Guidance for Industry
`Sterile Drug Products Produced by
`Aseptic Processing — Current Good
`Manufacturing Practice
`
`DRAFT GUIDANCE
`This guidance document is being distributed for comment purposes only.
`
`Comments and suggestions regarding this draft document should be submitted within 60 days of
`publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug
`Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be
`identified with the docket number listed in the notice of availability that publishes in the Federal
`Register.
`
`For questions regarding this draft document contact (CDER) Richard Friedman, 301-594-0098;
`(CBER) Robert Sausville, 301-827-6201; (ORA) Robert Coleman, 404-253-1295.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`Office of Regulatory Affairs (ORA)
`
`August 2003
`Pharmaceutical CGMPs
`
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`

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`Guidance for Industry
` Sterile Drug Products Produced by
`Aseptic Processing — Current Good
`Manufacturing Practice
`
`Additional copies are available from:
`Office of Training and Communication
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
` http://www.fda.gov/cder/guidance/index.htm
`
`or
`
` Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
` Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
` http://www.fda.gov/cber/guidelines.htm.
`(Tel) Voice Information System at 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`Office of Regulatory affairs (ORA)
`
`August 2003
`Pharmaceutical CGMPs
`
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`Contains Nonbinding Recommendations
`
`Draft — Not for Implementation
`TABLE OF CONTENTS
`
`INTRODUCTION................................................................................................................. 1
`I.
`II. BACKGROUND ................................................................................................................... 2
`A. Regulatory Framework .................................................................................................................2
`B. Technical Framework....................................................................................................................2
`III. SCOPE ................................................................................................................................... 3
`IV.
`BUILDINGS AND FACILITIES .................................................................................... 4
`A. Critical Area – Class 100 (ISO 5) .................................................................................................5
`B. Supporting Clean Areas ................................................................................................................6
`C. Clean Area Separation ..................................................................................................................7
`D. Air Filtration ..................................................................................................................................7
`1. Membrane ........................................................................................................................................7
`2. High-Efficiency Particulate Air (HEPA) .........................................................................................8
`E. Design............................................................................................................................................ 10
`V. PERSONNEL TRAINING, QUALIFICATION, & MONITORING............................ 13
`A. Personnel....................................................................................................................................... 13
`B. Laboratory Personnel..................................................................................................................15
`C. Monitoring Program....................................................................................................................15
`VI. COMPONENTS AND CONTAINER/CLOSURES......................................................... 16
`A. Components.................................................................................................................................. 16
`B. Containers/Closures..................................................................................................................... 18
`1. Preparation.................................................................................................................................... 18
`2. Inspection of Container Closure System........................................................................................19
`VII. ENDOTOXIN CONTROL................................................................................................ 19
`VIII. TIME LIMITATIONS...................................................................................................... 20
`IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION ...................... 21
`A. Process Simulations ..................................................................................................................... 21
`1. Study Design ................................................................................................................................. 22
`2. Frequency and Number of Runs ....................................................................................................23
`3. Duration of Runs............................................................................................................................ 23
`4. Size of Runs.................................................................................................................................... 24
`5. Line Speed...................................................................................................................................... 24
`6. Environmental Conditions ............................................................................................................. 24
`7. Media ............................................................................................................................................ 25
`8. Incubation and Examination of Media-Filled Units...................................................................... 25
`9. Interpretation of Test Results......................................................................................................... 26
`B. Filtration Efficacy ........................................................................................................................ 27
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`Contains Nonbinding Recommendations
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`Draft — Not for Implementation
`C. Sterilization of Equipment and Container and Closures ......................................................... 29
`1. Sterilizer Qualification and Validation.......................................................................................... 29
`2. Equipment Controls and Instrument Calibration .......................................................................... 30
`X. LABORATORY CONTROLS .......................................................................................... 32
`A. Environmental Monitoring ......................................................................................................... 33
`1. General Written Program.............................................................................................................33
`2. Establishing Levels and a Trending Program ............................................................................... 34
`3. Sanitization Efficacy ......................................................................................................................34
`4. Monitoring Methods ..................................................................................................................... 35
`B. Microbiological Media and Identification ................................................................................. 36
`C. Prefiltration Bioburden............................................................................................................... 36
`D. Alternate Microbiological Test Methods ................................................................................... 37
`E. Particle Monitoring...................................................................................................................... 37
`XI. STERILITY TESTING ...................................................................................................... 38
`A. Choice of Methods........................................................................................................................ 39
`B. Media.............................................................................................................................................39
`C. Personnel.......................................................................................................................................39
`D. Sampling and Incubation ............................................................................................................ 39
`Investigation of Sterility Positives .............................................................................................. 40
`E.
