Contents

SUBCHAPTER 500 - INSPECTION INFORMATION

501 - AUTHORITY TO ENTER AND INSPECT

See IOM 701 for discussion of statutory authority.

FDA Investigator's Responsibility - Your authority to enter and inspect establishments is predicated upon specific obligations to the firm as described below. It is your responsibility to conduct all inspections at reasonable times and within reasonable limits and in a reasonable manner. Proceed with diplomacy, tact and persuasiveness.

Credentials - Display your credentials to the top management official be it the owner, operator, or agent in charge. See IOM 511.

NOTE: Although management may examine your credentials and record the number and your name, do not permit your credentials to be photocopied. Federal Law (Title 18, U.S.C. 701) prohibits photographing, counterfeiting, or misuse of official credentials.

Written Notice - After showing the firm's representative your credentials, issue the original, properly executed, and signed FDA 482, Notice of Inspection, to the top management official. Keep the carbon copy for submission with your report.

Written Observations - Upon completing the inspection and before leaving the premises, provide the highest management official available your inspectional findings on an FDA 483 - Inspectional Observations. See Section 704(b) of the FD&C Act [21 U.S.C. 374 (b)] and IOM 512 & 516.

Receipts - Furnish the top management official the original of the FDA-484 - Receipt for Samples describing any samples obtained during the inspection. See IOM 513.

Written Demand for Records - In low-acid canned food and acidified food EI's, an FDA 482a - Demand for Records is required under 21 CFR 108.35(h) and 21 CFR 108.25(g) to obtain records required by 21 CFR 113 and 114.

Written Request for Information - In low-acid canned foods and acidified foods EI's, an FDA 482b, Request for Information, is required under 21 CFR 108.35(c)(3)(ii) and 21 CFR 108.25(c)(3)(ii) to obtain information concerning processes and procedures required under 21 CFR 113 and 114.

It is your obligation to fulfill these requirements because failure to do so may prevent use of evidence and information obtained during the inspection.

501.01 - Business Premises

Authority to inspect firms operating at a business location is described in IOM 501 and requires issuing management an FDA 482, Notice of Inspection, and presenting your credentials. A warrant for inspection is not necessary unless a refusal or partial refusal is encountered or anticipated.

501.02 - Premises Used for Living Quarters

All inspections where the premises are also used for living quarters must be conducted with a warrant for inspection unless:

Owner Agreeable - The owner or operator is fully agreeable and offers no resistance or objection whatsoever or;

Physically Separated - The actual business operations to be inspected are physically separated from the living quarters by doors or other building construction. These would provide a distinct division of the premises into two physical areas, one for living quarters and the other for business operations, and you do not enter the living area.

In both the latter cases, proceed as any other inspection with the appropriate presentation of credentials and issuance of a Notice of Inspection.

501.03 - Facilities where Electronic Products are Used or Held

Section 537(a) of the Radiation Control for Health and Safety Act of 1968 (P.L. 90-602) provides the FDA with the authority to inspect the facilities of manufacturers in certain circumstances.

It is lawful for FDA personnel to enter the facilities of an electronic product distributor, dealer, assembler or user for the purpose of testing an electronic product for radiation safety when the entry is voluntarily permitted. Congress has not specifically prohibited FDA from conducting such voluntary examinations and such examinations would clearly agree with the congressional declaration of purpose expressed in section 532(a) of the RCH&S Act.

Under the Medical Device Authority, electronic products utilized in human and/or veterinary medicine, e.g., x-ray, laser, ultra-sound, diathermy, etc. can be considered prescription devices. In these cases the authority of Section 704 of the FD&C Act [21 U.S.C. 374] can be used to obtain entry to inspect the user facility. If the Medical Device Authority is utilized, credentials must be displayed and a FDA 482, Notice of Inspection, must be issued.

501.04 - Multiple Occupancy Inspections

You are required to issue a Notice of Inspection, FDA 482, to each firm inspected. When firms have operations located in different sites or buildings, you should use judgment to determine when multiple FDA 482 forms need to be issued. For sites located a distance apart, it is preferable to issue an FDA 482 to the most responsible person at each site. One rule of thumb which can be used is if the sites or buildings are within walking distance, your original Notice of Inspection can be considered sufficient to cover both. During your initial interview with management, after you issue the FDA 482, make sure you clearly indicate the facility and sites you intend to inspect. If management requests separate Notices, cooperate and issue them. There is no harm in issuing more than one to cover a single inspection operation at multiple sites as long as you clearly explain the situation in your narrative report.

