Resultados y resumen del análisis

Inspections of manufacturing establishments by representatives of regulatory agencies all tend to concentrate in areas of compliance with applicable Good Manufacturing Practice regulations. In the United States these are found in the Code of Federal Regulations (CFR) at 21 CFR, Parts 210 and 211 (Code of Federal Regulations 1997). The FDA also published a

Proposed Rule (FDA 1996) amending and clarifying certain parts of the cGMP regulations. Some examples of sections of these regulations that would have an impact on recognition and acceptance of alternative test methods are the following.

• 211.22(c)—The quality control unit has the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.

• 211.84(d)(6)—Each lot of a component that is liable to microbiological contamination shall be subjected to microbiological tests before use.

• 211.94 (d)—Standards, specifications, and methods of testing shall be written and followed for drug product containers and closures.

• 211.100 (a)—There shall be written procedures for production and process controls and they shall be reviewed and approved by the quality control unit.

• 211.110(c)—In-process materials shall be tested for identity, strength, quality and purity as appropriate and approved or rejected by the quality control unit.

• 211.113(a)—Appropriate written procedures shall be established to prevent objectionable organisms in nonsterile drug products.

• 211.113(b)—Appropriate written procedures shall be established to prevent microbiological contamination of sterile drug products.

• 211.160(b)—Laboratory controls shall include the establishment of scientifically sound specifications and test procedures. • 211.165(b)—There shall be appropriate laboratory testing of each batch of drug product required to be free of

objectionable microorganisms.

• 211.165(e)—The accuracy, sensitivity, specificity and reproducibility of test methods shall be established and documented.

• 211.167(a)—There shall be appropriate laboratory testing for each batch of sterile drug product. • 211.194(a) (2)—The suitability of all test methods shall be verified under actual conditions of use.

In the CGMP amendments proposed by the FDA in 1996, several new definitions (e.g., methods validation, process validation, out-of specification) and new sections were added to update these regulations and clarify the FDA’s commitment to the importance of validation in the production of pharmaceutical products.

The FDA has also issued two Inspection Guides that are pertinent to our subject: (1) Guide to Inspections of Pharmaceutical Quality Control Laboratories (FDA 1993a) and (2) Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories (FDA 1993b).

These guides contain general instructions to FDA inspectors on conducting product-specific inspection audits to measure compliance with the CGMP requirements and with the manufacturer’s applications. These may be New (or Abbreviated) Drug Applications (NDAs or ANDAs) or Biologics License Applications (BLAs), and the inspections may be pre-approval (PAI) or biennial inspections. The FDA inspectors are required to observe the laboratory in operation to evaluate compliance with CGMPs and with the manufacturer’s commitments in the above applications. They will examine the standard operating procedures (SOPs) for completeness, and the actual test procedures must conform to the written SOPs. If all laboratory procedures are compendial, then validation data can be minimized, although many manufacturers perform full validation studies as a matter of course. Alternative assays must be fully validated; the data for these studies will be closely examined by the regulators. There is considerable guidance available on the validation of nonmicrobiological (e.g., chemical) test methods that provide specific instruction regarding the demonstration of equivalence between new and existing methods. Some examples include Chapter 1225 of USP 25 (USP 2002a) and ICH documents Q2A and Q2B. In contrast, very little guidance specific to the validation of microbiological testing has been published. The inherent variability of microbiological assays makes them more difficult to validate than other assay procedures. Lack of specific guidelines for proper validation also makes it more difficult for an FDA inspector or an FDA microbiologist, reviewing test documentation, to assess whether an alternative method has been adequately validated. The authors of this book hope that documents such as the PDA Technical Report mentioned earlier and Chapter 12 herein will help to shed light on this problem and make it easier to validate microbiological assays in the future.

Although both Inspection Guides are informative, the Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories (FDA 1993b) gives more insight into the information that the FDA will require when inspecting microbiology laboratories. The guide states that, along with other nonsterile products, the FDA has “…seen a number of problems associated with the microbiological contamination of topical drug products, nasal solutions and inhalation products.” The guide also quotes Chapter 1111 of USP 25 (Microbiological Attributes of Non-Sterile Pharmaceutical Products: USP 2002b) as follows: “The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential hazard to the user.” The FDA expects each manufacturer to develop microbiological acceptance criteria for their nonsterile products by using product-specific USP REGULATORY RECOGNITION AND ACCEPTANCE 151

monographs, USP General Chapters (e.g., <61>, Microbial Limit Tests), and the scientific literature to determine which organisms are objectionable in the product.

