GOOD MANUFACTURING PRACTICES

(SubPart – E & F)

By

Mr. Hardik K. Patel

Lecturer (M.Pharm, MBA)

A. R. College of Pharmacy &

G. H. Patel Institute of Pharmacy,

Vallabh Vidyanagar - 388120

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Sub Part – E:

Control of Components and Drug Product Containers and

Closures

Sub Part – F:

Production and Process Controls

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Sub Part – E :

Control of Components and Drug Product

Containers and Closures

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There shall be written procedures describing in sufficientdetail the receipt, identification, storage, handling, sampling,testing and approval or rejection of components and drugproduct containers and closures; such written procedures shallbe followed.

Components and drug product containers and closures shall atall times be handled and stored in a manner to preventcontamination.

Bagged or boxed components of drug product containers orclosures shall be stored off the floor and suitably spaced topermit cleaning and inspection.

Each container or grouping of containers for components ordrug product containers, or closures shall be identified with adistinctive code for each lot in each shipment received. Thiscode shall be used in recording the disposition of each lot. Eachlot shall be appropriately identified as to its status (i.e.,quarantined, approved or rejected).

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RECEIPT AND STORAGE OF UNTESTED COMPONENTS,

DRUG PRODUCT CONTAINERS AND CLOSURES

o Upon receipt and before acceptance, each container or grouping of

containers of components, drug product containers and closures shall be

examined visually for appropriate labeling as to contents, container

damage or broken seals and contamination.

o Components, drug product containers and closures shall be stored under

quarantine until they have been tested or examined, as appropriate, and

released. Storage within the area shall conform to the general

requirements.

o Visual examination of materials on receipt is an important quality step.

This should confirm that the correct material has been delivered, and if

any physical damage has occurred its potential impact on quality needs

to be considered.

o Broken seals on containers may indicate that the container has been

opened somewhere during transit, and the material may have been

exposed to unacceptable environmental conditions. 5

TESTING AND APPROVAL OR REJECTION OFCOMPONENTS, DRUG PRODUCT CONTAINERS ANDCLOSURES

a) Each lot of components, drug product containers andclosures shall be withheld from use until the lot hasbeen sampled, tested, or examined, as appropriateand released for use by the quality control unit.

b) Representative samples of each shipment of each lotshall be collected for testing or examination. Thenumber of containers to be sampled and the amountof material to be taken from each container shall bebased upon appropriate criteria such as statisticalcriteria for component variability, confidence levelsand degree of precision desired, the past qualityhistory of the supplier, and the quantity needed foranalysis. 6

c) Samples shall be collected in accordance with the followingprocedures:o The containers of components selected shall be cleaned where

necessary, by appropriate means.

o The containers shall be opened, sampled and resealed in a mannerdesigned to prevent contamination of their contents and contaminationof other components, drug product containers, or closures.

o Sterile equipment and aseptic sampling techniques shall be usedwhen necessary.

o If it is necessary to sample a component from the top, middle andbottom of its container, such sample subdivisions shall not becomposited for testing.

o Sample containers shall be identified so that the following informationcan be determined: name of the material sampled, the lot number, thecontainer from which the sample was taken, the date on which thesample was taken and the name of the person who collected thesample.

o Containers from which samples have been taken shall be marked toshow that samples have been removed from them.

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d) Samples shall be examined and tested as follows:

1)At least one test shall be conducted to verify the identity of each component of

a drug product. Specific identity tests, if they exist, shall be used.

2)Each component shall be tested for conformity with all appropriate written

specifications for purity, strength, and quality. In lieu of such testing by the

manufacturer, a report of analysis may be accepted from the supplier of a

component, provided that at least one specific identity test is conducted on

such component by the manufacturer, and provided that the manufacturer

establishes the reliability of the supplier’s analyses through appropriate

validation of the supplier’s test results at appropriate intervals.