The following instructions are to be followed when: more than one firm operates in the same facility and applies to situations covered by 21 CFR 201.1(c), et al.

1. Issue one FDA 482, Notice of Inspection, for the location inspected, but list all known firms using that location. Issue the FDA 482 to the person in charge. If multiple firms are represented on site by separate people, give them each a copy of the FDA 482. If necessary issue additional FDA 482(s).
   If you later determine other firms besides those listed on the original FDA 482 are using the facility, issue a revised FDA 482 to cover those firms.
2. Inspect the firm premises according to your assignment including each firm listed on the FDA 482.
   1. Ask to examine records of each firm. If there are no records for a firm on site, report this fact.
   2. If the lessee firm's records are on site, but they have no representative available and the lessor firm states permission to examine records must come from elsewhere, request them to quickly obtain permission for record examination and offer to provide a copy of the FDA 482.
   3. Determine individual responsibility for each firm operating on the premises at the time of the inspection. Give detailed information of the responsibilities between the lessee/lessor firms.
3. Closeout discussion with management should be conducted with all firm representatives present at the same time. However, if requested by the firm(s), the discussion may be done separately.
4. Report the inspection into FACTS as one inspection using the FEI/Registration number of the lessor firm.
5. One EIR will be written incorporating all of the facts into one narrative. Each firm's separate operations should be reported under a separate EIR heading for each firm's operations.

501.05 - Authority for Examinations and Investigations

Section 702(a) of the FD & C Act [21 U.S.C. 372 (a)] authorizes examinations and investigations for the purpose of enforcing the Act.

501.06 - Authority to Implement Section 702(e)(5) of the FD&C; Act

Background - Section 702(e) of the FD & C Act [21 U.S.C. 372 (e)] contains certain authorities relating to counterfeit drugs including the authority to seize ("confiscate") counterfeit drugs and containers, counterfeiting equipment, and all other items used or designed for use in making counterfeit drugs prior to the initiation of libel proceedings. This authority has been delegated, with certain restrictions, to holders of official credentials consistent with their authority to conduct enforcement activities. Additional authority in 702(e) to make arrests, to execute and serve arrest warrants, to carry firearms, or to execute seizure by process under Section 304 of the FD&C Act [21 U.S.C. 334] have not been delegated.

The agency does intend to utilize the authority contained in Section 702(e) to execute and serve search warrants, but such use does not require delegation from the ACRA.

Section 702(e)(5) contains authority for such delegated persons to confiscate all items which are, or which the investigator has reasonable grounds to believe are, subject to seizure under Section 304(a)(2). Items subject to seizure, and thus to confiscation under Section 702(e)(5), includes most things associated with counterfeit drugs. Confiscation authority does not, however, extend to vehicles, records, or items (i.e., the profits) obtained as a result of counterfeiting.

Scope - Under this delegation, with supervisory concurrence and prior to the initiation of libel proceedings, investigators and inspectors are authorized to confiscate: (1) any counterfeit drug, (2) any container used to hold a counterfeit drug, (3) any raw material used in making a counterfeit drug, (4) any labeling used for counterfeit drug, (5) any equipment used to make a counterfeit drug including punches, dies, plates, stones, tableting machines, etc., (6) any other thing which you have reasonable grounds to believe is designed or used in making a counterfeit drug.

NOTE: You and your supervisor must be constantly aware of the potential dangers involved in confiscating property from individuals. Special care should be taken to ensure your safety. Arranging for teams of investigators to conduct the investigation, or arranging for assistance by local police, or other agencies with police powers, should be considered in planning the confiscation of counterfeit materials.

