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U.S. Department of Health and Human Services

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Enforcement Actions

Drew Scientific Co. Limited 04-Apr-07

Department of Health and Human Services

Public Health Service
Food and Drug Administration
  2098 Gaither Road
Rockville MD 20850

WARNING LETTER

APR 04 2007

VIA FEDERAL EXPRESS

Richard De Piano
Senior Chairman and CEO
Drew Scientific Co. Limited
Escalon Medical Corp.
575 East Swedesford Road, Suite 100
Wayne, PA 19087

Dear Mr. De Piano:

During an inspection of your firm located in Barrow In Furness Cumbria, United Kingdom on November 11, 2006 through November 13, 2006, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Glycomat Pink Reagent Kit and the DS30 Hcy-homocysteine Test Kit. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.

This inspection revealed that these devices are 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 (C.F.R.), Part 820. The 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 procedure. The validation activities and results shall be documented, as required by 21 C.F.R. § 820.75(a). For example:

a. The firm failed to establish acceptance criteria for the validation of the freeze drying process for the manufacturing of DS30 Hcy Assay Kit prior to initiating the validation.

b. Validation was performed on reagent D only; however, the firm freeze dries three other reagents in the DS30 Hcy Assay Kits (reagent A, B and G).

c. The firm varied eleven different parameters; however, they did not evaluate the parameters used during the routine freeze drying process.

d. The firm's routine batch size of reagent D is composed of [redacted] vials; however, the validation batch of [redacted] vials was split between the 11 studies performed as part of the validation. Therefore, no one study represented the size of an actual production.

e. The firm was unable to produce process validation documentation including installation qualification records for the freezer or lyophilizer. After an exhaustive search, the firm was unable to locate any installation qualification records.

2. Failure to establish and maintain procedures for implementing corrective and preventive actions that include requirements for analyzing sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 C.F.R. § 820.100(a)(1). For example:

During FDA's previous inspection of the firm in March 2004, FDA investigators observed that the firm did not identify non-conformance reports and internal audits as quality data in the firm's CAPA procedures . During FDA's most recent inspection of the firm, FDA investigators reviewed the firm's revisions to the CAPA procedures. These revisions indicated that the firm fails to identify management reviews as possible sources of quality data. The firm's only sources of quality data identified in the procedures were internal and external audits, customer complaints, and non-conformance reports. Failure to include management reviews as a source of quality data could prohibit the firm from identifying existing and potential causes of non-conforming products.

3. Failure to establish and maintain procedures for implementing corrective and preventive actions that include requirements for investigating the cause of nonconformities relating to product, processes, and the quality system, as required by 21 C.F.R. § 820.100(a)(2). For example:

OIVD's review of the CAPA procedures [redacted] determined that the procedures failed to include requirements for investigating the cause of non-conformities relating to the product, process, or quality system . The procedure merely indicates that Root Cause is identified through Customer Complaint and Returned Goods Authorization procedure, [redacted]. The procedure does not require personnel to complete an investigation.

4. Failure to establish and maintain procedures for implementing corrective and preventive actions that include requirements for verifying or validating the effectiveness of the corrective and preventive action as required by 21 C.F.R. § 820.100(a)(4). For example:

OIVD's review of the CAPA procedure [redacted] determined that the procedure failed to include requirements for verifying or validating the corrective and preventive action. The procedure indicates only that Corrective Action is implemented and that observations and suggestions for improvements shall be deemed Preventive Action. The procedure does not require that verification and/or validation activities be completed prior to implementing actions.

5. Failure to establish and maintain procedures for implementing corrective and preventive actions that include requirements for implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems and to include requirements for ensuring that information is disseminated to those directly responsible for ensuring the quality of the product as required by 21 C.F.R. § 820.100(a)(5) & (6). For example:

OIVD's review of the CAPA procedure [redacted] determined that the procedure failed to include requirements for implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems. The procedure indicates only that Corrective Action is implemented and all is recorded in the complaint file. There is no requirement that the firm record changes in the firm's procedure and implementation of preventive actions. In addition, the firm's CAPA procedure indicates that personnel bring suggestions to immediate management, but there is no requirement that information is to be disseminated to all of those directly responsible for ensuring the quality of products.

6. Failure to investigate a complaint involving the possible failure of a device, the labeling or the packaging to meet any of its specifications, as required by 21 C.F.R. § 820.198(c). For example:

According to section [redacted] of the firm's complaint handling procedure, prior to closing complaint records, a review will ensure that there is an investigation report, a root cause has been found, and corrective actions have been implemented. Five out of the five complaint records reviewed by the investigator did not contain sufficient documentation of the firm's activities as outlined in their procedures. The records indicated that the firm failed to identify a root cause for the device failure. Also, the corrective actions described in the records do not address the possible causes of the complaint.

