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Joint PDA / PhFUWA Task Force on Sterile Bulk Pharmaceutical Chemicals

Co-Chairmen

James P. Agalloco, Agalloco & Associates, Inc.

Max S. Lazar, Hoffmann-La Roche, Inc.

Members

James E. Akers, Ph.D., Akers Kennedy & Associates, Inc.

Barbara J. Bassler, Ph.D., Hoechst Marion Roussel GmbH

Edgard Craenhals, Ph.D., Interchem Corp.

Samir Hanna, Ph.D., Bristol-Myers Squibb Co.

Karl L. Hofmann, Bristol-Myers Squibb Co.

Russell E. Madsen, PDA

Timothy R. Marten, Ph. D., Zeneca Pharmaceuticals

Leonard Mestrandrea, Ph.D., Schering-Plough

David A. Moyer, Phoenix Regulatory Associates, Ltd.Gordon Munro, Ph.D., Medicines Control Agency

Terry E. Munson, ParexeUKemper-Masterson, Inc.

Barry A. Perlmutter, Process Efficiency Products

Jeffrey Probasco, SmithKline Beecham

Robert S. Pullen, Pfizer, Inc.

Max Sokol, Schering-Plough Research Institute

Gary E. Strayer, Merck & Company, Inc.

Constance C. Taylor, Merck & Company, Inc.

John Teward, Ph.D., Glaxo Wellcome Inc.

Timothy L. Tuley, Eli Lilly & CompanyStelios C. Tsinontides, Ph.D., Merck & Company, Inc.

Colin Walters, Schering-Plough Research Institute

Thomas X. White, PhRMA

Alpaslan Yaman, Ph.D., Novartis Pharmaceuticals Corp.

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Note: Sidney Priesmeyer, FDA, St. Louis Branch, served as non-voting liaison for this project;

he was not a member of the committee itself.

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Process Simulation Testing

for Sterile Bulk Pharmaceutical Chemicals

Technical Report No. 28

PDAlPhRMA

August 1998

Vol. 52, No. 5 / September-October 1998, Supplement



PREFACE

This document provides guidance relative to the validation of aseptic processing activities associated

with the production of sterile bulk pharmaceutical chemicals. It draws upon the concepts and

principles developed in PDA’s and PhFU4A’s prior publications on aseptic processing technology

(1, 2, 3). Our goal in this effort is to expand upon these documents to provide assistance for

individuals and firms producing sterile bulk pharmaceutical chemicals. The preparation of sterilematerials in the quantity and scale used in the manufacture of bulk pharmaceutical chemicals

generally requires equipment and procedures quite different from those used in the manufacture of

finished pharmaceuticals. The uniqueness of the production methods for sterile bulks precludes the

direct extrapolation of the process simulation approaches employed for aseptically produced sterile

formulations.

This technical report was disseminated in draft for public review and comment prior to publication.

Many of the submitted comments have been included in the final document. We believe this

approach accomplished the widest possible review of the document and ensures its suitability as a

valuable guide to industry in the area of process simulation testing for sterile bulk pharmaceuticalchemicals.

This document should be considered as a guide; it is not intended to establish any mandatory or

implied standard.

James P. Agalloco - PDA

Max S. Lazar - PhRMA

(Co-Chairmen, Joint PDA/PhRMA Task Force on Sterile Bulk Pharmaceutical Chemicals)

ii PDA Journal of Pharmaceutical Science &Technology



Table of Contents

1 INTRODUCTION ..................... 11.1 Purpose .......................... 11.2 Sterile Bulk Pharmaceutical hemicals . 11.3 Scope ............................ 1

1.4 Sterile BPC ProductionTechnology .... 11.4.1 ClosedSystems ............. I1.4.2 OpenSystems .............. 2

1.5 Considerations .................... 2

2 PROCESS SIMULATION CONCEPTSANDPRINCIPLES ......................... 22.1 Number and Frequency f Tests ....... 22.2 Worst Case ....................... 2

3 PROCESSSIMULATION TEST METHODS 33.1 Total ProcessSimulat ion . . . . . . . . . . . . . 33.2 Unit Operation(s)Simulations . . . . . . . . . 3

9 INTERPRETATION OF RESULTS ANDACCEPTANCE CRITERIA . . . . . . . . . . . . . . 89.1 Background . . . . . . . . . . . . . . . . . . . . . . . 89.2 Approachesor AcceptanceCriteria . . . . 8

9.2.1 Quantita tive . . . . . . . . . . . . . . . . 89.2.2 Quali tative . . . . . . . . . . . . . . . . 10

10 FAILURE INVESTIGATION ANDCORRECTIVE ACTION . . . . . . : . . . . . . . . 10

11 PERIODIC’REASSESSMENT . . . . . . . . . . 10

APPENDIX 1, SELECTION AND STERILIZATIONOF TEST MATERIALS . . . . . . . . . . . . . . . . 11

APPENDIX 2, DEFINITIONS . . . . . . . . . . . . . . 13

APPENDIX 3, REFERENCES . . . . . . . . . . . . . . 15

4 TEST MATERIALS USED IN PROCESSSIMULATION ........................ 44.1 Growth Medium Simulations ......... 44.2 PlaceboMateria l Simulation .......... 44.3 Simulation Without Material .......... 54.4 ProductionMaterial Simulati on ........ 5

5 EVALUATION OF SIMULATION TESTMATERIALS . . . . . . . . . . . . . . . . . . . . . . . . . 55.1 Evaluationof Enti re Test Materia l . . . . . . 55.2 Evaluation of Test Material Samples . . . 6

6 DOCUMENTATION . . . . . . . . . . . . . . . . . . . 6

7 ENVIRONMENTAL MONITORING . . . . . . 7

8 ELEMENTS OF PROCESS SIMULATIONTESTS.. ............................. 78.1 Interventions ...................... 78.2 Duration of Simulation .............. 78.3 Production Batch Size/ProcessSimulation

Test Size .......................... 78.4 IncubationConditions ............... 78.5 Manual Procedures ................. 88.6 Stafftng Considerations ............. 88.7 Campaigns ....................... 8

Vol. 52, No. 5 / September-October 1998, Supplement iii



1 INTRODUCTION might contribute o the microbiologicalcontaminationof the product.

1.1 Purpose

1.2 Sterile Bulk Pharmaceutical Chemicals

The preparation of sterile bulk pharmaceuticalchemicals requires the combination of classicalchemical / biological production methods with the

well-defined concepts or the preparationof sterilematerials. The integration of these fields entailsprocess quipment ndoperating rocedures hich areoften substantiallydifferent from ordinary practice neither discipline. This document outlines processsimulation practices for sterile bulk pharmaceuticalchemicals (sterile BPCs), utilizing concepts drawnfrom bothbulk pharmaceuticalhemicaloperationsnd

sterile product manufacturi ngand adapted o fit theuniquenatureof thesematerials. t presents ptions ordetermining the adequacy of aseptic operationsperformed during large scale manufacturingwhile

allowing for realistic acceptance riteria for suchoperations.