3)Containers and closures shall be tested for conformance with all appropriate

written procedures. In lieu of such testing by the manufacturer, a certificate of

testing may be accepted from the supplier, provided that at least a visual

identification is conducted on such containers/closures by the manufacturer

and provided that the manufacturer establishes the reliability of the supplier’s

test results through appropriate validation of the supplier’s test results at

appropriate intervals.8

4) When appropriate, components shall be microscopically

examined.

5) Each lot of a component, drug product container, or

closure that is liable to contamination with filth, insect

infestation, or other extraneous adulterant shall be

examined against established specifications for such

contamination.

6) Each lot of a component, drug product container, or

closure that is liable to microbiological contamination

that is objectionable in view of its intended use shall be

subjected to microbiological tests before use.

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Vendor certification is a system that assures that a supplier’sproduct is produced under controlled conditions, resulting inconsistent quality conformance. Being based on the principle ofdefect prevention, rather than defect detection and inspection, itsignificantly reduces the need for customer inspection.

Vendor certification is a supplier–customer partnership and canonly be successful with the full involvement and agreement ofboth partners. Several key steps are involved in the certificationprocess.

Customer Teamso Several functions need to be involved in establishing a vendor

certification process. Typically the team will include representatives frommanufacturing, package engineering, purchasing and quality assurancewith support, as appropriate, from other disciplines such as finance,research and development. The initial task of the team will be to definethe objectives and potential benefits and to write a process that can beused as a basis for discussion with suppliers.

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Supplier Selections

The initial selection of potential partners should take intoaccount the supplier’s history in terms of quality, delivery andsupport service as well as the importance of the specificmaterial to the business. Vendor certification has a higherchance of success with a supplier who already has a highcommitment to quality and customer service. Also, when onesuccessful certification has been implemented and benefitscan be perceived, the program will gain added emphasis.

Initial Supplier Contacts

The proposed process will be discussed with the supplier.After agreement on the concept, which must include seniormanagement, the individual components of the process canbe reviewed and adapted for mutual satisfaction.

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Process Elements

Supplier process:- Some or all of the customer vendor certification team should visit

the supplier’s plant to gain an understanding of the productionprocess and the key elements which impact on the achievement ofquality standards.

Specifications:- A detailed review should be made of product specifications with

particular reference to legal requirements (compendia, FDA, etc.)and fitness for use. This latter point is likely to require a supplierunderstanding of the customer’s process; in this way it may bepossible to relax certain less critical specification parameters whiletightening or increasing the level of assurance on more criticalparameters.

Process evaluation:- The supplier must have suitable equipment to monitor process.

This equipment must be routinely calibrated and test methodsvalidated. Statistical process control techniques will usually beapplied to demonstrate that the process remained under control,within acceptable operating ranges.

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Process and Specification Changes

Another important element in the vendor certification processis the procedure for handling any changes to the processor the specification. Any proposed changes must be clearlydocumented, with reasons and supporting data, and bereviewed and accepted by the customer prior to introduction.Some changes may require customer evaluation and evenFDA approval before acceptance.

Customer Inspection

After it has been confirmed that a supplier has a controlledprocess, there usually will be a period when both partiesevaluate material quality and compare data.

This provides the needed assurance that supplier andcustomers have comparable evaluation ability and minimizesfuture potential for disagreements that are due to test resultsrather than atypical product.

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Supplier Reporting

Since vendor certification is a partnership, it is important thatboth supplier and customer are kept informed of each other’sdifficulties. The supplier must notify the customer of any atypicalsituations or process deviations prior to shipping material sothat any additional testing or evaluations may be performed.

Decertification

Certification results in a high level of reliance on the supplier:reduced incoming inspection, reduced inventories, higheroutput.

Any failure by the supplier can therefore have seriousconsequences and may require decertification of that supplierfor that material.

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The main result of vendor certification is an assured

reduction in quality variability which provides several

benefits.

