles can be included if necessary.It should include:a) Preliminary steps that must be done before beginning the actual procedure.b) Safety considerations: Precautions for work with physical, chemical, or biological hazards(cotainment facility clothing, masks, hoods, goggles, gloves, cleanup of spills etc.).c) The chronological instructions. It is useful to number the steps so that repeat steps can bereferred to rather than making the SOP very long.d) Calculations: Explanations and sample of how to do any required calculations.ReportingWHAT NEXT:a) Indicate where the results should be recorded.
b) Explain what to do if there are problems during the test.c) Indicate that deviations to the procedure must be approved and recorded.d) Identify the person to whom the final results should be reported.Reference documents:List other SOPs which directly affect or are relevant to this procedure. For example, the SOP formaking a buffer used in the procedure, or the SOP for the operation of a piece of equipment usedin the procedure.WHO/VSQ/96.03 17
8. Forms for recording dataForms for recording the data generated during the performance of a procedure areespecially important for analytical assays (either in-process tests or quality controlrelease tests) and are appropriate for many other procedures as well (equipment calibration,environmental monitoring, cleaning procedures, etc). Such data record forms(also called datasheets, worksheets, data collection forms) can be appendices to theSOP, or separately numbered documents, but are recommended as a most appropriateway to ensure that the required data is taken. (Laboratory notebooks where data areentered informally on blank pages with no specified data fields are not consideredappropriate for GMP operations).These data record forms are completed by the technician while performing a proceduredescribed in an SOP. The forms include brief instructions which correspond tothe SOP. The forms are designed to record all the data required for a specific SOP inthe order that data are to be taken. The forms include blanks for the required raw data,dates, times, identification of equipment, identification of technicians, and places forsignatures or initials where appropriate. The technicians enter the raw data as theycarry out the procedure and fill in blanks, tick off on checklists, or checking off ofchecklists, or circle appropriate answers. The datasheets should be designed to keepwriting to a minimum. Checklists are appropriate for equipment and materials preparation;blanks are suitable for lot numbers, dates, times, temperatures, identificationnumbers, room numbers, fridge or freezer numbers, calibration values, raw data readings,calculations; circling answers can be used for Y/N or Pass/Fail, or for choosingamong options, etc.Each form should have the name of the company, the title, the number and revisionnumber of the form (or of the SOP if it is an appendix), the number of the SOP, pagenumbers, and signature and date blanks for the operator (technician) and for the verificationsignature (for accuracy, completeness, and compliance). The data to be collectedare specifically described and approved in the SOP. There should be instructionsfor the correction of data: mistakes made during data entry must be crossed outand the correct value entered and initialled. There must be no erasures or use of “whiteout”.Once completed, and verified by a supervisor, the completed form is approved, filedand/or distributed according to the instructions in the SOP (e.g. data to authorizedperson or department for approval). The original should be kept in a secure location,and a copy should go to the batch processing record file.PB Good manufacturing requirements -- Part 1: SOPs and master formulae
Format for a data record formData Record Form #....... rev #....... Name of facility.........................................page....... of .......SOP reference number....................Title _________________________________PreparationMaterials checklist (buffers, glassware, supplies, QC approved dates if required)Equipment checklist (including specific numbers if there is a choice)Buffer, media, cleaning solution, etc preparation if necessary. Reference to SOP
Step by step InstructionsPresented in the order in which the work is routinely performed.Brief instructions with blanks for all data to be filled in.Dates and times for all operations, especially if procedure takes several days, or if there arespecification limits to be met.Blank for verification signature for critical steps where necessary.Blanks for calculations as required and in order performed.Instructions for sending intermediate samples for testing, if appropriate.Instructions for storage during any waiting periods.Criteria for repeating test or procedure.Instructions for reporting any deviations, or problems.Instructions for correcting mistakes (no erasures, cross-out, add correct information andinitials)SignaturesOperator (technician) _____________________________ Date ____________Verification (supervisor)___________________________ Date ____________Instructions for filing and approvalState where completed data sheet is to be delivered, copied, and filed.Submit to QC or QA for review and approval of the data.WHO/VSQ/97.01 19
9. Example SOPsSeveral SOPs have been prepared in the format proposed for SOPs (some includeforms for recording data) and other examples provide the content requirements forpreparing SOPs for several other procedures.9.1 Samples of SOPs prepared in the proposed format.SOP # ABC-1 Operation, Maintenance and Calibration of Incubator Model Numberzzz, from Supplier XXX.SOP # ABC-2 Batch Processing Record ReviewSOP # ABC-3 Determination of Lf/mL for Tetanus by the Ramon TitrationMethod.SOP # ABC-4 Reporting of Production Incidents/Deviations and Resulting Actions.SOP # ABC-5 Responsibilities of Quality Operations (QO) Departments.SOP # ABC-6 Quality Audits, GeneralSOP # ABC-7 Method for Sampling Raw Materials and Production Components20 Good manufacturing requirementsName of Facility ABC Vaccine Manufacturing Company page 1 of 3SOP Number ABC-1Title Operation, Maintenance and Calibration of Incubator Model Number zzz, from Supplier XXXRevision number 2Written by ____________________ Edited by _____________________________________Authorization signature _______________ Department (QA/QC) __________ Date __________Effective date Aug 21, 1994 Replaces: Revision 1 dated: Jan 2, 19921. PurposeThis procedure explains the operation, maintenance and calibration of Supplier XXX, IncubatorModel Number zzz.2. ScopeThis SOP is for the incubator located in the QC microbiology laboratory. It will be used to incubatesamples for growth of microorganisms such as media; environmental control samples; water testsamples; api identification samples; and for other microbiological tests. This incubator must notbe used for any other purposes than those indicated.3. Responsibility3.1 The QC microbiologist is responsible for the correct operation, routine maintenance or setting,and cleaning and disinfecting of the incubator, and recording all operations in the incubatorlog. The QC lab manager is responsible for ensuring these procedures are followed.3.2 The Maintenance department is responsible for making adjustments and repairs to the incubatorand for recording them in the maintenance log.3.3 QA must be notified of any repairs via an incident/deviation report.
3.4 QA is responsible for performing the yearly calibrations and for assessing the need for revalidationafter repairs.4. Materials and Equipment4.1 Incubator, Supplier XXX, model zzz, serial no. 000-000Description: Temp range: +5 to 70 °CTemp uniformity: ±0.25 @ 37°CChamber volume: 10 ft3
Interior electric outletSafety over-temperature protectionDigital microprocessor control system4.2 Thermometer (certified), model T, Manufacturer Z, range 0-80oC4.3 Cleaning solutions: AA, BB4.4 NIST (or other standard) -traceable reference thermometer zz4.5 Maintenance logWHO/VSQ/96.03 215. Procedure5.1 Operation5.1.1 Turn on power.5.1.2 Set temperature: press UP or DOWN on the arrow pad.5.1.3 Let temperature stabilize for 60 minutes.5.1.4 Set high limit thermostat (briefly summarize according to manual or refer to sectioninthe manual).5.2 Temperature verification: Every day (the first activity when arriving at the laboratory)5.2.1 Check the calibration date of the certified thermometer (to be recertified every 3-6weeks)5.2.2 Check the temperature on the digital readout and with the certified thermometer andrecord in the Incubator log book.5.2.3 Notify supervisor and Engineering Department:1) if digital readout and thermometer temperatures differ by > 0.5°C2) if thermometer is outside the accepted range specified on the incubator5.3 Maintenance: Monthly5.3.1 Prepare a solution of the cleaning reagent (rotate cleaning agent each month)5.3.2 Wash interior surfaces and shelves.5.4 Calibration: Once a year QA will calibrate the incubator at three different temperatures(eg 25°C, 35°C, 45°C)5.4.1 Set the first calibration temperature as in step 5.1.25.4.2 Place the reference thermometer in the center of the incubator ensuring the bulbdoes not touch the shelves.5.4.3 Wait 60 minutes for the incubator temperature to stabilize.5.4.4 Compare the reading on the reference thermometer with the digital display.5.4.5 If there is a difference:5.4.5.1 Put the display into calibration mode by pressing on up and down arrowssimultaneously for 5 seconds until decimal points are flashing.5.4.5.2 Press up or down arrows to change temperature setting to match the referencetemperature and the certified thermometer.5.4.5.3 Allow the incubator temperature to stabilize and repeat step 5.4.4 and ifnecessary step 5.4.5.5.4.6 Repeat section 5.4.1 to 5.4.5 for two other temperatures.SOP Number: ABC-1 Rev 2 Name of facility ABC Vaccine Manuf Co. page 2 of ..3..Short title: Incubator model zzz____22 Good manufacturing requirements6. Reporting6.1 Record each use in the incubator log (date, time, temperature, high limit, operator, samples,date out)6.1.1 All samples in the incubator must be clearly marked.6.2 Record maintenance information and calibration data in the log (date, time, cleaning solution,operator).6.3 Record all calibration data in the incubator log (date time, set temperatures, digital temperature,thermometer temperature, operator)6.4 Report all problems in the operation of the incubator immediately to the supervisor.6.5 Update calibration sticker.7. Reference Documents
SOP:___ Preparation and Testing of Cleaning SolutionsXXX Incubator Manual for model zzz.SOP:___ Thermometer Certification Method for Model T, Manufacturer Z, range 0-80°CSOP Number: ABC-1 Rev 2 Name of facility ABC Vaccine Manuf Co. page 3 of ..3..Short title: Incubator model zzz____WHO/VSQ/96.03 23INCUBATOR LOGIncubator # _______________________________ Location: ___________________________Data record form: rrr Rev 2 Name of facility ABC Vaccine Manuf Co. page 1 of ..2..SOP Number: ABC-1Samples enteredDate/Time(yr/mo/d/hr)SamplesenteredTemperature(High limit)OperatorinitialsDate out(yr/mo/d/hr)Operatorinitials
( )( )( )( )( )(01)
24 Good manufacturing requirementsINCUBATOR MAINTENANCE LOG (a logbook, or sections of a logbook ,for each of thesemaintenance records is needed)Incubator # _______________________________; Location: _________________________Data record form: rrr Rev 2 Name of facility ABC Vaccine Manuf Co. page 2 of ..2..SOP Number: ABC-1Daily temperatureDate / Time(yr/mo/d/hr)Daily temperature Operator initials(02)
Routine maintenance -- monthlyDate / Time(yr/mo/d/hr)Maintenancecleaning solutionOperator initials(03)
Annual calibrationDate / Time(yr/mo/d/hr)CalibrationthermometerDigital readout AdjustedtemperatureOperatorinitials123123123
123123123123123123(04)
WHO/VSQ/96.03 25Name of Facility ABC Vaccine Manufacturing Company page 1 of 2SOP Number ABC-2Title Batch Processing Record ReviewRevision number 3Written by ___________________________ Edited by _______________________________Authorization signature __________________ Department (QA/QC) ________ Date _________Effective date March 21, 1994 Replaces: Revision 2 dated: Jan 2, 1993 .1. PurposeThe purpose of this SOP is to describe the procedure of batch processing record review andapproval. Batch processing records are reviewed to determine compliance with all the approvedwritten procedures before a batch is released for the next stage of processing or for distribution.2. ScopeThis SOP applies to the Production Department and the Quality Control Department. It may alsoapply to some operations by the Research Department.3. Responsibility3.1 It is the responsibility of the Department Manager to review each batch processing recordafter the lot has been produced.3.2 It is the responsibility of Quality Assurance to review every batch record for completenessand accuracy.3.3 It is the responsibility of QA to review and update this SOP as required.4. Materials and Equipment: Batch processing records.5. Procedure5.1 When the batch processing record has been assembled and reviewed by the Department, itis submitted to QA for review and approval5.2 Review:5.2.1 Accurate component lot numbers5.2.2 Completed formsAll blanks filled inAll choices markedAll initials, signatures, and second signatures presentAll data entered in ink5.2.3 All dates agree5.2.4 CorrectionsCrossout of original with a single line, initialled and dated.26 Good manufacturing requirementsSOP Number: ABC-2 Rev 3 Name of facility ABC Vaccine Manuf Co. page 2 of ..2..Short title: Batch Record Review____5. Procedure, continued5.2 Review, continued5.2.5 Calculations correct5.2.6 Summary pages agree with in-process records5.2.7 Autoclave data agrees with charts5.2.8 Expiration dates for in-house solutions are accurate: components were not expired atthe time of preparation.
5.2.9 Solutions are used before expiry date5.2.10 All data meet criteria of acceptance5.2.11 Deviations were recorded, dated and initialed by the operator and countersigned bythe Department Manager.5.2.12 All pages are in the Batch Processing Record.5.3 Approval: Batches must be approved before release for distribution. Any unexplained discrepancyor failure of a batch, or any of its components, to meet any of the specificationsmust be investigated through an Incident/Deviation Report. If necessary, the investigationswill extend to other batches of the same product which might be associated with the specificfailure or discrepancy.6. Reference DocumentsSOP #_____: Reporting of Production Incidents/Deviations and Resulting Actions.Master Production Record Form for productBatch Record Summary Sheet for product.WHO/VSQ/96.03 27Data record form: xxx Rev 3 Name of facility ABC Vaccine Manuf Co. page 1 of ..1..SOP reference number: ABC-2QA: Batch processintg records review and approval logDept. Lot #DatereceivedReceivedbyDatereviewedReviewedbyComments(05)
28 Good manufacturing requirementsName of Facility ABC Vaccine Manufacturing Co. page 1 of 3SOP Number ABC-3Title Determination of Lf/mL for Tetanus by the Ramon Titration Method .Revision number 0Written by ___________________________ Edited by ______________________________Authorization signature ____________________ Department (QA/QC) ______ Date _________Effective date May 12, 1993 Replaces new1. PurposeThis SOP describes the Ramon titration method for determining the Lf/mL of tetanus.2. ScopeThis procedure is used to determine the Lf/ml of tetanus toxin, tetanus toxoid, or tetanus vaccine,adsorbed.3. Responsibility3.1 The production department technicians are responsible for performing in-process Lf tests,and the production supervisor is responsible for ensuring that this SOP is followed.4. Materials and EquipmentNote: when performed for in-process tests in the clean room, the equipment, reagents and glasswaremust be prepared and approved for clean room use.4.1 Chemicals and reagents4.1.1 Saline solution (0.85% NaCl).4.1.2 Reference antitoxin, equine. Commercial preparation meeting WHO standards dilutedto 100 Lf/mL with 0.85% NaCl (aliquoted and stored at 4°C, and has not passed expirydate).4.1.3 Standard tetanus vaccine. Commercial preparation meeting WHO specifications, andan in-house standard.4.1.4 Sodium citrate (powder).4.2 Equipment4.2.1 Waterbath set at 45°C. Model WB4.2.2 Lamp for observation of flocculation4.2.3 Balance, model B.4.2.4 Clock or stopwatch4.2.5 Convex lensWHO/VSQ/96.03 29
SOP Number: ABC-3 Rev 0 Name of facility ABC Vaccine Manuf Co. page 2 of ..3..Short title: Lf test for tetanus____4. Materials and Equipment, cont’d4.3 Glassware and supplies4.3.1 Pipettes, 1, 2, 4, 10 mL4.3.2 Flocculation tubes (10 for each sample and control)4.3.3 Flocculation tube racks4.3.4 Sterile 50 and 100 mL screw capped bottles4.3.5 Jar with disinfectant for used pipettes4.3.6 Spatula5. Procedure5.1 IntroductionIf an antigen and antibody are mixed in equivalent proportions, a complex is formed whichwill precipitate or flocculate. Tetanus toxin and toxoids, as well as AlPO4 absorbed tetanustoxoid vaccine where the gel can be dissolved and the toxoid released, will flocculate withspecific proportions of a reference antitoxin. This is an immunological binding assay, not abiological potency assay. The test can also be used for determining the efficiency of absorptionof toxoid to AlPO4 in tetanus vaccine by centrifugation of the AlPO4-bound vaccine andmeasuring the toxoid in the supernatant. The Lf of the supernatant is compared to the totalLf of the dissolved vaccine. A vaccine should have 80% or more of the toxoid absorbed.5.2 Principle of the test.The principle of the test is to incubate fixed amounts of toxin or toxoid with varying amountsof reference antitoxin, in the presence of an electrolyte, and recording the dilution which firstflocculates. Kf is the time it takes to the first flocculation. For tetanus this is usually 20-40minutes.5.3 Safety precautions5.3.1 Wear protective gloves, and mask when working with tetanus toxin.5.3.2 In the production area, wear the required clean room dress.5.4 Sample preparation.5.4.1 No preparation is required for toxin or fluid toxoid. Absorbed toxoid must be releasedby dissolving the AlPO4 with sodium citrate to solubilize the toxoid. Lf cannot be quantitativelydetermined for toxoid bound to AlOH because it cannot be completely dissolved.5.4.2 For absorbed vaccine, weigh out 0.5 g of sodium citrate and add to a vial of vaccinecontaining 5.5 mL. Incubate at 37°C for 24 to 48 hours until the aluminum phosphate gel hasdissolved (solution is completely clear).5.4.3 The standard tetanus toxoid vaccine which is used as a positive control in the testmust be dissolved before use as described in 5.4.2.30 Good manufacturing requirementsSOP Number: ABC-3 Rev 0 Name of facility ABC Vaccine Manuf Co. page 3 of ..3..Short title: Lf test for tetanus____5. Procedure, cont’d5.5 Test procedure5.5.1 Adjust water bath to 45°C.5.5.2 Label the flocculation tubes 1-10 for each reference standard and sample to be tested:1-1 to 1-10; 2-1 to 2-10, etc.5.5.3 Pipette increasing amounts of the 100 Lf/mL reference antitoxin into each set of 10tubes in the following amounts: 0.05; 0.10; 0.15; 0.16; 0.17; 0.18, 0.19; 0.20; 0.21, 0.22 mLs.5.5.4 Prepare a dilution of the test toxin or toxoid to about 15-20 Lf/mL in saline solutionbased on the estimate of Lf/mL.5.5.5 Prepare a dilution of the standard toxoid vaccine (dissolved as instructed in paragraph5.4.3) in saline solution to 20 Lf/mL.5.5.6 Add normal saline to each tube to bring the volume of each flocculation tube to 1 mL(ie 0.95 mL to tube 1 of each set, 0.90 mL to tube 2 of each set, etc).5.5.7 Add 1 mL of diluted sample or standard vaccine to the respective set of 10 flocculationtubes. Add quickly to have the same start time for all tubes.5.5.8 Mix thoroughly by gentle shaking of each tube.5.5.9 Incubate all tubes in racks in the water bath with 1/3 of the reaction mixture immersedin the water of the waterbath.5.5.10 Record the time and observe each vial closely for flocculation every 3 minutes.5.5.11 Record the tube of each set which first shows flocculation, and record the time, Kf, ofeach sample.5.5.12 Record the second and third tube showing flocculation for each sample set.
