18. Factory Inspections
AUTHORITY AND COVERAGE
Conduct During the Inspection
After the Inspection
BASIC POINTS FOR AN INSPECTION PLAN
Restraining Orders and Injunctions
Notice of Inspection
Receipt for Samples
List of Observations
Establishment Inspection Report
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.
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.
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.
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:
- to verify conditions in the factory;
- to establish interstate movement of finished devices and their components; or,
- to fulfill a request from FDA's Center for Devices and Radiological Health (CDRH).
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.
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.
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 8006382041 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.]
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).
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.
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.
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.
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.
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.
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.
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).
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|
|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 and components used to manufacture the firm's blood filters include:
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.
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
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:
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.
The above mixture is dated and given a lot number and placed into a sized tumbling device (Rich Hopper) for blending for 6 hours.
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.
After flushing with mold release agents, the system is lubricated using a glycerin lubricant manufactured by Sigma Labs, Miami, Florida.
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.
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.
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.
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.
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@.
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.
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.
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:
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
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.
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.
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.
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:
Cardio General Hospital
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.
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.
There were no samples collected during this inspection.
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
LAL test procedures
15. Environmental air sampling procedures
USP/NF bubble point testing procedures
17. Device history record, blood filter, lot #00401, released 3/29/80
EtO residue study, 1976 & 1980
19. Safety/Toxicity study, 1976
20. EtO sterilization validation study, 1980
21. Letter, 2/1/84, from
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
1. CP 7378.830 Systems analysis report
2. CP 7378.830A Sterile device compliance program pages 2-10 & 15-18
Thomas E. Cardamone
New York District
MODEL WARNING LETTER
RETURN RECEIPT REQUESTED
RESPONSIBLE INDIVIDUAL, TITLE
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) .