quality system comparison - completed

NSF 363Quality Management System Comparison

Instructions: Enter the text from the corresponding documents below the document heading; ISO 9001, IPEC-PQG, and ICH Q10. The ISO 9001 text should include both ISO 9001:2008 and the draft GMP Annex. The IPEC-PQG text is from the IPEC-PQG Excipient GMP guide.4 Quality Management SystemISO 9001:

IPEC-PQG:ICH Q104.1 General Requirements ISO 9001:The organization shall establish, document, implement and maintain a quality management system and continually improve its effectiveness in accordance with the requirements of this International Standard.

The organization shalla) determine the processes needed for the quality management system and their

application throughout the organization (see 1.2),b) determine the sequence and interaction of these processes,c) determine criteria and methods needed to ensure that both the operation and control

of these processes are effective,d) ensure the availability of resources and information necessary to support the operation

and monitoring of these processes,e) monitor, measure where applicable, and analyse these processes, andf) implement actions necessary to achieve planned results and continual improvement of

these processes.

These processes shall be managed by the organization in accordance with the requirements of this International Standard.

Where an organization chooses to outsource any process that affects product conformity with requirements, the organization shall ensure control over such processes. Control of such outsourced processes shall be identified within the quality management system.

NOTE 1 Processes needed for the quality management system referred to above include processes for management activities, provision of resources, product realization and measurement, analysis and improvement.

NOTE 2 An “outsourced process: is a process that the organization needs for the quality management system and which the organization chooses to have performed by and external party.

NOTE 3 Ensuring control over outsourced processes does not absolve the organization of the responsibility of conformity to all customer, statutory and regulatory requirements. The type and extent of control to be applied to the outsourced process can be influenced by the factors such as

a) The potential impact of the outsourced process on the organization’s capability to provide product that conforms to requirements,

b) The degree to which the control for the process is shared,c) The capability of achieving the necessary control through the application of 7.4.

GMP Annex:Where manufacturing, testing or other operations that could affect excipient quality are outsourced, the organization shall demonstrate that the applicable GMP principles in accordance with this Annex are applied to those operations. (see 7.4.1)IPEC-PQG:The principles outlined in this Guide provide a comprehensive basis for the quality


management system used in the manufacture of pharmaceutical excipients. Excipient manufacturers should identify the quality management processes required to assure excipient quality.

Where manufacturing, testing or other operations that could affect excipient quality are outsourced the responsibility for quality remains with the excipient manufacturer and control measures should be defined (see also 7.4.2).ICH Q101.5 ICH Q10 Objectives Implementation of the Q10 model should result in achievement of three main objectives which complement or enhance regional GMP requirements.

1.5.1 Achieve Product Realisation To establish, implement and maintain a system that allows the delivery of products with the quality attributes appropriate to meet the needs of patients, health care professionals, regulatory authorities (including compliance with approved regulatory filings) and other internal and external customers.

1.5.2 Establish and Maintain a State of Control To develop and use effective monitoring and control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes. Quality risk management can be useful in identifying the monitoring and control systems.

1.5.3 Facilitate Continual Improvement To identify and implement appropriate product quality improvements, process improvements, variability reduction, innovations and pharmaceutical quality system enhancements, thereby increasing the ability to fulfil quality needs consistently. Quality risk management can be useful for identifying and prioritising areas for continual improvement.

1.6 Enablers: Knowledge Management and Quality Risk Management Use of knowledge management and quality risk management will enable a company to implement ICH Q10 effectively and successfully. These enablers will facilitate achievement of the objectives described in Section 1.5 above by providing the means for science and risk based decisions related to product quality.

1.6.1 Knowledge Management Product and process knowledge should be managed from development through the commercial life of the product up to and including product discontinuation. For example, development activities using scientific approaches provide knowledge for product and process understanding. Knowledge management is a systematic approach to acquiring, analysing, storing and disseminating information related to products, manufacturing processes and components. Sources of knowledge include, but are not limited to prior knowledge (public domain or internally documented); pharmaceutical development studies; technology transfer activities; process validation studies over the product lifecycle; manufacturing experience; innovation; continual improvement; and change management activities.

1.6.2 Quality Risk Management Quality risk management is integral to an effective pharmaceutical quality system. It can provide a proactive approach to identifying, scientifically evaluating and controlling potential risks to quality. It facilitates continual improvement of process performance and product quality throughout the product lifecycle. ICH Q9 provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality.


1.7 Design and Content Considerations

(a) The design, organisation and documentation of the pharmaceutical quality system should be well structured and clear to facilitate common understanding and consistent application.

(b) The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognising the different goals and knowledge available for each stage.

………………………………(d) The pharmaceutical quality system should include appropriate processes, resources

and responsibilities to provide assurance of the quality of outsourced activities and purchased materials as described in Section 2.7.

(c) Management responsibilities, as described in Section 2, should be identified within the pharmaceutical quality system.

(d) The pharmaceutical quality system should include the following elements, as described in Section 3: process performance and product quality monitoring, corrective and preventive action, change management and management review.

(e) Performance indicators, as described in Section 4, should be identified and used to monitor the effectiveness of processes within the pharmaceutical quality system.

4.2 Documentation Requirements ISO 9001:4.2.1 GeneralThe quality management system documentation shall include

a) documented statements of a quality policy and quality objectives,b) a quality manual,c) documented procedures required by this International Standard,d) documents needed by the organization to ensure the effective planning, operation and

control of its processes, ande) records required by this International Standard (see 4.2.4).

NOTE 1 Where the term “documented procedure” appears within this International Standard, this means that the procedure is established, documented, implemented and maintained. A single document may address the requirements for one or more procedures. A requirement for a documented procedure may be covered by more than one document.

NOTE 2 The extent of the quality management system documentation can differ from one organization to another due to

a) the size of organization and type of activities,b) the complexity of processes and their interactions, and

c) the competence of personnel.

NOTE 3 The documentation can be in any form or type of medium.

GMP Annex:The quality management system documentation shall include:d) documented procedures required in this Annex.

4.2.2 Quality manualThe organization shall establish and maintain a quality manual that includes

a) the scope of the quality management system, including details of and justification for any exclusions (see 1.2),


b) the documented procedures established for the quality management system, or reference to them, and

c) a description of the interaction between the processes of the quality management system.

GMP AnnexThe organization shall establish and maintain a quality manual that includes or references:

d) a definition of the extent to which this Annex applies to its quality management system and its business processes, and

e) a definition of the point at which GMP applies to the manufacturing process.

4.2.3 Control of documentsDocuments required by the quality management system shall be controlled. Records are a special type of document and shall be controlled according to the requirements given in 4.2.4.

A documented procedure shall be established to define the controls neededa) to approve documents for adequacy prior to issue,b) to review and update as necessary and re-approve documents,c) to ensure that changes and the current revision status of documents are identified,d) to ensure that relevant versions of applicable documents are available at points of use,e) to ensure that documents remain legible and readily identifiable,f) to ensure that documents of external origin are identified and their distribution

controlled, andg) to prevent the unintended use of obsolete documents, and to apply suitable

identification to them if they are retained for any purpose.

GMP AnnexDocuments that impact product quality shall have a defined owner and be reviewed and approved by the Quality Unit before issue. (See also 5.5.1).

If electronic signatures are used on documents they shall be controlled to provide equivalent security to that given by a hand written signature.

4.2.4 Control of recordsRecords shall be established and maintained to provide evidence of conformity to requirements and of the effective operation of the quality management system. Records shall remain legible, readily identifiable and retrievable. A documented procedure shall be established to define the controls needed for the identification, storage, protection, retrieval, retention time and disposition of records.

GMP AnnexRecords shall include pertinent subcontractor quality data. Electronic records shall be subject to the same controls as those required for other records.

Entries in quality records shall be clear, indelible and made directly after performing the activity (in the order performed), signed and dated by the person making the entry. Corrections to entries shall be signed and dated, leaving the original entry still legible.

IPEC-PQG:4.2.1 GeneralThe excipient manufacturer should have a system in place to control documents and data


that relate to the requirements of the quality management system.

4.2.2 Quality Manual The excipient manufacturer should prepare a quality manual describing the quality management system, the quality policy and the commitment of the excipient manufacturer to applying the appropriate GMP and quality management standards contained in this Guide. This manual should include the scope of the quality management system, reference to supporting procedures and a description of the interaction between quality management processes.

4.2.3 Control of Documents The excipient manufacturer should establish and maintain procedures for the identification, collection, indexing, filing, storage, maintenance and disposition of controlled documents, including documents of external origin that are part of the quality management system.

Procedures used in the manufacture of excipients should be documented, implemented and maintained. In addition, there should be formal controls relating to procedure approval, revision and distribution. These controls should provide assurance that the current version of a procedure is being used throughout the operational areas and previous revisions of documents have been removed.

Documents and subsequent changes to documents should be reviewed and approved by designated qualified personnel before issuance to the appropriate areas, as identified in the documents. Documents that impact product quality should be reviewed and approved by the quality unit (see also 5.5.1).

Controlled documents may include a unique identifier, date of issue and revision number to facilitate identification of the most recent document. The department with the responsibility for issuing the documents should be identified. Where practical, changes and the reasons for the change should be documented.

Electronic documentation should meet the requirements for the document control system stated above. If electronic signatures are used on documents, they should be controlled to provide equivalent security to that given by a handwritten signature. Electronic documents and signatures may also need to satisfy local regulatory requirements.

4.2.4 Control of Records The excipient manufacturer should establish and maintain procedures for the identification, collection, indexing, filing, storage, maintenance and disposition of records.

Records should be maintained to demonstrate achievement of the required quality and the effective operation of the quality management system. Records should be legible and identifiable with the product involved. Pertinent subcontractor quality data should be an element of these records.

Entries in records should be clear, indelible, made directly after performing the activity (in the order performed), signed and dated by the person making the entry. Corrections to entries should be signed and dated, leaving the original entry legible.


Records should be kept for a defined period. This period should be appropriate to the excipient, its expiry date or re-evaluation interval. Records should be stored and maintained in such a manner that they are readily retrievable, in facilities that provide a suitable environment to minimize deterioration or damage. ICH Q104.2.1 General

1.7 Design and Content Considerations

(a) The design, organisation and documentation of the pharmaceutical quality system should be well structured and clear to facilitate common understanding and consistent application.

……………………(c) The size and complexity of the company’s activities should be taken into consideration

when developing a new pharmaceutical quality system or modifying an existing one. The design of the pharmaceutical quality system should incorporate appropriate risk management principles. While some aspects of the pharmaceutical quality system can be company-wide and others site-specific, the effectiveness of the pharmaceutical quality system is normally demonstrated at the site level.

4.2.2 Quality Manual

1.8 Quality Manual

A Quality Manual or equivalent documentation approach should be established and should contain the description of the pharmaceutical quality system. The description should include:

(b) The quality policy (see Section 2);(f) The scope of the pharmaceutical quality system; (g) Identification of the pharmaceutical quality system processes, as well as their

sequences, linkages and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting pharmaceutical quality system processes in a visual manner;

Management responsibilities within the pharmaceutical quality system (see Section 2).

