Contents

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 [21U.S.C. 355] requires that new drugs be approved by FDA. Therefore, the purposes of a drug inspection are:

1. To determine whether a firm is distributing drugs that lack required FDA approval;
2. To determine and evaluate a firm's adherence to the concepts of sanitation and good manufacturing practice;
3. To assure production and control procedures include all reasonable precautions to ensure the identity, strength, quality, and purity of the finished products;
4. 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;
5. To obtain correction of those deficiencies;
6. To determine if new drugs are manufactured by the same procedures and formulations as specified in the New Drug Application documents;
7. To determine the drug labeling and promotional practices of the firm;
8. To assure the firm is reporting NDA field alerts as required by 21 CFR 314.81;
9. To determine if the firm is complying with the requirements of the Prescription Drug Marketing Act (PDMA) and regulations; and
10. To determine the disposition of Drug Quality Reports (DQRS) received from the Division of Compliance Risk Management and Surveillance/CDER; and
11. To determine if the firm is complying with Adverse Drug Experience reporting requirements as required by 21 CFR sections 310.305 (prescription drugs without approved NDA/ANDA, and 314.80, 314.98, and 314.540 (application products). 

5.5.1.1 - Preparation and References

5.5.1.2 - Inspectional Approach

Follow Compliance Program Guidance Manual (CPGM) 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.  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.

CPGM 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,  CPGM 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:

1. Reviewing the firm's complaint files early in the inspection to determine relative numbers of complaints per product.
2. Inspecting the quarantine, returned, reprocessed, and/or rejected product storage areas to identify rejected product.
3. Identifying those products which have process control problems and batch rejections via review of processing trends and examining annual reviews performed under 21 CFR 211.180(e).
4. 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.

5.5.4 - GUARANTEES AND LABELING AGREEMENTS

Determine the firm's policies relative to receiving guarantees for raw materials, and issuing guarantees on their products. Also determine firm's practices regarding shipment of unlabeled drugs under labeling agreements. See IOM 5.3.7.2.

5.5.5 - OTHER INSPECTIONAL ISSUES

5.5.5.1 - Intended Use

Please see the discussion of jurisdiction in section IOM 5.10.4.3.6.

5.5.5.2 - Drug Approval Status

The investigator should ascertain whether the drugs manufactured by the firm are covered by an NDA, ANDA, OTC monograph, or marketed under a claim of "grandfather" status.

5.5.5.3 - OTC Drugs

If you have questions about misbranding, new drug status, drug/cosmetic, or drug/food (dietary supplement) status, call the OTC Drugs Team in the Division of New Drugs and Labeling Compliance in the CDER Office of Compliance (HFD-312 – telephone 301-827-8930).  

In rare cases, a drug may be unapproved and inappropriate for marketing under any circumstances (i.e., it cannot be reconditioned or reformulated into a product appropriate for marketing). If you encounter products in this category, contact your supervisor to determine if a CGMP inspection is warranted.

5.5.5.4 - Drug/Dietary Supplement Status

In instances where the drug/dietary supplement status of a product is unclear, the investigator should collect all related labeling and promotional materials including pertinent Internet web sites. This labeling and promotional material is often useful in determining the intended use of a product (See 21 CFR 201.128). Labeling, promotional materials and Internet web sites often contain information, for example, disease claims, that can be used to determine the intended use of a product and thereby if it is a dietary supplement or a drug and an unapproved new drug.

5.5.5.5 - Approved Drugs

Check the current programs in your CPGM, Section 505 of the FD&C Act [21 U.S.C. 355] and 21 CFR part 314 for required information. You may take the District’s copy of the NDA into the plant as a reference during the inspection. Document and report all deviations from representations in the NDA even though they may appear to be minor.

5.5.5.6 - Investigational Drugs

Follow the instructions in pertinent programs in your CPGM or as indicated in the specific assignment received.

5.5.5.7 - Clinical Investigators and/or Clinical Pharmacologists

Inspections in this area will be on specific assignment previously cleared by the Administration. Follow guidance in the CPGM or assignment.

5.5.6 - CDER BIO-RESEARCH MONITORING

Inspectional activities in the bio-research monitoring (BIMO) programs involve all product areas and Centers, including In Vivo Bio-equivalence, Good Laboratory Practice (GLP) for Non-Clinical Laboratories, Institutional Review Boards (IRB), Sponsors, Monitors, Contract Research Organizations, and Clinical Investigators (CI). In most instances, inspections conducted under this program will be done on assignment from the respective Center and occasionally with the participation of Center personnel as part of the inspection team.

During team inspections with Center personnel, the Field Investigator is the team leader. See IOM 5.1.2.5. The Compliance Program Guidance Manual (CPGM) for each program provides a description of the program and detailed instruction for conducting inspections.

Districts will make the initial classification of inspections and the Center issuing the assignment will make the final decision after review.

5.5.7 - ADVERSE EVENT REPORTING

5.5.8 - DRUG INSPECTION REPORT

See IOM 1.1 English language requirement. The requirements in IOM 5.10.4.3, and any applicable Compliance Program Guidance Manuals can be used to help you prepare your report.
This does not cover the reporting requirements for a directed inspection with a narrow focus, such as a complaint follow-up or investigation into a recall. In those cases, use your judgment and guidance in IOM 5.10.4 about the depth of reporting required. Follow the instructions and format for a human drug inspection report as contained in IOM 5.10.4.2 and 5.10.4.3.
This human drug inspection report does not require full and detailed narratives for every area for every inspection. The firm's state of compliance, the previous inspectional report and information, complexity of operations and other aspects all are determinants in how much reporting will be necessary. In many cases, brief summaries addressing the format areas will be sufficient.

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