Chapter 3 ESTABLISHMENT INSPECTIONS
Subchapters 300 - 330
General, Management Relations,
Evidence Development, Food
- SubChapter 300 GENERAL
- 301 AUTHORITY
- 302 INTERNATIONAL ESTABLISHMENT INSPECTION
- 303 PRECAUTIONS
- 304 LABEL REVIEW
- Subchapter 310 MANAGEMENT RELATIONS
- 310.1 General
- 311 NOTICE OF INSPECTION
- 312 REPORTABLE OBSERVATIONS
- 313 RECEIPT FOR SAMPLES
- 314 REFUSALS
- 315 DISCUSSION WITH MANAGEMENT
- 316 POST INSPECTION NOTIFIFCATON
- 317 ESTABLISHMENT INSPECTION REPORT
- Subchapter 320 EVIDENCE DEVELOPMENT
- 320.1 Techniques
- 321 FACTORY SAMPLES
- 322 EXHIBITS
- 323 PHOTOCOPIES AND PHOTOGRAPHS
- 324 RECORDINGS
- 325 RESPONSIBLE INDIVIDUALS
- 326 GUARANTEES AND LABELING AGREEMENTS
- 327 DISTRIBUTION AND DOMESTIC FOLLOW-UP
- Subchapter 330 FOOD
Section 201 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) defines interstate commerce as "commerce between any state and any place outside thereof." Therefore, products from foreign countries and the firms producing them are considered to be in interstate commerce.
Section 702 authorizes examinations and investigations while Section 704 provides for FDA inspections.
Various other sections of the FD&C Act and/or regulations provide for the registration, and/or other preapproval requirements. These authorities include the provision of inspection (including foreign establishments) to determine the adequacy of their submissions, processes, and facilities. These sections of the FD&C Act and/or regulations include:
- Section 505, the new drug provisions.
- Section 515, the device premarket approval provisions.
- 21 CFR 108.25 and 108.35, the acidified and low acid canned food requirements.
- 21 CFR 820.1 the medical device Quality System regulations require foreign manufacturers to permit FDA inspections or the devices manufactured at that facility will be considered adulterated.
FDA has authority to request inspections in foreign countries. If foreign firms refuse to permit such inspection and there is the appearance of a violation, FDA has the option of not granting approval of the application and refusing entry of those products when offered for import.
The intent of the international inspection program is to ensure that products manufactured in foreign countries meet the same standards of quality, purity, potency, safety, and efficacy as required of domestic manufacturers.
Preannounce inspections are necessary when conducting international inspections. This is due primarily to the potential waste of resources if the establishment is not operating or not producing the product in question, political sensitivities, availability of English speaking personnel, local holidays, etc.
A request containing the proposed inspection dates is made to the foreign manufacturer either by direct contact or through an U.S. agent. Upon their agreement the inspection is conducted.
Only products subject to preapproval requirements and/or those exported to the U.S. are covered during the EI. The enforcement action taken against a foreign firm or product is administrative; such as withdrawing approval of an NDA/ANDA/ Premarket (PMA) or Automatic Detention of a firm's products. Following an international inspection, regulatory action can be taken against the product in the U.S.; i.e. seizure or recall.
The degree and depth of coverage is dependent on various factors such as:
- The product(s) involved.
- Previous history of the firm.
- The applicable guidance provided.
- The violative conditions found as the inspection progresses.
When finished dosage forms, high risk devices or sterile products are involved, more time may be provided than when bulk drugs or non-sterile products are being covered. The investigators are also given the flexibility to extend the inspection beyond the prescheduled time if violative conditions are revealed which require further investigation.
Frequently firms will request that the investigator sign various papers, documents, etc., within their plant. These could include visitor's logs, a waiver exempting the firm from any responsibility or liability should an accident occur, etc. The investigator/analyst should exercise caution and good judgment prior to signing any document. You should use tact and diplomacy when declining to sign any document. See IOM Section 502.2.
Team inspections conducted outside of the U.S. are essentially no different than those conducted domestically. The investigator/ analyst should be guided by the IOM Section 502.4 regarding team leader responsibilities and procedures to be followed during team inspections. See the IOM for additional information.
