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 means numerical limits, ranges, or other criteria for tests that are used for or in making a decision to accept or reject a unit, lot, or batch of a PET drug product.

Act means the Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. 321 et seq.).

Active pharmaceutical ingredient means a substance that is intended for incorporation into a finished PET drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis or monitoring of a disease or a manifestation of a disease in humans, but does not include intermediates used in the synthesis of such substance.

Batch means a specific quantity of PET drug intended to have uniform character and quality, within specified limits, that is produced according to a single production order during the same cycle of production.

Batch production and control record means a unique record that references an accepted master production and control record and documents specific details on production, labeling, and quality control for a single batch of a PET drug.

Component means any ingredient intended for use in the production of a PET drug, including any ingredients that may not appear in the final PET drug product.

Conditional final release means a final release made prior to completion of a required finished-product test because of a malfunction involving analytical equipment.

Final release means the authoritative decision by a responsible person in a PET production facility to permit the use of a batch of a PET drug in humans.

Inactive ingredient means any intended component of the PET drug other than the active pharmaceutical ingredient.

In-process material means any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and is used in, the preparation of a PET drug.

Lot means a batch, or a specifically identified portion of a batch, having uniform character and quality within specified limits. In the case of a PET drug produced by continuous process, a lot is a specifically identified amount produced in a unit of time or quantity in a manner that ensures its having uniform character and quality within specified limits.

Lot number, control number, or batch number means any distinctive combination of letters, numbers, or symbols from which the complete history of the production, processing, packing, holding, and distribution of a batch or lot of a PET drug can be determined.

Master production and control record means a compilation of instructions containing the procedures and specifications for the production of a PET drug.

Material release means the authoritative decision by a responsible person in a PET production facility to permit the use of a component, container and closure, in-process material, packaging material, or labeling in the production of a PET drug.

PET means positron emission tomography.

PET drug means a radioactive drug that exhibits spontaneous disintegration of unstable nuclei by the emission of positrons and is used for providing dual photon positron emission tomographic diagnostic images. The definition includes any nonradioactive reagent, reagent kit, ingredient, nuclide generator, accelerator, target material, electronic synthesizer, or other apparatus or computer program to be used in the preparation of a PET drug. “PET drug” includes a “PET drug product” as defined in this section.

PET drug product means a finished dosage form of a PET drug, whether or not in association with one or more other ingredients.

PET drug production facility means a facility that is engaged in the production of a PET drug.

Production means the manufacturing, compounding, processing, packaging, labeling, reprocessing, repacking, relabeling, and testing of a PET drug.

Quality assurance means a system for ensuring the quality of active ingredients, PET drugs, intermediates, components that yield an active pharmaceutical ingredient, analytical supplies, and other components, including container-closure systems and in-process materials, through procedures, tests, analytical methods, and acceptance criteria.

Receiving facility means any hospital, institution, nuclear pharmacy, imaging facility, or other entity or part of an entity that accepts a PET drug product that has been given final release, but does not include a common or contract carrier that transports a PET drug product from a PET production facility to a receiving facility.

Specifications means the tests, analytical procedures, and appropriate acceptance criteria to which a PET drug, PET drug product, component, container-closure system, in-process material, or other material used in PET drug production must conform to be considered acceptable for its intended use. Conformance to specifications means that a PET drug, PET drug product, component, container-closure system, in-process material, or other material used in PET drug production, when tested according to the described analytical procedures, meets the listed acceptance criteria.

Strength means the concentration of the active pharmaceutical ingredient (radioactivity amount per volume or weight at the time of calibration).

Sub-batch means a quantity of PET drug having uniform character and quality, within specified limits, that is produced during one succession of multiple irradiations, using a given synthesis and/or purification operation.

Verification means confirmation that an established method, process, or system meets predetermined acceptance criteria.

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.

(a) Application solely to PET drugs. The regulations in this part apply only to the production, quality assurance, holding, and distribution of PET drugs. Any human drug that does not meet the definition of a PET drug must be manufactured in accordance with the current good manufacturing practice requirements in parts 210 and 211 of this chapter.

(b) Investigational and research PET drugs. For investigational PET drugs for human use produced under an investigational new drug application in accordance with part 312 of this chapter, and PET drugs produced with the approval of a Radioactive Drug Research Committee in accordance with part 361 of this chapter, the requirement under the act to follow current good manufacturing practice is met by complying with the regulations in this part or by producing PET drugs in accordance with Chapter 823, “Radiopharmaceuticals for Positron Emission Tomography - Compounding,” May 1, 2009, pp. 365-369, 32d ed. of the United States Pharmacopeia (USP) National Formulary (NF) (USP 32/NF 27) (2009). The Director of the Federal Register approves this incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy from the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, Geeta M. Tirumalai, 301-816-8352, e-mail: gt@usp.org, Internet address: http://www.usp.org/USPNF/notices. You may inspect a copy at the Food and Drug Administration Biosciences Library, 10903 New Hampshire Ave., Silver Spring, MD, 20993-0002, 301-796-3504, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

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.