4.2.3 Control of DocumentsNo requirements4.2.4 Control of RecordsNo requirements4.3 Change Control ISO 9001:GMP AnnexThere shall be a documented procedure for the evaluation and approval of changes that may impact upon the quality of the excipient. The evaluation and approval of changes shall occur prior to the implementation of the changes. A unit independent from production shall approve changes that may impact on the quality of the excipient. Where the impact on the quality of the excipient is significant, change1 shall be communicated to customers and, as applicable, regulatory authorities (see 7.2.3).

The responsibilities and requirements for evaluating, managing, implementing change and maintaining records (see 4.2.4) shall be defined in a documented procedure.IPEC-PQG: 4.3 Change Control

1


The excipient manufacturer should establish and maintain procedures to evaluate and approve changes that may have an impact on the quality of the excipient. For example, this may include changes to:

• raw materials or packaging and their sources, • material specifications, • test methods, • manufacturing and analytical equipment, • production processes, • manufacturing or packaging sites etc.

A function that is independent from production (such as regulatory affairs, quality assurance, etc.) should have the responsibility and authority for the final approval of changes.

Customers and, if necessary, regulatory authorities [for example, for Drug Master Files (DMFs) or Certificates of Suitability to the European Pharmacopoeia (CEPs)] should be notified of significant changes from established production and process control procedures that may affect excipient quality (see also 7.2.3 and Appendix C). The IPEC-Americas Significant Change Guide for Bulk Pharmaceutical Excipients provides criteria that the excipient manufacturer can use to determine when to involve the pharmaceutical customer, based on the likelihood that a proposed change will impact their drug product.

IPEC Americas Significant Change Guide Version 2 2009ICH Q104.3 Change Control 1.7 Design and Content Considerations

(f) The pharmaceutical quality system should include the following elements, as described in Section 3: process performance and product quality monitoring, corrective and preventive action, change management and management review.

5 Management Responsibility ISO 9001:No text – title is a header onlyIPEC-PQG:No Text

ICH Q102. MANAGEMENT RESPONSIBILITY Leadership is essential to establish and maintain a company-wide commitment to quality and for the performance of the pharmaceutical quality system.5.1 Management Commitment ISO 9001:Top management shall provide evidence of its commitment to the development and implementation of the quality management system and continually improving its effectiveness by

a) communicating to the organization the importance of meeting customer as well as statutory and regulatory requirements,

b) establishing the quality policy,c) ensuring that quality objectives are established,d) conducting management reviews, ande) ensuring the availability of resources.

GMP Annex:f) ensuring that GMP objectives are established, and


g) communicating to the organization the importance of conforming to GMP.IPEC-PQG:5.1 Management Commitment

Top management should demonstrate to the organisation the importance it places on customer satisfaction and compliance with the appropriate regulations and standards. This should be accomplished through the development of a quality policy and establishment of quality objectives. Progress towards the documented quality objectives should be reviewed at planned intervals

ICH Q102.1 Management Commitment

(a) Senior management has the ultimate responsibility to ensure an effective pharmaceutical quality system is in place to achieve the quality objectives, and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the company.

(b) Management should: (1) Participate in the design, implementation, monitoring and maintenance of an

effective pharmaceutical quality system; (2) Demonstrate strong and visible support for the pharmaceutical quality system

and ensure its implementation throughout their organisation; (3) Ensure a timely and effective communication and escalation process exists to

raise quality issues to the appropriate levels of management; (4) Define individual and collective roles, responsibilities, authorities and inter-

relationships of all organisational units related to the pharmaceutical quality system. Ensure these interactions are communicated and understood at all levels of the organisation. An independent quality unit/structure with authority to fulfil certain pharmaceutical quality system responsibilities is required by regional regulations;

(5) Conduct management reviews of process performance and product quality and of the pharmaceutical quality system;

(6) Advocate continual improvement; (7) Commit appropriate resources.

5.2 Customer Focus ISO 9001:Top management shall ensure that customer requirements are determined and are met with the aim of enhancing customer satisfaction (see 7.2.1 and 8.2.1).GMP Annex:The organization shall enable the customer to assess the continued effectiveness of its quality management system, records, manufacturing processes, buildings and facilities. 5.2 Customer Focus IPEC-PQG:It is the responsibility of top management to ensure that customer requirements are determined and met. The excipient manufacturer should permit the customer or their representative to conduct audits to review its quality management system, manufacturing processes, buildings and facilities.5.2 Customer Focus ICH Q10As pharmaceutical manufacturers are the end of the manufacturing chain, customers are then “consumers” of their products and not further actors in the supply chain. In this regard we have to translate the ISO term “customer to mean regulator and government.


I could not find any succinct sections in ICH Q10 that mapped simply to this section.5.3 Quality Policy ISO 9001:Top management shall ensure that the quality policy

a) is appropriate to the purpose of the organization,b) includes a commitment to comply with requirements and continually improve the

effectiveness of the quality management system,c) provides a framework for establishing and reviewing quality objectives,d) is communicated and understood within the organization, ande) is reviewed for continuing suitability.

GMP Annex:Top management shall ensure that the quality policy:

f) includes a commitment to the implementation of GMP.IPEC-PQG:5.3 Quality Policy Top management should demonstrate its commitment to the corporate quality policy and ensure that it is implemented within the operational unit. The quality policy should support continual improvement of the quality management system. Management should participate in the development of the company's quality policy and provide the resources necessary for its development, maintenance and deployment.ICH Q105.3 Quality Policy 2.2 Quality Policy

(a) Senior management should establish a quality policy that describes the overall intentions and direction of the company related to quality.

(b) The quality policy should include an expectation to comply with applicable regulatory requirements and should facilitate continual improvement of the pharmaceutical quality system.

(c) The quality policy should be communicated to and understood by personnel at all levels in the company.

(d) The quality policy should be reviewed periodically for continuing effectiveness.5.4 Planning ISO 9001:5.4.1 Quality objectivesTop management shall ensure that quality objectives, including those needed to meet requirements for product [see 7.1 a)], are established at relevant functions and levels within the organization. The quality objectives shall be measurable and consistent with the quality policy.

GMP Annex:5.4.1 Quality objectives

Top management shall set objectives for adherence to GMP.

5.4.2 Quality management system planningTop management shall ensure that

a) the planning of the quality management system is carried out in order to meet the requirements given in 4.1, as well as the quality objectives, and

b) the integrity of the quality management system is maintained when changes to the quality management system are planned and implemented.


GMP Annex5.4.2 Quality Management system planning

No additional requirements.IPEC-PQG:5.4.1 Quality Objectives Top management should set objectives for adherence to GMP to ensure that the excipient manufacturer maintains and improves its performance. Objectives should be deployed throughout the organisation and should be measurable and consistent with the quality policy. 5.4.2 Quality Management System Planning Top management should provide adequate resources to ensure conformance to the provisions of this Guide. There should be a process for the identification of resources needed for adherence to GMP. A gap analysis based on audits by internal personnel, customers, regulatory agencies or outside contractors and this Guide could be used for the purpose of identifying resource requirements. Top management should ensure that the integrity of the quality management system is maintained when changes are planned and implemented.ICH Q105.4 Planning2.3 Quality Planning

(a) Senior management should ensure the quality objectives needed to implement the quality policy are defined and communicated.

(b) Quality objectives should be supported by all relevant levels of the company. (c) Quality objectives should align with the company’s strategies and be consistent with

the quality policy. (d) Management should provide the appropriate resources and training to achieve the

quality objectives. (e) Performance indicators that measure progress against quality objectives should be

established, monitored, communicated regularly and acted upon as appropriate as described in Section 4.1 of this document

5.5 Responsibility, Authority and Communication ISO 9001:5.5.1 Responsibility and authorityTop management shall ensure that responsibilities and authorities are defined and communicated within the organization.

GMP Annex:5.5.1 Responsibility and authority

A unit independent from production such as the Quality Unit shall be responsible for: ensuring quality critical activities are undertaken as defined, approving suppliers of quality critical materials and services, approving or rejecting raw materials, packaging components, intermediates and

finished excipients, reviewing production records to ensure that if errors have occurred, they have

been fully investigated, approving changes to quality critical equipment, processes, specifications,

procedures, test methods (see 4.3), investigating failures and complaints approving or rejecting the excipient if it is manufactured, processed, packaged, or

held under contract by another company, and


developing and implementing an internal audit program.

This independent unit is referred to as “the Quality Unit” throughout this document and may delegate some of these activities if appropriate controls are in place and are documented.

Documentation showing the inter-departmental relationships as well as relationship to top management shall demonstrate the independence of the Quality Unit.

Personnel whose role has an impact on excipient quality shall have written job descriptions.

5.5.2 Management representativeTop management shall appoint a member of the organization's management who, irrespective of otherresponsibilities, shall have responsibility and authority that includes

a) ensuring that processes needed for the quality management system are established, implemented and maintained,

b) reporting to top management on the performance of the quality management system and any need for improvement, and

c) ensuring the promotion of awareness of customer requirements throughout the organization.

NOTE The responsibility of a management representative can include liaison with external parties on matters relating to the quality management system.

GMP AnnexNo additional requirements.

5.5.3 Internal communicationTop management shall ensure that appropriate communication processes are established within the organization and that communication takes place regarding the effectiveness of the quality management system.

GMP AnnexGMP and regulatory requirements shall be communicated as appropriate to roles in the organization.

Top management shall be promptly notified about any quality critical situations in accordance with a documented procedure.

IPEC-PQG:5.5.1 Responsibility and Authority

Responsibility and authority should be clearly defined by top management and communicated within the organisation.

It should be the responsibility of a unit independent of production, such as the quality unit, to:

ensure quality-critical activities are undertaken as defined, approve suppliers of quality-critical materials and services, approve or reject raw materials, packaging components, intermediates and


finished excipients, ensure that there is a review of production records to ensure that no errors have

occurred or, if errors occur, that they are fully investigated, participate in reviewing and authorising changes to processes, specifications,

procedures and test methods that potentially affect quality (see also 4.3) and in investigating failures and complaints,

retain responsibility for approval or rejection of the excipient if it is produced, processed, packaged or held under contract by another company,

develop and implement a self inspection programme of the quality management system.

The excipient manufacturer may delegate some of the quality unit’s activities to other personnel if appropriate controls (for example periodic audits, training and documentation) are in place.

An organisation chart by function should show inter-departmental relationships as well as relationships to top management of the company. Personnel who have an impact on excipient quality should have job descriptions.

5.5.2 Management Representative The excipient manufacturer should appoint a management representative with sufficient authority to ensure that the provisions of this Guide are properly implemented. The representative should periodically report to top management on conformance to the quality management system, including changing customer and regulatory requirements.

5.5.3 Internal Communication The excipient manufacturer should ensure appropriate systems are established to communicate GMP and regulatory requirements, quality policies, quality objectives and procedures throughout the organisation. The communication should also provide information about the effectiveness of the quality management system.

Top management should be notified in a timely manner of quality-critical situations, such as product retrievals, in accordance with a documented procedure.

ICH Q105.5 Management Responsibility2.5 Internal Communication

(a) Management should ensure appropriate communication processes are established and implemented within the organisation.

(b) Communications processes should ensure the flow of appropriate information between all levels of the company.

(c) Communication processes should ensure the appropriate and timely escalation of certain product quality and pharmaceutical quality system issues.

