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Monday, July 14, 2008

Laboratory controls Sterile Pharmaceutical Drug Products

Guidance for Sterile Pharmaceutical Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice.

X. LABORATORY CONTROLS


21 CFR 211.22(b) states that “Adequate laboratory facilities for the testing and approval (or rejection) of components, pharmaceutical drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.”

21 CFR 211.22(c) states that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the pharmaceutical drug product.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups during the course of the following procedures:  (10) Aseptic processing, which includes as appropriate:  (iv) A system for monitoring environmental conditions; ”

21 CFR 211.56(b) states that “There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.”

21 CFR 211.56(c) states, in part, that “There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or pharmaceutical drug products and shall be followed * * *.”

21 CFR 211.110(a) states, in part, that “To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. 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 pharmaceutical drug product .”


21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of pharmaceutical drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”

21 CFR 211.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: (1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration. (2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified. (3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified. (4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.”

21 CFR 211.165(e) states that “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with § 211.194(a)(2).”

21 CFR 211.192 states, in part, that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed * * *.”


A. Environmental Monitoring

1. General Written Program

In aseptic processing, one of the most important laboratory controls is the environmental monitoring program. This program provides meaningful information on the quality of the aseptic processing environment (e.g., when a given batch is being manufactured) as well as environmental trends of ancillary clean areas. Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination occurs (211.42 and 211.113).
Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and scientifically sound methods. The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures. Written procedures should include a list of locations to be sampled. Sample timing, frequency, and location should be carefully selected based upon their relationship to the operation performed. Samples should be taken throughout the classified areas of the aseptic processing facility (e.g., aseptic corridors, gowning rooms) using scientifically sound sampling procedures. Sample sizes should be sufficient to optimize detection of environmental contaminants at levels that might be expected in a given clean area.
It is important that locations posing the most microbiological risk to the product be a key part of the program. 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. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production. Critical surfaces that come in contact with the sterile product should remain sterile throughout an operation. When identifying critical sites to be sampled, consideration should be given to the points of contamination risk in a process, including factors such as difficulty of setup, length of processing time, and impact of interventions. Critical surface sampling should be performed at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing. Detection of microbial contamination on a critical site would not necessarily result in batch rejection. The 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.
Environmental monitoring methods do not always recover microorganisms present in the sampled area. In particular, low-level contamination can be particularly difficult to detect. Because false negatives can occur, consecutive growth results are only one type of adverse trend. Increased incidence of contamination over a given period is an equal or more significant trend to be tracked. In the absence of any adverse trend, a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate. In all room classes, remedial measures should be taken in response to unfavorable trends.
All environmental monitoring locations should be described in SOPs with sufficient detail to allow for reproducible sampling of a given location surveyed. Written SOPs should also address elements such as (1) frequency of sampling, (2) when the samples are taken (i.e., during or at the conclusion of operations), (3) duration of sampling, (4) sample size (e.g., surface area, air volume), (5) specific sampling equipment and techniques, (6) alert and action levels, and (7) appropriate response to deviations from alert or action levels.
2. Establishing Levels and a Trending Program
Microbiological monitoring levels should be established based on the relationship of the sampled location to the operation. The levels should be based on the need to maintain adequate microbiological control throughout the entire sterile manufacturing facility. One should also consider environmental monitoring data from historical databases, media fills, cleanroom qualification, and sanitization studies, in developing monitoring levels. Data from similar operations can also be helpful in setting action and alert levels, especially for a new operation.
Environmental monitoring data will provide information on the quality of the manufacturing environment. Each individual sample result should be evaluated for its significance by comparison to the alert or action levels. Averaging of results can mask unacceptable localized conditions. A result at the alert level urges attention to the approaching action conditions. A result at the action level should prompt a more thorough investigation. Written procedures should be established, detailing data review frequency and actions to be taken. The quality control unit should provide routine oversight of near-term (e.g., daily, weekly, monthly, quarterly) and long-term trends in environmental and personnel monitoring data.
Trend reports should include data generated by location, shift, room, operator, or other parameters. The quality control unit should be responsible for producing specialized data reports (e.g., 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. Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data.
Written procedures should define the system whereby the most responsible managers are regularly informed and updated on trends and investigations.
3. Disinfection Efficacy
The suitability, efficacy, and limitations of disinfecting agents and procedures should be assessed. The effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces.
To prevent introduction of contamination, disinfectants should be sterile, appropriately handled in suitable (e.g., sterile) containers and used for no longer than the predefined period specified by written procedures. Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility. Many common disinfectants are ineffective against spores. For example, 70 percent isopropyl alcohol is ineffective against Bacillus spp. spores. Therefore, a sound disinfectant program also includes a sporicidal agent, used according to a written schedule and when environmental data suggest the presence of sporeforming organisms.
Disinfection procedures should be described in sufficient detail (e.g., preparation, work sequence, contact time) to enable reproducibility. Once the procedures are established, their adequacy should be evaluated using a routine environmental monitoring program. If indicated, 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.
4. Monitoring Methods
Acceptable methods for monitoring the microbiological quality of the environment include:
a. Surface Monitoring
Environmental monitoring involves sampling various surfaces for microbiological quality. For example, product contact surfaces, floors, walls, and equipment should be tested on a regular basis. Touch plates, swabs, and contact plates can be used for such tests.
b. Active Air Monitoring
Assessing microbial quality of air should involve the use of active devices including but not limited to impaction, centrifugal, and membrane (or gelatin) samplers. Each device has certain advantages and disadvantages, although all allow testing of the number of organisms per volume of air sampled. We recommend that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. Manufacturers should be aware of a device's air monitoring capabilities, and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency, cleanability, ability to be sterilized, and disruption of unidirectional airflow. Because devices vary, the user should assess the overall suitability of a monitoring device before it is placed into service. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures.

