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18 FACTORY INSPECTIONS
INTRODUCTION
AUTHORITY AND COVERAGE
Inspection Plan
Inspection Refusals
Inspection Preliminaries
Conduct During the Inspection
Close-out Meeting
After the Inspection
BASIC POINTS FOR AN INSPECTION PLAN
REGULATORY SANCTIONS
Adulteration
Misbranding
Management Letter
Warning Letter
Seizure
Detention
Restraining Orders and Injunctions
Recalls
Penalties
EXHIBITS
Notice of Inspection
Receipt for Samples
Affidavits
List of Observations
Establishment Inspection Report
Warning Letter
FDA determines compliance with the GMP requirements set forth
in the Quality System (QS) regulation primarily by factory inspections.
An FDA inspection of an establishment, however, can be initiated
for a number of reasons. The reasons may be general, such as routine
scheduling or a need to obtain data on industries new to FDA or,
the reasons may be specific, such as investigation of a consumer
or trade complaint, a product defect report, an adverse reaction,
or a death. FDA also conducts inspections under the Compliance
Status Information Systems (Com STAT) on behalf of the Veterans
Administration (VA), Department of Defense (DOD), and Health Resources
and Services Administration (HRSA). Upon arrival, the investigator
presents his/her credentials and issues a Notice of Inspection
form FDA 482. At the end of the inspection, observations are recorded
on form FDA 483, List of Observations, and discussed with the
manufacturer's management. Later the investigator will write an
Establishment Inspection Report (EIR), which is a detailed record
of the inspection and findings.
Section 704(a) of the Food, Drug, and Cosmetic (FD&C) Act
gives FDA the authority to conduct GMP inspections of medical
device manufacturers. During these inspections, facilities, manufacturing
processes, records, and corrective action programs are examined
by an FDA investigator. The results provide information necessary
to evaluate a manufacturer's compliance with the device QS regulation
(21 CFR 820).
Anyone who manufactures or stores a medical device can be inspected.
A manufacturer is any person who designs, manufactures, fabricates,
assembles, or processes a finished device. Manufacturer includes
but is not limited to those who perform the functions of contract
sterilization, installation, relabeling, remanufacturing, repacking,
or specification development, and initial distributor(s) of devices
from foreign entities performing these functions.
Inspection Plan
This chapter offers ideas on ways that a manufacturer might prepare
for, undergo, and respond to an FDA inspection. First and foremost,
it is important to plan ahead! Before being visited by an FDA
investigator, a manufacturer should have in place an inspection
procedure which takes into account, and prepares a manufacturer
for, any eventuality. It should detail company policy regarding
an inspection and, very importantly, designate those individual(s)
who will work with the FDA investigator. Try to anticipate situations
and have written procedures covering them. These procedures will
provide continuity from one inspection to another and help assure
that corporate policies are followed by employees receiving and
accompanying the investigator.
Each person designated as an FDA contact should be chosen carefully
and be thoroughly familiar with the inspection procedure and company
operations. An inspection will take longer if the contact person
cannot answer questions without continually referring to the written
procedures. The contact should be familiar with FDA regulations
and practices and be able to anticipate problems or requests.
FDA contacts be should knowledgeable about plant operations, and
able to answer or obtain answers to the investigator's questions.
Other individuals, with similar qualifications, should be designated
to fill in during absences of the primary contact. A manufacturer
might want secondary contacts to accompany the FDA investigator
even when the primary contact is present in order for the secondary
contact to become familiar with FDA methods and procedures.
Along with the designated contact, the manufacturer may want operations
managers to accompany the investigator, such as the production
manager, QA manager, etc. These individuals should be familiar
with the plant operations and company policy, and be able to answer
questions about procedures and processes. However, a manufacturer
should keep the number of individuals accompanying the investigator
to a minimum to prevent problems such as contradictory statements.
Receptionists should be informed that FDA investigators will eventually
visit and have procedures to follow when they arrive. These procedures
should include instructions to call the FDA contact person and
what to do or who to contact when that person is not available.
Inspection Refusals
As noted above, Section 704(a) of the FD&C Act gives FDA authority
to conduct inspections. Refusing an inspection may set up an adversarial
situation and arouse an investigator's suspicion regarding the
manufacturer's compliance with the QS regulation. If a manufacturer
refuses an inspection without a valid reason, FDA may obtain a
warrant which grants entry for an inspection. Refusals to permit
inspection are noted in the manufacturer's file maintained by
FDA and may be interpreted as a lack of cooperation. Moreover,
refusal to permit an inspection is a prohibited act under section
301(f) of the FD&C Act, which may result in sanctions that
include criminal prosecution and injunction.
There may be instances, however, when a manufacturer needs to
ask the investigator to return at a later time to conduct the
inspection. Explain why it is best that an inspection be done
at a later time. For instance, if the FDA contact person(s) is
not in the factory and no one knowledgeable about the manufacturer's
operations is available, it may be appropriate to ask the investigator
to come back. However, FDA investigators do expect to be admitted
if a device factory is operating. The rationale is that if a factory
is operating, someone should be in charge and that individual
should understand factory operations and procedures. If the factory
is not in operation or not yet manufacturing any medical devices,
this should be explained to the investigator. The FDA representative
may still want to go through the factory to make sure it is not
in operation -- manufacturers should have a policy covering this
situation. It is advisable, in this situation, to allow the investigator
to walk through the factory to verify that it is not in operation.
If the factory is not in operation, advise the investigator when
operations will begin. The investigator will consider the request
and circumstances, then determine whether to proceed with the
inspection.
Inspection Preliminaries
Before an inspection begins, an investigator is required to show
his/her credentials. The credentials have a picture of the investigator
and identify him/her as a representative of FDA.
After presenting credentials, the investigator will issue form
FDA 482, Notice of Inspection. This form is issued to the owner,
operator, or agent in charge of the factory or to the designated
FDA contact. The bottom portion of the Notice of Inspection contains
excerpts from Section 704 of the FD&C Act. The investigator
will complete the top portion of the form by filling in the manufacturer
name, address, name of the individual given the signed form, date,
and time of inspection. The investigator then signs the form.
The FDA contact person should always be prompt. It is important
not to keep the Investigator waiting because misunderstandings
can occur regarding the manufacturer's intentions.
Conduct During the Inspection
Awareness of what is going on at all times by the contact person
of the manufacturer during the inspection is important. Therefore,
once started, the inspection should be given priority. If the
contact person is distracted by other business, the inspection
may be prolonged and the investigator's questions concerning suspected
deficiencies may be misunderstood or answered inadequately. Familiarity
with the circumstances surrounding any deficiencies listed on
form FDA 483 (the list of deviations presented at the close of
the inspection) is vital in discussion of these with the investigator.
During inspections, the FDA contact person will deal with many
issues such as viewing records, copying, photos of the manufacturing
site, tape recordings, differences of opinion, immediate corrections,
promises, samples, notes, etc. All of these issues should be addressed
by a company procedure.
There should be a procedure for responding to requests for design
history records, device master records, quality system records,
device history records, change control records, complaint files,
and shipping records. All records required by the QS regulation
shall be made available to the investigator for review and copying
(820.180). Therefore, records required by the QS regulation shall
be readily accessible. The procedures covering review of records
by the investigator should identify who will retrieve records,
how many records can be reviewed at one time and, who should be
present to answer questions raised by the investigator.
Because all records required by the QS regulation shall be available
for copying, management should decide on a policy concerning record
copying during inspections. In all situations, the contact should
make duplicate copies and keep these together as a record of the
documents that the investigator copied.
If any records copied by an investigator contain confidential
information, they should be identified, i.e., by a confidential
stamp. This identification does not automatically prevent release
of these records under the Freedom of Information (FOI) Act; however,
the FOI officer filling a request is then made aware that the
manufacturer considers the information confidential. Information
deemed confidential by the FOI Act or 21 CFR part 20 shall not
be released by the agency. Reserve "confidential" marking
to only those items that are genuinely confidential..
FDA investigators sometimes photograph equipment, conditions,
and product at a facility. FDA feels that picture taking is a
normal inspection activity. Include this policy in the inspection
procedure.