6. Reporting6.1 Enter all data on Data Record Form # 3216.2 Record all deviations to the procedure on the data record form.6.3 Report to Supervisor if any problems occur during the test.6.4 Sign completed data record form and deliver to supervisor for verification.7. Reference Documents:SOP ___: Operation, Maintenance, and Calibration of the WB WaterbathSOP ___: Operation, Maintenance, and Calibration of the Balance, model BSOP ___: Preparation of Sterile 0.85% Sodium Chloride Solution.SOP ___: Preparation and Testing of the Reference AntitoxinWHO/VSQ/96.03 31Lf FLOCCULATION TEST: TETANUSDate: _______________________________ Operator: _____________________________Test sample: Crude toxin [ ] Detoxified Toxoid [ ] Bulk Concentrate [ ]Final Adj Bulk [ ] Final container [ ]Lot/Batch number: Initial test [ ]Repeat test [ ]: Reason: First assay invalid [ ]; First test failed [ ]Preparation: Note: for in-process tests in the clean room, the equipment, reagents and glasswaremust be prepared and approved for clean room use.Data record form: 321 Rev 0 Name of facility ABC Vaccine Manuf Co. page 1 of ..5..SOP reference number: ABC-3A: Glassware and supplies checklistItemAmountrequiredSOP ref Initialspipettes, 1 mL SOP glassware cleaningand sterilizationpipettes, 2 mL "pipettes, 4 mL "pipettes, 10 mL "flocculation tubes "flocculation tube racks "50 ml. screw cappedbottles, sterile"100 ml screw-cappedbottles,sterile"disinfectant SOP Preparationspatulas NAgloves SOP safety precautionsmasks SOP safety precautions(06)
B. Equipment checklistItem EquipmentNumberSOP ref CalibrationDateInitialsWaterbath SOP #Lamp NABalance, model B SOP #Clock/Timer NAConvex lens NA(07)
32 Good manufacturing requirementsData record form: 321 Rev 0 Name of facility ABC Vaccine Manuf Co. page 2 of ..5..SOP reference number: ABC-3Lf Test for tetanus continued: Lot/Batch number ________ Date _________3. Incubate at 37 deg C for 24-48 hoursHr/min Initials Verified byTime on _______ _______ _______________Time off _______ _______ _______________Elapsed time _______ _______ _______________
Elapsed time must be between 24-48 hours ____________________Preparations verified by: __________________________________________ProcedureA: Sample preparation:Required for the reference standard tetanus vaccine and for AlPO4-absorbed test samplesonly.1. Check water bath temperature is at 37 deg C ______ Initials _______ Verified _______2. Weigh out 0.5 gms of sodium citrate for the reference standard tetanus vaccine and for each5.5 mL of ALPO4-absorbed test sample.Weighed by __________________________________Weights verified by ____________________________C. Reagent checklistItem Lot#/expiry SOP refQC approvaldateInitials0.85% NaCl SOP #ref antitoxin SOP #standard tetanusvaccineSOP #sodium citrate SOP #(08)
Itemtare weightw1 (gm)tare pluscitrate w2(gm)weight ofcitratew2-w1 (gm)Add 0.5 gmto vaccinevialreference stdtetanus vaccinetest lot ________(09)
WHO/VSQ/96.03 33Data record form: 321 Rev 0 Name of facility ABC Vaccine Manuf Co. page 3 of ..5..SOP reference number: ABC-3Lf Test for tetanus continued: Lot/Batch number ________ Date _________4. Set water bath temperature to 45 deg CInitials ______Verified _______5. Label tubes: reference std: 1-1 to 1-10 _______ _________test sample 2-1 to 2-10 _______ _________6. Prepare dilution of reference standard tetanus vaccine and test samplea) reference standard tetanus vaccine to 20 Lf/mLLf/mL of vaccine __________ (A)Volume of vaccine 1 mLVolume of saline in mL (B)Volume of saline to be added/1 mL vaccine: B = ( A - 1 ) = ______ mL20Dilution factor for vaccine = ____________b) test sample to 15-20 Lf/mL (17.5 av)Estimated Lf/mL __________ (C)Volume of sample 1 mLVolume of saline in mL (D)Volume of saline to be added/1 mL vaccine: D = ( C - 1 ) = ______ mL17.5Dilution factor for test sample = ____________Calculations Initials _________ Verified _________7. Add first the ref antitoxin, then saline to the tubes as indicated in the table
Initials ______Add one mL of the std vaccine to the first set of 10 tubes and the test sample to the secondset of 10 tubes. Mix each tube by shaking gentlyInitials _______PB Good manufacturing requirements -- Part 1: SOPs and master formulae8. Put racks of tubes in water bath with 1/3 of the reaction volume immersed in the waterTime incubation started _________ Initials ______ Verified by ________9. Observe each tube every 3 minutes for flocculation.Record the time of the first 3 tubes showing flocculation in the tables.Calculate Kf for first 3 tubesKf = (time of flocculation) - (time incubation started)Data record form: 321 Rev 0 Name of facility ABC Vaccine Manuf Co. page 4 of ..5..SOP reference number: ABC-3Lf Test for tetanus continued: Lot/Batch number ________ Date _________Compontent Tube#Volume in mLs1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10Ref antitoxin @ 100 Lf/mL .05 .10 .15 .16 .17 .18 .19 .20 .21 .22Saline, 0.85 % .95 .90 .85 .84 .83 .82 .81 .80 .79 .78Standard vaccine @ 20 Lf/mL 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0(10)
Compontent Tube#Volume in mLs2-1 2-2 2-3 2-4 2-5 2-6 2-7 2-8 2-9 2-10Ref antitoxin @ 100 Lf/mL .05 .10 .15 .16 .17 .18 .19 .20 .21 .22Saline, 0.85 % .95 .90 .85 .84 .83 .82 .81 .80 .79 .78Standard vaccine @ 20 Lf/mL 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0(11)
REF STD VACCINETUBE#Volume in mLs1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10Antitoxin/tube (Lf/mL) .05 .10 .15 .16 .17 .18 .19 .20 .21 .22Flocculation #1,#2,#3Time flocculation seenKf in minutes(12)
REF STD VACCINETUBE#Volume in mLs1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10Antitoxin/tube (Lf/mL) .05 .10 .15 .16 .17 .18 .19 .20 .21 .22Flocculation #1,#2,#3Time flocculation seenKf in minutes(13)
Initials ______ Verified by ________WHO/VSQ/97.01 3510. Calculationsa) Standard tetanus vaccine:Lf/mL of first tube to show flocculation _______Lf/mL x dilution factor = Lf/mL of standard vaccine = _______Acceptance criteria: 20 ± 3 Lf/mL:Assay valid ____ Assay Invalid _______b) Test sample:Lf/mL of first tube to show flocculation _______Lf/mL x dilution factor = Lf/mL of test sample = ________Acceptance criteria: xx ± z Lf/mL: (will depend on the test sample)Pass ____ Fail ______11. Repeat test:If the reference vaccine does not meet the acceptance criteria, the test is invalid and the full test isrepeated.If the assay is valid and the test sample fails to meet the acceptance criteria, the full test may [ ],may not [ ] be repeated.12. Deviations to the procedure: No [ ] Yes [ ]If yes, list deviations
Operator (technician) ___________________ Date _____________________Verification (supervisor) _________________ Date _____________________Submit to QC or QA for review and approval of the data and deviations,if any.QA/QC Review:PASS __________________________________________________(signature, date)FAIL __________________________________________________(signature, date)Data record form: 321 Rev 0 Name of facility ABC Vaccine Manuf Co. page 5 of ..5..SOP reference number: ABC-3Lf Test for tetanus continued: Lot/Batch number ________ Date _________36 Good manufacturing requirementsName of Facility ABC Vaccine Manufacturing Company page 1 of 2SOP Number ABC-4 Title Reporting of Production Incidents/Deviations and Resulting ActionsRevision number 2 .Written by ____________________________ Edited by _______________________Authorization signature ___________________ Department (QA/QC) _______ Date_______Effective date June 12, 1993 Replaces Revision 1 dated: Aug. 20 19891. PurposeThe purpose of this SOP is to describe the method for reporting production incidents and deviationsfrom established written procedures, or deviations from established specifications and theactions taken.2. ScopeThis SOP applies to the Production Department.3. Responsibility3.1 It is the responsibility of the entire production staff, supervisors and manager to follow thisprocedure. The supervisor of each production section (facility operations, fermentation, purification)is responsible for any deviation, for the decisions taken following a productionincident and for ensuring that the QA department is notified in a timely manner.3.2 It is the responsibility of QA to review and update this SOP as required.4. Materials and Equipment: None5. Procedure5.1: Definitions:5.1.1 Incident: Brief excursion from specifications not directly affecting product quality,purity, or safety.Examples: Process temperature briefly out of specifications; equipment malfunction notaffecting the product (ie particle counter malfunction).5.1.2 Deviation: Process parameter out of specification; product quality, purity or safety inquestion.Examples: Yield, appearance, temperature, pH, flow rate, incubation time, fill volume out ofspecifications; contamination in inoculum; critical equipment malfunctions (ie autoclave);volume or product reconciliation problem .5.1.3 Critical Deviation: Process performed incorrectly. Product quality, purity, safetyaffected. Examples: Incorrect reagent or concentration used; product mislabeled.WHO/VSQ/96.03 37SOP Number: ABC-4 Rev 2 Name of facility ABC Vaccine Manuf Co. page 2 of ..2..Short title: Incident/Deviation Reports____5. Procedure Cont’d5.2: Procedure:5.2.1 Document all incidents and deviations on Data Record Form # __.NOTE: All incidents and deviations must be recorded and initialed at the time of the event inthe batch processing records to indicate that an incident or deviation occurred. This noteshould describe the event and any corrective action taken. It must be initialed and dated bythe appropriate supervisor5.2.2 Corrective action should be recommended by the appropriate supervisor or superior.This person will approve by signing the process records.5.2.3 Notification: The following persons must be notified:Incident:Supervisor - immediatelyDept Manager - ReviewQA Manager - ReviewVP Operations - NA
Deviation:Supervisor - immediatelyDept Manager - immediatelyQA Manager - immediatelyVP Operations - ReviewCritical Deviation:Supervisor - immediatelyDept Manager - immediatelyQA Manager - immediatelyVP Operations - immediately5.2.4. Records:Form # ___ will be used by the production department to document the incident/deviationand the action taken.Form # ___ will be used by QA to maintain a log of incidents/deviations and to assign asequential number to each event.QA will follow-up the recommendations for action and prepare a final report when the recommendationshave been implemented.QA will file the original report in the QA files and send a copy to the production department.6. Reference DocumentsData Record Form # _____: Incident/Deviation Report.Data Record Form # _____: QA Doc: Incident/Deviation Report Log38 Good manufacturing requirementsData record form: zzz Rev 2 Name of facility ABC Vaccine Manuf Co. page 1 of ..2..SOP Number: ABC-4INCIDENT/DEVIATION REPORTReport #: ____________________________________Department:__________________________________Date:________________________________________Reported by: __________________________________Incident [ ] Deviation [ ] Critical Deviation [ ]Date of occurrence:______________________________________Component/intermediate/product/lot number affected: ______________________________1) Description of incident/deviation (include process, lot number, which production step, result):2) Number of previous occurrences to same product over previous year (dates, lots affected):3) Action taken (who was notified, when, who approved action, what was done, previous actionsfor previous occurrences):4) Justification for action (previous events, literature, advice of superiors, identity of superiors):5) Significance of event on process or product (effect on yield, recovery, stability):6) Remedial action to prevent re-occurrence (ie revise SOP or datasheets/record forms, retrainpersonnel, repair or revalidate equipment):WHO/VSQ/96.03 39INCIDENT/DEVIATION REPORTReport prepared by Date:_____________Corrective action approved by:__________________ Date:_____________Reviewed by: :_____________________________ Date:_____________Reviewed by::_______________________________ Date:_____________QA Reviewer::_______________________________ Date:_____________QA Comments and recommendations:QA Follow-up (recommendations completed?)VP Operations Review::_____________________________ Date: _____________Date Report Finalized::_____________________________ QA: _______________Data record form: zzz Rev 2 Name of facility ABC Vaccine Manuf Co. page 2 of ..2..SOP reference number: ABC-440 Good manufacturing requirementsData record form: ttt Rev 2 Name of facility ABC Vaccine Manuf Co. page 1 of ..1..SOP reference number: ABC-4QA: Incident/Deviation report logReport # Date DeptClassificationProduct Lot # Description(14)
WHO/VSQ/96.03 41SOP Number ABC-5 Title Responsibilities of Quality Operations (QO) Departments .Revision number 0
Written by ____________________ Edited by ________________________Authorization signature ________________ Department (Management) ______ Date ____Effective date April 12, 1995 Replaces new1. PurposeThis SOP describes the basic responsibilities of Quality Operations at the ABC Vaccine ManufacturingCompany.2. ScopeThis SOP applies to all Quality Control and Quality Assurance staff of the company.3. ResponsibilityThe QO Director, the QC Manager and the QA Manager are responsible for following this SOP andfor revising the SOP as needed.4. Materials and EquipmentNone.5. Procedure5.1: QC Responsibilities5.1.1 The QC department has the responsibility and authority to approve or reject all components(raw materials), drug product containers, closures, in-process materials, packagingmaterials, labeling, and drug products.5.1.2 The QC department has the responsibility and authority to provide adequate laboratorytest facilities to test and accept or reject components and the container-closure system,and delivery system, if attached, to be used in the manufacture, processing, packing andholding of the intended parenteral drug product. The QC department has the authority toreject such a system if it does not comply with the provisions of this part, or if, in the opinionof the QC department, it is not capable of holding the product invulnerable to contaminationunder the intended or contemplated conditions of shipment, storage and use.5.1.3 The responsibilities and procedures applicable to the QC Department are in writingand such written procedures should be followed.Name of Facility ABC Vaccine Manufacturing Company page 1 of 242 Good manufacturing requirements5. Procedure, Cont’d5.2: QA Responsibilities5.2.1 The QA Department has the responsibility and authority to accept or reject the design,engineering, and physical facilities of the plant, the equipment, the manufacturing processand control procedures to be used in the manufacture, processing, packing, and holding ofeach parenteral drug product. The QA Department has the authority to reject any such plantequipment process or procedure if it does not comply with the provisions of this part or if, inthe opinions of the QA Department, it is not suitable or adequate to assure that the drugproduct has the characteristics it purports or is represented to possess.5.2.2 The QA Department has the responsibility for approving or rejecting all procedures orspecifications impacting on the identity, strength, quality, purity and stability of the drug product.5.2.3 The QA Department has the responsibility and authority to approve or reject anychanges in previously approved plant, equipment processes, procedures, and containerclosuresand delivery systems before utilization in the manufacture, processing, packing,and holding of a parenteral drug product.5.2.4 The QA Department has the authority to review production records to assure that noerrors have occurred, that they have been fully investigated.5.2.5 The QA Department has the responsibility and authority to handle the “certification/calibration” programme of major equipment.5.2.6 The QA Department has the responsibility and authority to review the QC testingrecords.5.2.7 The responsibilities and procedures applicable to the QA Department are in writingand such written procedures should be followed.6. Reference Documents(the relevant National or International GMP Guidelines)SOP Number: ABC-5 Rev 0 Name of facility ABC Vaccine Manuf Co. page 2 of ..2..Short title: QO Responsibilities____WHO/VSQ/96.03 43SOP Number ABC-6 Title Quality Audits, GeneralRevision number 2Written by ____________________ Edited by ________________________Authorization signature ___________________________ Department: QA Date ___________Effective date May 12, 1994 . Replaces Revision 1 dated: April 12 1992