Many firms may pose unique safety hazards or problems. This includes things such as, manlifts and ladders, Ethylene Trioxide (ETO) ionizing radiation, etc. Refer to the IOM for guidance concerning these areas.
Each investigator who visits a firm involving radioactive products, sterilization by radiation, or tests ionizing radiation emitting products, must wear a thermo luminescent dosimeter (TLD) to estimate external exposure. These are available at the District office. Do not place the TLD in luggage which may be passed through X ray detection equipment.
Take care when inspecting firms that manu-facture or process viral, biological or other products from animal origins. Refer to the IOM for guidance in these areas. It may be necessary to wear gowns, masks, rubber gloves, etc., in such establishments. Be guided by how the firm's employees dress.
A good recommendation is to NOT touch anything unnecessarily in such firms. Hands should be washed thoroughly after leaving each work area. Use scrupulous personal hygiene at all times.
Certain biological manufacturers may require the investigator to show proof of a gamma globulin injection prior to entry into the processing areas. If scheduled to inspect such firms, determine if the above is required and arrange for appropriate protection.
Our concern over microbiological contamination emphasizes the need for you to be alert to criticism or allegations you contributed to, or caused contamination at the firm. It is common sense to adhere to good sanitation practices so as to refute any such criticisms.
When inspecting clean rooms or areas involving aseptic processing, try to avoid entry. If entry is necessary, follow the same procedures as required of the firm's employees. If their sterile program appears weak, take the necessary proper precautions when possible.
The firm will generally provide protective clothing Use disposable hair, head, hand, and foot coverings where appropriate. For example, certain solvents such as phenylacetic acid, used in the production of penicillin V, is absorbed by leather soled shoes. This results in destruction of the soles and a foul odor. Individuals may wish to carry some type of shoe covers such as "Totes" to protect footwear against damage by solvents.
See IOM Section 504.
Wear safety glasses or safety goggles during inspections as needed. Wear ear plugs or protective ear guards in high noise or constant noise situations.
Wear safety shoes, hard hats and proper gloves during inspections where necessary. Generally, the firm will provide these.
Required protective clothing for entry into "clean rooms," etc. will be provided by firms. The traveler may wish to take a lab coat or coveralls for general use if desired.
Be alert for possible situations which might require the need for respirators. If it appears necessary, request the firm to provide an appropriate type of respirator. Refer to IOM for further guidance.
Three areas of concern regarding respirators are: 1. Inspection of sterilizers using ETO (ethylene oxide); 2. Inspection of bulk chemical producers of carcinogenic materials; and 3. Bulk pharmaceutical chemical producers utilizing solvent extraction processes (i.e. Hexane, Toluene, etc.).
Be aware of warning signs indicative of toxic conditions while performing inspections. Symptoms such as headache, nausea, dizziness, shortness of breath, etc., may be considered warning signs of a toxic atmosphere. It is advisable to leave when these symptoms are experienced.
Do not undertake a critical review of labels unless so instructed by the assignment. If, however, blatant discrepancies are noticed in the firm's labeling, inform responsible management of your observations, discuss the problems in the EIR and collect copies for submission with the report. See IOM Section 505.2.
An investigator/analyst's activities must always be conducted with honesty, diplomacy, tact, and persuasiveness.
There is potential for communication problems due to language differences. Personnel at the plant may appear to be very fluent in English but may have a problem with rapid speech, slang, and varying accents. Even though the firm may provide translators, these individuals may not be knowledgeable of technical terms. Therefore, you should speak slowly and distinctly. It may be helpful to verify answers by repeating the response or asking several related questions.
When engaged in idle conversation with management, be aware they may not under-stand American humor. Be sensitive regarding conversations about politics, religion, or similar topics. Be aware that, the reverse may also be true, i.e., they may understand English better than you think. So that there is no misinterpretation, use caution in what, or how you say things to inspection team members.
Normally some firms have an agenda prepared for the entire inspection. Be courteous and polite and inform them that an overview of the plant’s operation is very helpful, however due to the limited time of the inspection we would like to focus on the purpose of the assignment.