`XII. BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION ........ 43
`APPENDIX 1: ASEPTIC PROCESSING ISOLATORS....................................................... 45
`APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY.......................................................... 50
`APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS.... 53
`REFERENCES............................................................................................................................ 55
`RELEVANT GUIDANCE DOCUMENTS............................................................................... 56
`GLOSSARY................................................................................................................................. 57
`
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`Draft — Not for Implementation
`Contains Nonbinding Recommendations
`Guidance for Industry1
`Sterile Drug Products Produced by
`Aseptic Processing — Current Good Manufacturing Practice
`
`
`This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current
`thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
`bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
`the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
`staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
`the appropriate number listed on the title page of this guidance.
`
`I.
`
`INTRODUCTION
`
`This draft guidance is intended to help manufacturers meet the requirements in the Agency's
`current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when
`manufacturing sterile drug and biological products using aseptic processing. This guidance,
`when finalized, will replace the 1987 Industry Guideline on Sterile Drug Products Produced by
`Aseptic Processing. This revision updates and clarifies the 1987 guidance.
`
`For sterile drug products subject to a new or abbreviated drug application (NDA or ANDA), this
`guidance document should be read in conjunction with the 1994 guidance on the content of
`sterile drug applications, entitled Guideline for the Submission of Documentation for
`Sterilization Process Validation in Applications for Human and Veterinary Drug Products. The
`1994 submission guidance describes the types of information and data that should be included in
`drug applications to demonstrate the efficacy of a manufacturer's sterilization process. This draft
`guidance compliments the 1994 guidance by describing procedures and practices that will help
`enable a sterile drug manufacturing facility to meet CGMP requirements relating, for example, to
`facility design, equipment suitability, process validation, and quality control.
`
`FDA's guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`
`
`1 This guidance was developed by the Office of Compliance in the Center for Drug Evaluation and Research
`(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Office of Regulatory
`Affairs (ORA).
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`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`The text boxes included in this guidance discuss specific sections of parts 210 and 211 of the
`Code of Federal Regulations (CFR), which address current good manufacturing practice for
`drugs. The intent of including the citations in the text boxes is to aid the reader by providing a
`portion of an applicable regulation being addressed in the guidance. The citations included in the
`text boxes are not intended to be exhaustive. Readers of this document should reference the
`complete CFR to ensure that they have complied, in full, with all relevant sections of the
`regulations.
`
`II.
`
`BACKGROUND
`
`This sections describes briefly both the regulatory and technical reasons why the Agency is
`developing this guidance document.
`
`A.
`
`Regulatory Framework
`
`This draft guidance pertains to current good manufacturing practice (CGMP) regulations (21
`CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic
`processing. For biological products regulated under 21 CFR parts 600 through 680, sections
`210.2(a) and 211.1(b) provide that where it is impossible to comply with the applicable
`regulations in both parts 600 through 680 and parts 210 and 211, the regulation specifically
`applicable to the drug product in question shall apply. In the event that it is impossible to
`comply with all applicable regulations in these parts, the regulations specifically applicable to the
`drug in question shall supersede the more general.
`
`B.
`
`Technical Framework
`
`There are basic differences between the production of sterile drug products using aseptic
`processing and production using terminal sterilization.
