Tr 28 a Pi Validation

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Joint PDA / PhFUWA Task Force on Sterile Bulk Pharmaceutical


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 & Company Stelios C. Tsinontides, Ph.D., Merck & Company, Inc. Colin Walters, Schering-Plough Research Institute Thomas X. White, PhRMA Alpaslan Yaman, Ph.D., Novartis Pharmaceuticals Corp.


Note: Sidney Priesmeyer, FDA, St. Louis Branch, served as non-voting liaison for this project; he was not a member of the committee itself.


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 sterile materials 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 pharmaceutical chemicals. 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)


PDA Journal of Pharmaceutical Science &Technology

Table of Contents 1

INTRODUCTION ..................... 1.1 Purpose .......................... 1.2 Sterile Bulk PharmaceuticalChemicals . . 1.3 Scope ............................ 1.4 Sterile BPC ProductionTechnology .... 1.4.1 Closed Systems ............. 1.4.2 Open Systems .............. 1.5 Considerations.....................

1 1 1 1 1 I 2 2

2 PROCESS SIMULATION CONCEPTS AND PRINCIPLES ......................... 2 2.1 Number and Frequencyof Tests ....... 2 2.2 Worst Case ........................ 2 3

PROCESSSIMULATION TEST METHODS 3 3.1 Total ProcessSimulation . . . . . . . . . . . . . 3 3.2 Unit Operation(s)Simulations . . . . . . . . . 3


INTERPRETATION OF RESULTS AND ACCEPTANCE CRITERIA . . . . . . . . . . . . . . 8 9.1 Background . . . . . . . . . . . . . . . . . . . . . . . 8 9.2 Approachesfor AcceptanceCriteria . . . . 8 9.2.1 Quantitative . . . . . . . . . . . . . . . . 8 9.2.2 Qualitative . . . . . . . . . . . . . . . . 10

10 FAILURE INVESTIGATION AND CORRECTIVE ACTION . . . . . . : . . . . . . . . 10 11 PERIODIC’REASSESSMENT. . . . . . . . . . . 10 APPENDIX 1, SELECTION AND STERILIZATION OF TEST MATERIALS . . . . . . . . . . . . . . . . 11 APPENDIX 2, DEFINITIONS . . . . . . . . . . . . . . 13 APPENDIX 3, REFERENCES . . . . . . . . . . . . . . 15


TEST MATERIALS USED IN PROCESS SIMULATION ........................ 4 4.1 Growth Medium Simulations.......... 4 4.2 PlaceboMaterial Simulation .......... 4 4.3 Simulation Without Material .......... 5 4.4 ProductionMaterial Simulation ........ 5


EVALUATION OF SIMULATION TEST MATERIALS . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.1 Evaluation of Entire Test Material . . . . . . 5 5.2 Evaluation of Test Material Samples. . . . 6


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




ELEMENTS OF PROCESS SIMULATION TESTS.. ............................. 7 8.1 Interventions ...................... 7 8.2 Duration of Simulation .............. 7 8.3 Production Batch Size/ProcessSimulation Test Size .......................... 7 8.4 Incubation Conditions ............... 7 8.5 Manual Procedures ................. 8 8.6 Stafftng Considerations.............. 8 8.7 Campaigns ........................ 8

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might contributeto the microbiologicalcontamination of the product. 1.2

The preparation of sterile bulk pharmaceutical chemicals requires the combination of classical chemical / biological production methods with the well-defined concepts for the preparationof sterile materials. The integration of these fields entails processequipmentand operatingprocedureswhich are often substantiallydifferent from ordinary practicein either discipline. This document outlines process simulation practices for sterile bulk pharmaceutical chemicals (sterile BPCs), utilizing concepts drawn from bothbulk pharmaceuticalchemicaloperationsand sterile product manufacturingand adaptedto fit the uniquenatureof thesematerials.It presentsoptionsfor determining the adequacy of aseptic operations performed during large scale manufacturing while allowing for realistic acceptancecriteria for such operations. The aseptic proceduresutilized in the production of sterile BPCs can be evaluated using a process simulationmethodology.However,in certaininstances the use of a microbiological growth medium in a bulk manufacturingplant can posesignificant problems. It is often necessaryto considerother simulationoptions which pose less potential risk to the manufacturing area. It is useful to utilize a narrower definition of a process simulation in these cases. The following defmitions make a clear distinction betweenpossible methods: ProcessSimulation (without microbiological growth media) Method of evaluating an aseptic process employing methods which closely approximatethose used for sterile materials using an appropriateplacebomaterial. Process Simulation (with microbiological growth media) Method of evaluatingan asepticprocessusing a microbial growth medium employing methods which closely approximatethose usedfor sterile materials(4). The process simulation test also provides a way to evaluate changes made to an aseptic processing operationwhich might affect the sterility of the final product. It can be useful in identifying potential weaknessesin an asepticprocessingoperationwhich

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Sterile Bulk Pharmaceutical


For the purposes of this document, a sterile bulk pharmaceuticalchemicalis definedasa sterilematerial derivedfrom chemical,fermentationor semi-synthetic sourceswhich is final packagedor storedin bulk form. The bulk material may be an active pharmaceutical ingredient (API) or an excipient. Sterile BPCs are typically solids, but may be solutionsor suspensions. 1.3


This document addressesthe validation of aseptic processingduring sterilebulk manufacturingactivities (referredto asprimary manufacturingin many partsof the world). It describesmethodsandproceduresfor the conduct of process simulation tests, including crystallization, separation, purification, drying, milling, blending and bulk packagingof sterile bulk pharmaceutical chemicals which are aseptically produced. Aseptic operations required in the preparationof sterileformulationsarenot a part of this documentand havebeenaddressedby PDA elsewhere (4). 1.4

