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US FDA guidlines | Sterilization (Microbiology) | Food And Drug Administration
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............................................................................................................................ B....................................................................................... 42
APPENDIX 1: ASEPTIC PROCESSING ISOLATORS........................................................ 1.................... 2..
BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION ............................................... 55 GLOSSARY...................................................................................... Containers................. 49 APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS.............................. 4.......................................................................................................................................... 32 General Written Program .................................................................... 36 Particle Monitoring.........................................................................................................Contains Nonbinding Recommendations
STERILITY TESTING . 39
XII......................... 33 Disinfection Efficacy........................... 38 Sampling and Incubation ...... 29 2....................................................................... Equipment Controls and Instrument Calibration ......................................................................... Qualification and Validation ........................... 34 Monitoring Methods......... 44 APPENDIX 2: BLOW-FILL......................... B.......................................................... 30
X................................SEAL TECHNOLOGY........................................................................................................................................................................................ D........ 52 REFERENCES....................... C........................................................................................................................................................................................................................................................................................................ 34 Microbiological Media and Identification ......
LABORATORY CONTROLS ..............
A................................................................................... 35 Prefiltration Bioburden ...................................... 32 Establishing Levels and a Trending Program ................. 36 Alternate Microbiological Test Methods ................................................ 31
Environmental Monitoring ............................................. 36
XI.. and Closures ............ 54 RELEVANT GUIDANCE DOCUMENTS........................ 38 Investigation of Sterility Positives .. 3......................................................... E...... 28 1..... 37
Microbiological Laboratory Controls ....................... C.................. Sterilization of Equipment..................................... 56
this guidance document should be read in conjunction with the 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 (Submission Guidance). equipment suitability. unless specific regulatory or statutory requirements are cited. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. For sterile drug products subject to a new or abbreviated drug application (NDA or ANDA) or a biologic license application (BLA). This guidance replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing (Aseptic Processing Guideline). The 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. call the appropriate number listed on the title page of this guidance. This guidance compliments the Submission Guidance by describing procedures and practices that will help enable a sterile drug manufacturing facility to meet CGMP requirements relating. contact the FDA staff responsible for implementing this guidance. guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations. The use of the word should in Agency guidances means that something is suggested or recommended. If you cannot identify the appropriate FDA staff. to facility design. This revision updates and clarifies the 1987 guidance. If you want to discuss an alternative approach. and quality control.
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). do not establish legally enforceable responsibilities. for example. Instead.Contains Nonbinding Recommendations
Guidance for Industry1 Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. but not required. including this guidance. FDA's guidance documents. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
This 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. 1
. process validation.
with all relevant sections of the regulations. Aseptic processing involves more variables than terminal sterilization. The intent of including these quotes in the text boxes is to aid the reader by providing a portion of an applicable regulation being addressed in the guidance. supplementary requirements for biological products are in 21 CFR 600-680. Technical Framework
There are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization.Contains Nonbinding Recommendations The text boxes included in this guidance include specific sections of parts 210 and 211 of the Code of Federal Regulations (CFR). Before aseptic assembly into a final product. it is critical that containers be filled and sealed in an extremely high-quality environment. Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful. in full.2(a) and 211. and closure have low bioburden. 2
. B. In an aseptic process. the drug product. but they are not sterile. the individual parts of the final product
Due to their nature. and then brought together. II. Terminal sterilization usually involves filling and sealing product containers under high-quality environmental conditions. Readers of this document should reference the complete CFR to ensure that they have complied. All components and excipients for these products are rendered sterile. The product in its final container is then subjected to a sterilization process such as heat or irradiation.2 Because there is no process to sterilize the product in its final container. container. §§ 210. A. In most cases. certain products are aseptically processed at an earlier stage in the process. as appropriate. Regulatory Framework
This 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. and closure are first subjected to sterilization methods separately. BACKGROUND
This section describes briefly both the regulatory and technical reasons why the Agency is developing this guidance document. which address current good manufacturing practice for drugs. the product. and release of the final product is contingent on determination of sterility.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. Cellular therapy products are an example. For biological products regulated under 21 CFR parts 600 through 680. container. Although the focus of this guidance is on CGMPs in 21 CFR 210 and 211. or in their entirety. the regulation specifically applicable to the drug product in question shall supercede the more general regulations. The quotes included in the text boxes are not intended to be exhaustive. See Appendix III.
some dual-chamber syringes) that would not be possible if terminal sterilization were employed. and review of production records.Contains Nonbinding Recommendations are generally subjected to various sterilization processes. environmental monitoring. It is a well-accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible.g.
Nearly all drugs recalled due to nonsterility or lack of sterility assurance in the period spanning 1980-2000 were produced via aseptic processing. For example. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product.3 Sterile drug manufacturers should have a keen awareness of the public health implications of distributing a nonsterile product. process design. a manufacturer can explore the option of adding adjunct processing steps to increase the level of sterility assurance. or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control. A terminally sterilized drug product. and closures. components. on the other hand. quality control. Each of these manufacturing processes requires validation and control. containers. rubber closures are subjected to moist heat.. In such cases. Poor CGMP conditions at a manufacturing facility can ultimately pose a life-threatening health risk to a patient. some final packaging may afford some unique and substantial advantage (e. and liquid dosage forms are subjected to filtration. cleanroom design. However. For example. thus limiting the possibility of error. The use of isolators for aseptic processing is also discussed. the guidance addresses primarily finished drug product CGMP issues while only limited information is provided regarding upstream bulk processing steps. 3
. undergoes final sterilization in a sealed container. terminal sterilization of drug products is not addressed. This guidance updates the 1987 Aseptic Processing Guideline primarily with respect to personnel qualification. Although this guidance document discusses CGMP issues relating to the sterilization of components. III. Any manual or mechanical manipulation of the sterilized drug. A list of references that may be of value to the reader is included at the conclusion of this document. containers. SCOPE
This guidance document discusses selected issues and does not address all aspects of aseptic processing. glass containers are subjected to dry heat.
separate or defined areas of operation in an aseptic processing facility should be appropriately controlled to attain different degrees of air quality depending on the nature of the operation. (ii) Temperature and humidity controls. in part. or purity of the drug product beyond the official or other established requirements. designed to prevent microbiological contamination of drug products purporting to be sterile. (vi) A system for maintaining any equipment used to control the aseptic conditions.42(b) states. closures. and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. processing. and products exposed. identity. drug product containers. hard surfaces that are easily cleanable. strength.42(c) states.”
As provided for in the regulations. walls. (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions. labeling. inprocess materials. identity.” 21 CFR 211.” 21 CFR 211. Design of a given area involves satisfying microbiological and particle criteria as defined by the equipment.63 states that “Equipment used in the manufacture. micro-organisms. quality. as well as the operational activities conducted in the area. shall be used when appropriate on air supplies to production areas * * *. 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. BUILDINGS AND FACILITIES
21 CFR 211. in part. or absorptive so as to alter the safety. that “The flow of components. and ceilings of smooth.113(b) states that “Appropriate written procedures. or holding of a drug product. maintained. including prefilters and particulate matter air filters. which includes as appropriate: (i) Floors. packing.67(a) states that “Equipment and utensils shall be cleaned. quality. (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure. strength.
. and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety. shall be established and followed. or drug products shall not be reactive.46(c) states. Such procedures shall include validation of any sterilization process.” 21 CFR 211.” 21 CFR 211. (iv) A system for monitoring environmental conditions. or holding of a drug product shall be of appropriate design. components. humidity.” 21 CFR 211. that “Operations shall be performed within specifically defined areas of adequate size. packing. that “Air filtration systems.” 21 CFR 211. processing.46(b) states that “Equipment for adequate control over air pressure.65(a) states that “Equipment shall be constructed so that surfaces that contact components. regardless of whether flow is laminar or nonlaminar. in-process materials.Contains Nonbinding Recommendations IV. or purity of the drug product beyond the official or other established requirements. dust. and drug products through the building or buildings shall be designed to prevent contamination. adequate size. in part. and temperature shall be provided when appropriate for the manufacture.” 21 CFR 211. additive.
1).ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. 90mm.000 ISO Designationb 5 6 7 8 > 0.000 3. An adequate aseptic processing facility monitoring program also will assess conformance with specified clean area classifications under dynamic conditions on a routine basis.000 Microbiological Active Air Action Levelsc (cfu/m3 ) 1e 7 10 100 Microbiological Settling Plates Action Levelsc. it is essential that the environment in which aseptic operations (e. equipment in place. with personnel present.. Appropriately designed air handling systems minimize particle content of a critical area. One aspect of environmental quality is the particle content of the air. Activities conducted in such areas include manipulations (e. aseptic connections. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. in part. Initial cleanroom qualification includes. containers.520 35. d... To maintain product sterility. c. Particles are significant because they can enter a product as an extraneous contaminant.Contains Nonbinding Recommendations Clean area control parameters should be supported by microbiological and particle data obtained during qualification studies.g. cfu/4 hours) 1e 3 5 50
a. Critical Area – Class 100 (ISO 5)
A critical area is one in which the sterilized drug product. e.
Two clean areas are of particular importance to sterile drug product quality: the critical area and the supporting clean areas associated with it. an assessment of air quality under as-built. The following table summarizes clean area air classifications and recommended action levels of microbiological quality (Ref. equipment setup.d (diam.
TABLE 1. 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
. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A.Air Classificationsa Clean Area Classification (0. and closures are exposed to environmental conditions that must be designed to maintain product sterility (§ 211.Values represent recommended levels of environmental quality.g. filling) are conducted be controlled and maintained at an appropriate quality. b. and operations ongoing).e.5 um particles/ft3) 100 1000 10. and can also contaminate it biologically by acting as a vehicle for microorganisms (Ref. sterile ingredient additions) of sterile materials prior to and during filling and closing operations. It is important for area qualification and classification to place most emphasis on data generated under dynamic conditions (i.200 352. This area is critical because an exposed product is vulnerable to contamination and will not be subsequently sterilized in its immediate container. static conditions.520. A.000 100.42(c)(10)).5 µm particles/m3 3. 2).Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.The additional use of settling plates is optional.
45 meters/second (90 feet per minute) has generally been established.
A velocity of 0. Regular monitoring should be performed during each production shift. with a range of plus or minus 20 percent around the setpoint. interventions) and equipment design.5 Proper design and control prevents turbulence and stagnant air in the critical area. it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e.Contains Nonbinding Recommendations of no more than 3520 in a size range of 0. powder) particles that. by their nature. or personnel practices.g. We recommend conducting nonviable particle monitoring with a remote counting system.g. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. air can be sampled in a manner that.5 µm and larger when counted at representative locations normally not more than 1 foot away from the work site. for additional guidance on particle monitoring. and closures. Initial qualification of the area under dynamic conditions without the actual filling function provides some baseline information on the non-product particle generation of the operation. In these instances. to the extent possible. and during filling/closing operations. HEPA-filtered4 air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. 3). Air monitoring samples of critical areas should normally yield no microbiological contaminants.g. be feasible to measure air quality within the one-foot distance and still differentiate background levels of particles from air contaminants. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. We recommend affording appropriate investigative attention to contamination occurrences in this environment. It is important to note that even successfully qualified systems can be compromised by poor operational. We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product. Once relevant parameters are established. 6
. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref.E. See Section X.. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters. The studies should be well documented with written conclusions. In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. within the airflow. in these cases. do not pose a risk of product contamination. maintenance. containers. It may not.. and include evaluation of the impact of aseptic manipulations (e.. characterizes the true level of extrinsic particle contamination to which the product is exposed. This level of air cleanliness is also known as Class 100 (ISO 5). from an adjoining lower classified area). Some operations can generate high levels of product (e. Higher velocities may be appropriate in operations generating high levels of particulates.
These environments are soundly designed when they minimize the level of particle contaminants in the final product and control the microbiological content (bioburden) of articles and components that are subsequently sterilized. Supporting Clean Areas
Supporting clean areas can have various classifications and functions. 7
. equipment cleaning). and it is critical that the time a door can remain ajar be strictly controlled (Ref. Manufacturers can also classify this area as Class 1. in-process materials. An area classified at a Class 100. The Agency recommends that pressure differentials between cleanrooms be monitored continuously throughout each shift and frequently recorded. a substantial overpressure (e.. Maintaining a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide beneficial separation. To maintain air quality.04-0. Many support areas function as zones in which nonsterile components. formulated products.g. at a minimum. it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas. If this pressure differential drops below the minimum limit. the aseptic processing room and adjacent cleanrooms have the same classification. outward airflow should be sufficient to minimize ingress of contamination. Significantly higher air change rates are normally needed for Class 10.000 and Class 100 areas. In some cases. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness.. FDA recommends that the area immediately adjacent to the aseptic processing line meet.5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination.Contains Nonbinding Recommendations B. For example.06 inches of water gauge. The nature of the activities conducted in a supporting clean area determines its classification. Air change rate is another important cleanroom design parameter. In any facility designed with an unclassified room adjacent to the aseptic processing room. C.g. All alarms should be documented and deviations from established limits should be investigated. held.000 (ISO 8) air cleanliness level is appropriate for less critical activities (e. Class 10. airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. at least 12. Clean Area Separation
An essential part of contamination prevention is the adequate separation of areas of operation.