`
`Terminal sterilization usually involves filling and sealing product containers under high-quality
`environmental conditions. Products are filled and sealed in this type of environment to minimize
`the microbial content of the in-process product and to help ensure that the subsequent
`sterilization process is successful. In most cases, the product, container, and closure have low
`bioburden, but they are not sterile. The product in its final container is then subjected to a
`sterilization process such as heat or irradiation.
`
`In an aseptic process, the drug product, container, and closure are first subjected to sterilization
`methods separately, as appropriate, and then brought together.2 Because there is no process to
`
`2 Due to their nature, certain products are aseptically processed at an earlier stage in the process, or in their entirety.
`Cell-based therapy products are an example. All components and excipients for these products are rendered sterile,
`and release of the final product is contingent on determination of sterility. See Appendix III.
`
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`sterilize the product in its final container, it is critical that containers be filled and sealed in an
`extremely high-quality environment. Aseptic processing involves more variables than terminal
`sterilization. Before aseptic assembly into a final product, the individual parts of the final
`product are generally subjected to several sterilization processes. For example, glass containers
`are subjected to dry heat sterilization; rubber closures are subjected to moist heat sterilization;
`and liquid dosage forms are subjected to sterile filtration. Each of these aseptic manufacturing
`processes requires thorough validation and control. Each process also could introduce an error
`that ultimately could lead to the distribution of a contaminated product. Any manual or
`mechanical manipulation of the sterilized drug, components, containers, or closures prior to or
`during aseptic assembly poses the risk of contamination and thus necessitates careful control. A
`terminally sterilized drug product, on the other hand, undergoes a single sterilization process in a
`sealed container, thus limiting the possibilities for error.3
`
`Manufacturers should have a keen awareness of the public health implications of distributing a
`nonsterile product. Poor CGMP conditions at a manufacturing facility can ultimately pose a life-
`threatening health risk to a patient.
`
`III.
`
`SCOPE
`
`This guidance document discusses selected issues and does not address all aspects of aseptic
`processing. For example, the guidance addresses primarily finished drug product CGMP issues
`while only limited information is provided regarding upstream bulk processing steps. This
`guidance updates the 1987 guidance primarily with respect to personnel qualification, cleanroom
`design, process design, quality control, environmental monitoring, and review of production
`records. The use of isolators for aseptic processing is also discussed.
`
`Although this guidance document discusses CGMP issues relating to the sterilization of
`components, containers, and closures, terminal sterilization of drug products is not addressed. It
`is a well-accepted principle that sterile drugs should be manufactured using aseptic processing
`only when terminal sterilization is infeasible. However, some final packaging may afford some
`unique and substantial advantage (e.g., some dual-chamber syringes) that would not be possible
`if terminal sterilization were employed. In such cases, a manufacturer can explore the option of
`adding adjunct processing steps to increase the level of sterility confidence.
`
`A list of references that may be of value to the reader is included at the conclusion of this
`document.
`
`
`3 Nearly all drugs recalled due to nonsterility or lack of sterility assurance in the period spanning 1980-2000 were
`produced via aseptic processing.
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`Draft — Not for Implementation
`Contains Nonbinding Recommendations
`
`IV.
`
`BUILDINGS AND FACILITIES
`
`
`
`21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of
`adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations
`as are necessary to prevent contamination or mixups during the course of the following procedures: *** (10)
`Aseptic processing, which includes as appropriate: *** (iii) An air supply filtered through high-efficiency
`particulate air filters under positive pressure ***; (iv) A system for monitoring environmental conditions;
`*** (vi) A system for maintaining any equipment used to control the aseptic conditions.”
`
`21 CFR 211.46(b) states that “Equipment for adequate control over air pressure, micro-organisms, dust,
`humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or
`holding of a drug product.”
`
`21 CFR 211.46(c) states, in part, that “Air filtration systems, including prefilters and particulate matter air
`filters, shall be used when appropriate on air supplies to production areas.”
`
`As provided for in the regulations, aseptic processing facilities must have separate areas of
`operation that are appropriately controlled to attain different degrees of air quality depending on
`the nature of the operation. Design of a given area should be based on satisfying microbiological
`and particle standards defined by the equipment, components, and products exposed, as well as
`the particular operation conducted in the area.