Sterile BPC Production Technology

The preparationof sterile bulk materials entails the completionof a seriesof unit operationsunderaseptic conditions. The equipmentutilized for these aseptic unit operationsis sterilizedusing a validatedprocedure prior to the introductionof the sterileBPC. Depending upon the process,the equipmentmay be classified as either a “closed” or an “open” system (see below). While it is recognized that a “closed” system is generallypreferred,there are processand equipment limitations suchthat “open”systemsarethe only means availablefor the executionof certainunit operations. 1.4.1

Closed Systems

A “closed”systemis one which is designedto prevent the ingressof microorganisms.A “closed”systemcan be more accurately defined by characteristicsof its operation than by a description of its physical attributes. A “closed”system: - Is sterilized-in-placeorsterilizedwhile closed prior to use - Is pressure and/or vacuum tight to some predefinedleak rate

Can be utilized for its intended purpose without breachto the integrity of the system Can be adaptedfor fluid transfers in and/or out while maintaining asepsis Is connectableto other closed systemswhile maintaining integrity of all closed systems (e.g., Rapid Transfer Port, steamed connection, etc.) Utilizes sterilizing filters which are integrity tested and traceableto each product lot. By virtue of their design, closed systems provide a substantially increased measure of protection to the materials processedwithin. Where a sterile BPC can be processedin its entirety within closed systems,no contamination should be possible. A truly closed systemcan be validated as suchand neednot be further challenged through process simulation. Sterilization validation of the closed system should be performed and documented. Processsimulation as describedin this document would only apply to asepticoperations where “open” systemsare employed. 1.4.2

Open Systems

An “open” system lacks one or more of the featuresof a “closed”system.




Number and Frequency of Tests

For a new facility or production process, process simulations are performed as part of the overall validation. Initial processsimulationtestsgenerallyare conductedafter equipment qualification, sterilization processvalidation, and personneltraining have been * performed, and environmental monitoring has demonstratedthat the new facility is under the desired state of control (8, 9, 10). If a processsimulation test fails in the absence of this supportive work, identification of a possiblecausewill be more difficult. Generally, three consecutive successful process simulation tests are performed when evaluatinga new facility or process. Prior to releaseof the new facility, or new processfor production use, acceptableresults from thesetestsshould be achievedto demonstratethe reproducibility of the process. In existing facilities, there should be a processsimulation test program for each aseptic process. Additional process simulation tests should be performed to evaluate changes to procedures,practicesor equipmentconfiguration (See Section 11 - Periodic Reassessment). 2.2


Worst Case


A holistic approach must be used to adequately validate and control aseptic processes. A process simulation test is only a point-in-time representationof the capabilities of an aseptic processing system, including environment, equipment, procedures and personnel. It doesnot ensurethat sterile bulk materials produced at other times will have the same level of microbiological quality. However, through control and validation of related processes,such as environmental monitoring, qualification ofpersonnel andvalidation of cleaning and sterilization cycles, it is possible to maintain the level of asepsisdemonstratedduring the processsimulation test. Therefore, it is important to validate the related sanitization and sterilization processes independently, such as sterilization/depyrogenationof the product, sterilization of the processequipmentincluding product contactsurfaces, sterilization of containers (intermediate and final packagedbulk), and supportsystemssuchas air, water, or nitrogen (5,6,7).



One of the more prevalent techniques used in the validation of pharmaceutical processes is the employment of “worst case”scenarios. The use of “worst case”situationsis intendedto provide a greater challengeto the process,system or equipment being validated than that experienced under routine processingconditions. If, under the circumstancesof the “worst case” challenge, acceptable results are achieved, then there is greater confidence in the reliability of the systemunder more normal situations. Processsimulation tests readily lend themselves to “worst case” challenges. Some of the types of challengeswhich may be employedwhere possibleare: - using materials,equipment,utensilsand other items which have remained in the aseptic processing area for extended periods after sterilization - using the maximum production crew necessaryto processthe batch - increasing the time period between the completion of equipmentsterilization and the start of the processsimulation - using a growth promoting medium or placebo material in the processsimulation test rather than an inhibitory material

PDA Journal of Pharmaceutical

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performing a process simulation test after completion of the last lot in a production campaign

“open”system,through subdivision into containersfor shipment. Advantages

In the developmentof protocols or proceduresusedfor the definition of process simulation tests, the use of “worst case”challengessuch as thosedescribedabove is an essential element of a well-founded program. Risk assessmentapproachessuch as hazard analysis and critical control point (HACCP), failure effects mode analysis (FEMA) or fault tree analysis (FTA) may be used to determineappropriatechallenges. 3



The simulation may be able to follow the process more closely than a seriesof smaller simulations. Requ&es less time to complete than a series of smaller simulations. Disadvantages If contaminationis detectedthe identification and correction of sources is more difficult than in a unit operationsimulation.


