Good Manufacturing Practice

Agenda• Good Manufacturing Practices• Contamination• General Employee Hygiene• Food Handling Practices

Good Manufacturing PracticesDeal with contamination

• by people• by food materials• by packaging materials• by hazardous materials• by miscellaneous materials

General Employee HygieneHygiene

All employees working in direct contact with food, food contact surfaces and food packaging must conform to hygienic practices. This protects against food contamination by microorganisms or unwanted material.Prevent contamination

Careless employee practices can cause product contamination. The best way to avoid contamination is to prevent it.

How do we prevent contamination?Any behavior that could result in food contamination such as eating,

use of tobacco, chewing gum or other unhygienic practices, is not allowed in food handling areas

Hygiene and Communicable Diseases• clothing• hair• personal habits• hand washing• personal effects and

jewelry• illness and disease• injuries• visitors• training

Production employees• Bathe daily• No perfume, aftershave, fragrant creams• No jewellery• No false nails or nail polish• Fingernails should be trimmed short• Use metal detectable bandages covered with gloves• No eating, drinking or chewing gum

Clothing• Everyone must wear pants and covered sleeves.

• Separate shoes (no open toes or high heels) are to be worn in the factory. • Personal belongings and street clothing must be stored in locker rooms.

Illness• Doctor’s certificate on hiring• Inform your supervisor or HR if you are ill with symptoms that could

contaminate ingredients or products• No medication allowed in factory• Ensure that a clean bandage covers any open wounds

Hand washingAll employees must wash their hands thoroughly:• when they enter food handling areas• before starting work• after handling contaminated materials• after breaks• after using toilet facilities

Food Handling PracticesPersonnel• Do not leave gloves, masks, etc. lying around while on break or at

shift end. • Crates, boxes, containers or buckets must not be placed directly on the

floor.• Store brooms and dust pans at stations provided.

Product• Keep hand contact with ingredients to a minimum.• Check ingredients for expiration dates to ensure that fresh ingredients

are used.• Cooling product should always be kept covered.

Equipment, containers and utensils• Ensure that all containers, including those holding rework, are properly

labelled and are kept covered.• Use white or brown containers to store ingredients and rework.• Use gray containers for garbage. Garbage containers must be kept

covered.Cloths Use white cloths to wipe hands regularly and dispose of soiled cloths immediately. No moist cloths are to be left in the production area. Use yellow cloths to clean the floor and objects (e.g. step stools) that come into contact with the floor. Utensils• Scrapers for moulds and tabletops are not to be used on the floor.• Production equipment/utensils must be thoroughly cleaned and sanitized

with alcohol after use.Premises• Keep unscreened doors and windows closed.• Report any pests or evidence of pests such as flies, insects, mice

droppings.Equipment• Return tools and attachments to their proper place after use.

• Check product surfaces before starting equipment. Remove any foreign objects or dirt.

• Replace brushes that lose bristles.Personnel Practices• Do not lean, sit or step on product surfaces.• Do not handle ingredients or products with either cut or infected hands.• Do not engage in horseplay.• Keep hand contact with ingredients and product to a minimum.

Sanitation• Keep contact surfaces clean and free of contamination from tools, cords,

cleaning utensils, machine parts, lubricants and paper.• Clean all spills promptly. • Keep everything off the floor and the area clean and floors swept. • Work areas should be cleaned regularly throughout the shift.• Keep your immediate working area swept or dust mopped. Wipe or mop

up spilled liquids promptly.• Scrape the floor around the work area after completing a job.• Leave your work area clean at the end of your shift.

Receiving and Storage• Ensure that all pallets and materials are kept at least 18” away from the

walls.• Inspect torn bags and boxes and then repair if appropriate.• Brush off bags and boxes before opening them.• Store ingredients and products at the appropriate temperature.• Use ingredients in the proper rotation (oldest stock first)• Handle ingredients or products carefully to avoid spilling• Do not return products or ingredients to the production line after they

have touched the floor or any other surface that is not clean.Maintenance and Repairs• Ensure area is segregated from production by use of tarps.• Do not leave maintenance supplies in the product zone. • Return all tools and attachments to their proper place after use.• Ensure the production area is clear of all tools and hazards before

production startsRetail store• Monitor and maintain proper temperatures• Rotate ingredients using FIFO and check for expired items.• Check best before dates and the quality of the food before using.• Refrigerate cold foods immediately upon receipt.• Sanitize equipment, cutting boards, work surfaces and utensils.• Always wash hands after handling money.

