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4.3 Equipment Maintenance 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. Is it acceptable to manufacture penicillin products in the same facility as cephalosporin? What should investigators look for when inspecting a firm's cleaning validation program? 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. Does FDA approve materials of construction for equipment? For example, are there any specific CGMP requirements regarding ferrite content and other properties of 316L stainless steel used in storage tanks for pharmaceutical water systems?Reference: FDA does not approve or prohibit specific equipment or materials (with rare exceptions such as the requirements relating to asbestos filters found at 21 CFR 211.72). A storage tank or other piece of equipment is subject to the general CGMP requirements addressing equipment suitability. For example, section 211.65 requires surfaces that contact components, in-process materials, or drug products not be reactive, additive, or absorptive so as to adversely affect product quality. Section 211.63 requires that equipment be of appropriate design to facilitate operations for its intended use and for cleaning and maintenance. Section 211.67 requires firms to clean, maintain, and sanitize equipment at appropriate intervals to prevent malfunctions or contamination that would adversely affect product quality. To illustrate, it's important that interior surfaces of a sanitary storage tank are capable of being cleaned, sanitized, and (if needed) sterilized. For such sanitary equipment, design provisions to prevent backsiphonage (see Section 211.48) and stagnation are among the attributes that prevent microbial contamination of a drug product. Likewise, smooth interior surfaces (e.g., welds) help prevent collection of microbial contamination and formation of a biofilm. (See the above inspection guide for more information on biofilms.) So choosing materials or components for any equipment involves evaluating whether there is any potential for an adverse impact on drug product quality. In this respect, various compatibility considerations (e.g., leachables, interaction with formulations/sanitizers, ability of material to withstand sterilization) can often take on the most CGMP significance. Ultimately, provided that such CGMP requirements are met, firms are afforded the flexibility to select the material and grade which best satisfies the needs of their particular application. Given this information, it should be no surprise that the CGMP regulations do not include specifics on what ferrite content is appropriate in stainless steel. However, a number of references may provide a useful starting point when researching issues such as sanitary design standards, surface grit/smoothness, pits, folds, crevices, and steel composition (including ferrite content). The milk industry has publications (e.g., "3-A Accepted Practices for Permanently Installed Sanitary Product Pipelines and Cleaning Systems") written jointly with the U.S. Public Health Service regarding sanitary design. ANSI (American National Standards Institute) also publishes documents addressing design of seamless and sanitary piping. Such literature should be available through a search on the American Iron and Steel Institute (1000 16th Street, N.W., Washington, D.C. 20036) website at www.steel.org. A search on words such as "seamless" and "weld" at www.nssn.org will yield further relevant references. 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 3) September, 1999. If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?Reference: There are a number of possible scenarios under this question. Under CGMP, FDA would expect the contract laboratory to have a quality control unit. The lab's QC unit has the CGMP responsibility to ensure the analytical results obtained are accurate for the tested material. This means the contract laboratory needs to investigate any OOS result with the purpose of ascertaining such accuracy. This would be accomplished by ensuring that personnel performed the tests properly using: (1) The current validated analytical procedure; (2) correct reagents and reference standards; and, (3) equipment that has been properly maintained and calibrated. There are basically two possible results of the lab's investigation. 1) If the lab determines the analyst made an error, or that instrument malfunction occurred, the test results may be invalidated. The analysis would be re-run according to the approved analytical method. The re-run test results would be considered the original results, and these results would be reported to the manufacturer. The lab does not have a CGMP obligation to report the initial (invalidated) results to the manufacturer; however, the lab must, per 211.194, retain the records pertaining to those initial results. 