The application of these general procedures to any specific asepticproceduremay require modification of the methods described herein. These adaptations should be accomplished in a manner which will not improve the resultsof the simulation, relativeto routine operations. The conduct of processsimulation testsfor sterile bulk pharmaceuticalsentails simulation of the processfrom the point of sterilization through to the completion of bulk packaging. The processsimulation test needsto be conductedfor only the open portion of the process (see Section 1.4.1). In many modem facilities, this may be limited to the final packaging of the sterile BPC. Sterile bulk processesgenerally consist of a series of unit operations which in total comprise the production processes. For the purposes of process simulation it may be appropriateto conductevaluations around either a single operation or a group of operations. Provided that all of the unit operations utilized in the production of a sterile BPC have been evaluated in an appropriate manner, the segmented approach to simulation can be as suitable as a comprehensivetest involving all of the unit operations in a single simulation. The decision whether to perform the processsimulation as a single integrated test or in trials basedupon one or more unit operations must consider the pros and cons of each approach. It should be recognizedthat the decision to conduct an overall simulation or step-wisesimulation approachis independent of the use of microbiological growth media or other materials in the simulation. 3.1

Total Process Simulation

In this type of simulation, the entire asepticprocessis evaluated in a trial which follows the process from where the sterile materials are first manipulatedin an

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/ September-October 1998,Supplement

In the event of failure, the entire simulation must be repeatedafter corrective measureshave been taken. Will generally require the use of a single test material (either liquid or’solid) throughout the entire simulation which may introduce significant differences in the simulation and in how contaminationmight occur when comparedto the routine production process. 3.2

Unit Operation(s)


In this form of simulation, a seriesof individual trials are conductedcovering all of the steps in the aseptic process. Where the simulation is performed in several steps,the establishmentof an acceptancecriterion must addressthe cumulative contribution from each of the unit operations. Thus the total numbersof organisms detectedover the entire processmust be considered. Advantages If contamination is detected, the corrective measurescan focus on a smaller portion of the overall process. Evaluation of the effects of changesto a specific part of the processcan be restricted to a limited number of steps. In the eventof failure of a portion of an individual simulation, only that simulation which failed may needto be repeatedafter correctiveaction hasbeen taken. In some aseptic processes,this approach may

resemblethe actual processmore closely.

acceptancecriteria requirementsin the protocol. Advantages

Allows for the use of either liquid or solid test materials in different parts of the overall simulation, which may more closely resemble actual production.

Allows for the direct evaluation of the aseptic processingprocedures. Less reliance on environmentalconditions in the evaluationof the process.

Disadvantages Requiresmore time to perform than a total process simulation.

Disadvantages The microbiological growth media may be overly sensitiveto antibiotic materialsand other innately inhibitory materials.

May require some degree of overlap to evaluate the overall process. The methods required to evaluateindividual unit operations may require more handling of sterile materials to accommodatea segmentedprocess simulation.

Cleaning of the processequipmentafter exposure to themicrobiological growth mediamay represent a new cleaning procedure which must be developedand validated.

A larger number of environmental monitoring samples must be taken during each of the individual processsimulations. 4



Independent of the decision on whether the aseptic processis to be simulated in total or in unit operation fashion, considerationmust be given to the selectionof a material to be utilized in the simulation. The choices are: a microbiological growth promoting media, placebomaterial, simulation without material or actual product material (generally an excipient). With each choice there are of course certain advantagesand disadvantages. If a test material is utilized, a further decision between a liquid or powder material is also required. Those firms which have chosento segment the process simulation according to the various unit operations,may elect to make different selectionsfor the test material in different parts of their overall program. For example,in sterile BPC simulationswith a crystallization step, a liquid material may be used during simulation of the early steps, and a powder material in those stepswhich follow the crystallization step. SeeAppendix 1 for information on the selection, sterilization and use of test materials. 4.1

It adds increased risk of microbiological contaminationof the facility by providing a major nutrient sourcewhen normal materials used may be innocuousor bactericidal.

Growth Medium Simulations

A microbial growth medium in either liquid or solid state is processedin lieu of the production materials. The microbiological growth media may be tested for microbial count or sterility depending upon the

Detection of contamination in large containers may be difficult. Quantities of microbiological growth media required may be excessive. Processsimulation may have little resemblanceto the actual processbecauseof concernsregarding the media’s growth promotion capability under routine operatingconditionswithin the equipment. 4.2

Placebo Material Simulation

A placebo material is substituted for the production materialsand handledin a representativemanner. The placebomaterial can be sampledfor microbial count or sterility testing dependingupon the acceptancecriteria requirementsof the protocol. Advantages Can use materials which are able to tolerate the actualprocessingconditionsutilized in the aseptic process. Placebo materials can be chosen such that their removal from the processingequipment after the simulation can be readily accomplished.

PDA Journal of Pharmaceutical

Science &Technology

Placebo materials can be substantially less expensivethan product or microbiological growth media, which can be a significant concernin large processequipment.

contact surfaces, Not readily quantifiable. 4.4

Someof the actual materialsutilized in the aseptic processmay be utilized. Disadvantages Sterility or microbial count testing must be performed in order to assess whether any microorganismsare present.




A simulation which is performed using actual production materials (generally an excipient). The materialcan be sampledfor microbial count or sterility testing depending upon the acceptance criteria requirementsof the protocol. Advantages The processbeing simulatedmay utilize identical processingconditionsas thoseused in production.

Cleaning of the processequipmentafter exposure to the placebo may represent a new cleaning procedurewhich must be developedandvalidated.

The materialsusedfor the simulation areknown to be compatiblewith the processingequipment.

The placebomaterial must be evaluatedfor lack of inhibitory effects on microorganisms.

No specialized cleaning of the equipment is necessary, the routine methods used after the production can be employed with confidence.

The sterilization of powder placebos must be validated. Testing of large quantities of material may be required. 4.3


Sterility testing or microbial count determination must be performed.