If the manufacturer disagrees with any observation made by the
investigator, be sure to discuss with the investigator the reason
for the observation. You may find that there was a misunderstanding
that can easily be corrected. When explaining situations or answering
questions, be honest. Don't make up answers, as this could lead
to additional problems. If you don't know the answer, say so.
Personnel with responsibility for representing a manufacturer
during an inspection should refer to the FDA regulations and guidances,
whenever possible, rather than base discussions and disagreement
on personal opinion.
If there are questions for which you don't have immediate answers,
promise to research the questions. A list of these unanswered
questions is a reminder to get the answers and give them to the
investigator. The investigator usually records the questions,
and resolving unanswered questions may help avoid inaccuracies
on the form FDA 483 and in the establishment inspection report
prepared by the investigator at the end of the inspection.
If possible, any GMP deficiencies that the investigator notes,
and on which you agree, should be corrected immediately. However,
before implementing an immediate corrective action, manufacturers
should first evaluate their action to assure that is the best
action to take to avoid future quality problems. The investigator
should be made aware of these corrections as this will show intent
to comply with the regulations and commitment to quality assurance.
Corrective actions that are verified by FDA during the inspection
will be documented in the investigator's EIR.
If correction cannot be made during the inspection, management
may want to consider providing an estimated timetable for correction.
However, the manufacturer should not present or commit to a timetable
that may be difficult or impossible to meet. If a timetable cannot
be immediately developed, try to get one to FDA as soon as possible.
As with any production change, it is a good idea to discuss possible
corrective actions with affected company personnel before promising
correction to FDA. This concept was discussed in Chapter 8, Device
Master Record, and Chapter 9, Document and Change Control, and
may prevent promises that have adverse effects on other areas
of production. Hastily conceived corrections can cause greater
problems in the long run.
Any commitments made to FDA should have top management concurrence.
It can be detrimental to the manufacturer to be committed to a
course of action that cannot be completed or that management refuses
to pursue. Therefore, only persons with the authority to do so
should make commitments.
During an inspection, investigators may collect samples. These may be used for a variety of investigational purposes including:
CDRH may request samples for a number of reasons, such as surveys
of device manufacturers and investigation of user complaints.
It is a wise policy for a manufacturer to collect and store duplicate
samples whenever an investigator collects samples. If problems
are uncovered by FDA, testing of these duplicate samples by the
manufacturer may confirm FDA results or form a basis for discussion
of FDA findings.
When an FDA investigator collects samples he/she will issue a
form FDA 484, Receipt for Samples. Where indicated, interstate
movement of the shipments from which these samples were taken
will be documented by the investigator with copies of shipping
records. The investigator will then prepare an affidavit (forms
FDA 463a, 463, 1664a or 1664b) referencing these documents. A
responsible employee of the manufacturer will be asked to read
the affidavit, identify inaccuracies for correction, and to verify,
by signature and/or initials, that the documents referenced in
the affidavit pertain to the shipment(s) in question. This action
is to formally document interstate receipt or distribution of
medical devices. Therefore, the manufacturer should include in
its inspection procedure the company policy on the reading and
signing of affidavits. Refusal to sign an affidavit is usually
noted on the affidavit and in the EIR.
Having accurate and complete knowledge of what an investigator
has done is an important part of handling an FDA inspection. Good
notes record this information. Comments and suggestions made by
the investigator, unanswered questions, and promises should all
be recorded. General information on the areas of the plant the
investigator visited, to whom he spoke, etc., can help when commenting
on form FDA 483 items, making corrections to the facilities or
QA system, or advising top management of the results of an inspection.
Notes will also be useful in fulfilling promises or obtaining
answers to previously unanswered questions. When the items on
the FDA 483 are presented, accurate notes help to prevent surprises.
Good notes can also help to prepare well thought out and adequate
answers to FDA 483 items even before these items are presented
at the close-out meeting.
Close-out Meeting
At the end of an FDA inspection, the investigator conducts a close-out
meeting. It is usually held immediately after the inspection,
but may take place a day or so later, especially if it takes a
long time to prepare form FDA 483. During this meeting, the investigator
discusses with company management the observations recorded on
form the FDA 483 and other observations not listed that the Investigator
wishes to bring to management's attention. The manufacturer should
compare the form FDA 483 against notes taken during the inspection
to confirm the accuracy and completeness of the investigator's
recorded observations. Close-out meetings present an opportunity
for all parties to correct such misunderstandings. Inaccurate
observations will be changed or deleted as appropriate. Top management
should be present at the close-out meeting to provide information
regarding any planned corrective actions to be taken and schedules
for these actions.
The investigator should be reminded of any corrections that have
been made. Corrections that have been made during the inspection
will be documented in the investigator's establishment inspection
report (EIR) if verified by the investigator if time allows, but
these observations will still appear on the FDA 483. Mention your
plans to make corrections, and provide a timetable for these future
actions. Answers given at this meeting will be recorded by the
investigator.
Again, it is important that the company individual promising corrections
and setting timetables have the authority to do so. Future inspections
will cover those areas where correction was promised as well as
other appropriate areas.
After the Inspection
Completion of the inspection by FDA should signal the start of
certain activities by the manufacturer, if these activities have
not already been initiated, such as discussion of deficiencies
with appropriate department employees to advise them of corrections
to be made and time frames involved.
Unresolved form FDA 483 items should be reviewed by company technical
and legal personnel. If a decision is made that corrective action
is not needed and there is disagreement with the investigator's
opinion regarding the deficiency, state this, along with the rationale
and documentary evidence, in a letter to the FDA District Office
responsible for the inspection. Even if a manufacturer agrees
with all the items on the FDA 483, it is a good idea to respond
to each item in a letter, along with documentation showing how
the corrections have been implemented, to the District Office.
The response to the FDA 483 observations should include system
corrections and not just "band-aiding" the specific
observations. It is very important that the root cause is investigated,
where it can be determined, corrected and that appropriate preventive
actions take place. This reply shows a commitment to quality assurance
and "officially" presents the company's case to FDA.
This reply should help resolve any doubts that the inspection
report might raise about a manufacturer.
The final step for a manufacturer is to determine what can be
learned from the inspection, so that the business can operate
in a better state of control, improve quality assurance, and assure
future QS compliance.
The following is a concise summary of the major points made in
this chapter. This summary should help the manufacturer formulate
an inspection plan.
BASIC POINTS
FOR AN INSPECTION PLAN
1. Be prepared for the eventual inspection by trying diligently to comply with applicable medical device regulations and preparing an inspection plan. If needed, assistance is available from DSMA, Phone 800�8�41 and other offices of the Center for Devices and Radiological Health.
Note: DSMA and CDRH can not provide assistance during an
FDA inspection by the District office, nor can DSMA provide assistance
during an ongoing FDA regulatory action.
2. Receptionists should know who to call when an FDA investigator
visits.
3. Determine that an FDA investigator is calling by examining
his/her credentials.
4. Receptionists or initial contact persons should inform all
key employees that an FDA investigator is present.
5. Someone, but not a large number of individuals, should accompany
the investigator and be with the investigator at all times.
6. If the investigator is not familiar with the manufacturer,
describe the product line and operations before entering the manufacturing
area.
7. At the beginning, review with the investigator all company
policies and programs.
8. Employees should be cooperative and seek to avoid conflict.
Base discussions on the laws, regulations, guidances, etc.
9. Don't start an argument with, get up-tight with, or lie to
the FDA investigator.
10. Understand the investigator's questions before answering.
If needed, ask for an explanation. Refer each question to the
most suitable employee.
11. Be sensitive to the compliance role of the FDA investigator;
do not threaten to call his/her supervisor when the investigator
is doing his/her job.
12. Deviations noted by the investigator should be corrected as
soon as possible.
13. Keep duplicate copies or samples of material given to the
FDA investigator.
14. During the exit interview, make sure that all deviations are
adequately discussed. If there is disagreement, present all of
the company information and any regulations and official interpretations
that support the company=s viewpoint.
15. Immediately submit to the local FDA District office a written
reply to the FDA 483. Make sure you address all of the observations.
State how and when you expect to make corrections. If you disagree
with an observation, give reasons and references to regulations,
guidances, etc., for your position.
16. Be reasonable in setting schedules for corrective actions
-- don't state impossible deadlines or drag out completion schedules.
