CHAPTER § 1.06 Violations of FDA's Good Manufacturing Practice Requirements
| Jurisdiction | United States |
§ 1.06 Violations of FDA's Good Manufacturing Practice Requirements
[1] Introduction
FDA has promulgated requirements for "current good manufacturing practices" ("cGMPs") to ensure that drug products are manufactured, processed, and packaged appropriately and safely.452 The FDCA authorizes FDA to ensure compliance with cGMP requirements.453 In authorizing FDA enforcement of cGMP requirements, the Act states that a drug product will be considered adulterated if it is not manufactured in accordance with cGMP requirements.454 Further, the FDCA grants the FDA authority to conduct regular inspections of drug production facilities to ensure compliance with cGMP requirements.455 Facilities found to be in violation of GMPs during inspections may be subject to FDA enforcement action.
The 1962 Drug Amendments to the FDCA (also known as the Kefauver-Harris Amendments) first introduced the concept of cGMP requirements.456 In 1963, FDA passed regulations more precisely defining these requirements.457 These regulations underwent several revisions between 1971 and 1995.458 Further, the regulations were subject to various changes in accordance with the Food and Drug Administration Modernization Act of 1997 ("FDAMA").459
As they exist today, the cGMP regulations are broad requirements. They do not define specific processes to be followed, but rather impose general standards or guidelines by which specific processes are to be designed and implemented. Unlike FDA guidance documents, however, cGMP requirements are contained in regulations promulgated by FDA, and thus are binding with the force and effect of law.460
FDA has based the cGMP regulations on three primary principles. First, "[q]uality, safety, and effectiveness must be designed and built into a product."461 Second, "quality cannot be inspected or tested into a finished product."462 Third, "each step of the manufacturing process must be controlled to [ensure] that the finished product will be acceptable."463
GMP regulations contain 10 sections covering these general areas:
Organization and Personnel—Outlines the need for, and appropriate duties of, a quality control unit. Describes requirements for adequate qualifications and training of personnel.464
Buildings and Facilities—Requires facilities to be of appropriate size and structure to facilitate GMP compliance. Certain operations must be housed in separate areas, and all facilities must be arranged to allow for adequate maintenance, cleaning, and operation.465
Equipment—Determines design, size, location, and maintenance of pertinent equipment.466
Control of Components and Drug Product Containers and Closures—Outlines procedures for receiving, identifying, sorting, handling, sampling, testing, and approving components and drug product containers and closures.467
Production and Process Controls—Requires facilities to maintain written procedures to execute batch production and processing in a manner that ensures the appropriate identity, strength, quality, and purity of the drug.468
Packaging and Labeling Controls—Requires the sampling, examination, and testing of packaging and labeling before its use.469
Holding and Distribution—Requires written procedures for warehouse storage and distribution methods.470
Laboratory Controls—Requires the development and maintenance of laboratory control mechanisms, such as established specifications, standards, and test procedures to ensure that drugs are of the appropriate identity, strength, quality, and purity.471
Records and Reports—Requires the maintenance of records pertaining to the manufacture of drug products.472
Returned and Salvaged Drug Products—Outlines the procedures used to ensure that returned and salvaged drug products are properly identified, held, tested, and reprocessed, if appropriate.473
[2] FDA Factory Inspections
[a] Parameters of FDA Inspections
As mentioned, the FDCA authorizes FDA to perform regular inspections of drug manufacturing facilities to ensure compliance with GMP requirements. FDA inspections evaluate the efficiency and adequacy of measures taken to ensure the identity, strength, quality, and purity of manufactured drug products474 While FDA is authorized to perform routine inspections at least once every 2 years,475 FDA can also initiate "for cause" inspections for a number of other reasons, such as: a follow-up to a warning letter or enforcement action; as a response to complaints from consumers/ industry members/employees; as part of a product recall; as part of a pre-approval inspection; or as part of a special enforcement initiative such as the investigation of certain serious adverse events.476
The FDCA requires that FDA inspections be conducted "at reasonable times and within reasonable limits and in a reasonable manner."477 Generally, a "reasonable time" means any time during which regulated activities are being conducted (i.e., normal business hours).478 Many elements of what constitutes a "reasonable manner" are still being determined. For instance, it is still questionable whether FDA has authority to take photographs during an inspection, although FDA and several courts have now taken the position that the authority to photograph is incidental to the authority to inspect.479 The FDCA also provides that "each such inspection shall be commenced and completed with reasonable promptness."480 In reality, the understanding of the term "promptness" may vary widely. Previous FDA inspections have spanned anywhere from a few days to several weeks.481
[b] FDA Inspection Process
[i] Pre-Inspection Preparation
FDA investigators follow a particular procedure during an inspection. First, the investigator will reference the FDA Investigation Operations Manual ("IOM"), which is the primary guidance document for field investigators regarding policies and procedures for FDA inspections.482 This manual includes a wide range of information regarding inspections and inspection reports and directs the conduct of all fundamental investi-gational activities and procedures.
[ii] Arrival and Initiation of Inspection
When the FDA investigator arrives at a facility, he or she is required to produce his or her credentials and a notice of inspection (Form FDA-482).483 Inspections are generally conducted on an impromptu basis; however, as a courtesy, FDA may provide manufacturers with prior notice of its intent to inspect.484 While court decisions have differed on whether an administrative warrant is required to inspect, FDA generally conducts inspections without first obtaining warrants.485 Consent to an inspection is also generally presumed because the drug industry has historically been highly regulated. Simply entering into the business is often considered implied consent to be inspected.486
FDA has explicit authority to address the delay, denial, limiting, or refusal of an inspection under Section 707 of the FDCA.487 In the case of drug inspections, if efforts to schedule a pre-announced inspection are met with unreasonable delays by the establishment, it may constitute a delay of an inspection under Section 501(j) of the FDCA.488
[iii] Conducting the Inspection
In conducting an inspection, FDA is only entitled to statutorily mandated information. Other information may be granted to the investigator with the company's consent. Historically, FDA has taken the position that only statutorily mandated information will be requested during an inspection. In practice, however, the responsibility of knowing what is statutorily required is typically placed on the company being inspected.
Under the FDCA, investigators may have access to information bearing on whether drugs intended for human use "have been or are being manufactured, processed, packed, transported, or held in any such place, or otherwise bearing on violation of [the] Act."489 Although this language is quite broad, the statute also carves out specific exceptions to the material that must be disclosed to FDA during an inspection. The FDCA prohibits the inspection of financial data, sales data other than shipping figures, pricing data, personnel data other than information establishing the qualifications of technical and professional personnel, and certain research data except to the extent such information may need to be disclosed under other requirements such as product approval and reporting obligations.490 The FDCA also does not authorize inspections of retail pharmacies; licensed practitioners; persons engaged in non-clinical research, teaching, or chemical analysis; and those persons specifically exempted by regulation.491 In addition, FDA policy generally prohibits investigators' review of internal audit records or reports, supplier audit records, and management reviews.492
[iv] Conclusion of Inspection
Upon completion of an inspection, FDA officials and company management will typically engage in post-inspection discussion, focusing on the investigator's findings.493 Companies may opt not to take part in this exit discussion, although helpful information is often gained at this time with respect to determining the corrective actions necessary to satisfy FDA that the company complies or understands the actions needed to comply with applicable FDA requirements.
Upon conclusion of the inspection, the investigator may also note his or her inspectional observations on a Form FDA-483.494 These documents contain observations related to unsatisfactory conditions, such as actual or potential violations of cGMP standards, identified by the investigator.495 While indicative of problematic inspectional observations, issuance of an FDA-483 is relatively...
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