Without Material

This is a simulation performed in the absence of materials. This approach is well suited to the evaluation of operating procedures and personnel performing discrete aseptic manipulations, e.g., subdivision into final containers. The aseptic production processes are simulated using the procedures, personnel, equipment and components ordinarily utilized in the aseptic process. After completion of the simulation, extensive microbial sampling of product contact surfacesand personnelis performed. The surfacesamplingresultsareutilized to determinemicrobial count or sterility dependingupon the acceptancecriteria requirementsof the protocol. Advantage The absence of materials eliminates cleaning (except for sampling residues,if any), microbial count or sterility testing, inhibition and recovery studies associatedwith the use of either a growth media or a placebo material. Disadvantages Relies on the microbial evaluation of product

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The productionmaterialmust be evaluatedfor lack of inhibitory effects on microorganisms, or a neutralizingagentmust be addedduring the testing The productionmaterialsmay be extremely costly. Testing of large quantities of material may be required. 5




Regardless of the material chosen for use in the simulation trial, it is important to evaluatethat material to determinewhether microorganismswere presentas well as its microbial growth support characteristics. Similar to the precedingsectionof this documentthere are inherent advantagesand disadvantagesassociated with the various test methods. 5.1

Evaluation of Entire Test Material

An approachin which the entire quantity of material (either growth medium or placebo) utilized in the simulation is evaluated. This can be accomplishedby

filtration (after reconstitution for solid materials) through an appropriate sterilizing grade filter or by direct incubation of filled containers. The filter is tested to quantify the microbial bioburden of the material. Care must be taken to test (and reconstitute if necessary) using methods, controls, procedures, equipment and facilities which will not introduce contamination into the material being tested. The entire quantity ofmaterial canbe subjectedto microbial count or sterility testingdependingupon the acceptance criteria requirementsof the protocol

to the testing. The samplescan be testedfor microbial count or sterility depending upon the acceptance criteria requirementsof the protocol Advantages Resemblesthe sampling of routine production materialsfor sterility. If sampling is performed at mult,iple intervals it may be able to pinpoint the source of contamination.

Advantages A smaller quantity of material is tested. Evaluates all of the material processed in the equipment. Best suited for comprehensivetest of the process in a single simulation. Disadvantages Testing of large quantities of material is required which can prove quite cumbersome. Validation of sampling and testing methods, including the sterilization of all apparatus. Limited information is available for use in detectingthe sourceof contaminationin the event of failure. Isolation and identification of microorganisms from the filter may be difficult with certain materials. The test (and reconstitution) procedures may introduce contamination into the sample. Poorly suited to powder materials where the handling requiredto preparethe material for test in this fashion has substantial potential for the introduction of contamination. Direct incubation mandatesa pass/fail acceptance criteria. 5.2

Evaluation of Test Material


After completion of the processsimulation, samplesof the test material are taken from the equipmentand/ or containers.When a liquid material hasbeensampledit may be tested directly. Powder materials require reconstitution with a sterile diluent such as WFI prior


Disadvantages Samplesonly a portion of the material utilized in the simulation and may not detect low levels of contamination, especially with a powdered material. In-process sampling for the purposesof process simulation may not be a part of the routine BPC processand could introduce contaminants. Isolation and identification of microorganisms from the filter may be difficult with certain materials. DOCUMENTATION

Documentationis one of the most important elements of a process simulation test program. Regulatory bodieswill rely heavily on the documentationto judge the adequacyof the simulation. The first step is to define the processto be simulated. The processgenerally is defined as all stepsfrom the sterilization of the sterile BPC, solvents, reactants, containers and to the point the final sterile BPC is sealedin its shippingcontainer. The processdefinition should include a description of all points that require asepticintervention. Oncethe processhasbeenclearly defined, the simulation protocol(s) or procedurescan be written. Thesedocumentsshould include but not be limited to the following information: - Identification of the processto be simulated - Identification of the process train and equipmentto be used - Type of container/closureto be used - Number of personnelparticipating - Test material to be used - Environmentalmonitoring to be performed

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Science & Technology



A copy of the batch record to be used Acceptancecriteria to be utilized Description of the documentationrequired for the final report Rationale for the “worst case”parameters chosen.

The above list should not be consideredall-inclusive. Other factors may have to be considered due to the nature of the processto be simulated. Execution of the protocol is generally performed through a batchrecord. The batchrecordgives detailed instructions on how to perform the processsimulation test(s). It should be written in the same format as a normal batch record and contain the normal data and sign-off elements. Information which normally would be attachedto a batch record also shouldbe attachedto the simulation batch record, i.e., sterilization records for equipment,containers,and utensils, etc. The next step is to document the following: - Number of organismsdetected,if any - Results of environmentaltesting performed. The final report is a summation of the data from the batch record, bioburden testing of simulation material and environmental monitoring samples. Based upon this information, a conclusion is formulated regarding the acceptability of the manufacturing process and facility. 7



Details concerning elements of an effective environmental monitoring program, including sample site selection,samplefrequency,alert and action levels, methodology and interpretation of data, can be found in the literature (11). 8




This sectioncontains important generalinformation to consider when conducting process simulation tests. These issues play an important role in effectively simulating the production process. 8.1


Process simulation tests must include the normal activities which occur during an aseptic process(i.e., equipment adjustments, container-closure resupply, sampling,etc.) in order to substantiatethe acceptability of those practices in routine operation. It is possible

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that non-planned interventions may occur during the simulation and that it will be necessaryto correct for fluid leakage, equipment malfunction, etc. To the extentthat thesetypes of problemsoccur on their own, and arerectified during a successfulprocesssimulation test, they can be defended as acceptable during ordinary operations(4, 12). 8.2