17. A follow-up report covering findings and corrections should
be distributed to appropriate company employees.
Responsible officials, who are in positions of authority at regulated
manufacturing sites, have a primary legal duty to implement whatever
measures are necessary to ensure that their products, facilities,
and operations are in compliance with the law. The law presumes
these individuals are fully aware of their responsibilities.
Whenever FDA determines, as a result of an inspection, investigation,
complaint, or other source, that a product is, or may become,
adulterated or misbranded, several actions may be taken. These
actions may be in the form of a warning letter to the manufacturer;
or result in the seizure or detention of a product; or an injunction
of the firm and/or responsible individuals; or result in prosecution
of the manufacturer and/or responsible individuals. The actions
vary depending on the degree of danger to the public or willingness
of the manufacturer to correct violations. [Following are several
sections of the Food, Drug, and Cosmetic (FD&C) Act commonly
used in misbranding or adulteration charges. In this reprint,
some key words are bolded for emphasis. Added notes are in brackets.]
Adulteration
Section 501 (351). A drug or device shall be deemed to be adulterated --
(a)(1) If it consists in whole or in part of any filthy, putrid,
or decomposed substance; or
(2)(A) If it has been prepared, packed, or held under insanitary
conditions whereby it may have been contaminated with filth, or
whereby it may have been rendered injurious to health;
(c) If it is not subject to the provisions of paragraph 9(b) of
this section* and its strength differs from, or its purity or
quality falls below, that which it purports or is represented
to possess.
[* Paragraph 9(b) refers to drugs].
(h) If it is a device and the methods used in, or the facilities
or controls used for its manufacture, packing, storage, or installation
are not in conformity with applicable requirements under Section
520(f)(l) or an applicable condition prescribed by an order under
Section 520(f)(2).
Misbranding
Section 502 (352). A drug or device shall be deemed to be misbranded
--
(a) If its labeling is false or misleading in any particular.
If in a package form unless it bears a label containing (1) the
name and place of business of the manufacturer, packer, or distributor;
and (2) an accurate statement of the quantity of the contents
in terms of weight, measure, or numerical count ...
(f) Unless its labeling bears (1) adequate direction for use;
and (2) such adequate warnings against use in those pathological
conditions or by children where its use may be dangerous to health,
or against unsafe dosage or methods of duration of administration
or application, in such manner and form, as are necessary for
the protection of users ...
(j) If it is dangerous to health when used in the dosage or manner,
or with the frequency or duration prescribed, recommended, or
suggested in the labeling thereof.
A device may be considered misbranded for other administrative
reasons such as failure of the manufacturer to register, formally
list the product, or failure to submit a premarket notification
(21 CFR Part 807).
When it is consistent with the public interest, it is FDA's policy
to: advise regulated manufacturers of potentially violative products,
practices, or conditions; advise manufacturers of violations requiring
correction; and, give manufacturers an opportunity to make corrections
voluntarily before initiating legal or administrative action.
Management Letter
When top management is not present during the issuance of the FDA 483 at the end of the inspection,
FDA may send a Management Letter to top management such as the
president, CEO, etc., to assure that top management has a copy
of the FDA 483. Because the Management Letter is only a brief
transmittal letter, it is not to be considered or confused with
the Warning Letter described below.
It is imperative that the manufacturer respond to any recommendations
or observations made by the FDA investigator or other official.
A written response to the FDA 483, along with documentation to
show how the manufacturer has or intends to remove or correct
the objectionable conditions or practices, can assure the FDA
that the manufacturer has corrected or intends to correct listed
violations. The manufacturer should prepare such a response even
if they do not hear from FDA in writing. To repeat, a plan of
corrective action is very important. Management should evaluate
the FDA 483 and their management letter. If they feel any misunderstanding
can be resolved by discussion, they may also request a meeting
with district management to discuss violations and the manufacturer's
proposed courses of action. This approach gives a first hand opportunity
to present the case to FDA.
Warning Letter
A Warning Letter is a specifically worded and formatted enforcement
letter written by top management of an FDA field or headquarters
unit to top management of a manufacturer. The letter is sent by
FDA primarily to draw the company's attention to violations and,
thereby, obtain prompt correction. A Warning Letter is intended
to effect correction of deficiencies noted: during an inspection;
from an investigation of a product complaint; or from information
received from other sources. A purged Warning Letter is reprinted
at the end of this chapter.
A Warning Letter may be issued by FDA instead of immediately seizing
product or obtaining an injunction against the manufacturer. The
Warning Letter contains a formal warning to the manufacturer advising
that specific sections of the law have been violated and, unless
corrective action is taken, the FDA is prepared to impose legal
and/or administrative sanctions. Sanctions include seizure, prosecution,
injunction, and civil penalties. Unless otherwise indicated, within
15 working days after receiving a Warning Letter, a formal response
should be made by the manufacturer to FDA. The manufacturer should
state the specific steps it has taken to correct noted violations,
including an explanation of each step taken to prevent the recurrence
of similar violations. If corrective action cannot be completed
within 15 working days, state the reason for the delay and the
time within which the corrections will be completed.
A Warning Letter is also a prior warning and notification to responsible
company officials of possible civil or criminal action to be taken
by FDA.
Responsible individuals should not assume they will always receive
a Warning Letter before FDA initiates administrative action or
recommends an injunction, seizure, civil penalty, and/or criminal
proceeding. FDA is under no legal obligation to warn manufacturers
or individuals that they or their products are in violation of
the law, before initiating formal regulatory action.
Remember, the issuance of a Warning Letter to the manufacturer
by FDA does not preclude the initiation of other concurrent action,
such as seizure, as part of an overall enforcement strategy.
Seizure
A seizure is a civil court action against a specific quantity
of goods whereby FDA seeks to remove these goods from commercial
channels. After seizure, no one may tamper with the seized goods
except by permission of the court. The claimant of the seized
merchandise may file a claim and an answer, or may take no action.
If no action is taken,the government will move to have the goods
forfeited to the government by default. If a claimant decides
to contest the Government's charges, the case will be scheduled
for trial. A third option allows the owner of the goods to request
permission of the court to bring the goods into compliance with
the law. The owner of the goods is required to provide a bond
(money deposit) to assure that the orders of the Court will be
performed and the owner will be ordered to pay for FDA supervision
of any activities by the company to bring the goods into compliance.
Detention
An administrative detention prohibits the distribution or use
of adulterated or misbranded devices encountered during inspections.
The detention usually lasts up to 30 days, and can last longer,
until FDA has considered what action it should take concerning
the devices, or has initiated legal action if appropriate. During
the detention, detained devices may not be used, moved, altered,
or tampered with in any manner by any person.
Restraining Orders and Injunctions
A Temporary Restraining Order (TRO) is sought by FDA before an
injunction and is designed to stop the alleged violative practice
until the court can hear evidence that may lead to an injunction.
A TRO imposes restraint upon a defendant for not more than 10
days; this period may be extended by the courts.
An injunction is a court order that restrains a person or manufacturer
from violating the law, e.g., to prevent interstate distribution
of violative products, and to correct conditions in the establishment
in which the violation occurred. FDA may also seek a preliminary
injunction. To obtain this preliminary form of relief, the government
needs only to show that the law has been violated, and that it
will probably continue to be violated unless the court enjoins
the violative behavior.
Recalls
The Food and Drug Administration prefers to promote compliance
by means other than through the courts. Recall by the manufacturer
of violative products from the market is generally the fastest
and most effective way to protect the public. A recall may be
initiated by the manufacturer or shipper of the product, or initiated
by FDA. The first step in a product recall is for the manufacturer
or distributor to contact the nearest FDA field office for guidance.
FDA can provide technical assistance to small and large manufacturers
on how to conduct an effective recall.
It is recommended that manufacturers develop plans which can be
put into effect immediately if a recall emergency arises. Accurate
and complete product and shipping records are vital to the success
of a product recall. Products should be labeled (direct or by
code) to show date and place of manufacture.