For example, gram-negative organisms such as Burkholderia (formerly Pseudomonas) cepacia are considered objectionable in many products, but there are no test methods in the USP for this organism, so the manufacturers are expected to develop their own assay. The guide also asks inspectors to examine the manufacturer’s methods for recovery of damaged organisms by inactivating preservatives in the product or using different incubation times and temperatures. FDA laboratories use the test procedures in the Bacteriological Analytical Manual (BAM 8th edition; FDA; CFSAN; AOAC International) to “… optimize the recovery of all potential pathogens and to quantitate and speciate all recovered organisms.” Manufacturers would do well to imitate this practice so that they can identify any potential problems in their products before release, thus heading off possible regulatory action by the FDA in the future.

Part V of the Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories titled Methodology and Validation of Test Procedures, advises the inspectors to “…evaluate the methodology for microbiological testing…” and, if it is a PAI, to “…compare the method being used against the one submitted in the application.” It also repeats the USP statement that “…an alternate method may be substituted for compendial tests, provided it has been properly validated as giving equivalent or better results.” Other than stating that it “…would be virtually impossible to completely validate test procedures for every organism that may be objectionable..,” the FDA gives no specific guidance here on how to evaluate the validation data that a manufacturer might present. The final decision is left to the discretion of the inspector. This has been an item of concern to those manufacturers who feel that FDA inspectors may not always have the technical knowledge needed to understand and evaluate the newer technology.

The guide does reference the use of automated microbial identification systems and states, “The utilization of automated systems for the identification of microorganisms is relatively common in the parenteral manufacturer where isolates from the environment, water systems, validation and people are routinely identified.” The FDA is also using these systems in its own laboratories and has considerable experience in validating them.

Finally, Guidance on General Principles of Process Validation (FDA 1987) and Guidance on Sterile Drug Products Produced by Aseptic Processing (FDA 1987) give further insight into the elements and concepts the FDA considers as acceptable parts of a validation program. The former document states, “Although the particular requirements of process validation will vary according to…the nature of the…product (e.g., sterile vs. non-sterile) and the complexity of the process, the broad concepts stated in this document have general applicability and provide an acceptable framework for building a comprehensive approach to process validation.”

The most recent legal precedent in the United States that relates to laboratory testing is the now-famous Barr decision (United States v. Barr Laboratories, Inc. 1993). This decision dealt primarily with failing test results (called “out-of- specification” results or OOS by the court), averaging test results, retesting, and validation studies. Many of the findings provide specific guidance on what actions the FDA can require from quality control laboratories within the context of the CGMP regulations. The FDA has also incorporated this analysis of the CGMPs into its Guide to Inspections of Pharmaceutical Quality Control Laboratories and as part of the 1996 proposed amendments to the CGMP regulations. The Barr decision has had a major impact on what was regarded as “standard industry practices” regarding OOS results, retesting, and failure investigations. The latter have become a class of documents that must be maintained by the manufacturer and are subject to review during inspections by regulatory agencies. In the part of the ruling related to assay validations, the court began by reiterating the requirements in the CGMPs for assay validation and repeated the statement that the suitability of testing methods must be verified under actual conditions of use. The court ruling also found that a manufacturer can show that its methods are validated in one of three ways: “(1) If the method was approved as part of its ANDA; (2) if the method is the same as that used in the current version of the USP; or (3) if a firm validates its method through a validation study. If the method falls into one of these three categories, firms need only show that the method works under conditions of actual use. However, if firms either adopt methods the USP does not recognize or modify USP procedures, they must validate these procedures. Systems suitability data alone are insufficient for validation. Statistics in itself is absolutely not a validation process. Statistics merely aids in the evaluation of the validation data.” If we wanted to further generalize the spirit of this ruling, we would substitute other registration documents for the term “ANDA” and other compendia for the USP.

Subsequent to the court ruling, the two ICH Guidelines mentioned previously (Q2A and Q2B) were published in the

Federal Register; they describe the validation of analytical procedures. Thus, manufacturers who choose to use the new rapid microbiological methods as alternate test methods must realize that they will be subject to the same (or greater) regulatory scrutiny regarding OOS results, retesting, averaging, and failure investigation as they would be if they were using classical methods.

Laboratory control issues such as environmental monitoring, raw material, and component testing and sampling procedures have been a constant source of inspection citations from the FDA (known as “483 items” from the FDA form on which they are written) and other regulatory authorities. Recent presentations by personnel from the Medicines Control Agency (MCA) in the United Kingdom and the FDA show that these issues are still at or near the top of CGMP deficiencies found at both U.S.

and European pharmaceutical manufacturers. Both CBER and FDA field inspectors listed the following as two of their most frequent citations during presentations at PDA meetings in 1997 and 1998: “Failure to properly validate microbial test methods” and “Laboratory controls not based on scientifically sound and appropriate specifications.” Because the majority of the rapid microbiological methods are intended for use in these types of assays (e.g., water testing, environmental monitoring, microbial limit testing, and antimicrobial effectiveness testing), it stands to reason that they will continue to be a focus of CGMP inspections.