The FDA website contains the following guidance regarding drug inspections:
5.5 - DRUGS
5.5.1 - DRUG INSPECTIONS
Authority for inspection is discussed in IOM 2.2. FD&C Act Sections 501(a)-(d) [21 U.S.C. 351(a)-(d)] describe the ways in which a drug may be or may become adulterated. Section 502 of the FD&C Act [21 U.S.C. 352] does the same, with respect to misbranding. Section 505 of the FD&C Act [21 U.S.C. 355] requires that new drugs be approved by FDA. Therefore, the purposes of a drug inspection are:
- To evaluate a firm's adherence to the concepts of sanitation and good manufacturing practice; i.e.,production and control procedures include all reasonable precautions to ensure the identity, strength, quality, and purity of the finished products;
- To identify deficiencies that could lead to the manufacturing and distribution of products in violation of the Act, e.g., non-conformance with Official Compendia, super/sub potency, substitution;
- To determine whether a firm is distributing drugs that lack required FDA approval including counterfeit or diverted drugs;
- To obtain correction of those deficiencies;
- To determine if new drugs are manufactured by the same procedures and formulations as specified in the New Drug Application documents;
- To determine the drug labeling and promotional practices of the firm;
- To assure the firm is reporting NDA field alerts as required by 21 CFR 314.81 and Biological Product Deviation Reports (BPDRs) for therapeutic biological products as required by 21 CFR 600.14;
- To determine if the firm is complying with the requirements of the Prescription Drug Marketing Act (PDMA) and regulations; and
- To determine the disposition of Drug Quality Reports (DQRS) received from the Division of Compliance Risk Management and Surveillance/CDER; and
- To determine if the firm is complying with postmarket Adverse Drug Experience reporting requirements as required by 21 CFR sections 310.305 (prescription drugs without approved NDA/ANDA), 314.80, 314.98, and 314.540 (application drug products), and 600.80 (therapeutic biological products), and Section 760 of the FD&C Act (non-application nonprescription products) [21 U.S.C. 379aa].
5.5.1.1 - Preparation and References
Become familiar with current programs related to drugs. Determine the nature of the assignment, i.e., a specific drug problem or a routine inspection, and if necessary, consult other district personnel, such as chemists, microbiologists, etc., or center personnel, such as office of compliance staff. Review the district files of the firm to be inspected including:
- Establishment Inspection Reports,
- District Profiles,
- OTC monographs and other pertinent references for non-application products,
- Drug Applications (New, Abbreviated and Investigational) and the Knowledge Transfer Memo, if the Center has provided it for a specific pre-approval inspection,
- Therapeutic Biologics License Applications,
- Sample results,
- Complaints and Recalls,
- Regulatory files,
- Drug Quality Reports (DQRs), NDA Field Alert Reports (FARs), and Biological Product Deviation Reports (BPDRs),
- Drug Registration and Listing
During this review identify products which:
- Are difficult to manufacture,
- Require special tests or assays, or can not be assayed,
- Require special processes or equipment, and
- Are new drugs and/or potent low dosage drugs.
Are misbranded, unapproved, fraudulent, or compounded drugs containing ingredients that have been withdrawn or removed from the market for safety reasons.
Review the factory jacket, FACTS OEI and registration/listing data, and all complaint reports which are marked follow-up next inspection. These complaints are to be investigated during the inspection and discussed with management. See IOM 5.2.7.
Become familiar with current regulations and programs relating to drugs, CP 7356.002, et al. When making GMP inspections, discuss with your supervisor the advisability of using a microbiologist, analyst, engineer, or other technical personnel to aid in evaluating those areas of the firm germane to their expertise. Review the FD&C Act, Chapter V, Drugs and Devices. Review parts of 21 CFR 210/211 applicable to the inspection involved and Bioavailability (21 CFR 320). In the case of APIs, review FD&C Act section 501(a)(2)(B) [21 U.S.C 351(a)(2)(b)] and the ICH industry guideline entitled "Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients."
Review the current editions of the United States Pharmacopeia (USP), and Remington's Pharmaceutical Sciences for information on specific products or dosage forms. For compounding pharmacies, review USP Chapters 795 and 797. IOM 1.10.3 also provides a link to a consolidated list of pertinent guides and guidelines which may be applicable during drug inspections.
Review 21 CFR 203 "Prescription Drug Marketing", 21 CFR 205 "Guidelines for State Licensing of Rx Drug Distributors", and CP 7356.022, Enforcement of the Prescription Drug Marketing Act (PDMA).
Before conducting drug preapproval inspections (CP 7346.832) it is important to be familiar with the application and coordinate accomplishment of Center goals communicated by (1) inspectional memos, (2) pre-inspection briefings, and/or (3) Center participation on the inspection team.