Recently, FDA has observed that when a manufacturer discovers
a risk presented by a medical device, it often voluntarily notifies
appropriate persons of this risk in order to reduce or eliminate
it. In some cases these notifications meet the definition of recall
in 21 CFR Part 7.3(g). There is a proposed rule 21 CFR 810 issued
on June 14, 1994, that would establish procedures to implement
the medical device recall authority provided in the SMDA. This
authority will add to other remedies already available to FDA
including rectification, repair, replacement, and refund.
Because of concern that a notification might be classified as
a recall, manufacturers have sometimes delayed issuing a notification
while discussions are held with FDA. To try to eliminate delays
in situations where public health might be at risk, FDA published,
"Medical Device Notification and Voluntary Safety Alert Guideline,"
in March 1984, which contains procedures that manufacturers should
use in notifying or alerting health professionals who prescribe
or use a medical device. These procedures also describe the steps
used by FDA in the notification and safety alert process.
Penalties
FDA has authority to impose civil penalties. Manufacturers are
liable for a maximum of $15,000 per violation of the FD&C
Act, with a cap of $1,000,000 per proceeding. See Section 303
of the FD&C Act for details of additional penalties. Also,
see the Safe Medical Devices Act of 1990 for more details on FDA's
authority to impose penalties.
Associated with inspections are various FDA forms. Examples of
forms are included at the end of this chapter. The form (FDA)
numbers are in the lower left corner of each sheet.
Notice of Inspection
The first form is the FDA 482 (Notice of Inspection) which is
issued at the beginning of the inspection. It includes blanks
for basic information on the manufacturer, the investigator's
name, and contains a reprint of applicable sections of the FD&C
Act and Public Health Service Act. This form is to be signed by
the investigator and given to the individual noted on the form.
Receipt for Samples (page 18-14)
If an investigator collects samples, form FDA 484 (Receipt for
Samples) is issued to the company agent. A copy of the receipt
needs to be submitted with the firm's invoice or other billing
documents if payment has been agreed to by the firm and the FDA
Investigator. This form contains the name of the individual given
the form, manufacturer information, and sample description. The
investigator signs the form and issues it to the individual noted
on the form.
Affidavits (pages 18-15 to 18-18)
The next four forms are used where interstate movement of devices
is documented by collection of shipping records. The investigator
prepares an affidavit (forms FDA 463a, 1664a, or 1664b) referencing
these shipping records. A brief statement is included along with
space for a description of the documents that relate to the interstate
movement of the sample in question. Each form is signed by the
investigator and the person giving the information. On one of
the sample forms, FDA 463a, the individual giving the information
refused to sign the affidavit; and in this case the investigator
added a statement to explain the lack of a signature.
List of Observations (page 18-19)
During an inspection, an investigator will note what is considered
to be GMP deviations, or deviations from a manufacturer's established
procedures. These observations comprise the form FDA 483 (List
of Observations) which is issued to the company. The observations
are listed in the large blank area of the form, and the form is
signed by the investigator. (Page 18-19)
Establishment Inspection Report (pages 18-20 to 18-34)
The final example is the "Establishment Inspection Report".
After completion of an inspection, an investigator prepares a
comprehensive EIR covering a manufacturer's operations, items
on the FDA 483, plus the details that support the FDA 483, and
any corrective actions taken by the manufacturer. A manufacturer
may receive an unpurged copy of their EIR report under the Freedom
of Information (FOI) Act by requesting it in writing from their
local FDA District Office. Copies of EIR's requested through FOI
by other than the inspected manufacturer will be purged of confidential
or trade secret information. The fictitious sample EIR near the
end of this chapter has certain lines highlighted to simulate
purging. The normally purged material is left in the simulated
EIR to show the type of information that would be purged.
Warning Letter (pages 18-35 & 18-36)
ESTABLISHMENT REPORT (EIR) PURGED
SUMMARY OF FINDINGS
This inspection was conducted in accordance with the NYK-DO June
1986 Workplan, under CP 7378.830 Inspection of Medical Device
Manufacturers, and under CP 7378.830A Sterilization of Medical
Devices. This inspections was also conducted to follow up medical
device complaint M-00210, dated 5/31/84, re: leaking of a Cardio-Minipor
IV Filter (no specific lot number).
This firm produces various sterile disposable blood filters and
cardiovascular catheters. This inspection was limited to the firm's
sterile blood filter which is intended for extracorporeal use
as indicated during any cardiopulmonary bypass procedure (open
heart surgery). This product is currently classified as a noncritical
device.
Previous inspection 6/82 was performed as a follow up to PHI-DO
memo 4/2/82 (J.L. Smith) requesting information on validation
studies, and the firm's controls for testing for sterility and
ETO residues. PHI-DO=s inspection of a contract
sterilizer, Minix Lab, Erie, PA, revealed the
firm had no validation study and that the firm failed to follow
its own established ETO process parameters. NYK-DO=s
6/82 inspection revealed that sterility testing and controls were
adequate, that an ETO residue study had been
conducted and that the firm was conducting a validation study.
No FD 483 was issued, and no samples were collected.
Next previous inspection, 12/20/81, was conducted as a follow
up of two medical device problem reports, M32012 and M32190, both
concerning leakage during use of the firm's IV filter. Inspection
revealed that the product probably failed due to its being used
as pressures in excess of 600 mm Hg, as filters from the same
lot passed this specification upon retesting. No FD 483 was issued.
The current inspection revealed some deficiencies in the firm's
master device record for the blood filters. No other deficiencies
were noted. The deficiencies were listed on an FD 483, which was
presented to and discussed with management at the close of the
inspection. Deficiencies noted in the master device record are:
1. it does not list acceptance criteria for incoming components;
2. it does not list that components made of plastic are to receive
an IR spectrographic analysis;
3. it does not list that the cellulose acetate
filtering material is about 120 mesh, nor does
it list the quantity of this material that is used to manufacturer
blood filters;
4. the operation sheets have not been signed by all approving
officials;
5. the engineering diagrams for the housing, and top end cap do
not bear the signature/initials of an approving corporate official.
Management promised correction of the noted deficiencies, and
stated that they had already attended to the first point (Ex.
8). No samples were collected during this inspection.
Investigation of complaint M-00210 revealed that the IV filter
had probably been subjected to pressures in excess of 600 mm mercury.
The product is labeled for use below 600 mm mercury.
Current inspection also revealed that the firm intends to discontinue
using Minix Lab as the contract sterilizer. The
firm intends to develop/perform its own ETO sterilization
procedures within the next year.
On 6/7 to 9/84, I was accompanied by John Goodguy. Mr. Goodguy
represents the Center for Devices and Radiological Health, Division
of Small Manufacturers Assistance. Mr. Goodguy wanted to become
familiar with the way FDA field offices were conducting medical
device inspections. Mr. Goodguy=s tight schedule did not permit
him to accompany me for the complete inspection.
HISTORY OF BUSINESS
The firm is a New York State corporation with the following corporate
officers:
| Mrs. Alice B. Potts | Chairman of the Board |
| Mr. John (NMI) Fogg | President |
| Mr. William L. Pearl | Senior Vice President |
| Mr. Walter Y. Ratkowski | Vice President and General Manager |
Cardio-Medical Products, Inc. is a wholly owned subsidiary of
Medical Products USA, Inc. and both firms occupy the same premises.
The corporate officers of Medical Products USA, Inc. are:
| Dr. Michael P. Heart | Chairman of the Board |
| Mrs. Alice B. Potts | President |
| Dr. Mary L. Day | Executive Vice President |
| Mr. John (NMI) Fogg | Senior Vice President |
Filters are manufacturers under the Cardio Minipor trade name
and in general are intended for hospital use. The firm manufacturers
four types of filters, as follows:
1. Blood Dialysis Filters
2. Cardiopulmonary Bypass Blood Filters
3. Infusion Line Filter
4. IV Filter
The firm operates 3 shifts (24 hours per day) Mon.-Fri., except
for two weeks around Christmas. The firm also closes for two weeks
in July for major cleaning operations. The firm is currently registered
as a medical device establishment.
PERSONS INTERVIEWED AND INDIVIDUAL RESPONSIBILITY
At the start of the inspection credentials were shown and an FD
482, Notice of Inspection, was issued to Mr. John (NMI) Fogg,
President. Credentials were also shown to Dr. Paul M. Turner,
Ph.D., Quality Assurance manager, and to Mr. Thomas (NMI) Romano,
Quality Control Manager.
