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3.2 Environmental Control ProgramThis page will address various regulatory issues related to this section of the GMP Institute framework. Click below to view the issues that are relevant to you. Are firms required to use HEPA filters in the manufacture of tablets and capsules? Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site? Penicillin Issues Is it acceptable to manufacture penicillin products in the same facility as cephalosporin? Is there an acceptable level of penicillin residue in non-penicillin drug products? What is the purpose of an environmental monitoring program in aseptic processing? What are some major factors that ensure the environment does not contaminate product throughout a batch's manufacture?Reference: The environmental monitoring program is a vital part of a quality control unit's CGMP responsibility to monitor and ensure ongoing control of an aseptic process. The CGMP regulations, at section 211.113 require firms to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. This section is particularly applicable to sterile drug products made by aseptic processing, and the aseptic guideline addressed at length various aspects of environmental monitoring. An environmental monitoring program is vital for aseptic processing operations because it: 1) Provides crucial information on the quality of the aseptic processing environment during manufacturing; 2) prevents release of a potentially contaminated batch if appropriate quality standards (defined by a firm's written procedures) are not fulfilled; and, 3) prevents future contamination by detecting adverse trends. In addressing the environmental monitoring program, the aseptic guideline discussed regular sampling and testing of the manufacturing environment, including air, floors, walls, and equipment surfaces. Evaluating the quality of air and surfaces in cleanrooms should start with a well-defined and specific written program, including validated test methods. As explained in the guideline, among issues normally addressed by an environmental monitoring program are: sample location, appropriate sampling frequency, timing of sample collection, duration of sampling, size of sample, specific sampling equipment and techniques, limits, identification of microorganisms, trending systems, and procedures to promptly address out of limit results or adverse trends. A number of major variables influence environmental control, all of which need to be addressed by appropriate written SOPs, in accordance with section 211.113. It is important that a personnel qualification and monitoring program address operator practices, critical in maintaining environmental control of the aseptic processing area. In addition, the CGMPs at section 211.46 require equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product. In this context, the Heating, Ventilation, and Air Conditioning (HVAC) system design and controls play a key role in providing an adequate environment (e.g., particulate cleanliness, air pressure, and airflow) for aseptic processing. Adequate cleaning and sanitizing procedures, facility design, equipment design, personnel flow, and material flow are among other key variables which significantly impact on the suitability of the environment in which aseptic processing operations are conducted. Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. Are firms required to use HEPA filters in the manufacture of tablets and capsules?References: No. The CGMP regulations do not specifically require tablet and capsule manufacturing facilities to maintain high-efficiency particulate air (HEPA) filtered air. The regulations, at 211.46, do require use of equipment for adequate control over air pressure, microorganism, dust, humidity and temperature when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak to measures to prevent cross contamination, and the key phrase is "as appropriate". Do not confuse the 211.46 provisions with 211.42(c)(10)(iii) which calls for aseptic processing areas to be equipped, as appropriate, with an air supply filtered through HEPA filters. Whereas such filtration is the norm for aseptic areas, tablet and capsule production rooms seldom need the same level of air filtration. Despite the lack of an explicit CGMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 5, Number 3) September, 1997. Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?References: No. Sampling an environment for particulates during static (at rest) times is of minimal utility in assessing actual processing conditions. On the other hand, operational (dynamic) monitoring performed throughout aseptic processing is needed. Here's why. Aseptic processing operations are designed to exclude living microorganisms, endotoxins, and particulates from the finished product. It is generally accepted that monitoring of particulate concentration in classified (environmentally controlled) areas during operations serves as a direct indicator of changes in local air quality while indirectly indicating the increased potential for the introduction of microorganisms to the monitored area. Occasional static monitoring during periods of no operation to ensure particulate levels remain well below an area's classification level would be useful as a facility maintenance parameter. However, firms should obtain data from dynamic monitoring (during operations) as a routine batch control. Firms should monitor frequently throughout manufacturing, and in proximity to the work surfaces and exposed product or container/closures. For example, in class 100 areas, samples should be taken about one foot away from the work surface. Many firms now have the capability to monitor nonviables continuously; however, failure to monitor continuously is not objectionable. High levels of particulates generally represent a departure from processing norms, indicating, for example, unusual personnel activity which challenges the intended cleanroom design parameters. It is therefore important that the Quality Control unit investigate such "particulate excursions." Finally, when qualifying a cleanroom, firms conduct studies to establish the room's air classification. Although the classification studies include assessment of particulate levels under static conditions, the final classification should be derived from data generated while equipment is in place and operations are ongoing. Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov Reprinted from FDA's Human