Visitors to Production Areas• Should always be accompanied.• Must be appropriately dressed - hair coverings, booties over street shoes,

gloves, sleeve covers, etc.

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Production and Process validationGMP• The good practices outlined are to be considered general guides and they

may be adapted to meet individual needs.GMPare aimed primarily at diminishing the risks inherent in any pharmaceutical production• Cross –contamination; unexpected contaminants• Mix-ups; confusion (false labels)

Good practices in production• Principle: production operations must follow clearly defined procedures

in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.

Good practices in production:General• All handling of materials and products;

– receipt– cleaning– quarantine– sampling– storage– labelling– dispensing– processing– packaging– distribution

• should be done in accordance with written procedures and recorded.

Good practices in production:General• Any deviation from instructions or procedures should be avoid as far as

possible.– If deviations occur: should be done in accordance with an

approved procedure– approved in writing by a designated person

• Checks on yields and reconciliation of quantities to ensure that there are no discrepancies outside acceptable limits.

• Operation on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix-up or cross-contamination.

• At all time during processing– all materials– bulk containers– major items of equipment– rooms – packaging lines

• being used should be labeled or identified• Access to production premises should be restricted to authorized

personnel.

• Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.

• In-process controls are usually performed within the production area.– The performance should not have any negative effect on the

quality of the product or another product.

Good practices in production: Prevention of cross-contamination during production

When dry materials and products are used in production, special precaution should be taken to prevent the generation and dissemination of dust.– proper air control e.g. supply and extraction of air of suitable

quality

Contamination of a starting material or of a product by another material or product must be avoid.– accidental cross-contamination arises from

uncontrolled release of dust, gases, particles, vapours. sprays or organisms from materials and products in process

residues on equipment intruding insects operators’ clothing, skin, etc.

– most hazardous, highly sensitizing materials living organisms, hormones, cytotoxic substances, and

others Avoided by taking appropriate technical e.g.

– carrying out production in dedicated and self-contained areas– conducting campaign production followed by appropriate cleaning

in accordance with a validated cleaning procedure– providing appropriately designed airlocks, pressure differentials

and air supply and extraction systems minimizing the risk of contamination caused by recirculation or re-entry

of untreated or insufficiently treated air wearing protective clothing using cleaning and decontamination procedures of known effectiveness using a closed system in production testing for residues using cleanliness status labels on equipment Measures to prevent cross-contamination and their effectiveness should

be checked periodically according to SOP Production areas periodic

environmental monitoring

Good practices in production: Processing operations Before any processing operation

work area and equipment • clean and free from any starting materials, products,

product residues, labels or documents not required for the current operation

Any necessary in-process controls and environmental controls should be carried out and recorded

Indicate the failures of equipment or services (e.g. water, gas) to equipment

defective EQ withdrawn after use, production EQ

• cleaned without delay,• stored under clean and dry conditions in separate area

Time limits for storage of EQ after cleaning and before use Containers for filling should be cleaned before filling Any significant deviation from the expected yield

recorded and investigated Checks

pipelines and other pieces of EQ used for transportation of products

Pipe used for conveying distilled or deionized water sanitized and stored according to written procedures (action limits

for microbiological contamination and measures EQ and instruments

serviced and calibrated at prespecified interval records maintained checked daily or prior to use clearly indicated the date of calibration and servicing, recalibration

(label attached to instrument) Repair and maintenance operations

not present any hazard to the quality of the products

GMP for biological products :Production• SOP for manufacturing operations: available, up date• Starting material: source, origin, method of manufacture, QC• Media and culture shall be added to fermenter and other vessels under

carefully controlled conditions, avoid contamination• Media should be sterilized in situ. In line sterilizing filters for routine

addition of gases, media, acids, alkalis, deforming agents, etc. to fermenter should be used where possible.