During this inspection, I was also introduced to: William L. Pearl,
Senior Vice President; Walter Y. Ratkowski, Vice President and
General Manager; Charles Miller, Asst. QC Manager; Alice Oprice,
QA Technical Assistance; Joseph DiRisio, Metrologist; Harold Miller,
Operations Manager; and Katherine Anderson, Materials Manager.
Mr. Fogg and/or Dr. Turner accompanied me during most of the inspection
and supplied most of the relevant information. Some relevant information
was also supplied by the above named individuals.
At the close of the inspection and FD 483, Inspectional Observations,
was issued to and discussed with Mr. Jonn (NMI) Fogg, President.
Key officers/plant personnel are as follows:
| John (NMI) Fogg | President |
| William L. Pearl | Senior Vice President |
| Walter Y. Ratkowski | Vice President and General Manager |
| Dr. Paul M. Turner | Quality Assurance Manager |
| Thomas (NMI) Romano | Quality Control Manager |
| Charles Miller | Asst. Quality Control Manager |
| Harold Miller (brother) | Operations Manager |
| Joseph DiRisio | Metrologist |
| John Dace | Vice President |
Mr. John Fogg stated he was the firm's president and chief executive
officer, and bore overall responsibility and authority for the
firm's activities (see Ex. 1, pg. 4). Mr. Fogg stated that he
could authorize capital expenditures on his own authority, and
that he did not have to obtain authorization from any official
of the parent firm before making a capital expenditure. Mr. Fogg
stated he was responsible for authorizing research and development
programs, marketing programs, allocation of space, new construction,
plant maintenance, acquisition of capital equipment, labeling
changes, and for authorizing any studies such as validation studies,
bioburden studies, and residue studies.
Mr. Fogg stated that William L. Pearl, Sr. VP, was responsible
to him for engineering; that Dr. Paul M. Turner, QA Manager, was
responsible to him for the QA program; that Thomas Romano, QC
Manager, was responsible to him for the routine review and approval
of device history records and for the release of lots from quarantine;
that Harold Miller, Operations Manager, was responsible to him
for production and warehouse activities; and that Walter Ratkowski,
VP and General Manager, was responsible to him for sales and marketing
operations. Mr. Fogg stated he has a BS in Chemistry from Furman
University, Greenwich, South Carolina, has been with
the firm since 1962, and has been president for about the last
eight years.
During the inspection Mr. Fogg directed various employees, such
as Dr. Turner, Mr. Romano, Mr. Harold Miller, and Ms. Oprice to
provide me with requested information. These requests for information
were honored by the various employees.
William L. Pearl, Sr. VP, stated he was responsible to John Fogg
for engineering. These responsibilities include reviewing and
approving engineering diagrams, research and development projects
for new equipment and new products, and performing major equipment
overhauls. Mr. Pearl has been with the firm since 1969 and has
a BS in Mechanical Engineering from Duke University, Durham,
North Carolina.
Walter Y. Ratkowski, VP and General manager, is responsible for
sales and marketing operations to John Fogg. As a follow up to
a product occurrence report (complain) Mr. Ratkowski is responsible
for determining if and when complimentary replacement units are
to be sent out. Mr. Ratkowski has a BS in Chemical Engineering
from the University of Toronto and has been with
the firm since 1968.
Paul M. Turner, QA manager, stated he was responsible to John
Fogg for the quality assurance program of Cardio-Medical Products,
Inc. These responsibilities include the periodic auditing of production,
lab quality control, and metrology procedures, implementing studies
authorized by Mr. Fogg, and ensuring that the firm meets its regulatory
responsibilities and complies with GMP regulations. Dr. Turner
stated that it was his responsibility to prepare and submit 510(k)s
to the FDA. Dr. Turner has his Ph.D. in Chemistry from Western
Michigan University, Kalamazoo, Michigan and has been
with the firm since 1976.
Thomas Romano, QC Manager, stated he is responsible to Mr. Fogg
for renewing and approving device history records to determine
if a lot of finished filters can be released from quarantine and
entered into inventory, for the inspection and approval of incoming
components, for the activities and records of the QC labs in performing
tests on incoming components, in process products, environmental
plates, bioburden, and pyrogen.
Mr. Romano stated he coordinates complaint investigations by reviewing
complaints and deciding which department(s) will be responsible
for investigating the complaint, and is responsible for sending
out responses to complaints when necessary. Mr. Romano stated
that Mr. Charles Miller, Asst. QC Manager, assists him in his
duties. Mr. Miller is also responsible for maintaining the firm's
reserve samples, which are used for stability study purposes only.
Mr. Romano has his BS in Chemistry from Wright State,
Dayton, Ohio and has been with the firm since 1978. Mr.
Charles Miller has his BS in Biology from Yale University,
New Haven, Connecticut and has been with the firm since
1977.
Joseph DiRisio, QA Metrologist, stated he was responsible to Dr.
Turner for all of the firm's metrology (measurement and calibration)
functions, and that he originated the firm's metrology manual
(Ex. 4). Mr. DiRisio stated he was formerly the metrologist for
American Armature Co., Cleveland Ohio and that
he has been with the firm since 1976.
Harold Miller, Operations Manager, stated he was responsible to
John Fogg for production and warehouse operations. Mr. Miller
is also responsible for ordering raw materials and for routine
maintenance and clean up operations. Mr. Miller has his BS in
Mathematics from New York University and has
his MS in Industrial Engineering from Columbia University,
New York, New York and has been with the firm since 1979.
GUARANTEES AND LABELING AGREEMENTS
The firm does not offer and FD&C guarantees. Dr. Turner stated
that the firm does have agreements with some of their component
suppliers whereby suppliers have agreed to notify Cardio-Medical
of any changes in components. testing or procedures related to
the manufacture of the components. Dr. Turner provided me with
copies of these agreements (Ex. 10). These agreements appear to
satisfy the GMP regulation re: critical component supplier agreements,
although the firm is not required to have these agreements as
the device is currently classified as a non-critical device. The
firm also ships some filters in bulk to overseas divisions/subsidiaries
of Cardio-Medical Products, Inc. without the need of a labeling
agreement.
FIRM'S TRAINING PROGRAM
The firm's training program for production employees consists
of on-the-job training and lectures. Mr. Fogg stated that any
formal training given to employees is documented and recorded
in the employee=s personnel file. I requested Mr. Fogg to remove
the documentation of Mr. Joseph DiRisio=s training from his personnel
file for my review. Training was adequately documented.
RAW MATERIALS
Raw materials and components used to manufacture the firm's blood
filters include:
| Materials | Suppliers |
Components used to manufacture the firm's filters are listed in
Ex. 6 Suppliers' addresses are listed in Ex. 7.
Components are stored in the firm's warehouse, located down the block at 2700 Ogden Street. Incoming components are stored in a chaged quarantine area in the warehouse. When components are inspected and found to be acceptable, cartons containing the components are each ink stamped AACCEPTED.@ The firm does not use the system of designating quarantined components with a AQUARANTINE@ stamp of sticker, and then subsequently identifying the component as AACCEPTED@ or AREJECTED.@
Mr. Fogg stated that Quality Control inspectors inspect incoming components for characteristics as specified in the master device record. Ex. 8 is an example of the characteristics for some of the blood filter components listed in the master record. Though QC inspects components for these characteristics, no pass-fail specifications were noted during the inspection. This was pointed out to Mr. Fogg and Dr. Turner. By the conclusion of the inspection, Mr. Romano had drafted up such a specification, as is shown on Page 1 of Ex. 8.
All incoming components are assigned a control number, which reflects
the purchase order number (P.O.#). For example, if P.O.#23466
is for 200 cartons of filtermesh and the order is received from
the supplier in several shipments, then the cartons in the first
shipment will be identified with control number 23466-1, and the
cartons in the second shipment will be identified 23466-2, and
so on until all the cartons shipped under this purchase order
are received. This information is recorded manually as well as
fed into the firm's computer. The computer is used for inventory
control and facilitates the firm's first-in, first-out policy.