The tighter specification ranges usually result inhigher yields and reduced equipment downtimes forthe supplier, thereby providing an opportunity toreduce prices or minimize price increases.

More consistently compliant batches can result inlower inventories for both supplier and customer. Thisreduces the cost of carrying inventory.

Reduced testing by the customer eliminates sometesting costs but more importantly can makematerials available to production more quickly.

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Components, drug product containers, and closures

approved for use shall be rotated so that the oldest

approved stock is used first. Deviation from this

requirement is permitted if such deviation is temporary

and appropriate.

Using oldest stock first helps to reduce the possibility of

contamination.

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Components, drug product containers and closures shall beretested or reexamined, as appropriate, for identity, strength,quality and purity and approved or rejected by the qualitycontrol unit in accordance with necessary, e.g., after storagefor long periods or after exposure to air, heat or otherconditions that might adversely affect the component, drugproduct container or closure.

This reevaluation will not usually require full testing but onlyexamination of those parameters known to be subject tochange.

Under normal circumstances materials will be used beforethey become eligible for reevaluation. Consequently, whenreevaluation is necessary the reason for the material still beingaround should be investigated. The usual reasons includeminimum purchase quantities and changes in forecast, butoccasionally this can identify a flaw in the purchasing orplanning processes. 17

Rejected components, drug product containers, and closures

shall be identified and controlled under a quarantine system

designed to prevent their use in manufacturing or processing

operations for which they are unsuitable.

FDA investigators frequently use a visit to the reject area as a

potential source of deficiencies. If rejections occur it is possible

to assume that the vendor process is not adequately under

control, and an evaluation of the cause should have been

performed and documented.

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o Drug product containers and closures shall not be reactive,additive, or absorptive so as to alter the safety, identity,strength, quality, or purity of the drug beyond the official orestablished requirements.

o Container closure systems shall provide adequateprotection against foreseeable external factors in storageand use that can cause deterioration or contamination of thedrug product.

o Drug product containers and closures shall be clean andwhere indicated by the nature of the drug, sterilized andprocessed to remove pyrogenic properties to assure thatthey are suitable for their intended use.

o Standards or specifications, methods of testing and whereindicated, methods of cleaning, sterilizing and processing toremove pyrogenic properties shall be written and followed fordrug product containers and closures.

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The United States Pharmacopeia's, provides information onspecifications and test methodology for a range of containermaterials. These include:

Light transmission for glass and plastics

Chemical resistance for glass

Arsenic extraction from Type 1 glass

Biological tests on plastics used for parenterals

Physicochemical tests on plastics used for parenterals

Biological tests on plastics used for ophthalmic products

Chemical tests on polyethylene containers for dry oraldosage forms.

These tests may also be modified to apply to the use of plasticsother than polyethylene and the use of plastics with liquiddosage forms. The USP is currently drafting a monograph onpolyethylene terephthalate (PET). Where other plastics areinvolved, any specific signal compounds may need evaluation,e.g., vinyl chloride monomer levels from polyvinylchloride (PVC)containers. 20

1) Vendor audit reports listed significant observations. There

were no vendor responses.

2) Sampling of containers/closures is not based on appropriate

statistical criteria.

3) The firm has not included a pyrogen and/or bacterial

endotoxin specification for active drug substance raw

material.

4) Several batches of tablets were rejected because the active

raw material did not meet the firm’s established bulk density

specifications. No explanation was given in the process

validation report as to how bulk density affects the finished

product.

5) The firm is aware that . . . has shown marked degradation

over time but no testing was performed on current lots in

order to justify the one year material storage time limitation.

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1) There shall be written procedures for production and process

control designed to assure that the drug products have the

identity, strength, quality and purity they purport or are

represented to possess. Such procedures shall include all

requirements in this subpart. These written procedures,

including any changes, shall be drafted, reviewed and

approved by the appropriate organizational units and

reviewed and approved by the quality control unit.