1. PurposeThe objective of this SOP is to describe the method of auditing departments in order toensure compliance with regulations and guidelines, as well as internal standards and policies.The purpose of an internal audit is to monitor the production and quality control departmentsfor compliance with GMP, regulatory and product quality requirements and to recognizeand address any deficiencies. A Contract Manufacturing Audit is an evaluation of facilitiesand systems operated by another company which performs part of the manufacturingprocess (ie bulk product, or final filling). A Vendor Audit is an evaluation of a supplier of rawmaterials or other products and components purchased for use in production.2. ScopeThis SOP applies to all audits conducted by the Quality Assurance Department. It includesaudits of all internal departments associated with ABC Vaccine Manufacturing Company’sproduction facility, Contract Manufacturers, and Vendors. It does not include record reviewswhich are described in SOP #______.3. Responsibility3.1 It is the responsibility of the Quality Assurance Department to inspect departments at leastannually to ensure compliance with national or international regulations and guidelines, aswell as internal standards and policies. QA is also responsible for auditing contract manufacturersand vendors, as needed. It is also this department's responsibility to documenteach auditing event.3.2 It is the responsibility of each department to provide access to their facilities at QA's request.Each department is also responsible for responding in writing within 30 days to QA recommendationsfor action to be taken.3.3 It is the QA Manager's responsibility to review and revise this SOP as necessary.4. Materials and EquipmentAs required for each type of audit.Name of Facility ABC Vaccine Manufacturing Company page 1 of 344 Good manufacturing requirements5. Procedure5.1 Philosophy:The purpose of an audit is to evaluate the systems, processes and functions of a departmentas a team. It should not be considered as a personal evaluation or critique. The departmentpersonnel together with the auditors will determine the course of action to improve compliancewith the applicable regulations and guidelines.5.2 Preparation for Audit:5.2.1 Review the last internal audit and National Control Authority inspection reports. Notethe citations and comments so that these can be evaluated during the audit.5.2.2 Contact the department for a work schedule and agree on meeting dates.5.3 Audit:5.3.1 The audit is to take place during normal working hours. If production is performedduring several shifts, special emphasis should be placed on conducting audits during shiftswhen the level of supervisory staff is reduced.5.3.2 During the audit, it is important to work in cooperation with department personnel. It isalso important to get as much information as possible about the current procedures bya. Asking open-ended questionsb. Listening and understandingc. Restating responsesd. Allowing time for responsese. Showing flexibility and a constructive attitudef. Choosing proper vocabulary5.3.3 The audit is to be carried out using the approved audit checklist.5.4 After Audit:5.4.1 The QA auditors will write up an official report of the findings on the department. Thesecomments will be classified as follows:a. Critical: a problem that directly affects the product, for example:1. open sterile products in a non-aseptic area2. no traceability of componentsb. Major: a problem that may affect the product, for example:1. equipment not calibrated2. untrained operatorsc. Minor: an issue that does not directly affect the product, for example:1. crossouts and corrections not initialed or dated
SOP Number: ABC-6 Rev 2 Name of facility ABC Vaccine Manuf Co. page 2 of ..3..Short title: Quality audits____WHO/VSQ/96.03 455. Procedure, Cont’d5.4.2 The auditors will hold a meeting with the department personnel to discuss the findingsand agree on improvements to be made.5.4.3 The department will respond to the findings with the improvements to be made andtheir expected completion dates.5.4.4 The auditors will follow up on those issues to ensure that they are being resolved andthat compliance has improved. A follow-up report will be prepared.5.4.5 The QA department will maintain a log of all audits5.5 Frequency of auditsQA will schedule an announced audit for each department at least once per year. A rolling 6month schedule of audits is considered ideal. Unannounced audits may occur at any time.When outside regulatory authorities inspect the facilities, QA should also write up their ownreport and meet with the departments as outlined in section 5.4.6. Reference Documents:6.1 SOP #___: Batch Record Review6.2 SOP #___: Quality Assurance Self Inspection6.3 Data Record Form #__: Quality Assurance Audit Log6.4 Relevant GMP guidelines and regulations regarding self audits and outside audits.SOP Number: ABC-6 Rev 2 Name of facility ABC Vaccine Manuf Co. page 3 of ..3..Short title: Quality audits____46 Good manufacturing requirementsData record form: xyz Rev 2 Name of facility ABC Vaccine Manuf Co. page 1 of ..1..SOP reference number: ABC-6Quality assurance audit logYearAudit No.DepartmentContractorVendorAudit dates Meeting date Date of response(15)
WHO/VSQ/96.03 47SOP Number ABC-7 Title Method for Sampling Raw Materials and Production ComponentsRevision number 0Written by ____________________ Edited by ________________________Authorization signature ___________________ Department (QA/QC) _______ Date _________Effective date May 12, 1994 . Replaces new .1. PurposeThe purpose of this SOP is to describe the method for sampling and testing raw materials andother production components.2. ScopeThis SOP applies to the Receiving/Warehousing and Quality Control Departments.3. Responsibility3.1 It is the responsibility of the Receiving/Warehousing Department and the Quality ControlDepartment to follow this procedure.3.2 The Quality Control Manager is responsible for ensuring that this procedure is followed.3.3 It is the responsibility of QC to review and update this SOP as required.4. Materials and Equipment(Need to give the specifics of the sampling equipment and supplies, sampling hoods/booths/areasin the warehouse area)5. Procedure5.1 General Requirements:5.1.1 Handling and storage of the materials must ensure prevention of contamination.5.1.2 Bagged or boxed materials are stored off the floor (on shelves or on pallets) and aresuitably spaced in order to permit cleaning and inspection.5.1.3 Each container or grouping of containers for raw materials or drug product containersor closures, are identified with a distinctive code number for each lot in each shipmentreceived. This code is used in recording the disposition of each lot. Each lot is identified by acoloured sticker as to its status as follows:Yellow sticker Receiving/QuarantineGreen sticker Released
Red sticker RejectedName of Facility ABC Vaccine Manufacturing Company page 1 of 448 Good manufacturing requirements5. Procedure, Cont’d5.2 Receipt and Storage of Materials requiring Testing or Examination by QC:5.2.1 Upon receipt and before acceptance, each shipment is examined visually as to itsintegrity and proper labeling. This inspection is performed by the warehouse operator in thereceiving area, who applies the yellow stickers, containing all necessary details:- Date- Company code number- Receiving number- Package number (of total)- Supplier's lot number5.2.2 Materials are stored under quarantine until tested or examined, and released or rejectedby Q.C. For each material, the Q.C. reviews the "entry" documents, the yellow stickersand a copy of the certificate of analysis, if available.5.3 Sampling:5.3.1 Representative samples of each shipment of each lot are collected for testing or examinationby the Q.C. operator. Quantity of sample should be at least three times that neededto perform all tests other than for sterility and pyrogen testing (single test)For solid materials: Less than 250g 5-15% of weight250-5000g 2.5-10% of weight>5000g 125-260gFor liquid materials: samples are taken into clean test tubes.Samples are taken according to a sampling plan (see Appendix).5.3.2 Sampling is performed in a way designed to prevent contamination. Sterile equipmentand aseptic sampling techniques are used when necessary.5.3.3 If it is necessary to sample a raw material from the top, middle and bottom of itscontainer, such samples are not mixed for testing.5.3.4 Sampled containers are identified by a specific “sampled” sticker containing the dateand name of operator.5.4 Testing and Approval or Rejection:5.4.1 At least one test is conducted to verify the identity of each raw material. Identity testsare performed according to monographs appearing in the USP, EP, WHO or other acceptedmethods.5.4.2 When no official monograph exists, an internal SOP is prepared.SOP Number: ABC-7 Rev 0 Name of facility ABC Vaccine Manuf Co. page 2 of ..4..Short title: Sampling raw materials____WHO/VSQ/96.03 49SSOP Number: ABC-7 Rev 0 Name of facility ABC Vaccine Manuf Co. page 3 of ..4..Short title: Sampling raw materials____5. Procedure, Cont’d5.4.3 Each raw material is tested for conformity with all appropriate specifications for purity,strength and quality. If the tests are conducted by the manufacturer or supplier of the rawmaterial, a certificate of analysis is required. For raw materials which are intended to be apart of a finished Product, tests for purity, strength and quality are performed by the Q.C.,according to tests appearing in existing monograph (USP, EP, WHO or BP).For suppliers who have been audited and approved by QA, only the identity test is requiredto be performed by QC.5.4.4 When the tests performed by the Q.C. lab are completed, the documentation is signedand transferred back to the warehouse for release (or rejection). The Q.C. operators areresponsible for applying the green (or red) stickers.5.4.5 In the Q.C. lab, there is a separate file for each raw material, drug product containeror closure, where the test results and copies of the documentation are filed.5.5 Retesting:In accordance with shelf-life requirements for raw materials (determined by the QC department),raw materials are retested periodically. A list of raw materials for retesting, its time table and typesof tests, is attached to the general list of raw materials used for manufacture of each drug product.A Raw Material Retest Record Sheet is prepared and a dated and signed retest sticker is appliedby the Q.C. operator on each retested package.5.6. Retention Samples:A well identified sample of each raw material tested and released is set aside for retention in a
specified, labeled storage location (except for volatile or evaporating materials).6. Reference Documents:Annex 1: Raw Materials Sampling Plan.Data Record Form # ___: Receiving Entry LogData Record Form # ___: Raw Materials Inspection and Sampling ReportData Record Form # ___: Raw Material Retest Record50 Good manufacturing requirementsAnnex 1: RAW MATERIALS SAMPLING PLAN (Ref: Mil-Std-105D)The following schedule is recommended for sampling.Number of Containers or Units to be Sampled per Lot or Batch in each ShipmentSOP Number: ABC-7 Rev 0 Name of facility ABC Vaccine Manuf Co. page 4 of ..4..Short title: Sampling raw materials____B. Inactive raw materias and primary packaging componentsNo. of containers or units Number to be sampled2-8 29-15 316-25 526-50 851-90 1391-150 20151-280 32281-500 50501-1200 801201-3200 1253201-10000 20010001-35000 31535001-150000 500150001-500000 800500001 and over 125017
A. Active raw materialsNo of containers in shipment Number to be sampled2-15 216-25 326-90 491-150 8151 and over 1316
C. Other packaging componentsNo. of packages in shipment Number to be sampled2-15 216-50 351-150 5151-500 8501-3200 133201-35000 2035001-500000 32500001 and over 5018
WHO/VSQ/96.03 51
9.2 Content requirements for SOPs for several types of procedures(i) Entry and Exit: Clean and Sterile Production Areas(ii) Internal Inspection Procedures(iii) Control of Biological Starting Materials(iv) Environmental Monitoring of Cleanrooms: Sampling Method(v) Label Control and Issuance(vi) Procedure for Cleaning(vii) Specification Sheets for Raw Materials52 Good manufacturing requirements(i) SOP: ENTRY AND EXITEXAMPLE: Entry and exit of people, supplies, starting materials, product intermediates whenthey are stored outside the cleanrooms, and exit of QC samples for in-process tests, and removalof wastes must follow defined procedures and be documented where necessary. SOPs must beprepared for each entry/exit point (e.g.: personnel entry room/airlock, pass-through, equipmententry airlock ). Airlock entries are cleaned during routine cleaning programme and controlled by
the environmental monitoring programme therefore the entry procedure does not include theseoperations. Pass-throughs for supplies must include decontamination procedure before and aftertransfer.SOP ___: Personnel Entry and Exit: Clean and Sterile Production Areas1. PurposeTo provide detailed instructions for gowning and entry into cleanrooms.2. ScopeDescribe the location of each cleanroom area where the procedure applies. Indicate that theinstructions must be followed by all persons entering the production areas every time they enterand exit.3. ResponsibilityAuthorized production staff, hired cleaning staff, building cleaning staff, and any person specificallyauthorized by the production manager to enter the production area, must follow these instructions.The production manager is responsible for ensuring the procedure is followed.4. Materials and EquipmentDescribe the facilities in the entry rooms (lockers, showers, shoe racks, dividing bench, etc.).List the garments, disinfectants, and other materials used in the entry airlock.disinfectant soapcleanroom entry log booksterile maskssterile gownsterile glovessterile head coverssterile shoe coverscleanroom shoesalcohol spraygarment disposal bag or binWHO/VSQ/96.03 53(i) SOP: ENTRY AND EXIT, continued5. Procedurea) Preparation- describe the preparation of disinfectant soap such as dilution, rotation etc.- describe procedure for changing from street clothes to lab clothes for non-critical areas.b) Entry procedures. Clear instruction for the following:- instructions for signing entry log book- describe clothes and ornaments to be removed and where to store.- describe showering or washing required- describe order of putting on cleanroom garments- describe use of alcohol spray during the gowning process- describe the final step of donning shoe covers and stepping over bench- describe precautions to prevent contamination of gloves during entry into clean room.c) Exit procedures.- describe the removal and disposal of each garment- refer to the SOP for personnel monitoring (swabs) on exit.- signing out in the log book- describe showering or washing if required.6. ReportingAn Entry Exit Log Sheet of Log Book should be prepared to record staff, dates and times.Identify what information needs to be included in the Entry/Exit Log.7. Reference DocumentsReferences to other SOP documents that are needed to perform parts of the cleaning operation.For example:SOP for Cleaning of Garments.SOP for Disinfectant TestingSOP for Personnel Monitoring.54 Good manufacturing requirements(ii) SOP : INTERNAL INSPECTIONEXAMPLE: General requirements of an SOP written for the process of performing a QA Audit/Self Inspection.SOP _____: Internal Inspection Procedures1. PurposeTo describe the self inspection method to ensure compliance with WHO GMP guidelines.