The aseptic procedures tilized in the production ofsterile BPCs can be evaluated using a processsimulationmethodology.However, n certain nstancesthe useof a microbiologicalgrowth medium n a bulkmanufacturing lant can posesignificant problems. tis often necessaryo considerothersimulationoptionswhich pose less potential risk to the manufactur ingarea. It is useful to utilize a narrowerdefinition of aprocess simulation in these cases. The following

defmitions make a clear distinction betweenpossiblemethods:

ProcessSimulation (without microbiologi cal growthmedia)

Method of evaluating an aseptic processemploying methods which closelyapproximate hoseused or sterile materialsusing an appropriate lacebomaterial.

Process Simulation (with microbiological growthmedia)

Methodof evaluating naseptic rocess singa microbial growth medium employingmethods which closely approximate hoseused or sterile materials 4).

The processsimulation test also provides a way toevaluate changes made to an aseptic processingoperationwhich might affect the sterility of the finalproduct. It can be useful in identifying potentialweaknessesn an asepticprocessing perationwhich

For the purposesof this document, a sterile bulkpharmaceuticalhemical s definedasa sterilematerial

derived rom chemical, ermentation r semi-syntheticsources hich is final packaged r stored n bulk form.The bulk material may be an active pharmaceuticalingredient API) or an excipient. Sterile BPCs aretypically solids, but may be solutionsor suspensions.

1.3 Scope

This document addresses he vali dation of asepticprocessing uring sterilebulk manufactur ing ctivities(referred o asprimary manufacturing n many partsoftheworld). It describes ethods ndproceduresor the

conduct of process simulation tests, includingcrystallization, separation, purification, drying,milling, blending and bulk packagingof sterile bulkpharmaceutical chemicals which are asepticallyproduced. Aseptic operations required in theprepara tion f sterile ormulationsarenot a part of thisdocument ndhavebeenaddressed y PDA elsewhere

(4).

1.4 Sterile BPC Production Technology

The preparationof sterile bulk materials entails the

completionof a seriesof unit operations nderasepticconditions. The equipmentutilized for these asepticunit operationss sterilizedusinga validatedprocedureprior to the ntroductionof the sterileBPC. Dependingupon he process, he equipmentmay be classifiedaseither a “closed” or an “open” system (see below).While it is recognized that a “closed” system isgenerallypreferred, here are processand equipmentlimitationssuch hat “open”systems re he only meansavailable or the executionof certainunit operations.

1.4.1 Closed Systems

A “closed” system s onewhich is designedo preventthe ngress f microorganisms.A “closed” systemcanbe more accuratelydefined by characteristicsof itsoperation than by a descripti on of its physicalattributes. A “closed” system:

- Is sterilized-in-placeorsterilized hile closedprior to use

- Is pressure and/or vacuum tight to somepredefined eak rate

Vol. 52, No. 5 I September-October 1998, Supplement



Can be utilized for its intended purposewithout breach o the integrity of the systemCan be adapted or fluid transfers n and/orout while maintaining asepsisIs connectable o other closed systemswhilemaintaining integrity of all closed systems(e.g., Rapid Transfer Port, steamed

connection, etc.)Utilizes sterilizing filters which are integritytestedand traceable o eachproduct lot.

By virtue of their design, closed systems provide asubstantially increasedmeasureof protection to thematerials processedwithin. Where a sterile BPC canbe processed n its entirety within closed systems,nocontamination should be possible. A truly closedsystemcan be validatedassuchandneednot be furtherchallenged hrough process simulation. Sterilizationvalidation of the closed system should be performed

and documented. Processsimulation as described nthis documentwould only apply to asepticoperationswhere “open” systemsare employed.

1.4.2 Open Systems

An “open” system acks one or more of the featuresofa “closed” system.

2 PROCESS SIMULATION CONCEPTS

AND PRINCIPLES

2.1 Number and Frequency of Tests

For a new facility or production process, processsimulations are performed as part of the overall

validation. Initial process imulation estsgenerallyareconductedafter equipment qualification, sterilizationprocessvalidation, and personnel raining have been *performed, and environmental monitoring hasdemonstratedhat the new facility is under he desiredstate of control (8, 9, 10). If a processsimulation testfails in the absence of this supportive work,identification of a possiblecausewill be more difficult.Generally, three consecutive successful processsimulation ests are performed when evaluatinga newfacility or process. Prior to release f the new facility,or new process or production use, acceptable esults

from these estsshouldbe achieved o demonstratehereproducibility of the process. In existing facilities,there should be a processsimulation test program foreach aseptic process. Additional processsimulationtests should be performed to evaluate changes toprocedures, racticesor equipmentconfiguration (SeeSection 11 - Periodic Reassessment).

2.2 Worst Case

1.5 Considerations

A holistic approach must be used to adequately

validate and control aseptic processes. A processsimulation est s only a point-in-time representation fthe capabilities of an aseptic processing system,including environment, equipment, procedures andpersonnel. t doesnot ensure hat sterile bulk materialsproduced at other times will have the same evel ofmicrobiological quality. However, hroughcontrol andvalidation of related processes, uch as environmentalmonitoring, qualification ofpersonnelandvalidation ofcleaning and sterilization cycles, it is possible tomaintain the level of asepsisdemonstrated ur ing theprocesssimulation test. Therefore, t is important to

validate the related sanitization and sterilizationprocesses independently, such as steriliza-tion/depyrogenationof the product, sterilization of theprocessequipment ncluding product contactsurfaces,sterilization of containers (intermediate and finalpackagedbulk), andsupportsystems uchasair, water,or nitrogen (5,6,7).