Do not issue the following forms: Notice of Inspection (FDA-482), Demand for Records (FDA-482a) and Request for Information (482b). The exception is when conducting inspections of U.S. military blood banks in foreign countries the FDA-482 are issued.
At the time an observation is noted during the inspection, it should be mentioned to firm’s management to avoid surprises at the exit interview.
Listed observations should be significant, but experience has shown that foreign firms respond better to observations left in writing on an FDA 483, rather than those discussed verbally. Therefore, if a situation needs attention or correction, that situation should be included on the FDA 483. Good judgment is necessary when deciding whether conditions are objectionable in view of their relation to other conditions or controls at the given time and place. Objectionable conditions should relate to products which could be offered for export to the USA.
Inspectional Observations, Form FDA 483, should be issued in accordance with IOM Section 512. Report all objectionable conditions noted during the inspection in the issuance of an FDA 483. There may also be specific guidance in the assignments or compliance programs, which supplement the general instructions already mentioned. The report of observations should be presented to top management at the conclusion of the inspection.
Keep the report of objectionable conditions concise and avoid redundancy. Include locations, dates of occurrence, lot numbers, etc., as appropriate. Similar items should be grouped together. Examples should be given to describe a condition with broad or general scope. Do not quote regulations on the FDA 483. Do not report opinions, conclusions, or characterize conditions as "Violative."
You should assure that all copies of the Inspectional Observations are legible. If a typewriter is available the FDA 483 may be typed. Refer to IOM.
You should be thoroughly familiar with the IOM Section 512.2 regarding specific non-reportable observations.
In program areas other than devices, the decision to annotate FDA-483 observations is left to each district. Because DFI is the district for all international firms, it is our policy not to annotate FDA-483s in the international arena. This guidance does not apply in cases where an observation is materially incorrect. In these cases, the observations should be corrected. In addition, firms are encouraged to reply in writing to the FDA-483 observations with the supporting documentation.
A reportable item will not be deleted from the FDA-483 even if the firm has promised or completed a corrective action.
See IOM Section 512.3.
As required by the IOM, report deficiencies with contract requirements that result in non-acceptance.
Issue original to the most responsible individual present.
As soon as possible after issuance of the FDA-483, provide a copy to DFI with your recommendation including a short summary of findings by fax at (301) 443-6919 or (301) 827-6685.
Refer to Section 390.2.
Remember to obtain a statement on the firm's letterhead stationary describing what was collected and the purpose of the collection. This is particularly true when a drug product is being sampled. This information should be readily available to customs officials upon their request.
If refusals of information or documents that you are entitled to are encountered during an inspection, you should collect the pertinent facts and report them in the EIR under a heading titled "Refusals." Do not forget to enter the appropriate data in FACTS. Refer to the IOM Section 514.
Upon completion of the inspection, you should meet with the highest ranking management official(s) possible to discuss the inspectional findings. Report all discussions in the EIR.
During the discussion with management, be frank, courteous and responsive. Discuss all observations and explain their significance.
Investigators/analysts do not have the authority to tell management their firm is approved or not approved. However, discussions regarding the significance of observations made should be ongoing during the inspection so there will be no surprises at the closing discussion with management. Inform the firm that these are your findings and that it will be further evaluated by the Center for final decision.
Do not be overbearing or arbitrary in attitude or actions. Do not argue if management voices a different view.
Investigators/analysts are often asked to provide copies of GMP regulations, drug listing information, applicable guidances, etc. You should make a reasonable effort to have the documents available for the firm to photocopy.
Accurately record in your notes and EIR all responses to each observation made by management. Suggest to management that they respond to FDA in writing concerning all actions taken as a result of the observations.
(Encourage photographs or applicable documentation be included in the response where appropriate to demonstrate corrections.)
In making recommendations to the firm, deal with what needs to be done, rather than how they should do it.
Do NOT volunteer information about another firm or their practices. Do not respond to casual exploratory questions or remarks from management about competitors or competitors’ processes. You may thereby avoid voluntarily, or unknowingly divulging information which may be privileged or confidential.
See IOM Section 516.1.
International inspections are subject to the FOI Act. International inspection reports are routinely requested and provided under the FOI Act.