2. ScopeThe inspection of all internal departments associated with vaccine manufacture.3. Responsibility- Indicate that the QA department is responsible for auditing the facility at least once a year,fully documenting the inspection and preparing a written report with the recommendationsand actions required for improvement for each department.- Also state that it is the responsibility of each department to provide access to the QA investigatorand to respond to any actions stated in the QA inspection report within a predeterminedtime period after the receipt of the written report.- Indicate that QA must then re-inspect to determine if the corrected action is satisfactory andreport these comments.- State that the QA manager is responsible for keeping the SOP current.4. Materials and Equipment As required.5. Procedure: Indicate clearly the following steps:a) Principle: Evaluate systems, processes and functions of a department to determinewhether actions are required to improve compliance with the guidelines.b) Preliminary:- Prepare, or ensure that the QA checklist is prepared.- Review earlier (internal or external) inspections, reports actions required, actions taken andany comments that would indicate specific items to be inspected.- Set up schedule for each department for the date and time of the annual audit.- Unannounced audit can be made at any time.WHO/VSQ/96.03 55(ii) SOP : INTERNAL INSPECTION, continued5. Procedure, continuedc) Audit: Using prepared checklist to go through the departments:,- Reviewing the premises (state of repair, cleanliness, env monitoring data, etc.),- Appropriate attire worn in each area,- Appropriate personnel behaviour in specific areas,- Equipment (state of repair, cleanliness, logbooks, calibration), preventive maintenance),- Records and documents for completeness, accuracy, dating and signatures.- Signs and labels are clear and accurate,- Traceability of components,- Training files,- Appropriate control of open products- Appropriately segregated storage.- Inspection of the production areas should be done from outside the area wherever possible:d) Report: Make a report of the non-compliant items, and propose actions to be taken. Noteespecially critical problems such as breaches in aseptic procedures, or documents inadequatefor traceability.6. Reporting- Checklist is to be used to document the initial findings and to identify what areas need to beimproved.- This must be expanded in a detailed written report.- There should be a time limit for the presentation of the report- There should be a time limit for each department to comply with an action request- There should be a scheduled follow-up inspection especially for serious problems.7. Reference documents- References to other SOP documents- WHO GMP Guidelines56 Good manufacturing requirements(iii) SOP: BIOLOGICAL STARTING MATERIALSEXAMPLE: For every cell, bacteria and virus used to manufacture the vaccine, there must betesting, verification and documentation of the original strain, stocks and inoculation materials toensure the quality for use in production.SOP____ : Control of Biological Starting Materials1. PurposeTo describe the information required, to identify and characterize stocks and inoculation materialsfor production of vaccines.2. ScopeFor all cells, virus, bacterial strains used in the manufacture or testing of vaccines. To be preparedfor all new stocks and revised for existing stocks if any changes in the storage or maintenance
occur.3. ResponsibilityProduction should prepare a record for each stock.QC is responsible for reviewing and approving the specifications.4. Materials and EquipmentAs required (computer, logbooks, record sheets, etc.).5. Procedurea) Record the name, source, history, date received, passage level, growth medium, storagemedium, state (lyophilized or liquid culture) and any other relevant details of the originalstrain.b) Record the dates of the approval of the strain by the national control authority.c) Record the tests required, tests performed and results (in house results or results providedwith the strains).d) Provide details of the seed lot system used to create the seed lots (primary or secondary)and cell banks (master and working):Growth mediumFreeze mediumStorage conditionsNumber of passagesPooling, aliquotingNumber of aliquots for each seed lot or cell bank(Refer to WHO TRS for each vaccine for the required details)WHO/VSQ/96.03 57(iii) SOP : BIOLOGICAL STARTING MATERIALS, continued5. Procedure, continuede) Provide list of tests to be performed to characterize the seed lots or cell banks, includingstability tests.f) Attach results of characterization tests or give location of characterization files, including QCapproval.g) State location of the inventory log or computer file which records the disposition of the seedlots or cell banks.h) List the tests and specifications for characterizing the working stock performed before inoculatinga production run. Give the SOP numbers for the test procedures (refer to WHO TRSfor each vaccine for the recommended tests).i) List the schedule of periodic retesting of seed lots and/or cell banks as appropriate for therespective type.6. ReportingAn appropriate record sheet should be prepared for each type of strain. The completed recordsheet to be kept on file, and updated by production department as required.7. Reference DocumentsWHO TRS for each specific vaccine (sections on cell and seed stock controls)SOPs for characterization methods.SOPs for relevant QC release tests.58 Good manufacturing requirements(iv) SOP: SAMPLING FOR ENVIRONMENTAL MONITORINGEXAMPLE: General requirements for an SOP written for taking the samples for environmentalmonitoring.SOP ___: Environmental Monitoring of Cleanrooms: Sampling Method1. PurposeTo provide a complete description of the methods and schedules for taking samples for monitoringthe air and surfaces (including personnel ) in all production areas for non-viable and viablecounts to ensure compliance with predetermined cleanliness levels.2. ScopeFor taking the required samples for the routine monitoring of all classified, clean and aseptic areasof vaccine production.3. Responsibilitya) QC tests and approves materials for monitoring microbial (viable) counts.b) Production department responsible for performing the sampling procedures.c) QC or QA is responsible for testing microbial count and reporting results.d) QA is responsible to ensure procedure is followed. and to investigate if acceptable levels areexceeded.4. Materials and Equipment
List swabs, contact plates, settling plates as appropriate.Particle counter (electronic or vacuum apparatus with filter trap)Microbial sampling apparatus.Disinfectant for decontaminating surfaces of wrapped plates or swabs.Chart of sampling locations for each room.5. Procedure:a) Principle: Cleanliness classes are an accepted requirement in the manufacture of biologicals.All GMP guidelines specify critical aseptic areas (exposed sterilized components and drugproduct, eg during filling) and controlled areas (all production and preparation of unsterilizedproduct and components).b) Specify the safety precautions to be taken during monitoring (e.g. aseptic handling).c) Preliminary steps. Provide details of:Floor plans of rooms and sampling locations identified.Schedule and frequency of monitoring of rooms and personnel according to room function.Requisition of appropriate number of plates from QC in advance.Monitoring equipment maintenance and calibration verified.WHO/VSQ/96.03 59(iv) SOP: SAMPLING FOR ENVIRONMENTAL MONITORING, continued5. Procedure, continuedd) Day of sampling: Give step-by-step instructions for the following:Delivery of sealed sterile plates or swabs by QC to the pass-through with record sheet.Decontaminating outer surfaces of packaging in pass-through before entering clean area.Checking plates/swabs for sterility (no visible growth).Transporting labelled plates/swabs to locations indicated on the schedule chart.e) Microbial Sampling of air and surfaces including personnel.Give details forUnwrapping plates or swabs.Marking with date, time, room number, initials, location code, other identification.Specific instructions for taking swabs or exposing plates.Rewrapping after completion of sampling.Advising QC and returning to QC via the pass-through.Completion of the Production Section of the Data sheet.f) For counting of non-viable particles (production)Give detailed instructions for particle counting method used.Give methods of calculating the particle count from the data.6. ReportingFill in record sheets indicating any deviations to the sampling schedule or procedure.Electronic particle count data from cleanrooms are to be recorded and reported to QA .7. Reference documentsDepending on the methods used, list other relevant SOPs or reference documents that are usedfor environmental monitoring assessment.SOP: __ Operation, maintenance, and calibration of the air sampler.SOP: __ Operation, maintenance, and calibration of the particle counter.SOP: __ Moving of plates/swabs in and out of a controlled or critical area.SOP: __ Preparation of plates and swabs for environmental monitoring of clean rooms byQC.SOP: __ Plate and swab counts: incubation and assessment by QC.SOP: __ QC procedure for qualification of media used for environmental monitoring.SOP: __ QC procedure for identifying and quantifying microorganisms found during environmentalmonitoring.SOP: __ QC evaluation of environmental monitoring samples(Acceptance criteria must be established for surfaces and personnel. For air seereference document FED-STD-209E. Alert and action levels, and procedures to followif these levels are reached e.g. report to supervisor, report to QA, stop production,quarantine product, complete incident/deviation report, perform an investigation,must be defined prior to proceeding with the monitoring.)SOP: __ Training procedures for good cleaning practices.SOP: __ Entry, exit and gowning procedures for cleanrooms.SOP: __ Monitoring schedule for cleanroom temperature and humidity, air flow, air balanceand air pressures, and door and air lock function.SOP: __ Cleaning and disinfection of cleanrooms.WHO GMP for Pharmaceutical Products, TRS 823, 1992
FED-STD-209E: Standards and Methods for Particle Counting of Classified Cleanrooms.60 Good manufacturing requirements(iv) SOP: SAMPLING FOR ENVIRONMENTAL MONITORING, continuedENVIRONMENTAL MONITORING: SCHEDULE FOR SAMPLINGOn a floor plan of each room requiring monitoring, identify the sampling locations, surfaces andequipment for air and surface monitoring and assign a code number to be used for the followingtables. Indicate the frequency as daily, weekly, bi-weekly, depending on the activity and classificationof the room.A. Air monitoringRoom# ClassViable air sampler Particle samplingLocation Frequency Location Frequency19
B. Surface monitoringRoom# ClassSurface sampling Equipment samplingLocation Frequency Location Frequency20
WHO/VSQ/96.03 61(iv) SOP: SAMPLING FOR ENVIRONMENTAL MONITORING, continuedEXAMPLE: ENVIRONMENTAL MONITORING DATA RECORD SHEETA: Surface Monitoring, Viable CountsQC to Complete and deliver with Materials:Media Type (contact plate or swab type): .Lot#: _________ QC release date: ___________Exp. date: __________________Production to Complete _______________ QC to Enter Test Results: SOP _____Date of Sampling: ___________________ Date of Results: _________________Operator performing the sampling: __________________________B: Personnel Monitoring, Viable CountsQC to Complete and deliver with Materials:Media Type (contact plate or swab type): ___________________________________Lot#: _________ QC release date: ___________Exp. date: __________________Production to Complete QC to Enter Test Results: SOP _____Date of Sampling: ___________________ Date of Results: _________________Operator performing the sampling: _______________________________________RoomnumberActivity LocationcodeResultsCFUColony ID Performedby21
Staff Name Location(chest, mask,gloves, other)PerformedbyResults CFU Colony ID Performedby22
62 Good manufacturing requirements(v) SOP: LABEL CONTROL AND ISSUANCE.EXAMPLE: Final product labels must be under strict control and be reconciled before and afterevery use. This is a critical operation for any manufacturer to ensure that the correct labels with thecorrect lot number and expiry date have been applied to the final container. Therefore, thereshould be accurate records of all label usage from purchase orders, receiving counts, issuancecounts, and individual label reconciliations.The same control is applied to product boxes or cartons and package leaflets. This examplediscusses only labels for the final vials or ampoules.SOP ___: Label Control and Issuance1. PurposeTo describe the system for the complete and accurate control of all final product vial labels andtheir reconciliation.2. Scope
Applies to all final product vial labels that are used in the Labelling and Packaging Department.3. ResponsibilityIndicate the persons or departments responsible for label control and issuance for the organization.4. Materials and EquipmentStorage boxesSecure storage location for labels5. ProcedureThe actual procedure will depend on whether the product lot number and expiry date are stampedby hand or automatically by the labelling machine.a) Purchasing/Receiving enters shipment information for preprinted (excluding lot no. and expirydate) labels into receiving log according to the SOP, stores in quarantine, and informsQC.b) QC checks labels against specifications and approves or rejects the shipment (SOP # __),and delivers to person responsible for storing and distributing labels.c) Prepare a Label Reconciliation Form for each lot of labels. Keep a running balance on theform as the labels are used. (This form is for controlling large quantities of labels which areissued in smaller amounts for many different lots of the same product)WHO/VSQ/96.03 63(v) SOP: LABEL CONTROL AND ISSUANCE, continued5. Procedure, continuedd) Prepare an Issued Label Control Form on receipt of a request from the Labelling/PackagingDepartment for labels for a specific product. (The Issued Label Control Form remains withthe issued labels to provide control of their use.)e) Prepare the required and extra labels for each request.Quantity Requested: Additional Provided:1-300 5301-750 10751-1,000 151,001-3,000 203,001-5,000 255,001 + 1/2%f) Verify the label count by two individuals; put labels and the Issued Label Control Form intolabel control boxes or envelopes.g) Complete the Label Reconciliation Form, after the labels are printed, to record the amountrequested by the Labelling/Packaging Department on the Label Control Form.h) Deliver the labels and IssuedLabel Control Form to the Labelling/Packaging department (byQA inspector or other designated person).i) If additional labels are required, the Labelling/Packaging Department must request the requirednumber of additional labels on the Issued Label Control Form; and the additionallabels are added into the Label Reconciliation Form by the QA and Labelling/PackagingDepartment personnel.j) At the end of the day return any unused labels to the label secure storage. Person responsiblesigns for the labels.k) Label ReconciliationWhen labelling is finished, the Labelling/Packaging Supervisor completes the Issued LabelControl Form by filling in the number of labels used for the following items:(a) number used for Issued Label Control Form(b) number used for boxes(c) number used for final containers(d) number damaged during labelling operations or unused labelsThe total number of labels used and destroyed must equal the total number printed andissued.64 Good manufacturing requirementsIssuing department Labelling/Packaging departmentLabel issued by: _____________Date: __________Label checked by: __________Date: __________Control number: __________Number received: __________Received by: __________Date: __________
Additional received: __________Received by: __________Date: __________Total issued: ._________Addt'l issued: __________Number used: __________For batch record: __________for containers__________for boxes __________Number of additional used: __________For batch record: __________for containers __________for boxes __________Total issued:__________Amount returned:__________Returns counted by:__________Date: __________Amount destroyed: __________Destroyed by: __________Date: __________Amount returned: __________Amount damaged: __________Returned by:__________Date: __________23
(v) SOP: LABEL CONTROL AND ISSUANCE, continuedEXAMPLE: Issued Label Control FormPRODUCT NAME _________________________________________________PRODUCT CONTROL NO ___________ PRODUCT LOT NO ____________PRODUCT EXPIRATION DATE ___________WHO/VSQ/96.03 65(v) SOP: LABEL CONTROL AND ISSUANCE, continuedLabel Reconciliation FormPRODUCT NAME _________________________________________________LABEL SIZE ____________________________________________________SUPPLIER ___________________________ P.O. # ___________________COMPANY CODE # ______________________RECEIVING # _________________________QUANTITY ORDERED _________ QUANTITY RECEIVED _______ DATE ________QC RELEASE DATE ______________________INVENTORIED BY ________________________ DATE ___________________CHECKED BY ____________________________ DATE ___________________StartingbalanceAmountremovedBalance WithdrawnbyDate CheckedbyDate24
66 Good manufacturing requirements(vi) SOP: CLEANINGEXAMPLE: General requirements of an SOP written for any of the following processes:Facility Cleaning: floors, walls, ceilings, work and equipment surfaces, etc.Equipment Cleaning/Sanitizing: CIP, COP, SIP, washing the inside of blenders, filters, andtanks, etc.General Glassware and Lab ware Cleaning: by hand or by automatic washer, etc.SOP ___: Procedure for Cleaning1. PurposeTo provide detailed instructions for the specific cleaning procedure.2. ScopeDescribe where this particular procedure is to be performed (in a controlled or general area, onspecific equipment or in a specific room, etc.).
Indicate when the procedure is to be performed and how often it must be performed. (Everydayat 2 PM, once a week etc.)3. ResponsibilityState who is responsible for performing the procedure whether it be production staff, hiredcleaning staff, building cleaning staff, etc.State the title of the manager responsible for ensuring the procedures are followed.4. Materials and EquipmentList the materials needed to complete the procedure, including the whole range of materials, equipmentand utilities. The following are a few examples of the types of items one might include in thislist:Cleaning agents or disinfecting agents to be usedSwabs, cloths, mops, buckets, hosing, etc.Vacuum cleanerAutomatic dishwasher5. Procedurea) the preparation of cleaning agents or detergents such as dilution, rotation etc.b) safety precautions for any toxic agents being usedc) dress code requiredd) clear and concise step by step instructions for the entire cleaning operation - number ofwashes, number of rinses, drying method, disposal or regeneration of cleaning materials.6. ReportingIdentify what information needs to be documented, before, during or after the cleaning procedure,and where it is to be recorded. See example of a Cleaning Log, below.WHO/VSQ/96.03 67(vi) SOP: CLEANING, continued7. Reference DocumentsReferences to other SOP documents that are needed to perform parts of the cleaning operation.For example:SOP for storage of cleaning agents.SOP for gowningSOP for the moving of equipment in and out of a clean or aseptic areaSOP for the operation of an automatic dishwasher, or vacuum cleaner68 Good manufacturing requirements(vi) SOP: CLEANING, continuedCleaning Operation LogOperation Description: .Fill in the date, time, product, cleaning agents before entering, fill out name after cleaning iscompleteWHO/VSQ/96.03 69(vii) SOP: RAW MATERIALS SPECIFICATION SHEETSEXAMPLE: Specifications list for each raw material or component to be used in production orquality control testing of product.SOP ______: Specification Sheets for Raw Materials1. PurposeTo describe the requirements for preparation of a specification sheet for raw materials.2. ScopeSpecifications are required for each raw material (chemical or biological), packaging component(vials, stoppers, seals, labels, leaflets) or any other material which comes in contact with the drugduring manufacture (tubing, tanks, centrifuge bottles, storage containers, filters, pipe valves, syringes,replaceable caps, etc.).3. Responsibilitya) The department requiring the material is responsible for setting the specifications.b) QA is responsible for approving the specifications and approving the suppliers of the material.c) The QC department is responsible for testing or assessing each material against the setspecifications before it can be released for use in production, packaging, or for QC tests.d) The QA Department is responsible for assigning an in-house code number to each material.4. Materials and Equipment :None5. Procedure :Prepare a Raw Materials Specification Sheet for each material from data provided.a) the approved name of the product (common chemical where appropriate) any alternate namesand in-house code number.b) the chemical composition, formula, weight, size or other description as appropriate.