c. Passive Air Monitoring (Settling Plates)

Another method is the use of passive air samplers, such as settling plates (petri dishes containing nutrient growth medium exposed to the environment). Because only microorganisms that settle onto the agar surface are detected, settling plates can be used as qualitative, or semi-quantitative, air monitors. Their value in critical areas will be enhanced by ensuring that plates are positioned in locations posing the greatest risk of product contamination. As part of methods validation, the quality control laboratory should evaluate what media exposure conditions optimize recovery of low levels of environmental isolates. Exposure conditions should preclude desiccation (e.g., caused by lengthy sampling periods and/or high airflows), which inhibits recovery of microorganisms. The data generated by passive air sampling can be useful when considered in combination with results from other types of air samples.

B. Microbiological Media and Identification

Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure, and the overall environmental picture provides valuable information for an investigation. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or, where appropriate, genus) level. In some cases, environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments, such as Class 100,000 (ISO 8), can often be instrumental in detecting such trends. At minimum, the program should require species (or, where appropriate, genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid, current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).

Genotypic methods have been shown to be more accurate and precise than traditional biochemical and phenotypic techniques. These methods are especially valuable for investigations into failures (e.g., sterility test; media fill contamination). However, appropriate biochemical and phenotypic methods can be used for the routine identification of isolates.

The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control. Consistent methods will yield a database that allows for sound data comparisons and interpretations. The microbiological culture media used in environmental monitoring should be validated as capable of detecting fungi (i.e., yeasts and molds) as well as bacteria and incubated at appropriate conditions of time and temperature. Total aerobic bacterial count can be obtained by incubating at 30 to 35oC for 48 to 72 hours. Total combined yeast and mold count can generally be obtained by incubating at 20 to 25oC for 5 to 7 days.

Incoming lots of environmental monitoring media should be tested for their ability to reliably recover microorganisms. Growth promotion testing should be performed on all lots of prepared media. Where appropriate, inactivating agents should be used to prevent inhibition of growth by cleanroom disinfectants or product residuals (e.g., antibiotics).

C. Prefiltration Bioburden

Manufacturing process controls should be designed to minimize the bioburden in the unfiltered product. In addition to increasing the challenge to the sterilizing filter, bioburden can contribute impurities (e.g., endotoxin) to, and lead to degradation of, the drug product. A prefiltration bioburden limit should be established.

D. Alternate Microbiological Test Methods

Other suitable microbiological test methods (e.g., rapid test methods) can be considered for environmental monitoring, in-process control testing, and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e.g.,USP).

E. Particle Monitoring

Routine particle monitoring is useful in rapidly detecting significant deviations in air cleanliness from qualified processing norms (e.g., clean area classification). A result outside the established classification level at a given location should be investigated as to its cause. The extent of investigation should be consistent with the severity of the excursion and include an evaluation of trending data. Appropriate corrective action should be implemented, as necessary, to prevent future deviations.

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This Guidance is published by US FDA on September 2004


We also recommend our readers to visit US FDA'S website for undated guidances on sterile drug products

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