Inspectional Guidance - Guidance provided for implementing the authority to confiscate drug counterfeits is as follows:

1. The authority is not to be utilized unless there has been an agency determination the drug to be confiscated is a counterfeit and it is a drug which "without authorization, bears a trademark, *** or any likeness" of a legitimate product. The determination usually is based upon evidence supplied by the firm whose product is being counterfeited. A written agency determination will issue to the District Director from the Office of Enforcement, in conjunction with the Office of Regional Operations, and the Center for Drug Evaluation and Research.
2. When engaged in counterfeit investigations, you should proceed as follows upon encountering items to be confiscated.
   1. Evaluate safety needs and check the location to ensure it is safe to proceed. Do not attempt to remove an item by force. If it appears there will be resistance, contact the local police, or other agencies with police powers for backup, if not already done in advance.
   2. Inventory the items to be confiscated.
   3. Prepare a written receipt and offer it to the person in charge.
   4. Remove the items, if possible, from the premises (if they cannot be removed, secure them under seal).
   5. Place all items removed under lock at a secure location. In most cases, confiscated items will be stored at the district or resident post office until they are seized.

Follow up Guidance - After items are confiscated, certain actions must be taken to bring confiscated items under the control of the court. Proceed as follows:

1. After an item is confiscated, immediately notify your supervisor.
2. Supervisors must then notify the appropriate compliance units of the items confiscated.
3. Compliance units should initiate seizure proceedings against any items confiscated.
4. ORO/DFI should be advised of any action utilizing this authority.

Search Warrants - Section 702(e)(2) contains authority to execute and serve search warrants. Proceed as instructed by your district after a search warrant has been obtained.

501.07 - Products Imported Under the Provisions of Section 801(d)(3) of the FD & C Act

The FDA Export Reform and Enhancement Act of 1996 (PL 104-134 and 104-180) amended the FD&C Act by adding Section 801(d)(3) ("Import for Export") which permits the importation of unapproved drug and medical device components, food additives, color additives, and dietary supplements intended for further incorporation or processing into products destined for export from the United States. Section 801(d)(3) was subsequently amended by Section 322 of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (Bioterrorism Act), Public Law 107-188, which specified certain requirements an importer has to satisfy in order to import a product under this Section.

These requirements include:

1. a statement confirming the intent to further process such article or incorporate such article into a product to be exported,
2. the identification of all entities in the chain of possession of the imported article,
3. a certificate of analysis "as necessary to identify the article" (unless the article is a device), and
4. executing a bond providing for liquidated damages in the event of default, in accordance with U.S. Customs. This bond remains in effect until the final product is exported and destroyed.

In addition, the initial owner or consignee must keep records showing the use of the imported articles, and must be able to provide upon request a report showing the disposition or export of the imported articles. An article imported under this section, and not incorporated or further processed, must be destroyed or exported by the owner or consignee. Failure to keep records or to make them available to FDA, making false statements in such records, failure to export or destroy imported articles not further incorporated into finished products, and introduction of the imported article or final product into domestic commerce are Prohibited Acts under Section 301(w).

Filers making entry under the Import for Export provisions must either identify entry submissions with the OASIS Affirmation of Compliance "IFE" (Import for Export), or supply FDA with written documentation stating the product is entered under the Import for Export provisions. A Certificate of Analysis (as necessary) and identification of all involved entities must be submitted in writing to the import district. The import district will forward all written documentation to the home district of the initial owner or consignee for incorporation into the appropriate Establishment File.

Before conducting an Establishment Inspection, contact your district's designated individual with access to OASIS/EEPS Reports to obtain a printout of any import entries made by the establishment under the Import for Export provisions through OASIS. In addition, check the district factory file for copies of any Import for Export documents forwarded from the district where entry was filed. During the inspection examine the firm's records to determine the disposition of any items identified at time of entry as intended for incorporation into products for export. Document any instances in which such products were introduced into domestic commerce or cannot be accounted for (see IOM 602).

502 - INSPECTIONAL APPROACH

An establishment inspection is a careful, critical, official examination of a facility to determine its compliance with laws administered by FDA. Inspections may be used to obtain evidence to support legal action when violations are found, or they may be directed to obtaining specific information on new technologies, good commercial practices, or data for establishing food standards or other regulations.

The kind and type of inspection you conduct will normally be defined by the program, assignment, or your supervisor; according to the following definitions:

Comprehensive Inspection - directs coverage to everything in the firm subject to FDA jurisdiction to determine the firms compliance status; or

Directed Inspection - directs coverage to specific areas to the depth described in the program, assignment, or as instructed by your supervisor.

See IOM Subchapter 140 for information on safety, use of protective gear, dealing with potential hazards and other safety issues.