c) indicate the quality or grade of product.d) list the specific characteristics to be tested including the specifications.e) list the SOPs of the test procedure(s) to be used to determine if the material meets specifications.f) list of approved supplier and alternate suppliers, catalogue number or other specific identificationnumber.6. ReportingProvision of the Raw Material Specification List to the Purchasing/Receiving Department for ensuringthat materials of the correct quality are ordered from approved suppliers and that incomingmaterials are appropriately quarantined until released by QC.70 Good manufacturing requirements(vii) SOP: RAW MATERIALS SPECIFICATION SHEETS, continued7. Reference DocumentsSOP __: Supplier Audit and ApprovalReferences to accepted standard methods (eg):Pharmacopeia,WHO manualsWHO/VSQ/96.03 71(vii) SOP: RAW MATERIALS SPECIFICATION SHEETS, continuedRaw Material Specification SheetA:Approved Name: ___________________________ In-house Code Number: _______________Alternate Name: ___________________________________Formula: __________________ Weight: ___________________ Size: ________________ .Quality or Grade ______________________________Description:Storage conditions: _____________________________Approved Suppliers and product catalogue number___________________________________ # ______________________________________________________________________ # ______________________________________________________________________ # ___________________________________B:Characteristic Specification Test Methodology(SOP # or Other Standard)______________________ ______________________ _______________________________________________ ______________________ _______________________________________________ ______________________ _______________________________________________ ______________________ _______________________________________________ ______________________ _______________________________________________ ______________________ _______________________________________________ ______________________ _________________________PB Good manufacturing requirements -- Part 1: SOPs and master formulae
10. Master formulaeThe instructions for the manufacturing method are also written procedures but arenot called SOPs. The full procedure is detailed in a Master Formula which details thepreparations to be made, the equipment to be used, and the method to be followed.GMP documents from WHO and other countries all require that a Master Formula beprepared and approved for each batch size of every product manufactured. The MasterFormula describes in detail all the manufacturing instructions for that specific batchof product.The MF explains detailed step-by-step instructions for the production process: thedetails include the specific types and amounts of components and raw materials; thedetails of the processing parameters; indicates what in process quality controls arerequired; specifications for intermediates; environmental monitoring and control. TheMF is written with blank spaces at each point where data or information is to be recordedto document that the production events occurred as directed. For some steps,the MF may refer to an SOP which describes a specific part of the production process.In various GMP documents, the term for this master document differs slightly. WHO
and Canada use the term “Master Formulae”; in the USA GMP Regulations the termis “Master Production and Control Record”; in the EU GMP guidelines the term is“Manufacturing Formulae and Processing Instructions”, and the Australian GMPGuidelines calls it “Master Formulae and Processing Instructions”. However, regardlessof the term used, the information to be provided is essentially the same in each ofthese GMP documents.The Master Formula (MF) is the document that explains the detailed steps included ina facility’s method for producing a batch of product. The MF can be prepared as a setof documents: one for each segment of the full production process (e.g. for the productionof an intermediate such as a batch of harvest or for the formulation/fillingprocess from final bulk), or a single overall document that contains parts which describethe separate batch products that make up the full process from the startingmaterials to the final vialed product. If the MFs are prepared for batches of intermediateproducts, there will be several documents which together describe the full productionprocess for a particular product from beginning to end. If the MF describes thefull process, then the parts of the MF will describe production process for an intermediateproduct..The sections described in the MF should correspond to the chronological operationsfor the major manufacturing steps. It should have a first section with componentpreparation such as cleaning, equipment preparation, raw material preparation, etc.(It can be convenient to divide the sections up on a day-by-day basis). There must beWHO/VSQ/97.01 73
spaces provided for approval initials for each step as it is performed, and any deviationsthat may occur must be recorded at the time in the margins. Verification signaturesor initials of another operator may be required for critical processes and spaceshould be provided accordingly for these steps. Space for review by a supervisor mustbe included. All products, equipment and facility areas listed in the MF should havereference numbers associated with them to permit traceability.The format for the MF should be a formal document with the company name, productname, batch size, site of manufacture, a document number with revision number, andapproval signatures and dates. Each page should be numbered and spaces should beprovided to fill in the lot number of the batch and for approval signatures.The MF, and any revisions, must be approved, with dated signatures, by both Productionand QA officials. The original should be filed in a safe place and approved copiesare made for each production run. The lot number of the batch is filled in on eachpage, and approval signatures and information are filled in as required and distributedfor use for each production order.An SOP describing the writing, approval, distribution and use of the MF should beprepared.An example of a Master Formula for a hypothetical biological product is found inAppendix 6.Batch Processing RecordsA batch processing record is built up by filling in all the blanks on an approved MasterFormulae sheets. An approved copy of the MF is requested by the production departmentfor each production run of a batch. The Batch Processing Record Documentmust be verified by QA or QC as an exact replica of the current MF before beingreleased for a batch production run. It is ideal to have the batch processing recorddivided by day (see format in later section of this guide) so that only the requiredblank pages of the batch processing record are taken into the production area for eachday of a production run.Batch
Batches are defined as a specific quantity of a drug or material that is produced in asingle manufacturing operation having a uniform character and quality and which meetspredetermined specifications. Depending on the production method of the materialbeing manufactured, a batch can be the result of a continuous production process of adrug, or a defined part of the production process. For example, a batch can be theproduction of a crude harvest of a bacterial or viral vaccine from a fermentation run;or it can be a bulk purified product manufactured from raw materials or from crudeharvest; or it can be the formulation and filling of a bulk into the final containerproduct. In each of these examples, the “batch” is the product of a process with adefined starting and ending point, and usually with a storage period at both beginningand end. Each of these separate production events would have a separate batch recorddocumenting the procedures and process parameters carried out.PB Good manufacturing requirements -- Part 1: SOPs and master formulae
Batch Processing Record ReviewA product record, is assembled from the batch processing records, lyophilization record,environmental monitoring records, inspection reports, sterilization records, qualitycontrol records, etc. The final release of the product can only occur when the entireproduct record has been reviewed and approved by a Production Manager and QCand QA departments according to an SOP for Batch Processing Record Review andApproval.WHO/VSQ/97.01 75
Format for a Master FormulaCover PageName of Facility ABC Vaccine Manufacturing Company page 1 of 8Master Formula: Doc # 888 Revision number 2Product Name _______________ Product Code _______________ Batch Size _______________Written by _________________ Edited by _____________________________Production Approval Signature _________________ Date ____________Authorization Signature _________________ Department (QA/QC) ________ Date ___________Effective date_________________ Replaces Rev 1 .76 Good manufacturing requirementsPart 1: FermentationBatch size _________________ Fermentation Lot No. _______Theoretical Yield ____________Date Started: ______________ Operators ________________________________Date Finished: ______________ ________________________________Day 1: Preparation:This section should list all the preparative work and checks which are required before beginningthe procedure. A checklist for: facility preparation; production location; equipment preparation;reagent preparation; and for preparation and entry of incoming supplies needed for the days operationsis found in this section of the record. The checklist should give reference to the SOPnumbers followed during the preparation, expiry dates of reagents where applicable, QC approvaldates for starting materials, raw materials, supplies and reagents, and dates of cleaning and calibrationof equipment.Day 1: Manufacturing InstructionsThis section contains the step by step instructions for the process performed on Day 1 in sequentialorder. There should be blanks for all information and data to be entered and spaces forsignatures, initials and dates. All steps including sampling for QC tests should be indicated. Manyoperations will be recorded by checking a box to indicate the step was performed. Timed operationsshould have a space to fill in the beginning time and the finishing time. Weighings shouldhave a space to record the tared weight and final weight. Any calculations should be presented asa formula with blanks to fill in. All critical steps and blanks for times and weights and all calculationsshould have an additional blank space for the initials of second operator who verifies thereading or calculation. If an item of measuring equipment has a printed readout, the verificationsignature is not necessary, but the printout must be attached to the record as well as the valueentered in the appropriate blank on the record.
Day 1: CleanupA checklist of the step-by-step instructions for the procedure for cleaning up after the days productionis completed including: waste disposal, removal of reagents, storage of intermediates if appropriate,status of equipment, cleaning procedures performed before leaving. Blanks andcheckboxes and spaces for signatures, initials and dates are on the checklist.Day 1: ReportingThe days record is delivered to the Production manager at the end of the day.The Production Manager reviews and signs each page of the record.MF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page __2_ of _8__Product name: _______________ Code # ________WHO/VSQ/96.03 77MF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page __3_ of _8__Product name: _______________ Code # ________Part 1: Fermentation, continued Date: _______ Lot # ______Day 2: PreparationPreparation information for the steps for the continuation of the fermentation process performedon the second day are to be provided in a checklist with all the appropriate information (see day 1).Supplies and reagents brought in for day 2, and any calibrations, cleaning or preparation of equipmentdone on day 2 must be entered on the checklist.Day 2: Manufacturing InstructionsContinued step-by-step instructions for all the steps of the process performed on day 2, blanksand checkboxes for entering data, and spaces for signatures, initials and dates.Day 2: CleanupA checklist of the step-by-step instructions for the procedure for cleaning up after the days productionis completed including: waste disposal, removal of reagents, storage of intermediates if appropriate,status of equipment, cleaning procedures performed before leaving Blanks andcheckboxes and spaces for signatures, initials and dates are on the checklist.Day 2: ReportingThe day’s record is delivered to the Production Manager at the end of the day.The Production Manager reviews and signs each page of the record in the appropriate blanks.This format continues for the full number of days for this fermentation part of theproduction process. The batch for fermentation will end with the storage of the singleor pooled harvests, depending on the manufacturing process.PB Good manufacturing requirements -- Part 1: SOPs and master formulaeMF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page _4_ of _8__Product name: _______________ Code # ________Part 1: Fermentation, continued Date: _______ Lot # ______Day X: PreparationPreparation information for the steps for the continuation of the fermentation process performedon the last day are to be provided.Supplies and reagents brought in for the last day, and any calibrations, cleaning or preparation ofequipment done on the last day must be entered on a checklist.Day X: Manufacturing InstructionsSimilar step-by-step instructions for the procedure for the final day’s processing, blanks andcheckboxes for entering data, and spaces for signatures, initials and dates.The final step will be the sampling of the batch to send to the QC department for testing and theinstructions for labelling and quarantine storage of the finished fermentation batch (single or pooledharvests).Day X: CleanupA checklist of the step-by-step instructions for the procedure for cleaning up after the days productionis completed including waste disposal, removal of reagents, storage of intermediates if appropriate,status of equipment, cleaning procedures performed before leaving. There should be blanksand checkboxes for entering data, and spaces for signatures, initials and dates.Day X: ReportingThe day’s record is delivered to the Production Manager at the end of the day. The ProductionManager reviews and signs each page of the record.The above pages should be formatted so that each day’s instructions begin on a newpage. This will limit the number of pages to be taken into the production area eachday.The detailed manufacturing steps for the batch of harvest will finish with the completionof the batch processing records filled out in the production area. However, these
will be followed by a review of the production process and a review of the yields, QCtest results, and QC or QA review and approval of the batch records and release of theproduct from quarantine to release storage as an approved starting material for thenext part of the production process.WHO/VSQ/97.01 79MF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page _5_ of _8__Product name: _______________ Code # ________Part 2: Purification ProcessBatch size: ___________ Purified Bulk Lot No. _______Theoretical Yield: ___________Harvest lots used: ____________________________Date Started: ______________ Operators ____________________________________Date Finished: ______________ ____________________________________The same type of day-by-day instructions for the preparation, step-by-step procedure,and cleanup is prepared for the purification process - from harvest to purifiedbulk.The single or bulk harvests now become the starting material to be entered in thepreparation lists for day 1 of purification.The QC release of the of the harvest(s) is required before beginning this part of production.There should be a space to enter the date of production and the date of QCapproval in the preparation section of this record.The final step will again be the sampling of the purified bulk to be sent to QC fortesting and labelling and putting into quarantine storage.This format continues for the full number of days for this purification part of theproduction process.The batch for purification will end with the storage the purified bulk.The production steps will be followed by a review of the production process and areview of the yields, QC test results, and QC or QA review and approval of the batchrecords and release of the product from quarantine to release storage as an approvedstarting material for the next part of the production process.PB Good manufacturing requirements -- Part 1: SOPs and master formulaeMF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page _6_ of _8__Product name: _______________ Code # ________Part 3: Final Bulk FormulationBatch size: ___________ Purified Bulk Lot No. _______Theoretical Yield: ___________Harvest lots used: ____________Date Started: ______________ Operators____________________________________Date Finished: ______________ ____________________________________Again, the same type of day-by-day instructions for the preparation, step-by-step procedure,and cleanup is prepared for the purification process - from purified bulk to thefinal formulated bulk.The purified bulk is the starting material to be entered in the preparation lists for day1 of formulation.The QC release of the of the purified bulk is required before beginning this part ofproduction. There should be a space to enter the date of production and the date ofQC approval in the preparation section of this record.The final step of this part of the production process will again be the sampling of thefinal formulated bulk to be sent to QC for testing and labelling and putting into quarantinestorage.This format continues for the full number of days for this formulation part of the
production process.The batch for formulation will end with the storage the final formulated bulk.The production steps will be followed by a review of the production process and areview of the yields, QC test results, and QC or QA review and approval of the batchrecords and release of the product from quarantine to release storage as an approvedstarting material for the next part of the production process.WHO/VSQ/97.01 81MF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page _7_ of _8__Product name: _______________ Code # ________Part 4: Filling/Lyophilization/Sealing of Ampoules orFilling/Lyophilization of Vials orFilling/Stoppering/Capping of Vials (liquid product) andInspectionBatch size: ___________ Final Lot No. _______Theoretical Yield: ___________Final Bulk Lot: ___________Date Started: ______________ Operators ____________________________________Date Finished: ______________ ____________________________________Again, the same type of day-by-day instructions for the preparation, step-by-step procedure,and cleanup is prepared for the purification process - from final formulatedbulk to final filled container. Inspection of 100% of the vials should be performed andthe numbers of vials rejected and the reasons for rejection should be recorded. TheMF should contain a list of the defects to be looked for (cracks, particles, colour, turbidity,crooked stoppers, poor seals, etc).The final formulated bulk is now the starting material to be entered in the preparationlists for day 1 of filling or filling/lyophilization.The QC release of the of the final formulated bulk is required before beginning thispart of production. There should be a space to enter the date of production and thedate of QC approval in the preparation section of this record.A filling order is prepared and delivered to the Filling Department to initiate this partof production.This format continues for the full number of days for this filling or filling/lyophilizationpart of the production process.The final step of this part of the production process will be the inspection of the finalcontainers, applying quarantine stickers,transferring to quarantine storage, and advisingQC that the fill is completed and ready for them to take samples for testing.The production steps will be followed by a review of the production process and areview of the yields, QC test results, and QC or QA review and approval of the batchrecords and release of the product from quarantine to release storage as an approvedstarting material for the next part of the production process.PB Good manufacturing requirements -- Part 1: SOPs and master formulaeMF Doc: 888 Rev 2 Name of facility ABC Vaccine Manuf Co. page _8_ of _8__Product name: _______________ Code # ________Part 5: Labelling and PackagingBatch size: ___________ Final Lot No. _______Date Started: ______________ Operators ____________________________________Date Finished: ______________ ____________________________________Again, the same type of instructions for the preparation, step-by-step procedure, andcleanups prepared for the labelling and packaging process - from unlabelled final containerto the labelled/packaged final container.The final unlabelled containers are the starting materials to be entered in the preparation