2) If the laboratory determines that there was no analyst error, and that no instrument malfunction occurred, then the results must be considered accurate and reported to the pharmaceutical manufacturer. In the event of outcome number two, the pharmaceutical manufacturer would have analytical results indicating the material does not meet its specifications. Under CGMP, an investigation must take place. The manufacturer is responsible for investigating the production process to determine if any mistakes were made--things to consider could include charge-in of components, mixing times, and quality of components. Storage conditions of the analyzed material, and the sampling method used also need to be reviewed to ascertain whether the tested material might not have been representative of the batch. If the manufacturer's investigation fails to find a cause, it might also consider whether the contract laboratory is suspect (i.e., if perhaps the lab made an unrecognized error.) The CGMPs do not, however, explicitly require the manufacturer to extend its investigation to the lab's operations. However, it is considered CGMP for manufacturers to qualify their contract laboratories. At comment paragraph 94 of the September 29, 1978 CGMP revisions, 43 FR 45034, the agency said "[a] manufacturer does have a responsibility, however, to see that the outside laboratory used is qualified to do the work and that the work is performed satisfactorily." As part of its investigation, the manufacturer might take the opportunity to requalify the contract laboratory, or may consider changing contract laboratories. Retesting could also be part of this process. It must be stressed that in this situation the manufacturer has information that the batch does not meet its quality standards, and unless that information can be invalidated, it must be used to reach a batch disposition decision, namely, whether to destroy the batch, or reprocess it to bring it into compliance. Contact for further information: Russ Rutledge, HFD-325, 301-594-0098, e-mail: rutledgec@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. What should investigators look for when inspecting a firm's cleaning validation program?Reference: The objective of cleaning validation is to ensure that a specific cleaning process will consistently clean to predetermined limits so as to prevent contaminants (product or cleaning process related) from adversely affecting the safety and quality of the next product manufactured. As stated in the Guide to Inspections of Validation of Cleaning Processes, determine if firms have a written, well established and validated cleaning program. Basic steps include the development of a sensitive, accurate and precise analytical method for the determination of an acceptable limit, something necessary for any analytical test method developed in conformance with CGMPs. In addition, as discussed in the guide, determine if firms have and follow specific written procedures as to how cleaning will be performed, as well as how the cleaning validation will be conducted (including sampling procedures and analytical methods). Determine if the validation protocol addresses different sampling surface types, hardest to clean areas, and specific equipment, including utensils. FDA expects the validation studies will be completed in accordance with written protocols and that the final validation report will include the appropriate conclusions with management concurrence. Performing testing of cleaned equipment, in accordance with written procedures, would be consistent with 21 CFR 211.67(b). Contact for further info: Patricia L. Alcock, HFD-322, (301) 594- 0095; e-mail: alcockp@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 2) June 1998. Does FDA have impurities acceptance limits for cleaning validation and subsequent cleaning verification?Reference: FDA has always been concerned with the issue of contamination and cross contamination. Such contamination may include not only carry over from a previous product or residual cleaning solvents, but also detergents and surfactants. Except for penicillin, FDA has not established standard acceptance limits for cleaning validation. Due to the wide variation in both equipment and products produced, it would be unrealistic for the agency to determine a specific limit. In the CGMP context, however, firms need to establish limits that reflect the practical capability of their cleaning processes, as well as the specificity of the analytical test method. We have found that some firms have incorrectly applied as their acceptance limit the 0.1% impurity identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process or related compounds and not extraneous impurities caused by cross contamination. It is important that acceptance limits reflect the capability of the cleaning process. When determining the acceptance limit, relevant factors generally include: (1) Evaluation of the therapeutic dose carryover; (2) toxicity of the potential contaminant; (3) concentration of the contaminant in the rinses; (4) limit of detection of the analytical test method; and, (5) visual examination. While we suggest that these factors be considered, relying only on visual examination would not be scientifically sound. Contact for further info: Patricia L. Alcock, HFD-322, (301) 594- 0095; e-mail: alcockp@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 2) June 1998. Should non-pharmaceuticals be manufactured in common equipment with active pharmaceutical ingredients (APIs)?Reference: FDA has not specifically addressed this issue in a formal document. However, a fundamental tenet of current good manufacturing practice is that equipment does not contaminate the drugs -- that is, alter drug safety, quality or purity beyond established specifications. If you encounter instances in which non-pharmaceuticals are made in the same equipment as APIs, consider this basic tenet, and evaluate the suitability of using common equipment on a case by case basis. Some non-pharmaceuticals pose unacceptable risks of cross-contamination and product mix-ups, and should therefore not normally be manufactured in common equipment with APIs. In some cases, in addition to separate equipment, it would be appropriate to use a separate facility for pharmaceutical