2) Written production and process control procedures shall be

followed in the execution of the various production and

process control functions and shall be documented at the

time of performance. Any deviation from the written

procedures shall be recorded and justified. 23

There shall be adequate written procedures that have beenapproved by responsible persons and for which there isdocumentation that the procedures have been followed.

Written standard operating procedures (SOPs) define howthings are to be done and provide a basis for the training of newor relocated personnel.

SOPs are a fundamental extension of the cGMPs—the latterideally should define what is to be achieved, while the SOPsprovide company specific approaches on how to meet theserequirements.

There should be a master SOP, which describes the overallprocedure—how to initiate/revise an SOP, format, who shouldreview and approve (with defined areas of responsibility),frequency of routine review (often every two years), mechanismof issue and replacement of outdated versions, training.

The master batch record, which provides full details of how aproduct is to be manufactured. 24

The procedures for production and process control are to bereviewed and approved by quality control. This does not meanthat QC are to be considered expert in each area of theoperation. For example, the production document wouldnormally be reviewed initially by production and/or technicalservices; the role of QC would be to confirm this review by aresponsible person and to further review the document forpossible adverse impacts on quality and safety.

When reviewing the production and process controldocumentation it will be essential to check that:

a) The various requirements referenced in the cGMPregulations (especially the other subsections of Subpart F)have been adequately addressed.

b) The documents are in compliance with the relevantsections of any NDA and ANDA.

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The FDA is currently reevaluating approval requirements withrespect to production changes. The objectives are to reduce thework load at the FDA, harmonize via ICH and allow quickerimplementation of changes.

The FDA approach in this area of change tends to illustrate theFDA suspicion of industry that if not tightly controlled it willbehave unprofessionally.

Unfortunately, there have been a few examples to support thisattitude. With respect to a bulk drug, prior FDA approval isrequired for a change in solvent or route of synthesis, for adifferent production facility if it involves changes in equipmenttypes or the facility has not been inspected by the FDA in theprevious 2 years, relaxation of limits and deletion ofspecification or new analytical methods.

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c) There are appropriate supporting data such as process

validation, analytical method validation and product stability.

d) The document does not affect the ‘‘grandfather’’ status of old

drugs.

e) The reasons for any proposed changes from previous

procedures are clearly defined and supported.

f) The appropriate functions, such as production and technical

services have been reviewed and signed off.

g) The procedures are compatible with any compendial

requirements (such as USP). Part 314 does allow for

compliance with compendial changes to be included in the

annual report.27

Next comes the verification step. A combination of some, or

preferably all, of the following approaches provides data on

compliance.

1. Regular monitoring of compliance by supervisors and

managers as they do their daily work. This can be informal

but it allows immediate identification and correction of

potential compliance problems.

2. A more systematic review of compliance can also be

performed by supervisors and managers on a less frequent

basis—perhaps monthly. This again would be done by

comparing actual activities with written procedures.

3. Quality assurance along with departmental management,

perform an audit of each function. Alternatively a numerical

weighting system can be used. Management would be

expected to evaluate the audit report, identify the root

causes of any noted deficiencies and to specify appropriate

corrective action. 28

4. Independent audit from outside of the plant adds another level of review.This is similar to 3 above but may involve personnel from another facilityor corporate staff. Also included in this category are regulatory auditssuch as those by the FDA. One effective approach to independent auditis to adopt the process approach as used by the Malcolm BaldrigeNational Quality Award.

5. The routine quality assurance check of batch records also provides basicinformation on compliance. This should also be used to review deviationfrequency, evaluation and corrective action and to confirm compliancewith FDA registration data.

• It should be emphasized that if the data generated in 1, 2, and 5 above areused to identify and correct basic problems, then the audits described in 3and 4 should simply provide confirmation of compliance.

• Traditionally, independent audits (4 above) were used to identify areas ofnoncompliance.