lists for day 1 of labelling.The QC release of the of the unlabelled filled lot is required before beginning this partof production. There should be a space to enter the date of QC approval in thepreparation section of this record.The final step of this part of the production process will be the sampling of the finallabelled vials to be sent to QC for identity testing, and putting into quarantine storageuntil released by QC.A labelling order is prepared and delivered to the Labelling/Packaging department toinitiate this part of production.The batch for labelling/packaging ends with the quarantine storage of the final labelledcontainers.The production steps will be followed by a review of the production process and areview of the yields, QC test results, and QC or QA review and approval of the batchrecords and release of the product from quarantine to release storage for shipment.WHO/VSQ/97.01 83
11. Priorities for thepreparation of SOPs andmaster formulaeThe WHO Guidelines for Good Manufacturing Practice (ref. 21, 27) and all othernational and international GMP Regulations and Guidelines (ref. 3, 5, 7, 11, 18, 19)clearly indicate that written procedures must be established and followed to be incompliance with GMP. The term "written" occurs many times and covers all production,control, and administrative operations.Each manufacturer should evaluate the present status of their documentation systemand prepare a list of SOPs, forms and other documents needed to meet WHO GMPrequirements. If many documents are to be written, it is most productive if the staffperforming the procedure writes the initial draft, another operator or the supervisorreviews and revises it, and the department head accepts the final version. The staffperforming the procedure usually know it the best, and it also is easier for a supervisorto revise several SOPs than prepare them. Signatures of the personnel from QC orQA department, as appropriate, must be obtained for final approval. An SOP for thereview and approval of SOPs for each department should be one of the first administrativeprocedures to be developed.In most cases, it is fairly easy to prepare the written procedure for the QC testing ofraw materials, in-process intermediates and final product for traditional vaccines currentlyin production. Most of these tests are well described in WHO technical reports(ref 24-26) and manuals (ref. 22, 23, 28-31). Many chemical and biochemical assays areavailable in Pharmacopoeia, in Chemical Society Standards, and others and are internationallyrecognized standardized methods. Each of these assays can be printed inthe format presented in this guide, or in another suitable format adopted by the manufacturer.These standard procedures should be put into the manufacturer’s formalSOP format.It should also be straightforward to prepare Master Formulae for the manufacturinginstructions for manufacturers’ current vaccines. The steps of the production process,the equipment and materials used, and the time-frames should be well defined.SOPs for equipment operation, maintenance, and calibration can also be put in written
form fairly quickly because very often the equipment manuals provide the detailedinformation needed.However, the requirement for written procedures is not limited to the productionmethod, equipment operation and test methods. The more difficult SOPs to prepareare those describing control of materials at every stage, monitoring of storage conditions,requirements for storage segregation, SOPs for gowning, cleaning, fumigatingthe facility, monitoring equipment, monitoring the facility air and surfaces, SOPs forPB Good manufacturing requirements -- Part 1: SOPs and master formulae
entry of materials in and out of the clean and aseptic areas, SOPs for personnel healthand hygiene, animal care SOPs (raising, feeding, treating, health, cleaning and maintenanceof animal facilities, cage washing, quarantine of animals, etc.), SOPs for testingcell, viral and bacterial characteristics, SOP for egg candling, SOPs for self-inspectionsand audits, SOPs for sampling, and even an SOP for writing, revising SOPs, and onefor controlling the distribution of all the other SOPs. (Forms for recording the data orinformation obtained during the course of carrying out these procedures must be generatedfor each SOP, as appropriate, to ensure accurate records).All of these procedures have an impact on the quality of the product because each isconcerned with the quality of the incoming materials, with the operating conditionsand cleanliness of premises and equipment used, and with the animals, or biologicalmaterials used to produce or test the product.Three Vaccine Manufacturers have contributed a list of the titles of their SOPs. Thelists are in Appendix 2 and can be used as a reference for assessing the SOPs needed fora vaccine production facility.WHO/VSQ/97.01 85
Appendix 1:List of document requirementsStandard Operating ProceduresRaw Materials Specifications/Product CodesSupplier ApprovalReceipt and StorageSampling ProceduresQC Testing, Inspection,Quarantine, Release and ApprovalBiological Starting Materials Specifications(e.g. Cells, Eggs, Animals, Source, Name, Characteristics, HistoryVirus, Bacteria) Seed Lot System and StorageTests before use in ProductionSupplier (Approval, Ordering, etc.)Animal CareAnimal protocol reviewFacility Systems Operation, Maintenance and Calibration(e.g. HVAC*, water, clean steam)Cleaning of FacilityEnvironmental MonitoringEntry and Exit to CleanroomsGowningProduct FlowSupply FlowStaff FlowAir Flow
Waste Flow and DisposalGarment Cleaning and SterilizationGlassware Cleaning and SterilizationDisinfectant/FumigationPest ControlEquipment (Production and QC) OperationCleaning/Sterilization (Surface, CIP, SIP, COP)*Preparation of Cleaning SolutionsResidual Product and Cleaning AgentsPreventive MaintenanceCalibrationMonitoringCalibration of Certified NIST Instruments* HVAC = heating, ventilation, air-conditioning; CIP = Clean-in-Place; SIP = Sterilize-in-Place;COP = Clean-out-of-PlacePB Good manufacturing requirements -- Part 1: SOPs and master formulaeProduction Master FormulaeIn-Process Tests (Production)Preparation of Process Buffers and SolutionsEnvironmental SamplingLabelling and Packaging Label and Package Review and ControlSpecificationsReconciliation of LabelsExpiration DatesQuality Control Testing and Release of Final ProductTesting and Release of Intermediate/Bulk ProductAnalytical AssaysSamples: Test and RetentionSummary Protocol of QC ResultsStability StudiesReference Standard and Control (Maintenance andTesting)Recertification/Recalibration of QC EquipmentPreparation of Reagents and Materials for QC TestsQuality Assurance Batch Record ReviewInspection/Internal AuditsValidation Protocol ApprovalsProduct RecallProduct ComplaintsContractor AuditVendor AuditDocument Control, Revision, and Distribution(Change Control)Employee Records, Health RecordsTraining (Technical and GMP)SOP Writing and ApprovalsAdverse Event ReportsChange ControlStorage Temperature MonitoringProduct Distribution ProceduresDistribution RecordsQuarantine, Release, Rejection and StorageMaster Validation PlanWHO/VSQ/97.01 87
Appendix 2:List of SOP titles from threevaccine manufacturersThe SOP titles listed on the following pages have been contributed by the collaboratorson this project. These lists have been reproduced as an Appendix to this Guide toSOPs to provide examples of the number and diversity of SOPs needed for vaccineproduction and testing. They are listed in the order given by the contributor.Massachusetts Public Health Biologic Laboratories, Jamaica Plain,MassachusettsSOPs related to DTP VaccineSOP TitleCard Identification of Animals Released from TestControl & Documentation of Veterinary Drugs for Animal QuartersAnnual Review of Animal Facility SOP'sFinal Review of Adverse Reactions by LotObtaining a Recall Distribution Mailing List and LabelsGenerating Weekly Vaccine Distribution ReportsGenerating Weekly Report by Product and LotReceiving and Logging of Vendor Supplied ProductInventory of ProductsGenerating a Lot Reconciliation ReportGenerating Biologic Monthly Distribution ReportsGenerating Monthly Distribution Bar ChartProcedure for Using Three-Part Maintenance FormsRepair Logs for Refrigeration and Air Conditioning UnitsDocumentation Requirements for Fractionation RenovationDocumentation of a Standard Operating ProcedureSupervisory Review of Standard Operating ProceduresInitiation of Filling NumbersInitiation of Lot History RecordsSOP and In-process Form Change ControlStandard Operating Procedure and In-Process Form Computerized Document StorageSOP for Document ChangesPreparing Documents for TypingMethod for Correcting Entries on all RecordsAnnual Review of Standard Operating ProceduresReporting Problems with VendorsReporting of Production Incidents / Deviations & Resulting ActionsAnnual Review of SOP's and In-Process FormsUsing the WordPerfect Macro / TemplateUsing the Lotus Template for In-Process FormsAnnual review of QA DocumentationPB Good manufacturing requirements -- Part 1: SOPs and master formulaeProduct RecallsProduct ComplaintsPreparation of Biologic Laboratory Investigation ReportsQA Batch Record ReviewChange ControlData Analysis of VAERS Updates
Issuing Documents for Reference ManualsReview and Acceptance of SOP's from Contract OrganizationsMaintenance of B. Pertussis CulturesLyophilization of Pertussis CulturesGrowing Challenge Culture for the Pertussis Potency TestPreparation of 10% Aluminum Chloride SolutionPreparation of High Phosphate Buffer (HPB)Preparation of 5N Acetic Acid SolutionPreparation of 1.12 M Phosphate Concentrate SolutionPreparation of ALCL3 and Sodium Trihydrate SolutionPreparation of 0.29M Na3PO4-12H2O SolutionPreparation of Tryptic Soy BrothMedia Preparation for the Production of Diphtheria ToxinCertification of Reagents Used in the Diphtheria Production MediumPreparation of Wadsworth BrothPreparation of 1% Peptone SolutionPreparation of Accessory Metal SolutionSiliconing of Vial TraysCalculation of Aseptic Filling YieldsDetermination of Tetanus Culture Purity: Production LotsProduction of Pertussis vaccineFiltration of Dow Silicone 365 EmulsionTetanus FiltrationFiltration of Crude tetanus ToxinSterilization of the 13mm and 20mm Flange and Split Vial StoppersDepyrogenation of Vials Using the Despatch Dry heat OvenSet-Up and Sterilization of a Single DUS-10 SyringeDetoxification of Tetanus ToxinDecontamination of Used Equipment & Glassware in Tetanus ProductionDetermination of Optimal Concentration of Ammonium Sulfate for Toxoid or ToxinPurificationFinal Component Diphtheria or Tetanus Toxoid PoolsPurification of Diphtheria Toxoid - Ammonium Sulfate MethodPurification of Diphtheria Toxoid by the Batch Column Method, Using SephadexDEAE A-50Intradermal Toxicity Test for Detoxification of Diphtheria ToxinTetanus Toxicity Test per Minimum RequirementsMLD Determination of Tetanus Toxin from Production lotsTest for Reversed Tetanus ToxoidDiphtheria Toxoid Reversion TestPassivation Records and Testing of Welds in newly Installed SystemsFilter Integrity Test and SterilizationVisual Inspection of Final Vial Rejects by QAFloor Cleaning (Animal Rooms and Corridors)Weekly Cleaning of Animal RoomsCleaning of the Hall WallsChanging of the Tacky mats in the Animal facilityWeekly Inspection of the Animal FacilityDrain CleaningWHO/VSQ/97.01 89Restrictions in a Class 2 Containment RoomWorking in a Level 2 Containment Room in the Animal QuartersRestrictions in the Animal Quarters AreaFloor Patching in Animal QuartersCollection, Autoclaving and Packaging of Sharps ContainersDisinfectant Change Method
Gowning for Aseptic Filling OperationsGowning Requirements within the Filling and Distribution DepartmentPreparing the Aseptic Fill Area for Janitorial CleaningCleaning of the Filling Area BG-34 by the Janitorial StaffGowning for Aseptic Vaccine Formulation OperatorsCleaning Procedure for Compositing AreaCalibration of Cage Washer ThermocouplesCalibration of HydrometersCalibration of Sanitary GaugesCalibration of RCS (Biotest) Viable Air SamplerAnnual Standardization of Diphtheria Flocculating AntitoxinNecropsy / Sampling Procedure for Moribund or Dead AnimalsProcedure for Aseptic, Survival Surgery in RodentsCardiac Puncture in Guinea PigsObtaining Blood Samples from Mice via Tail NicksI.P. (intraperitoneal) injections of Guinea PigsDrug Procurement in the Animal QuartersI.M. (intramuscular) injections of Mice, Guinea Pigs, and RabbitsRetro-Orbital Bleeding of mice with AnesthesiaCardiac Puncture in RabbitsRetro-Orbital Bleeding in MiceCardiac Puncture in MiceProcedure for Ordering AnimalsEntering Computer Generated Orders for Shipping Biologic ProductsPrinting Packing Slips and Mailing Labels for Computerized OrdersProcedure to follow when bitten by a Laboratory AnimalOff-Hour Notification of High/Low Temperature AlarmsProtocol Certification in Animal QuartersMonitoring of GMP Training for the MPHBLTraining program for MPHBL StaffOperator certification for SOP'sCFR Readings for Biologic Lab StaffTraining Program for Compositing ProceduresDisposition of Returned ProductControl Testing of Liquid Media Used with Milliflex SystemPreventive Maintenance, Ingersoll-Rand Air CompressorPreventive Maintenance, Sullair Air CompressorPreventive Maintenance, Van-Air DryersPreventive Maintenance and Maintenance of AutoclavesPreventive Maintenance Animal Quarters Filtration SystemOperation & Maintenance for the HVAC and Cold RoomsPM Compressed Air Systems - KaeserPreventive Maintenance ProgramChanging Tubing at WFI Ports - FillingMonitoring Cold Rooms - FillingShipping/Receipt of Bulk Product TanksMonitoring of Equipment, Diphtheria SectionCleaning & Set-Up of Equip. in Sterile Fill Area (Rm. BG-34) Before a FillInitial Set-Up and Operation of Metromatic Vial WasherPB Good manufacturing requirements -- Part 1: SOPs and master formulaePreparation of Bulk Product Tanks for Aseptic FillingsIdentification of Major EquipmentPreparation of Tyvek Bags for Lyophilized FillsPreparation of Goggles for Aseptic FillingsSet-Up and Operation of Ultrafiltration SystemPreparation of Rubber Stoppers
Compositing Preparations and ArrangementAssembly of Tanks Used in Vaccine Formulation and Bulk to FillPreparation and Assembly of Transfer Apparatus (TA) / SiphonsPreparation and Assembly of Transfer Graduate CylinderPreparation of Gowning Packages for Vaccine CompositingSet-Up & Operation of the HIAC/ROYCO Particle Counter Model 5250Operation of Filling AutoclaveTurbomatic 3000 Operation for Cleaning GlasswareUse of Jouan KR22i High Speed Refrigerated CentrifugeOperation of the Sorvall (Toxoid Purification) CentrifugeOperation of the BioTest RCS Air SamplerCleaning Procedure for Mouse CagesCleaning Procedure for Guinea Pig and rabbit Cages and PansCage Washing Procedure for Laboratory Animal CagesCleaning Procedure for Cage RacksIncinerator CleaningAcid Cleaning Procedure for Stainless Steel PansCalibrating Balances in the Animal QuartersCleaning Procedure for Cage WasherCage Washer OperationProcedure for Cleaning the Bedding Disposal HoodCleaning of Dus Syringes and Chase Filling Machine (M-3) PartsCleaning of Vials the Metromatic Vial WasherRoutine Calibration of Fairbanks-Morse Scale (Serial #6269896)Calibration of OHAUS Brainweigh B3000DNomenclature of Diphtheria Toxins and ToxoidsCleaning Procedures for Filter Holders & Pressure PotsLaboratory Tests -- Diphtheria ProductionTryptic Soy Agar Slit Sampler Plate PreparationSOP's and In-Process Forms: Organization and DistributionSending Products for Concurrent TestingBulk sampling Certification / Masterfile CreationGuidelines for Document PreparationGeneral Safety testSterility Testing Using Direct InoculationNumber of Final Vials Needed for QC Testing and ReservesResponsibilities of the QC UnitSterility Testing Using Membrane FiltrationThimerosal determinationPersonnel Training in QCElements of a Successful Training ProgramControl Testing of Thioglycollate Broth and Tryptic Soy Broth for Sterility Testing viaMembrane FiltrationGowning Requirements for Sterility Room (BG9A) OperationsSample Distribution of Final Vial, Bulk, and Stability SamplesAnnual Review of SOP'sPurity Check of Biological IndicatorsFinal Vial Visual Inspection of VaccinesGrowth-promoting Ability of Broth Used in Sterility Testing Using the Steritest System orDirect Membrane FiltrationWHO/VSQ/97.01 91Growth-Promoting Ability of Broth Used in Sterility Testing using Direct InoculationGrowth-Promoting Ability of Commercial Broth Used in Sterility Testing Using the DirectInoculation (Sealed Containers)Fluid Thioglycollate Broth Preparation (for Sterility Testing)Tryptic Soy broth (For Sterility Testing)
Labelling Procedure for Quarantined and Released Products and Procedure for Release forDistributionDate of Manufacture, Dating Period, Storage Period for Blood Products and VaccinesFinal Container product Reserve SamplesDetection and Quantitation of Residual Tetranitromethane in Pertussis ToxoidsDTP Pertussis Potency Computer ProgramUse and Function of the IEC Centra-W Cell WasherUse and Function of the Dade Automatic Centrifuge II (DAC II)Operation of the Milliflex-100 SystemNIST EquipmentTest for Potency of Precipitated or Adsorbed Tetanus Toxoid (DTP, DT, Td, and T)Test for Potency of Precipitated or Adsorbed Diphtheria Toxoid (DTP, DT, TD, and the AKcomponent of Td)Procedure for the Potency Test of Pertussis VaccineThe Lf Test for Diphtheria Toxoid in Tetanus and Diphtheria Toxoids for Adult useMouse Toxicity Test of DTPNitrogen Determination of Vaccine Components Using the Bradford assayValidation of Cleaning processes Using SwabsNephelometry Measurement by use of the Hach TurbidimeterTest for Residual Formalin in Toxoid PreparationPararosaniline Method for the Determination of Free Formaldehyde in VaccinesIdentity Testing of Biologic ProductsOptical Transmission Check for the DTP vaccineDetermination of the Residual Sodium Cholate Content in the Acellular Bordetella PertussisToxoidsPreparation Procedure for CompositingStability Program for all MPHBL productsStability Testing of Bacterial VaccinesPreparation and Scheduling of the Cleaning / Disinfecting SolutionsSchedule for the Cleaning and Monitoring of the Sterility Room (BG9A)Procedure for Thermometer CertificationEvaluation of New Cleaning AgentsQC personnel MonitoringCalibration of Cliniscan II DensitometerCertification of PipettesSilicate TestingQuarterly Microbial Monitoring of City waterAnnual Environmental Monitoring for Viable Organisms in production areas of the BiologicLaboratoriesWater Quality TestsMicrobial Monitoring of Environment During the Filling ProcessUse of Microbial Monitoring Plates in the Compositing environmentQuarterly Calibration of Cold Rooms, Incubators, and water BathsQuarantine and Release of a Bulk Product (Blood Product, Bacterial Vaccine, Placebomedium)Usage of the QC Requisition Form for TestingReagents Used in Preparation of Diphtheria Toxin mediumCalibration of Pressure GaugesPrep of 20% Cysteine SolutionMonitoring of UV Germicidal LightsWaters High Performance Liquid Chromatograph Model 840PB Good manufacturing requirements -- Part 1: SOPs and master formulaeOhaus Galaxy Model 160Ohaus Model B1500 DMettler Model AE 200 & 50 - Calibration and OperationQC Testing of Trypticase Soy Broth Medium for Broth Fills Validation