Equal to 0. it is important that the environmental quality of the aseptic processing room be restored and confirmed.000 (ISO 7) standards (see Table 1) under dynamic conditions. a positive pressure differential of at least 10-15 Pascals (Pa)6 should be maintained between adjacent rooms of differing classification (with doors closed).000 (ISO 8) supporting rooms. or transferred. When doors are open. 4).000 (ISO 6) or maintain the entire aseptic filling room at Class 100 (ISO 5). For Class 100. equipment. and container/closures are prepared.
D. Use of hydrophobic filters. Gas filters (including vent filters) should be dry. These filters are often used to produce a sterile compressed gas to conduct operations involving sterile materials. Safeguards should be in place to prevent a pressure change that can result in contamination due to back flow of nonsterile air or liquid. alternate methods can be used to test HEPA filters in the hot zones of these tunnels and ovens. Condensate on a gas filter can cause blockage during use or allow for the growth of microorganisms. such testing should be performed twice a year for the aseptic processing room. nitrogen. Among the filters that should be leak tested are those installed in dry heat depyrogenation tunnels and ovens commonly used to depyrogenate glass vials. alarms) of an emerging low pressure problem to preclude ingress of unclassified air into a classified room. and tanks containing sterilized materials. For example. 2. An effective system facilitates restoration of operating conditions to established.. We recommend that filters that serve as sterile boundaries or supply sterile gases that can affect product be integrity tested upon installation and periodically thereafter (e. Integrity tests are also recommended after activities that may damage the filter. Additional testing may be appropriate when air quality is found to be unacceptable. free from oil) and its microbiological and particle quality after filtration should be equal to or better than that of the air in the environment into which the gas is introduced.e. Sterilized holding tanks and any contained liquids should be held under positive pressure or appropriately sealed to prevent microbial contamination. prevents problematic moisture residues. pressure differential specifications should enable prompt detection (i. or as part of an investigation into a media fill or drug product sterility failure. as well as application of heat to these filters where appropriate. such as components and equipment. and carbon dioxide are often used in cleanrooms and are frequently employed in purging or overlaying.g. Integrity test failures should be investigated. Thereafter. Membrane filters can be used to filter a compressed gas to meet an appropriate high-quality standard. 1. through the frames. For example.. 8
. lyophilizer vacuum breaks.g. leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. and filters should be replaced at appropriate.Contains Nonbinding Recommendations A suitable facility monitoring system will rapidly detect atypical changes that can compromise the facility’s environment. Air Filtration Membrane
A compressed gas should be of appropriate purity (e. end of use). High-Efficiency Particulate Air (HEPA)7
HEPA filter integrity should be maintained to ensure aseptic conditions. Leak testing should be performed at installation to detect integrity breaches around the sealing gaskets.. qualified levels before reaching action levels. we recommend that sterile membrane filters be used for autoclave air lines.
The same broad principles can be applied to ULPA filters. Compressed gases such as air. or through various points on the filter media. For example. defined intervals. facility renovations might be the cause of disturbances to ceiling or wall structures. Where justified.
at a sampling rate of at least one cubic foot per minute. Downstream readings represent an average over the entire filter surface.Contains Nonbinding Recommendations Any aerosol used for challenging a HEPA filter should meet specifications for critical physicochemical attributes such as viscosity.97 percent of particulates greater than 0. on the other hand. The challenge involves use of a polydispersed aerosol usually composed of particles with a light-scattering mean droplet diameter in the submicron size range. Variations in velocity can cause turbulence that increases the possibility of contamination.9 including a sufficient number of particles at approximately 0. Some aerosols are problematic because they pose the risk of microbial contamination of the environment being tested. HEPA filter leak testing alone is insufficient to monitor filter performance. It is important to conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters). It is important to introduce an aerosol upstream of the filter in a concentration that is appropriate for the accuracy of the aerosol photometer. This comprehensive scanning of HEPA filters should be fully documented. or seal. filter frame. The purpose of performing regularly scheduled leak tests. Dioctylphthalate (DOP) and poly-alpha-olefin (PAO) are examples of appropriate leak testing aerosols. 9
. There is a major difference between filter leak testing and efficiency testing. it is greater than 0. Accordingly. An efficiency test is a general test used to determine the rating of the filter. A single probe reading equivalent to 0.8 An intact HEPA filter should be capable of retaining at least 99. An appropriate scan should be conducted on the entire filter face and frame.
Although the mean is normally less than one micron. and the filter face scanned on the downstream side with an appropriate photometer probe. Efficiency tests are not intended to test for filter leaks. A subsequent confirmatory retest should be performed in the area of any repair. The downstream leakage measured by the probe should then be calculated as a percent of the upstream challenge. Velocities of unidirectional air should be measured 6 inches from the filter face and at a defined distance proximal to the work surface for HEPA filters in the critical area.3 micron sized particles and assesses filter media.3µm. HEPA filters should be replaced when nonuniformity of air velocity across an area of the filter is detected or airflow patterns may be adversely affected. repair in a limited area.3 µm in diameter.01 percent of the upstream challenge would be considered as indicative of a significant leak and calls for replacement of the HEPA filter or. The measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies. Velocity monitoring at suitable intervals can provide useful data on the critical area in which aseptic processing is performed. the evaluation of any alternative aerosol involves ensuring it does not promote microbial growth. The leak test should be done in place. when appropriate.3 µm.
The efficiency test uses a monodispersed aerosol of 0. is to detect leaks from the filter media. Performing a leak test without introducing a sufficient upstream challenge of particles of known size upstream of the filter is ineffective for detecting leaks. at a position about one to two inches from the face of the filter.
or an isolator. 10
. thus eliminating a repeated manual activity within the critical area. drug manufacturers are responsible for ensuring that equipment specifications. For example. Transport and loading procedures should afford the same protection. 4). Automation of other process steps. Any intervention or stoppage during an aseptic process can increase the risk of contamination. To prevent changes in air currents that introduce lower quality air. The sterile drug product and its container-closures should be protected by equipment of suitable design. a partially closed sterile product should be transferred only in critical areas. should be minimized. personnel intervention can be reduced by integrating an on-line weight check device. Limiting the duration of exposure of sterile product elements. container-closures. Other appropriate technologies that achieve increased sterility assurance are also encouraged. Regarding the latter. The layout of equipment should provide for ergonomics that optimize comfort and movement of operators. and that these essential certification activities are conducted satisfactorily. Carefully designed curtains and rigid plastic shields are among the barriers that can be
Appropriately designed transfer equipment provides these conditions and can be qualified for this purpose. providing the highest possible environmental control. The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. test methods. Rather than performing an aseptic connection. movement adjacent to the critical area should be appropriately restricted. and designing equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5) clean area are essential to achieving high assurance of sterility (Ref. The number of personnel in an aseptic processing room should be minimized.Contains Nonbinding Recommendations Although contractors often provide these services. or the surrounding environment. Products should be transferred under appropriate cleanroom conditions. E. To prevent contamination. the number of transfers into the critical area of a traditional cleanroom. its critical area. including the use of technologies such as robotics. Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation.10 Facility design should ensure that the area between a filling line and the lyophilizer provide for Class 100 (ISO 5) protection. lyophilization processes include transfer of aseptically filled product in partially sealed containers. most significant. can further reduce risk to the product. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product. The flow of personnel should be designed to limit the frequency with which entries and exits are made to and from an aseptic processing room and. optimizing process flow. For example. and acceptance criteria are defined. Design
Note: The design concepts discussed within this section are not intended to be exhaustive. sterilizing the preassembled connection using sterilize-in-place (SIP) technology also can eliminate a significant aseptic manipulation.
its design should not disturb unidirectional airflow. Airlocks and interlocking doors will facilitate better control of air balance throughout the aseptic processing facility. Use of devices for on-line detection of improperly seated stoppers can provide additional assurance. walls. Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems or other utilities. For example.63) to facilitate ease of sterilization. Equipment should not obstruct airflow and.Contains Nonbinding Recommendations used in appropriate locations to achieve segregation of the aseptic processing line. in critical areas. utensils) as it transfers from lesser to higher classified clean areas to prevent the influx of contaminants. materials should be disinfected according to appropriate procedures or. It is critical to adequately control material (e. Equipment should be appropriately designed (§ 211. Airlocks should be installed between the aseptic manufacturing area entrance and the adjoining unclassified area. Use of an isolator system further enhances product protection (see Appendix 1). when used in critical areas. In this regard. Horizontal surfaces or ledges that accumulate particles should be avoided. Cleanrooms also should not contain unnecessary equipment. Ceilings and associated HEPA filter banks should be designed to protect sterile materials from contamination. such as local protection until completion of the crimping step. and ceilings should be constructed of smooth. Due to the interdependence of the various rooms that make up an aseptic processing facility. in-process supplies. Processing equipment and systems should be equipped with sanitary fittings and valves. It is essential that any drain installed in an aseptic processing facility be of suitable design. Cleanrooms are normally designed as functional units with specific purposes.. Written procedures should address returning a facility to operating conditions following a shutdown. Floors. and the impact of construction activities on facility control. fixtures. rendered sterile by a suitable method. It is also important to ensure ease of installation to facilitate aseptic setup. equipment.g. Examples of adequate design features include seamless and rounded floor to wall junctions as well as readily accessible corners. If stoppered vials exit an aseptic processing zone or room prior to capping. Use of a double-door or integrated sterilizer helps ensure direct product flow.000 (ISO 8) areas. often from a lower to a higher classified area. written procedures should address how materials are to be introduced into the aseptic processing room to ensure that room conditions remain uncompromised. or materials.
. appropriate assurances should be in place to safeguard the product. it is essential to carefully define and control the dynamic interactions permitted between cleanrooms. The effect of equipment design on the cleanroom environment should be addressed. drains are considered inappropriate for classified areas of the aseptic processing facility other than Class 100. With rare exceptions. Other interfaces such as personnel transitions or material staging areas are appropriate locations for air locks. The materials of construction of cleanrooms ensure ease of cleaning and sanitizing. hard surfaces that can be easily cleaned.
drug product containers. that they have been fully investigated.” 21 CFR 211.25(b) states that “Each person responsible for supervising the manufacture.” 21 CFR 211. closures. and arm coverings. quality. The quality control unit shall be responsible for approving or rejecting drug products manufactured. in-process materials. or any combination thereof. packing. identity. labeling.22(a) states that “There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components.” 21 CFR 211. in-process materials. processed. QUALIFICATION. 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. training.28(c) states that “Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas. shall be established and followed. & MONITORING
21 CFR 211.Contains Nonbinding Recommendations V. if errors have occurred. such as head. processing. packing. or held under contract by another company. closures. that “Operations shall be performed within specifically defined areas of adequate size. hand. processing. quality. or any combination thereof.” 21 CFR 211. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.25(a) states that “Each person engaged in the manufacture.42(c) states. training. to enable that person to perform the assigned functions. and experience. Such procedures shall include validation of any sterilization process. strength.28(b) states that “Personnel shall practice good sanitation and health habits. packing.113(b) states that “Appropriate written procedures. and the authority to review production records to assure that no errors have occurred or. packed. to perform assigned functions in such a manner as to provide assurance that the drug product has the safety. PERSONNEL TRAINING. or holding of a drug product shall have education. and experience. or holding of each drug product.” 21 CFR 211. processing. drug product containers.22(c) states that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity.” 21 CFR 211. and purity that it purports or is represented to possess.28(d) states that “Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components. strength. face.”
. which includes as appropriate: * * * (iv) A system for monitoring environmental conditions * * *. and purity of the drug product. and drug products.” 21 CFR 211. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. processing. or holding of a drug product shall wear clean clothing appropriate for the duties they perform.” 21 CFR 211. and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products.28(a) states that “Personnel engaged in the manufacture.” 21 CFR 211. packing. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products. shall be worn as necessary to protect drug products from contamination. in part.25(c) states that “There shall be an adequate number of qualified personnel to perform and supervise the manufacture. designed to prevent microbiological contamination of drug products purporting to be sterile. packaging material. or holding of a drug product shall have the education. Protective apparel.” 21 CFR 211.