chemical manufacturing. This separation is an internationally recognized concept. For example, the World Health Organization (WHO) Guide to Good Manufacturing Practices discusses the use of separate facilities for the production of certain "non-pharmaceutical products." It adds that "the production of technical poisons, such as pesticides and herbicides," should not take place on the "premises used for the manufacture of pharmaceutical products." As a general principle, the risks posed by unanticipated mix-ups or cross-contamination should be considered with particular emphasis on chemicals: (1) Known to pose any acute or long term toxicity concerns; or, (2) of incompletely characterized toxicity. Toxicological assessments normally include information such as acute data (e.g., LD50 determinations) using different routes of administration, mutagenicity, carcinogenicity, teratogenicity, sensitization, and irritation. Investigators should be aware that lack of toxicological assessments is not uncommon. These risks are influenced by the nature and intended use of the drug products that will incorporate the API. For example, those risks may be of greater concern when the APIs will be used in dosage forms intended for: (1) Large doses, (2) long term therapy; (3) treating open wounds; (4) injection; or, (5) inhalation. Even when an API manufacturer considers these issues, and determines that the non-pharmaceutical is "harmless" and can be made in common equipment with APIs, it is important that the manufacturer still follows CGMPs for APIs. Contact for further info: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 2) June 1998. Do the CGMP regulations require equipment to be labeled with calibration dates? Do the regulations distinguish critical from noncritical equipment for this purpose?Reference: No and no. The CGMP regulations do not require that each piece of equipment bear status labeling as to its state of calibration or maintenance. However, per 211.67, 211.68, and 211.160, equipment must be calibrated and/or maintained according to an established schedule, and records must be kept documenting such activities. The regulations do not distinguish critical from noncritical equipment for calibration and maintenance purposes. However, the need for calibrating a given piece of equipment depends on its function. In general, things that measure materials warrant calibration. In addition, the 1978 preamble to the CGMP regulations states that 211.68(a) is intended to control equipment having an effect on product quality. Prudence dictates this be interpreted broadly. Equipment not requiring calibration/maintenance need not be tracked or included in the firm's calibration/maintenance program. During an inspection a firm should be able to document when a specific piece of equipment was last calibrated/maintained, the results or action, and when its next calibration/maintenance is scheduled. The absence of such documentation is a CGMP deviation. While the absence of a calibration/maintenance tag is not objectionable, the presence of a calibration/ maintenance tag alone should not be assumed to satisfy regulatory demands, and the supporting documentation should be audited. The firm should also be able to support its decision to not include a particular piece of equipment in the calibration/maintenance program. Don't confuse use of calibration tags with the CGMP requirement, at section 211.105, that major equipment be identified with a distinctive number or code that is recorded in batch records. This identification requirement is intended to help document which pieces of equipment were used to make which batches of drug product. Contact for further information: Brian Hasselbalch, HFD-325, (301)594-0098: e-mail: hasselbalchb@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 5, Number 4) December, 1997. Is it acceptable for a manufacturer to replace faulty or out of calibration instrumentation with "spare/backup" instruments that have been previously calibrated but stored at a remote location?Reference: Yes, provided the replacement instruments remain within calibration, meet established specifications, and haven't been stored longer than the established calibration interval. The heart of the issue is equipment suitability. Let us assume that the spare instrument is, first of all, the same make and model as what it is supposed to replace, thus ensuring that performance characteristics of the two are the same and the analytical method at hand is not modified. If that's the case, then the spare instrument may be stored anywhere storage conditions don't adversely affect its performance (reliability, accuracy and precision). Before any lab instrument is put into use, the CGMP regulations require that the firm ensure it is within calibration specifications. If the "spare" instrument may drift out of calibration during storage, as might be the case if it has moving parts, then we would expect the firm to recalibrate the instrument before putting it into service. Remember that some instruments are so delicate that just moving them from one place to another causes them to go out of calibration. Finally, section 211.160(b) of the CGMP regulations requires firms to calibrate laboratory instrumentation at appropriate intervals according to a written program. If the storage period for the "spare" in question exceeded that interval, we would expect firms to re-calibrate the instrument prior to use. Reprinted
from FDA's Human Drug CGMP
Notes, (Volume 5 Number 2), June, 1997. |
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