Inspections, Compliance, Enforcement, and Criminal Investigations
Gel-Med International 05-Feb-04
Department of Health and Human Services
Public Health Service
Center for Devices and Radiological Health
FEB 5 2004
VIA FEDERAL EXPRESS
Mr. Petr Stehlicek
Gel-Med International, Spol. S-R-O.
Kamenne Zehrovice 27301, Czech Republic
Dear Mr. Stehlicek:
On September 15, 17, 18, 22, and 23, 2003, an investigator from the Food and Drug Administration (FDA) inspected your establishment located at Karlovarska 20, Kamenne Zehrovice, Czech Republic, 27301.
Violations of the Quality System Regulation
The investigator determined that your manufacturing and quality assurance system for Dilapan-S Hygroscopic Cervical Dilators, which are intended for the dilation of the cervix uteri prior to termination of pregnancy up to 16 weeks gestation, do not comply with FDA's Quality System (QS) Regulation for medical devices, which is located at Title 21, Code of Federal Regulations (CFR), Part 820. These violations cause your devices to be adulterated within the meaning of Section 501(h) the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(h)).
Specifically, the investigator observed the following:
1. Failure to validate, with a high degree of assurance, a process whose results cannot be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(a). See also 21 CFR 820.250.
a. Your firm's [redacted] cleaning agent was discontinued and replaced with [redacted], another cleaning agent, in January 2002. You failed to complete the cleaning validation for [redacted]
b. Your firm's cleaning validation for 4 cleaning agents failed to include sufficient numbers of samples based on valid statistical rationale. The cleaning agents "[redacted]" included 6 samples, '[redacted]" included 2 samples, "[redacted]" included 26 samples, and "[redacted]" included 14 samples.
c. Your firm's validation of injection molding of [redacted] lacks a relevant number of samples based on valid statistical rationale. For each run of different size [redacted] only [redacted] samples are inspected out of 1,000 plus handles.
d. Your firm's water system validation failed to include sufficient numbers of samples based on valid statistical rationale. One sample was taken from one outlet during 3 consecutive days. No documentation was available to demonstrate the above samplings are based on valid statistical rationale. Failure to establish and maintain procedures for implementing corrective and preventive action, including requirements for analyzing all sources of quality data to identify existing and potential causes of nonconforming, or other quality problems, as required by 21 CFR 820.100(a)(1). For example, your firm's analysis of quality data from 2002 to present did not include analysis by specific failure mode.
2. Failure to establish and maintain procedures for implementing corrective and preventive action, including requirements for analyzing all sources of quality data to identify existing and potential causes of nonconforming, or other quality problems, as required by 21 CFR 820.100 (a)(1). For example, your firm's analysis of quality data from 2002 to present did not include analysis by specific failure mode.
3. Failure to establish and maintain procedures for the documentation and review of design changes before their implementation, as required by 21 CFR 820.30(i).
4. Failure of your firm's design validation to ensure that your devices conform to defined user needs and intended uses, as required by 21 CFR 820.30(g). For example, your firm's stability studies on the shelf life for Dilapan-S failed to include 3 batches in its real time study and 1 year accelerated study after the 3 month test interval. Your
firm's protocol requires [redacted] batches to be run in the stability studies. Your firm only had results for 2 batches for the entire real time and 1 year accelerated study intervals.
5. Failure to conduct quality audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22.. Specifically, . your firm did not complete some internal audits according to schedule. Your firm's audit procedure states audits will be conducted at least yearly.
a. The design control section has not been audited since 7/13/2001 and was scheduled for October 2003.
b. The management responsibility, quality system, document control, quality records, and quality manual sections have not been audited since 9/17/2001 and were
scheduled for October 2003.
c. The contract review, purchasing control, and servicing sections were scheduled to be done in November 2001, but were not audited until 9/10/2002.
Additionally, the FDA investigator obtained information that your firm has discontinued the testing of [redacted], a probable carcinogen, on each lot of the "Dilapan-S Hygroscopic Cervical Dilator", medical devices prior to release. The original application for premarket approval (PMA) [redacted] was approved on April 28, 1986. There have been subsequent supplements, but none of these permits your firm to stop [redacted] testing. The original PMA indicates an acceptable limit (50 ppb) of [redacted] per device, and that [redacted] testing is performed on each lot prior to release. Although the amount of residual [redacted] is expected to be low, failure to conduct testing of [redacted] may place patients at risk for exposure to unacceptable levels of a probable carcinogen. For this reason, discontinue of [redacted] testing affects the safety of this device, and requires the submission to FDA of a notice describing and supporting this change 30 days prior to its implementation, in accordance with section 515(d)(6) of the Act and 21 CFR 814.39.
A review of our records has determined that you did not submit a 30-day notice prior to discontinuing [redacted] testing for each lot of Dilapan. Because you have not given FDA 30 days notice of your intent to discontinue testing, marketing the Dilapan-S without conducting this testing is a violation of the law. This device is adulterated under section 501(f)(1)(B) and is misbranded under section 502(o) of the Act. The device is adulterated under the Act because you do not have an approved Premarket Approval Application (PMA) to demonstrate that the device is safe and effective without conducting this testing. The device is misbranded under the Act because you have not submitted a section 510(k) premarket notification to show that the device is substantially equivalent to other devices that are legally marketed. For a product requiring premarket approval before marketing, the notification required by section 510(k) of the act is deemed to be satisfied when a premarket approval application (PMA) is pending before the agency. 21 CFR 807.81 (b).
Therefore, your firm needs to resume [redacted] testing immediately for each lot of Dilapan-S, as stated in the original PMA submission.
If you would like to pursue the removal of [redacted] testing from the approved manufacturing process for the Dilapan-S, you need to submit a 30-day notice in accordance with 21 CFR 814.39(f). FDA may notify you, within 30 days of receipt of this notice, that you are required to submit a PMA supplement addressing this change. In those circumstances, you must receive FDA approval prior to implementation of the change.
Conclusion and Requested Action
We have not received a response from you regarding the specific violations noted in the FDA 483 issued at the close of the inspection.
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 applicable requirement of the Act and FDA. regulations. The specific violations noted in this letter and in the FDA 483 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. You also must promptly initiate
permanent corrective and preventive action on your quality system.
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 Class III devices to which the quality system regulation deficiencies are reasonably related will be cleared or approved until the violations have been corrected. Also, no Certificates to Foreign Governments will be issued by FDA until the violations related to the subject devices have been
In addition, the subject devices may be detained upon entry into the United States without physical examination until these violations are corrected.
Please notify this office in writing, within fifteen (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 prevent the recurrence of these and 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.
Your response should be sent to:
Consumer Safety Officer
U.S. Food & Drug Administration
Center for Devices & Radiological Health
Office of Compliance, HFZ-332
2098 Gaither Road
Rockville, MD 20850
Larry D. Spears for Timothy A. Ulatowski
Office of Compliance
Center for Devices and Radiological Health