Duration of Simulation

Processsimulationtestsshouldbe of sufficient duration to evaluatethe normal manipulationsnecessaryfor the process. Activities such as initial set-up activities, changing equipment and manual maintenance operationsshouldbe included in the processsimulation tests. Process simulation tests also should be of sufficient duration to include a representativenumber ofroutine andatypical interventionswhich might occur during an actualproduction operation. Where they are part of normal operations,gown changes,breaks and shift changesshould be simulated. The time duration of the process simulation has greatest relevance in operations such as milling and subdivision where repetitive tasks are performed and personnel borne contaminationmay be of greaterrelevance. 8.3

Production Test Size

Batch Size/Process Simulation

A process simulation test should utilize sufficient material to exposemost, if not all contact surfacesto the material. It is essential that the aseptic manipulationsin the simulation closely resemblethose utilized in production, howeverthe actualnumberneed not be identical. 8.4

Incubation Conditions

It is widely accepted that process simulation tests should be incubated for a minimum of 14 days. The temperature at which the medium is incubated, however, varies from firm to firm. The temperature chosen should be based upon its ability to recover microorganismsnormally found environmentally or in the product bioburden. This same panel of microorganismsshould be used in growth testing the medium-filled containers. A single incubation temperature in the range of 20-35°C may be used. Data should be available to show the suitability of the selectedincubationtemperatureto support the growth of environmental and pre-sterilization bioburden isolates.The selectedtemperatureshould be controlled and monitoredcontinuouslythroughout the incubation period.



Manual Procedures

When the productionbatch size is small, theremay be greater prevalence of manual operations in the preparationof sterileproducts. The processsimulation of a manual process of this sort is carried out in accordancewith the methodsand practicesoutlined in this document,with one addition. Each operatorwho performs this type of manual process should be individually evaluatedto establishthe acceptabilityof their aseptictechnique. 8.6

Staffing Considerations

The selection of acceptance criteria for aseptic processingvalidationis the centralissueto be resolved in the conductof processsimulationtests. This section offers guidance which can be used to establish appropriatelimits and acceptancecriteria for aseptic processsimulationtests.

Each personwho works in an asepticproductionsuite should participate in a successfulprocesssimulation test on a periodic basis.


Approaches for Acceptance Criteria




Thedominantmethodologyfor the validationof aseptic processesutilized for drug product compoundingand filling utilizes a mediaprocesssimulationapproach.In conjunction with the execution of this evaluation,a firm typically selectsanacceptancecriteria (often 0.1% of the total number of units filled) (8). Direct application of the process simulation acceptance criteria for asepticfilling to sterilebulk pharmaceutical chemicals is inappropriatefor a number of reasons including: relatively few largecontainersarerequired, inspectionaldifficulties in largecontainers,the amount ofmicrobiologicalgrowth mediarequired,andcleaning growth mediafrom processequipment.An adaptation of the approach is possible which relies on a quantitativeassessment of contaminationlevels.


Multiple lots of sterile BPCs may be produced following a single sterilization without intervening cleaning of the equipmentrequiring a breech in the integrity of the system. The process simulation program should confirm the acceptability of this productionmode. 9




The adoption of limits and acceptancecriteria for processsimulationtestsis one of the more contentious subjects within the industry in recent years (13). Whatever the number of organisms allowed in a processsimulation,the ultimate goal for the numberof organismsin any processsimulationtest (at either the bulk or filling stage)shouldbe zero (4). There are, however, significant technicalproblemsin achievingthis goal. Microbiological growth mediaand simulatedproductsdo not matchrealproductsperfectly in terms of their processing characteristics and microbiological growth support properties. Microbiological growth media differ in many respects from the products they are intendedto simulate; for example, there are differences in solubility, pH, filtration rates and filterability and viscosity. With powderedproducts,theprocesssimulationtestinvolves reconstitutingpowderedmedia or simulatedproduct, introducing extra processing equipment or manipulation,with the inherentrisk of contamination. Since a microbiological growth medium is designed


specifically to support or stimulate the growth of microorganisms,it is a more rigorous challengethan processedproducts,which often provide neutral and sometimeshostile microbial growth environments. Thus,a limit of somelow numberotherthan zerooften is chosen.


Processsimulationtesting is conductedusing either a placebomaterial,productmaterialor a growth medium (either solid or fluid) which contacts equipment surfacesin like mannerto the productbeingsimulated. After completionof the simulationtest, the material is evaluated. The number of colony forming units detectedin the materialcan be usedto project a worst case contaminationrate based on the smallest bulk production batch and the largest finished product container of the product being simulated (i.e., the fewestnumberof finishedproductunits filled from the entirebatch). The processsimulationtestpassesif the contamination rate projects to not more than the chosenlimit. The examplesthat follow are basedon a limit of 1 positive unit in 5,000 finished dosageunits (or NMT 0.0002 CFU/unit). Survey data showsthis is the limit often appliedto processsimulationtestingof finisheddosage forms (12). In the absenceof specific guidancefor

PDA Journal of Pharmaceutical Science &Technology




sterile bulks, finished product survey data provides a valuable reference, however other limits may be appropriatebased on experiencewith the particular processand processsimulation methodology. The simulation batch size may differ from the production batch size provided the aseptic manipulationsare essentiallythe same,and adequate mixing and agitation of the simulation batch can be achievedin the processequipment. When material from more than one processtrain is combinedproducethe finished sterilebulk and it is not possible to simulate the entire process,the projected contaminationrate for the finished bulk is the sum of the process simulation test results from each individually evaluatedprocesstrain. Considerthe following examples:

1. The contamination level for the simulation batch is IO CFU. It projects to IO CFU in the production batch. 2. Determine the minimum number of dosage forms producedfrom theproduction batch. 200,000 g/batch / 5 g/unit = 40,000 units/batch 3. Calculate the maximum CFU/unit and compare to the limit of NMT 0.0002 CFU/unit. IO CFU/batch / 40,000 units/batch = 0.00025CFWunit Since the projected contamination rate 0.00025 CFU/unit exceeds the limit of NMT 0.0002 CFU/unit the processsimulation test fails.