5.6 Management Review ISO 9001:5.6.1 GeneralTop management shall review the organization's quality management system, at planned intervals, to ensure its continuing suitability, adequacy and effectiveness. This review shall include assessing opportunities for improvement and the need for changes to the quality management system, including the quality policy and quality objectives.


Records from management reviews shall be maintained (see 4.2.4).

5.6.2 Review inputThe input to management review shall include information on

a) results of audits,b) customer feedback,c) process performance and product conformity,d) status of preventive and corrective actions,e) follow-up actions from previous management reviews,f) changes that could affect the quality management system, andg) recommendations for improvement.

5.6.3 Review outputThe output from the management review shall include any decisions and actions related to

a) improvement of the effectiveness of the quality management system and its processes,

b) improvement of product related to customer requirements, andc) resource needs.

GMP Annex:No additional requirementsIPEC-PQG:5.6.1 General

The top management of the company should hold periodic reviews of the quality management system to confirm the organisation’s continued conformance to this Guide.

The review should be recorded and include assessing opportunities for improvement and the need for changes to the quality management system.

5.6.2 Review Input Management review inputs should include for example:

results of internal and external audits, customer feedback of the company performance, product conformity and process performance, action items from the previous management review, customer complaints, status of corrective or preventive actions, changes that could affect the quality management system.

5.6.3 Review Output The management review should identify the resources needed and opportunities presented for improvement of the quality management system and improvement of product conformance to customer and regulatory requirements. A record should be made of actions recommended and taken.

ICH Q105.6 Management Review2.6 Management Review

(a) Senior management should be responsible for pharmaceutical quality system governance through management review to ensure its continuing suitability and effectiveness.

(b) Management should assess the conclusions of periodic reviews of process


performance and product quality and of the pharmaceutical quality system, as described in Sections 3 and 4.

3.2.4 Management Review of Process Performance and Product Quality Management review should provide assurance that process performance and product quality are managed over the lifecycle. Depending on the size and complexity of the company, management review can be a series of reviews at various levels of management and should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review.

(a) The management review system should include: (1) The results of regulatory inspections and findings, audits and other

assessments, and commitments made to regulatory authorities; (2) Periodic quality reviews, that can include:

(i) Measures of customer satisfaction such as product quality complaints and recalls;

(ii) Conclusions of process performance and product quality monitoring;

(iii) The effectiveness of process and product changes including those arising from corrective action and preventive actions.

(3) Any follow-up actions from previous management reviews.

(b) The management review system should identify appropriate actions, such as: (1) Improvements to manufacturing processes and products; (2) Provision, training and/or realignment of resources; (3) Capture and dissemination of knowledge.

Table IV: Application of Management Review of Process Performance and Product Quality throughout the Product Lifecycle

Pharmaceutical Development

Technology Transfer

Commercial Manufacturing

Product Discontinuation

Aspects of management review can be performed to ensure adequacy of the product and process design.

Aspects of management review should be performed to ensure the developed product and process can be manufactured at commercial scale.

Management review should be a structured system, as described above, and should support continual improvement.

Management review should include such items as product stability and product quality complaints.

4.1 Management Review of the Pharmaceutical Quality System Management should have a formal process for reviewing the pharmaceutical quality system on a periodic basis. The review should include:

(a) Measurement of achievement of pharmaceutical quality system objectives; (b) Assessment of performance indicators that can be used to monitor the

effectiveness of processes within the pharmaceutical quality system, such as:

(1) Complaint, deviation, CAPA and change management processes;


(2) Feedback on outsourced activities; (3) Self-assessment processes including risk assessments, trending, and audits; (4) External assessments such as regulatory inspections and findings and

customer audits 4.2 Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality System Factors monitored by management can include:

(a) Emerging regulations, guidance and quality issues that can impact the Pharmaceutical Quality System;

(b) Innovations that might enhance the pharmaceutical quality system; (c) Changes in business environment and objectives; (d) Changes in product ownership.

4.3 Outcomes of Management Review and Monitoring The outcome of management review of the pharmaceutical quality system and monitoring of internal and external factors can include:

(e) Improvements to the pharmaceutical quality system and related processes; (f) Allocation or reallocation of resources and/or personnel training; (g) Revisions to quality policy and quality objectives; (h) Documentation and timely and effective communication of the results of the

management review and actions, including escalation of appropriate issues to senior management.

6 Resource Management ISO 9001:No requirementIPEC-PQG:No requirementICH Q10Section 2.4 a. Management should determine and provide adequate and appropriate resources (human, financial, materials, facilities and equipment) to implement and maintain the pharmaceutical quality system and continually improve its effectiveness6.1 Provision of Resources ISO 9001:The organization shall determine and provide the resources need

a) to implement and maintain the quality management system and continually improve its effectiveness, and

b) to enhance customer satisfaction by meeting customer requirements

GMP AnnexC) to meet the GMP requirements of this Annex.

IPEC-PQG:6.1 Provision of ResourcesThere should be sufficient qualified personnel and resources (e.g., equipment, materials,buildings and facilities) to implement, maintain and improve the quality management systemand to produce, package, test, store and release each excipient in a manner consistent withthis GuideICH Q106.1 Provision of Resources


Section 2.4 b. Management should ensure that resources are appropriately applied to a specific product, process or site.6.2 Human Resources ISO 9001:6.2.1. GeneralPersonnel performing work affecting product quality shall be competent on the basis of appropriate education, training, skills and experience

GMP AnnexRecords shall be maintained listing the name, address and qualifications of consultants who provide advice concerning any aspect of the Quality Management System and the type of service they provide.

6.2.2 Competence, awareness and trainingThe organization shall:

a) determine the necessary competence for personnel performing work affecting product quality,

b) provide training or take other actions to satisfy these needs,c) evaluate the effectiveness of the actions takend) ensure that its personnel are aware of the relevance and importance of their activities

and how they contribute to the achievement of the quality objectives, ande) maintain appropriate records of education, training, skill and experience

GMP Annexf) ensure training, including GMP as it relates to the employee’s function, is conducted

by qualified individuals, and , g) ensure GMP refresher training is conducted periodically

GMP Annex6.2.3 Personnel HygieneWhere excipients are exposed to potential environmental contaminants, the organization shall apply appropriate controls to ensure the product is not contaminated.

Personnel shown to have an apparent illness or open lesions that may adversely affect the safety or quality of the excipient shall be excluded from direct contact with raw materials, packaging components, intermediates, and finished excipient.

The storage and use of food, drink, personal medication, tobacco products or similar items shall be restricted to certain designated locations separate from manufacturing areas.IPEC-PQG:6.2.1 GeneralPersonnel performing work affecting the quality of excipients should have the appropriate combination of education, training and experience for their assigned tasks.

Consultants advising on the design, production, packaging, testing or storage of excipients 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 listing the name, address and qualifications of consultants and the type of service they provide.

6.2.2 Competence, Awareness and Training


The excipient manufacturer should establish and maintain procedures for identifying training needs and providing the necessary training to personnel performing activities affecting excipient quality. Appropriate records of training should be maintained. Training should address the particular operations that the employee performs and GMP as it relates to the employee’s functions. Qualified individuals should conduct GMP training with sufficient frequency to ensure that employees remain familiar with applicable GMP principles. Management should establish adequate and continued personal hygiene training for personnel who handle materials so that they understand the precautions necessary to prevent contamination of excipients.

The training program should ensure personnel understand that deviations from procedures may have an impact on the customer’s product quality.

6.2.3 Personnel HygieneTo protect excipients from contamination protective apparel such as head, face, hand and arm coverings should be worn as appropriate to the duties performed. Jewelry and other loose items, including those in pockets, should be removed or covered. Only authorized personnel should enter those areas of the buildings and facilities designated as limited access areas.

Personnel should practice good sanitation and health habits. Any person shown to have an apparent illness or open lesions (by either medical examination or supervisory observation) that may adversely affect the safety or quality of the excipient should be excluded from direct contact with raw materials, packaging components, intermediates and finished excipients until the condition is corrected or determined by competent personnel not to jeopardize the safety or quality of the excipient. Personnel should be instructed to report to supervisory personnel any health conditions that may have an adverse effect on excipients.

The storage and use of food, drink, personal medication, tobacco products or similar items should be restricted to certain designated locations separate from manufacturing areas.ICH Q10No requirement

6.3 Infrastructure ISO 9001:The organization shall determine, provide and maintain the infrastructure needed to achieve conformity to product requirements, infrastructure includes, as applicable

a) buildings, workspace and associated utilitiesb) process equipment (both hardware and software), andc) supporting services (such as transport or communication)

GMP AnnexThe infrastructure shall be managed, operated, cleaned and maintained in and to avoid contamination of raw materials, intermediates and the excipient. Where the infrastructure is critical to excipient quality, the controls shall be documented.

Equipment which may impact excipient quality shall be commissioned before use to ensure that it is functioning as intended. The use, cleaning and maintenance of quality critical equipment shall be recorded.

Production processes associated with highly sensitizing or toxic materials shall be in


dedicated equipment separate from that used for excipient manufacture, unless appropriate measures to avoid cross-contamination have been implemented and the effectiveness of these measures have been demonstrated.

Process materials which are intended to come into contact with the excipient (e.g. lubricants, steam additives, filter media etc) shall be controlled to ensure that they are appropriate for the intended use.

Computerized systems that may impact upon excipient quality shall have sufficient controls for operation, maintenance, back-up or archiving, and measures to prevent unauthorized access or changes to software, hardware or data.

Water used in the manufacture of excipients shall be monitored to confirm it is of a suitable quality for its intended use. Storage containers and their attendant manifolds, filling and discharge lines shall be identified.IPEC-PQG:6.3 InfrastructureThe infrastructure should be managed, operated, cleaned and maintained in accordance withGMP principles to ensure excipient quality and to avoid contamination (including, where critical to excipient quality, control of particulate matter, microbiological control and control of water quality).

6.3.1 Buildings and FacilitiesThe prevention of contamination should be considered in the design of the manufacturing processes and facilities, particularly where the excipient is exposed. Buildings and facilities used in the production, processing, packaging, testing or storage of an excipient should be maintained in a good state of repair and should be of suitable size, construction and location to facilitate cleaning, maintenance and correct operation appropriate to the type of processing.

Manufacturing processes associated with the production of highly sensitizing or toxic products (for example, herbicides, pesticides etc.) should be located in dedicated facilities or use equipment separate from that used for excipient manufacture. If this is not possible then appropriate measures (for example, cleaning, inactivation) should be implemented to avoid cross-contamination. The effectiveness of these measures should be demonstrated.

There should be adequate facilities for the testing of raw materials, packaging components, intermediates and finished excipients.

6.3.2 EquipmentEquipment used in the production, processing, packaging, testing or storage of an excipient should be maintained in a good state of repair and should be of suitable size, construction and location to facilitate cleaning, maintenance and correct operation, depending on the type of processing (for example, batch versus continuous).

Equipment should be commissioned before use to ensure that it is functioning as intended.

Where equipment is located outdoors there should be suitable control to minimize the risk to


excipient quality from the environment (for example, processing within a closed system).

6.3.2.1 Equipment ConstructionProcess equipment should be constructed so that contact surfaces will not be reactive, additive or absorptive and thus not alter the quality of the excipient. Substances required for operation, such as lubricants or coolants, should preferably not come into contact with raw materials, packaging materials, intermediates or finished excipients. Where contact is possible, substances suitable for use in food applications should be utilized.