Before conducting an inspection that may involve postmarketing adverse drug experience reporting, you should review 21 CFR Sections 310.305, 314.80, 314.98, 314.540, and 600.80, Section 760 of the FD&C Act[21 U.S.C. 379aa], CP 7353.001, and the training video, 'Field Investigators: Adverse Drug Effects (ADE) Detectives,' available online at http://www.fda.gov/Training/ForHealthProfessionals/ucm091001.htm.
The Office of Manufacturing and Product Quality (OMPQ) in CDER has established two mechanisms for you to obtain technical assistance before, during, or after an inspection:
- Office of Manufacturing and Product Quality (OMPQ) Subject Contacts. This list contains the names and phone numbers of OMPQ individuals identified as technical specialists in various areas.
- Questions and Answers on Current Good Manufacturing Practices for Drugs (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124740.htm). This forum is intended to provide timely answers to questions about the meaning and application ofCGMPs for human, animal, and biological drugs, and to share these widely. These questions and answers generally clarify statements of existing requirements or policy.
5.5.1.2 - Inspectional Approach
Follow Compliance Program Guidance Manual (CP) 7356.002 and others as appropriate when conducting CGMP inspections. In-depth inspection of all manufacturing and control operations is usually not feasible or practical. A risk-based systems audit approach is recommended in which higher risk, therapeutically significant, medically necessary, and difficult to manufacture drugs are covered in greater detail during an inspection. (Note: The status of a drug as medically necessary is determined by CDER, Office of New Drugs, Drug Shortages; They can be reached at 301-796-1300 and via email - drugshortages@fda.hhs.gov) The latter group includes, but is not limited to, time release and low dose products, metered dose aerosols, aseptically processed drugs, and formulations with components that are not freely soluble.
CP 7356.002 incorporates the systems-based approach to conducting an inspection and identifies six (6) systems in a drug establishment for inspection: Quality, Facilities and Equipment, Materials, Production, Packaging and Labeling and Laboratory Control Systems. The full inspection option includes coverage of at least four (4) of the systems; the abbreviated inspection option covers of at least two (2) systems. In both cases, CP 7356.002, indicates the Quality System be selected as one of the systems being covered. During the evaluation of the Quality System it is important to determine if top management makes science-based decisions and acts promptly to identify, investigate, correct, and prevent manufacturing problems likely to, or have led to, product quality problems.
When inspecting drug manufacturers marketing a number of drugs meeting the risk criteria, the following may help you identify suspect products:
- Reviewing the firm's complaint files early in the inspection to determine relative numbers of complaints per product.
- Inspecting the quarantine, returned, reprocessed, and/or rejected product storage areas to identify rejected product.
- Identifying those products which have process control problems and batch rejections via review of processing trends and examining reviews performed under 21 CFR 211.180(e).
- Reviewing summaries of laboratory data (e.g., laboratory workbooks), OOS investigations, and laboratory deviation reports.
5.5.1.3 - CDER Bio-research Monitoring
Bio-research monitoring (BIMO) assignments for drugs will generally be issued by the Center for Drug Evaluation and Research (CDER) (see IOM 5.5.6).
5.5.2 - DRUG REGISTRATION & LISTING
Registration and listing is required whether or not interstate commerce is involved. See Exhibit 5-12 and IOM 2.9.1.1 for additional information.
Two or more companies occupying the same premises and having interlocking management are considered one establishment and usually will be assigned a single registration number. See IOM 5.1.1.11 - Multiple Occupancy Inspections for additional information.
Independent laboratories providing analytical or other laboratory control services on commercially marketed drugs must register.
FACTS will indicate if the establishment is registered for the current year. If you determine registration and listing is required, advise your supervisor. After checking for past registration, cancellation, etc., the district will provide the firm with the proper forms and instructions.
Each establishment is required to list with FDA every drug in commercial distribution, whether or not the output of such establishment or any particular drug so listed enters interstate commerce. During the establishment inspection, you should remind the firm of its responsibilities for ensuring its drug listing accurately reflects the current product line and updating its listing as necessary to include all product changes, NDC changes, and discontinuations in accordance with 21 CFR 207. If registration and listing deficiencies are found, document it in your EIR, collect a documentary sample and/or contact your supervisor.
5.5.3 - PROMOTION AND ADVERTISING
21 CFR 202.1 which pertains only to prescription drugs, covers advertisements in published journals, magazines, other periodicals, and newspapers, and advertisements broadcast through media such as radio, television, and telephone communication systems. Determine what department or individual is responsible for promotion and advertising and how this responsibility is demonstrated. Ascertain what media (radio, television, newspapers, trade journals, etc.) are utilized to promote products.
Do not routinely collect examples of current advertising. Advertising should be collected only on assignment, or if, in your opinion, it is clearly in violation of Section 502(n) of the FD&C Act [21 U.S.C. 352 (n)] or 21 CFR 202.1.