PET Drugs--Current Good Manufacturing Practice (CGMP); Small Entity Compliance Guide | Guideline Explorer

Current Good Manufacturing PracticeProcess ValidationEnvironmental monitoringProcess VerificationSystem suitability testingQuality AssuranceInstallation QualificationOperational QualificationPerformance Qualification

Description

This guidance is intended to help small businesses understand and comply with FDA’s organ-specific labeling regulation for over-the-counter (OTC) internal analgesic, antipyretic, and antirheumatic (IAAA) drug products. The regulation requires IAAA manufacturers to label their products with specific warnings and related information to alert consumers about potential liver injury and stomach bleeding associated with IAAA drug products. Manufacturers must be in compliance with the final rule beginning on April 29, 2010. The Food and Drug Administration (FDA) has prepared this guidance in accordance with section 212 of the Small Business Regulatory Fairness Act (Public Law 104-121).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

PET Drugs

Positron emission tomography drugs, which had exceptions for labeling requirements.

Stakeholders

Small Business

Target audience for the compliance guide

Small Entity

Target audience for the compliance guide

Designated individual

reviews laboratory testing and batch records for release

Releasing authority

reviews and approves laboratory determination before product release

PET Drug Producer

Entity responsible for justifying identity testing rationale

Qualified vendors

Suppliers that consistently meet all quality specifications

Nuclear Pharmacy

Entity receiving released PET drug products; Facility receiving pharmacy bulk packages for dispensing

Quality Assurance Function

Responsible for oversight and execution of quality activities.

Regulatory Context

Regulatory Activities

NDA

New Drug Application

Parametric release

Regulatory pathway for terminal sterilization without sterility testing

ANDA

Abbreviated New Drug Application

Document Types

Master Production and Control Records

Standardized records for manufacturing processes; must be prepared, dated, and signed to assure uniformity

Complaint Files

Records of written and oral complaints

Distribution Records

Records maintained to facilitate location of recalled products

Batch Production Record

Records documenting the manufacturing of a batch

Batch Production and Control Record

Created for each new batch to document production and testing

Certificate of Analysis

Document indicating analytical results of testing; record relied on to control L. monocytogenes in ingredients; document provided for a food prior to or upon receipt of the food; COA documentation

Batch Production and Control Records

Records documenting the production of a specific batch; must be prepared for each batch of medical gas produced

Production Batch Records

Reviewed for accuracy and completeness before final release.

Attributes

Short half-life

Characteristic of PET radionuclides affecting handling

Radiochemical Yield

Action limit required in master production records

Technical Details

Substances

Radionuclide

component of a therapeutic radiopharmaceutical that undergoes decay; The radioactive component of a radiopharmaceutical.; The radioactive component of the pharmaceutical.

ammonia N 13

PET drugs with a very short half-life (e.g., ammonia N 13); PET drug with very short half-life produced in multiple sub-batches

Water for Injection

used for final rinses in depyrogenation by washing

FDG F 18

Example of a PET drug where finished-product testing ensures correct components; Example of a PET drug where identity is established during finished-product testing; every batch undergoes full finished-product testing (e.g., FDG F 18); example of PET drug where kryptofix may be a specific impurity

70 percent isopropyl alcohol

Disinfectant used for sanitizing nonsterile items.

Testing Methods

Stability Testing

Testing used to justify leveraging data across products

Periodic Quality Indicator Test

noncritical test performed in addition to specification tests

Sterility Tests

Procedures defined in USP <71> to ensure absence of contaminating microorganisms.

system suitability test

a system suitability test using reference standards be conducted

Gas Chromatography used for impurities or assay.

HPLC

High-Performance Liquid Chromatography used for impurities or assay.

bubble-point test

validated filter integrity test (e.g., the bubble-point test)

Integrity testing

Integrity testing of membrane filters should always be performed postfiltration

media fills

personnel to perform aseptic processing can be assessed by conducting media fills

Identity Testing

Must be performed if finished-product testing does not ensure correct components

Processes

Aseptic Processing

implied manufacturing process under QS regulation

Reprocessing

End-user sterilization validation

Aseptic techniques

Required for parenteral interventions and biopsies.

