Contents

SUBCHAPTER 540 - DRUGS

540 - DRUG INSPECTIONS

Authority for inspection is discussed in IOM 701. 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 much the same, with respect to drug labeling. Therefore, the purpose of a drug inspection is:

1. to determine and evaluate a firm's adherence to the concepts of sanitation and good manufacturing practice;
2. to assure production and control procedures include all reasonable precautions to ensure the identity, strength, quality, and purity of the finished products;
3. to identify deficiencies which could lead to the manufacturing and distribution of products in violation of the Act, e.g., non-conformance with Official Compendiums, super/sub potency, substitution;
4. to obtain correction of those deficiencies;
5. to determine if new drugs are manufactured by essentially the same procedures and formulations as specified in the New Drug Approval documents;
6. to determine the drug labeling and promotional practices of the firm;
7. to assure the firm is reporting NDA field alerts as required by 21CFR314.81;
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 Division of Risk Management and Surveillance/CDER.

540.01 - 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. Review the district files of the firm to be inspected including:

1. Establishment Inspection Reports,
2. District Profiles,
3. New and Investigational Drug Applications,
4. Sample results,
5. Complaints,
6. Regulatory files,
7. Antibiotic Applications.
8. Drug Quality Reports (DQRS) & NDA Field Alert Reports (FARS)

During this review identify products which:

1. Are difficult to manufacture,
2. Require special tests or assays, or can not be assayed,
3. Require special processes or equipment, and
4. Are new drugs and/or potent low dosage drugs.

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 516.

Become familiar with current regulations and programs relating to drugs, CPGM 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).

Review the current editions of the United States Pharmacopeia (USP), and Remington's Pharmaceutical Sciences for information on specific products or dosage forms. Also IOM Chapter 10 provides 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). Survey summary reports are posted on the Division of Compliance Risk Management and Surveillance/CDER website for the Districts' review in planning drug inspections.

540.02 - Inspectional Approach

In-depth inspection of all manufacturing and control operations is usually not feasible or practical. An audit approach is recommended in which therapeutically significant drugs and those drugs, which are difficult to manufacture, are covered in greater detail.

The bioavailability regulations, 21 CFR 320, cover those drugs, which are therapeutically significant and for which manufacturing changes can affect efficacy. Some manufacturers have difficulty in complying with the dissolution specifications established for many products. Also, significant problems are not uncommon with timed release or delayed release drugs requiring multiple dissolution (release) tests.

If reworked products are encountered, validation of their manufacturing procedures and justification for reworking should be reviewed. Written investigation reports, which are required for any product failing to meet an established specification, should also be reviewed and evaluated.

For those drug manufacturers marketing a number of drugs posing potential bioavailability problems, identify suspect products by:

1. Reviewing the firm's complaint files early in the inspection to determine relative numbers of complaints per product.
2. Inspecting the quarantine and/or rejected product storage area to identify rejected product.
3. Examining annual reviews performed under 21 CFR 211.180(e) to determine those products which have a high reject rate.
4. Reviewing summaries of laboratory data or laboratory workbooks.

Attempts should also be made to determine the attitude or philosophy of top management and how they react to problems, such as, batch rejections, and how they investigate product failures.

540.03 - 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 545).

541 - DRUG REGISTRATION & LISTING

Registration and listing is required whether or not interstate commerce is involved. See Exhibit 540 and IOM 771.01 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 501.04 - Multiple Occupancy Inspections for additional information.

Vitamin manufacturers are required to register unless their products are used solely in food supplements and do not become drugs or components of drugs. In most cases, bulk vitamin manufacturers should register unless they can demonstrate the ultimate use and labeling of their products in foods or food supplements. Independent laboratories providing analytical or other laboratory control services on commercially marketed drugs must register.

The 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.

542 - PROMOTION AND ADVERTISING

21 CFR 202.1which 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.

543 - 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 526.

544 - NEW DRUGS, ANTIBIOTICS, INVESTIGATIONAL DRUGS

544.01 - 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.

Further, the presence of synthetic ephedrine HCl, or the manipulation of red yeast rice to increase the presence of lovastatin, can exclude a product from being considered a dietary supplement within the meaning of the FD&C Act, 201(ff) [21 U.S.C. 321 (ff)].

Check the current programs in your CPGM, Section 505 of the FD&C Act [21 U.S.C. 355] and 21 CFR 314.1 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.

Antibiotics - Provide the same inspectional coverage as for other drugs. Refer to the approved antibiotic application to facilitate your evaluation of the firm's operation.

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

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.

545 - 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 502.04. 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.

546 - Adverse Event Reporting

21 CFR Parts 310.305, 314.80, and 314.98 require reporting of adverse events occurring in connection with the use of marketed FDA regulated human drug products. Responsible firms include holders of NDAs and ANDAs, and applicants, and manufacturers, packers and distributors of marketed prescription drug products that are not the subject of approved NDAs or ANDAs. Firms must maintain current Standard Operating Procedures (SOPs) and must maintain records of documents related to adverse events. Responsible firms must submit the event information to FDA in reports. The events must be evaluated to determine if they have had a serious outcome such as death, disability, hospitalization, life threatening, or were included in the current labeling for the product.

For headquarters-initiated investigations, field investigators should contact the assigning Office of Compliance staff prior to beginning the investigation to obtain specific instructions and current documents to be used during the investigation.

549 - DRUG INSPECTION REPORT

See IOM 100 English language requirement. The requirements in IOM 593.03, “General Elements” below, 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 593 about the depth of reporting required.
NOTE: The information is arranged by report section headings used in IOM 593.03 and you may use the sub-headings as needed. The data should be presented in a logical manner with similar data grouped together. Some information such as the firm name & FEI number may be placed in the report header. You can combine section headings. When you do, cover the items requested under each heading description in the combined heading.
For each of the General Element Areas, guidance about the expected content of the section is provided for only those elements not covered in IOM 593.03. This format 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.

GENERAL ELEMENTS

It may be necessary to include this additional information for initial inspections, when there has not been a complete narrative for a number of years or for other reasons.

Table of Contents- For long reports, list report sections with page numbers.

Summary

Areas and Functions not Inspected - Generally describe any areas or processes of the firm not covered during your inspection.

History

Customers

1. For foreign inspections, list US consignees to whom the firm's product is shipped.
2. For API and component manufacturers, this includes consignees who use the product in their manufacturing of products intended for the US market, if known.
3. For domestic firms, identify the general types of customers and provide the names and addresses for several regular customers of a few of the firm's products.

Jurisdiction (Products Manufactured and/or Distributed)

Packaging & Labeling - The label, labeling and promotional materials are a critical part of determining a product's intended use.

1. In instances where a regulatory action is being considered based on product labels, labeling, and/or other promotional materials, including any Internet websites, it is imperative all such documentation be collected. This would include all written, printed or graphic matter upon the immediate container of an article or accompanying such article (the product's label and labeling, see FD&C Act, 201(k) and (m) [21 U.S.C. 321(k) and (m)] and IOM 435.01). Accompanying labeling could include for example, brochures, pamphlets, circulars, and flyers, as well as audio and video tapes.
2. You should also review and copy all related Internet web sites for information concerning, for example, promotional statements made for the firm's products.
3. In cases where there may be a dispute about whether a product is a drug or a dietary supplement, all materials which claim a product can be used for the treatment of any disease should be collected.

Individual Responsibility

U.S. Agent/Broker - Report the name, title, physical and mailing address, phone and fax number and e-mail address of any US Agent or broker who represents the company when dealing with FDA.

Consultants

1. For individuals hired by the firm to provide guidance and advice, obtain their names, addresses, and qualifications.
2. Identify those associated with key or critical processes such as sterilization validation.

Manufacturing/Design Operations

Description of Facility - Describe the overall layout of the facility. Include critical facility features or equipment such as the HVAC system, room classifications, sterilization equipment, systems design for cross contamination prevention and other specialty designs. A diagram may be included.

Equipment - Generally describe the firm's manufacturing equipment. Equipment is not expected to be described in detail unless it is new, significantly changed, related to a deviation from GMPs, or requested in the inspection assignment. This section would include information about qualification, calibration, maintenance, cleaning and validation. Your descriptions can be presented in subheadings if the information is extensive.

