I I

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. 0
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.

0
 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)

ii PDA Journal of Pharmaceutical Science &Technology

Table of Contents

1 INTRODUCTION ..................... 1 9 INTERPRETATION OF RESULTS AND

1.1 Purpose .......................... 1 ACCEPTANCE CRITERIA . . . . . . . . . . . . . . 8
1.2 Sterile Bulk PharmaceuticalChemicals . . 1 9.1 Background . . . . . . . . . . . . . . . . . . . . . . . 8
1.3 Scope ............................ 1 9.2 Approachesfor AcceptanceCriteria . . . . 8
1.4 Sterile BPC ProductionTechnology .... 1 9.2.1 Quantitative . . . . . . . . . . . . . . . . 8
1.4.1 Closed Systems ............. I 9.2.2 Qualitative . . . . . . . . . . . . . . . . 10
1.4.2 Open Systems .............. 2
1.5 Considerations..................... 2 10 FAILURE INVESTIGATION AND
CORRECTIVE ACTION . . . . . . : . . . . . . . . 10
2 PROCESS SIMULATION CONCEPTS AND
PRINCIPLES ......................... 2 11 PERIODIC’REASSESSMENT. . . . . . . . . . . 10
2.1 Number and Frequencyof Tests ....... 2
2.2 Worst Case ........................ 2 APPENDIX 1, SELECTION AND STERILIZATION
OF TEST MATERIALS . . . . . . . . . . . . . . . . 11
3 PROCESSSIMULATION TEST METHODS 3
3.1 Total ProcessSimulation . . . . . . . . . . . . . 3 APPENDIX 2, DEFINITIONS . . . . . . . . . . . . . . 13
3.2 Unit Operation(s)Simulations . . . . . . . . . 3
APPENDIX 3, REFERENCES . . . . . . . . . . . . . . 15
4 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

5 EVALUATION OF SIMULATION TEST

MATERIALS . . . . . . . . . . . . . . . . . . . . . . . . . 5
5.1 Evaluation of Entire Test Material . . . . . . 5
5.2 Evaluation of Test Material Samples. . . . 6

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

7 ENVIRONMENTAL MONITORING . . . . . . 7

8 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

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

 1 INTRODUCTION
1.1 Purpose
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
Vol. 52, No. 5 I September-October 1998, Supplement
might contributeto the microbiologicalcontamination
of the product.
1.2 Sterile Bulk Pharmaceutical Chemicals
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 Scope
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.
1.5 Considerations
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 steriliza-
tion/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).
2 PDA Journal of Pharmaceutical
2 PROCESS SIMULATION CONCEPTS
AND PRINCIPLES
2.1 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
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
Science &Technology
 - performing a process simulation test after
completion of the last lot in a production
campaign
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 PROCESS SIMULATION TEST
METHODS
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
Vol. 52, No. 5 / September-October
1998,Supplement
“open”system,through subdivision into containersfor
shipment.
Advantages
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.
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) Simulations
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.
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.
Disadvantages
Requiresmore time to perform than a total process
simulation.
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.
A larger number of environmental monitoring
samples must be taken during each of the
individual processsimulations.
4 TEST MATERIALS USED IN PROCESS
SIMULATION
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 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
acceptancecriteria requirementsin the protocol.
Advantages
Allows for the direct evaluation of the aseptic
processingprocedures.
Less reliance on environmentalconditions in the
evaluationof the process.
Disadvantages
The microbiological growth media may be overly
sensitiveto antibiotic materialsand other innately
inhibitory materials.
Cleaning of the processequipmentafter exposure
to themicrobiological growth mediamay represent
a new cleaning procedure which must be
developedand validated.
It adds increased risk of microbiological
contaminationof the facility by providing a major
nutrient sourcewhen normal materials used may
be innocuousor bactericidal.
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.
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.
Cleaning of the processequipmentafter exposure
to the placebo may represent a new cleaning
procedurewhich must be developedandvalidated.
The placebomaterial must be evaluatedfor lack of
inhibitory effects on microorganisms.
The sterilization of powder placebos must be
validated.
Testing of large quantities of material may be
required.
4.3 Simulation 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
Vol. 52, No. 5 I September-October 1998, Supplement
contact surfaces,
Not readily quantifiable.
4.4 Production Material Simulation
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.
The materialsusedfor the simulation areknown to
be compatiblewith the processingequipment.
No specialized cleaning of the equipment is
necessary, the routine methods used after the
production can be employed with confidence.
Sterility testing or microbial count determination
must be performed.
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 EVALUATION OF SIMULATION TEST
MATERIALS
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
Advantages
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 Samples
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
6 PDA Journal of Pharmaceutical
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.
A smaller quantity of material is tested.
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 m
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
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 ENVIRONMENTAL MONITORING
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 ELEMENTS OF PROCESS
SIMULATION TESTS
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 Interventions
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
Vol. 52, No. 5 / September-October 1998, Supplement
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 Batch Size/Process Simulation
Test Size
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.
7
 8.5 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
Each personwho works in an asepticproductionsuite
should participate in a successfulprocesssimulation
test on a periodic basis.
8.7 Campaigns
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 INTERPRETATION OF RESULTS AND
ACCEPTANCE CRITERIA
9.1 Background
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
8 PDA Journal of Pharmaceutical Science &Technology
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.
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.
9.2 Approaches for Acceptance Criteria
9.2.1 Quantitative
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, r
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.
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 n,
forms (12). In the absenceof specific guidancefor ,
 sterile bulks, finished product survey data provides a
valuable reference, however other limits may be
0 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:
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
0 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
3. Calculate the maximum CFU/unit and
compare to the limit of NA4T 0.0002
CFU/unit.
2 CFU/batch / 20,000 units/batch =
0.0001 CFU/unit
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.
Example 2
Minimum productionbatchsize200 kg, maximum
finished drug product fill 5 g, chosenplacebosize
60 kg, 10 CFU detectedin the simulation.
0 simulation test passes.
Vol. 52, No. 5 / September-October 1998, Supplement
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.
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.
1. The combined contamination level for the
simulation batchesis 10 CFU. It projects to
10 CFU in the production batch.
2. Determine the minimum number of dosage
forms producedfiom theproduction batch.
200,000 g/batch / 1 g/unit = 200,000
units/batch
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
Since the projected contamination rate 0.00005
CFU/unit does not exceed the limit of NMT
0.0002 CFU/unit the cumulative process
9
 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 Qualitative
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.
consecutive process simulation tests should be
performedto demonstratethe ability to consistently
produceacceptableproduct.
11 PERIODIC REASSESSMENT
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 on-
going monitoring of the facility or process.