Calibration procedure for the Gas Chromatograph Perkins Elmer 8310Calibration of the Hitachi U-2000 SpectrophotometerTesting of Incoming Materials: Vials, seals, and StoppersTesting of Incoming Materials: Venusa IV Sets (Red Cross)Testing of Miscellaneous Incoming Materials: Gaskets, Connectors, O-Rings, etc.Control Testing of 0.1% Peptone Used in Sterility Testing (RQC of Peptone)Testing of Incoming Materials: bags, Pyrogen-Free Tubes, Celite (SuperCel)Testing of Incoming materials: TubingControl Testing of Rodac Plates, Settling Plates, TSA Plates, and RCS StripsControl Testing of ReagentsControl Testing of 0.1% Peptone Used in Sterility testingPurity Check with the use of HPLC for Niacin, Vitamin B1, Vitamin B6, and UracilAcetic AcidIdentity Test for Boric AcidIdentity Test for Bromocresol GreenCalcium ChlorideCalcium pantothenateCasamino Acid (technical)N-Z Case, certified Casamino AcidsIdentity Test for Citric AcidIdentity Test for Crystal VioletIdentity Test for Cupric SulfateCyanocobalaminIdentity Test Ammonium OxalateID / Purity Testing of B CyclodextrinL-CysteineCysteineIdentity Test for DEAE-SEPHADEX (anion exchanger)DextroseID / Purity Test for DithiothreitolIdentity / Purity Tests for EthanolamineFerric ChlorideIdentity Test of N-Acetyl DL Trytophan with the use of UV SpectrophotometryFerrous Sulfate IDFormaldehyde IdentificationIdentity test for FetuinIdentity / Purity test of Glutamic AcidIdentity / Purity Tests of Monosodium GlutamateIdentity of GlutathioneGlycerin IdentificationIdentity Test for GlycineHydrochloric AcidIodineIdentity of Kanamycin SulfateManganese ChlorideIdentity Test for AgarMagnesium SulfateMaltoseMagnesium ChlorideIdentity Test for Mercuric SulfateIdentity Test for Methyl RedNonfat Dry Milk - CarnationWHO/VSQ/97.01 93NiacinPhenol IdentificationPimelic Acid Identification
Potassium Chloride identificationIdentity Test for Aluminum ChloridePotassium IodidePotassium Phosphate, Dibasic IdentificationPotassium Phosphate, Monobasic IdentificationIdentity Test for Potassium SulfateIdentity Test for Potassium ThiocyanateIdentity / Purity Tests of prolineProteose Peptone IdentificationPyridoxine Hydrochloride IdentificationIdentity Testing of RiboflavinSilver NitrateB AlanineIdentity Test of Safranin-oIdentity Testing for Dow Corning 365 siliconeSodium Acetate IdentificationSodium BicarbonateSodium BorateIdentity Test for Sodium CarbonateIdentity testing for Sodium CaprylateSodium CholateSodium ChlorideID Test for Sodium HydroxideIdentity Test for Aluminum SulfateSodium LactateSodium Phosphate Dibasic AnhydrousSodium Phosphate Monobasic MonohydrateSodium Phosphate Tribasic 12-hydrateID Test for Sodium ThiosulfateStarchSucroseID / Purity Test for Tetranitromethane (TNM)Identity Thiamine HydrochlorideThimerosalIdentity Test for Sulfuric AcidIdentity Test for Barium ChlorideThioglycolic AcidID / Purity of Tris (Hydroxymethyl) AminomethaneUracilIdentity Test of yeast extractZinc SulfateIdentity Test of Phosphoric AcidID Test of the Antifoam ReagentID Testing of Ascorbic AcidID / Purity Tests for Chloroform (CHC13)ID Test and Purity Determination for UreaIdentity Test for BiotinID of (Acid Sanitizer) Phosphoric AcidID of Caustic Chlorinated CIP ChemicalCyanogen BromidePotassium Hydroxide identificationIdentity Test for Actigel-ALD Superflow and Coupling SolutionsIdentity Testing of SepharosePB Good manufacturing requirements -- Part 1: SOPs and master formulaeSodium CyanoborohydriteSodium Phosphate Dibasic 7 Hydrate
Purity & Specific Gravity determinations for 95% EthanolOperating the FTIR Model 1620 for Chemical ID and Purity CheckQC Testing of Incoming Component Raw MaterialsTesting of Incoming Materials: FiltersTesting of Incoming materials: Tucks, Circulars, and LabelsFiltration of formalized tetanus ToxinTetanus Toxin / Toxoid production : Flow ChartTetanus Toxin / Toxoid Production: Flow ChartCentrifugation of SamplesCertification of Toxin Producing Ability of Casein DigestsCalcium determinations of Casein Digests Used for TetanusGlassware Cleaning and Validation of CleaningBacterial Monitoring of tetanus BSC'sCalibration of Ohaus 4000D Toploading BalanceUse and Calibration of Orion #501 pH MeterMonitoring of Incubator, Cold Room, Freezer, and Refrigerator FunctionsStandardization of ThermometersWHO/VSQ/97.01 95
Biomanguinos/FIOCRUZ, Yellow Fever Vaccine Production Facility,BrazilSOPs related to producing vaccine against yellow feverList A:Autoclave operationAutoclave control using biological indicatorsBiosafety sign standardizationClothes washing machine operationColoration verification of vaccine against yellow feverControl and filing of diluent and vaccine protocolsControl and filing of equipment and instrument manualsDaily temperature controlEggs type SPF transilluminationEggs type SPF selectionEggs type SPF incubationElaboration and application of Defective Fraction Control ChartsEmbryonic pulp freezing and storageEmbryonic pulp thawingFilling process of vaccine against yellow feverFine balance calibrationFine balance operationFurnishment of animals, animal derived products and raw materialsGuidelines related to personnel access to the facilities of Bio-manguinhosGuidelines for requisition of imported materialsHandling and storage of materialsHot air oven operationHumidity controlInoculation in eggs type SPFInternal audits preparation and executionLabelling of references used in SOPsMaterial receptionMax-min. thermometer verificationNon-conformity report and corrective actionParticle counter and air velocity measurements in Laminar Flow UnitspH determination of vaccine against yellow feverpH meters calibrationFilling machine operation
Post-inoculation embryos collecting and embryonic pulp preparationPreparation of material to be sterilized in autoclavesPreparation of material to be sterilized in hot air ovensPressure gauge calibrationProduct codificationReference standards calibration planResidual humidity determination of vaccine against yellow feverRoom cleaning and disinfecting standardizationRTD Thermometer operationSpecification for specific pathogen free animal facilitiesSpecification for vaccine against yellow feverSpecification of diluent of vaccine against yellow feverSterilization process execution in autoclaveSterilization process execution in hot air ovenSOPs elaboration process and formatSOPs verification, approval and releasing of revised versionPB Good manufacturing requirements -- Part 1: SOPs and master formulaeSOPs codification systemSOPs controlSuppliers rating and qualification auditsUniform standardizationUse and control of labels devoted to indicate calibration stage of instrumentsVisual inspection of vaccine against yellow feverWater purification system monitoring processList B:Ammonia determination of diluent of vaccine against yellow fever and measlesArchive storage of produced immunobiologicsAspiration of embryonic pulpAspiration of viral suspensionAutoclave operationAutomatic packaging line operationButyl rubber stopper specificationCentrifugation of embryonic pulpChloride determination of diluent of vaccine against yellow fever and measlesClosing of vaccine against yellow feverCollecting of distilled water sample to be sent to chemical controlConductibility determination of diluent of five-dose vaccine against yellow fever and measlesCulture media sterilization processDispatch of vaccine against yellow feverFormulation of vaccine against yellow feverFilling of vaccine against yellow feverFreeze-drying of vaccine against yellow feverGlass vial specification for parenteralsIdentity test of vaccine against yellow feverInfected material sterilization processInoculation purpose material sterilization processLabel printer machine operationManual packaging line operationMean volume determination of diluent of vaccine against yellow fever and measlesMean weight determination of vaccine against yellow feverNeedles maintenanceOven operationPackaged immunobiologic storagePackaging material preparation and controlpH determination of diluent of vaccine against yellow fever and measlesPotency determination of embryonic pulp of vaccine against yellow fever
Potency determination of vaccine against yellow feverPreparation of Beaker to be used in disinfecting of aseptic areaPreparation of disinfectant to be used in aseptic areaPreparation of 70% diluted alcohol to be used in aseptic areaPreparation of Formalin solution fumigationPreparation of glass protector for needlesPreparation of material for collecting purposePreparation of material for inoculation purposePreparation of material to be used in vaccinesPreparation of plastic stopper cover for 1.000 mL bottlesPreparation of rubber stopper cover for 1.000 mL bottlesPreparation of stoppers for culture media tubesPreparation of stoppers for ErlenmeyerPreparation of stoppers for Measuring CylindersPreparation of sulphochromic solutionPreparation of iodinated alcohol solutionWHO/VSQ/97.01 97Production process of diluent of vaccine against yellow feverPreparation and execution of internal auditsReception and storage of immunobiologics to be packagedReception, inspection and labelling of material in storage areaReport and corrective action of non-conformities found in receipt or final productsSampling plans for receipt, in process and final inspectionSending of released immunobiologic for dispatchingSiliconization of rubber stoppers to 3 mL vialsSterilization process of materials to be used in collectingSterilization process of materials to be used in vaccineStorage of vaccine against yellow feverThermostability determination of vaccine against yellow feverWashing of rubber stoppers for 1.000 mL bottlesWashing of rubber stoppers for 3 mL vialsWashing process of material for incubating and collecting purposes and to be used in vaccineWater distillationPB Good manufacturing requirements -- Part 1: SOPs and master formulae
Gerencia General de Biologicos y Reactivos, Mexico City, MexicoSOP for DTP Vaccine• Raw material sampling• Raw material testing• Cleaning and sanitization of clean rooms• Washing of glass material• Sterilization of glass material• Preparation of culture medias• Preparation and sterilization of clean clothes• Preparation seed lot system• Inoculation of fermentors• Harvest of cultures• Detoxification of cultures and toxins• Separation of cells• Purification of Toxoids• Aseptic filtration of Toxoids• Sampling products in process and final products• Preparation of adjuvant• Blending• Filling, stoppering and sealing
• Inspection• Labeling• Sterilization in ovens and autoclavesQuality controlControl of single harvests• The bacterial grow rate opacity, pH and rate of toxin production• Purity• PurificationControl of bulk purified Toxoid• Sterility• Specific toxicity• Reversion to toxicity• Antigenic purity• Formalin contentWHO/VSQ/97.01 99
Control of final bulk• Preservative content• Adjuvant content• Sterility• Specific toxicity• Potency• pHControl final product• Identity• Sterility• Potency• Innocuity• Adjuvant content• Preservative content• pH• Inspection• StabilityOther• Personal training• Change control procedures• Formats• Reports• AppendicesPB Good manufacturing requirements -- Part 1: SOPs and master formulae
Appendix 3:List of reference articlesand publications(1) American Association for the Accreditation of Laboratory Animal Care.Outline for Description of Institutional Animal Care and Use Program, (withreference to Guide for the Care and Use of Laboratory Animals. DHHSPublication, Revised 1985), 1992(2) Austin P.R., Design and Operation of Pharmaceutical Bio-cleanrooms andAseptic Areas. Contamination Control Seminars, Michigan, 1994
(3) Australia. Therapeutic Goods Administration, Australian Code of GoodManufacturing Practice For Therapeutic Goods-Medicinal Products, August1990(4) Canada, Drugs Directorate Guidelines. Acceptable Methods. Health ProtectionBranch, Health Canada, 1994(5) Canada, Drugs Directorate Guidelines. Good Manufacturing Practices(GMP) Guidelines, Consultation Draft Fourth Edition. Health ProtectionBranch, Health Canada, 1995(6) Chapman K.G., Fields T.J., Smith B.C., “Q.C.” Pharmaceutical Technology,January 1996, pp74-79(7) Commission of the European Communities. Guide to Good ManufacturingPractice for Medicinal Products. The Rules Governing Medicinal Products inthe European Community, Volume IV, Jan 1992(8) Commission of the European Communities. Stability Tests on Active Ingredientsand Finished Products (July 1988). Guidelines on the Quality, Safetyand Efficacy of Medicinal Products for Human Use, The Rules GoverningMedicinal Products in the European Community, Volume III, 1988(9) DeSain C., Documentation Basics That Support Good Manufacturing Practices.Advanstar Communications, OH, 1993(10) DeSain C., Standard Operating Procedures and Data Collection Forms,Documentation Basics, BioPharm, October 1991, pp 22-29(11) Guideline for Good Manufacturing Practice in Egypt, Faculty of Pharmacy,Cairo University, Central Administration of Pharmacy, WHO, 1994(12) IES. Microorganisms in Cleanrooms, Contamination Control DivisionRecommended Practice 023.1. IES-RP-CC023.1, Institute of EnvironmentalSciences(13) IES. Testing Cleanrooms, Contamination Control Recommended Practice006.2, IES-RP-CC006.2, Institute of Environmental SciencesWHO/VSQ/97.01 101
(14) International Organization for Standardization. Quality Systems: ISO 9000-1, ISO 9001, ISO 9002, ISO 9003, ISO 9004-1, Geneva, 1994(15) Lanese J., A Model Standard Operating Procedure for Validation, The DocumentationDepartment. Vol 1, Number 4, Journal of Validation Technology,August 1995, pp60-77(16) Peine I.C., Quality Assurance Compliance, Procedures for Pharmaceuticaland Biotechnology Manufacturers. Interpharm Press, IL, 1994(17) The Gold Sheet, FDA's Inspection Concern for Bulk Pharmaceutical ChemicalFirms, Quality Control Reports, The Gold Sheet, FDC Reports Inc., 1995(18) U.S. Code of Federal Regulations, Current Good Manufacturing Practice forFinished Pharmaceuticals (Part 211), Food and Drug Administration, DHHS,21 CFR CH.1, 4-1-95 Edition(19) U.S. Code of Federal Regulations, Current Good Manufacturing Practice inManufacturing, Processing, Packing or Holding of Drugs; General (Part210), Food and Drug Administration, DHHS, 21 CFR CH.1, 4-1-95 Edition(20) USP. Microbiological Evaluation of Clean Rooms and Other ControlledEnvironments <1116>, In-Process Revision, Pharmacopoeial Forum, TheUnited States Pharmacopoeial Convention, Inc., Volume 21, Number 2,March-April 1995(21) WHO Expert Committee on Biological Standardization, Good ManufacturingPractices for Biological Products. Technical Report Series No. 822 Annex1, WHO Geneva, 1992
(22) WHO Expert Committee on Biological Standardization. Guidelines forPerforming One-Dilution Tests for Ensuring that Potencies of Diptheria andTetanus Toxoid Containing Vaccines are Above the Minimum Required byWHO, WHO Geneva, BS/89.1618, 1989(23) WHO Expert Committee on Biological Standardization. Potency Determinationin Mice of Diptheria Toxoid in Vaccines by Serum Neutralization ofDiptheria Toxin in Vero Cell Cultures, WHO Geneva, BS/89.1613 Rev. 1,1990(24) WHO Expert Committee on Biological Standardization. Requirements forDiphtheria, Tetanus, Pertussis and Combined Vaccines. Technical ReportSeries No. 800 Annex 2, WHO Geneva, 1990(25) WHO Expert Committee on Biological Standardization. Requirements forPoliomyelitis Vaccine (oral). Technical Report Series, No. 800 Annex 1, WHOGeneva, 1990(26) WHO Expert Committee on Biological Standardization. Requirements forYellow Fever Vaccine (and Addendum 1987), Technical Report Series No.594, Annex 1, 1975, and Technical Report Series No.771 Annex 9, 1988, WHOGeneva,(27) WHO Expert Committee on Specifications for Pharmaceutical Preparations.Good Manufacturing Practices for Pharmaceutical Products. TechnicalReport Series No. 823 Annex 1, WHO Geneva, 1992(28) WHO Laboratory Methods for the Testing for Potency of Diptheria (D),Tetanus (T), Pertussis (P) and Combined Vaccines, WHO, Geneva, RestrictedDocument, BLG/92.1PB Good manufacturing requirements -- Part 1: SOPs and master formulae
(29) WHO Laboratory Methods for the Titration of Live Virus Vaccines UsingCell Culture Techniques, For laboratories operating in support of the ExpandedProgramme on Immunization, Biologicals Unit, WHO, Geneva,Restricted Document, BLG/EPI/89.1(30) WHO Manual of Laboratory Methods for Potency Testing of Vaccines usedin the WHO Expanded Programme on Immunization. WHO/BLG/95.1(31) WHO Production and Control of Tetanus Vaccine (Training Curriculum).WHO/VSQ/GEN/94.01- 94.11(32) Whyte W., Donaldson N., How to Clean a Cleanroom. Microcontamination,November 1987Added during review and editing:(33) U.S. Current Manufacturing Practice: Proposed Amendment of CertainRequirements for Finished Pharmaceuticals, Food and Drug Administration,Federal Register, vol 61, No 87, May 1996.(34) Loftus B.T., Nash R.A. Pharmaceutical Process Validation. Marcel DekkerInc., 1984, p 227.WHO/VSQ/97.01 103
Appendix 4:Glossary(Numbers in parentheses are the Reference numbers in Appendix 3. WHO definitionshave been used when available.)acceptance criteria: The product specifications and acceptance/rejection criteria,such as acceptable quality level and unacceptable quality level, with an associated
sampling plan, that are necessary for making a decision to accept or rejecta lot or batch (or any other convenient subgroups of manufactured units). (19)action levels: Microbiological levels in the controlled environment, specified in thestandard operating procedures, which when exceeded should trigger aninvestigation and a corrective action based on the investigation. (20)air sampler: Devices or equipment used to sample a measured amount of air in aspecified time to determine the particulate or microbiological status of air inthe controlled environment. (20)airborne particulate count (or total particulate count): Particles detected are 0.3 um,0.5 um, and larger. When a number of particles is specified, it is the maximumallowable number of particles per cubic meter of air (or per cubic foot of air).(20)airborne viable particulate count (or Total airborne aerobic microbial count): Whena number of microorganisms is specified, it is the maximum number ofcolony-forming units (CFU) per cubic meter of air (or per cubic foot of air)that is associated with a Cleanliness Class of controlled environment based onthe Airborne particulate count. (20)airlock : An enclosed space with two or more doors, which is interposed betweentwo or more rooms, e.g., of differing classes of cleanliness. for the purpose ofcontrolling the airflow between those rooms when they need to be entered.An airlock is designed for and used by either people or goods. (27)alert levels : Microbial levels, specified in the standard operating procedures, whichwhen exceeded should result in an investigation to ensure that the process isstill within control. Alert levels are specific for a given facility and are establishedon the basis of baseline developed under an environmental monitoringprogram. These Alert levels can be modified depending on the trend analysisdone in the monitoring program. Alert levels are always lower than Actionlevels. (20)aseptic processing: A mode of processing pharmaceutical and medical products thatinvolves the separate sterilization of the product and of the package (containers/closures or packaging material for medical devices) and the transfer of theproduct into the container and its closure under microbiologic criticallycontrolled conditions. (20)PB Good manufacturing requirements -- Part 1: SOPs and master formulae