Release of information under the FOI Act is the responsibility of a FOI Officer. Do not specify or speculate what may or may not be released. Do not object if the firm wishes to identify certain exhibits as confidential or trade secret.
Because the EIR is releasable under FOI, refrain from making judgments as to the acceptability or non-acceptability of the firm in the EIR.
Foreign establishments have traditionally and will continue to receive post inspection notification from FDA upon evaluation and closure of each inspection.
EIRs from international inspection will be sent to the firm from Centers or DFI as applicable. See FMD 145.
Inspectional procedures and techniques to detect adulteration and contamination, etc., are described in the IOM and specific guides to inspections. (See ww.fda.gov/ora/inspection_ref). Do not be limited by this. Strive to increase your knowledge of inspectional procedures and techniques. Feel free to discuss inspectional techniques and methods with colleagues at the district office and with other international travelers.
Refer to Sub Chapter 390 Sampling.
In general, fewer exhibits are usually required for international EIs than for domestic EIs. Usually there is no need to collect filth exhibits. However, when unusual conditions are encountered the collection of such exhibits should not be dismissed. Identify all exhibits (photocopies and photographs) as described in the IOM Section 523.
Collect photocopies of those documents that demonstrate and/or support objectionable conditions noted during the EI. You should obtain a representative sample to support each violation. It is not necessary to collect multiple exhibits of the same objectionable condition.
Diagrams of the establishment, floor plans, flow charts, and schematics are useful in preparing a clear concise report.
Photocopies, Photographs, or even hand copies of production logs, batch records, laboratory control records, etc., are useful exhibits and may be included in the EIR.
It is sometimes most effective to take photographs of conditions causing or potentially causing the product to be violative. Do not use flash photography where there is a potentially explosive condition (e.g., very dusty areas or possible presence of explosives or flammable vapors).
The IOM Section 523.1 has more details regarding in-plant photographs.
If a firm requests to tape record or video record your inspectional activities, be guided by the IOM. Be tactful and diplomatic to discourage this practice with responsible management. Report all instances of recordings in the EIR. See IOM Section 524.
Determine and report the full legal name and title of persons interviewed, who supplied relative facts, and the name/title/address, and phone number of the top management officials to whom FDA correspondence should be directed.
The IOM Section 525 has more detailed guidance regarding responsible individuals.
If the firm issues FD&C Guarantees and/or has labeling agreements for products shipped into the U.S., you should obtain copies of these guarantees and labeling agreements. They should be submitted with the EIR.
Obtain shipping records of products exported to the U.S. either for distribution or for further processing and export. The U.S. Agent, firm supplied, products shipped, volume of distribution and intended purpose of use should be identified in the EIR.
If violative conditions are observed during the inspection, be sure to describe the impact of the violations on raw materials or finished products offered for U.S. distribution. Shipping records, distribution records, etc. must be obtained for use in follow-up activities. If conducting a preapproval inspection that is violative, be sure to identify other products, already in U.S. distribution, which may adversely be affected by the identified deficiencies and obtain necessary documents to facilitate follow-up.
In the past, FDA's international activities concerning food products have been limited to low acid canned food (LACF), infant formula and shellfish and seafood sanitation inspections.
Review the IOM and any applicable ORA Guides to Inspections prior to leaving on international inspections. A list of Inspection Guides available from DFI is listed on the Internet. See FDA Home Page under Office of Regional Operations.
Refer to Section 201.
Do not issue a written Demand for Records (482a) and Request for Information (482b) while conducting inspections of LACF's or acidified food plants.
The IOM contains general guidance for procedures utilized in conducting inspections of food plants. Reference IOM, Section 530, and the ORA Guide to the Inspection of Low Acid Canned Food Manufacturers for Inspectional Guidance
It is necessary to conduct can seam examinations and to evaluate the firm's capability to perform such examinations.
Forms FDA 3146 (Domestic Acidified and Low Acid Canned Food Inspection Report) and Form FDA 3146a (Domestic LACF Retort Data Sheet) must also be completed for international inspections.
During inspections of LACF and acidified food producers, be alert for damaged products in the firm's warehouse. Evidence of leaking containers may indicate a potential problem with processing of the product. If time permits, do a modified field exam of finished canned products.