• The emphasis should be on self-evaluation (1 and 2), which is more likelyto be successful than the utilization of a police-type activity.

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Change control should include changes to raw materials,packaging components, labeling, expiration dating,formulation, production process, production equipment(including major maintenance), critical plant systems, facilities,computerized systems, specifications, and test methods.

The evaluation of the change, which must be documented, willinclude:1. Identification of potential impact and the evaluations to be performed,

such as accelerated stability, revalidation, retraining.

2. Regulatory impact (all countries involved) and approvals required.

3. Schedule for implementation.

4. Clear definition of the proposed change with the reason for the change.

5. Definition of who needs to approve the change and a record of theirconcurrence.

6. Post-introduction review to confirm that the change did not have anyadverse impact.

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Written production and control procedures shall include thefollowing, which are designed to assure that the drug productsproduced have the identity, strength, quality, and purity theypurport or are represented to possess:

The batch shall be formulated with the intent to provide not lessthan 100 percent of the labeled or established amount of activeingredient.

Components for drug product manufacturing shall be weighed,measured, or subdivided as appropriate. If a component isremoved from the original container to another, the newcontainer shall be identified with the following information:o Component name or item code

o Receiving or control number

o Weight or measure in new container.

o Batch for which component was dispensed, including its product name,strength, and lot number 31

Actual yields and percentages of theoretical yield shall be

determined at the conclusion of each appropriate phase of

manufacturing, processing, packaging or holding of the

drug product. Such calculations shall be performed by one

person and independently verified by a second person.

Theoretical yield is defined as the maximum quantity that

could be produced, based on the quantities of components

used, in the absence of any loss or error in production.

Theoretical yield consists of the summation of the weights

of all raw materials entering the production cycle.

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All compounding and storage containers, processing linesand major equipment used during the production of abatch of a drug product shall be properly identified at alltimes to indicate their contents and when necessary, thephase of processing of the batch.

Major equipment shall be identified by a distinctiveidentification number or code that shall be recorded in thebatch production record to show the specific equipmentused in the manufacture of each batch of a drug product.

In cases where only one of a particular type of equipmentexists in a manufacturing facility, the name of theequipment may be used in lieu of a distinctive identificationnumber or code.

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To assure batch uniformity and integrity of drug products,written procedures shall be established and followed thatdescribe the in-process controls and tests, or examinations tobe conducted on appropriate samples of in process materialsof each batch. Such control procedures shall include, but arenot limited to, the following, where appropriate:

1) Tablet or capsule weight variation

2) Disintegration time

3) Adequacy of mixing to assure uniformity and homogeneity

4) Dissolution time and rate

5) Clarity, completeness, or pH of solutions

Valid in-process specifications for such characteristics shall beconsistent with drug product final specifications and shall bederived from previous acceptable process average. 34

The FDA in ‘‘Guidelines on General Principles of ProcessValidation’’ defines process validation as ‘‘establishingdocumented evidence which provides a high degree ofassurance that a specific process will consistently produce aproduct meeting its predetermined specifications and qualitycharacteristics.’’

The designing of quality into a product and its productionprocesses, coupled with supporting validation data, increasesthe potential for consistently achieving quality standards andreduces dependence on both in-process and end-producttesting.

When the concept of validation was introduced the FDArecognized two approaches: retrospective and prospective.Retrospective validation involved an in-depth evaluation of alarge number of consecutive batches of product to correlateprocessing conditions and analytical results.

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Prospective validation involves several stages: product and

process design; equipment installation and operational

qualification (IQ and OQ); services qualification; process

performance; performance evaluation.

Figure 1 Validation stages.

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For each phase of validation, protocols should be compiled andapproved by the relevant functions. These protocols shouldclearly define the work to be performed and the acceptancecriteria. On completion the data should be evaluated againstthe acceptance criteria and where acceptable the validationapproved.

During the product development phase there should beinteractive involvement of all appropriate technical functions,usually R & D, engineering, manufacturing, technical services,and quality control.