Such movements disrupt the unidirectional airflow. the risk to finished product sterility also increases. After initial training. as appropriate. closures. or critical surfaces with any part of their gown or gloves. to minimize the risk of contamination. Appropriate training should be conducted before an individual is permitted to enter the aseptic manufacturing area. microbiology. careful movement should be followed throughout the cleanroom. Between uses. Supervisory personnel should routinely evaluate each operator’s conformance to written procedures during actual operations. containers. After initial gowning. • Keep the entire body out of the path of unidirectional airflow
Unidirectional airflow design is used to protect sterile equipment surfaces. The principle of slow. Disruption of the path of unidirectional flow air in the critical area can pose a risk to product sterility. placed in sterilized containers). it is critical for operators involved in aseptic activities to use aseptic technique at all times. Personnel should not directly contact sterile products. Similarly.g. sterile gloves should be regularly sanitized or changed. patient safety hazards posed by a nonsterile drug product. Instruments should be replaced as necessary throughout an operation. gowning. • Approach a necessary manipulation in a manner that does not compromise sterility of the product
. and product. containerclosures. presenting a challenge beyond intended cleanroom design and control parameters. sterile instruments should be held under Class 100 (ISO 5) conditions and maintained in a manner that prevents contamination (e. and the specific written procedures covering aseptic manufacturing area operations. hygiene.. Fundamental training topics should include aseptic technique. and operated aseptic process minimizes personnel intervention. • Move slowly and deliberately
Rapid movements can create unacceptable turbulence in a critical area. maintained. As operator activities increase in an aseptic processing operation. cleanroom behavior.Contains Nonbinding Recommendations A. Personnel
A well-designed. To ensure maintenance of product sterility. Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: • Contact sterile materials only with sterile instruments
Sterile instruments should always be used in the handling of sterilized materials. the quality control unit should provide regular oversight of adherence to established. written procedures and aseptic technique during manufacturing operations. personnel should participate regularly in an ongoing training program.
protective goggles. a proper aseptic manipulation should be approached from the side and not above the product (in vertical unidirectional flow operations). glove fingers.g. operators should refrain from speaking when in direct proximity to the critical area. and microorganisms shed from. Following an initial assessment of gowning. Written procedures should detail the methods used to don each gown component in an aseptic manner. There should be an established program to regularly assess or audit conformance of personnel to relevant aseptic manufacturing requirements.
. To protect exposed sterilized product. personnel should to maintain gown quality and strictly adhere to appropriate aseptic techniques. We recommend that this assessment include microbiological surface sampling of several locations on a gown (e. chest). The Agency recommends gowns that are sterilized and nonshedding. hoods. Gloves should be sanitized frequently.Contains Nonbinding Recommendations To maintain sterility of nearby sterile materials.. Written procedures should adequately address circumstances under which personnel should be retrained. Sampling sites should be justified. For any aseptic processing operation. An aseptic gowning qualification program should assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures. and elastic gloves are examples of common elements of gowns). forearm. an operator should not engage in any activity that poses an unreasonable contamination risk to the gown. An adequate barrier should be created by the overlapping of gown components (e. The gown should provide a barrier between the body and exposed sterilized materials and prevent contamination from particles generated by. the body.g. If an element of a gown is found to be torn or defective. and cover the skin and hair (face-masks. or reassigned to other areas. if adverse conditions occur. facemask. Annual requalification is normally sufficient for those automated operations where personnel involvement is minimized and monitoring data indicate environmental control. • Maintain Proper Gown Control
Prior to and throughout aseptic operations. requalified. periodic requalification will provide for the monitoring of various gowning locations over a suitable period to ensure consistent acceptability of aseptic gowning techniques. Only personnel who are qualified and appropriately gowned should be permitted access to the aseptic manufacturing area. Also. it should be changed immediately. gloves overlapping sleeves).. additional or more frequent requalification could be indicated. beard/moustache covers.
identification. Asepsis is fundamental to an aseptic processing operation. aseptic technique. that “Samples shall be examined and tested as follows: * * * (6) Each lot of a component.” 21 CFR 211.80(b) states that “Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.”
.84(d) states. VI. reassignment of the individual to operations outside of the aseptic manufacturing area. drug product container. C. Processes and systems cannot be considered to be in control and reproducible if the validity of data produced by the laboratory is in question. Monitoring should be accomplished by obtaining surface samples of each operator's gloves on a daily basis. and personnel qualification in aseptic manufacturing also are applicable to those performing aseptic sampling and microbiological laboratory analyses.80(a) states that “There shall be written procedures describing in sufficient detail the receipt. Sanitizing gloves just prior to sampling is inappropriate because it can prevent recovery of microorganisms that were present during an aseptic manipulation. including those that may not appear in such drug product. an investigation should be conducted promptly. Monitoring Program
Personnel can significantly affect the quality of the environment in which the sterile product is processed. or in association with each lot. Microbiological trending systems. those requiring repeated or complex aseptic manipulations). such written procedures shall be followed. are discussed in more detail under Section X.e. 5). gowning requalification. Follow-up actions can include increased sampling.. and in certain instances.” 21 CFR 211.” 21 CFR 211. or closure that is liable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use. handling. The quality control unit should establish a more comprehensive monitoring program for operators involved in operations which are especially labor intensive (i. and assessment of the impact of atypical trends. When operators exceed established levels or show an adverse trend.3(b)(3) states that “Component means any ingredient intended for use in the manufacture of a drug product. An ongoing goal for manufacturing personnel in the aseptic processing room is to maintain contamination-free gloves and gowns throughout operations. storage. in part. A vigilant and responsive personnel monitoring program should be established. sampling.Contains Nonbinding Recommendations B. increased observation. and approval or rejection of components and drug product containers and closures. Laboratory Personnel
The basic principles of training. This sampling should be accompanied by an appropriate sampling frequency for other strategically selected locations of the gown (Ref. retraining. testing. COMPONENTS AND CONTAINER/CLOSURES
21 CFR 210. Laboratory Controls.
with the resulting mixture sterilized. However. designed to prevent microbiological contamination of drug products purporting to be sterile. Endotoxin load data are significant because parenteral products are intended to be nonpyrogenic. sterilizing. Such procedures shall include validation of any sterilization process.” 21 CFR 211..
See Appendix III for discussion of certain biologic components that are aseptically handled from the start of the process. Irradiation can be used to sterilize some components. sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. There should be written procedures and appropriate specifications for acceptance or rejection of each lot of components that might contain endotoxins. Several methods can be suitable for sterilizing components (see relevant discussion in Section IX). In aseptic processing. bioburden. Any components failing to meet defined endotoxin limits should be rejected. and other excipients. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (or lyophilization) of the component as a sterile powder. Water for Injection (WFI). Examples of components include active ingredients.Contains Nonbinding Recommendations
21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and. conducting carefully designed heat penetration and distribution studies is of particular significance for powder sterilization because of the insulating effects of the powder. this method involves more handling and manipulation and therefore has a higher potential for contamination during processing. A widely used method is filtration of a solution formed by dissolving the component(s) in a solvent such as Water For Injection. where indicated. methods of cleaning.”
A.94(d) states that “Standards or specifications.11 Knowledge of bioburden is important in assessing whether a sterilization process is adequate. USP. Studies should be conducted to demonstrate that the process is appropriate for the component.
A drug product produced by aseptic processing can become contaminated through the use of one or more components that are contaminated with microorganisms or endotoxins.g. and. The solution is passed through a sterilizing membrane or cartridge filter. each component is individually sterilized or several components are combined. 16
. However.” 21 CFR 211. endotoxin) of each component that could be contaminated and establish appropriate acceptance limits. shall be established and followed. methods of testing.113(b) states that “Appropriate written procedures. It is important to characterize the microbial content (e. where indicated by the nature of the drug. Dry heat sterilization is a suitable method for components that are heat stable and insoluble. Filter sterilization is used where the component is soluble and is likely to be adversely affected by heat. and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.
and determination of residuals) should be specified and monitored closely. gas concentration. depyrogenated containers and closures. pressure. For example. mass). Residuals from EtO processes typically include ethylene oxide as well as its byproducts.12 Subjecting glass containers to dry heat generally accomplishes both sterilization and depyrogenation. Where applicable.g. degassing. certain issues should receive attention. Validation study data should demonstrate that the process reduces the endotoxin content by at least 99. the parameters and limits of the EtO sterilization cycle (e. Written procedures should specify the frequency of revalidation of these processes as well as time limits for holding sterile. 17
. We recommend use of rinse water of high purity so as not to contaminate containers. The process used will depend primarily on the nature of the container and/or closure materials. and should be within specified limits. humidity.C. For gases such as Ethylene Oxide (EtO). exposure time. We recommend that these methods be carefully controlled and validated to evaluate whether consistent penetration of the sterilant can be achieved and to minimize residuals. 1. a sterilization validation using a biological indicator challenge would not be indicated. The challenge studies can generally be performed by directly applying a reconstituted endotoxin solution onto the surfaces being tested.. The adequacy of the depyrogenation process can be assessed by spiking containers and closures with known quantities of endotoxin. See Section IX. or other suitable means.g. irradiation. multiple WFI rinses can be effective in removing pyrogens from these containers. Positive controls should be used to measure the percentage of endotoxin recovery by the test method. EtO is an effective surface sterilant and is also used to penetrate certain packages with porous overwrapping. For parenteral products.
When this level of depyrogenation by dry heat has been successfully validated using endotoxin challenge. Validation of dry heat sterilization and depyrogenation should include appropriate heat distribution and penetration studies as well as the use of worst-case process cycles. Plastic containers can be sterilized with an appropriate gas. nonpyrogenic. Containers/Closures Preparation
Containers and closures should be rendered sterile and. aeration. The validation study for such a process should be adequate to demonstrate its ability to render materials sterile and non-pyrogenic. Plastic containers used for parenteral products also should be non-pyrogenic. Pre-sterilization preparation of glass containers usually involves a series of wash and rinse cycles. final rinse water should meet the specifications of WFI. temperature. USP. container characteristics (e.Contains Nonbinding Recommendations B. for parenteral drug products. These cycles serve an important role in removing foreign matter. followed by measuring endotoxin content after depyrogenation.9 percent (3 logs) (see Section VII). Biological indicators are of special importance in demonstrating the effectiveness of EtO and other gas sterilization processes.. and specific loading configurations to represent actual production runs. The endotoxin solution should then be allowed to air dry.
depyrogenation can be achieved by multiple rinses of hot WFI.192. the initial rinses for the washing process should employ at least Purified Water. Any damaged or defective units should be detected.. quality. Normally. The time between washing. Validation data from the washing procedure should demonstrate successful endotoxin removal from rubber materials. and removed.
.g. Equipment suitability problems or incoming container or closure deficiencies can cause loss of container closure system integrity. A potential source of contamination is the siliconization of rubber stoppers. USP. and sterilizing should be minimized because residual moisture on the stoppers can support microbial growth and the generation of endotoxins. during inspection of the final sealed product. extra attention is indicated in the validation of processes that use heat with respect to its penetration into the rubber stopper load (See Section IX. The finished dosage form manufacturer should review and assess the contractor's validation protocol and final validation report. In accord with 211. Any defects or results outside the specifications established for in-process and final inspection are to be investigated in accord with § 211. Functional defects in delivery devices (e. At minimum.Contains Nonbinding Recommendations Rubber closures (e. If damage that is not readily detected leads to loss of container closure integrity. a manufacturer who establishes the reliability of the supplier’s test results at appropriate intervals may accept containers or closures based on visual identification and Certificate of Analysis review.. syringe device defects. followed by final rinse(s) with WFI for parenteral products. improved procedures should be rapidly implemented to prevent and detect such defects.g. Safeguards should be implemented to strictly preclude shipment of product that may lack container closure integrity and lead to nonsterility. Silicone used in the preparation of rubber stoppers should meet appropriate quality control criteria and not have an adverse effect on the safety.84(d)(3). Inspection of Container Closure System
A container closure system that permits penetration of microorganisms is unsuitable for a sterile product. drying (where appropriate). delivery volume) can also result in product quality problems and should be monitored by appropriate in-process testing.C). Because rubber is a poor conductor of heat. For example. stoppers and syringe plungers) can be cleaned by multiple cycles of washing and rinsing prior to final steam or irradiation sterilization. failure to detect vials fractured by faulty machinery as well as by mishandling of bulk finished stock has led to drug recalls. 2. or purity of the drug product. Contract facilities that perform sterilization and/or depyrogenation of containers and closures are subject to the same CGMP requirements as those established for in-house processing. of minimal endotoxin content.
Drug product components. strength. in-process materials. containers. quality. or purity of the drug product beyond the official or other established requirements. sanitized. base. If adequate procedures are not employed. additive. Sterilizing-grade filters and moist heat sterilization have not been shown to be effective in removing endotoxin. and manufacturing equipment are among the areas to address in establishing endotoxin control. and/or sterilized..” 21 CFR 211. storage time limitations. quality. where indicated by the nature of the drug. or removed from equipment surfaces by cleaning procedures. Some clean-in-place procedures employ initial rinses with appropriate high purity water and/or a cleaning agent (e. Endotoxin on equipment surfaces can be inactivated by high-temperature dry heat. packing. Adequate cleaning.Contains Nonbinding Recommendations VII.” 21 CFR 211. acid.. 7). Equipment should be designed to be easily assembled and disassembled. Certain patient populations (e. and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety.” 21 CFR 211. and storage of equipment will control bioburden and prevent contribution of endotoxin load.63 states that “Equipment used in the manufacture. adequate size. Equipment should be dried following cleaning. surfactant). there shall be appropriate laboratory testing to determine conformance to such requirements. neonates). sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. or those administered a parenteral in atypically large volumes or doses can be at greater risk for pyrogenic reaction than anticipated by the established limits based on body weight of a normal healthy adult (Ref. identify. The test procedures shall be in writing and shall be followed. followed by final rinses with heated WFI.”