Mr. Romano described the components inspection procedure. Components
are inspected for the characteristics specified in the deice master
record (see Ex. 8) which requires that 10% of the log, up to 1,000
units, be inspected. A QC inspector can accept the lot if he finds
no defective units; otherwise a deficient lot will have to be
approved by the firm's Materials Review Board (William Pearl,
John Fogg, and Thomas Romano).
During the inspection a QC Inspector was noted to be inspecting
an incoming lot of housing units for the blood filter. Upon questioning,
the inspector stated that he checks the housing units using a
B&L 200X stereoscopic microscope and standardized
micrometer. The inspector stated he checked
each sampled unit for burro and sharp edges using the microscope.
The micrometer was used to check the wall thickness of the housing.
The tolerance spec for the wall thickness was 0.01 cm.
Using one of several microscopes, the firm's QC lab checks the
cellulose acetate filtering material for mesh
count of every lot of mesh received, and records the results of
the inspection in a log book. This log book cross-references the
purchase order number of the lot.
OPERATIONS
The firm occupies a two story building in a light industrial area:
the first floor is mainly for plant operations and the second
floor is mainly for office space. As previously stated, the premises
are shared between Cardio-Medical Products, Inc. and Medical Products
USA. Cardio-Medical Products has 65 employees, working three shifts
Mon.-Fri. The firm is closed for two weeks around Christmas and
In July. The firm has a warehouse at 2700 Ogden Street which is
used to store raw materials and finished products. Finished products
ready for ETO sterilization are shipped to the contract sterilizer
via company trucks. Finished products ready for distribution to
consignees are usually shipped via UPS.
Mr. Fogg estimated that his firm manufactured about 10,000
blood filters last year, of which about 3,000
were used for arterial use, and about 7,000 were
used for cardionomy use. Blood filters are manufactured to be
compatible with either 2 inch or 1 inch connectors. The bulk of
the firm's blood filters are manufactured with 2 inch connectors.
The manufacturing operations are listed and described in the master
device record=s AOPERATION SHEETS.@ Ex. 11 is an example of some
of the AOPERATION SHEETS.@ In essence, the manufacturing process
consists of the following operations:
1. Molding of plastic parts. Appropriate quantities of
virgin resin (60%) and regrind resin (20%) are selected and weighed.
Red #12 is added and the material is mixed.
2. The above mixture is dated and given a lot number and
placed into a sized tumbling device (Rich Hopper) for blending
for 6 hours.
3. Prior to using the molding, machine is purged of any
previous materials. A mixture of mold release agents is used.
This is forced thru the system using air at 50 PSI.
4. After flushing with mold release agents, the system
is lubricated using a glycerin lubricant manufactured by Sigma
Labs, Miami, Florida.
5. The molding machine is set up using the appropriate
mold. The firm has 4 different molds. Two molds are used for the
arterial filter, one for 1 inch connectors and one for 2 inch
connectors. The other 2 are for cardionomy filters, again 1 for
1 inch and the other for 2 for 2 inch connectors.
6. When the plastic parts have been molded, the cellulose
acetate filtering material must be inserted. This is done by a
special machine which places one layer of material on top of another.
The completed filter has a total of 60 layers for the arterial
model and 75 for the cardionomy model.
7. After the cellulose acetate has been inserted into
the filter, the end cap is placed on the open end and bonded using
a bonding epoxy. This operation is performed using a specially
designed capping machine. Epoxy is applied to the cap at one state
of the machine operation, then the cap is inserted into the body
of the filter. The machine then twists the cap into place.
8. Once the cap and body have been applied, the polyurethane
tubing is attached to either end of the filter. The tubing is
received in a large spool and cut to the properlength using a
Ronfro tube cutter model 54.
9. The finished filter is then placed into its metal housing
and then into polypropalene bags which are sealed using a Smith
#2 heat sealing machine. The bags are then loaded into cartons,
10 filters to a carton for shipment to the contract sterilizer.
Each carton is labeled as Acaution, this product has not yet undergone
sterilization@.
10. When the sterilized product is returned, samples are
removed and the cartons placed in a quarantine area. When the
results of the sterility test are received, the cartons are marked
Aapproved for packaging.@ The final step in the process is the
packaging of the filters into labeled cardboard unit packages.
This is accomplished using a Packo Packaging machine model #8245.
Once packaged, the product is stored in a quarantined area until
released for shipping.
Samples designated for testing are pulled by QC. The firm performs
its own Bubble Point SSP/NF testing of each lot
of filters prior to ETO sterilization. See Ex.
16 for USP/NF Bubble Point testing procedures
and Ex. 17, pages 20-22, for some Bubble Point
log book records. See Ex. 14 for bioburden testing procedures
and Ex. 17, pages 23 and 24, for LAL Pyrogen Testing
log book records.
Filters designated for sterility testing are held separate from
the rest of the lot until the lot is ready for shipment to the
contract sterilizer. Samples designated for pyrogen and safety
(toxicity) testing, by outside labs, area also pulled at this
time.
The firm's QC lab was noted to have on hand the Jones
Bubble Point Testing Apparatus to test the filters prior
to ETO sterilization. These were calibrated
at 0.001 ml. of air per cubic inch.
The firm also performs its own LAL pyrogen testing.
This pyrogen testing is performed on the IV filter only, as only
these filters have a Lewis Crenshaw filtering
media. All other filters have Wren media, which
are not as likely to support bacterial growth as Lewis
Crenshaw media. The firm's QC lab had Pyro Gen
Lab test serum and testing apparatus. Review of LAL
testing records going back 6 months revealed no positive results.
Charles Miller, Asst. QC Manager, stated that QC lab uses a 40%
alcohol solution as first a rinse on the filter, a 25% solution
as a second rinse to collect the solution used for pyrogen testing
and a 10 unit sample for each testing run.
The rest of the cartons in the lot are pelletized and the pallets
are completely wrapped with large sheets of cardboard and banded
with steel bands to discourage tampering. Each pallet is identified
with a Cardio-Medical sterilization lot number, which is a number
that can be correlated to the contract sterilizer=s sterilization
lot number. Each pallet is also identified with a contents statement,
indicating the product numbers, day lot numbers, and the number
of cartons of each lot contained on the pallet. A Cardio-Medical
truck will take up to 6 pallets of products to the contract sterilizer,
Minix Lab, Brie, PA about once a week. The filters
designated for testing by outside labs are shipped along with
the pallets to the contract sterilizer. Through contractual agreements
Cardio-Medical has notified the contract sterilizer of the desired
placement of the test samples within the sterilizer, as shown
in Ex. 20, Pg. 3. For each sterilization lot Cardio-Medical notifies
the contract sterilizer which samples are not to be sent to which
outside labs. A Cardio-Medical truck will pick up he lot after
it has been sterilized, and return it to the Cardio-Medical warehouse
at 2700 Ogden Street, where the lot is placed in quarantine until
the test results are returned and approved.
In the meantime, QC personnel will open up 6
cartons from each day lot of all the day lots in each sterilization
lot and inspect the plastic bags for any air leaks/burst bags.
If any air leaks/burst bags are found, then every carton in the
day lot is opened to determine how extensive the problem is. Leaks/burst
bags indicate either the bags were not sealed properly and/or
that the contract sterilizer pulled a vacuum larger than they
should have during the ETO sterilization cycle.
Lots found with the significant numbers of leaks/burst bags are
re-bagged and subjected again to ETO.
Once the QC Manager approves of the QC inspection tests and approves
of the outside testing lab results (sterility, pyrogen, and safety),
then he will sign the lot release report (Ex. 17, Pg. 1) which
permits the release of the lot from quarantine and entry into
inventory.
Mr. Charles Miller stated that he maintains the firm's reserve
samples which are collected 10 times a year and are used for shelf
life studies (see Ex. 22). No other reserve samples are taken.
Shelf life studies testing includes tests for Bubble Point,
Porosity and Sterility.
Regarding components and products rejected during processing,
Mr. Fogg stated that all rejects are discarded, rather than shipped
back to the supplier. Mr. Fogg stated that his firm preferred
to use only components made from polypropylene,
and that to avoid any of the problems associated with recycling,
his firm did not ship rejected components (rejected during processing)
back to the suppliers. Rejects are taken to the Smith
& Company incinerator about 5 times
a year for destruction. Mr. Fogg stated that his firm documented
these destructions, and showed me the records coving the most
recent destruction.
