Inspections, Compliance, Enforcement, and Criminal Investigations

SUBCHAPTER 5.5 - DRUGS

Table of contents

 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:

  1. 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;
  2. 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;
  3. To determine whether a firm is distributing drugs that lack required FDA approval including counterfeit or diverted drugs;
  4. To obtain correction of those deficiencies;
  5. To determine if new drugs are manufactured by the same procedures and formulations as specified in the New Drug Application documents;
  6. To determine the drug labeling and promotional practices of the firm;
  7. To ensure 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;
  8. To determine if the firm is complying with the requirements of the Prescription Drug Marketing Act (PDMA) and regulations; and
  9. To determine the disposition of Drug Quality Reports (DQRS) received from the Drug Surveillance and Data Reporting Branch (DSDRB)/CDERHighlighted to denote updated text ; and
  10. 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:

  1. Establishment Inspection Reports,
  2. District Profiles,
  3. OTC monographs and other pertinent references for non-application products,
  4. Drug Applications (New, Abbreviated and Investigational) and the Knowledge Transfer Memo, if the Center has provided it for a specific pre-approval inspection,
  5. Therapeutic Biologics License Applications,
  6. Sample results,
  7. Complaints and Recalls,
  8. Regulatory files,
  9. Drug Quality Reports (DQRs), NDA Field Alert Reports (FARs), and Biological Product Deviation Reports (BPDRs)
  10. Drug Registration and Listing 

During this review identify products which:

  1. Are difficult to manufacture,
  2. Are complex dosage forms,Highlighted to denote updated text
  3. Require special tests or assays, or can not be assayed,
  4. Require special processes or equipment,
  5. Are new drugs and/or potent low dosage drugs ,
  6. Are misbranded, unapproved, fraudulent, or compounded drugs containing ingredients that have been withdrawn or removed from the market for safety or effectivenessHighlighted to denote updated text reasons, or compounded drugs that contain bulk active ingredients that are not components of FDA-approved drugs.Highlighted to denote updated text

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 A 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. See IOM 1.10.3  for special regulatory information by product category.

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.

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: 

  1. 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.
  2. Questions and Answers on Current Good Manufacturing Practices for Drugs. This forum is intended to provide timely answers to questions about the meaning and application of CGMPs 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.  For information contact Office of Compliance/Recalls and Shortages Branch via email at cderrecalls@fda.hhs.gov)Highlighted to denote updated text 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:

  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 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 DESI or "grandfather" status.

 5.5.5.3 - Drug Status Questions

If you have questions about misbranding, new drug status, drug/cosmetic, drug/food (dietary supplement) status, or compounded drugs, call the Office of Unapproved Drugs and Labeling Compliance in the CDER Office of Compliance (301-796-3100).Highlighted to denote updated text  In order to make these determinations, drug product labeling is needed.

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 CP, 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 CP 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 CP 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 (CP) 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/Risk Evaluation and Mitigation Strategies (REMS)

FD&C Act section 760 [21 U.S.C. 379aa] and 21 CFR sections 310.305, 314.80, 314.98, and 314.540 require reporting of adverse events associated with the use of human drug products and section 600.80 requires reporting of adverse events associated with the use of biological products (including therapeutic biological products). Responsible firms include holders of NDAs and ANDAs, and manufacturers, packers and distributors that are named on the labels of all FDA approved drug products and all prescription drug products. Both foreign and domestic firms are required to develop written procedures and to maintain records related to adverse events. Firms must evaluate adverse event data to determine if the event has had a serious outcome such as death, disability, hospitalization, or was a life threatening event, and if the event was expected (labeled) or unexpected (unlabeled) for the product. Responsible firms must submit adverse event information to FDA in expedited or periodic reports, as described in the regulations.

Refer to the Compliance Program Guidance Manual (CP) (section 7353.001) for the description of the program and for detailed instructions for conducting inspections.

FD&C Act Section 505-1 [21 U.S.C. 355-1] gives the FDA the authority to require Risk Evaluation and Mitigation Strategies (REMS) for certain drugs to ensure that the benefits outweigh the risks.

Since every REMS program varies, the detailed instructions for conducting inspections will be given to the investigator prior to each inspection.

 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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Page Last Updated: 08/20/2014
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