Endotoxin contamination of an injectable product can occur as a result of poor CGMP controls. endotoxins can be contributed by both upstream and downstream processing equipment. or purity of the drug product beyond the official or other established requirements.65(a) states that “Equipment shall be constructed so that surfaces that contact components. 6. ENDOTOXIN CONTROL
21 CFR 211.g.g.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free. or drug products shall not be reactive. or holding of a drug product shall be of appropriate design. identity. closures. drying. cleaned. and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. strength. maintained.67(a) states that “Equipment and utensils shall be cleaned.94(c) states that “Drug product containers and closures shall be clean and. Such clinical concerns reinforce the importance of exercising appropriate CGMP controls to prevent generation of endotoxins. unless the equipment proceeds immediately to the sterilization step. processing. or absorptive so as to alter the safety.” 21 CFR 211. those receiving other injections concomitantly.
65. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION
21 CFR 211.” 21 CFR 211. for example. The time limits established for the various production phases should be supported by data. A.” 21 CFR 211. Bioburden and endotoxin load should be assessed when establishing time limits for stages such as the formulation processing stage. containers and closures.”
When appropriate. and purity they purport or are represented to possess. shall be established and followed.” “Equipment construction.67 address.84(c) states. but are an important part of the quality systems established by a firm. designed to prevent microbiological contamination of drug products purporting to be sterile. equipment. “Equipment design.” and “Equipment cleaning and maintenance. in part. time limits must be established for each phase of aseptic processing (§ 211. Such a time limit should also prevent a significant increase in upstream bioburden and endotoxin load. Because they can provide a substrate for microbial attachment. TIME LIMITATIONS
21 CFR 211.Contains Nonbinding Recommendations VIII. triggering an evaluation of the need for revalidation or requalification. product exposure while on the processing line.” 21 CFR 211. time limits for the completion of each phase of production shall be established to assure the quality of the drug product.113(b) states that “Appropriate written procedures. A change in facility. and 211. Process Simulations
. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. and storage of sterilized equipment. Such procedures shall include all requirements in this subpart * * *.111). maximum use times for those filters used upstream for solution clarification or particle removal should also be established and justified.”
This section primarily discusses routine qualification and validation study recommendations. IX. Time limits should include. respectively. strength. Such procedures shall include validation of any sterilization process.63. that “Samples shall be collected in accordance with the following procedures: * * * (3) Sterile equipment and aseptic sampling techniques shall be used when necessary. Change control procedures are addressed only briefly. or test method should be evaluated through the written change control program. filtration processes. 211. Such deviation shall be justified and documented. that “There shall be written procedures for production and process control designed to assure that the drug products have the identity.111 states that “When appropriate. The total time for product filtration should be limited to an established maximum to prevent microorganisms from penetrating the filter.100(a) states. and location. process. quality. size. the period between the start of bulk product compounding and its sterilization. in part.
Results are then interpreted to assess the potential for a unit of drug product to become contaminated during actual operations (e. breaks. This process simulation. at start-up. filling. start-up. Media fill studies should closely simulate aseptic manufacturing operations incorporating.g.113). when applicable Aseptic assembly of equipment (e. FDA recommends that the media fill program address applicable issues such as: • • Factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g. An aseptic processing operation should be validated using a microbiological growth medium in place of the product.. sterile ingredient additions. operator fatigue) Representative number. normally includes exposing the microbiological growth medium to product contact surfaces of equipment. as appropriate. compatibility with equipment)
.. sizes. aseptic connections.. the container.. charging containers and closures as well as sterile ingredients) or transfers Shift changes. Study Design
A media fill program should incorporate the contamination risk factors that occur on a production line.g. stoppages. and the closure) are brought together under conditions that contaminate any of those elements. critical environments. aseptic filling and closing operations must be adequately validated (§ 211.. sterilization. and complexity of normal interventions that occur with each run. as well as nonroutine interventions and events (e.Contains Nonbinding Recommendations To ensure the sterility of products purporting to be sterile. maintenance. worst-case activities and conditions that provide a challenge to aseptic operations. closing). during processing) Number of personnel and their activities Representative number of aseptic additions (e. The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug formulation. type. The sealed containers filled with the medium are then incubated to detect microbial contamination.g. type. and gown changes (when applicable) Type of aseptic equipment disconnections/connections Aseptic sample collections Line speed and configuration Weight checks Container closure systems (e. and process manipulations to closely simulate the same exposure that the product itself will undergo..g. also known as a media fill. equipment adjustments) Lyophilization. 1.g. Environmental monitoring data from the process simulation can also provide useful information for the processing line evaluation. container closure systems. and accurately assesses the state of process control.
or end product sterility testing showing contaminated products may be cause for revalidation of the system. container closure system changes. routine semi-annual qualification conducted for each processing line will evaluate the state of control of the aseptic process. The same vigilance should be observed in both media fill and routine production runs.13 All personnel who are authorized to enter the aseptic processing room during manufacturing. Frequency and Number of Runs
When a processing line is initially qualified. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. anomalies in environmental testing results. Duration of Runs
One example might be the movement of personnel into and out of the aseptic processing and gowning change rooms during a shift change.Contains Nonbinding Recommendations • Specific provisions in written procedures relating to aseptic processing (e. the evaluation of a production shift should address its unique time-related and operational features. For example. Subsequently. while multiple runs with divergent results signal a process that is not in control.. Media fills should not be used to justify practices that pose unnecessary contamination risks. and shift changeover. process simulation run(s) should be performed to confirm that deficiencies have been corrected and the process has returned to a state of control. facility and equipment modifications. Participation should be consistent with the nature of each operator’s duties during routine production. should be incorporated into the design of the semi-annual qualification program. We recommend that at least three consecutive separate successful runs be performed during initial line qualification. including technicians and maintenance personnel. When data from a media fill indicate the process may not be in control. Once corrections are instituted. conditions permitted before line clearance is mandated)
A written batch record. 2.g. extended shutdowns. substantive conclusions as to the cause of the media fill failure. 22
. line configuration changes. Each change to a product or line change should be evaluated using a written change control system. Activities and interventions representative of each shift. This approach is important because a single run can be inconclusive. an investigation should be conducted to determine the origin of the contamination and the scope of the problem. documenting production conditions and simulated activities. For example. should participate in a media fill at least once a year. 3. significant changes in personnel. individual media fills should be repeated enough times to ensure that results are consistent and meaningful. Any changes or events that have the potential to affect the ability of the aseptic process to exclude contamination from the sterilized product should be assessed through additional media fills. When an investigation fails to reach well-supported. should be prepared for each media fill run. three consecutive successful runs in tandem with increased scrutiny of the production process may be warranted.
as well as appropriate consideration of the duration of the actual aseptic processing operation. The duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions. 8). manually intensive filling lines). When the possibility of contamination is higher based on the process design (e.g. or extensive manual manipulations. Line Speed
The media fill program should adequately address the range of line speeds employed during production.Contains Nonbinding Recommendations The duration of aseptic processing operations is a major consideration in media fill design.. 4. operated at relatively high speeds. Although the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production operations. use of high line speed is often most appropriate in the evaluation of manufacturing processes characterized by frequent interventions or a significant degree of
.000 units. A generally acceptable starting point for run size is in the range of 5. Each media fill run should evaluate a single line speed. While conventional manufacturing lines are usually automated. should be used. the duration of the process simulation should generally be no less than the length of the actual manufacturing process to best simulate contamination risks posed by operators. generally at or approaching the full production batch size.000 to 10. Vials should not be frozen. For example. When aseptic processing employs manual filling or closing. some processes still include considerable operator involvement. and precautions should be taken that ensure that the medium remains in an aerobic state to avoid potentially inhibiting the growth of microorganisms. while those occurring rarely can be simulated periodically. For operations with production sizes under 5. 5. FDA recommends that unsealed containers be exposed to partial evacuation of the chamber in a manner that simulates the process. a process conducted in an isolator (see Appendix 1) can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation. These factors should be carefully evaluated when designing the simulation to adequately encompass conditions and any potential risks associated with the larger operation. a larger number of units. and the speed chosen should be justified. Interventions that commonly occur should be routinely simulated. the number of media filled units should at least equal the maximum batch size made on the processing line (Ref. and designed to limit operator intervention. In contrast. other appropriate models can be justified.000. For lyophilization operations. The number of units filled during the process simulation should be based on contamination risk for a given process and sufficient to accurately simulate activities that are representative of the manufacturing process. Size of Runs
The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination. Media fill size is an especially important consideration because some batches are produced over multiple shifts or yield an unusually large number of units.
g. The media selected should be demonstrated to promote growth of grampositive and gram-negative bacteria. the origin of any contamination found during the simulation should nonetheless be investigated and the media fill promptly repeated. Each unit should be filled with an appropriate quantity and type of microbial growth medium to contact the inner container closure surfaces (when the unit is inverted or thoroughly swirled) and permit visual detection of microbial growth. fluid thioglycollate medium) should be considered in special circumstances. Use of anaerobic growth media (e. If the growth promotion testing fails. maximum number of personnel present and elevated activity level). and.Contains Nonbinding Recommendations manual manipulation. However. sterilization of equipment. if the medium is handled properly and is promptly followed by the cleaning. such as soybean casein digest medium.. sanitizing. 8. To the extent standard operating procedures permit stressful conditions (e. Incubation and Examination of Media-Filled Units
Media units should be incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture..g. 6.. 7. Incubation conditions should be established in accord with the following general guidelines:
The cause of the growth promotion failure should also be investigated. Use of slow line speed is generally appropriate for evaluating manufacturing processes with prolonged exposure of the sterile drug product and containers/closures in the aseptic area. subsequently processed products are not likely to be compromised. 24
. Growth promotion units should be inoculated with a <100 CFU challenge. a microbiological growth medium. where necessary. Media
In general. Some drug manufacturers have expressed concern over the possible contamination of the facility and equipment with nutrient media during media fill runs. should be used. Stressful conditions do not include artificially created environmental extremes. and yeast and mold (e. The QC laboratory should determine if USP indicator organisms sufficiently represent productionrelated isolates. or under production controls and precautions taken in preparation for the media fill.14 The production process should be accurately simulated using media and conditions that optimize detection of any microbiological contamination. An inaccurate assessment (making the process appear cleaner than it actually is) can result from conducting a media fill under extraordinary air particulate and microbial quality. USP indicator organisms). it is important that media fills include analogous challenges to support the validity of these studies.g. Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge. Environmental Conditions
Media fills should be adequately representative of the conditions under which actual manufacturing operations are conducted. such as reconfiguration of HVAC systems to operate at worst-case limits.
batch records (i. a thorough investigation should be conducted to determine its cause (see Section VI. When a firm performs a final product inspection of units immediately following the media fill run.Contains Nonbinding Recommendations • Incubation temperature should be suitable for recovery of bioburden and environmental isolates and should at no time be outside the range of 20-35oC.15 Where procedures lack specificity. 25
.. If appropriate. for production and media fills) should clearly document conformance with this procedure. Incubation time should not be less than 14 days. units that lack integrity should be rejected. We recommend incorporating
To assess contamination risks during initial aseptic setup (before fill). All suspect units identified during the examination should be brought to the immediate attention of the QC microbiologist. training. If written procedures and batch documentation are adequate to describe an associated clearance. In no case should more units be removed during a media fill intervention than would be cleared during a production run. Written procedures regarding aseptic interventions should be clear and specific (e. the units should be incubated for at least 7 days at each temperature (starting with the lower temperature). Erroneously rejected units should be returned promptly for incubation with the media fill lot.g.
Each media-filled unit should be examined for contamination by personnel with appropriate education. and experience in inspecting media fill units for microbiological contamination. other methods can also be considered to ensure visual detection. if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed.e. and would not necessarily be included in the acceptance criteria for the media fill.g. there would be insufficient justification for exclusion of units removed during an intervention from incubation. any unit found to be damaged should be included in the data for the media fill run. Any decision to exclude such incubated units (i. all integral units should proceed to incubation. because the units can be representative of drug product released to the market. non-integral) from the final run tally should be fully justified and the deviation explained in the media fill report.. The ability of a media fill run to detect potential contamination from a given simulated activity should not be compromised by a large-scale line clearance. we recommend substituting clear containers (with otherwise identical physical properties) for amber or other opaque containers.. Incubation temperature should be maintained within +2.5oC of the target temperature. After incubation is underway. valuable information can be obtained by incubating all such units that may be normally removed. To allow for visual detection of microbial growth. If a correlation emerges between difficult to detect damage and microbial contamination. the intervention units removed during media fills do not need to be incubated. For example.B). providing for consistent production practices and assessment of these practices during media fills. If QC personnel do not perform the inspection. cosmetic defect) should be incubated. Units found to have defects not related to integrity (e. If two temperatures are used for the incubation of the media filled units. intervention type. quantity of units removed). These units are typically incubated separately. there should be QC unit oversight throughout any such examination.e..
Contains Nonbinding Recommendations appropriate study provisions to avoid and address a large line clearance that results in the removal of a unit possibly contaminated during an unrelated event or intervention. Whenever contamination exists in a media fill run. 9. following investigation. Interpretation of Test Results
The process simulation run should be observed by the QC Unit. Modern aseptic processing operations in suitably designed facilities have demonstrated a capability of meeting contamination levels approaching zero (Ref. When filling more than 10.One (1) contaminated unit should result in an investigation.One (1) contaminated unit should result in an investigation. The number of contaminated units should not be expected to increase in a directly proportional manner with the number of vials in the media fill run.