`
`Critical areas and support areas of the aseptic processing operation should be classified and
`supported by microbiological and particle data obtained during qualification studies. Although
`initial cleanroom qualification should include some assessment of air quality under as-built and
`static conditions, the final room or area classification should be derived from data generated
`under dynamic conditions (i.e., with personnel present, equipment in place, and operations
`ongoing). The aseptic processing facility monitoring program should also assess conformance
`with specified clean area classifications under dynamic conditions on a routine basis.
`
`The following table summarizes clean area air classifications (Ref. 1).
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`TABLE 1- Air Classificationsa
`
` Clean Area
`Classification
`(0.5 um particles/ft3)
`100
`1000
`10,000
`100,000
`
`ISO
`Designationb
`
`> 0.5 um
`particles/m3
`
`5
`6
`7
`8
`
`3,520
`35,200
`352,000
`3,520,000
`
`Microbiological
`Active Air Action
`Levelsc (cfu/m3 )
`1e
`7
`10
`100
`
`Microbiological Settling
`Plates Action Levels,c,d
`(diam. 90mm; cfu/4 hours)
`1e
`3
`5
`50
`
`a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.
`b-
`ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle
`concentration is equal to Class 100 and approximately equals EU Grade A.
`c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological levels
`due to the nature of the operation.
`d- The additional use of settling plates is optional.
`e-
`Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.
`
`Two clean areas are of particular importance to sterile drug product quality: the critical area and
`the supporting clean areas associated with it.
`
`A.
`
`Critical Area – Class 100 (ISO 5)
`
`A critical area is one in which the sterilized drug product, containers, and closures are exposed to
`environmental conditions designed to preserve sterility. Activities conducted in this area include
`manipulations (e.g., aseptic connections, sterile ingredient additions) of sterile materials prior to
`and during filling and closing operations.
`
`This area is critical because the product is not processed further in its immediate container and is
`vulnerable to contamination. To maintain product sterility, the environment in which aseptic
`operations (e.g., equipment setup, filling) are conducted should be of appropriate quality. One
`aspect of environmental quality is the particle content of the air. Particles are significant because
`they can enter a product and contaminate it physically or, by acting as a vehicle for
`microorganisms, biologically (Ref. 2). Particle content in critical areas should be minimized by
`appropriately designed air handling systems.
`
`Air in the immediate proximity of exposed sterilized containers/closures and filling/closing
`operations would be of appropriate particle quality when it has a per-cubic-meter particle count
`of no more than 3520 in a size range of 0.5 micron and larger when counted at representative
`locations normally not more than 1 foot away from the work site, within the airflow, and during
`filling/closing operations. This level of air cleanliness is also known as Class 100 (ISO 5).
`Deviations from this critical area monitoring parameter should be documented as to cause and
`significance.
`
`Measurements to confirm air cleanliness in aseptic processing zones should be taken with the
`particle counting probe oriented in the direction of oncoming airflow and at the sites where there
`is most potential risk to the exposed sterilized product and container-closures. Regular
`monitoring should be performed during each shift. Nonviable particle monitoring with a remote
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`counting system is generally less invasive than the use of portable particle counting units and
`provides the most comprehensive data. See Section X.D. Particle Monitoring.
`
`Some powder filling operations can generate high levels of powder particles that, by their nature,
`do not pose a risk of product contamination. It may not, in these cases, be feasible to measure air
`quality within the one-foot distance and still differentiate background levels of powder particles
`from air contaminants. In these instances, air should be sampled in a manner that, to the extent
`possible, characterizes the true level of extrinsic particle contamination to which the product is
`exposed. Initial certification of the area under dynamic conditions without the actual powder
`filling function should provide some baseline information on the nonproduct particle generation
`of the operation.
