PART 212—CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION TOMOGRAPHY DRUGS Authority: 21 U.S.C. 321, 351, 352, 355, 371, 374; Sec. 121, Pub. L. 105-115, 111 Stat. 2296. Source: 74 FR 65431, Dec. 10, 2009, unless otherwise noted. Subpart A—General Provisions § 212.1 What are the meanings of the technical terms used in these regulations? The following definitions apply to words and phrases as they are used in this part. Other definitions of these words may apply when they are used in other parts of this chapter. Acceptance criteria Act et seq. Active pharmaceutical ingredient Batch Batch production and control record Component Conditional final release Final release Inactive ingredient In-process material Lot Lot number control number batch number Master production and control record Material release PET PET drug PET drug product PET drug production facility Production Quality assurance Receiving facility Specifications Strength Sub-batch Verification § 212.2 What is current good manufacturing practice for PET drugs? Current good manufacturing practice for PET drugs is the minimum requirements for the methods to be used in, and the facilities and controls used for, the production, quality assurance, holding, or distribution of PET drugs intended for human use. Current good manufacturing practice is intended to ensure that each PET drug meets the requirements of the act as to safety and has the identity and strength, and meets the quality and purity characteristics, that it is supposed to have. § 212.5 To what drugs do the regulations in this part apply? (a) Application solely to PET drugs. (b) Investigational and research PET drugs. [email protected], http://www.usp.org/USPNF/notices. http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. Subpart B—Personnel and Resources § 212.10 What personnel and resources must I have? You must have a sufficient number of personnel with the necessary education, background, training, and experience to perform their assigned functions. You must have adequate resources, including facilities and equipment, to enable your personnel to perform their functions. Subpart C—Quality Assurance § 212.20 What activities must I perform to ensure drug quality? (a) Production operations. (b) Materials. (c) Specifications and processes. (d) Production records. (e) Quality assurance. Subpart D—Facilities and Equipment § 212.30 What requirements must my facilities and equipment meet? (a) Facilities. (b) Equipment procedures. (c) Equipment construction and maintenance. Subpart E—Control of Components, Containers, and Closures § 212.40 How must I control the components I use to produce PET drugs and the containers and closures I package them in? (a) Written procedures. (b) Written specifications. (c) Examination and testing. (1)(i) If you conduct finished-product testing of a PET drug product that includes testing to ensure that the correct components have been used, you must determine that each lot of incoming components used in that PET drug product complies with written specifications by examining a certificate of analysis provided by the supplier. You are not required to perform a specific identity test on any of those components. (ii) If you do not conduct finished-product testing of a PET drug product that ensures that the correct components have been used, you must conduct identity testing on each lot of a component that yields an active ingredient and each lot of an inactive ingredient used in that PET drug product. This testing must be conducted using tests that are specific to each component that yields an active ingredient and each inactive ingredient. For any other component, such as a solvent or reagent, that is not the subject of finished-product testing, you must determine that each lot complies with written specifications by examining a certificate of analysis provided by the supplier; if you use such a component to prepare an inactive ingredient on site, you must perform an identity test on the components used to make the inactive ingredient before the components are released for use. However, if you use as an inactive ingredient a product that is approved under section 505 of the act (21 U.S.C. 355) and is marketed as a finished drug product intended for intravenous administration, you need not perform a specific identity test on that ingredient. (2) You must examine a representative sample of each lot of containers and closures for conformity to its written specifications. You must perform at least a visual identification of each lot of containers and closures. (d) Handling and storage. (e) Records. Subpart F—Production and Process Controls § 212.50 What production and process controls must I have? You must have adequate production and process controls to ensure the consistent production of a PET drug that meets the applicable standards of identity, strength, quality, and purity. (a) Written control procedures. (b) Master production and control records. (1) The name and strength of the PET drug; (2) If applicable, the name and radioactivity or other measurement of each active pharmaceutical ingredient and each inactive ingredient per batch or per unit of radioactivity or other measurement of the drug product, and a statement of the total radioactivity or other measurement of any dosage unit; (3) A complete list of components designated by names and codes sufficiently specific to indicate any special quality characteristic; (4) Identification of all major pieces of equipment used in production; (5) An accurate statement of the weight or measurement of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations are permitted in the amount of component necessary if they are specified in the master production and control records; (6) A statement of action limits on radiochemical yield, i.e., the minimum percentage of yield beyond which investigation and corrective action are required; (7) Complete production and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed; and (8) A description of the PET drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling. (c) Batch production and control records. (1) Name and strength of the PET drug; (2) Identification number or other unique identifier of the specific batch that was produced; (3) The name and radioactivity or other measure of each active pharmaceutical ingredient and each inactive ingredient per batch or per unit of radioactivity or other measurement of the drug