10 FAILURE INVESTIGATION AND

CORRECTIVE ACTION

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 n
validated as though it were a new process. Multiple

10 PDA Journal of Pharmaceutical Science &Technology

 APPENDIX 1, SELECTION AND
STERILIZATION OF TEST MATERIALS
0 of a suitable sterilization method for the chosen
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
0 requiredfor the process.
Vol. 52, No. 5 / September-October 1998, Supplement
Sterilizationof TestPowder (placeboor growth media)
-Part ofthe selectionprocessrequiresthe identification
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 <71>, USP 23 / NF 18, P.
1687,USP, Rockville, MD, 1995.
11
 container) of the USP growth promotion organisms-
Bacillus 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. Post-
incubationgrowth 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.

12 PDA Journal of Pharmaceutical Science & Technology

 APPENDIX 2, DEFINITIONS
0 aseptic (asepsis)
Freefrom disease-producing
microorganisms.
asepticfilling
Part of aseptic processing where a pre-
sterilized 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)
0 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.
Vol. 52, No. 5 / September-October 1998, Supplement
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.
13
 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.
14
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.
PDA Journal of Pharmaceutical Science & Technology
 APPENDIX 3, REFERENCES
1. Technical Monograph No. 2, “Validation of
Aseptic Filling for SolutionDrug Products,”PDA,
1980.
2. Technical Report No. 6, “Validation of Aseptic
Drug PowderFilling Processes,”PDA, 1984.
3. “Sterile Bulk Pharmaceutical Chemicals: A
PhRMA Position Paper,”PhRMA QC Section
Bulk Pharmaceuticals
Committeeand SterileBulk
PharmaceuticalChemicalsSubcommittee,Pharm.
Technol.,August 1995.
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 2 11>,‘I
USP 23 / NF 18, USP, Rockville, MD, pp. 1976-
1981, 1995.
6. Validation of Aseptic PharmaceuticalProcesses,
Ed. by F. Carleton& J. Agalloco, Marcel Dekker,
New York, 1986.
Vol. 52, No. 5 I September-October 1998, Supplement
7. Sterile Pharmaceutical Products: Process
Engineering Applications, Ed. by K. E. Avis,
Interpharm,IL, 1995.
8. “Guidelineon Sterile Drug ProductsProducedby
Aseptic Processing,”FDA, 1987.
9. “Annex 4, GeneralRequirementsfor the Sterility
of Biological Substances.Part A, Section 2,”
World Health Organization,1973.
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.
15
 PDA Journal of
Pharmaceutical Science and Technology
Supplement, September-October 1998 Volume 52
EDITOR: Joseph B. Schwartz

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Formerly the
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ISSN 1076-397X