One of the more prevalent techniques used in thevalidation of pharmaceutical processes is the

employment of “worst case” scenarios. The use of“worst case”situations s intended o provide a greaterchallenge o the process,system or equipment beingvalidated than that experienced under routineprocessing onditions. If, under he circumstances fthe “worst case” challenge, acceptable results areachieved, then there is greater confidence in thereliability of the systemunder more normal situations.Processsimulation tests readily lend themselves o“worst case” challenges. Some of the types ofchallengeswhich may be employedwherepossibleare:

- using materials,equipment,utensilsand other

items which have remained in the asepticprocessing area for extended periods aftersterilization

- using the maximum production crewnecessaryo process he batch

- increasing the time period between thecompletionof equipmentsterilization and hestart of the processsimulation

- usinga growth promoting medium or placebomaterial in the processsimulation test ratherthan an inhibitory material

2 PDA Journal of Pharmaceutical Science &Technology



- performing a process simulation test aftercompletion of the last lot in a productioncampaign

In the developmentof protocols or procedures sed orthe definition of process simulation tests, the use of“worst case” challenges uch as hosedescribedabove

is an essential element of a well-founded program.Risk assessment pproaches uch as hazard analysisand critical control point (HACCP), failure effectsmode analysis (FEMA) or fault tree analysis (FTA)may be used o determineappropriatechallenges.

3 PROCESS SIMULATION TEST

METHODS

The application of these general procedures o anyspecific asepticproceduremay require modification ofthe methods described herein. These adaptations

should be accomplished n a manner which will notimprove he resultsof the simulation, elative o routineoperations.

The conduct of processsimulation ests or sterilebulkpharmaceuticals ntails simulation of the process romthe point of sterilization through to the completion ofbulk packaging. The processsimulation test needs obe conducted or only the open portion of the process(see Section 1.4.1). In many modem facilities, thismay be limited to the final packaging of the sterileBPC. Sterile bulk processesgenerally consist of a

series of unit operations which in total comprise theproduction processes. For the purposes of processsimulation t may be appropriate o conductevaluationsaround either a single operation or a group ofoperations. Provided that all of the unit operationsutilized in the production of a sterile BPC have beenevaluated in an appropriate manner, the segmentedapproach to simulation can be as suitable as acomprehensiveest nvolving all of the unit operationsin a single simulation. The decision whether toperform the processsimulation as a single integratedtest or in trials basedupon one or more unit operations

must consider he pros and cons of each approach. Itshould be recognized hat the decision to conduct anoverall simulation or step-wisesimulation approach sindependent of the use of microbiological growthmedia or other materials n the simulation.

3.1 Total Process Simulation

In this type of simulation, the entire asepticprocess sevaluated n a trial which follows the process romwhere the sterile materials are first manipulated n an

“open” system, hrough subdivision nto containers orshipment.

Advantages

The simulation may be able o follow the processmore closely than a seriesof smaller simulations.

Requ&es ess time to complete than a series ofsmaller simulations.

Disadvantages

If contamination s detected he identification andcorrection of sources s more difficult than in aunit operationsimulation.

In the event of failure, the entire simulation mustbe repeatedafter corrective measureshave been

taken.

Will generally require the use of a single testmaterial (either liquid or’ solid) throughout theentire simulation which may introduce significantdifferences in the simulation and in howcontaminationmight occur when compared o theroutine production process.

3.2 Unit Operation(s) Simulations

In this form of simulation, a seriesof individual trials

are conductedcovering all of the steps n the asepticprocess. Where he simulation s performed n severalsteps, he establishment f an acceptance riterion mustaddress he cumulative contribution from each of theunit operations. Thus the total numbersof organismsdetectedover the entire processmust be considered.

Advantages

If contamination is detected, the correctivemeasures an focus on a smaller portion of theoverall process.

Evaluation of the effects of changes o a specificpart of the processcan be restricted to a limitednumber of steps.

In the eventof failure of a portion of an individualsimulation, only that simulation which failed mayneed o be epeated fter correctiveactionhasbeentaken.

In some aseptic processes, his approach may

Vol. 52, No. 5 / September-October998, upplement



resemble he actual processmore closely. acceptance riteria requirements n the protocol.

Allows for the use of either liquid or solid testmaterials in different parts of the overallsimulation, which may more closely resembleactual production.

Disadvantages

Requiresmore ime to perform than a otal processsimulation.

May require some degreeof overlap to evaluatethe overall process.

The methods required o evaluate ndividual unitoperations may require more handling of sterilematerials to accommodatea segmentedprocesssimulation.

A larger number of environmental monitoringsamples must be taken during each of theindividual processsimulations.

4 TEST MATERIALS USED IN PROCESS

SIMULATION

Independent of the decision on whether the asepticprocess s to be simulated n total or in unit operationfashion, considerationmust be given to the selectionofa material o be utilized in the simulation. The choices

are: a microbiological growth promoting media,placebomaterial, simulation without material or actualproduct material (generally an excipient). With eachchoice there are of course certain advantagesanddisadvantages. f a test material is utilized, a furtherdecision between a liquid or powder material is alsorequired. Those firms which have chosen o segmentthe process simulation according to the various unitoperations,may elect to make different selections orthe test material in different parts of their overallprogram. For example, n sterile BPC simulationswitha crystallization step, a liquid material may be used

during simulation of the early steps, and a powdermaterial n those stepswhich follow the crystallizationstep. SeeAppendix 1 or information on the selection,sterilization and use of test materials.

4.1 Growth Medium Simulations

A microbial growth medium in either liquid or solidstate s processed n lieu of the production materials.The microbiological growth media may be tested ormicrobial count or sterility depending upon the

Advantages

Allows for the direct evaluation of the asepticprocessingprocedures.

Less reliance on environmentalconditions in theevaluationof the process.

Disadvantages

The microbiological growth media may be overlysensitive o antibiotic materialsand other nnatelyinhibitory materials.

Cleaning of the processequipmentafter exposureto themicrobiological growth mediamay representa new cleaning procedure which must be

developedand validated.