Equipment should be designed to minimize the possibility of contamination caused by direct operator contact in such activities as the unloading of centrifuge bags, use of transfer hoses (particularly those used to transfer powders) and the operation of drying equipment and pumps. The sanitary design of transfer and processing equipment should be evaluated. Equipment with moving parts should be assessed with regard to the integrity of seals and packing materials to control the risk of contamination.

6.3.2.2 Equipment MaintenanceDocumented procedures should be established and followed for maintenance of critical equipment used in the production, processing, packaging, testing or holding of the excipient. There should be records of the use and maintenance of quality-critical equipment. These records can be in the form of a log, computer database or other appropriate documentation.

6.3.2.3 Computer SystemsComputer systems that may impact upon excipient quality should have sufficient controls for operation and maintenance and to prevent unauthorized access or changes to computer software, hardware or data, including:

• systems and procedures that show the equipment and software are• performing as intended,• procedures for checking the equipment at appropriate intervals,• retention of suitable back-up or archival systems such as copies of the• program and files,• assurance that changes are verified and documented and only made• by authorized personnel.

6.3.3 UtilitiesUtilities (for example, nitrogen, compressed air, steam etc.) used in the production, storage or transfer of materials that could impact excipient quality should be assessed and appropriate action taken to control the risk of contamination and cross-contamination.

6.3.4 WaterWater used in the manufacture of excipients should be demonstrated to be of a suitable quality for its intended use. Unless otherwise justified process water should, at a minimum, meet WHO guidelines for drinking (potable) water quality.

If drinking (potable) water is insufficient to assure quality or tighter chemical and/or microbiological water quality specifications are required, appropriate controls and specifications should be set, for example, physical and chemical attributes, total microbial counts, limits on objectionable organisms and/or endotoxins.


Where water used in the process is treated by the manufacturer to achieve a defined quality the treatment process should be specified and monitored with appropriate action limits.

Water that comes into contact with the excipient should be supplied under continuous positive pressure (or other means of preventing back flow) in a system free of defects to control the risk of contamination to the excipient.ICH Q10No requirement

6.4 Work Environment ISO 9001:The organization shall determine and manage the work environment needed to achieve conformity to product requirements.

GMP AnnexThe work environment shall be managed and controlled to minimize risks of excipient contamination. A documented risk assessment shall be carried out to determine the necessary controls.

Where maintenance of the work environment is critical to excipient quality, the controls shall be documented.IPEC-PQG:6.4 Work EnvironmentWhere the excipient is exposed during manufacture it should be in an appropriate environment to minimize contamination. The manufacturer should apply suitable controls to maintain that environment.

6.4.1 Air HandlingWhere an air handling system is installed to provide protection to the excipient, the excipient manufacturer should demonstrate its effectiveness.

Excipient production unit air handling systems should be designed to prevent cross contamination. For dedicated areas processing the same excipient it is permissible to recycle a portion of the exhaust air back into the same area. The adequacy of such a system for multi-use areas, especially if several products are processed simultaneously, should be assessed for potential cross-contamination.

6.4.2 Controlled EnvironmentA controlled environment may be necessary to avoid contamination or degradation caused by exposure to heat, air or light. The degree of protection required may vary depending on the stage of the process.

Special environments required by some processes should be monitored to assure product quality (for example, inert atmosphere or protection from light). Where an inert atmosphere is required, the gas should be treated as a raw material. If interruptions in the special environment occur adequate evidence and appropriate rationale should be documented to show that such interruptions have not compromised the quality of the excipient. Such environmental concerns become increasingly important following purification of the excipient.

6.4.3 Cleaning and Sanitary ConditionsAdequate cleanliness is an important consideration in the design of excipient manufacturing


facilities. Buildings used in the production, processing, packaging or holding of an excipient should be maintained in an appropriately clean and sanitary condition according to the type of processing conducted (for example, open/closed systems).

Where maintenance of clean and sanitary conditions is critical to excipient quality, documented procedures should assign responsibility for cleaning and sanitation, describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used in cleaning the buildings and facilities. These procedures should be followed and cleaning should be documented.

Waste should be segregated and disposed of in a timely and appropriate manner. If waste is not disposed of immediately, it should be suitably identified.

6.4.4 Pest ControlBuildings should be free from infestation by rodents, birds, insects and other vermin. Some raw materials, particularly botanicals, may contain some unavoidable contamination, such as rodent or other animal filth or infestation. The manufacturer should have sufficient control methods to prevent the increase of such contamination or infestation in holding areas and its spread to other areas of the plant.

6.4.5 LightingAdequate lighting should be provided to facilitate cleaning, maintenance and proper operations.

6.4.6 DrainageIn areas where the excipient is open to the environment, drains should be of adequate size and, where connected directly to a sewer, should be provided with an air break or other mechanical device to prevent back-siphoning.

6.4.7 Washing and Toilet FacilitiesAdequate personal washing facilities should be provided, including hot and cold water, soap or detergent, air dryers or single service towels and clean toilet facilities easily accessible to working areas. Adequate facilities for showering and/or changing clothes should be provided, where appropriate.ICH Q10No requirement

7 Product Realization 7.1 Planning of Product Realization ISO 9001:In planning product realization, the organization shall determine the following, as appropriate:

a) quality objectives and requirements for the product;b) the need to establish processes and documents, and to provide resources specific to

the product;c) required verification , validation, monitoring, measurement, inspection and test

activities specific to the product and the criteria for product acceptance;d) records needed to provide evidence that the realization processes and resulting

product meet requirements.The output of this planning shall be in a form suitable for the organization’s method of operations.


GMP Annexe) documented testing programs for quality critical materials and excipients that include

appropriate specifications, sampling plans, test and release procedures, andf) environmental and hygiene control programs to minimize contamination of the

excipient.IPEC-PQG:7.1 Planning of Product Realization The excipient manufacturer should plan and develop the processes and controls needed for product manufacture.

These plans and controls should be appropriate to the production process, excipient specification, equipment and facilities used in the manufacture of the product.

Key aspects of the planning of a suitable process and its controls should include as appropriate:

documented testing programs for quality-critical materials including excipients that include appropriate specifications, sampling plans, test and release procedures,

generation and maintenance of records (see also 4.2.4) that provide evidence that these plans have been realised as intended and that enable traceability to be demonstrated (see also 7.5.3.1),

provision of resources to implement these plans, environmental and hygiene control programs to minimise contamination.

ICH Q107.1 Planning of Product Realization No requirement7.2 Customer-related Processes ISO 9001:7.2.1 Determination of requirements related to the productThe organization shall determine

a) requirements specified by the customer, including the requirements for delivery and post-delivery activities,

b) requirements not stated by the customer but necessary for specified or intended use, where known

c) statutory and regulatory requirements applicable to the product , d) any additional requirements considered necessary by the organisation

GMP AnnexChanges requiring notification and/or documented prior approval from the customer shall be determined.

7.2.2 Review of requirements related to the productThe organization shall review the requirements related to the product. This review shall be conducted prior to the organisation’s commitment to supply a product to the customer (e.g. submission of tenders, acceptance of contracts or orders, acceptance of changes to contracts or orders) and shall ensure that

a) product requirements are definedb) contract or order requirements differing from those previously expressed are resolved,

and c) the organization has the ability to meet the defined requirements.


Records of the results of the review and actions arising from the review shall be maintained.

Where the customer provides no documented statement of requirement, the customer requirements shall be confirmed by the organization before acceptance.

Where product requirements are changed, the organization shall ensure that relevant documents are amended and that relevant personnel are made aware of the changed requirements.


7.2.3 Customer communicationThe organization shall determine and implement effective arrangements for communicating with customers in relation to:

a) product informationb) enquiries , contracts or order handling, including amendmentsc) customer feedback, including customer complaints

GMP Annexd) significant changes. (See also 4.3 and 7.2.1)

If production of the excipient is outsourced then this shall be communicated to the customer.IPEC-PQG:7.2 Customer-related Processes7.2.1 Determination of Requirements Related to the Product

The excipient manufacturer should determine the excipient quality, labelling and delivery requirements of the customer. Additional requirements, whether customer-specific, legal or regulatory (for example pharmacopoeia material and general monographs), should be agreed by both parties. Requirements not stated by the customer but necessary for specified or intended use, where known, should be considered.

7.2.2 Review of Requirements Related to the ProductThe excipient manufacturer and customer should mutually agree upon the requirements identified in 7.2.1 before supply commences. The manufacturer should have the facility and process capability to meet consistently the mutually agreed specifications. Where the requirements determined in 7.2.1 are changed, this review should be repeated before supply recommences.

7.2.3 Customer CommunicationThere should be provision for providing accurate and pertinent communication to the customer. Master copies of documents such as specifications and technical reports should be controlled documents. Provision should be made for replying to customer enquiries, contracts and order handling requirements. Customer feedback and complaints should be documented. Customers should be notified of significant changes (see also 4.3). For additional change notification information refer to IPEC-Americas Significant Change Guide for Bulk Pharmaceutical Excipients.

ICH Q107.2 Customer-related Processes


No Text7.3 Design and Development ISO 9001:7.3.1 Design and development planningThe organization shall plan and control the design and development of the product.

During the design and development planning, the organization shall determinea) The design and development stagesb) The review, verification and validation that are appropriate to each design and

development stage, andc) The responsibilities and authorities for design and development

The organization shall manage the interfaces between different groups involved in design and development to ensure effective communication and clear assignment of responsibility.

Planning output shall be updated, as appropriate, as the design and development progresses.

GMP AnnexNo additional requirements

7.3.2 Design and development inputsInputs relating to product requirements shall be determined and records maintained. These inputs shall include

a) Functional and performance requirementsb) Applicable statutory and regulatory requirementsc) Where applicable, information derived from previous similar designs, andd) Other requirements essential for design and development

The inputs shall be reviewed for adequacy. Requirements shall be complete, unambiguous and not in conflict with each other.

GMP AnnexNo additional requirements

7.3.3 Design and development outputsThe outputs of design and development shall be in a form suitable for verification against the design and development input and shall be approved prior to use.

Design and development outputs shalla) Meet the input requirements for design and developmentb) Provide appropriate information for purchasing, production and service provision,c) Contain or reference product acceptance criteria, andd) Specify the characteristics of the product that are essential for its safe and proper use.


7.3.4 Design and development reviewAt suitable stages, systematic reviews of design and development shall be performed in


accordance with planned arrangementsa) To evaluate the ability of the results of design and development to meet requirements,

andb) To identify and problems and propose necessary actions.

Participants in such reviews shall include representatives of functions concerned with the design and development stage(s) being reviewed. Records of the results of the reviews and any necessary actions shall be maintained.


7.3.5 Design and development verificationVerification shall be performed in accordance with planned arrangements to ensure that the design and development outputs have met the design and development input requirements. Records of the results of the verification and any necessary actions shall be maintained.


7.3.6 Design and development validationDesign and development validation shall be performed in accordance with planned arrangements to ensure that the resulting product is capable of meeting the requirements for the specified application of intended use, where known. Wherever practicable, validation shall be completed prior to delivery or implementation of the product. Records of the results of validation and any necessary actions shall be maintained.