Depyrogenation

Sterilization and depyrogenation validation; Changes in vial sterilization or depyrogenation method

Sterilizing Filtration

Microbiological control process for PET drugs; Part of the synthesis and purification of PET drugs; drug is considered to be nonsterile until it is passed through a sterilizing grade filter

Process Verification

Requirement under 21 CFR 212.50(f)(2)

Sterilization

Required for contaminated equipment and media before disposal

Terminal Sterilization

Sterilization method for drug products

Identified Hazards

Hazards

Microbiological Contamination

Environmental factors affecting biological products

Radiolysis

radiation-related stability concern for PET drugs

biofilm

avoid microbial growth and development of biofilm

microbial growth

biological products provide a rich media for microbial proliferation

Bacterial Endotoxins

Risk addressed by pyrogenicity testing

Standards & References

External Standards

USP <85>

Endotoxin should be assessed following USP <85> Bacterial Endotoxins Test.

USP <71>

Sterility testing may be performed in accordance with USP <71>.

USP <823>

Radiopharmaceuticals for Positron Emission Tomography — Compounding

USP <1>

United States Pharmacopeia standard for Injections.

USP General Chapter <85>

Bacterial endotoxins testing standard; Endotoxin limits for subcutaneous administration

USP General Chapter <71>

Sterility Tests

USP General Chapter <1225>

Validation of Compendial Procedures

USP

United States Pharmacopeia standards for compendial drug substances; confirming conformance to the application-approved specification and USP

NIST traceable standards

Used for calibration of the Multichannel analyzer

USP General Chapter <621>

Requirements for system suitability tests in chromatography.

Specifications

Acceptance Criteria

limits for solid state form and particle size; Tightening acceptance criteria; Numerical limits or ranges for tests

ICH References (1)

ICH Q2A

Text on Validation of Analytical Procedures

View on FDA.gov Download PDF

Related CFR Sections (14)

21CFR212.110§ 212.110 How must I maintain records of my production of PET drugs?
(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.Read full regulation →
21CFR212.100§ 212.100 What do I do if I receive a complaint about a PET drug product produced at my facility?
(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.Read full regulation →
21CFR212.90§ 212.90 What actions must I take to control the distribution of PET drug products?
(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 Read full regulation →
21CFR212.80§ 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.Read full regulation →
21CFR212.71§ 212.71 What actions must I take if a batch of PET drug product does not conform to specifications?
(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 nonconformRead full regulation →
21CFR212.70§ 212.70 What controls and acceptance criteria must I have for my finished PET drug products?
(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.Read full regulation →
21CFR314.50§ 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA for a new chemical enRead full regulation →
21CFR212.61§ 212.61 What must I do to ensure the stability of my PET drug products through expiry?
(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 batcRead full regulation →
21CFR212.60§ 212.60 What requirements apply to the laboratories where I test components, in-process materials, and finished PET drug products?
(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.Read full regulation →
21CFR314.70§ 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA.Read full regulation →
21CFR212.50§ 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.Read full regulation →
21CFR212.40§ 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. 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 coRead full regulation →
21CFR361.1§ 361.1 Radioactive drugs for certain research uses.
(a) Radioactive drugs (as defined in § 310.3(n) of this chapter ) are generally recognized as safe and effective when administered, under the conditions set forth in paragraph (b) of this section, to human research subjects during the course of a research project intended to obtain basic informationRead full regulation →
21CFR212.30§ 212.30 What requirements must my facilities and equipment meet?
(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 adRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Quality control unit failed to exercise its responsibility

101

Failure to conduct at least one test to verify the identity of each component

Failure to establish adequate written procedures for production and process control

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

Failure to establish an adequate quality control unit

Failure to test samples of each component for identity and conformity

Failure to establish laboratory controls

Failure to thoroughly investigate any unexplained discrepancy

Failure to test samples of each component for identity

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics