Inspections, Compliance, Enforcement, and Criminal Investigations
Haidylena for Advanced Medical Industries 11-Aug-05
Department of Health and Human Services
Public Health Service
Center for Devices and Radiological Health
August 11, 2005
VIA FEDERAL EXPRESS
Dr. Hany Sorour
Haidylena for Advanced Medical Industries
26 Makram Ebeid St.
Nasr City-Cairo, Egypt 11371
Dear Dr. Sorour:
During an inspection of your firm located in 6th of October City, Egypt, on April 18 through April 21, 2005, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures dialyzers and blood line sets. These products are devices within the meaning of section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 321(h)).
This inspection revealed that these devices appear to be adulterated within the meaning of section 501(h) of the Act (21 U.S.C. 351(h)), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. Significant violations include; but are not limited to, the following:
1. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process shall be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a).
For example, at the time of the inspection your firm was unable to provide a validation report proving the sterile packaging used for the dialyzers and bloodlines can maintain the sterility of the devices throughout their five year shelf life. In fact, a report from a third party laboratory showed seal failure in one out of ten packages tested. The significance of this seal failure with respect to the packaging process was not investigated by your firm.
2. Failure to establish and maintain a validated process, as required by 21 CFR 820.75(b).
For example, samples of ethylene oxide (EO) sterilized dialyzers from different sterilization cycles were pooled prior to EO residue testing and only one result is obtained. [Redacted] does not call for the pooling of samples from multiple sterilization cycles. Records for finished device acceptance for [redacted] dialyzers indicate samples from three sterilization cycles were pooled.
3. Failure to thoroughly evaluate and investigate complaints involving the possible failure of a device to meet its specifications, as required by 21 CFR 820.198(c).
For example, a complaint received on January 01, 2005, regarding the possible lack of sterilization of a dialyzer produced by your firm was not properly investigated. Your firm did not conduct a review of the Device History Record (DHR) and the only corrective action taken was to test two retained samples to confirm sterility.
4. Failure to adequately establish and maintain procedures to ensure that device history records for each batch, lot or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record, as required by 21 CFR 820.184.
a) The ratio of components [redacted] was not calculated according to the procedure. Specifically, procedure [redacted] explains how to calculate the specifications for the polymer ratio used in the components. The results are recorded in the DHR. The FDA investigator reviewed the work instructions and production records and determined the calculation was not performed correctly. The production operator who performed these analyses could not recall how he obtained the results.
b) The device history record is reviewed only to ensure completeness; it is not reviewed to ensure that each lot of devices was manufactured in accordance to the device master record.
5. Failure to adequately inspect and test incoming product to verify conformance to specifications, as required by 21 CFR 820.80(b).
a) Lot # [redacted] was accepted even though it did not conform to specifications listed in TM.00050. The acceptance record for the lot does not indicate how many fibers were inspected for dimensional acceptance criteria. In addition, there was no evidence that the lot met its acceptance criteria.
b) Acceptance test results of incoming products were not fully documented. Fiber length test results are recorded as an average of all fibers sampled and tested. This is conducted without a means to determine if the sampled lot meets the specified requirements.
6. Failure to adequately establish and maintain procedures for acceptance or rejection of each finished device production run, lot or batch to meet acceptance criteria, as required by 21 CFR 820.80(d).
a) Your firm's procedure, [redacted], requires the original certificates of analysis (COA) of finished product dialyzers be sent to the Quality Assurance (QA) manager to be included in your final product approval record. According to the EIR, the QA manager has not received any COAs for medical devices manufactured in 2005. When the questioned, the QC manager claimed that the QA manager was responsible for release of finished product; however the QA manager claimed the QC manager was the responsible person.
b) Sampling plans are not based on valid statistical rationale. [Redated], which references procedure [redacted] calls for a [redacted] sampling plan with an AQL of [redacted] based on [redacted]. However, collected samples are not subject to all required quality attribute testing. Rather, the samples are divided among the various inspections and tests. Samples of incoming components are also divided. Splitting the product samples among several tests for the individual attributes compromises the integrity of the statistical sampling plan. Specifically, of the [redacted] HL110 dialyzers sterilized in lot # [redacted], 80 dialyzers were collected for final acceptance activities. These were divided between various tests, but the QC analyst could not remember how they were divided, i.e., the number of dialyzers subjected to each of the required tests could not be determined.
7. Failure to ensure that all documents are reviewed and approved prior to implementation and failure remove all obsolete documents from all points of use, as required by 21 CFR 820.40(a).
a) Obsolete documents were being used by a quality control employee. Specifically, procedure [redacted] has been superseded by [redacted]. A QC analyst performing tests was using the outdated version.
b) Quality Control documents, which include acceptance procedures, are not approved in accordance to [redacted]. Specifically, requires the review and approval of the Quality Assurance department for new procedures and changes to existing procedures.
8. Failure to ensure that management with executive responsibility has fully implemented an adequate and effective quality system at all levels of the organization, as required by 21 CFR 820.20.
For example, a company-wide memo dated March 2, 2005, sent from the QA manager, requested a quality system procedure implementation. However, there is no evidence that these procedures were implemented.
9. Failure to conduct quality audits to ensure 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. For example, according to the internal audit schedule, major subsystems of the quality system have not been audited, which include the quality control department regarding acceptance activities, document control and training.