502.01 - Depth of Inspection

The degree and depth of attention given various operations in a firm depends upon information desired, or upon the violations suspected or likely to be encountered. In determining the amount of attention to be given in specific cases, consider:

1. The current Compliance Program,
2. Nature of the assignment,
3. General knowledge of the industry and its problems,
4. Firm history, and
5. Conditions found as the inspection progresses.

502.02 - Signing Non-FDA Documents

Occasionally a firm will request you sign various documents including:

1. A waiver which will exempt the firm from any responsibility or liability should an accident occur and you are injured on the firm's premises,
2. Form letters concerning access to confidential information the firm does not want released,
3. Information/data you request during the inspection be put into writing, etc.

If you receive such a request, inform the firm you are not authorized to sign such documents, letters, requests, waivers, etc., but will report the firm's request in your EIR. The use of common sense is expected with this procedure. All FDA employees are authorized to sign-in and sign-out at a firm and to comply with security measures employed by the firm, including documenting the removal/replacement of seals to inspect vehicles and containers. See IOM 424 & 453.06. Obviously, the key issue is you are not authorized to waive, without supervisory approval, any of FDA's rights to inspect, sample, photograph, copy, etc. or to sign any interstate shipping record document which could infer the firm could not be prosecuted under the Act.

502.03 - Technical Assistance

If you determine specialized technical assistance is necessary in conducting inspections of new technologies, products or manufacturing procedures, it may be available through Regional or National experts, other ORA components or Center scientists and engineers. If specialized skills are necessary and are not available locally or through your Region, contact the Division of Field Investigations (DFI), (HFC-130) at (301) 827-5653. See FMD 142 and IOM 271.02 for additional information.

502.04 - Team Inspections

The use of teams to conduct inspections may be beneficial. Very often individuals well versed in an analytical or inspectional technique or technology can provide assistance and advice.

When inspection teams are involved in an inspection, one investigator will be designated as the team leader by the inspecting district or by the Division of Field Investigations (DFI/HFC-130) if a headquarters directed special inspection is involved. The team leader is in charge of the inspection and bears the overall responsibility for the inspection and the EIR. A team may consist of multiple investigators, laboratory personnel and other FDA employees, and your supervisor/coach, who may participate as part of the ORA Quality Assurance program.

Each team member is responsible for preparing those portions of the report pertaining to his/her activities. Team members shall identify their portion of the report so they can later identify that portion as the part he/she performed and reported. Since reports should be written in the first person, one system might be to head each portion with a statement "The following operation(s) was/were observed and reported by Investigator ___________", who can then report in the first person.

All team members must sign the original EIR. Ideally, all team members should sign the FDA 483, if one is issued. However, issuance of the FDA 483 should not be delayed, in the absence of a team member's signature. See IOM 512 for instructions for signing a multi-page FDA 483.

The Team Leader shall be responsible for:

1. Issuing unused diary notebooks for taking notes during the EI or investigation to headquarters personnel on the team. He/she is also responsible for instructions on their use, if necessary, and when the report is finished, for obtaining the headquarters individual's signature on the original EIR and completed and properly identified diaries and submitting them to the supervisor for filing. See IOM 193.
2. Directing the overall inspection to accomplish the objectives of the assignment including;
   1. planning the inspection,
   2. scheduling and coordinating team members' pre-inspection preparations,
   3. determining, to the extent possible, the firm will be open and operating,
   4. planning for needs of visiting scientists if applicable. When the team leader is not familiar with all the processes or technology involved in the inspection, provide for primary coverage of selected areas by other team members,
   5. determining an orderly, efficient, and effective approach and sequence to be used and discussing the inspection plan with the team,
   6. modifying the inspection plan as necessary during the EI, to permit following leads, documenting evidence, etc.,
   7. setting team policy on how communications with the firm are to be handled,
   8. discussing personal conduct in dealing with headquarters personnel as necessary,
   9. assuring an early understanding by team members of their roles in note taking and reporting,
   10. assuring communications are open among team members, especially if the team is allowed to separate and work independently,
   11. reviewing inspection progress at least daily, discussing remaining objectives with the team members, and setting objectives for the following day,
   12. continually assessing the progress of the inspection to evaluate how the inspectional approach is working and to keep the district supervisor advised of the inspection's progress,
   13. providing guidance and direction to team members as necessary,
   14. advising each team member of reporting responsibilities and dates when drafts are to be provided,
   15. following up promptly on any delays or failures to report as required, and
   16. assisting the supervisor with further follow up, as indicated.
3. Making sure any person who joins the team after the inspection has started presents credentials and issues a Notice of Inspection, FDA 482, to the firm prior to actually taking part in the EI;
4. Completing and/or correcting the computer generated coversheet;
5. Preparing the Summary of Findings;
6. Completing all headings of an administrative nature in the narrative report;
7. Compiling and submitting the complete final report; and
8. Resolving any disputes or differences of opinion among the team members, including items, which may be listed on the FDA 483.