For any run size. following investigation. following an investigation. any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill. Video recording of a media fill may serve as a useful aide in identifying personnel practices that could negatively affect the aseptic process. 26
. -.One (1) contaminated unit is considered cause for revalidation. Appropriate criteria should be established for yield16 and accountability (reconciliation of filled units). Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile. regardless of run size.000 to 10. The microorganisms should be identified to species level.000 units: -. When filling from 5. In addition. including consideration of a repeat media fill. no contaminated units should be detected. -.
Total units incubated/total number of units filled. The investigation should survey the possible causes of contamination. 9) and should normally yield no media fill contamination. Media fill record reconciliation documentation should include a full accounting and description of units rejected from a batch. and contaminated units should be reconcilable with the approximate time and the activity being simulated during the media fill. Any contaminated unit should be considered objectionable and investigated. 8. it should be considered indicative of a potential sterility assurance problem.Two (2) contaminated units are considered cause for revalidation. intermittent incidents of microbial contamination in media filled runs can be indicative of a persistent low-level contamination problem that should be investigated.000 units: -.Two (2) contaminated units are considered cause for revalidation. Recommended criteria for assessing state of aseptic line control are as follows: • When filling fewer than 5000 units. -.
The purpose of an aseptic process is to prevent any contamination.17 Currently.C. and revalidation.2 µm or smaller. 331(a)). The number of microorganisms in the challenge is important because a filter can contain a number of pores larger than the nominal rating.3 µm mean diameter). The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production. B.2µ are considered interchangeable nominal pore size ratings.S. when justified as equivalent or better than use of B. it may be appropriate to conduct bacterial retention studies with a bioburden isolate. harvested and used. FDA also recognizes that there might be some scientific and technical limitations on how precisely and accurately process simulations can characterize a system of controls intended to exclude contamination. Filtration Efficacy
Filtration is a common method of sterilizing drug product solutions. A media fill run should be aborted only under circumstances in which written procedures require commercial lots to be equally handled.18 Use of redundant sterilizing filters should be considered in many cases. producing a sterile effluent. diminuta. 27
. correction. Product bioburden should be evaluated when selecting a suitable challenge microorganism to assess which microorganism represents the worst-case challenge to the filter. regardless of acceptance criteria. which has the potential to allow passage of microorganisms. Bioburden of unsterilized bulk solutions should be determined to trend the characteristics of potentially contaminating organisms. Whatever filter or combination of filters is used. is a common challenge microorganism for 0. resulting in no passage of the challenge microorganism. an act that is prohibited under the FD&C Act (Section 301(a) 21 U.Contains Nonbinding Recommendations Accordingly. would be a signal of an adverse trend on the aseptic processing line that should lead to problem identification.22µ and 0. The microorganism Brevundimonas diminuta (ATCC 19146) when properly grown. The probability of such passage is considered to increase as the number of organisms (bioburden) in the material to be filtered increases. validation should include microbiological challenges to simulate worst-case production conditions for the material to be filtered and integrity test results of the filters used for the study. As with any process validation run. A sterilizing grade filter should be validated to reproducibly remove viable microorganisms from the process stream. 0. A manufacturer is fully liable for the shipment of any nonsterile unit. The manufacturing process controls should be designed to minimize the bioburden of the unfiltered product. In certain cases. it is important to note that invalidation of a media fill run should be a rare occurrence. A challenge concentration of at least 107 organisms per cm2 of effective filtration area should generally be used.2 µm rated filters because of its small size (0. Supporting documentation and justification should be provided in such cases. such filters usually have a rated pore size of 0.
This document does not address virus removal. A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit. recurring incidents of contaminated units in media fills for an individual line.
including microbial challenges. and Closures
Equipment surfaces that contact sterilized drug product or its sterilized containers or closures must be sterile so as not to alter purity of the drug (211. it is important to ensure that identical filters (e.67 and 211. a drug product could be filtered in a manner in which the worst-case combination of process specifications and conditions are simulated. are two integrity tests that can be used. of identical polymer construction and pore size rating) are used in production runs. However. A production filter’s integrity test specification should be consistent with data generated during bacterial retention validation studies. (7) temperature. Sterilization of Equipment. However. and filter. Sterilizing filters should be routinely discarded after processing of a single lot. Factors that can affect filter performance generally include (1) viscosity and surface tension of the material to be filtered. in those instances when repeated use can be justified. the sterile filter validation should incorporate the maximum number of lots to be processed. need not be conducted in the actual manufacturing areas. and should be routinely performed post-use. (4) pressures. process. when appropriately employed. C. can lead to erroneous conclusions. using an appropriately modified product (e. Where reasonable contamination potential exists. After a filtration process is properly validated for a given product. 12). For example. This step could be followed by filtration of the challenge organism for a significant period of time. (2) pH. such as maximum filter use time and pressure (Ref. Filter validation experiments.. it is essential that laboratory experiments simulate actual production conditions. When designing the validation protocol. Integrity testing of the filter(s) can be performed prior to processing. There are advantages to using production filters in these bacterial retention validation studies. the effects of the product formulation on the membrane's integrity can be assessed using an appropriate alternate method. (6) maximum use time. directly inoculating B. It is as important in aseptic processing to validate the
. it is important to address the effect of the extremes of processing factors on the filter capability to produce sterile effluent. (5) flow rates. lacking an antimicrobial preservative or other antimicrobial component) as the vehicle. When sufficiently justified.g. it is the responsibility of the filter user to review the validation data on the efficacy of the filter in producing a sterile effluent. under the same conditions. However. The data should be applicable to the user's products and conditions of use because filter performance may differ significantly for various conditions and products. Filter validation should be conducted using the worst-case conditions.113). (9) and the effects of hydraulic shock.g.. or into oil-based formulations. Containers. (3) compatibility of the material or formulation components with the filter itself. It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration. diminuta into products with inherent bactericidal activity against this microbe. The specific type of filter membrane used in commercial production should be evaluated in filter validation studies. Forward flow and bubble point tests. When the more complex filter validation tests go beyond the capabilities of the filter user.Contains Nonbinding Recommendations Direct inoculation into the drug formulation is the preferred method because it provides an assessment of the effect of drug product on the filter matrix and on the challenge organism. (8) osmolality. However. surfaces that are in the vicinity of the sterile product should also be rendered free of viable organisms. Any divergence from a simulation using the actual product and conditions of processing should be justified. tests are often conducted by outside laboratories or by filter manufacturers.
1. Moist heat and dry heat sterilization. alternate intervals can be defined. However. careful consideration should be given during sterilization validation to the nature or type of material chosen as the carrier of the biological indicator to ensure an appropriately representative study. containers. Empty chamber studies evaluate numerous locations throughout a sterilizing unit (e. When determining which
If appropriate. justified. It is important to remove air from the autoclave chamber as part of a steam sterilization cycle.19 Following sterilization. Qualification and Validation
Validation studies should be conducted to demonstrate the efficacy of the sterilization cycle. Validation of the sterilization process with a loaded chamber demonstrates the effects of loading on thermal input to the items being sterilized and may identify difficult to heat or penetrate items where there could be insufficient lethality to attain sterility. Sterility of aseptic processing equipment should normally be maintained by sterilization between each batch. temperature.g. We recommend placing biological indicators at appropriate downstream locations of the filter.g. These uniformity or mapping studies should be conducted with calibrated measurement devices. Batch production records should subsequently document adherence to the validated load patterns. The insulating properties of air interfere with the ability of steam to transfer its energy to the load. The specific load configurations. are the primary processes discussed in this document. The placement of biological indicators at numerous positions in the load. achieving lower lethality than associated with saturated steam. Heat penetration studies should be performed using the established sterilizer loads. is a direct means of confirming the efficacy of any sterilization procedure.. Potentially difficult to reach locations within the sterilizer load or equipment train (for SIP applications) should be evaluated. filter installations in piping can cause a substantial pressure differential across the filter. Requalification studies should also be performed on a periodic basis. transportation and assembly of equipment. the biological indicator should be placed adjacent to the temperature sensor so as to assess the correlation between microbial lethality and predicted lethality based on thermal input.. steam autoclave. as well as biological indicator and temperature sensor locations. large tanks.Contains Nonbinding Recommendations processes used to sterilize such critical equipment as it is to validate processes used to sterilize the drug product and its container and closure. dry heat oven) or equipment train (e. resulting in a significant temperature drop on the downstream side. For this reason. 29
. immobile piping) to confirm uniformity of conditions (e. In general. should be documented in validation records.g. and closures should be performed with strict adherence to aseptic methods in a manner that protects and sustains the product's sterile state. the most widely used.. including the most difficult to sterilize places. pressure). It also should be noted that the resistance of microorganisms can vary widely depending on the material to be sterilized. and supported by validation studies. For example. many of the heat sterilization principles discussed in this guidance are also applicable to other sterilization methods.
Devices used to monitor dwell time in the sterilizer should be periodically calibrated. 2. equipment should be properly designed with attention to features such as accessibility to sterilant.g. including biological challenges. For example. However. Equipment control should be ensured through placement of measuring devices at
. Some other examples include certain locations of tightly wrapped or densely packed supplies. D-value determinations can be conducted by an independent laboratory.Contains Nonbinding Recommendations articles are difficult to sterilize. special attention should be given to the sterilization of filters. For more information. we recommend that procedures address the following: • • • • Temperature and pressure monitoring devices for heat sterilization should be calibrated at suitable intervals. the sterile filter apparatus. Biological indicators should be stored under appropriate conditions. spore strips. glass ampuls) can be accepted in lieu of confirmatory testing of each lot. Change control procedures should adequately address issues such as a load configuration change or a modification of a sterilizer. For dry heat depyrogenation tunnels. the D-value of a biological indicator (e.
To ensure robust process control. securely fastened load articles. filling manifolds. If the reliability of a vendor’s Certificate of Analysis is established through an appropriate qualification program. The microbial count of a biological indicator should be confirmed.g. cycle specifications for such sterilization methods should be based on the delivery of adequate lethality to the slowest to heat locations. please also refer to the FDA guidance entitled Guideline for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. The sensing devices used for validation studies should be calibrated before and after validation runs. and periodic verification of the cycle. and pumps. change control. Written procedures should be established to ensure that these devices are maintained in a calibrated state. the reliability of the data generated by sterilization cycle monitoring devices should be considered to be of the utmost importance. sensors and transmitters) used to measure belt speed should be routinely calibrated. and proper condensate removal (as applicable). maintenance. The sterilizer validation program should continue to focus on the load areas identified as most difficult to penetrate or heat. and stopper load. Bacterial endotoxin challenges should be appropriately prepared and measured by the laboratory. a determination of resistance (D-value) should be performed for any biological indicator inoculated onto a substrate. instruments used to determine the purity of steam should be calibrated. lengthy tubing. hydrophobic filters. Devices that measure cycle parameters should be routinely calibrated. A sterility assurance level of 10-6 or better should be demonstrated for a sterilization process. Ultimately. or used in a way that is other than described by the vendor. devices (e.. Equipment Controls and Instrument Calibration
For both validation and routine process control. The suitability of the sterilizer should be established by qualification. Where applicable. piping slope.
in part. in part. X.56(c) states. and purity. Such procedures shall also require appropriate retesting of any component.” 21 CFR 211. drug product containers. drug product container. that “To assure batch uniformity and integrity of drug products. quality.” 21 CFR 211. and labeling used in the manufacture. Sterilizing equipment should be properly maintained to allow for consistent. (2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. fungicides. Where manual manipulations of valves are required for sterilizer or SIP operations. labeling. methods.” 21 CFR 211. such as equilibrium (come up) time is important in assuring that the unit continues to operate as per the validated conditions. shall be established and followed.22(c) states that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity. and materials to be used in cleaning the buildings and facilities. in part. labeling materials. Such procedures shall include validation of any sterilization process.42(c) states. in-process materials.113(b) states that “Appropriate written procedures. processing. drug product containers. that “Operations shall be performed within specifically defined areas of adequate size. fumigating agents. or closure that is subject to deterioration. in-process materials. or drug products and shall be followed * * *. 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. strength. components.” 21 CFR 211. The specifications shall include a description of the sampling and testing procedures used. and drug products shall be available to the quality control unit. quality. and drug products conform to appropriate standards of identity. such written procedures shall be followed.Contains Nonbinding Recommendations those control points that are most likely to rapidly detect unexpected process variability. written procedures shall be established and followed that describe the in-process controls. closures. these steps should be documented in manufacturing procedures and batch records. designed to prevent microbiological contamination of drug products purporting to be sterile. which includes as appropriate: * * * (iv) A system for monitoring environmental conditions. equipment. or examinations to be conducted on appropriate samples of in-process materials of each batch. and test procedures designed to assure that components. sampling plans. drug product containers. * * *. and cleaning and sanitizing agents.22(b) states that “Adequate laboratory facilities for the testing and approval (or rejection) of components.” 21 CFR 211. Such samples shall be representative and 31
. closures. packaging. satisfactory function.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications. Such written procedures shall be designed to prevent the contamination of equipment.56(b) states that “There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules. packaging materials.110(a) states. or holding of drug products. insecticides. and tests. standards. closures. drug product containers. packing.” 21 CFR 211. strength. that “There shall be written procedures for use of suitable rodenticides.” 21 CFR 211. Routine evaluation of sterilizer performance-indicating attributes. LABORATORY CONTROLS
21 CFR 211. and purity of the drug product. closures. Laboratory controls shall include: (1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components. Samples shall be representative and adequately identified. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product * * *.
and reproducibility of test methods employed by the firm shall be established and documented. including factors such as difficulty of setup. Environmental monitoring should promptly identify potential routes of contamination. and provisions for remedial action in the event accuracy and/or precision limits are not met.g.g. gowning rooms) using scientifically sound sampling procedures. including those for packaging and labeling. including the critical surfaces that come in contact with the product. that “All drug product production and control records. The monitoring program should cover all production shifts and include air. apparatus. When identifying critical sites to be sampled. It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities. sensitivity. and impact of interventions.Contains Nonbinding Recommendations
properly identified. specificity. and equipment surfaces. (3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products.