• Validation of sterilization.• Inactivation process: measures should be taken to avoid risk of cross-

contamination between treated and untreated products.• A wide equipment used for chromatography

• should be dedicated to purification of one product• should be sterilized or sanitized between batches• define the life span of columns and the sterilization method

• In-process controls play a specially important role in ensuring the consistent quality of biological products because certain deficiencies may not be revealed by testing the finished product.• Tests that are crucial for quality control but that cannot be carried

out on the finished product shall be performed at an appropriate stage of production.

• Samples of intermediate and final products shall be retained in sufficient amount and under appropriate storage conditions to allow the repetition or confirmation of a batch control.

• Certain operations require the continuous monitoring of data during a production process e.g.monitoring and recording of physical parameters during fermentation.

Validation: Definition Validation is the documented act of proving that any procedure, process,

equipment, material,activity or system actually leads to the expected result.

Validation studies analytical test equipment facility systems (air, water, steam, process; manufacturing processes,

cleaning, sterilization, sterile filling, lyophilization) Separate validation for lyophilizer/ lyophilization process cleaning of glassware/ cleaning

of facility sterilization process/ sterility test verify the system under test under the extremes expected during the

process to prove that the system remains in control. Critical equipment and processes are routinely revalidated at appropriate

intervals to demonstrate that the process remains in control.

Type of validation Prospective

• pre-planned protocol Concurrent

• base on data collected during actual performance of a process already implemented in a manufacturing facility

• suit manufacturers of long standing, have well-controlled manufacturing process

Retrospective • for production for a long time, but has not been validated

according to a prospective protocol and concurrent validation is not realistic option

• is not generally accepted Laboratory-and pilot-scale validations

• some production processes cannot be carried out in production facility

removal of impurities by individual purification steps in process - not acceptable to bring unacceptable impurities (endotoxin,

unwanted protein, contaminating bacteria and virus) spike into processFacility systems and equipment: Stage of validation

Design qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)

Systems and EQ; PQ=validation

Depending on the function and operation of some EQ

Depending on the function and operation of some EQpH meter, incubator, centrifuge, freezer; IQ,OQ

system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ

EQ: autoclave, oven, lyophilizer, continuous flow centrifuge; IQ, OQ, PQ

Process validation A process is a series of interrelated functions and activities using a variety

of specified actions and EQ which is designed to produce a defined result.

Process validation studies examine a process under normal operating conditions to prove that the

process is in control re-validation

modification to the process problems occur EQ or systems are changed

Process validation To validate the reproducibility and consistency of a process

full defined process is carried out using validated EQ at least 3 times, under established procedure process must successfully and consistently meet all acceptance

criteria at all steps throughout the procedure at least 3 times consecutively

Validated processWorst case: to ensure that process is acceptable in the extreme case

Process validation Example

cleaning sanitization fumigation depyrogenation sterilization sterile filling fermentation bulk production purification inactivation filling, capping, sealing lyophilization

specific process clearly described in Master formula or in SOP all EQ; identity, code number, construction, operation capacity,

actual operating range processing parameter; sufficiently detailed to permit complete

reproducibility (time period, pH, volume, temp.etc.) specification at each step

Very important specifications for a process undergoing validation be pre-

determined all critical processing parameters for which specifications have

been set, there must be equipment to measure all of those parameters during the validation study

Typical content requirements for process validations Cleaning, Fumigation, Sanitization Process

collecting liquid and swab samples for testing of residual product residual protein endotoxin tests microbial tests (bioburden) chemical tests (chlorine and phosphoric acid) residual cleaning agents conductivity tests pH