(a) Production operations. You must oversee production operations 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.

(b) Materials. You must examine and approve or reject components, containers, closures, in-process materials, packaging materials, labeling, and finished dosage forms to ensure compliance with procedures and specifications affecting the identity, strength, quality, or purity of a PET drug.

(c) Specifications and processes. You must approve or reject, before implementation, any initial specifications, methods, processes, or procedures, and any proposed changes to existing specifications, methods, processes, or procedures, to ensure that they maintain the identity, strength, quality, and purity of a PET drug. You must demonstrate that any change does not adversely affect the identity, strength, quality, or purity of any PET drug.

(d) Production records. You must review production records to determine whether errors have occurred. If errors have occurred, or a production batch or any component of the batch fails to meet any of its specifications, you must determine the need for an investigation, conduct investigations when necessary, and take appropriate corrective actions.

(e) Quality assurance. You must establish and follow written quality assurance procedures.

(a) Facilities. You must provide adequate facilities to ensure the orderly handling of materials and equipment, the prevention of mix-ups, and the prevention of contamination of equipment or product by substances, personnel, or environmental conditions that could reasonably be expected to have an adverse effect on product quality.

(b) Equipment procedures. You must implement procedures to ensure that all equipment that could reasonably be expected to adversely affect the identity, strength, quality, or purity of a PET drug, or give erroneous or invalid test results when improperly used or maintained, is clean, suitable for its intended purposes, properly installed, maintained, and capable of repeatedly producing valid results. You must document your activities in accordance with these procedures.

(c) Equipment construction and maintenance. Equipment must be constructed and maintained so that surfaces that contact components, in-process materials, or PET drugs are not reactive, additive, or absorptive so as to alter the quality of PET drugs.

(a) Written procedures. You must establish, maintain, and follow written procedures describing the receipt, login, identification, storage, handling, testing, and acceptance and/or rejection of components and drug product containers and closures. The procedures must be adequate to ensure that the components, containers, and closures are suitable for their intended use.

(b) Written specifications. You must establish appropriate written specifications for the identity, quality, and purity of components and for the identity and quality of drug product containers and closures.

(c) Examination and testing. Upon receipt, each lot of components and containers and closures must be uniquely identified and tested or examined to determine whether the lot complies with your specifications. You must not use in PET drug production any lot that does not meet its specifications, including any expiration date if applicable, or that has not yet received its material release. Any incoming lot must be appropriately designated as quarantined, accepted, or rejected. You must use a reliable supplier as a source of each lot of each component, container, and closure.

(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. You must handle and store components, containers, and closures in a manner that prevents contamination, mix-ups, and deterioration and ensures that they are and remain suitable for their intended use.

(e) Records. You must keep a record for each shipment of each lot of components, containers, and closures that you receive. The record must include the identity and quantity of each shipment, the supplier's name and lot number, the date of receipt, the results of any testing performed, the disposition of rejected material, and the expiration date (where applicable).

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. You must have written production and process control procedures to ensure and document that all key process parameters are controlled and that any deviations from the procedures are justified.

(b) Master production and control records. You must have master production and control records that document all steps in the PET drug production process. The master production and control records must include the following information:

(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. Each time a batch of a PET drug is produced, a unique batch production and control record must be created. The batch production record must include the following information:

(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. The production area and all equipment in the production area must be checked to ensure cleanliness and suitability immediately before use. A record of these checks must be kept.

(e) In-process materials controls. Process controls must include control of in-process materials to ensure that the materials are controlled until required tests or other verification activities have been completed or necessary approvals are received and documented.

(f) Process verification. (1) For a PET drug for which each entire batch undergoes full finished-product testing to ensure that the product meets all specifications, process verification, as described in paragraph (f)(2) of this section, is not required.

(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.

(a) Testing procedures. Each laboratory used to conduct testing of components, in-process materials, and finished PET drug products must have and follow written procedures for the conduct of each test and for the documentation of the results.

(b) Specifications and standards. Each laboratory must have sampling and testing procedures designed to ensure that components, in-process materials, and PET drug products conform to appropriate standards, including established standards of identity, strength, quality, and purity.

(c) Analytical methods. Laboratory analytical methods must be suitable for their intended use and must be sufficiently sensitive, specific, accurate, and reproducible.

(d) Materials. The identity, purity, and quality of reagents, solutions, and supplies used in testing procedures must be adequately controlled. All solutions that you prepare must be properly labeled to show their identity and expiration date.

(e) Equipment. All equipment used to perform the testing must be suitable for its intended purposes and capable of producing valid results.

(f) Equipment maintenance. Each laboratory must have and follow written procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, and that these activities are documented.