7.3.7 Control of design and development changesDesign and development changes shall be identified and records maintained. The changes shall be reviewed, verified and validated, as appropriate, and approved before implementation. The review of design and development changes shall include evaluation of the effect of the changes on constituent parts and product already delivered. Records of the results of the review of the changes and any necessary actions shall be maintained.

GMP AnnexNo additional requirements.IPEC-PQG:7.3 Design and Development ISO 9001 includes requirements for ensuring control over design and development activities. Companies involved in such activities are recommended to follow the requirements of ISO 9001. Full GMP is not always applicable during the design and development of new excipients and/or manufacturing processes. However, development batches of excipients that are intended for use in drug products should be manufactured in accordance with the applicable provisions of this Guide.ICH Q107.3 Design and Development IV.A. Life Stage Goals1. Pharmaceutical Development (3.1.1)


The goal of pharmaceutical development activities is to design a product and its manufacturing process to consistently deliver the intended performance and meet the needs of patients and healthcare professionals, and regulatory authorities and internal customers’ requirements. Approaches to pharmaceutical development are described in ICH Q8. The results of exploratory and clinical development studies, while outside the scope of this guidance, are inputs to pharmaceutical development.

2. Technology Transfer (3.1.2) The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement.

7.4 Purchasing ISO 9001:7.4.1 Purchasing ProcessThe organization shall ensure that purchased product conforms to specified purchase requirements. The type and extent of control applied to the supplier and the purchased product shall be dependent upon the effect of the purchased product on subsequent product realization or final product.

The organization shall evaluate and select suppliers based on their ability to supply product in accordance with the organization’s requirements. Criteria for selection, evaluation and re-evaluation shall be established. Records of the results of evaluations and any necessary actions arising from the evaluation shall be maintained.

GMP AnnexSuppliers of quality critical materials and services shall be approved by the Quality Unit after an evaluation of the suppliers quality management system, including adequate evidence that they can consistently meet agreed requirements.

The organization shall require that contract manufacturers or laboratories adhere to the relevant sections of this Annex. (See 4.1)

7.4.2 Purchasing InformationPurchasing information shall describe the product to be purchased, including , where appropriate,

a) Requirements for approval of product, procedures, processes and equipmentb) Requirements for qualification of personnelc) Quality management system requirements

The organization shall ensure the adequacy of specified purchase requirements prior to their communication to the supplier.

GMP AnnexThe organization shall ensure that it is notified of any significant changes to materials that may potentially impact excipient quality.

7.4.3 Verification of Purchased ProductThe organization shall establish and implement the inspection or other activities necessary for


ensuring that purchased product meets specified purchase requirements.

Where the organization or its customer intends to perform verification at the supplier’s premises, the organization shall state the intended verification arrangements and method of product release in the purchasing information.

GMP AnnexIncoming quality critical materials (including pre-printed labels) shall be physically or administratively quarantined until they have been tested or otherwise verified and approved for use. Where quarantine is not feasible, e.g. for materials supplied via pipelines, the excipient manufacturer shall establish an agreement with the supplier so that they are notified of material that does not meet specification.

Sampling shall be conducted in accordance with a documented procedure designed to prevent contamination and cross-contamination.

At least one analytical test shall be conducted to verify the identity of each delivered batch of raw material, unless they are hazardous or highly toxic or otherwise cannot be sampled. Materials which are not sampled shall have alternative controls in place to assure their quality.

Bulk deliveries shall have additional controls to assure freedom from contamination.

Processes to verify the purchased product shall be documented.IPEC-PQG:7.4 Purchasing 7.4.1 Purchasing Process

Excipient manufacturers should have a system for selecting and approving suppliers of quality-critical materials and services (for example subcontract manufacturers and laboratories). Supplier approval by the quality unit should require an evaluation of the supplier’s quality management system, including adequate evidence that they can consistently meet agreed requirements. This may require periodic audits of the supplier’s manufacturing facility. Records of these activities should be maintained.

Materials should be purchased against an agreed specification from approved suppliers.

7.4.2 Purchasing InformationPurchasing agreements should describe the material or service ordered including, where critical to excipient quality, the following:

the name, type, class, style, grade, item code number or other precise identification traceable to the raw material and packaging specifications,

drawings, process requirements, inspection instructions and other relevant technical data, including requirements for approval or qualification of product, procedures, process equipment and personnel,

adherence to the appropriate sections of this Guide for relevant contract manufacturers or laboratories,

a statement to notify the excipient manufacturer of significant changes in quality-critical raw materials.

7.4.3 Verification of Purchased Product


There should be procedures for the approval and release of quality-critical material.

Upon receipt, quality-critical materials should be placed in quarantine and should not be used prior to acceptance. Effective quarantine can be established with suitable identifying labels, signs and/or other manual documentation systems. When quarantine and stock control are managed with computer systems in lieu of a physical stock control, then system controls should prevent the use of unreleased material.

Quarantine may not be feasible for materials supplied via pipelines. In these cases the excipient manufacturer should establish an agreement with the supplier so that they are notified of material that does not meet specification.

Sampling activities should be conducted under defined conditions, in accordance with a defined sampling method and using procedures designed to prevent contamination and cross-contamination.

Quality-critical materials used in the manufacture of an excipient should be tested or otherwise verified prior to use. Verification should include availability and a check of the supplier certificate of analysis and, wherever feasible, at least an identification test. Testing schedules should be organised to separate those tests that are routine from those that are performed infrequently or only for new suppliers.

Bulk deliveries should have additional controls to assure material purity and freedom from contamination (for example dedicated tankers, tamper-evident seals, a certificate of cleaning, analytical testing and/or audit of the supplier).

These procedures, activities and results should be documented.ICH Q107.4 Purchasing III. Management Responsibility

G. Management of Outsourced Activities and Purchased Materials (2.7) The pharmaceutical quality system, including the management responsibilities described in this section, extends to the control and review of any outsourced activities and quality of purchased materials. The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials. These processes should incorporate quality risk management and include:

(a) Assessing prior to outsourcing operations or selecting material suppliers, the suitability and competence of the other party to carry out the activity or provide the material using a defined supply chain (e.g., audits, material evaluations, qualification).

(b) Defining the responsibilities and communication processes for quality-related activities of the involved parties. For outsourced activities, this should be included in a written agreement between the contract giver and contract acceptor.

(c) Monitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and the identification and implementation of any essential improvements.

(d) Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain.

7.5 Production and Service Provision ISO 9001:


7.5.1 Control of production and service provisionThe organization shall plan and carry out production and service provision under controlled conditions. Controlled conditions shall include, as applicable,

a) The availability of information that describes the characteristics of the product,b) The availability of work instructions, as necessary,c) The use of suitable equipment,d) The availability and use of monitoring and measuring equipmente) The implementation of monitoring and measurement, andf) The implementation of product release, delivery and post-delivery activities.

GMP AnnexControlled conditions shall include, as applicable:

a) The availability of information that specifies the characteristics of the product.No additional requirements.

b) The availability of work instructions, as necessaryFor batch processes an accurate reproduction of the appropriate master production instructions shall be issued to the production area. For continuous processes, there shall be a defined process and records shall be available.

Records for both batch and continuous processing, where critical to excipient quality shall include:

date/time each step was completed or date/time log of key parameters, identification of persons performing and directly supervising or checking each

significant step, operation or control parameter, identification of major equipment and lines used, cleaning of equipment and utensils conformance to specified operating ranges, material inputs to enable traceability, for example batch number and quantities

of raw material/intermediate, time it was added, etc, description of sampling performed, in-process and laboratory control results, labelling control records failures, deviation and their investigations, and results of final product inspection.

and as applicable: the quantity produced for the defined batch and a statement of the percentage

of theoretical yield, inspection of the packaging and labelling area before and after use, labelling

control records to ensure the correct label is applied to all containers,

Records of quality-critical equipment use shall allow the sequence of cleaning, maintenance and production activities to be determined. Where multi-purpose equipment is in use records shall identify the previous usage.

Packaging and labelling controls shall be documented and shall ensure: the correct label is applied to all containers. correct labels are printed and issued containing the correct information excess labels are immediately destroyed or returned to controlled storage


packaging and labelling facilities are inspected immediately before use to ensure that materials that are not required for the current operation have been removed

Where solvents are recovered and reused in same process or different process they shall meet appropriate specifications prior to reuse or mixing with other approved material.

The use of mother liquors or filtrates containing recoverable amounts of excipient, reactants or intermediates shall be documented and records maintained to enable traceability.

c) the use of suitable equipment,

The manufacturer shall design and justify equipment cleaning and sanitization procedures and provide evidence of their effectiveness.

Equipment and utensils shall be cleaned, and sanitised where critical to excipient quality. The cleaning status of equipment shall be identified.

For continuous processing the frequency of equipment cleaning shall be determined by the manufacturer and justified.

d) The availability and use of monitoring and measuring equipmentNo additional requirements.

e) The implementation of monitoring and measurement, In process sampling methods shall be documented. Sampling methods shall define the time and location of sampling, and shall ensure that the sample is representative and clearly labelled. In-process samples shall not be returned to production for incorporation into the final batch.

f) The implementation of product release, delivery and post-delivery activities No additional requirements.

7.5.2 Validation of processes for production and service provisionThe organization shall validate any processes for production and service provision where the resulting output cannot be verified by subsequent monitoring or measurement and, as a consequence, deficiencies become apparent only after the product is in use or the service has been delivered.

Validation shall demonstrate the ability of these processes to achieve planned results.

The organization shall establish arrangements for these processes including , as applicable,a) defined criteria for review and approval of the processes,b) approval of equipment and qualification of personnelc) use of specific methods and proceduresd) requirements for recordse) revalidation

GMP Annex


The consistent operation of the Excipient manufacturing process shall be demonstrated.

Where the intent of blending or mixing is to ensure final batch uniformity, it shall be demonstrated that such processing achieves a state of homogeneity.

7.5.3 Identification and traceabilityWhere appropriate, the organization shall identify the product by suitable means throughout product realization.

The organization shall identify the product status with respect to monitoring and measurement requirements throughout product realization.

Where traceability is a requirement, the organization shall control the unique identification of the product and maintain records.

GMP AnnexIdentification and traceability are specified requirements for quality critical raw materials, packaging materials, intermediates and finished excipients. Records shall allow traceability of the excipient from raw materials through delivery to initial customers. The methods used for traceability and identification of raw materials used in excipients produced by continuous processing shall be defined.

Excipient labels shall include:a) the name of the excipient and grade if applicable,b) the organisation’s name,c) the batch number, andd) any special storage conditions, if applicable.

7.5.4 Customer propertyThe organization shall exercise care with customer property while it is under the organization’s control or being used by the organization. The organization shall identify, verify, protect and safeguard customer property provided for use or incorporation into the product. If any customer property is lost, damaged or otherwise found to be unsuitable for use, the organization shall report this to the customer and maintain records.


7.5.5 Preservation of productThe organization shall preserve the product during internal processing and delivery to the intended destination in order to maintain conformity to requirements. As applicable, preservation shall include identification, handling, packaging, storage and protection. Preservation shall also apply to the constituent parts of a product.

GMP AnnexRecords of storage conditions shall be maintained if they are critical for the maintenance of raw material, intermediate or excipient quality characteristics. Storage and handling procedures shall be defined in order to protect containers and closures, minimise the risk of contamination, damage or deterioration of the excipient and avoid mix-ups.