7. Failure to ensure that buildings are of suitable design and contain sufficient space to prevent mix-ups and assure orderly handling, as required by 21 C.F.R. § 820.70(f). For example:

a. Currently the firm has one building that houses all raw materials, corrugated packing materials, compounding area, dispensing area, and quality control lab, but none of these areas is separated from the other. During a visual inspection of the manufacturing facility, the investigator noticed solutions and raw ingredients for various steps in the manufacturing process. These solutions were not differentiated between solutions being formulated and solutions that had already been formulated. When questioned by the investigator, the firm's technician indicated that he knew in what step of the manufacturing process each solution was to be used. These solutions are stored in tanks with stickers identifying the solution in the tank. Three empty tanks were found with stickers on them indicating that the tanks contained three different solutions. The firm has failed to ensure that the building design will prevent mix-ups of the tanks.

b. A white dried crystallized powder was observed on the tanks. The investigator asked how the tanks were cleaned of this residue and was informed that the tank was cleaned by rinsing the inside of the tank with water and allowing the water to run to the bottom. The investigator noted that there were no drains in the building to allow for adequate cleaning of the tanks. The firm has not ensured that the building contains sufficient space to perform necessary operations.

8. Failure to ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 C.F.R. § 820.70(g). For example:

a. During the investigator's visual inspection of the manufacturing facility, layers of dust and dried white powder were observed on the surface of the lyophilizer, tables, compounding tanks, water storage tanks, filter housing, water purification equipment and the walls of the building. This dust was also observed on various components of the water purification system.

b. Cobwebs were observed between the [redacted] C freezer, the walls surrounding it and the water purification system.

c. The investigator noticed a white dried crystallized powder on the top opening of the tanks as well as the outside wall of the tanks. The firm had no designated area for the tanks to be cleaned properly. The firm gave no reply when asked the last time the facility was cleaned.

d. Prior to performing process validation of the lyophilizer in 2004, the firm noticed there was damage to the equipment. More specifically, the firm's process validation report indicated that the wires on the lyophilizer were damaged. This physical damage was observed by the investigator during the current inspection. The firm failed to establish procedures to ensure that all equipment was appropriately designed, constructed, placed, and installed to facilitate use.

9. Failure to establish and maintain procedures to ensure that equipment identification, calibration dates, the individual performing each calibration, and the next calibration dates are documented and this documentation is displayed on or near each piece of equipment or readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment, as required by 21 C.F.R. § 820.72(a) & (b)(2). For example:

a. The firm failed to establish a maintenance and calibration program that ensures the calibration of the following equipment:

[redacted] C freezer (serial number [redacted])
• Vacuum gauge on the [redacted] brand vacuum (serial number [redacted])
• The temperature monitoring display/thermocouple on the freeze dryer control (serial number [redacted])

The above listed equipment is used in the freeze drying process of reagents A, B, D, and G of the homocysteine DS30 In-Vitro Diagnostic device.

b. The firm failed to produce calibration documentation, and no calibration or identification tags were observed on the following equipment:

• Vacuum gauge on the [redacted] brand vacuum (serial number [redacted])

• The temperature monitoring display/thermocouple on the freeze dryer control (serial number [redacted])

The above listed equipment is used in the freeze drying process of reagents [redacted] of the [redacted] In-Vitro Diagnostic device.

10. Failure to establish procedures to ensure that all obsolete documents are promptly removed from all points of use, or otherwise prevented from unintended use, as required by 21 C.F.R. § 820.40(a). For example:

The investigator requested a copy of the firm's CAPA procedures and was given an SOP that was obsolete. The investigator was told that the obsolete version should have been removed and was given the current version for review. This obsolete version of the SOP was not removed from all points of use.

11. Failure to establish procedures to ensure that employees who manage, perform, and assess work affecting quality have been assigned the appropriate responsibility and authority and provided the independence and authority to accomplish their work, as required by 21 C.F.R. § 820.20(b)(1). For example:

The firm's Quality Controller is responsible for ensuring the handling and timely review of complaints. However, the Quality Controller informed the investigator that manufacturing personnel tend to ignore her request for the status of investigation reports as indicated in the firm's procedures. The firm has failed to implement its procedures to ensure that employees who assess work affecting quality have the appropriate authority to accomplish their duties.

You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action, which may include detaining your devices without physical examination upon entry into the United States until the corrections are completed per section 801(a) of the Act (21 U.S.C. § 381(a)). Also, 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 contracts. Additionally, pre-market approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected. 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 documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. 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. If the documentation is not in English, please provide a translation to facilitate our review.

Your response should be sent to: James Woods, Deputy Director, Patient Safety and Product Quality, 2098 Gaither Road, Rockville, Maryland 20850. If you have any questions about the content of this letter please contact: Dana C. Jones at 240-276-1323 office or 240-276-0663 fax.

Finally, you should know that this letter is not intended to be an all-inclusive list of the 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.

Sincerely yours,

/S/

Steve I. Gutman
Director
Office of In Vitro Diagnostic Device
Evaluation and Safety
Center for Devices and
Radiological Health

Cc:

Ann Bolton (Drew Scientific Ltd., Cumbria U.K., General Manager)