Environmental Monitoring General Written Program
In aseptic processing. Written procedures should include a list of locations to be sampled. container. Evaluating the quality of air and surfaces in the cleanroom environment should start with a welldefined written program and scientifically sound methods. Such samples shall be representative and properly identified.” 21 CFR 211.192 states. and recording devices not meeting established specifications shall not be used. and recording devices at suitable intervals in accordance with an established written program containing specific directions. when a given batch is being manufactured) as well as environmental trends of ancillary clean areas. aseptic corridors.113).194(a)(2). This program provides meaningful information on the quality of the aseptic processing environment (e. approved written procedures before a batch is released or distributed * * *.” 21 CFR 211. 1. in part. Sample timing. shall be reviewed and approved by the quality control unit to determine compliance with all established. Detection of microbial contamination on a critical site would not necessarily result in batch rejection. It is important that locations posing the most microbiological risk to the product be a key part of the program. consideration should be given to the points of contamination risk in a process. Such validation and documentation may be accomplished in accordance with § 211. walls. Critical surface sampling should be performed at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing. frequency. Sample sizes should be sufficient to optimize detection of environmental contaminants at levels that might be expected in a given clean area. (4) The calibration of instruments. gauges. The
. length of processing time.. gauges. Instruments. apparatus..165(e) states that “The accuracy. schedules. Samples should be taken throughout the classified areas of the aseptic processing facility (e.42 and 211. Critical surfaces that come in contact with the sterile product should remain sterile throughout an operation.”
A. limits for accuracy and precision. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production. allowing for implementation of corrections before product contamination occurs (211. and closures. and location should be carefully selected based upon their relationship to the operation performed. floors. one of the most important laboratory controls is the environmental monitoring program.
(3) duration of sampling.Contains Nonbinding Recommendations contaminated critical site sample should prompt an investigation of operational information and data that includes an awareness of the potential for a low incidence of false positives. or other parameters. media fills. Trend reports should include data generated by location. shift. in developing monitoring levels.g. quarterly) and long-term trends in environmental and personnel monitoring data. monthly.. a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate. daily.. low-level contamination can be particularly difficult to detect. a search on a particular isolate over a year period) with the goal of investigating results beyond established levels and identifying any appropriate follow-up actions. One should also consider environmental monitoring data from historical databases. especially for a new operation.. operator.g. The quality control unit should provide routine oversight of near-term (e. The quality control unit should be responsible for producing specialized data reports (e.
. (2) when the samples are taken (i. Written procedures should be established. A result at the alert level urges attention to the approaching action conditions. (6) alert and action levels. weekly. cleanroom qualification. Averaging of results can mask unacceptable localized conditions. Environmental monitoring methods do not always recover microorganisms present in the sampled area. Environmental monitoring data will provide information on the quality of the manufacturing environment. Written procedures should define the system whereby the most responsible managers are regularly informed and updated on trends and investigations. surface area. room. (5) specific sampling equipment and techniques. All environmental monitoring locations should be described in SOPs with sufficient detail to allow for reproducible sampling of a given location surveyed. Increased incidence of contamination over a given period is an equal or more significant trend to be tracked. Each individual sample result should be evaluated for its significance by comparison to the alert or action levels. consecutive growth results are only one type of adverse trend. and sanitization studies. In the absence of any adverse trend. Establishing Levels and a Trending Program
Microbiological monitoring levels should be established based on the relationship of the sampled location to the operation. Written SOPs should also address elements such as (1) frequency of sampling. 2. Data from similar operations can also be helpful in setting action and alert levels.e. remedial measures should be taken in response to unfavorable trends. In all room classes. (4) sample size (e. Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data. during or at the conclusion of operations).. detailing data review frequency and actions to be taken. and (7) appropriate response to deviations from alert or action levels.g. The levels should be based on the need to maintain adequate microbiological control throughout the entire sterile manufacturing facility. air volume). Because false negatives can occur. In particular. A result at the action level should prompt a more thorough investigation.
Disinfection procedures should be described in sufficient detail (e. and membrane (or gelatin) samplers. microorganisms associated with adverse trends can be investigated as to their sensitivity to the disinfectants employed in the cleanroom in which the organisms were isolated. Touch plates. and equipment should be tested on a regular basis. spores. ability to be sterilized. centrifugal. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures. work sequence. walls. and limitations of disinfecting agents and procedures should be assessed. Each device has certain advantages and disadvantages.20 Because devices vary. We recommend that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency. appropriately handled in suitable (e. efficacy. although all allow testing of the number of organisms per volume of air sampled. swabs. 70 percent isopropyl alcohol is ineffective against Bacillus spp.. preparation.g. and disruption of unidirectional airflow. Manufacturers should be aware of a device's air monitoring capabilities. Disinfection Efficacy
The suitability. product contact surfaces. the user should assess the overall suitability of a monitoring device before it is placed into service. contact time) to enable reproducibility. For example. If indicated. b. and contact plates can be used for such tests. To prevent introduction of contamination. Once the procedures are established. Surface Monitoring
Environmental monitoring involves sampling various surfaces for microbiological quality. sterile) containers and used for no longer than the predefined period specified by written procedures. disinfectants should be sterile. floors.. 34
. cleanability. the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment. used according to a written schedule and when environmental data suggest the presence of sporeforming organisms. Active Air Monitoring
Assessing microbial quality of air should involve the use of active devices including but not limited to impaction.Contains Nonbinding Recommendations 3. their adequacy should be evaluated using a routine environmental monitoring program. a sound disinfectant program also includes a sporicidal agent. 4. Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility.
For example. Therefore. The effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces.g. Many common disinfectants are ineffective against spores. For example. Monitoring Methods
Acceptable methods for monitoring the microbiological quality of the environment include: a.
Passive Air Monitoring (Settling Plates)
Another method is the use of passive air samplers. Their value in critical areas will be enhanced by ensuring that plates are positioned in locations posing the greatest risk of product contamination.. current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).. caused by lengthy sampling periods and/or high airflows). can often be instrumental in detecting such trends. which inhibits recovery of microorganisms. air monitors. or semi-quantitative. appropriate biochemical and phenotypic methods can be used for the routine identification of isolates. At minimum. where appropriate. sterility test. Because only microorganisms that settle onto the agar surface are detected.
. B. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or. yeasts and molds) as well as bacteria and incubated at appropriate conditions of time and temperature. These methods are especially valuable for investigations into failures (e. such as Class 100. Total aerobic bacterial count can be obtained by incubating at 30 to 35oC for 48 to 72 hours.. and the overall environmental picture provides valuable information for an investigation. As part of methods validation. the quality control laboratory should evaluate what media exposure conditions optimize recovery of low levels of environmental isolates. genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid.g. settling plates can be used as qualitative. Genotypic methods have been shown to be more accurate and precise than traditional biochemical and phenotypic techniques. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure. In some cases. environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas.Contains Nonbinding Recommendations c. where appropriate. The microbiological culture media used in environmental monitoring should be validated as capable of detecting fungi (i. The data generated by passive air sampling can be useful when considered in combination with results from other types of air samples. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments. Consistent methods will yield a database that allows for sound data comparisons and interpretations. such as settling plates (petri dishes containing nutrient growth medium exposed to the environment). media fill contamination).000 (ISO 8). Microbiological Media and Identification
Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Exposure conditions should preclude desiccation (e.g. However. Total combined yeast and mold count can generally be obtained by incubating at 20 to 25oC for 5 to 7 days. genus) level.e. The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control. the program should require species (or.
g. rapid test methods) can be considered for environmental monitoring. In addition to increasing the challenge to the sterilizing filter..Contains Nonbinding Recommendations Incoming lots of environmental monitoring media should be tested for their ability to reliably recover microorganisms.g. and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e. Prefiltration Bioburden
Manufacturing process controls should be designed to minimize the bioburden in the unfiltered product. C. inactivating agents should be used to prevent inhibition of growth by cleanroom disinfectants or product residuals (e. clean area classification). The extent of investigation should be consistent with the severity of the excursion and include an evaluation of trending data.g. endotoxin) to. A result outside the established classification level at a given location should be investigated as to its cause.. and lead to degradation of. Where appropriate. E.A for additional guidance on particle monitoring. Appropriate corrective action should be implemented. Particle Monitoring
Routine particle monitoring is useful in rapidly detecting significant deviations in air cleanliness from qualified processing norms (e. Growth promotion testing should be performed on all lots of prepared media.g. the drug product. D... antibiotics).USP). bioburden can contribute impurities (e. See Section IV. as necessary. in-process control testing.
. A prefiltration bioburden limit should be established.g.. to prevent future deviations. Alternate Microbiological Test Methods
Other suitable microbiological test methods (e.
. including those for packaging and labeling. packing. Samples shall be representative and adequately identified. drug product containers. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated. Instruments. there shall be appropriate laboratory testing to determine conformance to such requirements. whether or not the batch has already been distributed. drug product container. (3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. and reproducibility of test methods employed by the firm shall be established and documented. sampling plans. or closure that is subject to deterioration. A written record of the investigation shall be made and shall include the conclusions and followup.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications. or examinations to be conducted on appropriate samples of in-process materials of each batch. apparatus. in-process materials. and recording devices not meeting established specifications shall not be used. the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures * * *.” 21 CFR 211.192 states that “All drug product production and control records.194(a)(2).” 21 CFR 211.110(a) states. quality.165(a) states.” 21 CFR 211. Laboratory controls shall include: (1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. (2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. standards. apparatus.” 21 CFR 211. and provisions for remedial action in the event accuracy and/or precision limits are not met.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free. approved written procedures before a batch is released or distributed. written procedures shall be established and followed that describe the in-process controls.Contains Nonbinding Recommendations XI. STERILITY TESTING
21 CFR 210. prior to release * * *. gauges. specificity. Such samples shall be representative and properly identified. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. in part. closures. strength. schedules. and drug products conform to appropriate standards of identity. (4) The calibration of instruments. gauges.165(e) states that “The accuracy. processing. The test procedures shall be in writing and shall be followed. and labeling used in the manufacture. The specifications shall include a description of the sampling and testing procedures used. and tests. shall be reviewed and approved by the quality control unit to determine compliance with all established.3(b)(21) states that “Representative sample means a sample that consists of a number of units that are drawn based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material being sampled. there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product. Such samples shall be representative and properly identified.” 21 CFR 211. labeling.” 21 CFR 211. Such procedures shall also require appropriate retesting of any component. and recording devices at suitable intervals in accordance with an established written program containing specific directions. or holding of drug products. at least annually. limits for accuracy and precision. drug product containers. and test procedures designed to assure that components. sensitivity. including the identity and strength of each active ingredient. in part.180(e) states. that “To assure batch uniformity and integrity of drug products. and purity. Such validation and documentation may be accomplished in accordance with § 211. that “For each batch of drug product.” 21 CFR 211. closures. in part. that “Written records required by this part shall be maintained so that data therein can be used for evaluating.
been nonsterile. appropriate microbiological challenge testing will demonstrate reproducibility of the method to reliably recover representative microorganisms. statistical evaluations indicate that the sterility test sampling plan "only enables the detection of contamination in a lot in which 10% of the units are contaminated about nine times out of ten in making the test" (Ref. understanding the test limitations. additional membrane filter washes.165.21 As a part of methods validation. A. modifications (e. increased dilution. The use of isolators for sterility testing minimizes the chance of a false positive test result. addition of inactivating agents) to the test method should be implemented to optimize recovery. A written program should be in place to maintain updated training of personnel and confirm acceptable sterility testing practices.
at the beginning.g. as described by USP. It is essential that the media used to perform sterility testing be rendered sterile and demonstrated as growth promoting. USP <71> “Sterility Tests” is the principal source used for sterility testing methods. Microbiological Laboratory Controls
Sterility testing methods are required to be accurate and reproducible. It is important that the samples represent the entire batch and processing conditions. Sampling and Incubation
Sterility tests are limited in their ability to detect contamination because of the small sample size typically used. Ultimately. and investigating manufacturing systems following a positive test. The testing laboratory environment should employ facilities and controls comparable to those used for aseptic filling operations. the danger exists of mistakenly attributing a positive sterility test result to a faulty laboratory even when the product tested could have. including information on test procedures and media. For example.Contains Nonbinding Recommendations Certain aspects of sterility testing are of particular importance. 13). including control of the testing environment. Poor or deficient sterility test facilities or controls can result in test failure. If production facilities and controls are significantly better than those for sterility testing. B. a manufacturing deficiency may go undetected.000-unit lot with a 0. Therefore.194 and 211.. and end of the aseptic processing operation in conjunction with processing interventions or excursions
. Samples should be taken: • •
. Personnel performing sterility testing should be qualified and trained for the task. methods validation studies should demonstrate that the method does not provide an opportunity for false negatives. there is a 98 percent chance that the batch would pass the test. middle.1 percent contamination level was sterility tested using 20 units. in accordance with 211. if a 10. in fact. If growth is inhibited. To further illustrate.