An excipient packaging system shall include the following features:


a) written packaging specifications, b) tamper evident seals,c) where containers are re-used, cleaning procedures including means of removing

previous labels, andd) containers that do not adversely interact with or contaminate the excipient,

Distribution records shall be retained to enable retrieval of a batch of excipient. IPEC-PQG:7.5 Production and Service Provision 7.5.1 Control of Production and Service Provision

Production activities should be carried out under controlled conditions (see also section 7.1).

Specific examples of important controls, some of which may not be applicable to all excipient manufacturers, are illustrated in the following sections.

7.5.1.1 Production Instructions and Records Production instructions and records are required but may differ for the type of operation, for example batch versus continuous processes.

There should be a controlled document that describes how the excipient is produced (for example master production instructions, master production and control records, process definitions etc.).

For batch processes an accurate reproduction of the appropriate master production instructions should be issued to the production area. For continuous processes a current processing log should be available.

Records should be available for each batch of excipient produced and should include complete information relating to the production and control of each batch. For continuous processes the batch and its records should be defined (for example based on time or defined quantity). Records may be in different locations but should be readily retrievable.

Records for both batch and continuous processing, where critical to excipient quality, should include:

date/time each step was completed or date/time log of key parameters, identification of persons performing and directly supervising or checking

each significant step, operation or control parameter, identification of major equipment and lines used, material inputs to enable traceability, for example batch number and

quantities of raw material/intermediate, time it was added, etc., in-process and laboratory control results, the quantity produced for the defined batch and a statement of the

percentage of theoretical yield, unless not quantifiable (for example as in some continuous processes),

inspection of the packaging and labelling area before and after use, labelling control records, description of excipient product containers and closures, description of sampling performed,


failures, deviation and their investigations, results of final product inspection.

7.5.1.2 Equipment CleaningThe manufacturer should design and justify cleaning and sanitisation procedures and provide evidence of their effectiveness. In multi-purpose plants the use of the “model product approach” (groups of product of similar type) may be used in justifying a suitable procedure.

Cleaning and sanitisation procedures should be documented. They should contain sufficient detail to allow operators to clean each type of equipment in a reproducible and effective manner. There should be a record confirming that these procedures have been followed.

Equipment and utensils should be cleaned and sanitised where critical to excipient quality and at appropriate intervals to prevent contamination and cross-contamination of the excipient. The cleaning status of equipment should be recorded appropriately.

Where multi-purpose equipment is in use it is important to be able to determine previous usage when investigating cross-contamination or the possibility of such contamination (see also 7.5.1.7).

During a production campaign incidental carry-over frequently occurs and is acceptable usually since clean-up between successive batches of the same excipient is not normally required to maintain quality levels. Products that leave residues that cannot be effectively removed should be produced in dedicated equipment.

For continuous processing the frequency of equipment cleaning should be determined by the manufacturer and justified.

7.5.1.3 Recovery of Solvents, Mother Liquors and Second Crop CrystallisationsWhere solvents are recovered and reused in the same process or different processes they should meet appropriate standards prior to reuse or mixing with other approved material.

Mother liquors or filtrates containing recoverable amounts of excipient, reactants or intermediates are frequently reused. Such processes should be documented in the production records or logs to enable traceability.

7.5.1.4 In-process Blending or MixingIn process blending or mixing to assure batch uniformity or to facilitate processing should be controlled and documented. If the intent of the operation is to ensure batch uniformity it should be performed so as to assure homogenous mixing of materials to the extent feasible and should be reproducible from batch to batch.

7.5.1.5 In-process Control In-process inspection and testing should be performed based upon monitoring the process or actual sample analysis at defined locations and times. Sampling


methods should be documented to ensure that the sample is representative and clearly labelled.

In-process samples should not be returned to production for incorporation into the final batch.

The results of in-process tests should be recorded and should conform to established process parameters or acceptable tolerances. Work instructions should define the procedure to follow and how to utilise the inspection and test data to control the process. There should be defined actions to be taken when the results are outside specified limits.

Where approval to continue with the process is issued within the production department, the specified tests should be performed by trained personnel and the results recorded.

7.5.1.6 Packaging and LabellingProcedures should be employed to protect the quality and purity of the excipient when it is packaged and to assure that the correct label is applied to all containers. Packaging and labelling operations should be designed to prevent mix-ups.

Procedures should be implemented to ensure that the correct labels are printed and issued and that the labels contain the correct information. The procedure should also specify that excess labels are immediately destroyed or returned to controlled storage. Excess labels bearing batch numbers should be destroyed. Packaging and labelling facilities should be inspected immediately before use to ensure that materials that are not required for the next packaging operation have been removed.

Where excipients are labelled on the packaging line, packaged in pre-printed bags or bulk-shipped in tank cars there should be documentation of the system used to satisfy the intent of the above procedures.

7.5.1.7 Records of Equipment UseRecords of quality-critical equipment use should be retained. These records should allow the sequence of cleaning, maintenance and production activities to be determined.

7.5.2 Validation of Processes for Production and Service ProvisionAn important factor in the assurance of product quality includes the adequate design and control of the manufacturing process because product testing alone is not sufficient to reveal variations that may have occurred. Each step of the manufacturing process should be controlled to the extent necessary to ensure that the excipient meets established specifications.

The concept of process validation is a key element in ensuring that these quality assurance goals are met. The process reactions, operating parameters, purification steps, impurities and key tests needed for process control should be documented, thus providing the basis for validation.


The full validation program that is typically performed in the pharmaceutical industry may not always be carried out by the excipient manufacturer. However, the excipient manufacturer should demonstrate the consistent operation of each manufacturing process, for example through process capability studies, development and scale-up reports etc.

7.5.3 Identification and Traceability 7.5.3.1Traceability

Quality-critical items, for example raw materials, packaging materials, intermediates and finished excipients should be clearly identified and traceable through records. These records should allow traceability of the excipient both upstream and downstream. Identification of raw materials used in batch production processes should be traceable through the batch numbering system or other appropriate system. Identification of raw materials used in excipients produced by continuous processing should indicate the timeframe during which a particular batch of raw material was processed through the plant.

Raw materials, including solvents, are sometimes stored in bulk tanks or other large containers, making precise separation of batches difficult. Nevertheless, the use of such materials should be documented in production records.

7.5.3.2Inspection and Test StatusThere should be a system to identify the inspection status of quality-critical items including raw materials, packaging materials, intermediates and finished excipients. Whilst storing materials in identified locations is preferred, any means that clearly identifies the test status is satisfactory. Continuously-fed materials may need special consideration in order to satisfy these requirements.

7.5.3.3LabellingLabelling for excipient packages is subject to national and international regulatory requirements, which may include transportation and safety measures. As a minimum, labels should include:

the name of the excipient and grade if applicable, the excipient manufacturer’s and/or distributor’s name, the batch number from which the complete batch history can be

determined, special storage conditions, if applicable.

7.5.4 Customer PropertyThe excipient manufacturer should establish and maintain procedures for verification, storage and maintenance of customer-supplied materials intended for incorporation into the customer's excipient. Verification by the manufacturer does not relieve the customer of the responsibility to provide an acceptable material. Material that is lost damaged or is otherwise unsuitable for use should be recorded and reported to the customer. In this case, procedures should be in place for acceptable disposition and replacement of the material. The manufacturer should also make provisions to protect other real and intellectual property that is provided by the customer (for example test


equipment, test methods and specifications).

7.5.5 Preservation of Product7.5.5.1Handling, Storage and Preservation

Excipients, intermediates and raw materials should be handled and stored under appropriate conditions of temperature, humidity and light so that their identity, quality and purity are not affected. Outdoor storage of raw materials (for example acids, other corrosive substances or explosive materials) or excipients is acceptable provided the containers give suitable protection against deterioration or contamination of their contents, identifying labels remain legible and containers are adequately cleaned prior to opening and use.

Records of storage conditions should be maintained if they are critical for the continuing conformance of the material to specification.

7.5.5.2 Packaging SystemsAn excipient packaging system should include the following features:

documented specifications and examination or testing methods, cleaning procedures where containers are reused, tamper-evident seals, containers that provide adequate protection against deterioration or

contamination of the excipient during transportation and recommended storage,

containers that do not interact with or contaminate the excipient, storage and handling procedures which protect containers and closures

and minimise the risk of contamination, damage or deterioration and which will avoid mix-ups (for example between containers that have different specifications but are similar in appearance).

If returnable excipient containers are re-used, previous labelling should be removed or defaced. If the containers are repetitively used solely for the same excipient, previous batch numbers or the entire label should be removed or completely obliterated.

7.5.5.3 Delivery and DistributionIdentification and traceability of quality-critical aspects are required of excipient manufacturers. Distribution records of excipient shipments should be kept. These records should identify, by excipient batch, where and to whom the excipient was shipped, the amount shipped and the date of shipment so as to facilitate retrieval if necessary. Where excipients are handled by a series of different distributors, it should be possible to trace them back to the original manufacturer and not just to the previous supplier.

The manufacturer should maintain the integrity and the quality of the product after final inspection and test. Where contractually specified, this protection should be extended to include delivery to the final destination. Excipients should only be supplied within their expiry and/or retest period.

ICH Q107.5 Production and Service Provision


IV.A. Life Stage Goals3. Commercial Manufacturing (3.1.3)

The goals of manufacturing activities include achieving product realization, establishing and maintaining a state of control, and facilitating continual improvement. The pharmaceutical quality system should assure that the desired product quality is routinely met, suitable process performance is achieved, the set of controls are appropriate, improvement opportunities are identified and evaluated, and the body of knowledge is continually expanded.

7.6 Control of Monitoring and Measuring Equipment ISO 9001:The organization shall determine the monitoring and measurement to be undertaken and the monitoring and measuring equipment needed to provide evidence of conformity of product to determined requirements.

The organization shall establish processes to ensure that monitoring and measurement can be carried out and are carried out in a manner that is consistent with the monitoring and measurement requirements.

Where necessary to ensure valid results, measuring equipment shalla) be calibrated or verified, or both, at specified intervals, or prior to use, against

measurement standards traceable to international or national measurement standards; where no such standards exist, the basis used for calibration or verification shall be recorded;

b) be adjusted or re-adjusted, as necessaryc) have identification in order to determine its calibration status;d) be safeguarded from adjustment that would invalidate the measurement resulte) be protected from damage and deterioration during handling, maintenance and

storage.

In addition, the organization shall assess and record the validity of the previous measuring results when the equipment is found not to conform to requirements. The organization shall take appropriate action on the equipment and any product affected.

Records of the results of calibration and verification shall be maintained.

When used in the monitoring and measurement of specified requirements, the ability of computer software to satisfy the intended application shall be confirmed. This shall be undertaken prior to initial use and reconfirmed as necessary.

GMP AnnexNo additional requirements.IPEC-PQG:7.6 Control of Measuring and Monitoring Devices

Measuring and test equipment, including computerised systems, identified as being quality-critical should be calibrated and maintained. This includes in-process instruments as well as test equipment used in the laboratory. The control program should include the standardisation or calibration of instruments and equipment at suitable intervals in accordance with an established documented program. This program should contain specific directions, schedules, limits for accuracy and precision and provisions for


remedial action in the event that accuracy and/or precision limits are not met. Calibration standards should be traceable to recognised national or Compendial standards as appropriate.