Component & Materials Control

1. Report procedures for the receipt, storage, and analysis of materials, including containers and closures, used to produce product.
2. Describe procedures for the control of released, quarantined, and rejected materials for raw materials, containers, closures, in-process material and finished products.

Reprocessing/Reworking

1. Describe the procedures used to reprocess or rework non-conforming material to bring it into compliance with specifications. This could include the repeating of a step or steps in the normal processing sequence. It may involve a method, which is not part of the validated process, or may not be part of the firm's NDA or NADA.
2. If you encounter reprocessing/reworking, report if the procedure is approved and the process validated.

Water Systems

1. Describe the major components of any water system used in manufacturing or processing, especially Purified Water and Water for Injection (WFI) Systems.
2. Include qualification and validation studies, plus maintenance and monitoring programs. System schematics may be attached as necessary.

Computer Systems

1. Describe the functions and validation program for all computer systems used to control manufacturing, control electronic record keeping and signatures, or any other GMP function.
2. Include data integrity, data security, and prevention of improper data manipulation.

Scale-Up Procedures

1. Describe the firm's procedures for scaling up from pilot to commercial size production.
2. Determine if equipment is available, parameters & specifications for full-scale production have been established, and if not, how the firm plans to establish them.

QA/QC Systems

1. Describe the firm's organization, responsibilities, and procedures for quality control and quality assurance.
2. Describe any deviations from regulatory or application requirements, or the firm's own quality control requirements.

Contracting Services/Vendors

1. Describe the location, site name and any manufacturing, laboratory or other testing operations performed at other sites.
2. Include the firm's procedures to audit contractors and vendors.

Product Reviews/Discrepancy/Failure Evaluation and Reporting Systems

1. Describe how the firm conducts its "annual product review" and summarize your coverage of one or more of these activities.
2. Summarize the firm's procedures for documenting and investigating systems, production, testing deviations, failures from validated processes and Out of Specification (OOS) results.

Records/Reports/Documentation Control- Describe the firms procedure for creation, approval and maintenance of required procedures, records, etc. for production, control, or distribution of pharmaceutical products. This includes raw data and other items such as annual product reviews, complaints, recalls and returned or salvaged drug product records. Includes electronic record / signature compliance. Includes QC control, approval, and review.

Planned Future Changes - Describe details of any proposed site changes or significant changes to the company's operation.

Complaints

Adverse Event Reports

1. Describe the firm's reporting procedures (including designated office with final authority) for receipt, tracking, surveillance and control activities.
2. Include a brief summary of what you reviewed.

Additional Information

Training Program - Obtain a description of the firm's training program for production and testing personnel. This should document if personnel are adequately trained to perform the specific operations within the firm, and reflect if personnel performing the manufacturing operations are trained in GMPs.

Laboratory Operations

Testing/Laboratory Operations- Describe testing operations performed to assure product quality. Include all procedures and record keeping, sampling, testing or examination of components, in-process materials, finished product, containers and closures, stability tests, OOS laboratory investigation procedures, validation of methods, reference standards, and calibration of analytical equipment.

Analytical Laboratories - Information about the structure of the firm's laboratories (QC, QA, R&D, and Microbiology), their locations, and the identification of different operations performed in these laboratories. The description may also include listing of instruments and equipment in these laboratories, as well as the names of supervisors or the organizational charts of these laboratories.

Lab Equipment Calibration & Qualification

1. A summary of the instruments used to test and monitor regulated products (number, types, and brands). Includes qualification, calibration and maintenance records reviewed, including in-house and vendor logbooks.
2. Microbiology sections may include laboratory autoclave and depyrogenation oven equipment certification or qualification. Laminar flow hoods, biosafety cabinets, pH meters, autoclaves, isolators, incubators, refrigerators or freezers including daily temperature records as well as maintenance or repairs, etc.

Microbiology Quality Control & SOPs - Suitability of specialty laboratory, procedures, equipment or facilities such as sterility testing and bacterial endotoxin testing; qualification of production equipment; depyrogenation tunnel/oven endotoxin challenges, biological indicators. Review of the qualification of production disinfectants using microbial challenges.