As relevant to the cleaning processAll analytical tests must be validated before

Typical content requirements for process validations Sterilization

sterilization filtration of solutions microbial challenge

filter integrity tests performance tests

Typical content requirements for process validations Depyrogenation process (dry heat, column chromatography, other)

endotoxin content reduction of 3 logs

Typical content requirements for process validations Sterile filling

test filling process perform filling process with nutrient media run at full scale for at least one fill size worst case; large volume and number of vials filled vials incubated, observed and test for contamination by

validated sterility test must be sterile for 3 consecutive runs media fill performed twice a year size of run must be large enough to detect low levels of

contamination e.g. contamination rate of 1/1000, 3000 units are needed to provide 95% confidence

Mock fermentation full scale fermentation of a representative fermentation process

to validate the parts of process involving connections, sampling, and additions of nutrients etc.

fermentor prepared and operated in simulated process with uninoculated nutrient media

process follow the full fermentation process 3 consecutive runs at each stage

Production processes(fermentation, bulk production, purification, filling, lyophilization)

run according to approved Master formula including all raw material, personnel, equipment, and facility preparations, in-process tests, processing, through to final testing of the batch lot.

all facility systems must be monitored 3 consecutive lots must be produced and all facility, EQ, support

systems, product spec, and process being validated must pass at all steps

Validation: Type of Documentation Validation master plan (VMP) Validation protocol (VP) Validation reports (VR) Standard operating procedures (SOPs)

Master validation plan (MVP) is a document pertaining to the whole facility that describes which EQ,

systems, methods and processes will be validated and when they will be validated.

provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation)

indicate what information is to be contained within each document indicate why and when revalidations will be performed who will decide what validations will be performed order in which each part of the facility is validated

indicate how to deal with any deviations state the time interval permitted between each validation

Validation: VMP Enables overview of entire validation project List items to be validated with planning schedule as its heart like a map

Validation: In summary, VMP should contain at least Validation policy Organizational structure Summary of facilities, systems, equipment, processes to be validated Documentation format for protocols and reports Planning and scheduling Change control Training requirements

Validation: Protocol Objectives of the validation and qualification study Site of the study Responsible personnel Description of the equipment SOPs Standards Criteria for the relevant products and processes

Validation: Report Title objective of the study Refer to the protocol Details of material Equipment Programmes and cycles use Details of procedures and test methods

Validation: changes that require revalidation Software changes; controllers Site changes; operational changes Change of source of material Change in the process Significant equipment changes Production area changes Support system changes

BbbbbbbbGuideline on Submission of Documentation for Prequalification of Multi-source (Generic)Finished Pharmaceutical Products (FPPs)Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis

Section 3. Finished pharmaceutical product(s) [FPP(s)]3.3 Formulation

Composition of all components that are mixtures (e.g., colourants, coatings, capsule shells, imprinting inks) should be given.

Where ranges of batch size are proposed for production –blending of batches or the use of sub-batches– the acceptability should be addressed.

Description of accompanying reconstitution diluent(s), if applicable 3.5 Manufacturing process

A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. Stages of manufacture, at which sampling is carried out for in-process control tests, should be indicated.

A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. For sterile products, details of sterilization processes and/or aseptic procedures used must be described.

Equipment should, at least, be identified by type (e.g., high-speed granulator, fluid bed drier) and working capacity, where relevant.

Steps in the process should have the appropriate process parameters identified, such as time, temperature, or pH.

Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified (e.g., blending

parameters, LOD of the compression blend, tablet hardness, in-process as well as final yields).

In certain cases, environmental conditions (e.g., experimentally documented temperature and relative humidity for granules) should be stated.

A copy of the master formula and a copy of a manufacturing record for a real batch should be provided.

Documented evaluation of at least three (3) production batches (approved batch size) should be submitted to provide assurance that the manufacturing process will reliably meet predetermined specifications.

3.6 Manufacturing Process Controls of Critical Steps and Intermediates Critical Steps: Tests and acceptance criteria should be provided (with

justification, including experimental data) performed at the critical steps of the manufacturing process, to ensure that the process is controlled.

Intermediates: Information on the quality and control of intermediates (e.g., granules blend for compression, tablet cores for film-coating) isolated during the process should be provided.

