CONTENTS
SubChapter 300 GENERAL
301 AUTHORITY
302 INTERNATIONAL ESTABLISHMENT INSPECTION
302.1 Coverage
302.2 Signing Non-FDA
Documents
302.3 Team Inspections
303 PRECAUTIONS
303.1 Protective
Devices
303.2 Eyes and Ears
303.3 Extremities
303.4 Protective
Clothing
303.5 Respirators
304 LABEL REVIEW
Subchapter 310 MANAGEMENT RELATIONS
310.1 General
311 NOTICE OF INSPECTION
312 REPORTABLE OBSERVATIONS
312.1 Non-reportable Observations
312.2 FDA-483 Annotations
312.3 Comstat/Contract Requirement Deficiencies
312.4 Distribution of the Form FDA 483
313 RECEIPT FOR SAMPLES
314 REFUSALS
315 DISCUSSION WITH MANAGEMENT
315.1 Procedure for Discussion of
Observations
315.2 Protection of Privileged Information
315.3 Freedom of Information (FOI) Act
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
330.1 General
330.2 Preparation and References
330.3 Authority
330.4 Authority to Obtain Records and Information in LACF and
Acidified Food Plants
330.5 Procedures
Subchapters 340 - 390
SUB CHAPTER 300 GENERAL
301 AUTHORITY
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.
302 - INTERNATIONAL ESTABLISHMENT INSPECTION
302.1 COVERAGE
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.
302.2 SIGNING NON-FDA DOCUMENTS
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.
302.3 TEAM INSPECTIONS
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.
303 – PRECAUTIONS
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.
303.1 PROTECTIVE DEVICES
303.2 EYES AND EARS
Wear safety glasses or safety goggles during inspections as needed.
Wear ear plugs or protective ear guards in high noise or constant
noise situations.
303.3 EXTREMITIES
Wear safety shoes, hard hats and proper gloves during inspections
where necessary. Generally, the firm will provide these.
303.4 PROTECTIVE CLOTHING
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.
303.5 RESPIRATORS
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.
304 LABEL REVIEW
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.
SUB CHAPTER 310 MANAGEMENT RELATIONS
310.1 GENERAL
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.
311 NOTICE OF INSPECTION
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.
312- REPORTABLE OBSERVATIONS
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.
312.1 NON-REPORTABLE OBSERVATIONS
You should be thoroughly familiar with the IOM Section 512.2
regarding specific non-reportable observations.
312.2 - FDA-483 ANNOTATIONS
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.
312.3-COMSTAT/CONTRACT REQUIREMENT DEFICIENCIES
As required by the IOM, report deficiencies with contract requirements
that result in non-acceptance.
312.4 DISTRIBUTION OF THE FORM FDA 483
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.
313 RECEIPT FOR SAMPLES
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.
314 REFUSALS
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.
315 DISCUSSION WITH MANAGEMENT (IOM Section
516)
315.1 PROCEDURE FOR DISCUSSION OF OBSERVATIONS
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.
315.2 PROTECTION OF PRIVILEGED INFORMATION
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.
315.3 FREEDOM OF INFORMATION (FOI) ACT
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.
316 - POST INSPECTION NOTIFICATION
Foreign establishments have traditionally and will continue to
receive post inspection notification from FDA upon evaluation
and closure of each inspection.
317- ESTABLISHMENT INSPECTION REPORT (EIR)
EIRs from international inspection will be sent to the firm from
Centers or DFI as applicable. See FMD 145.
SUB CHAPTER 320-EVIDENCE DEVELOPMENT
320.1 TECHNIQUES
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.
321 FACTORY SAMPLES
Refer to Sub Chapter 390 Sampling.
322 EXHIBITS
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.
323 PHOTOCOPIES AND PHOTOGRAPHS
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.
324 RECORDINGS
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.
325 RESPONSIBLE INDIVIDUALS
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.
326 GUARANTEES AND LABELING AGREEMENTS
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.
327 - DISTRIBUTION AND DOMESTIC FOLLOW-UP
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.
SUB CHAPTER 330 FOOD
330.1 GENERAL
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.
330.2 PREPARATION AND REFERENCES
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.
330.3 AUTHORITY
Refer to Section 201.
330.4 AUTHORITY TO OBTAIN RECORDS AND INFORMATION
IN LACF AND ACIDIFIED FOOD PLANTS
Do not issue a written Demand for Records (482a) and Request
for Information (482b) while conducting inspections of LACF's
or acidified food plants.
330.5 PROCEDURES
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.
|