product; (4) Each major production step (obtained from the approved appropriate master production and control record); (5) Weights (or other measure of quantity) and identification codes of components; (6) Dates of production steps and times of critical production steps; (7) Identification of major pieces of equipment used in production of the batch; (8) Testing results; (9) Labeling; (10) Initials or signatures of persons performing or checking each significant step in the operation; and (11) Results of any investigations conducted. (d) Area and equipment checks. (e) In-process materials controls. (f) Process verification. (2) When the results of the production of an entire batch of a PET drug are not fully verified through finished-product testing or when only the initial sub-batch in a series is tested, the PET drug producer must demonstrate that the process for producing the PET drug is reproducible and is capable of producing a drug product that meets the predetermined acceptance criteria. Process verification activities and results must be documented. Documentation must include the date and signature of the individual(s) performing the verification, the monitoring and control methods and data, and the major equipment qualified. Subpart G—Laboratory Controls § 212.60 What requirements apply to the laboratories where I test components, in-process materials, and finished PET drug products? (a) Testing procedures. (b) Specifications and standards. (c) Analytical methods. (d) Materials. (e) Equipment. (f) Equipment maintenance. (g) Test records. (1) A suitable identification of the sample received for testing. (2) A description of each method used in the testing of the sample, a record of all calculations performed in connection with each test, and a statement of the weight or measurement of the sample used for each test. (3) A complete record of all data obtained in the course of each test, including the date and time the test was conducted, and all graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, in-process material, or drug product for each lot tested. (4) A statement of the results of tests and how the results compare with established acceptance criteria. (5) The initials or signature of the person performing the test and the date on which the test was performed. § 212.61 What must I do to ensure the stability of my PET drug products through expiry? (a) Stability testing program. (b) Storage conditions and expiration dates. Subpart H—Finished Drug Product Controls and Acceptance § 212.70 What controls and acceptance criteria must I have for my finished PET drug products? (a) Specifications. (b) Test procedures. (c) Conformance to specifications. (d) Final release procedures. (1) An appropriate laboratory determination under paragraph (c) of this section is completed; (2) Associated laboratory data and documentation are reviewed and they demonstrate that the PET drug product meets specifications, except for sterility; and (3) A designated qualified individual authorizes final release by dated signature. (e) Sterility testing. (f) Conditional final release. (i) You have data documenting that preceding consecutive batches, produced using the same methods used for the conditionally released batch, demonstrate that the conditionally released batch will likely meet the established specifications; (ii) You determine that all other acceptance criteria are met; (iii) You retain a reserve sample of the conditionally released batch of drug product; (iv) You promptly correct the malfunction of analytical equipment, complete the omitted test using the reserve sample after the malfunction is corrected, and document that reasonable efforts have been made to prevent recurrence of the malfunction; (v) If you obtain an out-of-specification result when testing the reserve sample, you immediately notify the receiving facility; and (vi) You document all actions regarding the conditional final release of the drug product, including the justification for the release, all followup actions, results of completed testing, all notifications, and corrective actions to prevent recurrence of the malfunction involving analytical equipment. (2) Even if the criteria in paragraph (f)(1) of this section are met, you may not approve the conditional final release of the product if the malfunction involving analytical equipment prevents the performance of a radiochemical identity/purity test or prevents the determination of the product's specific activity. (3) You may not release another batch of the PET drug product until you have corrected the problem concerning the malfunction of analytical equipment and completed the omitted finished-product test. § 212.71 What actions must I take if a batch of PET drug product does not conform to specifications? (a) Rejection of nonconforming product. (b) Investigation. (c) Correction of problems. (d) Reprocessing. Subpart I—Packaging and Labeling § 212.80 What are the requirements associated with labeling and packaging PET drug products? (a) A PET drug product must be suitably labeled and packaged to protect the product from alteration, contamination, and damage during the established conditions of shipping, distribution, handling, and use. (b) Labels must be legible and applied so as to remain legible and affixed during the established conditions of processing, storage, handling, distribution, and use. (c) All information stated on each label must also be contained in each batch production record. (d) Labeling and packaging operations must be controlled to prevent labeling and product mix-ups. Subpart J—Distribution § 212.90 What actions must I take to control the distribution of PET drug products? (a) Written distribution procedures. (b) Distribution records. (1) The name, address, and telephone number of the receiving facility that received each batch of a PET drug product; (2) The name and quantity of the PET drug product shipped; (3) The lot number, control number, or batch number for the PET drug product shipped; and (4) The date and time you shipped the PET drug product. Subpart K—Complaint Handling § 212.100 What do I do if I receive a complaint about a PET drug product produced at my facility? (a) Written complaint procedures. (b) Complaint review. (c) Complaint records. (d) Returned products. Subpart L—Records § 212.110 How must I maintain records of my production of PET drugs? (a) Record availability. (b) Record quality. (c) Record retention period.