This chapter summarizes some of the various Good Manufacturing Practice requirements as stated in the Code of Federal Regulations Part 211. The FDA’s Compliance Program Guidance (CPG) is highlighted and explained as it pertains to active pharmaceutical ingredients and computer controls. Also covered are some key recommendations from the International Committee on Harmonization (ICH) and the American Society for Testing and Materials (ASTM). Reviewing and understanding the regulations and guidance documents of the performance of a process validation program is made much easier. This chapter provides insight into what is expected by the FDA, ICH, and ASTM for a complete and compliant process validation. CPG; CFR; risk management; quality systems; batch; mix-ups The US Food and Drug Administration (FDA) expects that pharmaceutical manufacturers follow the rules set forth to assure a quality product. With this, they expect that quality be built into the product, not tested into the product. This is the basis for the Quality by Design or QbD program.1 The law that governs the pharmaceutical industry is the Food, Drug, and Cosmetic Act (FD&C). This was originally promulgated in 1906 and revised over time. From this set of laws the FDA is authorized to establish and publish rules that support the FD&C. This is in the Code of Federal Regulations (CFR) Title 21. Parts 210 and 211 are known as the Good Manufacturing Practices (GMPs) for Finished Pharmaceuticals. As will be seen, the GMPs are interpretive, allowing the manufacturer to implement them as necessary for their product(s). Meeting the GMP requirements is not only necessary but also makes good business sense. The reason for this is that in any business one needs to know that the equipment and materials purchased are the ones specified and that they will all perform as expected. If they do not, there can be great losses to the company. In this chapter some of the key regulations that pertain to process validation will be reviewed. The selected regulations presented here are considered key to completing a successful process validation. Nonetheless, all of the other GMPs need to be reviewed and adhered to during the design and implementation of the process validation program (see Appendix A for the complete 21 CFR 211). In addition, some of the guidelines promulgated by the FDA are also reviewed. While not binding for the industry, these guidelines make good sense for meeting the expectations of the regulatory agencies. Chapter 5 of the FD&C act deals with pharmaceuticals. Section 501(a)(2)(B) of the act defines adulterated products and is the basis for the FDA’s authority. In addition to the documents and regulations summarized here, the FDA provides many guideline documents that should be referred to before a process validation is started (eg, The process Validation Guideline,2 Q7,3 Guide to Cleaning Validations,4 and many more—refer to the list in Appendix C). Along with the FDA guidelines the International Conference on Harmonization (ICH)5 also has a series of guidelines (also in Appendix C) to help understand and comply with all of the requirements of pharmaceutical manufacturing. These guidelines when fully approved by all parties (United States, EU, and Japan) become FDA guidance documents. In particular, there are three ICH guidelines that deserve special attention for preparing and for executing a compliant process validation program. Not only are they ICH guidelines but now they are also FDA guidelines. These are: Food, Drug, and Cosmetic Act SEC. 501 A drug or device shall be deemed to be adulterated “1(a) (1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess; or C (3) if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; or (4) if (A) it bears or contains, for purposes of coloring only, a color additive which is …” For purposes of paragraph 501(a)(2)(B), the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products. EXPLANATION: This has been interpreted as meaning that all drugs (veterinary or human) must meet the requirements set forth in 21 CFR 211 before they can be considered marketable. The term “current” is set forth to indicate that the expectation is that industry best practices current at the time of manufacture will be used and followed. Title 21 Code of Federal Regulations Sec. 211.100 Written procedures; deviations (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. (b) 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. Any deviation from the written procedures shall be recorded and justified. EXPLANATION: All functions related to the manufacture of a drug need to have a written record. This record includes the steps needed to manufacture the drug, the steps taken during the manufacture (ie, adding ingredients) and the time and person(s) performing the act. Initials or signatures indicating the completion of each step needs to be done at the time it was actually performed. Sec. 211.22 Responsibilities of quality control unit. (a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. (b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit. (c) 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 drug product. (d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed. EXPLANATION: This is one of the most critical regulations in the CFR. The Quality Unit has to approve or reject all components, documents, and investigations. They are to review the laboratory records as well. Sec. 211.192 Production record review 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. 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, whether or not the batch has already been distributed. 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. A written record of the investigation shall be made and shall include the conclusions and followup EXPLANATION: This specifies that the Quality Unit shall conduct reviews of all production records to determine compliance with all approved written procedures. Sec. 211.165 Testing and release for distribution. (a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible. (b) There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms. (c) Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed. (d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels. (e) 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). (f) Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria. EXPLANATION: The Quality Control laboratory needs to have written procedures just as the manufacturing area does. No Objectionable organisms6 should be present. The laboratory equipment and test procedures require qualification and validation (except if compendial methods are followed). Statistical evaluation of the data needs to be included in determining if the product is consistent with its prespecified release criteria. Sec. 211.160 General requirements (a) The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified. (b) 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 conformity to applicable 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.
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