503 - INSPECTION OF FOREIGN FIRMS

Inspectional requirements apply to all inspections, including foreign inspections. However, there are some exceptions. For instance the FDA 482 is not required, unless the firm is a US Military facility. Be guided by relevant Compliance Programs and the Guide to International Inspections and Travel Manual for other differences. See IOM 111.02.

504 - INSPECTIONAL PRECAUTIONS

Our concern over microbiological contamination emphasizes the need for you to be alert to criticism or allegations that you may have contributed to or caused contamination at a firm. This is especially important in drug firms and high-risk food firms, among others. You must adhere to good sanitation practices to refute any such criticisms. You could also unknowingly introduce or spread disease during inspections of or visits to animal production or sale facilities, conducting environmental investigations at poultry layer facilities, conducting dairy farm inspections or audits of state activities, investigating tissue residue reports or working in the veterinary bioresearch area. See IOM 519 for information outlining precautions for you to follow.

Exercise caution in all activities in the firm. Follow the firm's sanitation program for employees and wash and sanitize hands, shoes, vehicles and equipment as indicated. Restrict unnecessary movement between various areas in plants and when possible, complete your activities in one area before moving to the next.

When inspecting areas where sterility is maintained or sterile rooms are located (especially in pharmaceutical or device firms), follow the sterile program required of the firm's employees. In general it is unnecessary to enter sterile rooms except in the most extraordinary circumstances. These areas are usually constructed to provide visual monitoring. Take no unsterile items with you (notebook, pencils, etc.). In this type of situation you can enter your observations in your diary immediately after leaving the sterile area.

Always use aseptic techniques, including hand sanitizing, when collecting in-line and raw material samples, as well as finished product samples for microbiological examination. See IOM 426.

Do not use or consume a firm's products at any of a firm's facilities. This could be interpreted as accepting a product as being satisfactory and could possibly embarrass you and the Agency, both during the inspection and in the future. In general, consuming food products in a manufacturing area is considered an objectionable practice.

When conducting inspections of firm's using chemicals, pesticides, etc., ask to review the Material Safety Data Sheets (MSDS) for the products involved to determine what, if any, safety precautions you must take. This could include the use of respirators or other safety equipment.

504.01 - Clothing

Wear clean coveralls or other protective clothing for each inspection and if circumstances dictate, use a clean pair when returning from lunch, or upon entering certain machinery or critical areas.

Remove and secure all jewelry, pens, pencils, notebook, etc., so they cannot fall into the product or machinery. Do not depend on clips on pens, etc., to hold these items in your outer pockets.

Clean protective clothing should be either individually wrapped or placed in clean plastic bags and taped to protect from contamination. If the package has been sterilized, protect the package from possible contamination or puncture. The package should not be opened until you are ready to use the clothing. After use, clothing should be turned inside out as it is removed, and immediately placed in clean paper or plastic bags to prevent spread of contamination until washed and/or sterilized.

Use disposable hair and head coverings throughout the inspection and disposable hand and foot coverings in areas where floor tracking or cross contamination may be a factor. Use hard hats and other protective devices where the situation dictates.

If reusable protective boots are used, wash and sanitize before each use. Always use sterile disposable boot covers when entering machinery such as dryers or where unavoidable contact with product is a factor.

When discarding contaminated disposable head and boot coverings, it is suggested they be placed with used clothing for proper disposal after leaving the plant area.

See IOM 519.01 for protective clothing and equipment necessary when visiting livestock or poultry producing areas.