It adds increased risk of microbiologicalcontaminationof the facility by providing a majornutrient sourcewhen normal materials used maybe innocuousor bactericidal.

Detection of contamination in large containersmay be difficult.

Quantities of microbiological growth mediarequiredmay be excessive.

Process imulation may have ittle resemblanceothe actual processbecause f concerns egardingthe media’s growth promotion capability underroutine operating onditionswithin the equipment.

4.2 Placebo Material Simulation

A placebo material is substituted or the productionmaterialsandhandled n a representativemanner. Theplacebomaterialcanbe sampled or microbial count orsterility testing dependingupon he acceptance riteria

requirements f the protocol.

Advantages

Can use materials which are able to tolerate theactualprocessing onditionsutilized in the asepticprocess.

Placebomaterials can be chosen such that theirremoval from the processingequipment after thesimulation can be readily accomplished.

PDA Journal of Pharmaceutical Science &Technology



Placebo materials can be substantially lessexpensive han product or microbiological growthmedia, which can be a significant concern n largeprocessequipment.

Someof the actualmaterialsutilized in the asepticprocessmay be utilized.

Disadvantages

Sterility or microbial count testing must beperformed in order to assess whether anymicroorganismsare present.

Cleaning of the processequipmentafter exposureto the placebo may represent a new cleaningprocedurewhich must be developed ndvalidated.

The placebomaterial must be evaluated or lack of

inhibitory effects on microorganisms.

The sterilization of powder placebos must bevalidated.

Testing of large quantities of material may berequired.

4.3 Simulation Without Material

This is a simulation performed in the absence ofmaterials. This approach is well suited to the

evaluation of operating procedures and personnelperforming discrete aseptic manipulations, e.g.,subdivision into final containers. The asepticproduction processes are simulated using theprocedures, personnel, equipment and componentsordinarily utilized in the aseptic process. Aftercompletion of the simulation, extensive microbialsampling of product contact surfacesand personnel sperformed. The surfacesampling esultsareutilized todeterminemicrobial count or sterility dependinguponthe acceptance riteria requirementsof the protocol.

Advantage

The absence of materials eliminates cleaning(except for sampling residues, f any), microbialcount or sterility testing, inhibition and recoverystudies associatedwith the use of either a growthmedia or a placebomaterial.

Disadvantages

Relies on the microbial evaluation of product

contact surfaces,

Not readily quantifiable.

4.4 Production Material Simulation

A simulation which is performed using actual

production materials (generally an excipient). Thematerialcan be sampled or microbial count or sterilitytesting depending upon the acceptance criteriarequirementsof the protocol.

Advantages

The processbeing simulatedmay utilize identicalprocessing onditionsas hoseused n production.

The materialsused or the simulation areknown tobe compatiblewith the processingequipment.

No specialized cleaning of the equipment isnecessary, he routine methods used after theproduction can be employed with confidence.

Sterility testing or microbial count determinationmust be performed.

The productionmaterialmustbe evaluated or lackof inhibitory effects on microorganisms, or a

neutralizingagentmust be addedduring he esting

Theproductionmaterialsmay be extremelycostly.

Testing of large quantities of material may berequired.

5 EVALUATION OF SIMULATION TEST

MATERIALS

Regardless of the material chosen for use in thesimulation rial, it is important o evaluate hat material

to determinewhether microorganismswere presentaswell as its microbial growth support characteristics.Similar to the precedingsectionof this document hereare nherent advantages nd disadvantages ssociatedwith the various est methods.

5.1 Evaluation of Entire Test Material

An approach n which the entire quantity of material(either growth medium or placebo) utilized in thesimulation s evaluated. This can be accomplishedby

Vol. 52, No. 5 I September-October 1998, Supplement



filtration (after reconstitution for solid materials)through an appropriate sterilizing grade filter or bydirect incubation of filled containers. The filter istested to quantify the microbial bioburden of thematerial. Care must be taken to test (and reconstituteif necessary) using methods, controls, procedures,equipment and facilities which will not introduce

contamination into the material being tested. Theentire quantity ofmaterial canbe subjected o microbialcount or sterility testingdepending pon he acceptancecriteria requirementsof the protocol

to the testing. The samples an be ested or microbialcount or sterility depending upon the acceptancecriteria requirements f the protocol

Advantages

Resembles he sampling of routine production

materials or sterility.

If sampling is performed at mult,iple intervals itmay be able to pinpoint the source ofcontamination.

AdvantagesA smaller quantity of material s tested.

Evaluates all of the material processed n theequipment.

Best suited for comprehensive est of the processin a single simulation.

Disadvantages

Testing of large quantities of material is requiredwhich can prove quite cumbersome.

Validation of sampling and testing methods,including the sterilization of all apparatus.

Limited information is available for use indetecting he sourceof contamination n the eventof failure.

Isolation and identification of microorganismsfrom the filter may be difficult with certainmaterials.

The test (and reconstitution) procedures mayintroduce contamination nto the sample.

Poorly suited to powder materials where thehandling equired o prepare he material or test nthis fashion has substantial potential for theintroduction of contamination.

Direct incubation mandates pass/failacceptancecriteria.

5.2 Evaluation of Test Material Samples

After completion of the process imulation, samples fthe test material are aken from the equipmentand/ orcontainers.When a liquid material hasbeensampled tmay be tested directly. Powder materials requirereconstitution with a sterile diluent such as WFI prior

Disadvantages

Samplesonly a portion of the material utilized inthe simulation and may not detect low levels of

contamination, especially with a powderedmaterial.

In-process sampling for the purposesof processsimulation may not be a part of the routine BPCprocessand could introduce contaminants.

Isolation and identification of microorganismsfrom the filter may be difficult with certain m

materials.

DOCUMENTATION

Documentation s one of the most important elementsof a process simulation test program. Regulatorybodieswill rely heavily on the documentation o udgethe adequacy f the simulation.

The first step s to define the process o be simulated.The processgenerally s defined as all steps rom thesterilization of the sterile BPC, solvents, reactants,containers and to the point the final sterile BPC issealed n its shippingcontainer. The process efinitionshould nclude a description of all points that require

aseptic ntervention. Once he process asbeenclearlydefined, he simulation protocol(s) or procedurescanbe written. Thesedocuments hould nclude but not belimited to the following information:

- Identification of the process o be simulated- Identification of the process train and

equipment o be used- Type of container/closureo be used- Number of personnelparticipating- Test material o be used- Environmentalmonitoring to be performed

6 PDA Journal of Pharmaceutical Science & Technology



- A copy of the batch record o be used- Acceptancecriteria to be utilized- Description of the documentation equired or

the final report- Rationale for the “worst case” parameters

chosen.