Example 1 Example 3

Minimum productionbatchsize200 kg, maximum finished drug producttill 10g, chosenplacebosize 60 kg, 2 CFU detectedin the simulation.


1. The contamination level for the simulation batch is 2 CFU It projects to 2 CFU in the production batch. 2. Determine the minimum number of dosage forms producedfrom the production batch. 200,000 g/batch / 10 g/unit = 20,000 units/batch

1. The combined contamination level for the simulation batchesis 10 CFU. It projects to 10 CFU in the production batch.

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

2. Determine the minimum number of dosage forms producedfiom theproduction batch.

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

200,000 g/batch / 1 g/unit = 200,000 units/batch

Since the projected contamination rate 0.0001 CFU/unit does not exceed the limit of NMT 0.0002 CFU/unit the process simulation test passes.

3. Calculate the maximum CFU/unit and compare to the limit of NMT 0.0002 CFU/unit. IO CFU/batch / 200,000 units/batch = 0.00005CFU/unit

Example 2


Minimum productionbatchsize200 kg, maximum finished drug product fill 1g, chosenplacebosize 60 kg. The finished bulk is produced from materialfrom processtrains A andB, respectively, blended together in process train C. 3 CFU detectedin the processtrain A placebo, 5 CFU detectedin the processtrain B placebo,and2 CFU detected in the process train C placebo after simulation.

Minimum productionbatchsize200 kg, maximum finished drug product fill 5 g, chosenplacebosize 60 kg, 10 CFU detectedin the simulation.

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Since the projected contamination rate 0.00005 CFU/unit does not exceed the limit of NMT 0.0002 CFU/unit the cumulative process simulation test passes.


NOTE: Microbial count determination has similarities to the sterility test and contamination may be introduced as a consequenceof the test environment,personnelandproceduresemployed. Validation of the test method for the material is essentialto the successof this approach.

This methodology utilizes a widely accepted contaminationrate as the basis for the evaluationof sterile bulk operations. The use of a non-zero contamination rate mimics the approach used for dosageforms. The suggestedapproachrequirestight (albeit, not absolute) control over the extent of microbial contamination acceptable in a process simulation and allows for further improvement as technology and procedures are improved. Most importantly it enablesmeaningfulevaluationof aseptic processing procedures for sterile bulks using a quantitativeapproach. 9.2.2


Any process simulation can be evaluated using a qualitative(pass/fail)criterion. A qualitativeapproach can be usedwith any of the simulationmethods.While it can offer handling advantages (relative to quantitative testing), it precludesrecognition of the aseptic process simulation sampling and testing manipulationsas a possiblecontributorto the presence of organismssince zero growth is the only acceptable option. 10


consecutive process simulation tests should be performedto demonstratethe ability to consistently produceacceptableproduct. 11



Each firm should determine the frequency of and interval betweenperiodic simulation of eachprocess. An annualevaluationof the needto perform a process simulationshouldbe sufficient. Unscheduledprocesssimulationtestsmay be required following a significant change. In such cases,the number of process simulation tests may vary, dependinguponthe extentof the change.Examplesof suchchangesinclude: - Major modifications to the equipment (interchanging standard parts does not constitutea major equipmentmodification) - Modification to equipmentor facilities which potentially affectsthe air quality or airflow in the asepticenvironment - Increasesbeyond the maximum number of production personnel used in process simulationtesting - Major changes to the aseptic production processandforprocedures. It alsomay be necessaryto perform processsimulation testsin responseto adversetrendsor failures in the ongoing monitoring of the facility or process.


A comprehensivesamplingand identification scheme is crucial in the investigation and determinationof sourceof any detectedmicrobial contamination.In the instancewhen the processsimulationtestdoesnot meet the establishedacceptancecriteria, possiblesourcesof contamination should be investigated. A detailed history of the investigationneedsto be maintained. Basedupon the outcomeof the investigation,the cause of the failure is either assignableor not assignable.It may be clearly assignableto a singlesource,or vaguely associatedwith multiple systemsor processeswhich requireredefining. Ifthe causeis assignable,corrective action needsto be taken and documented. The root causeand the correctiveactionwill dictatethe number of processsimulationtestsrequiredto demonstratethat the processis operatingwithin the expectedparameters. If no cause can be found, the process should be validated as though it were a new process. Multiple



PDA Journal of Pharmaceutical Science &Technology





In the conduct of aseptic processsimulation tests for sterile BPC, the use of a sterile placebomaterial may be appropriate. Care must be taken in the choice of material to be used, and in its preparation,to avoid difficulties with the processsimulationtestingprogram. Dependingupon the specific processequipment,and operatingprocedures,it may be appropriateto utilize a liquid or a powder asa test material. Considerationcan alsobe given to the useof a growth promotingmaterial or an inert material. In certainsituationsmorethan one test material can be utilized for different parts of the simulation program. Whichevermaterial is utilized in the simulation, it should be processedand ultimately packagedasclosely aspossibleto the sterileBPC being simulated. Selectionof TestPowder - The selectionof powdertest material for use in process simulation testing must considerseveralfactors. The seeminglyobviouschoice of dry sterile microbiological growth media, itself, has proven less than successfulbecauseof its poor flow properties, which make its passagethrough sterile powder processequipment a considerablechallenge. The principal placebomaterialswhich havebeenused successfully are lactose, mannitol, and polyethylene glycol. The most common choice for a powdermedia is dry Soybean-CaseinDigest Medium (SCDM), though other choices are certainly possible. The chosenmaterial must be easily sterilizable,dispersible or dissolvable in the chosen medium with minimal agitation,haveno adverseeffect on growth promotion, and be easily handled in the simulation process equipment.