504.02 - PHS Recommendations - Basic Sanitary Practices

FDA personnel are not required by law to have health certificates, take physical exams or submit to requirements, which ensures their compliance with sanitary procedures in the performance of their official duties. However, it is critical you adhere to basic sanitation practices. See IOM 169.06.

The U.S. Public Health Service has designed a model sanitation code for use by state and local governments at their option. This code, "United States Public Health Service Food Service Sanitation Ordinance and Code", is contained in DHEW Publication No. (FDA) 78-2081 - "Food Service Sanitation Manual; - 1976". Your district has copies of the manual for use if necessary.

504.03 - Representatives Invited by the Firm to View the Inspection

While conducting an inspection, you may find the firm's management has invited individuals who are not directly employed by the firm to view the inspectional process (e.g., representatives from the press, trade associations, consumer groups, congressional staff, other company officials).

Regardless of whom the firm invites to observe the progress of an inspection, the presence of outside representatives should not disrupt the inspectional process. You should continue to conduct the inspection in a reasonable fashion. The presence of these individuals should have no impact on the manner in which the inspection progresses except you should take precautions to preserve the confidentially of any information you may have obtained as a result of the Agency's statutory authority. This is especially true when the inspection is recorded via videotaping, other photography, and/or audio recordings. Where applicable, refer to IOM 524 for procedures on how to prepare your own recording in parallel with the firm's recording.

It is the Agency's position that while the investigator must protect privileged information provided to him/her during the inspection, it is the firm's responsibility to protect privileged/confidential information observed or recorded by those individuals invited by the firm.

SUBCHAPTER 505 - GENERAL PROCEDURES & TECHNIQUES

The procedures and techniques applicable to specific inspections and investigations for foods, drugs, devices, cosmetics, radiological health, or other FDA operations are found in part in the IOM (inspectional and investigational policy/procedure), various Guides to Inspections of... (a "how to" guidance series), and the Compliance Program Guidance Manual (program specific instructions). Some procedures and techniques which may be applicable to overlapping areas or operations are as follows:

505.01 - Candling

Candling is defined as: "to examine by holding between the eye and a light, especially to test eggs in this way for staleness, blood clots, fertility and growth." Like most techniques learned through the food inspection programs, there are uses for this technique in other program areas such as looking for mold in bottled liquids which could be drugs, devices or biologics. Candling can also be useful in the examination of original documents to see below white-out or to look for over-writing.

Many types of products lend themselves to inspection by some type of candling. For these products, firms generally have candling equipment which may be built into the production lines or may be a separate operation.

Where checking products by candling, it may be possible to utilize the firm's candling equipment. Various other light sources for candling are also available including overhead projectors. Exercise care when using overhead projectors and protect the glass surface and the lens from scratches and damage. All candling is best accomplished when light outside the item being candled is masked so the light passes through the object rather than being diffused around it. A heavy paper or cardboard template can be quickly prepared at the time candling is done.

505.02 - Label Review

Do not undertake a critical review of labels unless instructed by the assignment, program, or your supervisor. Limit your comments to the mandatory label requirements required by the Acts. However, if after review of the formula, it is obvious an active ingredient or an otherwise mandatory ingredient statement does not appear on the label, such discrepancy may be called to management's attention. See also IOM 512.01 regarding labeling for blood and blood products.

If asked for other label comments, refer the firm to the appropriate Center to obtain a label review.

When the labeling is suspect or when you are requested to collect labels/labeling, collect three copies of all labels and accompanying literature for further review. For medical devices, if there is a question regarding the need for a new 510(k) or PMA supplement, it is essential the label and labeling be collected.

505.03 - Field Exams

A field examination is an on-site examination of a domestic product (or a foreign product in domestic channels of trade) sufficient in itself to determine if the product is in compliance with the Acts enforced by FDA.. A field exam can be conducted of any commodity in any location. If the examination does not reveal a violation or the appearance of a violation, a sample of the lot is usually not collected. If your exam reveals a violation or potential violation, you should collect an official sample. With the implementation of FACTS, your time spent conducting the field exam is reported even if you do collect a sample. Only the actual time spent in the collection of the sample would be reported as sample time.

Instructions on how to conduct a field exam are contained in "Guides To The Inspection of ***" and Compliance Programs. The Sample Schedules in Chapter 4 also provide guidance on lot examinations for special situations.