The above ist should not be consideredall-inclusive.Other factors may have to be considered due to thenature of the process o be simulated.

Execution of the protocol is generally performedthrough a batch ecord. The batch ecordgivesdetailedinstructions on how to perform the processsimulationtest(s). It should be written in the same ormat as anormal batch record and contain the normal data andsign-off elements. Information which normally wouldbe attached o a batch ecord also shouldbe attached othe simulation batch record, i.e., sterilization records

for equipment,containers,and utensils, etc. The nextstep s to document he following:

- Number of organismsdetected, f any- Results of environmental esting performed.

The final report is a summation of the data from thebatch record, bioburden esting of simulation materialand environmental monitoring samples. Baseduponthis information, a conclusion s formulated regardingthe acceptability of the manufacturing process andfacility.

7 ENVIRONMENTAL MONITORING

Details concerning elements of an effectiveenvironmental monitoring program, ncluding samplesite selection,sample requency,alert andaction evels,methodology and interpretation of data, can be foundin the literature (11).

8 ELEMENTS OF PROCESS

SIMULATION TESTS

This sectioncontains mportant general nformation to

consider when conducting process simulation tests.These issues play an important role in effectivelysimulating the production process.

8.1 Interventions

Process simulation tests must include the normalactivities which occur during an aseptic process i.e.,equipment adjustments, container-closure resupply,sampling,etc.) n order o substantiatehe acceptabilityof those practices n routine operation. It is possible

that non-planned nterventions may occur during thesimulation and that it will be necessary o correct forfluid leakage, equipment malfunction, etc. To theextent hat these ypes of problemsoccur on their own,andare ectified during a successful rocess imulationtest, they can be defended as acceptable duringordinary operations 4, 12).

8.2 Duration of Simulation

Process imulation estsshouldbe of sufficient durationto evaluate he normal manipulationsnecessary or theprocess. Activities such as initial set-up activities,changing equipment and manual maintenanceoperations houldbe ncluded n the process imulationtests. Process simulation tests also should be ofsufficient duration to include a representative umberofroutine andatypical nterventionswhich might occurduring an actualproduction operation. Where hey are

part of normal operations,gown changes,breaks andshift changes hould be simulated. The time durationof the process simulation has greatest relevance inoperations such as milling and subdivision whererepetitive tasks are performed and personnel bornecontaminationmay be of greater elevance.

8.3 Production Batch Size/Process Simulation

Test Size

A process simulation test should utilize sufficientmaterial to exposemost, if not all contact surfaces o

the material. It is essential that the asepticmanipulations n the simulation closely resemble hoseutilized in production,however he actualnumberneednot be identical.

8.4 Incubation Conditions

It is widely accepted hat process simulation testsshould be incubated or a minimum of 14 days. Thetemperature at which the medium is incubated,however, varies from firm to firm. The temperaturechosen should be based upon its ability to recover

microorganisms ormally found environmentally or inthe product bioburden. This same panel ofmicroorganismsshould be used n growth testing themedium-filled containers. A single incubationtemperature n the range of 20-35°C may be used.Data should be available o show the suitability of theselected ncubation emperature o support he growthof environmental and pre-sterilization bioburdenisolates.The selected emperature houldbe controlledand monitoredcontinuously hroughout he incubationperiod.

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8.5 Manual Procedures

When he productionbatchsize s small, heremay begreater prevalence of manual operations in theprepara tion f sterileproducts.Theprocess imulationof a manu al process of this sort is carried out inaccordance ith the methods ndpractices utlined n

this document,with oneaddition. Each operatorwhoperforms this type of manual process should beindividually evaluatedo establish he acceptabilityoftheir aseptic echnique.

8.6 Staffing Considerations

Each personwho works in an asepticproductionsuiteshould participate n a successfulprocesssimulationtest on a periodic basis.

8.7 Campaigns

Multiple lots of sterile BPCs may be producedfollowing a single sterilization without i nterveningcleaning of the equipment equiring a breech n theintegrity of the system. The process simulationprogram should confirm the acceptability of thisproductionmode.

9 INTERPRETATION OF RESULTS AND

ACCEPTANCE CRITERIA

9.1 Background

The adop tion of limits and acceptance riteria forprocess imulation ests s oneof the morecontentioussubjects within the i ndustry in recent years (13).Whatever the number of organisms allowed in aprocess imulation, he ultimategoal or the numberoforgani sms n any process imulation est (at either hebulk or filling stage)shouldbe zero 4).

There are , however, significant technicalproblems nachieving his goal. Microbiologicalgrowthmediaan dsimulated roducts o not match ealproducts erfectly

in terms of their processing characteristics andmicrobiological growth support properties.Microbiological growth mediadiffer in many espectsfrom the products hey are intended o simulate; forexample, there are differences in solubility, pH,filtration rates and filterability and viscosity. Withpowdered roducts,heprocess imulation est nvolvesreconstitutingpowderedmedia or simulatedproduct,introducing extra processing equipment ormanipulation,with the inherent isk of contamination.Since a microbiological growth medium is designed

specifically to support or stimulate the growth ofmicroorganisms,t is a more rigorous challenge hanprocessed roducts,which often provide neutral andsometimeshostile microbial growth environments.Thus,a imit of some ow numbe rother hanzerooftenis chosen.

The selection of acceptancecriteria for asepticprocessing alidation s the central ssue o be esolvedin the conductof process imulation ests. This sectionoffers guidance which can be used to establishappropr iate imits and acceptance riteria for asepticprocess imulation ests.