Selectionof TestLiquid - The selectionof a liquid test material is governed by several considerations. The use of a microbiological growth media is certainly possible;the most commonobjectionto their userelate to concernswith the cleaning of residual media after completion of the simulation, Liquid media which have been utilized for process simulation include SCDM and peptone broth. Dilution of the media to lower strengthsis employedandis acceptableprovided growth promotion can be demonstrated(see below). Potential placebo fluids may range from Water for Injection to one of the solvents employed in the process, assuming the solvent has no significant antimicrobial activity. Test liquids are generally sterilized by 0.2 micron filtration using the housings requiredfor the process.

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Sterilizationof TestPowder (placeboor growth media) -Part ofthe selectionprocessrequiresthe identification of a suitable sterilization method for the chosen material. The material being evaluated should be subjectedto a validatedsterilizationprocessprior to the processsimulation tests. The validation study should includeverification that the sterilizationprocesshasno significant adverseeffect on the material’sproperties. The most common sterilization method in use is irradiation in the samefinal containeras used for the sterile powder being simulated. Alternatively, the material can be sterilized by dry heat or filtration, followed by bulk lyophilization. Along with the placebomaterial preparedfor use in the filling trial, additionalmaterial in separatebagscan be utilized for sterility testing after sterilization. The test samplescan be testedif there is any questionregardingthe sterility of the material. Inhibition Testingfor Placebo Materials - Growth promotion testing, in which the chosen material is tested for potential inhibition, is performed using Bacillus subtilis (ATCC 6633) and Candida albicans (ATCC 10231)‘. Considerationshould be given to testingwith other microorganismscommonly found in the asepticprocessingareaenvironment,such asthose isolated during personnel monitoring and sterility testing. Replicatesamplesofthe placebomaterialsare inoculatedwith 1O-l 00 CFU of each of the challenge organisms and then dissolved/dispersedin sterile medium. Positive controlsarepreparedby inoculating replicate tubes of medium which do not contain the sterilizedplacebomaterial. Growth must be evident in all tubeswithin sevendaysafter incubationat20-25°C. Growth promotion for liquid placebosis performedin a similar fashion after inoculation, using either direct plating or membranefiltration of the liquid placebo. The filters arethen testedas if for a membranesterility test and growth must appear {within 7 days of incubationat 20-25“C. Growth Promotionfor Growth Media - Confirmation of the media’s growth promotion properties is an essential element. The conduct of media growth promotion evaluationis a relatively simple procedure, with a few basicrequirements.The media utilized for the growth promotionstudiesshouldbe drawnfrom the samematerialutilized for the processsimulation itself. The growth promotion units shouldbe inoculatedwith a low concentration (less than 100 organisms per

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


container) of the USP growth promotion organismsBacillus subtilis & Candida albicans. Consideration should be given to testing additional units with other organismscommonly found in the asepticprocessing area environment, such as the organisms isolated during personnelmonitoring, sterility testing, etc. Media growth promotion studies can be performed prior to, concurrentwith or after the completion of the process simulation incubation period. When growth promotion is performed before incubation, the acceptability of the media is confirmed prior to the simulation. Pre-simulationtesting cannot confirm the acceptability of the media used in the actual trial and either concurrentor post-incubationgrowth promotion must be employed as well. The use of concurrent testing appearspreferable as the results will then be available prior to completion of the incubation. Postincubationgrowth promotion provides a similar degree of assurance, but the delay in obtaining results effectively extends the length of time before the processsimulation results are definitive.



PDA Journal of Pharmaceutical

Science & Technology




aseptic (asepsis) Freefrom disease-producing microorganisms. asepticfilling Part of aseptic processing where a presterilized product is filled and/or packaged into sterile containersand closed. asepticprocessing Handling sterile materials in a controlled environment, in which the air supply, materials, equipment and personnel are regulatedto control microbial and particulate contaminationto acceptablelevels. asepticprocessingarea (APA) Controlledenvironment,consistingof several zones, in which the air supply, materials, equipment and personnel are regulated to control microbial and particulate contaminationto acceptablelevels. closedsystem(seesystem,closed)


colonyforming unit (CFU) Visible outcomeofgrowth ofmicroorganisms arising from a single’or multiple cells. environmentalmonitoringprogram Defined documented program which describes the routine particulate and microbiologicalmonitoringofprocessingand manufacturingareas,andincludesa corrective action plan when action levels are exceeded. It includesassessmentof environmentalair, surfacesand personnel. growth promotion test Test performedto demonstratethat mediawill supportmicrobial growth. microbial count determination A test performedto quantify the number of microorganisms present in a sample of material. Standard microbial methods are utilized to estimate the number of colony forming units (CFU) per unit massor volume.