audit: Inspection of facilities, functions, or records. (31)authorized person: A person responsible for the release of batches of finishedproduct for sale. In certain countries the batch documentation of a batch offinished product must be signed by an authorized person from the productiondepartment and the batch test results by an authorized person from thequality control department for batch release. (27)batch (or lot): A defined quantity of starting material, packaging material or productprocessed in a single process or series of processes so that it could heexpected to be homogeneous. In the case of continuous manufacture, thebatch must correspond to a defined fraction of the production, characterizedby its intended homogeneity. It may sometimes be necessary to divide a batchinto a number of sub-batches, which are later brought together to form a finalhomogeneous batch. (27)batch number (or lot number): A distinctive combination of numbers and/or letterswhich specifically identifies a batch on the labels, the batch records, thecertificates of analysis, etc. (27)batch numbering system: Standard operating procedure describing the details of the
batch numbering. (27)batch records: All documents associated with the manufacture of a batch of bulkproduct or finished product. They provide a history of each batch of productand of all circumstances pertinent to the quality of the final product. (27) (Inreference 27, batch records for production are called “batch processingrecords” and for the packaging operations “batch packaging records” )bioburden: Total number of microorganisms detected in or on an article prior to asterilization treatment.(20)biogenerator: A contained system, such as a fermentor, into which biological agentsare introduced along with other materials so as to effect their multiplication orthere production of other substances by reaction with the other materials.Biogenerators are generally fitted with devices for regulation, control, connection,material addition and material withdrawal. (7) (also called a bioreactor)biological agents: Microorganisms, including genetically engineered microorganisms,cell cultures and endoparasites, whether pathogenic or not. (7)bulk product: Any product that has completed all processing stages up to, but notincluding, final packaging. (27)calibration: The set of operations that establish, under specified conditions, therelationship between values indicated by an instrument or system for measuring(especially weighing), recording, and controlling- or the values representedby a material measure, and the corresponding known values of areference standard. Limits for acceptance of the results of measuring shouldbe established. (27)cell bank:cell bank system: A cell bank system is a system whereby successive batchesof a product are manufactured by culture in cells derived from the samemaster cell bank [fully characterized for identity and absence of contamination].A number of containers from the master cell bank are sued to prepare aworking cell bank. The cell bank system is validated for a passage level orWHO/VSQ/97.01 105
number of population doublings beyond that achieved during routine production.master cell bank: A culture of [fully characterized] cells distributed intocontainers in a single operation, processed together in such a manner as toensure uniformity and sorted in such a manner as to ensure stability. A mastercell bank is usually stored at -70 oC or lower.working cell bank: A culture of cells derived from the master cell bank intendedfor use in the preparation of production cell cultures. The working cellbank is usually stored at -70 oC or lower. (7)cell culture: The result from the in-vitro growth isolated from multicellular organisms.(7)certification: Documented testimaony by qualified authorities that a system qualification,calibration, validation, or revalidation have been performed appropriatelyand the results are acceptable. (34)clean area: An area with defined environmental control of particulate and microbialcontamination, constructed and used in such a way as to reduce the introductiongeneration, and retention of contaminants within the area. (27)clean room: A room in which the concentration of airborne particles is controlledto meet a specified airborne particulate Cleanliness Class. In addition, theconcentration of microorganisms in the environment is monitored; eachCleanliness Class defined is also assigned a microbiological level of air, surface,and personnel gear. (20)
clean/contained area: An area constructed and operated in such a manner that willachieve the aims of both a clean area and a contained areas at the same time.(7)component: any ingredient intended for use in the manufacture of a drug product,including those that may not appear in such drug product. (19)contained area: An area constructed and operated in such a manner (and equippedwith appropriate air handling and filtration) so as to prevent contamination ofthe external environment by biological agents from within the area. (7)containment: The action of confining a biological agent or other entity within adefined space.primary containment: A system of containment which prevents the escape ofa biological agent into the immediate working environment. It involves theuse of closed containers or safety biological cabinets along with secure operatingprocedures.secondary containment: A system of containment which prevents the escapeof a biological agent into the external environment or into other workingareas. It involves the use of rooms with specially designed air handling, theexistence of airlocks and/or sterilizers for the exit of materials and secureoperating procedures. In many cases it may add to the effectiveness of primarycontainment. (7)control: Controls resemble the unknown in composition and are assayed at thesame time under the same test conditions by the same method. The results ofthese tests are used in calculating the mean and standard deviation of the test.Controls are used to measure accuracy. (4)PB Good manufacturing requirements -- Part 1: SOPs and master formulae
controlled environment: Any area in an aseptic process system for which airborneparticulate and microorganism levels are controlled to specific levels, appropriateto the activities conducted within that environment. (20)corrective action: Actions to be performed that are in standard operating proceduresand that are triggered by exceeding Action levels. (20)critical process: A process that may cause variation in the quality of the pharmaceuticalproduct. (27)cross-contamination: Contamination of a starting material. intermediate product, orfinished product with another starting material or product during production.(27)environmental isolates: Microorganisms that have been isolated from samples fromthe environmental monitoring program and that represent the microflora of anaseptic processing system. (20)environmental monitoring program: Documented program, implemented throughstandard operating procedures, that describes in detail the procedures andmethods used for monitoring particulates as well as microorganisms in controlledenvironments (air, surface, personnel gear). The program includessampling sites, frequency of sampling, and investigative and corrective actionsthat must be followed if Alert or Action levels are exceeded. The methodologyused for trend analysis is also described. (20)finished product: A product that has undergone all stages of production, includingpackaging in its final container and labelling. (27)in-process control: Checks performed during production in order to monitor and ifnecessary to adjust the process to ensure that the product conforms to itsspecifications. The control of the environment or equipment may also beregarded as a part of in-process control. (27)
intermediate product: Partly processed material that must undergo further manufacturingsteps before it becomes a bulk product. (27)lot: (see terms listed under batch) (27)manufacture: All operations of purchase of materials and products, production,quality control, release, storage, shipment of finished products, and the relatedcontrols. (27)master formula: A document or set of documents specifying the starting materialswith their quantities and the packaging, materials, together with a descriptionof the procedures and precautions required to produce a specified quantity ofa finished product as well as the processing instructions, including the inprocesscontrols. (27)master record: A document or set of documents that serve as a basis for the batchdocumentation (blank batch record). (27)material flow: The flow of material and personnel entering controlled environmentsshould follow a specified and documented pathway that has been chosen toreduce or minimize the potential for microbial contamination of the product/closure/container systems. Deviation from the prescribed flow could result inincrease in potential for microbial contamination. Material/personnel flowcan changed, but the consequences of the changes from a microbiologicalWHO/VSQ/97.01 107
point of view should be assessed by responsible managers and must be authorizedand documented. (20)media growth promotion: Procedure that references Growth Promotion underSterility Tests to demonstrate that media used in the microbiological environmentalmonitoring program, or in media-fill runs, are capable of supportinggrowth of indicator microorganisms and of environmental isolates fromsamples obtained through the monitoring program. (20)packaging material: Any material including printed material employed in thepackaging of a pharmaceutical product excluding any outer packaging used fortransportation or shipment. Packaging materials are referred to as primary orsecondary according to whether or not they are intended to be in directcontact with the product. (27)procedures: Description of the operations to be carried out, the precautions to betaken and measures to be applied directly or indirectly related to the manufactureof a medicinal product. (7)process: Set of interrelated resources and activities which transform inputs intooutputs.(14)processing instructions: See master formula. (27)product contact areas: Areas and surfaces in a controlled environment that are indirect contact with either products, containers, or closures and the microbiologicalstatus of which can result in potential microbial contamination of theproduct/container/closure system. Once identified, these areas should betested more frequently than non-product-contact areas or surfaces. (20)production: All operations involved in the preparation of a pharmaceutical productfrom receipt of materials, through processing and packaging, to completion ofthe finished product. (27)quality assurance: A wide ranging concept covering all matters that individually orcollectively influence the quality of a product. It is the totality of the arrangementsmade with the object of ensuring that pharmaceutical products are ofthe quality required for their intended use. (27)quality control: The part of GMP concerned with sampling, spccifications, and
testing and with the organizations, documentation, and release procedureswhich ensure that the necessary and relevant tests are actually carried out andthat materials are not released for use, nor products released for sale or supply,until their quality has been judged to be satisfactory. (27)quality management: All activities of the overall management function that determinethe quality policy, objectives and responsibilities, and implement themby means such as quality planning, quality control, quality assurance andquality improvement within the quality system. (14)quality policy: Overall intentions and direction of an organization with regard toquality, as formally expressed by top management. (14)quality: Totality of characteristics of an entity that bear on its ability to satisfystated and implied needs. (14)quarantine: The status of starting or packaging materials, intermediates, or bulk orfinished products isolated physically or by other effective means while adecision is awaited on their release, rejection, or reprocessing. (27)PB Good manufacturing requirements -- Part 1: SOPs and master formulae
reconciliation: A comparison, making due allowance for normal variation, betweenthe amount of product or materials theoretically produced or used and theamount actually produced or used. (27)record: Provide a history of each batch of product, including its distribution, andalso of all other relevant circumstances pertinent to the quality of the finalproduct. (7)reference standard: Any material of known identity and purity or potency. Anofficial reference standard is one obtained from an official source such as BP,or USP, or WHO. A house reference standard may be obtained by thoroughcharacterization for identity and purity or potency relative to an officialreference standard, or by determination of absolute purity by other techniques.Depending on the intended use (qualitative or quantitative) and thenature of the assay, a greater or lesser degree of purity is acceptable. (4)sampling plan: A documented plan that describes the procedures and methods forsampling of a controlled environment, identifies the sampling sites, the frequencyand number of samples, that analysis of data, and the interpretation ofresults. (20)sampling sites: Documented geographical location, within a controlled environment,where sampling for microbiological evaluation is taken. In general,sampling sites are selected because of their potential for product/container/closure contacts. (20)seed lotseed lot system: A seed lot system is a system according to which successivebatches of a product are derived from the same master seed lot at a givenpassage level. For routine production, a working seed lot is prepared from themaster seed lot. The final product is derived from the working seed lot andhas not undergone more passages from the master seed lot than the vaccineshown in clinical studies to be satisfactory with respect to safety and efficacy.The origin and the passage history of the master seed lot and the working seedlot are recorded.master seed lot: A culture of a micro-organism distributed from a single bulkinto containers in a single operation in such a manner as to ensure uniformity,to prevent contamination and to ensure stability. A master seed lot in liquidform is usually stored at or below -70 oC. A freeze-dried master seed lot isstored at a temperature known to ensure stability.
working seed lot: A culture of a micro-organism distributed from the masterseed lot and intended for use in production. Working seed lots are distributedinto containers and stored as described above for master seed lots. (7)specification: A document describing in detail the requirements with which theproducts or materials used or obtained during manufacture have to conform.Specifications serve as a basis for quality evaluation. (27)standard operating procedure (SOP): An authorized written procedure givinginstructions for performing operations not necessarily specific to a givenproduct or material but of a more general nature (e.g., equipment operation,maintenance and cleaning; validation; cleaning of premises and environmentalcontrol; sampling and inspection). Certain SOPs may be used to supplementproduct-specific master and batch production documentation. (27)WHO/VSQ/97.01 109
sterility: An acceptably high level of probability that a product processed in anaseptic system does not contain viable microorganisms. (20)swabs: Devices provided that are used to sample irregular as well as regular surfacesfor determination of microbial status. The swab, generally composed of astick with an absorbent extremity, is moistened before sampling and used tosample a specified unit area of a surface. The swab is then rinsed in sterilesaline or other suitable menstruum and the contents plated on nutrient agarplates to obtain an estimate of the viable microbial load on that surface. (20)system: A regulated pattern of interacting activities and techniques that are unitedto form an organized whole. (27)theoretical yield: The quantity that would be produced at any appropriate phase ofmanufacture, processing, or packaging of a particular drug product, basedupon the quantity of components to be used, in the absence of any loss orerror in actual production. (19)PB Good manufacturing requirements -- Part 1: SOPs and master formulae
Appendix 5:SOPs contributed by vaccinemanufacturersMassachusetts Public Health Biologic Laboratories1) Final Vial Visual Inspection of Vaccines ...................................................... 1072) cGMP Training Program for Biologic Laboratory Staff ........................... 1183) Microbial Monitoring of Environment During the Filling Process ......... 1224) Pest Control Program ................................................................................... 1355) BCA Protein Assay. Test for Residual Product onCleaned Equipment and Surfaces ............................................................... 1386) Use of Biological Safety Cabinets (BSC) and Laminar Flow Hoods (LFH)144Biomanguinhos/FIOCRUZ, BrazilTranslation by Biomanguinhos1) Standard Operational Procedure Control................................................... 1472) 4500 Liter-Capacity Double Door Autoclave Operation ......................... 152Gerencia General de Biologicos y Reactivos, Secretaria De Salud, MexicoOriginals Contributed by Mexico. Translation by GCL Bioconsult
1) General Procedure for Cleaning and Disinfection of Aseptic Areas ....... 1572) Procedure to Determine (Adjuvant) Aluminum in DPT Vaccineand Tetanus Toxoid ...................................................................................... 166(The above items were pasted in from original forms so are not available in electronicformat.)WHO/VSQ/97.01 111
Appendix 6:Sample master formula for ahypothetical biologicalproductThe following Master Formula is an example of the details, blanks and check boxeswhich are used to describe the manufacturing process and provide a form for recordingand verifying the process as it is performed.This Master Formula is not for a real production process - it is a hypothetical harvestwhich goes through several production steps to become a final bulk. It is assumedhere that the bulk product is all made in one day. In a MF for an actual product, anybatch that took more than one day to produce would have sections of the MF for eachday giving the details of the preparation and the production process for each day.(The following pages were pasted in from original forms so are not available in electronicformat.)