Professional Documents
Culture Documents
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
PDAlPhRMA
August 1998
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.
6 DOCUMENTATION . . . . . . . . . . . . . . . . . . . 6
7 ENVIRONMENTAL MONITORING . . . . . . 7
May require some degree of overlap to evaluate The microbiological growth media may be overly
the overall process. sensitiveto antibiotic materialsand other innately
inhibitory materials.
The methods required to evaluateindividual unit
operations may require more handling of sterile Cleaning of the processequipmentafter exposure
materials to accommodatea segmentedprocess to themicrobiological growth mediamay represent
simulation. a new cleaning procedure which must be
developedand validated.
A larger number of environmental monitoring
samples must be taken during each of the It adds increased risk of microbiological
individual processsimulations. contaminationof the facility by providing a major
nutrient sourcewhen normal materials used may
4 TEST MATERIALS USED IN PROCESS be innocuousor bactericidal.
SIMULATION
Detection of contamination in large containers
Independent of the decision on whether the aseptic may be difficult.
processis to be simulated in total or in unit operation
fashion, considerationmust be given to the selectionof Quantities of microbiological growth media
a material to be utilized in the simulation. The choices required may be excessive.
are: a microbiological growth promoting media,
placebomaterial, simulation without material or actual Processsimulation may have little resemblanceto
product material (generally an excipient). With each the actual processbecauseof concernsregarding
choice there are of course certain advantagesand the media’s growth promotion capability under
disadvantages. If a test material is utilized, a further routine operatingconditionswithin the equipment.
decision between a liquid or powder material is also
required. Those firms which have chosento segment 4.2 Placebo Material Simulation
the process simulation according to the various unit
operations,may elect to make different selectionsfor A placebo material is substituted for the production
the test material in different parts of their overall materialsand handledin a representativemanner. The
program. For example,in sterile BPC simulationswith placebomaterial can be sampledfor microbial count or
a crystallization step, a liquid material may be used sterility testing dependingupon the acceptancecriteria
during simulation of the early steps, and a powder requirementsof the protocol.
material in those stepswhich follow the crystallization
step. SeeAppendix 1 for information on the selection, Advantages
sterilization and use of test materials.
Can use materials which are able to tolerate the
4.1 Growth Medium Simulations actualprocessingconditionsutilized in the aseptic
process.
A microbial growth medium in either liquid or solid
state is processedin lieu of the production materials. Placebo materials can be chosen such that their
The microbiological growth media may be tested for removal from the processingequipment after the
microbial count or sterility depending upon the simulation can be readily accomplished.
Best suited for comprehensivetest of the process Samplesonly a portion of the material utilized in
in a single simulation. the simulation and may not detect low levels of
contamination, especially with a powdered
Disadvantages material.
Testing of large quantities of material is required In-process sampling for the purposesof process
which can prove quite cumbersome. simulation may not be a part of the routine BPC
processand could introduce contaminants.
Validation of sampling and testing methods,
including the sterilization of all apparatus. Isolation and identification of microorganisms
from the filter may be difficult with certain m
Limited information is available for use in materials.
detectingthe sourceof contaminationin the event
of failure. DOCUMENTATION
Isolation and identification of microorganisms Documentationis one of the most important elements
from the filter may be difficult with certain of a process simulation test program. Regulatory
materials. bodieswill rely heavily on the documentationto judge
the adequacyof the simulation.
The test (and reconstitution) procedures may
introduce contamination into the sample. The first step is to define the processto be simulated.
The processgenerally is defined as all stepsfrom the
Poorly suited to powder materials where the sterilization of the sterile BPC, solvents, reactants,
handling requiredto preparethe material for test in containers and to the point the final sterile BPC is
this fashion has substantial potential for the sealedin its shippingcontainer. The processdefinition
introduction of contamination. should include a description of all points that require
asepticintervention. Oncethe processhasbeenclearly
Direct incubation mandatesa pass/fail acceptance defined, the simulation protocol(s) or procedurescan
criteria. be written. Thesedocumentsshould include but not be
limited to the following information:
5.2 Evaluation of Test Material Samples - Identification of the processto be simulated
- Identification of the process train and
After completion of the processsimulation, samplesof equipmentto be used
the test material are taken from the equipmentand/ or - Type of container/closureto be used
containers.When a liquid material hasbeensampledit - Number of personnelparticipating
may be tested directly. Powder materials require - Test material to be used
reconstitution with a sterile diluent such as WFI prior - Environmentalmonitoring to be performed
200,000 g/batch / 10 g/unit = 20,000 1. The combined contamination level for the
units/batch 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 2. Determine the minimum number of dosage
CFU/unit. forms producedfiom theproduction batch.
Since the projected contamination rate 0.0001 3. Calculate the maximum CFU/unit and
CFU/unit does not exceed the limit of NMT compare to the limit of NMT 0.0002
0.0002 CFU/unit the process simulation test CFU/unit.
passes.
IO CFU/batch / 200,000 units/batch =
Example 2 0.00005CFU/unit
Minimum productionbatchsize200 kg, maximum Since the projected contamination rate 0.00005
finished drug product fill 5 g, chosenplacebosize CFU/unit does not exceed the limit of NMT
60 kg, 10 CFU detectedin the simulation. 0.0002 CFU/unit the cumulative process
0 simulation test passes.
0 aseptic (asepsis)
Freefrom disease-producing
microorganisms.
opensystem(seesystem,open)
I I998 OFFICERS AND DIRECTORS PDA Journal of Pharmaceutical Science & Technology (ISSN
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Formerly the
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Copyright-PDA, Inc. 1998
ISSN 1076-397X