3.7 Process Validation and Evaluation3.7.1 New (for the generic manufacturer) FPPs

Data should be submitted in the application for prequalification demonstrating the validity (batch-to-batch reproducibility of FPP quality) of the manufacturing process.

Summary of the process validation and/or evaluation studies conducted (e.g., batch numbers, batch sizes, testing parameters, acceptance criteria), or

Summary of the proposed validation protocol for the critical steps or critical assays used in the manufacturing process (e.g., protocol number, parameters, results):

3.7 Process validation report3.7.1 New (for the generic manufacturer) FPPs

Tabulated batch analytical and in-process control data Certificates of analysis Batch production records Unusual findings, modifications or changes found necessary Conclusions

3.7 Process Validation and Evaluation3.7.2 Established (for the generic manufacturer) FPPs

Manufacturing as well as in-process and quality control testing data should be evaluated. All but NLT a total of 10-25 consecutive batches, manufactured over the period of the last 12 months, should be used when reviewing the results, to provide a statistically significant picture. Trend analysis should be presented.

Rejected batches should not be included in the analysis but must be reported together with the reports of failure investigations.

See Notes page 3.8.2 Excipients described in BP, PhInt, PhEur, or USP

All excipients, which are present in the product, should be listed, even those present in small amounts, such as printing inks.

Summary of the in-house specifications of compendial excipients and supplementary tests not included in the monograph(s):

For oils of plant origin (e.g., soy bean oil, peanut oil) demonstrate the absence of aflatoxins or biocides.

List of excipients that are of human or animal origin (including country of origin):

Summary of the information (e.g., sources, specifications, description of the testing performed, viral safety data) regarding adventitious agents for excipients of human or animal origin:

3.8.2 Excipients described in BP, PhInt, PhEur, or USP For excipients obtained from sources that are at risk of transmitting

Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) agents (e.g., ruminant origin), a letter of attestation (with supporting documentation) should be provided confirming that the material is not from a BSE/TSE affected country/area. A copy of the letter may be found in:

Certificate of analysis for one batch of each excipient from the approved supplier should be provided.

3.9.1 Specifications for the FPP Justification of the specifications (e.g., evolution of tests, analytical

procedures, and acceptance criteria, exclusion of certain tests, differences from compendial standard):

Acceptance criteria for degradants in FDC-FPPs should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, then its acceptance limits should be calculated with reference to the worst case (API with the

smallest area under the curve). Alternatively, the content of such impurities could be calculated in relation to their reference standards.

Dissolution testing specifications should include all active components of the finished dosage form and utilize relevant media.

Validation of analytical procedures: State if in accordance with ICH or not, and mention any deviations. (All control methods, regardless of whether they are applicable to control at release or to the shelf life should be discussed here).

Results of not less than three (3) batch analyses (including the date of manufacture, place of manufacture, batch size and use of batch tested) must be presented. The batch analysis must include the results obtained for all specifications at release.

Batch analysis results (n=?); do these confirm consistency and uniformity of the product? Do they indicate that the process is under control?

3.10 Container/closure system(s) and other packaging Description of the container closure systems, including unit count or fill

size, container size or volume: Materials of construction of each primary packaging component: Summary of specifications of each primary and functional secondary (e.g.,

foil pouches) packaging components: Identification of the material generally by infrared absorption

spectrophotometry, with indication of the position of characteristic absorption bands. The infrared spectrum of the reference material should be provided: other methods of identification may be appropriate.

Identification of the main additives in particular those which are likely to migrate into the contents (such as antioxidants, plasticisers, catalysts, initiators, etc.... and, for PVC, phthalates, adipates and organic tin compounds).

Identification of dyes by using chromatographic or any other appropriate method.

3.11 Stability testing The design of the formal stability studies for the finished product should

be based on knowledge of the behavior and properties of the API and the dosage form.

Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy.

It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.

Report and discuss the results of stability testing as described in Annex 2. Organize data for all attributes separately and evaluate each attribute in the report.

Shelf life acceptance criteria should be derived from consideration of all available stability information.