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opensystem(seesystem,open) process simulation (without microbiological growth media) Method of evaluating an aseptic process employing methods which closely approximatethose used for sterile materials using an appropriatematerial. process simulation (with microbiological growth media) Methodof evaluatingan asepticprocessusing a microbial growth medium employing methods which closely approximate those usedfor sterile materials. sterile Free of any viable organisms. NOTE: In practice, no such absolute statement regarding the absence of microorganisms can be proven (see sterilization). sterility assurancelevel (SAL) Probability that a batch of product is sterile. sterile bulk pharmaceuticalchemical A sterile material derived from chemical, fermentationor semi-syntheticsourceswhich is final packagedor storedin bulk form. The bulk material may be an active pharmaceutical,or excipient. Sterile BPCs can be solids, solutionsor suspensions. sterility test Test performed to determine if viable microorganismsare present. sterilization Validated processused to render a product free of viable organisms. NOTE: In a sterilizationprocess,the natureof microbiological death or reduction is described by an exponential function. Therefore, the number of microorganisms which survive a sterilization processcan be expressedin terms of probability. While the probability may be reduced to a very low number,it can never be reducedto zero.


system,closed A “closed” system is sterilized-in-place or sterilized while closedprior to use,is pressure and/or vacuum tight to some predefmedleak rate, can be utilized for its intendedpurpose without breechto the integrity of the system, can be adaptedfor fluid transfersin and/orout while maintaining asepsis,and connectableto other closed systems while maintaining integrity of all closed systems. system,open A system which fails to meet one or more of the criteria which define a closed system.


unit operation A processingactivity involving multiple steps which effects a single type of changeto the materials (e.g., reaction, crystallization, filtration, drying, milling, etc.) usually carried out in a single piece of equipment. worst case A set of conditions encompassingupper and lower processing limits and circumstances, including those within standard operating procedures,which posethe greatestchanceof processor product failure when comparedto ideal conditions. Such conditions do not necessarilyinduce product or processfailure.

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

7. Sterile Pharmaceutical Products: Process Engineering Applications, Ed. by K. E. Avis, Interpharm,IL, 1995.

2. Technical Report No. 6, “Validation of Aseptic Drug PowderFilling Processes,” PDA, 1984.

8. “Guidelineon Sterile Drug ProductsProducedby Aseptic Processing,”FDA, 1987.

3. “Sterile Bulk Pharmaceutical Chemicals: A PhRMA Position Paper,”PhRMA QC Section Bulk Pharmaceuticals Committeeand SterileBulk PharmaceuticalChemicalsSubcommittee,Pharm. Technol.,August 1995.

9. “Annex 4, GeneralRequirementsfor the Sterility of Biological Substances.Part A, Section 2,” World Health Organization,1973.

4. Technical Report No. 22, “Process Simulation Testing for Aseptically Filled Products,”PDA J. Pharm. Sci. Technol.,50 (Sl), 1996. 5. “Sterilization and Sterility Assurance,‘I USP 23 / NF 18, USP, Rockville, MD, pp. 19761981, 1995. 6. Validation of Aseptic PharmaceuticalProcesses, Ed. by F. Carleton& J. Agalloco, Marcel Dekker, New York, 1986.

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10. EU Guideto GoodManufacturingPractice.Annex 1 - Manufacture of Sterile Medicinal Products, EuropeanUnion, 1996. 11. PDA TechnicalReportNo. 13, “Fundamentalsof a Microbiological Monitoring Program,” SupplementS, .I. Parent. Sci. Tech.,44, 1990. 12. TechnicalReportNo. 24, “Current Practicesin the Validation of Aseptic Processing,”PDA J. Pharm. Sci. Technol.,51 (Sl), 1997. 13. “Guide to Inspection of Sterile Drug Substance Manufacturers,”FDA, 1994.


PDA Journal of Pharmaceutical Science and Technology Supplement, September-October 1998 EDITOR:




Chairman: Chairman-Elect: Secretary: Treasurer: Immediate Past Chairman:

Joyce H. Aydlett Robert B. Myers Floyd Benjamin R. Michael Enzinger, Ph.D. Raymond Shaw, Jr., Ph.D.

James E. Akers, Ph.D. Jennie Allewell Joyce L. DeYoung, Ph.D. Stephanie R. Gray Frederick A. Gustafson 0

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 President:

Volume 52 Joseph B. Schwartz PDA Journal of Pharmaceutical Science & Technology (ISSN 3076-397X) is published bimonthly by the PDA, Inc., 7500 Old Georgetown Rd., Suite 620, Bethesda, MD 20814. Scrhscriprions-Membership dues in the PDA, Inc., include an annual subscription to the Journal for each member and corporate representative. For an application form and information regarding membership, address the Association. Industrial, university and public libraries and government agencies may subscribe at the rate of $135.00 per year. Back issues of the journal are available from the Association for $30.00 plus $ I SO postage and handling per in stock reprint; or $45.00 plus $3.00 postage and handling for photocopies of reprints not in stock. Claims-Issues lost in trtinsit will not be replaced if claim is received more than 90 days from date of issue or if loss was due to failure to give notice of change of address. The Association cannot accept responsibility for delivery outside the United States when shipment has been made by first-class mail. Periodicals postage paid at Bethesda, Maryland and additional mailing offices. Postmaster: send address changes to the PDA Journal of Pharmaceutical Science & Technology, 7500 Old Georgetown Rd., Suite 620, Bethesda, MD 20814. Printed in the U.S.A.

Edmund M. Fry

Formerly the “Journal of ParenteralScienceandTechnology” Copyright-PDA, Inc. 1998 ISSN 1076-397X

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