Instruments and equipment not meeting established specifications should not be used and an investigation should be conducted to determine the validity of the previous results since the last successful calibration. The current calibration status of quality-critical equipment should be known and verifiable to users.

ICH Q107.6 Control of Monitoring and Measuring Equipment No Requirement8 Measurement, Analysis and Improvement ISO 9001:8.1 General The organization shall plan and implement the monitoring, measurement , analysis and improvement processes needed

a) to demonstrate conformity to product requirementsb) to ensure conformity to the quality management system, andc) to continually improve the effectiveness of the quality management system.

This shall include determination of applicable methods, including statistical techniques, and the extent of their use.

GMP AnnexNo additional requirements.IPEC-PQG:8.1 General The organization should plan and implement the monitoring, measurement and improvement activities required to demonstrate conformity of the excipient to customer requirements and to ensure conformity of the quality management system to this Guide.

The organization should evaluate opportunities for improvements through the measurement and analysis of product and process trends.ICH Q108.1 General Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained. An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement. The process performance and product quality monitoring system should:

(a) Use quality risk management to establish the control strategy. This can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. The control strategy should facilitate timely feedback / feed forward and appropriate corrective action and preventive action;

(b) Provide the tools for measurement and analysis of parameters and attributes identified in the control strategy (e.g., data management and statistical tools);

(c) Analyse parameters and attributes identified in the control strategy to verify continued operation within a state of control;


(d) Identify sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation;

(e) Include feedback on product quality from both internal and external sources, e.g., complaints, product rejections, non-conformances, recalls, deviations, audits and regulatory inspections and findings;

(f) Provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation.

Table I: Application of Process Performance and Product Quality Monitoring System throughout the Product Lifecycle


Technology Transfer Commercial Manufacturing


Process and product knowledge generated and process and product monitoring conducted throughout development can be used to establish a control strategy for manufacturing.

Monitoring during scale-up activities can provide a preliminary indication of process performance and the successful integration into manufacturing. Knowledge obtained during transfer and scale up activities can be useful in further developing the control strategy.

A well-defined system for process performance and product quality monitoring should be applied to assure performance within a state of control and to identify improvement areas.

Once manufacturing ceases, monitoring such as stability testing should continue to completion of the studies. Appropriate action on marketed product should continue to be executed according to regional regulations.

8.2 Monitoring and Measurement ISO 9001:8.2.1 Customer SatisfactionAs one of the measurements of the performance of the quality management system, the organization shall monitor information relating to customer perception as to whether the organization has met customer requirements. The methods for obtaining and using this information shall be determined.


8.2.2 Internal auditsThe organization shall conduct internal audits at planned intervals to determine whether the quality management system

a) conforms to the planned arrangements, to the requirements of ISO 9001:2008 and to the quality management system requirements established by the organization, and

b) is effectively implemented and maintained.

An audit programme shall be planned, taking into consideration the status and importance of the processes and areas to be audited, as well as the results of the previous audits. The audit criteria, scope, frequency and methods shall be defined. The selection of auditors and conduct of audits shall ensure objectivity and impartiality of the audit process. Auditors shall not audit their own work.

A documented procedure shall be established to define the responsibilities and requirements for planning and conducting audits, establishing records and reporting results.


Records of audits and their results shall be maintained.

The management responsibility for the area being audited shall ensure that any necessary corrections and corrective actions are taken without undue delay to eliminate detected nonconformities and their causes.

Follow-up activities shall include the verification of the actions taken and the reporting of verification results.


8.2.3 Monitoring and measurement of processesThe organization shall apply suitable methods for monitoring and, where applicable, measurement of the quality management system processes. These methods shall demonstrate the ability of the processes to achieve planned results. When planned results are not achieved, correction and corrective action shall be taken, as appropriate.

GMP AnnexThe need to notify customers when critical deviations from planned results occur shall be evaluated (see 7.2.1 and 7.2.3).

8.2.4 Monitoring and measurement productThe organization shall monitor and measure the characteristics of the product to verify that product requirements have been met. This shall be carried out at appropriate stages of the product realization process in accordance with the planned arrangements. Evidence of conformity with the acceptance criteria shall be maintained.

Records shall indicate the person(s) authorizing the release of product for delivery to the customer.

The release of product and delivery of service to the customer shall not proceed until the planned arrangements have been satisfactorily completed, unless otherwise approved by a relevant authority and, where applicable, the customer.

GMP AnnexIf the excipient manufacturer claims that their product is in compliance with a pharmacopoeia or an official compendium, then:

non-compendial analytical tests shall be demonstrated to be at least equivalent to those in the compendia, and

the method shall comply with applicable general chapters and notices.Written procedures shall be established to monitor and control the quality characteristics of excipients. These shall include, as applicable:

a) laboratory controls; including the preparation and use of laboratory solutions, reference standards,i. Laboratory controls shall include complete data derived from tests necessary

to ensure conformance with specifications and standards. Records of these controls shall include: identity of the sample, test method used,


raw data including sample preparation, calculations performed test results and how they compare with established specifications, and person who performed each test and the date(s) the tests were performed.

ii. There shall be a documented procedure and records for the preparation of laboratory reagents and solutions. Reagents and solutions shall be labelled with the proper name, concentration and expiry date.

iii. Primary reference reagents and standards shall be verified on receipt and appropriately stored. There shall be a documented procedure for the qualification of secondary reference standards against primary reference standards that includes their preparation, approval and storage. The re-evaluation period shall be defined for secondary reference standards and each batch shall be periodically re-qualified in accordance with a documented procedure.

b) excipient testing and release,i. There shall be a procedure to ensure that appropriate manufacturing

documentation, in addition to the test results, is evaluated prior to release of the finished excipient. The Quality Unit shall be responsible for the release of the finished excipient.

Note: For excipients produced by continuous processes assurance that the excipient conforms to documented specifications may be achieved through the results of in-process testing or other process control records.

c) investigation of out-of-specification test results,i. Out-of-specification (OOS) test results shall be investigated and documented

according to a documented procedure. d) the retention of samples of each batch of the excipient,

i. Where practical, a representative sample of each batch of the excipient shall be retained. The retention period shall be appropriate to the expiry or re-evaluation date. The retained samples shall be stored and maintained in such a manner that they are readily retrievable in facilities that provide a suitable environment. The sample size shall be at least twice the amount required to perform complete specification testing.

e) preparation and issue of certificates of analysis,f) the tests and limits for impurities,

i. Excipient manufacturers shall identify and set appropriate limits for known impurities, and

g) an evaluation of excipient stability,The organization shall evaluate excipient stability based on historic data or specific studies. The organization shall define and justify an expiry or retest period and ensure this is communicated to the customer

IPEC-PQG:8.2 Monitoring and Measurement 8.2.1 Customer Satisfaction

The excipient manufacturer should establish measurement activities to assess customer satisfaction. Such measurements can include customer complaints, return of excipients and customer feedback. This information should drive activities that strive to continuously improve customer satisfaction.

8.2.2 Internal Audit


The excipient manufacturer should carry out a comprehensive system of planned and documented internal quality audits. These should determine whether quality activities comply with planned arrangements and the effectiveness of the quality management system. Audits should be scheduled on the basis of the status and importance of the activity. Audits and follow-up actions should be carried out in accordance with documented procedures.

Audit results should be documented and discussed with management personnel having responsibility in the area audited. Management personnel responsible for the area audited should take corrective action on the nonconformities found.

Appendix A, Auditing Considerations will be of assistance in establishing an internal audit program.

8.2.3 Monitoring and Measurement of ProcessesThe excipient manufacturer should identify the tests and measurements necessary to adequately control manufacturing and quality management system processes. Where critical to excipient quality, techniques that are used to verify that the processes are under control should be established.

Corrective action should be taken to ensure the excipient meets requirements when deviations from planned results occur.

Periodic reviews of key indicators such as process quality attributes and process failures should be conducted to assess the need for improvements.

8.2.4 Monitoring and Measurement of ProductThe excipient manufacturer should establish the test methods and procedures to ensure the product consistently meets specifications.

Analytical methods should be fit for purpose. The analytical methods may be those included in the current edition of the appropriate pharmacopoeia or another accepted standard. However, the methods may also be non-compendial.

If the excipient manufacturer claims that their product is in compliance with a pharmacopoeia or an official compendium, then:

• non-compendial analytical tests should be demonstrated to be equivalent to those in the compendia,

• it should comply with applicable general chapters and notices.

8.2.4.1 Laboratory ControlsLaboratory controls should include complete data derived from tests necessary to ensure conformance with specifications and standards including:

• a description of the sample received for testing together with the material name, batch number or other distinctive code and date the sample was taken,

• a statement referencing each test method used, • a record of raw data secured during each test including graphs, chromatograms,

charts and spectra from laboratory instrumentation, identified to show the specific material and batch tested,

• a record of calculations performed in connection with the test,• test results and how they compare with established specifications,• a record of the person who performed each test and the date(s) the tests were

performed.

There should be a documented procedure for the preparation of laboratory reagents


and solutions. Purchased reagents and solutions should be labeled with the proper name, concentration and expiry date. Records should be maintained for the preparation of solutions including the name of the solution, date of preparation and quantities of material used.

Volumetric solutions should be standardized according to an internal method or by using a recognized standard. Records of the standardization should be maintained.

Where used, primary reference reagents and standards should be appropriately stored and need not be tested upon receipt provided that a certificate of analysis from the supplier is available. Secondary reference standards should be appropriately prepared, identified, tested, approved and stored. There should be a documented procedure for the qualification of secondary reference standards against primary reference standards.

The re-evaluation period should be defined for secondary reference standards and each batch should be periodically re-qualified in accordance with a documented protocol or procedure.

8.2.4.2 Finished Excipient Testing and ReleaseFinished excipient testing should be performed on each batch to ensure that the excipient conforms to documented specifications. There should be a procedure to ensure that appropriate manufacturing documentation, in addition to the test results, is evaluated prior to release of the finished excipient. The quality unit should be responsible for the release of the finished excipient.

For excipients produced by continuous processes assurance that the excipient conforms to documented specifications may be achieved through the results of in-process testing or other process control records.

8.2.4.3 Out-of-Specification Test ResultsOut-of-specification (OOS) test results should be investigated and documented according to a documented procedure.

Retest sample results may only be used to replace the original test result if it is demonstrated that the original result is erroneous based on a documented investigation.

When statistical analysis is used both the original and retest data must be included. The OOS procedure should define which statistical techniques are to be used and under what circumstances.

These same principles apply when the sample is suspected of not being representative of the material from which it was taken.

8.2.4.4 Retained SamplesWhere practical, a representative sample of each batch of the excipient should be retained. The retention period should be appropriate to the expiry or re-evaluation date. The retained samples should be stored and maintained in such a manner that they are readily retrievable in facilities that provide a suitable environment. The sample size should be at least twice the amount required to perform complete specification testing.

8.2.4.5 Certificates of AnalysisThe organization should provide certificates of analysis to the required specification for each batch of excipient. More details on the suitable contents of a certificate of


analysis can be found in the IPEC-Americas Certificate of Analysis Guide for Bulk Pharmaceutical Excipients and the UK Guidance on Certificates of Analysis from The Rules and Guidance for Pharmaceutical Manufacturers and Distributors.