This letter is not intended to be an all-inclusive list of violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
Given the serious nature of these violations of the Act, dialyzers and blood tubing sets manufactured by your firm imported or offered for import are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. 381(a), in that they appear to be adulterated. As a result, FDA may take steps to refuse these products, known as "detained without physical examination," until these violations are corrected.
In order to remove the devices from detention, you should provide a written response to this Warning Letter as described below and correct the violations described in this letter. We will notify you if your response is adequate, and we may need to re-inspect your facility to verify that the appropriate corrections have been made. In addition, U.S. 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 government contracts.
We received responses from [redacted] the U.S. Agent for Haidylena Medical, dated May 10 and 11, 2005, concerning our investigator's observations noted on the FDA 483. We reviewed the responses and have concluded that they are inadequate, as follows, in the order of violations noted above:
1. The responses to observation #4 noted on the FDA 483 are not adequate. [Redacted] provided a list of actions, including validation of [redacted] using production lots and review of the inadequacy of the sealing process from batch records, complaints and archive samples. However, there was no documentation provided to support the corrective actions.
2. The responses to observation #14b noted on the FDA 483 are not adequate. [Redacted] promised to discontinue the practice of pooling samples of multiple sub-cycles. In the event that a lot needs to be separated into sub-lots because of the limited capacity of the sterilization chamber, [redacted] indicated the number of samples for EO residue testing will be 20 per sub-lot until a validated method is developed. However, there was no documentation provided to support these corrective actions.
3. The responses to observation #11 noted on the FDA 483 are not adequate. [Redacted] promised to retrain all appropriate personnel that investigate complaints, notably the Quality Control (QC) Manager, laboratory analysts, etc. [Redacted} also promised to re-examine the complaint to determine if there could be any lot-related origin to the problem. However, there was no documentation provided to support this corrective action.
4. The responses to observation #9 noted on the FDA 483 are not adequate. [Redacted] indicated that an audit of all DHRs from January 2005 to the present, will be continued to identify any discrepancies for subsequent action; the calculation issue regarding the polyurethane component ratio will be reviewed to ensure that it complies with the DMR; all appropriate personnel will be retrained; and the technical adequacy of [redacted] twill be reexamined. Further, all calculations in the DHR will be subject to independent review by the Production Manager and the QA Manager prior to product release. However, there was no documentation provided to support these corrective actions. The responses to observation #10 noted on the FDA 483 are not adequate. [Redacted] indicated they would: create and implement work instructions describing content, preparation, and compilation of the DHR; perform a formal review of all elements necessary for appropriate release of batch, lot and unit products which will be incorporated into the new work instructions as part of a consolidated release procedure; and revise the DHR form [redacted] to ensure that appropriate evidence of review against the DMR is retained. However, there was no documentation provided to support these corrective actions.
5. The responses to observation #12 and #13 noted on the FDA 483 are not adequate. [Redacted] stated your firm will re-examine the adequacy of the method specified in [redacted] retrain QC on how to interpret the Certificate of Analysis (COA) from your supplier; and review relevance of acceptance criteria. However, there was no documentation provided to support the corrective actions.
6. The responses to observation # 14a noted on the FDA 483 are not adequate. [Redacted] indicated that [redacted] will be revised to clarify requirements for final inspection; work instruction [redacted] will be implemented for content, preparation, and compilation of the DHR and final product release; sections of [redacted] which conflict with [redacted] will be omitted; and authority for product release has been transferred from QC manager to the QA manager. However, there was no documentation provided to support the corrective actions. The responses to observation #5 noted on the FDA 483 are not adequate. [Redacted] promised to do a number of things, including: undertaking a complete review of TM (test methods) and QC documents and redesigning the sampling rationale for all QC activities [redacted] promised to provide updates to FDA. However, there was no documentation provided to support the corrective actions.
7. The responses to observation #6 and #8 noted on the FDA 483 are not adequate. [Redacted] made several commitments, including the plan to compile a list of all documents in QC and remove all superseded and obsolete versions from circulation, and to convene a document control working group with specific attention to QC documents. However, there was no documentation provided to support these corrective actions.
8. The responses to observation #1 noted on the FDA 483 are not adequate. [Redacted] promised a number of corrections, including: integration of the QC Manual and other necessary documents to be under the control of the overall Quality Management System (QMS); and to review all practices for products cleared for U.S. commercial distribution and make appropriate improvements. However, there was no documentation to support these corrective actions.
9. The responses to observation #3 noted on the FDA 483 are not adequate. [Redacted] promised to make corrections, including applying a new internal audit procedure to all areas identified by the FDA inspector. [Redacted] will review their 2005 internal audit program and will reassign dates for various functions accordingly. However, there was no documentation provided to support these corrective actions.
Please notify this office in writing within fifteen (15) working days from the date you receive this letter, of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include all documentation of the corrective action you have taken. If you plan to make any corrections in the future, include those plans with your response to this letter as well. If the documentation is not in English, please provide a translation to facilitate our review.
Your response should be sent to the Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Enforcement A, OB/GYN, Gastroenterology and Urology Devices Branch, 2098 Gaither Road, Rockville, Maryland 20850 USA, to the attention of Paul Tilton.
If you need help in understanding the contents of this letter, please contact Paul Tilton at the above address or at (240) 276-0115 or FAX (240) 276-0114.
Timothy A. Ulatowski
Office of Compliance
Center for Devices and Radiological Health