This should ensure that the product as designed by R & D hasa high probability of manufacturing success/consistency whentransferred into the production operation.

When the facilities, the supporting systems, and the equipmentare qualified, it is time to qualify (validate) the specificproduction processes. 37

The process validation protocol should include:

a) The facilities, services, and equipment to be used.

b) The key variables likely to impact on quality. These areusually identified during the product development processor from experience with similar products.

c) The range of conditions to be evaluated for each variable.The range of conditions to be evaluated should extendbeyond the anticipated operational ranges of the process. Ithas been suggested that the validation ranges shouldextend to the point where the process fails—‘‘worst case.’’

All test equipment, gauges and recorders used in thevalidation process should be calibrated immediately prior toand after each validation experiment.

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d) The samples to be taken; location, size, number andfrequency.

e) The tests to be performed and the methodology to beused. Analytical methods must be validated otherwiseany data generated will be of doubtful value.

f) The number of replicate process runs to be performed.

g) The acceptance criteria.

h) Details of who must review the data and where it is tobe retained for permanent reference.

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Revalidation:- A system must be established which initiates a

review of the need for revalidation whenever there is a change

in the equipment, facilities, process, services, formulation, or

source of components.

o Additionally because some changes may be made without notification it

may be advisable to consider revalidation either at predetermined

frequencies or if some atypical product behavior is noted—this could be

according to a reduced level protocol.

o On completion of process validation it is then possible to define the

operational parameters for the process which if followed should assure

compliant product.

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When appropriate, time limits for the completion of each phaseof production shall be established to assure the quality of thedrug product.

The main purpose of this regulation is to indicate that certainprocesses are sufficiently sensitive that time limits need to beestablished for their completion.

This could be especially important for:a) Material vulnerable to microbial attack. Bulk injections are

usually required to be filled into the final container within 48hours; otherwise any microbial contamination could result in highlevels of pyrogenic material.

b) Materials subject to oxidation may be protected with nitrogen.Effective nitrogen protection may be difficult at the bulk stage;also, failure of the nitrogen system could result in batch rejection.

c) Tablet granulations or other bulk solids may absorb or releasemoisture on storage, making them more difficult to process oreven accelerating decomposition. Batch records should clearlyindicate any time-scale restriction and dates and times should berecorded.

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Appropriate written procedures, designed to prevent

objectionable microorganisms in drug products not required to

be sterile, shall be established and followed.

o Every day the human body is invaded by countless numbers

of microorganisms, which are found in the food we eat, the

air we breathe, and the water we drink. Consequently, for

most products other than injections, there is no need for

sterility.

o For products that are not required to be sterile, the presence

of microorganisms could still constitute a problem. Certain

microorganisms are associated with human illness and

should be absent.

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The procedures and conditions required to assure

adequate microbial quality will vary according to the

specific products but are likely to include some or all, of

the following:

o Microbial monitoring of potentially susceptible raw

materials. This may require special negotiation with the

supplier if a microbiological specification is not a normal

requirement for his other customers.

o Equipment sanitation procedures that have been

proven effective especially for any specific known

deleterious or objectionable microorganisms.

o Processing conditions that minimize the potential for

microbial growth.

Formulations to include preservatives.

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Appropriate written procedures, designed to preventmicrobiological contamination of drug products purporting to besterile, shall be established and followed. Such proceduresshall include validation of any sterilization process.

Validation of heat sterilization (dry heat or autoclave) includes:o Heat distribution within the empty sterilization chamber.

o Heat penetration within the units of product for the various loading cyclesto be used.

o Lethality calculations based on kill of known numbers of resistantbacteria or spores, usually Bacillus stearothermophilus spores placed inunits that receive the least heat treatment.

o Bioburden data showing the numbers and types of organisms, withparticular reference to resistivity, likely to result from the components andthe process prior to sterilization.

o Perform studies outside the ranges of conditions that will routinely beused for sterilization cycles.