C. When available evidence is inconclusive. 2. any positive result is considered a serious CGMP issue that should be thoroughly investigated. it can still indicate product contamination. we recommend keeping separate trends by appropriate categories such as product. An initial positive test would be invalid only in an instance in which microbial growth can be unequivocally ascribed to laboratory error. batches should be rejected as not conforming to sterility requirements. sampling. To more accurately monitor potential contamination sources. the test should be invalidated immediately without incubation. the lot should be considered nonsterile and an investigation conducted. Only if conclusive and documented evidence clearly shows that the contamination occurred as part of testing should a new test be performed. product contamination is more likely than laboratory error. nucleicacid based) are valuable for investigational purposes. Where the degree of sterility test
. personnel. When microbial growth is observed. If any deviation is considered to have compromised the integrity of the sterility test. the comprehensive written investigation should include specific conclusions and identify corrective actions. A sterility positive result can be viewed as indicative of production or laboratory problems.. Investigation of Sterility Positives
Care should be taken in the performance of the sterility test to preclude any activity that allows for possible sample contamination. it should be documented.Contains Nonbinding Recommendations Because of the limited sensitivity of the test. if the organism is seldom found in the laboratory environment. and the entire manufacturing process should be comprehensively investigated since such problems often can extend beyond a single batch. or product bioburden. investigated. Advanced identification methods (e. When a deviation occurs during sterility testing. Microbiological monitoring data should be reviewed to determine if the organism is also found in laboratory and production environments. When comparing results from environmental monitoring and sterility positives. and remedied. container type. Identification (speciation) of the organism in the sterility test Sterility test isolates should be identified to the species level. The proper handling of deviations is an essential aspect of laboratory control. filling line. For example. both identifications should be performed using the same methodology. Record of laboratory tests and deviations Review of laboratory deviation and investigation findings can help to eliminate or implicate the laboratory as the source of contamination. After considering all relevant factors concerning the manufacture of the product and testing of the samples. The investigation's persuasive evidence of the origin of the contamination should be based on at least the following: 1.g. If the organism is found in laboratory and production environments. and testing personnel.
such trends can appear to be more indicative of laboratory error as a possible source of a sterility test failure. Product Presterilization Bioburden We recommend review of trends in product bioburden and consideration of whether adverse bioburden trends have occurred. Specifically. The adequacy of personnel practices and training also merit significant review and consideration. 6. In some instances. Accordingly.and long-term environmental trend analyses. For example. or shift associated with the suspect lot. For example. results showing little or no recovery of microorganisms can be misleading. records of air quality monitoring for filling lines
. However. 4. It is therefore important to look at both short. day. firms should not assume that the contamination is automatically more attributable to the laboratory and consequently overlook a genuine production problem. the investigation should include elements such as: • • Events that could have impacted on the critical zone Batch and trending data that indicate whether utility and/or support systems are functioning properly. 5. 3. Where a laboratory has a good track record with respect to errors. this history can lower suspicion of the lab as a source of contamination since chances are higher that the contamination arose from production. Production record review Complete batch and production control records should be reviewed to detect any signs of failures or anomalies that could have a bearing on product sterility. Consideration of environmental microbial data should not be limited to results of monitoring the production environment for the lot. the converse is not true. Upward trends in the microbial load in the aseptic area of the laboratory should be promptly investigated as to cause. especially when preceded or followed by a finding of an adverse trend or atypically high microbial counts. and corrected. it is essential that all sterility positives be thoroughly investigated. Monitoring of production area environment Trend analysis of microorganisms in the critical and immediately adjacent areas is especially helpful in determining the source of contamination in a sterility failure investigation. Microbial monitoring of the aseptic area of the laboratory and personnel can also reveal trends that are informative. Monitoring Personnel The review of data and associated trends from daily monitoring of personnel can provide important information indicating a route of contamination.Contains Nonbinding Recommendations sample manipulation is similar for a terminally sterilized product and an aseptically processed product. For instance. a higher rate of initial sterility failures for the latter should be taken as indicative of aseptic processing production problems. where a laboratory has a poor track record.
equipment) are among the factors that can provide an indication of the origin of the problem..
. or changes (e.g. Whether construction or maintenance activities could have had an adverse impact
7. problems. process. components. Past deviations. Manufacturing history The manufacturing history of a product or similar products should be reviewed as part of the investigation.Contains Nonbinding Recommendations could show a time at which there was improper air balance or an unusually high particle count.
While interventions and/or stoppages are normally recorded in the batch record. Such interventions should be documented with more detail than minor events. The requirement for review of all batch records and data for conformance with written procedures. Such procedures shall include all requirements in this subpart. steam generator) and proper functioning of equipment (e. WFI.” 21 CFR 211. operating parameters. Review of environmental and personnel monitoring data.. HEPA / HVAC. and purity they purport or are represented to possess. Sterility failures have often been attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process.188. shall be drafted. an extensive intervention can increase contamination risk. quality.”
Manufacturers should build process and environmental control activities into their aseptic processing operation.. as well as other data relating to acceptability of output from support systems (e. including any changes.100(a) states that “There shall be written procedures for production and process control designed to assure that the drug products have the identity. shall be reviewed and approved by the quality control unit to determine compliance with all established.186 and 211. reviewed. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211. These written procedures. strength." 21 CFR 211.192 states that “All drug product production and control records. Written procedures describing the need for line clearances in the event of certain interventions. should be established. integrity of various filters) are considered essential elements of the batch release decision. batch alarms report. approved written procedures before a batch is released or distributed. In particular. "Master production and control records" and "Batch production and control records. Any deviation from the written procedures shall be recorded and justified. including those for packaging and labeling. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated. In addition to lengthened dwell time of sterile product elements in the critical area. It is critical that these activities be maintained and strictly implemented on a daily basis.g. the manner of documenting these occurrences varies. Interventions that result in substantial activity near exposed product or container closures
.188 address. and approved by the appropriate organizational units and reviewed and approved by the quality control unit. line stoppages and any unplanned interventions should be sufficiently documented in batch records with the associated time and duration of the event. such as machine adjustments and any repairs. and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. A written record of the investigation shall be made and shall include the conclusions and followup. BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION
21 CFR 211. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.100(b) states that “Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance.” 21 CFR 211.Contains Nonbinding Recommendations XII.g. respectively. whether or not the batch has already been distributed.
192). that could affect product quality is a manufacturing deviation and must be included in batch records (211.
.100. however momentary. result in a local or full line clearance. 211. Any disruption in power supply. where appropriate.Contains Nonbinding Recommendations or that last beyond a reasonable exposure time should.
any product potentially impacted by the breach should be rejected. Integrity can be affected by power failures. as recovery of microorganisms would be inhibited. Where decontamination methods are used to render certain product contact surfaces free of viable organisms. It is expected that materials that permit heat sterilization (e. inadequate overpressure. aseptic processing equipment or ancillary supplies to be used within the isolator should be chosen based on their ability to withstand steam sterilization (or equivalent method). In addition. Filling Line Sterilization
To ensure sterility of product contact surfaces from the start of each operation. and glove integrity defects might not be promptly detected. Frequency The design of the interior and content of an isolator should provide for its frequent decontamination. we recommend monitoring the exit port for particles to detect any unusual results. F.Contains Nonbinding Recommendations The uniform distribution of a defined concentration of decontaminating agent should also be evaluated as part of these studies (Ref.. and gloves (or half-suits) as well as particle levels. When an isolator is used for multiple days between decontamination cycles. Isolation processes generally include periodic or even frequent use of one or more gloves for aseptic manipulations and handling of material transfers into and out of the isolator. Breaches of integrity should be investigated. Chemical indicators may also be useful as a qualitative tool to show that the decontaminating agent reached a given location. Personnel
Although cleanroom apparel considerations are generally reduced in an isolator operation. the contamination risk contributed by manual factors can not be overlooked. established during validation studies. 3. Nutrient media should be cleaned off of surfaces following a contact plate sample. If it is determined that the environment may have been compromised. the entire path of the sterile processing stream should be sterilized. within the isolator.g. holes in gloves and seams. with an understanding that contaminated isolator gloves
. Traditional aseptic processing vigilance remains critical. valve failure. sleeves. or half suits can be among the more difficult to reach places during decontamination. or other leaks. Environmental Monitoring
An environmental monitoring program should be established that routinely ensures acceptable microbiological quality of air. Air quality should be monitored periodically during each shift. E. A breach of isolator integrity should normally lead to a decontamination cycle. One should be aware that locations on gloves. G. 14). Media used for environmental monitoring should not be exposed to decontamination cycle residues. the frequency adopted should be justified. For example. This frequency. a minimum of a six-log reduction should be demonstrated using a suitable biological indicator. should be reevaluated and increased if production data indicate deterioration of the microbiological quality of the isolator environment. surfaces. SIP) will be rendered sterile by such methods.
113). meticulous aseptic technique standards must be observed (211. including appropriate use of sterile tools for manipulations.
. Accordingly.Contains Nonbinding Recommendations can lead to product nonsterility.
and monitoring.SEAL TECHNOLOGY Blow-fill-seal (BFS) technology is an automated process by which containers are formed. filled. the aseptic processing standards discussed elsewhere in this document should apply to blow-fill-seal technology. and (3) the mandrel is removed (just prior to sealing). In contrast to nonpharmaceutical applications using
. to form the parison and inflate it prior to filling. for example. Equipment Design and Air Quality
Most BFS machines operate using the following steps. any other surface that represents a potential contamination risk to the sterile product should be sterile. BFS machinery and its surrounding barriers should be designed to prevent the potential for extraneous contamination. A. depending on the design of the BFS machinery and the surrounding room. BFS equipment design typically calls for use of specialized measures to reduce particle levels that can contaminate the exposed product. container molding or filling steps). As with any aseptic processing operation. and sealed in a continuous operation. or better. In most operations. standards. should be used to sterilize the equipment path through which the product is conveyed. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. sterile-air is used.000 (ISO 8). HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e. qualification.Contains Nonbinding Recommendations APPENDIX 2: BLOW-FILL. and. This appendix discusses some of the critical control points of this technology.. less frequently. Refer to Section V of this document for guidance on personnel training. • • • • • • • • Heat a plastic polymer resin Extrude it to form a parison (a tubular form of the hot resin) Cut the parison with a high-temperature knife Move the parison under the blow-fill needle (mandrel) Inflate it to the shape of the mold walls Fill the formed container with the liquid product Remove the mandrel Seal
Throughout this operation. Except where otherwise noted below. or equivalent process. This manufacturing technology includes economies in container closure processing and reduced human intervention and is often used for filling and packaging ophthalmics. injectables. In addition. A validated steam-in-place cycle. it is critical that product contact surfaces be sterile. (2) the parison is moved under the blow-fill mandrel. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery. parison formation. The classified environment surrounding BFS machinery should generally meet Class 100.g. the three steps with the greatest potential for exposure to particle contamination and/or surrounding air are those in which (1) the parison is cut. respiratory care products.
particles) is critical for sterile drug product manufacture. control of air quality (i. leakers). B. and passes appropriate criteria (Ref.. Furthermore. Samples should be taken according to a comprehensive sampling plan that provides data representative of the entire filling operation. polymer extrusion/sterilization. 17) for plastics. Polymer suppliers should be qualified and monitored for raw material quality. Smoke studies and multi-location particle data can provide valuable information when performing qualification studies to assess whether proper particle control dynamics have been achieved throughout the critical area. sensitive. equipment designs that separate the filling zone from the surrounding environment provide additional product protection. It is critical that the operation be designed and set-up to uniformly manufacture integral units. the integrity of the cooling. if used for parenteral drugs. pure. nonpyrogenic. air pressure) provide information to monitor and facilitate ongoing process control. and sealing processes should be controlled. Continuous monitoring of particles can provide valuable data relative to the control of a blow-fill-seal operation. troubleshooting of equipment.g. fill weight. and unit weight variation are among the key issues to address in validation and qualification studies. microenvironments. As a final measure. For example.. cutting. Equipment sterilization. The choice of appropriate polymer material for a BFS operation includes assessing if a material is pharmaceutical grade. Batch Monitoring and Control
Various in-process control parameters (e. it is important to establish an adequate preventative maintenance program.e. product-plastic compatibility. 15). safe. C.g.Contains Nonbinding Recommendations BFS machinery. forming and sealing integrity. Barriers. Provisions for carefully controlled airflow can protect the product by forcing generated particles outward while preventing any ingress from the adjacent environment. heating and other utility systems associated with the BFS machine should be maintained and routinely monitored. Particles generated during the plastic extrusion.. It is essential to monitor the microbial air quality. However. Container closure defects can be a major problem in control of a BFS operation. Data gathered during such studies should ensure that BFS containers are sterile and. only a properly functioning process can realize these advantages. media fills. and related aseptic personnel procedures. We recommend affording special attention to setup. and appropriately directed high velocities of sterile air have been found useful in preventing contamination (Ref. Validation/Qualification
Advantages of BFS processing are known to include rapid container closure processing and minimized aseptic interventions. In addition to suitable design. This can generally be achieved by validating that time temperature conditions of the extrusion process are effective against endotoxin or spore challenges in the polymeric material. final product examination that is capable of identifying defective units (e. the inspection of each unit of a batch should include a reliable. Significant defects due
. pressure vacuums. leakers. container weight variation. because of its potential to contaminate the sterile drug product.
poorly formed closures.192. such as wall thickness.Contains Nonbinding Recommendations to heat or mechanical problems. or other deviations should be investigated in accordance with §§ 211.