METROLOGY
Mr. Joseph DiRisio, QA Metrologist, stated he was responsible
to Dr. Paul Turner for all the firm's metrology (measurement and
calibration) operations. Mr. DiRisio stated he maintains the logs
and records that show when equipment was last serviced, who serviced
it, what the calibration errors are, if any, and when the next
service calibration is scheduled. Each piece of production and
testing equipment is assigned a unique number for calibration
record purposes. As can be seen in Ex. 4, the firm has primary
standards, for which calibration is recorded traceable to the
National Bureau of Standards (NBS). Primary standards consist
of transfer equipment such as weight sets, lengths, thermocouples
and digital multi meters. These standards are calibrated by Calibra
Metrologist, Inc. White Plains, New York. Mr. DiRisio
showed me the metrology manual and some of the records covering
the servicing and calibration of equipment. Inspection revealed
that the firm's laminar-flow hoods were serviced by Lami
Flow, Ltd. New York, New York and that the firm has records
to show that the hoods were serviced about every 6 months going
back to 12/76. The most recent service was in 2/84.
POROSITY STUDIES
The firm has an ongoing porosity study program.
Products from each day's production are tested for porosity
by the firm's QC lab. Ex. 17, pages 23 and 24, are examples of
the records for routine porosity testing. Mr.
Fogg and Dr. Turner stated that routine porosity
testing was a good QA procedure to establish a long term history
of their products, and was much more valid than a one shot porosity
study.
VALIDATION OF STERILIZATION
ETO sterilization has always been performed by
an outside contracted firm, Minix Labs, Erie, PA.
Mr. Fogg stated that Minix has never disclosed
its ETO sterilization cycle parameters, feeling
that such information was proprietary and that such information
would not be released unless Cardio-Medical agreed not to make
use of this information for its own purposes and agreed to release
this information to any firm that might make use of this trade
secret information. Mr. Fogg stated that Cardio-Medical was not
able to agree to such a proposal. As such, Cardio-Medical asked
Minix Labs, Erie, PA to conduct a validation
study using Cardio-Medical's parameters, on Cardio-Medical's newest
product, the IV fluid filter/air eliminator. This study is attached
as Ex. 20, and was conducted in 1978. Mr. Fogg stated that this
study determined that ten to the minus 6 kill
could be achieved in 14 hours using their parameters,
and that, as a safety feature Minix Labs has
been asked to sterilize Cardio-Medical's filters to the equivalence
of 16 hours of Cardio-Medical's ETO
sterilization parameters.
The sterilization validation study (Ex. 20) lists the parameters
of the sterilization cycle (Pg. 1), the configuration of the test
samples (Pg. 3), the protocol of the study (Pg. 1), the records
and results of the study (Pages 8-34) and other information.
Mr. Fogg stated that his firm intended to discontinue using this
contract sterilizer, and start using a sterilization procedure
of their own, in about 6 months. Mr. Fogg stated that the proposed
sterilization procedures would involve placing cartons of filters
into each 3x2x1 foot aluminum orib. The orib would then
be filled with 80% ETO, 20% mix. After 10 hours of exposure, the
cartons would be removed from the orib and routed to the holding
room for 24 hours. Mr. Fogg stated that his firm has
been consulting with Steri Consultant, Inc and
would be consulting with FDA=s Dr. Bruch re this proposed ETO
sterilization procedure, and methods to validate this procedure.
DEVICE HISTORY RECORDS
Device history records are maintained by sequential Cardio-Medical
sterilization lot numbers. During this inspection, the most recently
completed device history record available for review was for sterilization
lot #340, for which the lot release report was signed on 5/29/84.
Sterilization lot #340 contains the records for 26 lots (Aday
lots@) of blood filters (see Pg. 17 of Ex. 17). Day lot #00441
was randomly picked as the device who=s record I would review.
Ex. 17 consists of most of the device history records relevant
to sterilization lot #340, day lot #00441, which consists of records
as follows:
PAGE SUBJECT
1 Lot release report
2-4 Component Materials Record - lists the lot numbers of the
components used in day lot #00441
5-13 Operation Cards - shows the who, what, when, and how many
of each manufacturing step; and that the lot was divided into
9 tote boxes for easy handling
14-15 Forms Traceability
16 Inspection of Vacuum Bag Integrity
17 Material Movement Report - shows which pallet day lot #00441
was placed on, out of 4 pallets
18-19 In Process Testing Report - shows that day lot #00441 was
subject to porocity testing and USP/NF Bubble testing
as well as LAL Pyrogen testing. The firm's LAL
pyrogen testing procedure is described in Ex. 16.
20-22 QC Lab Book - shows the results of Bubble Point
testing
23-24 QC Lab Book - shows the results of LAL
testing
25 Transfer Receiving Report - lists the products and quantities
shipped to the contract sterilizer
26 QC Lab Book - shows the day lots of quantities which were designated
for sterility testing by Steri Consult, Inc., Boston,
MA and the day lots which were designated for pyrogen
and safety testing by Test All Ltd., Patterson, NJ
27 Letter, dated 5/1/84, directing Steri Consult, Inc.
to test for pyrogens and safety
28 Letter, dated 5/1/84, directing Steri Consult, Inc.
to test filters for sterility
29 Letter, dated 5/9/84, re: results of pyrogen testing
30 Letter, dated 5/12/84, re: results of safety and testing
31-32 Letter, dated 5/6/84, re: results of sterility testing
33 Final Inspection Record - inspection of lot after sterilization
DEVICE MASTER RECORD
During this inspection the firm's device master record for their
Minipor Blood Filter was reviewed. Review of this record revealed
that it contained, or referred to, almost all of the information
required by the device GMPs (device specifications, manufacturing
processes, quality assurance procedures, and packaging and labeling
information). Only some minor deficiencies were noted. These are
discussed under Objectionable Conditions. Information relevant
to the device master record is contained in Exhibits 6 thru 16.
OBJECTIONABLE CONDITIONS
During this inspection the only objectionable conditions noted
were some minor deficiencies in the device master record for the
Minipor Blood Filters. These deficiencies were listed on an FD
483, Inspectional Observations, which was presented to and discussed
with management at the close of the inspection.
Deficiencies noted were:
1. it does not list acceptance criteria for incoming components;
2. it does not list that components made of plastic are to receive
an I.R. spectrographic analysis;
3. it does not list that the cellulose acetate
filtering material is about 120 mesh, and it
does not list the quantity of this material used to manufacture
the blood filters;
4. the Operation Sheets have not been signed by all approving
officials (Ex. II); and
5. the engineering diagrams for the housing, and top end caps
do not bear the signature or initials of an approving corporate
official (Ex. 12).
No other objectionable conditions were noted during this inspections.
MANUFACTURING CODES
The firm uses two manufacturing codes: a day lot code and a sterilization
date code. The day lot code is a code that represents the date
the product was manufactured (assembled). For example: A00441"
means the 4th day of 1984, the 1st shift, where 004 if the fourth
day, 4 is 1984, and 1 is the first shift. The sterilization date
code AJan 30 1984" is self explanatory.
The day lot code is ink stamped on every box and every carton,
prior to EtO sterilization. The sterilization
date code is ink stamped on every carton after the lot returns
form Ethylene Oxide sterilization. The firm does
not have a policy of coding the actual filter nor of coding the
stick-on label applied to the filters.
CONSUMER COMPLAINTS
During this inspection the firm's consumer complaint file was
reviewed, and a follow up was made of Medical Device Complaint
M-00210 dated 5/31/84, which concerned leaking of Cardio Minipor
IV Filter (no lot number given). Mr. Fogg stated that his firm
had investigated this complaint and had determined that the hospital
did not normally use their filters, and that the nurse that had
registered the complaint was not familiar with its use. A company
representative visited the hospital and talked with the nurse
about the application of the IV filter.
Mr. Fogg stated that the filter was designed for use at pressures
under 600 mm of mercury, and that at above 600 mm of mercury the
filer would crack in such a way as to maintain the integrity of
solutions on the downstream side of the filter, and also prevent
any air bubbles form getting into the system. M-00210 is attached
as Exhibit 23, pages 5-8. The labeling for the IV filter specifically
states that the filter is not to be used at above 600 mm pressure
of mercury.