9.2 Approaches for Acceptance Criteria

9.2.1 Quantitative

Thedominantmethodologyor thevalidationof aseptic

processes tilized for drug productcompounding ndfilling utilizesa mediaprocess imulationapproach. nconjunction with the execution of this evaluation,afirm typically selects nacceptanceriteria often0.1%of the total numbe r of units filled) (8). Directapplication of the process simulation acceptancecriteria or aseptic illing to sterilebulk pharmaceuti calchemicals s inappropriate or a nu mber of reasonsincluding: elatively few largecontainers re equired, r

inspectional ifficulties in largecontainers,heamountofmicrobiologicalgrowthmedia equired, ndcleaninggrowth media rom process quipment.An adaptation

of the approach is possible which relies on aquantitativeassessmentf contamination evels.

Process imulation esting s conducted sing either aplacebomaterial,productmaterialor a growth medium(either solid or fluid) which contacts equipmentsurfacesn like manner o the productbeingsimulated.After completionof the simulation est, he material sevaluated. The number of colony forming unitsdetected n the materialcan be used o project a worstcase contamination ate basedon the smallest bulkproduction batch and the largest finished product

container of the product being simulated (i.e., thefewestnumberof finishedproductunits illed from theentirebatch).

Theprocess imulation estpassesf the contaminationrate projects o not more than the chosen imit. Theexampleshat follow a rebased n a limit of 1 positiveunit in 5,000 inished dosageunits (or NMT 0.0002CFU/unit). Survey data shows his is the limit oftenapplied o process imulation estingof finisheddosageforms (12). In the absence f specific guidance or

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8 PDA Journal of Pharmaceutical Science &Technology



sterile bulks, finished product survey data provides avaluable reference, however other limits may beappropriatebased on experiencewith the particularprocessand process imulation methodology.

The simulation batch size may differ from theproduction batch size provided the aseptic

manipulationsare essentially he same,and adequatemixing and agitation of the simulation batch can beachieved n the processequipment.

When material from more than one process rain iscombinedproduce he finished sterilebulk and t is notpossible o simulate the entire process, he projectedcontamination ate for the finished bulk is the sum ofthe process simulation test results from eachindividually evaluated rocess rain.

Consider he following examples:

1. The contamination level for the simulationbatch s IO CFU. It projects to IO CFU in theproduction batch.

2. Determine the minimum number of dosageforms producedfrom theproduction batch.

200,000 g/batch / 5 g/unit = 40,000units/batch

3. Calculate the maximum CFU/unit andcompare to the limit of NMT 0.0002CFU/unit.

IO CFU/batch / 40,000 units/batch =0.00025CFWunit

Since the projected contamination rate 0.00025CFU/unit exceeds the limit of NMT 0.0002

CFU/unit the process imulation est fails.Example 1

Example 3

Minimum productionbatchsize200kg, maximumfinished drugproduct ill 10g, chosen lacebo ize60 kg, 2 CFU detected n the simulation.

1. The contamination level or the simulationbatch is 2 CFU It projects to 2 CFU in theproduction batch.

2. Determine the minimum number of dosage

forms producedfrom theproduction batch.


3. Calculate the maximum CFU/unit andcompare to the limit of NA4T 0.0002CFU/unit.

2 CFU/batch / 20,000 units/batch =0.0001CFU/unit

Since the projected contamination rate 0 .0001CFU/unit does not exceed the limit of NMT0.0002 CFU/unit the process simulation testpasses.

Example 2

Minimum productionbatchsize200kg, maximumfinished drug product ill 5 g, chosen lacebo ize60 kg, 10 CFU detected n the simulation.

Minimum productionbatchsize200kg, maximumfinished drug product ill 1g, chosenplacebosize60 kg. The finished bulk is produced frommaterial rom processrainsA andB, respectively,blended together in process train C. 3 CFUdetected n the process rain A placebo, 5 CFUdetectedn the process rain B placebo,and2 CFUdetected in the process train C placebo after

simulation.

1. The combined contamination level for thesimulation batches s 10 CFU. It projects to10 CFU in theproduction batch.

2. Determine the minimum number of dosageforms producedfiom theproduction batch.


3. Calculate the maximum CFU/unit andcompare to the limit of NMT 0.0002CFU/unit.

IO CFU/batch / 200,000 units/batch =0.00005CFU/unit

Since the projected contamination ate 0.00005CFU/unit does not exceed the limit of NMT0.0002 CFU/unit the cumulative processsimulation est passes.




NOTE: Microbial count determination hassimilarities to the sterility test and contaminationmay be introduced as a consequence f the testenvironment, ersonnel ndprocedures mployed.Validation of the test method or the material sessential o the success f this approach.

This methodology utilizes a widely acceptedcontamination ate as the basis or the evaluationofsterile bulk operations. The use of a non-zerocontamination rate mimics the approach used fordosage orms. The suggested pproach equires ight(albeit, not absolute) control over the extent ofmicrobial contamination acceptable in a processsimulation and allows for further improvement astechnology and procedures are improved. Mostimportantly t enablesmeaningfulevaluation f asepticprocessing procedures for sterile bulks using aquantitativeapproach.

9.2.2 Qualitative

Any process simulation can be evaluated using aqualitative pass/fail)criterion. A qualitativeapproachcanbeusedwith any of the simulationmethods.Whileit can offer handling advantages (relative toquantitative testing), it precludes ecognition of theaseptic process simulation sampling and testingmanipulations sa possible ontributor o the presenceof organi sms ince zero growth is the only acceptableoption.

10 FAILURE INVESTIGATION AND

CORRECTIVE ACTION

A comprehensive amplingand dentification schemeis crucial in the investigation and determinationofsourceof any detectedmicrobial contamination. n theinstancewhen heprocess imulation estdoes ot meetthe established cceptance riteria, possible ources fcontamination should be investigated. A detailedhistory of the investigationneeds o be maintained.

Based pon he outcomeof the nvestigation, he causeof the failure is either assignable r not assignable. tmay beclearly assignableo a singlesource, r vaguelyassociatedwith multiple systemsor processes hichrequire edefining. fthe causes assignable,orrectiveaction needs o be taken and documented. The rootcause nd he correctiveactionwill dictate he numbe rof process imulation ests equired o demonstra tehattheprocesss operatingwithin theexpected arameters.If no cause can be found, the process should bevalidatedas though it were a ne w process. Multiple

consecutive process simulation tests should beperformed o demonstratehe ability to consistentlyproduceacceptable roduct.