Long-term studies should cover the whole shelf life. When available long-term stability data on primary batches do not cover the proposed shelf-life period granted at the time of approval, a commitment should be made in writing to continue the stability studies post approval. The post-

approval stability protocol should also be provided and should be the same as that for the primary batches, unless otherwise scientifically justified.

Letter of commitmentWe, <name of applicant> undertake to continue long-term stability testing of <name of FPP> (batch numbers …….., ………. and ……………………) according to the stability protocol of primary batches, for a period of time sufficient to cover the whole pre-qualified shelf life (NLT 24 months ending ………………….) and to report any out-of-specification results immediately to WHO.

3.11.3 Selection of Batches At the time of submission data from stability studies should be provided

for batches of the same formulation and dosage form in the container closure system proposed for marketing.

Stability data on three primary batches are to be provided. One of the three batches should be of production scale, the remaining two batches at least pilot scale. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached.

3.12 Container labeling 3.12.1 Outer packaging or, where there is no outer packaging, on the

immediate packaging. Typical deficiencies: List of excipients known to be a safety concern for some patients –

e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine– are not indicated.

Storage instructions do not reflect stability conditions. 3.12.2 Blisters and strips

3.13 Product information for health professionals 3.14 Patient information and package inserts

Summary of Product Characteristics (SmPC) is frequently not approved by the national DRA. (Particular problem with artemisinin-derivative FPPs.)

The structure of SmPC does not follow that recommended by WHO. Pharmaceutical data are not counter-checked against the quality part of

the submission. Typical deficiencies include: Number(s) in the national register of FPPs. Date of first marketing authorisation/renewal of the authorisation.

Points to be communicated to the applicant A. General remark, if applicableB. Observations, informationC. Overall conclusion Reviewer’s conclusion, based on the review of the data on quality.D. Post-approval commitmentsThe reviewer lists the outstanding commitments, which the applicant had undertaken in writing before the FPP was listed on the prequalification list.Recommendations for inspectionThe reviewer list quality issues identified during the dossier assessment that require verification during a product-specific inspection.

Change control Guidance on variations to a prequalified dossier. Conditions and requirements for 40 minor changes are detailed. Typical

examples: Change of API manufacturer Change of manufacturing site Change of batch size

Guideline on stability testing for applications for variations to a prequalified FPP (draft).

Current regulatory developments Pharmaceutical manufacturing operations are inefficient and costly. Low efficiency is predominantly due to "self-imposed" constraints in the

system (e.g., static manufacturing processes, focus on testing as opposed to quality by design).

ICH guidance Q9 (draft) describes the level of risk-mitigation achieved through quality by design and process understanding.

Manufacturing processes of innovator and generic manufacturers are fundamentally the same.

Efforts are primarily directed towards reducing variability in process and product quality characteristics and are not for changing the fundamental design of a manufacturing process.

Empirical methods are probably approaching their theoretical maximum effectiveness. New scientific understanding and new technologies can provide science- and engineering-based approaches.

Current regulatory developments A process is well understood when:

all critical sources of variability are identified and explained variability is managed by the process product quality attributes can be accurately and reliably predicted

Process understanding inversely proportional to product quality risk. Real time product release is on the regulatory horizon. Main points again The manufacturing process should be clearly defined

(site, composition, batch size, equipment, flow diagram, narrative) and well documented.

APIs, excipients and primary packing materials should be bought only from approved suppliers.

Batch-to-batch consistency of FPP quality should be achieved through validation and annual evaluation of product and process control results.

Main points again The manufacturing process should be clearly defined (site, composition,

batch size, equipment, flow diagram, narrative) and well documented. APIs, excipients and primary packing materials should be bought only

from approved suppliers. Batch-to-batch consistency of FPP quality should be achieved through

validation and annual evaluation of product and process control results. Release specifications have to be reviewed at the end of stability studies

to establish if change of acceptance criteria is justified.

The SmPC and Patients’ leaflet should reflect the design, development and manufacturing information of the submission.

Attributes of prequalified FPPs should only be changed after approval of variation by WHO.