Drug CGMP Notes, (Volume 5 Number 2), June, 1997. Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site?Reference: Not necessarily. More important than a facility's proximity to sources of contamination is the adequacy of measures the firm takes to prevent such contamination from adversely affecting drug product quality. It would be far from prudent to locate a pharmaceutical establishment alongside a land reclamation facility (which conjures up visions of such potential sources of contamination as rodents, insects, birds, and ground water toxic leachates). The task of protecting the drug product and production environment from such contamination would be challenging, but not insurmountable. Field investigators who encounter such a situation should, of course, pay close attention to how the firm isolates production operations from potential contaminants. However, in the absence of demonstrated routes of contamination, we would not disapprove of the facility based solely on its proximity to the landfill. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 3, Number 1) March, 1995. What do the CGMPs mean by separate facilities? Must the buildings be totally separated, or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed? References: CGMP regulations [21 CFR 211.42(d) and 211.46(d)] require separation of penicillins from non-penicillins during processing. The discussion of the comments in the preamble to the regulations note that "…isolation of penicillin production operations…can be achieved by sealing off…the two operations." "…does not necessarily mean…separate buildings." Thus, there can be a "building within a building"- i.e. two buildings are not required. However, there must be total separation of operations, meaning every aspect of the operations must be separate. Adequate separation should include physical barriers and separate air handling systems. Personnel and equipment from the penicillin facility should not enter the non-penicillin facility. These should operate with well established written procedures and controls. The separation should be audited, procedures validated, and where necessary monitored. Even with separation, if any possibility of contamination exists, the non-penicillin products must be tested (21 CFR 211.176). An example of possible contamination could be inadequate controls over movement of equipment or personnel. Section 211.176 requires non-penicillin products to be tested for traces of penicillin where the possibility of exposure exists, and not marketed if detectable levels of penicillin are found. While this section prohibits marketing of products found to be contaminated with penicillin, it does not sanction marketing of non-penicillin products based only on test results that show no detectable levels of such contamination. Other CGMP requirements must still be met. For a discussion on this issue, please review the article "Is it acceptable under section 211.176 to release products to market as long as the products are tested and no penicillin is found?" published in "Human Drug CGMP Notes" (Volume 6, Issue 2, June 1998). Cross contamination issues have been a concern for a number of years, and continue to be problematic. In one penicillin cross-contamination case reviewed it was demonstrated how a non-penicillin facility was contaminated by a separate penicillin facility located in the same manufacturing campus. This occurred due to lack of controls regarding movements of personnel, equipment and materials. In another case, CDER concurred with a district recommendation to withhold approval on a sensitizing beta-lactam manufacturing facility that was adjacent to another drug processing building, due to the lack of containment controls which ensured against cross contamination of the other drugs. Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000. This same text is also reprinted in framework section 3.1. Is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i.e., the conversion of production facilities to a different product line on a routine basis) basis, with adequate cleaning validation procedures in place? References: No, it is not acceptable. The discussion of the comments in the preamble to the regulations state that "…it is important to make clear in these regulations that completely separate air-handling facilities for penicillin and non-penicillin production are required.". And "…because it is possible for air-handling systems between penicillin and non-penicillin production areas to be interconnected, ...the Commissioner finds it necessary to state that any such interconnection would be unacceptable." Campaign production of penicillin and any non-penicillin product in the same facility and with the same
equipment violates the CGMP regulations [211.42(d) and
.46(d)]. A concern is that the cleaning validation
process does not include the air handling system throughout the facility. This is important because
campaign production has the potential for recontamination of the air handling systems and facilities, and
can lead to cross contamination of non-penicillin products with penicillin. The concept of decontamination
is broader than a typical cleaning procedure validation, in that sampling is extended to include the A facility contaminated with penicillin could not begin non-penicillin production until extensive decontamination and clean-up of the facility is accomplished in accordance with the established procedures, and representative environmental samples demonstrate that the facility conforms with its decontamination protocol/specifications. Current technology makes decontamination of air handling systems difficult. This is because the decontamination/cleaning procedures would necessitate sampling and residual testing of other parts of the air handling system, to include the ductwork. This would be difficult because the air handling system throughout its length has uneven areas and crevices that create the possibility of penicillin residue build-up, with slough-off at undetermined periods during the non-penicillin production period. Thus penicillin contamination would not be uniformly distributed in the air handling system, and "representative" samples (retain, surface and/or air) may not be an accurate portrayal of the level of contamination. 21 CFR 211.176 indicates that where the possibility of exposure exists, non-penicillin products must be tested for traces of penicillin and not marketed if detectable levels are found. This means that representative samples from all batches of non-penicillin products produced in each campaign must be tested with an acceptable method and found non-detectable for the penicillin product produced prior to the start-up of the non-penicillin campaign. One case we reviewed demonstrated a positive environmental surface sample from the fan blade of an exhaust hood in the repack room for beta-lactam residue, even though the most recent beta-lactam repackaging operation had been performed more than six months prior to sampling. Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000. This same text is also reprinted in framework sections 3.1 and 6.2. Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?References: Beta-lactams are products with a chemical substructure that contains the beta-lactam ring. They have the potential to sensitize and cause allergic response in humans. Hypersensitivity, due to intolerance of beta lactam ingredients, can trigger reactions which range from a rash to life-threatening anaphylaxis. There is evidence that cross-sensitivity exists between penicillins and cephalosporins. Thus, patients who are intolerant of penicillin may also be intolerant of cephalosporins, and further, cephalosporins may induce anaphylaxis in patients with a history of penicillin anaphylaxis. The immune system is exquisitely sensitive and can distinguish between very subtle changes in chemical composition. Patients may be tolerant of a given drug but intolerant of another drug with closely related chemical structures. There is evidence that patients tolerant of penicillin may be intolerant of cephalosporins. CDER recognizes the considerable potential for cross-sensitivity and the possible life-threatening consequences of unintended exposure. Therefore, although not a specific requirement of sections 211.42 (d), 211.46(d) and 211.176, it is recommended that manufacturing operations for cephalosporins, penems and cephems, be separated from non-beta-lactam products and other beta-lactam drug products. For example cephalosporin type products would be separated from penicillin type products or non-beta-lactam products. Production of cephalosporin type products can be approached from two different regulatory/compliance perspectives: 1) If cephalosporins are considered to be non-penicillin drugs, they could not be manufactured in a facility lacking adequate separation from penicillin products. 2) For cephalosporin production with other non-beta-lactam drug products, similar health concerns exist for patients sensitive to cephalosporins who should not be exposed to it in a non-beta-lactam product. For fundamental CGMP reasons and because of the difficulties in demonstrating and validating appropriate sampling and testing methodology for measuring cross-contamination, penicillin production should be performed in facilities separated from non-beta-lactam drug products and other beta-lactam drug products unless adequate separation is demonstrated. We don’t know of a satisfactory shared facility as of today. Furthermore, if necessary, other sections of the CGMP regulations [i.e., 211.28; 211.42(b) & (c); 211.46(c); 211.67; and 211.80(b)] could be applied to control contamination between beta-lactam and non-beta-lactam drug products. In summary the Agency considers the separation of production facilities for sensitizing beta-lactam based products to be current good manufacturing practice. Contact for further information: Edwin Melendez, HFD-322; (301) 594-0095; e-mail: melendeze@cder.fda.gov Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000. Can a facility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicillin solid dosage forms provided there is no further penicillin production in the renovated facility?Reference: Yes. However, the decontamination process is extremely difficult and we are unaware of any firm that has successfully decontaminated a penicillin facility and converted it to production of non-penicillin products. Note that at section 211.176 the CGMP regulations require that if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin product must be tested for the presence of penicillin and not marketed if detectable levels are found using the codified method. Such a reasonable possibility may be present where decontamination has not been conducted effectively. That would put the responsible firm in a position of having to test each and every lot of non-penicillin product for the presence of penicillin. In sum, while the CGMP regulations would not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues makes the chore daunting. Contact for further info: Edwin Melendez, HFD-322, 301-594-0095; e-mail; melendeze@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. Is there an acceptable level of penicillin residue in non-penicillin drug products?Reference: Any detectable levels of penicillin residue are considered violative because 21 CFR 211.176 indicates that a non-penicillin drug product must not be marketed if detectable levels of penicillin are found when tested according to procedures specified in The Procedures for Detecting and Measuring Penicillin Contamination in Drugs. The current analytical standard for demonstrating adequate decontamination of facilities, separation within the same building, or measurement of cross-contamination is codified at 21 CFR 211.176 and 436.104 and has a limit of detectability of 0.006 ppm (as Penicillin G using S. Lutea) and a violative detection amount of 0.03 ppm. Note that the latter amount reflects the method's limits with respect to confidence and reproducibility and does not represent a tolerance level. This analytical methodology is limited to the detection of Penicillin G and ampicillin in a limited number of products listed in the referenced method, not including other beta-lactam antibiotics. In situations where this methodology is not workable, it is the firm's responsibility to develop, validate, and use other methodology with similar sensitivity. Contact for further info: Edwin Melendez, HFD-322, 301-594-0095; e-mail: melendeze@cder.fda.gov ; Dr. Richard Adams, HFD-643, 301-827-5849; e-mail: adamsr@cder.fda.gov . Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. If a firm's only operation is performing finished packaging operations for bulk tablet and capsule drug products, must it still maintain separate facilities and equipment for packaging penicillin products?Reference: Yes. The CGMP regulations explicitly require that operations relating to the manufacture, processing and packaging of penicillin be performed in facilities that are separate from those facilities used for other drugs. The regulations also require separate air-handling systems in facilities used for penicillin products. Furthermore, if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, CGMPs require that the non-penicillin drug be tested for the presence of penicillin. The CGMPs make no exceptions from the foregoing for operations that are limited to repackaging solid oral dosage forms. It should be noted that the requirement for separate facilities does not necessarily mean that operations relating to penicillin products must be conducted in separate buildings from other drugs. A separate area dedicated to penicillin products within a larger facility may be acceptable if penicillin containment can be established and validated. Contact for further info: Barry Rothman, HFD-325, 301-594-0098, e- mail: rothmanb@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 2) June 1998. |
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