11 PERIODIC REASSESSMENT

Each firm should determine he frequency of and

interval betweenperiodic simulation of eachprocess.An annualevaluation f the need o perform a processsimulationshouldbe sufficient.

Unschedu led rocess imulation estsmay be requiredfollowing a significant change. In such cases, henumber of process simulation tests may vary,depending p on he extentof the change.Examples fsuchchangesnclude:

- Major modifications to the equipment(interchanging standard parts does notconstitutea major equipmentmodification)

- Modification to equipment r facilities whichpotentiallyaffects he air quality or airflow inthe asepticenvironment

- Increases eyond he maximum number ofproduction personnel used in processsimulation esting

- Major changes o the aseptic productionprocess ndforprocedures.

It alsomay benecessaryo performprocess imulationtests n responseo adverserendsor failures n the on-going monitoring of the facility or process.

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APPENDIX 1, SELECTION AND

STERILIZATION OF TEST MATERIALS

In the conduct of asepticprocesssimulation ests forsterile BPC, the use of a sterile placebomaterial maybe appropriate. Care must be taken in the choice of

material to be used, and in its preparation, o avoiddifficulties with the process imulation estingprogram.Dependingupon the specific processequipment,andoperatingprocedures,t may be appropriateo utilize aliquid or a powderasa est material. Consideration analsobe given to the useof a growth promotingmaterialor an nert material. In certainsituationsmore hanonetest material can be utilized for different parts of thesimulation program. Whichevermaterial s utilized inthe simulation, it should be processed nd ultimatelypackaged sclosely aspossible o the sterileBPC beingsimulated.

Selectionof TestPowder The selectionof powder estmaterial for use in processsimulation testing mustconsider everal actors. Theseemingly bviouschoiceof dry sterile microbiological growth media, tself, hasproven less than successfulbecause f its poor flowproperties, which make its passage hrough sterilepowder processequipmenta considerable hallenge.The principal placebomaterialswhich havebeenusedsuccessfully are lactose, mannitol, and polyethyleneglycol. The most common choice or a powdermediais dry Soybean-CaseinDigest Medium (SCDM),

though other choices are certainly possible. Thechosenmaterial must be easily sterilizable,dispersibleor dissolvable n the chosen medium with minimalagitation,haveno adverse ffect on growth promotion,and be easily handled in the simulation processequipment.

Selectionof TestLiquid - The selectionof a liquid testmaterial is governedby severalconsiderations. Theuse of a microbiological growth media is certainlypossible; he most commonobjection o their use elateto concernswith the cleaning of residualmedia after

completion of the simulation, Liquid media whichhave been utilized for process simulation includeSCDM and peptonebroth. Dilution of the media tolower strengths s employedand s acceptable rovidedgrowth promotion can be demonstrated see below).Potential placebo fluids may range from Water forInjection to one of the solvents employed in theprocess, assuming the solvent has no significantantimicrobial activity. Test liquids are generallysterilized by 0.2 micron filtration using the housingsrequired or the process.

Sterilizationof TestPowder placeboor growth media)-Part ofthe selection rocess equires he dentificationof a suitable sterilization method for the chosenmaterial. The material being evaluated should besubjectedo a validatedsterilizationprocess rior to theprocess imulation ests. The validation study shouldincludeverification that he sterilizationprocess asno

significant adverse ffect on the material’sproperties.The most common sterilization method in use isirradiation n the same inal containeras used or thesterile powder being simulated. Alternatively, thematerial can be sterilized by dry heat or filtration,followed by bulk lyophilization. Along with theplacebomaterial prepared or use in the filling trial,additionalmaterial n separate agscan be utilized forsterility testingafter sterilization. The est samples anbe ested f there s any question egarding he sterilityof the material.

Inhibition Testing or Placebo Materials - Growthpromotion testing, in which the chosen material istested for potential inhibition, is performed usingBacillus subtilis (ATCC 6633) and Candida albicans(ATCC 10231)‘. Considerationshould be given totestingwith othermicroorganisms ommonly found nthe asepticprocessing reaenvironment, uchas hoseisolated during personnel monitoring and sterilitytesting. Replicate amples fthe placebomaterialsareinoculatedwith 1O-l 00 CFU of each of the challengeorganisms and then dissolved/dispersed n sterilemedium. Positivecontrolsareprepared y inoculating

replicate tubes of medium which do not contain thesterilizedplacebomaterial. Growth must be evident nall tubeswithin seven aysafter ncubationat20-25°C.Growth promotion or liquid placebos s performed na similar fashion after inoculation, using either directplating or membra ne iltration of the liquid placebo.The filters are hen estedas f for a membran e terilitytest and growth must appear {within 7 days ofincubationat 20-25 C.

Growth Promotion or Growth Media - Confirmationof the media’s growth promotion properties is an

essential element. The conduct of media growthpromotion evaluation s a relatively simple procedure,with a few basic equirements.The media utilized forthe growth promotionstudies houldbe drawn rom thesamematerialutilized for the process imulation tself.The growth promotionunits shouldbe noculatedwitha low concentration (less than 100 organisms per

’ Sterility Test <71>, USP 23 / NF 18, P.1687,USP, Rockville, MD, 1995.




container) of the USP growth promotion organismsBacillus subtilis & Candida albicans. Considerationshould be given to testing additional units with otherorganismscommonly found in the asepticprocessingarea environment, such as the organisms isolatedduring personnelmonitoring, sterility testing, etc.

Media growth promotion studies can be performedprior to, concurrentwith or after the completion of theprocess simulation incubat ion period. When growthpromotion is performed before incubation, theacceptability of the media is confirmed prior to thesimulation. Pre-simulation esting cannotconfirm theacceptability of the media used n the actual rial andeither concurrentor post-incubationgrowth promotionmust be employed as well. The use of concurrenttesting appearspreferable as the results will then beavailable prior to completion of the incubation. Post-incubationgrowth promotion providesa similar degree

of assurance, but the delay in obtaining resultseffectively extends the length of time before theprocesssimulation results are definitive.