(g) Test records. Each laboratory performing tests related to the production of a PET drug must keep complete records of all tests performed to ensure compliance with established specifications and standards, including examinations and assays, as follows:

(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.

(a) Stability testing program. You must establish, follow, and maintain a written testing program to assess the stability characteristics of your PET drug products. The test methods must be reliable, meaningful, and specific. The samples tested for stability must be representative of the lot or batch from which they were obtained and must be stored under suitable conditions.

(b) Storage conditions and expiration dates. The results of such stability testing must be documented and used in determining appropriate storage conditions and expiration dates and times for each PET drug product you produce.

(a) Specifications. You must establish specifications for each PET drug product, including criteria for determining identity, strength, quality, purity, and, if appropriate, sterility and pyrogens.

(b) Test procedures. Before you implement a new test procedure in a specification, you must establish and document the accuracy, sensitivity, specificity, and reproducibility of the procedure. If you use an established compendial test procedure in a specification, you must first verify and document that the test works under the conditions of actual use.

(c) Conformance to specifications. Before final release, you must conduct an appropriate laboratory determination to ensure that each batch of a PET drug product conforms to specifications, except for sterility. For a PET drug product produced in sub-batches, before final release, you must conduct an appropriate laboratory determination to ensure that each sub-batch conforms to specifications, except for sterility.

(d) Final release procedures. Except as conditional final release is permitted in accordance with paragraph (f) of this section, you must establish and follow procedures to ensure that each batch of a PET drug product is not given final release until the following are done:

(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. Sterility testing need not be completed before final release but must be started within 30 hours after completion of production. The 30-hour requirement may be exceeded due to a weekend or holiday. If the sample for sterility testing is held longer than 30 hours, you must demonstrate that the longer period does not adversely affect the sample and the test results obtained will be equivalent to test results that would have been obtained if the test had been started within the 30-hour time period. Tested samples must be from individual batches and not pooled. If the product fails to meet a criterion for sterility, you must immediately notify all facilities that received the product of the test results and provide any appropriate recommendations. The notification must be documented. Upon completion of an investigation into the failure to meet a criterion for sterility, you must notify all facilities that received the product of the findings from the investigation.

(f) Conditional final release. (1) If you cannot complete one of the required finished-product tests for a batch of a PET drug product because of a malfunction involving analytical equipment, you may approve the conditional final release of the product if you meet the following conditions:

(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.

(a) Rejection of nonconforming product. You must reject a batch of a PET drug product that does not conform to specifications. You must have and follow procedures to identify and segregate the product to avoid mix-ups. You must have and follow procedures to investigate the cause(s) of the nonconforming product. The investigation must include, but is not limited to, examination of processes, operations, records, complaints, and any other relevant sources of information concerning the nonconforming product.

(b) Investigation. You must document the investigation of a PET drug product that does not meet specifications, including the results of the investigation and what happened to the rejected PET drug product.

(c) Correction of problems. You must take action to correct any identified problems to prevent recurrence of a nonconforming product or other quality problem.

(d) Reprocessing. If appropriate, you may reprocess a batch of a PET drug product that does not conform to specifications. If material that does not meet acceptance criteria is reprocessed, you must follow procedures stated in the product's approved application and the finished product must conform to specifications, except for sterility, before final release.

(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.

(a) Written distribution procedures. You must establish, maintain, and follow written procedures for the control of distribution of PET drug products shipped from the PET drug production facility to ensure that the method of shipping chosen will not adversely affect the identity, purity, or quality of the PET drug product.

(b) Distribution records. You must maintain distribution records for each PET drug product that include or refer to the following:

(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.

(a) Written complaint procedures. You must develop and follow written procedures for the receipt and handling of all complaints concerning the quality or purity of, or possible adverse reactions to, a PET drug product.

(b) Complaint review. The procedures must include review by a designated person of any complaint involving the possible failure of a PET drug product to meet any of its specifications and an investigation to determine the cause of the failure.

(c) Complaint records. A written record of each complaint must be maintained in a file designated for PET drug product complaints. The record must include the name and strength of the PET drug product, the batch number, the name of the complainant, the date the complaint was received, the nature of the complaint, and the response to the complaint. It must also include the findings of any investigation and followup.

(d) Returned products. A PET drug product that is returned because of a complaint or for any other reason may not be reprocessed and must be destroyed in accordance with applicable Federal and State law.

(a) Record availability. Records must be maintained at the PET drug production facility or another location that is reasonably accessible to responsible officials of the production facility and to employees of FDA designated to perform inspections.

(b) Record quality. All records, including those not stored at the inspected establishment, must be legible, stored to prevent deterioration or loss, and readily available for review and copying by FDA employees.

(c) Record retention period. You must maintain all records and documentation referenced in this part for a period of at least 1 year from the date of final release, including conditional final release, of a PET drug product.