Review of the firm's complaint file revealed 10 complaints registered
since 12/78 (excluding the above complaint), which the firm has
assigned as number 91, 93, 94, 96, 97, 98, 100, 101, 102, and
103. Three complaints concerned Minipor blood filters, four complaints
concerned blood dialysis filters, and three complaints concerned
cardiovascular catheters concerning packaging defects, embedded
particulate matter, cracks and leaks.
Mr. Fogg stated that all complaints are evaluated and investigated.
Mr. Thomas Romano stated he evaluates all complaints to determine
which department(s) should investigate the complaint. If available,
sample of the subject lot are re-tested to determine if the complaint
can be duplicated. Complaints are evaluated to determine if the
complaint can be duplicated. Complaints are evaluated to determine
if changes in QC or production procedures are needed, and to see
if there are any patterns. Dr. Turner stated that during routine
production, lots are subject to 100% checks and to a statistical
check, in an effort to prevent any defects from leaving the plant.
Mr. Romano stated that copies of complaints and the investigations
are routinely routed to John Fogg, Dr. Paul Turner, and to William
Pearl.
PROMOTION & DISTRIBUTION
Mr. Fogg stated that the firm distributes its filters nationwide,
and overseas to Italy and Germany. Filters are sold to distributors
who, in turn, sell the filters to hospitals. The firm's service
representatives, both here and abroad, give lectures on the applications
and proper use of Cardio-Medical=s filters. Other promotion is
performed by salesmen who work for the distributors.
Mr. Fogg provided some recent shipments as follows:
Invoice - And Date | Consignee |
|
| B8925
3/14/84 |
| |
| B8845
3/2/84 |
| |
| B9045
3/28/84 |
| |
| B9051
3/29/84 |
| |
| B9054
3/30/84 |
| |
| B9055
2/29/84 |
| |
| B9058
3/30/84 |
| |
| B9069
4/2/84 |
| |
| B9076
4/2/84 | Cardio General Hospital
| |
| B9082
3/29/84 |
| |
| W8474
3/16/84 |
| |
| D21606
3/30/84 |
|
The above invoices are attached as Ex. 25. The invoices are noted
to reference the manufacturing (sterilization date. This date
is ink stamped on each carton (case). This coding and invoice
system will facilitate a recall, should one occur.
REFUSALS
There were no refusals during this inspection.
DISCUSSION WITH MANAGEMENT
At the close of the inspection, the FD 483, Inspection Observations,
was presented to and discussed with Mr. John (NMI) Fogg, President.
Dr. Paul M. Turner, Quality Assurance Manager, was also present
during this discussion. Inspectional observations concerned five
minor deficiencies in the device master record. Mr. Fogg stated
the point #1, acceptance criteria for components, had already
been corrected and gave me a copy of this document (see Ex. 8,
Pg. 1). Mr. Fogg stated that the other deficiencies were simply
oversights and could easily be corrected. No additional suggestions
were given. One comment was made, which was that the firm discuss
its proposed new EtO sterilization procedure
with someone in the Center for Devices and Radiological Health,
as this proposed procedure does not appear to have been commercially
use. Mr. Fogg stated he believed a number of hospitals and small
institutions were using this new EtO sterilization
procedure, but was not aware of any manufacturer using the procedure.
SAMPLES
There were no samples collected during this inspection.
EXHIBITS
1. QC Manual re: policy & organization
2. QA manager responsibilities
3. QC manager responsibilities
4. Metrology manual
5. Examples of calibration standards traceable to NBS
6. List of components used to manufacture filters
7. List of component suppliers
8. Component sampling and acceptance plan
9. Blood filter sampling & acceptance plan
10. Component supplier agreements
11. Device master record operation sheets
12. Device master record
13. Sterility assurance procedures
14. LAL test procedures
15. Environmental air sampling procedures
16. USP/NF bubble point testing procedures
17. Device history record, blood filter, lot #00401, released 3/29/80
18. EtO residue study, 1976 & 1980
19. Safety/Toxicity study, 1976
20. EtO sterilization validation study, 1980
21. Letter, 2/1/84, from Acme Sterilizers
22. Shelf life study plan, 1976
23. Consumer complaints
24. Medical device complaint M-00210, dated 5/31/84
25. Invoices of 12 recent shipments
26. List of devices manufactured
27. Labeling for blood filters
ATTACHMENTS
1. CP 7378.830 Systems analysis report
2. CP 7378.830A Sterile device compliance program pages 2-10 &
15-18
Thomas E. Cardamone
Investigator 800
New York District
MODEL WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
RESPONSIBLE INDIVIDUAL, TITLE
FIRM NAME
FIRM'S COMPLETE ADDRESS
Dear (Addressee) ,
During an inspection of your firm located in (City, State)
, on (dates) , our Investigator(s) determined that
your firm manufactures (type of device) . (Name of device)
are devices as defined by Section 201(h) of the Federal Food,
Drug, and Cosmetic Act (the Act).
The above-stated inspection revealed that these devices are adulterated
within the meaning of Section 501(h) of the Act, in that the methods
used in, or the facilities or controls used for manufacturing,
packing, storage, or installation are not in conformance with
the Good Manufacturing Practice (GMP) for Medical Devices Regulation,
as specified in Title 21, Code of Federal Regulations (CFR),
Part 820, as follows:
1. Failure to conduct planned and periodic audits of the quality
assurance program in accordance with written procedures. For example,
no audits of the quality assurance program have been performed
for at least 3 years.
2. Failure to investigate the failure of a device to meet performance specifications after a device has been released for distribution, and to make a written record of the investigation including conclusions and follow-up. For example, there are no records of failure investigations for Model ,
S/N , and Model , S/N , which were returned because they did not
operate properly.
3. Failure to maintain device history records for Model to demonstrate
that the devices are manufactured in accordance with the device
master record.
4. Failure to immediately review, evaluate and investigate any
complaint pertaining to injury, death, or any hazard to safety.
For example, there is no record of the investigation of a report
that a child's death associated with the use of Model at the Community
Medical Ctr. on/or about Feb. 8, 1991.
Additionally, the above stated inspection revealed that your devices are misbranded within the meaning of Section 502(t)(2) of the Act, in that your firm failed to submit information to the Food and Drug Administration as required by the Medical Device Reporting (MDR) Regulation, as specified in 21 CFR Part 803. Specifically, you failed to submit an MDR report to FDA after receiving information which reasonably suggested that one of your commercially distributed devices may have caused or contributed to a death. The February 8, 1991, incident report from the Community Medical Center in which a child standing in a crib fell over, caught his head in a AY@ formed by the crib rail and end post, and died, should have been reported as a death.
This letter is not intended to be an all-inclusive list of deficiencies
at your facility. It is your responsibility to ensure adherence
to each requirement of the Act and regulations. The specific violations
noted in this letter and in the FDA 483 issued at the closeout
of the inspection may be symptomatic of serious underlying problems
in your firm's manufacturing and quality assurance systems. You
are responsible for investigating and determining the causes of
the violations identified by the FDA. If the causes are determined
to be systems problems, you shall promptly initiate permanent
corrective actions.
Federal agencies are advised of the issuance of all Warning Letters
about devices so that they may take this information into account
when considering the award of contracts. Additionally, no premarket
submissions for devices to which the GMP deficiencies are reasonably
related will be cleared until the violations have been corrected.
Also, no requests for Certificates For Products For Export will
be approved until the violations related to the subject devices
have been corrected.
You should take prompt action to correct these deviations. Failure
to promptly correct these deviations may result in regulatory
action being initiated by the Food and Drug Administration without
further notice. These actions include, but are not limited to,
seizure, injunction, and/or civil penalties.
Please notify this office in writing within 15 working days of
receipt of this letter, of the specific steps you have taken to
correct the noted violations, including an explanation of each
step being taken to identify and make corrections to any underlying
systems problems necessary to assure that similar violations will
not recur. If corrective action cannot be completed within 15
working days, state the reason for the delay and the time within
which the corrections will be completed.
Your response should be sent to (Name) , Compliance Officer, Food and Drug Administration,
(City, State & Zip Code) .
Sincerely yours,
Updated 1/1/1997
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