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APPENDIX 2, DEFINITIONS

aseptic asepsis)Free rom disease-producingicroorganisms.

aseptic illingPart of aseptic processing where a pre-sterilized product is filled and/or packagedinto sterile containers ndclosed.

asepticprocessingHandling sterile materials in a controlledenvironment, in which the air supply,materials, equipment and personnel areregulated o control microbial andparticulatecontamination o acceptableevels.

asepticprocessingarea (APA)Controlledenvironment, onsisting f severalzones, in which the air supply, materials,equipment and personnel are regulated ocontrol microbial and particulatecontamination o acceptableevels.

closedsystem see ystem, losed)

colony orming unit (CFU)Visible outcome fgrowth ofmicroorganismsarising rom a single’ormultiple cells.

environmentalmonitoringprogram

Defined documented program whichdescribes the routine particulate andmicrobiologicalmonitoringofprocessing ndmanufacturing reas, nd ncludes correctiveaction plan when action evels are exceeded.It includesassessment f environmental ir,surfaces nd personnel.

growthpromotion testTestperformed o demonstratehatmediawillsupportmicrobial growth.

microbial count determinationA test performed o quantify the numberofmicroorganisms present in a sample ofmaterial. Standard microbial methods areutilized to estimate he number of colonyforming units (CFU) perunit massor volume.

opensystem see ystem,open)

process simulation (without microbiological growthmedia)

Method of evaluating an aseptic processemploying methods which closelyapproximate hose used or sterile materialsusingan appropriatematerial.

process simulation (with microbiological growthmedia)

Methodof evaluating naseptic rocess singa microbial growth medium employingmethods which closely approximate thoseused or sterilematerials.

sterileFreeof any viable organisms.

NOTE: In practice, no such absolutestatement regarding the absence ofmicroorganisms can be proven (seesterilization).

sterility assuranceevel (SAL)Probability hat a batchof product s sterile.

sterile bulkpharmaceutical hemical

A sterile material derived from chemical,fermentati on r semi-synthetic ourceswhichis final packaged r stored n bulk form. Thebulk material may be an activepharmaceuti cal, r excipient. Sterile BPCscan be solids,solutionsor suspensions.

sterility testTest performed to determine if viablemicroorganisms re present.

sterilization

Validated processused o render a productfree of viable organisms.

NOTE: In a sterilizationprocess,he natureofmicrobiological death or reduction isdescribed by an exponential function.Therefore, the n umber of microorganismswhich survive a sterilization processcan beexpressedn terms of probability. While theprobability may be reduced o a very lownumber, t can neverbe reduced o zero.




system,closed unit operationA “closed” system is sterilized-in-place orsterilized while closedprior to use, s pressureand/or vacuum ight to somepredefmed eakrate, can be utilized for its intendedpurposewithout breech o the integrity of the system,canbe adapted or fluid transfers n and/orout

while maintaining asepsis, ndconnectableoother closed systems while maintainingintegrity of all closedsystems.

A processing ctivity involving multiple stepswhich effects a single type of change o thematerials (e.g., reaction, crystallization,filtration, drying, milling, etc.) usually carriedout in a single piece of equipment.

worst caseA set of conditions encompassing pper andlower processing imits and circumstances,including those within standard operatingprocedures,which pose he greatest hanceofprocessor product failure when compared oideal conditions. Such conditions do notnecessarily nduceproduct or process ailure.

system,openA systemwhich fails to meet one or more ofthe criteria which define a closedsystem.




APPENDIX 3, REFERENCES

1.

2.

3.

4.

5.

6.

Technical Monograph No. 2, “Validation ofAseptic Filling for SolutionDrug Products,”PDA,1980.

Technical Report No. 6, “Val idation of Asepti c

Drug PowderFilling Processes,” DA, 1984.

“Sterile Bulk Pharmaceutical Chemicals: APhRMA Position Paper,” PhRMA QC SectionBulk Pharmaceuticals ommittee ndSterileBulkPharmaceutical hemicalsSubcommittee, harm.Technol.,August 1995.

Technical Report No. 22, “Process SimulationTesting for Aseptically Filled Products,”PDA J.Pharm. Sci. Technol .,50 (Sl), 1996.

“Sterilization and Sterility Assurance<I 2 11 ,‘IUSP 23 / NF 18,USP, Rockville, MD, pp . 1976-1981, 1995.

Validation of Aseptic Pharmaceutical rocesses,Ed. by F. Carleton& J. Agalloco, Marcel Dekker,New York, 1986.

7.

8.

9.

10.

11.

12.

13.

Sterile Pharmaceutical Products: ProcessEngineering Applications, Ed. by K. E. Avis,Interpharm, L, 1995.

“Guidelineon SterileDrug ProductsProduced y

Aseptic Processing,” DA, 1987.

“Annex 4, GeneralRequirementsor the Sterilityof Biological Substances.Part A, Section 2,”World Health Organization,1973.

EU Guide o GoodManufacturingPractice.Annex1 - Manufactureof Sterile Medicinal Products,EuropeanUnion, 1996.

PDA TechnicalReportNo. 13, “Fundamentals fa Microbiological Monitoring Program,”

Supplement , I. Parent. Sci. Tech.,44, 1990.

TechnicalReportNo. 24, “CurrentPracticesn theValidationof AsepticProcessing,” DA J. Pharm.Sci. Technol., 1 (Sl), 1997.

“Guide to Inspection of Sterile Drug SubstanceManufacturers,” DA, 1994.

Vol. 52, No. 5 I September-October 1998, Supplement 15



PDA Journal of

Pharmaceutical Science and TechnologySupplement, September-October 1998 Volume 52

EDITOR: Joseph B. Schwartz

I998 OFFICERS AND DIRECTORS PDA Journal of Pharmaceutical Science & Technology (ISSN

Chairman: Joyce H. Aydlett

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Secretary: Floyd Benjamin

Treasurer: R. Michael Enzinger, Ph.D.

Immediate PastChairman: Raymond Shaw, Jr., Ph.D.

James E. Akers, Ph.D.

Jennie Allewell

Joyce L. DeYoung, Ph.D.

Stephanie R. Gray

Frederick A. Gustafson

Martin W. Henley

Henry K. Kwan, Ph.D.

Nikki V. Mehringer

Robert F. Morrissey, Ph.D.

Terry E. Munson‘Toshiaki Nishihata, Ph.D.

Glenn E. Wright

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Georgetown Rd., Suite 620, Bethesda, MD 20814.

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Copyright-PDA, Inc. 1998ISSN 1076-397X

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