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Treatments of product components and processing equipmentto remove particulate matter, sterilize and depyrogenize arecritical to effective aseptic processing. This will includeampoules, vials, stoppers, filters, intermediate storagevessels, tubing, filling equipment, gowns, masks and gloves.The processes for each of these must be validated.

Environmental qualifications must include:o Air quality: At point of use (e.g., filling) air should be supplied by HEPA-

filtered laminar flow air at about 90 feet per minute and with a pressuredifferential to adjacent areas of 0.05 inches of water. Nonviable particlecounts should be less than 100 per cubic foot equal to or larger than 0.5micron.

o People: The presence of people in an area or room will impact on airquality. The validation study should include the maximum number ofpeople expected to be present at any time during the process.

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Time limitations: Liquid preparations and wet components areprone to microbial multiplication, including the possibility ofmicroorganisms passing through filters. Maximum time framesfor key steps need to be confirmed.

Product filtration: The filtration system used to ‘‘sterilize’’ thedrug product, usually 0.22 micron, should be challenged usinga suitable small organism, usually Pseudomonas diminutia. Thenumber of organisms used in the challenge will be in excess ofthe maximum bioburden levels measured in unfiltered solutions.

Media fills: The overall effectiveness of the aseptic process isthen validated using liquid media fills.o Initially three media fills are considered desirable.

o A minimum of 3000 units should be filled to provide a 95% probability ofdetecting contamination at a level of one in one thousand.

o Each shift and each employee used for aseptic processing should beincluded in the validation runs.

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Revalidation- As with any process, revalidation should be

considered whenever there is a change in the product,

components, process, facility, equipment or people.

Additionally, since the aseptic process is so people dependent,

regular revalidation is essential.

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Written procedures shall be established and followedprescribing a system for reprocessing batches that do notconform to standards or specifications and the steps to betaken to insure that the reprocessed batches will conform withall established standards, specifications and characteristics.

Reprocessing shall not be performed without the review andapproval of the quality control unit.

The failure of a batch of product to meet the quality standardsmust be viewed as a failure of the quality control process. Themain causes of failure include:1) Malfunction of equipment or services.

2) Noncompliance with defined procedures by operating personnel.

3) Atypical behavior of materials that comply with their specification.

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It is essential that the evaluation of reprocessed

batches is approved by quality management.

Factors to be considered would include:a) Whether any specification tests are not performed routinely, reliance

being placed on validation data. Examples of this could include

dissolution performed only at the uncoated stage of a film coated

tablet— recoating may affect this—or content uniformity.

b) Whether the reprocessing might have affected product stability and

its shelf life. This could happen for a liquid product requiring a reheat

stage to fully dissolve some raw materials.

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1) Annual revalidation of the sterility test room was not

performed as required by the firm’s procedures.

2) The master formula does not state a time limit for holding

filtered bulk drug compound prior to filling and terminal

sterilization.

3) Lack of validation of the manufacturing of the various

coating solutions such as gelatin solution, sub coating

powder, and syrup solution.

4) Batch manufacturing instructions do not provide sufficient

written detail to ensure the uniformity of the production

process from batch to batch.

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5) There is no final summary by management to verify that the validation data

has been reviewed, that all requirements of the protocols have been met,

and that the systems are considered validated.

6) The validation program for drug products is incomplete and fails to provide

for physical specifications for drug substance, sampling approximately the

equivalent weight of a dosage unit to demonstrate blend uniformity, in-

process individual weight variation, comparison of dissolution and

granulation studies between bio-batches and production batches.

7) The SOP for validation or revalidation does not require that specifications

and acceptance criteria be determined prior to validation.

8) There were no SOPs for the QA investigations of product failures,

laboratory failure investigations, and stability investigations.

9) Validation is inadequate in that it does not include tablet thickness,

hardness, weight, or dimensions.

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