8.2.4.6 ImpuritiesWhere possible, excipient manufacturers should identify and set appropriate limits for impurities. The limits should be based upon appropriate safety data, limits as described in official compendia or other requirements and sound GMP considerations. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established limits.

Many excipients are extracted from or purified using organic solvents.

These solvents are normally removed by drying. It is important that excipient specifications include tests and limits for solvent residues.

8.2.4.7 StabilityWhile many excipient products are stable and may not require extensive testing to assure stability, the stability of excipients is an important factor contributing to the overall quality of the drug product. For excipients that have been on the market for a long time historical data may be used to indicate stability.

Where historical data do not exist a documented testing and/or evaluation program designed to assess the stability characteristics of the excipient should be undertaken. The results of such stability testing and/or evaluation should be used in determining appropriate storage conditions and retest or expiry dates. The testing program should include the following:

• the number of batches, sample sizes and test intervals,• storage conditions for samples retained for testing,• suitable stability-indicating test methods,• storage of the excipient in containers that simulate the market container, where

possible.

The stability of excipients may be affected by undetected changes in raw materials or subtle changes in manufacturing procedures or storage conditions. Excipients may also be shipped in a variety of packaging types that can affect their stability (for example, plastic or glass bottles, metal or plastic drums, bags, tank cars or other bulk containers, etc.).

Some excipients may be available in different grades (for example, various molecular weights of a polymer or different monomer ratios, different particle sizes, bulk densities etc.) or may be mixtures of other excipients. These excipients may be very similar to others within a product group. Minor quantitative differences of some of the components may be the only significant variation from one product to another. For these types of excipients, a “model product” approach may be appropriate to assess the stability of similar excipients. Stability studies of this type should involve selection of several “model products” that would be expected to simulate the stability of the product group being assessed.

This selection should be scientifically sound and documented. Data from stability studies of these “model products” can be used to determine theoretical stability for similar products.

8.2.4.8 Expiry/Retest PeriodsAn expiry or retest period should be assigned to each excipient and communicated to


the customer. Common practice is to use a retest period, rather than an expiry period.ICH Q108.2 Monitoring and Measurement No requirement8.3 Control of Nonconforming Product ISO 9001:The organization shall ensure that product which does not conform to product requirements is identified and controlled to prevent its unintended use or delivery. A documented procedure shall be established to define the controls and related responsibilities and authorities for dealing with non-conforming product.

Where applicable, the organization shall deal with nonconforming product by one or more of the following ways;

a) By taking action to eliminate the detected non-conformityb) By authorizing its use, release or acceptance under concession by a relevant authority

and, where applicable, by the customer:c) By taking action to preclude its original intended use or application;d) By taking action appropriate to the effects, or potential effects, of the nonconformity

when nonconforming product is detected after delivery or use has started;When nonconforming product is corrected it shall be subject to re-verification to demonstrate conformity to the requirements.

Records of the nature of nonconformities and any subsequent actions taken, including concessions obtained, shall be maintained.

GMP Annex

e) Reprocessing shall only occur when it has already been documented that the excipient may be manufactured in that manner, and

f) Reworking shall only occur after the Quality Unit has documented a review of the risk to excipient quality.

As applicable, when performing the risk assessment, consideration shall be given to:

new impurities that may be introduced as a result of reworking, additional testing to control the reworking, records and traceability to the original batches, suitable acceptance criteria for the reworked excipient, impact on stability or the validity of the re-evaluation interval, and performance of the excipient notifying the authorities where the product has been registered

Records of reprocessing and reworking activities shall be retained.

There shall be a procedure defining how to manage the retrieval of an excipient.

Returned excipients shall be identified as such and quarantined until an evaluation of their quality has been completed by the Quality Unit(s). Records shall include the reason for return and the decision made as to the final disposition.

IPEC-PQG:8.3 Control of Nonconforming Product Raw material, intermediate or finished excipient found not to meet its specification should be clearly identified and controlled to prevent inadvertent use or release for sale. A record of nonconforming product should be maintained. Incidences of non-conformance should be


investigated to identify the cause. The investigation should be documented and action taken to prevent recurrence.

There should be a documented procedure defining how the retrieval of an excipient from distribution should be conducted and recorded.

Procedures should exist for the evaluation and subsequent disposition of nonconforming products. Nonconforming product should be reviewed in accordance with documented procedures to determine if it may be:

• reprocessed/reworked to meet the specified requirements,• accepted by the customer with their agreement,• re-graded for other applications,• destroyed.

8.3.1 ReprocessingRepetition of an activity that is a normal part of the manufacturing process (reprocessing) should only occur when it has already been documented that the excipient may be made in that manner. In all other cases, the guidance for reworking should be followed.

8.3.2 ReworkingAn activity that is not a normal part of the manufacturing process (reworking) should only be conducted following a documented review of risk to excipient quality and approval by the quality unit. As appropriate, when performing the risk assessment, consideration should be given to:

• new impurities that may be introduced as a result of reworking,• additional testing to control the reworking,• records and traceability to the original batches,• suitable acceptance criteria for the reworked excipient,• impact on stability or the validity of the re-evaluation interval,• performance of the excipient.

When the need to rework an excipient is identified an investigation and evaluation of the cause is required.

The equivalence of the quality of reworked material to original material should also be evaluated and documented to ensure that the batch will conform to established specifications and characteristics.

Batches of excipients that do not conform to specifications individually must not be blended with other batches that do conform in an attempt to hide adulterated or sub-standard material.

8.3.3 Returned ExcipientsReturned excipients should be identified and quarantined until the quality unit has completed an evaluation of their quality. There should be procedures for holding, testing reprocessing or reworking of the returned excipient. Records for returned products should be maintained and should include the name of the excipient and the batch number, reason for the return, quantity returned and ultimate disposition of the returned excipient.

ICH Q108.3 Control of Nonconforming Product No requirement


8.4 Analysis of Data ISO 9001:The organization shall determine, collect and analyse appropriate data to demonstrate the suitability and effectiveness of the quality management system and to evaluate where continual improvement of the effectiveness of the quality management system can be made. This shall include data generated as a result of monitoring and measurement and from other relevant sources.

The analysis of data shall provide information relating toa) customer satisfactionb) conformity to product requirementsc) characteristics and trends of processes and products, including opportunities for

preventive actiond) suppliers.

GMP AnnexNo additional requirements.IPEC-PQG:8.4 Analysis of Data The excipient manufacturer should develop methods for evaluating the effectiveness of its quality management system and use those data to identify opportunities for improvement.

Such data can be derived from customer complaints, product reviews, process capability studies, internal and customer audits. The analysis of such data may be used as part of the management review (see also 5.6).

A periodic review of key indicators such as product quality attributes, customer complaints and product nonconformities may be conducted to assess the need for improvements

ICH Q108.4 Analysis of Data No requirement8.5 Improvement ISO 9001:8.5.1 Continual ImprovementThe organization shall continually improve the effectiveness of the quality management system through the use of the quality policy, quality objectives, audit results, analysis of data, corrective and preventive actions and management review.


8.5.2 Corrective actionThe organization shall take action to eliminate the causes of nonconformities in order to prevent recurrence. Corrective actions shall be appropriate to the effects of the nonconformities encountered.

A documented procedure shall be established to define the requirements fora) reviewing nonconformities (including customer complaints)b) determining the causes of nonconformitiesc) evaluating the need action to ensure that nonconformities do not recurd) determining and implementing action needed


e) records of the results of action takenf) reviewing the effectiveness of the corrective action taken

GMP AnnexInvestigations shall extend to other batches that may have been associated with the nonconformity

8.5.3 Preventative actionThe organization shall determine action to eliminate the causes of potential nonconformities in order to prevent their occurrence. Preventive actions shall be appropriate to the effects of the potential problems.

A documented procedure shall be established to define requirements fora) determining potential nonconformities and their causesb) evaluating the need for action to prevent occurrences of nonconformitiesc) determining and implementing action neededd) records of results of action takene) reviewing the effectiveness of preventive action taken.

GMP AnnexNo additional requirements.IPEC-PQG:8.5 Improvement 8.5.1 Continual Improvement

The excipient manufacturer should take proactive measures to continuously improve manufacturing and quality management system processes. To identify opportunities for continual improvement, analysis of the following performance indicators may be considered:

• causes of nonconforming product,• results of internal and external audits,• customer returns and complaints,• process and operational failures.

8.5.2 Corrective ActionThe excipient manufacturer should establish, document and maintain procedures for:

• determining the root causes of nonconformities,• ensuring that corrective actions are implemented and effective,• implementing and recording changes in procedures resulting from corrective

action.

8.5.3 Preventive ActionThe excipient manufacturer should establish, document and maintain procedures for:

• initiating preventive actions to deal with problems at a level corresponding to the risks,

• implementing and recording changes in procedures resulting from preventive action.

ICH Q108.5 Improvement 3.2.2 Corrective and preventative (CAPA) SystemThe pharmaceutical company should have a system for implementing corrective actions and preventive actions resulting from the investigation of complaints, product rejections, non-


conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring. A structured approach to the investigation process should be used with the objective of determining the root cause. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9. CAPA methodology should result in product and process improvements and enhanced product and process understanding.

Table II: Application of Corrective Action and Preventive Action System throughout the Product Lifecycle

Development Technology Transfer

Commercial Manufacturing


Product or process variability is explored. CAPA methodology is useful where corrective actions and preventive actions are incorporated into the iterative design and development process.

CAPA can be used as an effective system for feedback, feed forward and continual improvement.

CAPA should be used and the effectiveness of the actions should be evaluated.

CAPA should continue after the product is discontinued. The impact on product remaining on the market should be considered as well as other products which might be impacted

3.2.3 Change Management SystemInnovation, continual improvement, the outputs of process performance and product quality monitoring and CAPA drive change. In order to evaluate, approve and implement these changes properly, a company should have an effective change management system. There is generally a difference in formality of change management processes prior to the initial regulatory submission and after submission, where changes to the regulatory filing might be required under regional requirements.

The change management system ensures continual improvement is undertaken in a timely and effective manner. It should provide a high degree of assurance there are no unintended consequences of the change.

The change management system should include the following, as appropriate for the stage of the lifecycle:

(a) Quality risk management should be utilised to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk;

(b) Proposed changes should be evaluated relative to the marketing authorisation, including design space, where established, and/or current product and process understanding. There should be an assessment to determine whether a change to the regulatory filing is required under regional requirements. As stated in ICH Q8, working within the design space is not considered a change (from a regulatory filing perspective). However, from a pharmaceutical quality system standpoint, all changes should be evaluated by a company’s change management system;

(c) Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs and Medical), to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set;

(d) After implementation, an evaluation of the change should be undertaken to confirm the change objectives were achieved and that there was no deleterious impact on


product quality.

Table III: Application of Change Management System throughout the Product Lifecycle


Technology Transfer Commercial Manufacturing


Change is an inherent part of the development process and should be documented; the formality of the change management process should be consistent with the stage of pharmaceutical development.

The change management system should provide management and documentation of adjustments made to the process during technology transfer activities.

A formal change management system should be in place for commercial manufacturing. Oversight by the quality unit should provide assurance of appropriate science and risk based assessments.

Any changes after product discontinuation should go through an appropriate change management system

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