.100 and 211. container or closure interface deficiencies.
each component in the formulation would be rendered sterile and mixed aseptically. Special considerations include those for: A. For example. In other instances. product manipulations. therefore. Microbiological and airborne particle monitoring should be performed during operations. In such cases. The environment of the room surrounding the Class 100 (ISO 5) environment should be Class 10. the product and all components or other additions are rendered sterile prior to entering the manufacturing process.g.12 for general biological product standards for sterility.000 (ISO 7) or better. products containing aluminum adjuvant are formulated aseptically because once they are alum adsorbed.. With other products.A for more
See 21 CFR 610. The studies should include worst-case conditions such as maximum duration of open operations and maximum number of participating operators. but prior to cleaning. Process simulation studies covering the steps preceding filling and sealing should be designed to incorporate all conditions.Contains Nonbinding Recommendations APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS The purpose of this appendix is to supplement the guidance provided in this document with information on products regulated by CBER or CDER that are subject to aseptic processing at points early in the manufacturing process. and procedures involving exposure of product contact surfaces to the environment. there is a point in the process after which they can no longer be rendered sterile by filtration. The scope of this appendix includes aseptic processing activities that take place prior to the filling and sealing of the finished drug product. Personnel monitoring should be performed in association with operations. or that require aseptic processing through the entire manufacturing process because it is impossible to sterile filter the final drug product. bulk drug substances or products should be tested for sterility. should demonstrate that process controls are adequate to protect the product during manufacturing. aseptic connection) that expose a product or product contact surfaces should be performed under unidirectional airflow in a Class 100 (ISO 5) environment. The transport of sterile bulk tanks or other containers should be simulated as part of the media fill. It is critical that all transfers.24 Procedures (e. In some cases. It is also important that process simulations incorporate storage of sterile bulk drug substances or product and transport to other manufacturing areas. they cannot be sterile-filtered. the final drug product cannot be sterile-filtered and. Please refer to Section IX. These studies should incorporate all product manipulations. additions. transports. For instance. the product would be handled aseptically at all steps subsequent to sterile filtration. there should be assurance of bulk vessel integrity for specified holding times. However. Microbial surface monitoring should be performed at the end of operations. When a product is processed aseptically from the early stages. Aseptic processing from early manufacturing steps
Some products undergo aseptic processing at some or all manufacturing steps preceding the final product closing step. from the early process steps. The process simulation. 52
. the process simulations do not need to mimic total manufacturing time if the manipulations that occur during manufacturing are adequately represented. and storage stages be carefully controlled at each step of the process to maintain sterility of the product. and interventions that could impact on the sterility of the product.
These products are frequently released from the manufacturing facility and administered to patients before final product sterility testing results are available. For example. and endotoxin testing should be performed and meet acceptance criteria prior to product release. Where possible. particularly between the harvest. B. Process simulation studies for the formulation stage should be performed at least twice per year. Aseptic processing of cellular therapy products and cell-derived products
Cellular therapy and some cell-derived products (e.
. Cellular therapy products often have short processing times at each manufacturing stage. In situations where results of final sterility testing are not available before the product is administered. such as microscopic examination. and product release. such as after the last manipulation of the product prior to harvest.Contains Nonbinding Recommendations guidance on media simulation studies. additional sterility tests can be performed at intermediate stages of manufacture. Gram stain (or other bacterial and fungal stain). additional controls and testing should be considered.. semi-purified extracts) represent a subset of the products that cannot be filter-sterilized and therefore undergo aseptic manipulations throughout the manufacturing process. lysates. closed systems should be used during manufacturing.g. formulation of the final product. Other tests that may indicate microbial contamination.
1998.. Sigwarth. 4.610-2.Retention Capabilities of Membrane Filters. 16. 2002. 1989. W. Publication NHB 5340. 12. and Reinmuller. l972. A. United States Pharmacopoeia
. 7. Isolators used for Aseptic Processing and Sterility Testing. A. December l. 13. 3. July. J. Inc. "Personnel Issues in Aseptic Processing. Recommendations of PQRI Aseptic Processing Working Group. 26. and E. NASA Standard for Cleanroom and Work Stations for Microbially Controlled Environment. 15. 6. 1996. Contamination Control of Aerospace Facilities. January/February 2003. 1998.. 57. Ljungqvist.. Technical Report No. "Sterilizing Filtration of Liquids. 14. “Current Practices in the Validation of Aseptic Processing. 1. “Validation of Bacterial . Elsevier Scientific Publishing Company. and A. 8. “Pyrogens in Parenteral Pharmaceuticals. “Blow-Fill-Seal Technology: Part I. J. 9. 10. June. Pall. l978. Product Quality Research Institute. Centers for Disease Control and Prevention.2 (August l967). Grandics.. Sullivan. and J. Cleanroom Design: Minimizing Contamination Through Proper Design. Air Force. T. B. “Effect of Carrier Materials on the Resistance of Spores of Bacillus stearothermophilus to Gaseous Hydrogen Peroxide.Contains Nonbinding Recommendations REFERENCES 1. Stark. and M. 47(29)." Pall Corporation Colloids and Surfaces.” PDA Journal of Pharmaceutical Science and Technology. February. 2. 11. Peter. A Design for Particulate Control.. Kirnbauer. Morbidity and Mortality Weekly Report. Nov. Technical Order 00-25-203. Technical Report No. 2002. Lord.. Interpharm Press. D." Parenteral Drug Association. March. Price. Classification of Air Cleanliness. 2003. 5.S." Biopharm. Inc. B.. Vol. April 2000. 1998." Pharmaceutical Technology. l (l980) 235-256. Amsterdam. 36. V. Pharmaceutical Inspection Convention Cooperation Scheme (PIC/S). Leahy. No. B. J. 1997. "Particulate Retention by Bacteria Retentive Membrane Filters. "Clinical Sepsis and Death in a Newborn Nursery Associated with Contaminated Medications" – Brazil.” Pharmaceutical Technology." Parenteral Drug Association.” Pharmaceutical Technology. et al. ISO 14644-1: Cleanrooms and Associated Controlled Environments. Levchuk. U.
which was issued in 1998.Contains Nonbinding Recommendations RELEVANT GUIDANCE DOCUMENTS Some relevant FDA guidance documents include: Guidance for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products Guideline for Validation of Limulus Amebocyte Lysate Test as an End Product Endotoxin Test for Human and Animal Parenteral Drugs. Biological Products. it will represent the Agency's thinking on this topic. Sterile Drug Process Inspections ICH Q5A. Once final. (Inspection Technical Guide) Bacterial Endotoxins/Pyrogens. and Medical Devices Guide to Inspections of Lyophilization of Parenterals Guide to Inspections of High Purity Water Systems Guide To Inspections of Microbiological Pharmaceutical Quality Control Laboratories Guide To Inspections of Sterile Drug Substance Manufacturers Pyrogens: Still a Danger.
. (Inspection Technical Guide) Compliance Program Guidance Manual 7356.002 A. Guidance on Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin See also the draft guidance Container and Closure Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products. (Inspection Technical Guide) Heat Exchangers to Avoid Contamination.
A room designed.A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product.A physical partition that affords aseptic processing area (ISO 5) protection by partially separating it from the surrounding area. Aseptic Processing Facility.An area with defined particle and microbiological cleanliness standards. when exceeded.An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem..
.The classified part of a facility that includes the aseptic processing room and ancillary cleanrooms. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification. and controlled to prevent particle and microbiological contamination of drug products. Incoming lot D-value and microbiological count define the quality of the BI.A building.The total number of microorganisms associated with a specific item prior to sterilization.Contains Nonbinding Recommendations GLOSSARY Air lock. or segregated segment of it. Aseptic Manufacturing Area. The challenge microorganism is selected based upon its resistance to the given process.g. solution.A small room with interlocked doors.A room in which one or more aseptic activities or processes is performed. this term is synonymous with “aseptic processing facility” as used in the segregated segment context. maintained. Alert levels are always lower than action levels. Barrier. constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). Alert Level. Asepsis. materials. Clean Area. containing cleanrooms in which air supply. Biological Indicator (BI). Aseptic Processing Room. Bioburden.An established microbial or airborne particle level that. container or closure) and placed within appropriate sterilizer load locations to determine the sterilization cycle efficacy of a physical or chemical process. Cleanroom. and equipment are regulated to control microbial and particle contamination. Action Level. should trigger appropriate investigation and corrective action based on the investigation.A population of microorganisms inoculated onto a suitable medium (e. For purposes of this document. The intent of an aseptic processing airlock is to preclude ingress of particulate matter and microorganism contamination from a lesser controlled area.
A decontaminated unit.An area designed to maintain sterility of sterile materials. endotoxin).g. lipopolysaccharide) present in the bacterial cell wall.Heating.3 µm particle retaining efficiency of 99. closures. HEPA filter.A program that establishes. One colony forming unit is expressed as 1 CFU. the capability of an individual to don the complete sterile gown in an aseptic manner. and sterility is maintained throughout processing. ventilation.A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more microorganisms to microbiological growth media.Any ingredient intended for use in the manufacture of a drug product. Disinfection. Critical surfaces. supplied with Class 100 (ISO 5) or higher air quality.Process by which surface bioburden is reduced to a safe level or eliminated. Gowning Qualification.. HVAC. Endotoxin. continuous isolation of its interior from the external environment (e. Isolator.. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.An aseptic manipulation or activity that occurs at the critical area.. both initially and on a periodic basis.g. and air conditioning. Sterilized product.g.A pyrogenic product (e. that provides uncompromised.Conditions relating to clean area classification under conditions of normal production. Some disinfection agents are effective only against vegetative microbes. D value. Critical surfaces are rendered sterile prior to the start of the manufacturing operation. There are two major types of isolators:
.A process used to destroy or remove pyrogens (e. surrounding cleanroom air and personnel).See Clean Area. Intervention.The time (in minutes) of exposure at a given temperature that causes a one-log or 90 percent reduction in the population of a specific microorganism. Depyrogenation. Dynamic. and equipment may be exposed in critical areas. Decontamination. Clean Zone. including those that may not appear in the final drug product. Critical Area . containers.97 percent. while others possess additional capability to effectively kill bacterial and fungal spores.High efficiency particulate air filter with minimum 0. Colony Forming Unit (CFU).A process that eliminates viable bioburden via use of sporicidal chemical agents.Surfaces that may come into contact with or directly affect a sterilized product or its containers or closures.Contains Nonbinding Recommendations Component.
Terminal sterilization.Ultra-low penetration air filter with minimum 0. Pyrogen. Sterile Product.Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. Sterilizing grade filter.. Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. producing a sterile effluent. and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area. Operator. filler. including line set-up.Contains Nonbinding Recommendations Closed isolator systems exclude external contamination from the isolator’s interior by accomplishing material transfer via aseptic connection to auxiliary equipment.An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector. Unidirectional flow. maintenance..An airflow moving in a single direction. will remove all microorganisms from a fluid stream. or other personnel associated with aseptic line activities. Openings are engineered (e.3 µm particle retaining efficiency of 99.22. in a robust and uniform manner.Any individual participating in the aseptic processing operation. Validation. and components of the finished drug product. a probability of a nonsterile unit of greater than one in a million). Overkill sterilization process.999 percent. when appropriately validated. Quality Control Unit. sterile product refers to one or more of the elements exposed to aseptic conditions and ultimately making up the sterile finished drug product. ULPA filter.A process that is sufficient to provide at least a 12 log reduction of microorganisms having a minimum D value of 1 minute. finished drug products for the purpose of achieving a predetermined sterility assurance level (SAL) of usually less than 10-6 (i.The application of a lethal agent to sealed.For purposes of this guidance. rather than use of openings to the surrounding environment. These elements include the containers.e. Closed systems remain sealed throughout operations.A substance that induces a febrile reaction in a patient. closures. using continuous overpressure) to exclude the entry of external contamination into the isolator.
. Laminar flow.g.An organizational element with authority and responsibility as defined by 211.A filter that.
Contains Nonbinding Recommendations Worst case. including those within standard operating procedures.A set of conditions encompassing upper and lower processing limits and circumstances.
. that pose the greatest chance of process or product failure (when compared to ideal conditions). Such conditions do not necessarily induce product or process failure.
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