`
`Air in critical areas should be supplied at the point of use as HEPA-filtered laminar flow air at a
`velocity sufficient to sweep particles away from the filling/closing area and maintain
`unidirectional airflow during operations. The velocity parameters established for each
`processing line should be justified and appropriate to maintain unidirectional airflow and air
`quality under dynamic conditions within a defined space (Ref. 3).4
`
`Proper design and control should prevent turbulence or stagnant air in the aseptic processing line
`or clean area. Once relevant parameters are established, airflow patterns should be evaluated for
`turbulence or eddy currents that can act as a channel or reservoir for the accumulation of air
`contaminants (e.g., from an adjoining lower classified area). Air pattern analysis or smoke
`studies should be conducted that demonstrate unidirectional airflow and sweeping action over
`and away from the product under dynamic conditions. The studies should be well documented
`with written conclusions, including an evaluation of the impact of aseptic manipulations.
`Videotape or other recording mechanisms have been found to be useful in assessing airflow
`initially as well as facilitating evaluation of subsequent equipment configuration changes.
`However, even successfully qualified systems can be compromised by poor operational,
`maintenance or personnel practices.
`
`Air monitoring of critical areas should normally yield no microbiological contaminants.
`Contamination in this environment should receive investigative attention.
`
`B.
`
`Supporting Clean Areas
`
`Supporting clean areas can have various classifications and functions. Many support areas
`function as zones in which nonsterile components, formulated products, in-process materials,
`equipment, and container/closures are prepared, held, or transferred. These environments should
`be designed to minimize the level of particle contaminants in the final product and control the
`microbiological content (bioburden) of articles and components that are subsequently sterilized.
`
`The nature of the activities conducted in a supporting clean area should determine its
`classification. An area classified at Class 100,000 (ISO 8) would be used for less critical
`
`4 A velocity from 0.45 to 0.51 meters/second (90 to 100 feet per minute) is generally established, with a range of
`plus or minus 20 percent around the setpoint. Higher velocities may be appropriate in operations generating high
`levels of particulates.
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`activities (such as initial equipment preparation). The area immediately adjacent to the aseptic
`processing line should, at a minimum, meet Class l0,000 (ISO 7) standards (see Table 1) under
`dynamic conditions. Depending on the operation, manufacturers can also classify this area as
`Class 1,000 (ISO 6) or maintain the entire aseptic filling room at Class 100 (ISO 5).
`
`C.
`
`Clean Area Separation
`
`Adequately separating areas of operation is an important part of contamination prevention. To
`maintain air quality in areas of higher cleanliness, it is important to achieve a proper airflow and
`a positive pressure differential relative to adjacent less clean areas. Rooms of higher air
`cleanliness should have a substantial positive pressure differential relative to adjacent rooms of
`lower air cleanliness. For example, a positive pressure differential of at least 12.5 Pascals (Pa)5
`should be maintained at the interface between classified and unclassified areas. This same
`overpressure should be maintained between the aseptic processing room and adjacent rooms
`(with doors closed). When doors are open, outward airflow should be sufficient to minimize
`ingress of contamination, and the time that a door can remain ajar should be strictly controlled
`(Ref. 4). Pressure differentials between cleanrooms should be monitored continuously
`throughout each shift and frequently recorded, and deviations from established limits should be
`investigated.
`
`An adequate air change rate should be established for a cleanroom. For Class 100,000 (ISO 8)
`supporting rooms, airflow sufficient to achieve at least 20 air changes per hour would be
`typically acceptable. For areas of higher air cleanliness, significantly higher air change rates will
`provide an increased level of air purification.
`
`Facility monitoring systems should be established to rapidly detect atypical changes that can
`compromise the facility’s environment. Operating conditions should be restored to established,
`qualified levels before reaching action levels. For example, pressure differential specifications
`should enable prompt detection (i.e., alarms) of an emerging low pressure problem to preclude
`ingress of unclassified air into a classified room.
`
`D.
`
`1.
`
`Air Filtration
`
`Membrane
`
`A compressed gas should be of appropriate purity (e.g., free from oil and water vapor) and its
`microbiological and particle quality should be equal to or better than air in the environment into
`which the gas is introduced. Compressed gases such as air, nitrogen, and carbon dioxid