Stability Testing, Protocol & Storage Conditions - An evaluation of the firm's stability program which includes the review of applicable SOPs, assuring that the firm is adhering to application commitments, proper sampling and storage conditions.

Sample Accountability & Tracking - A description of the firm's sampling procedures including sample receipt, tracking, and storage in the laboratory.

Sampling and Testing for Acceptance and Rejection of Raw Materials - A description of the firm's sampling and testing protocols for the acceptance or rejection of raw materials (components, containers and closures) to be used in manufacturing of the pharmaceutical products.

Analyst's Notebooks

1. Review SOP's relating to analysts' notebooks, data recording, etc.
2. A review of the accuracy and completeness of the data recorded in analysts' notebooks or worksheets should be done and include review of raw data from associated chromatography, spectra, etc. and other sources generated by laboratory instruments. This review encompasses all analytical testing performed in the laboratory including raw material testing of active ingredients and excipients, in-process, release, stability testing, etc.

Standards/Reagents/Chemicals/Media

1. A description of the firm's testing, standardization, handling, and storage of laboratory reference standards, standard solutions, media, reagents, and chemicals.
2. For a microbiology laboratory, the following may be included: media preparation and formulation, sterilization, storage, growth promotion, bacteriostasis/fungistasis testing, culture handling, storage or identification, etc.
3. Media uses such as analytical testing, environmental and personnel monitoring, production media fills, and growth support for biological indicators must also be documented. Included are outside media, reagent, or equipment suppliers, etc.

Analytical Method Validation - A description of the firm's method validation program. Review should include: accuracy, precision, specificity, detection limit, limit of quantification, linearity, range, ruggedness, and robustness.

Computer System Validation - Information, which identifies any computer systems used to perform critical functions in the laboratory. A definition of each system should include both hardware and software descriptions along with a description of the functionality of each system. The validation status of each system will be reviewed which will include evaluation of: Developmental validation documentation (if appropriate); change control of software, hardware and associated end user SOP's; Backup systems for controlling software and data files; Security systems to protect program and data integrity; and System design controls which ensure traceability for any altered records. It is important to ensure the Quality Unit at the firm is involved with establishing and maintaining control over all critical computer system related activities.

Method Transfer

1. Information regarding the proper analytical method transfer from R&D laboratories to the QC or contract laboratories where actual analytical testing is conducted. Includes information about the written method transfer protocol, any method-specific training provided to the analysts involved in performing the methods transfer work at the receiving laboratory, any difficulties experienced by the receiving lab, any correspondence between the coordinating and receiving labs regarding any deviation issues during the official transfer process.
2. Also, report any observations or comments regarding the analytical work, raw analytical data or summary report.

OOS Results

1. Information about the adequacy of the laboratory's protocol for the handling and investigation of out of specification (OOS) test results. The assessment should include discussion about the relevant areas, such as: procedures for reporting laboratory errors, responsibilities of laboratory personnel, retesting/resampling, timeframes, requirements for additional testing, guidance regarding when to expand the investigation to an outside laboratory, final evaluation of all test results, conclusions, investigation records, and follow up procedures.
2. In addition, if raw analytical data for any OOS investigation(s) is reviewed, any deficiencies or deviations found should be discussed.

Training Protocol for Lab Personnel - Description of the firm's training program for laboratory personnel. Records should be complete to ensure that personnel are adequately trained to perform specific laboratory functions within the firm.

Contract Testing Lab

1. The written agreement or contract between a contract servicing laboratory and a pharmaceutical company must be reviewed to ensure the agreement states the responsibilities of the contract lab as far as tests performed, the number of tests to be performed, procedures related to OOS results, and the methodology to be used to perform the test(s).
2. Review and generally report in what form and how results are reported to the receiving laboratory.
3. Review the firm's control of all pertinent operations as discussed above in this section.

Stability Program- Evaluate the company's stability program. Include discussions of deficiencies in SOPs, sampling, chamber maintenance, chamber temperature and humidity specifications, and any stability sample failures.