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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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DiaPharma Group Inc 3/22/11


Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

Cincinnati District Office
Central Region
6751 Steger Drive
Cincinnati, OH 45237-3097
Telephone: (513) 679-2700
FAX: (513) 679-2775

March 22, 2011



Madeleine Burmester
President and CEO
DiaPharma Group, Inc.
8948 Beckett Rd.
West Chester, OH 45069-2939

Dear Ms. Burmester:

During an inspection of your firm located in West Chester, Ohio on March 01, 2011 through March 08, 2011, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is the specification developer and distributor of in-vitro diagnostic Factor X test kits. 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. These violations include, but are not limited to, the following:

1. Failure to establish adequate procedures for corrective and preventive action per 21 C.F.R. § 820.100(a). 

Specifically, your firm's corrective and preventative action procedure, SOP #820.100 "Corrective & Preventative Action Procedure (CAPA)," does not identify all data sources which should be analyzed for the identification of potential causes of non-conforming product such as customer complaints, returned product, and incoming inspection reports. Your CAPA procedure only includes management reviews and internal quality audits as the two sources of quality data. Your firm has never conducted an internal quality audit, and has only had two management reviews since 5/15/2007. In addition, your firm has never conducted any analysis of data, such as trending, across different sources of quality data, such as complaints, returned product, incoming inspection results, etc.

2. Failure to confirm that design output meets design input requirements by design verification, per 21 C.F.R. § 820.30(f). 

Specifically, the DiaPharma Factor X Development & Design Procedure, dated 8/2/2007, documents the following discrepancies:

a. In regards to precision, an acceptance criteria of (b)(4) was established. The outputs document a range of (b)(4) study of (b)(4). Upon review of the raw data set, it was noted that 3 of the 6 (b)(4) values exceed the (b)(4) acceptance criteria. There is no data documented in the outputs for the (b)(4) of the criteria. Upon review of a data set provided for the (b)(4) study, it was noted that (b)(4) values exceeded the (b)(4) acceptance criteria.

b. In regards to accuracy, an acceptance criteria of (b)(4) was established. Upon review of the Output section of this document, it was noted that upon testing of (b)(4) individuals, the data showed a correlation coefficient (b)(4). This value does not meet the acceptance criteria, and upon questioning where this (b)(4) came from, no documentation was able to be produced.

3. Failure to conduct design validation to ensure the device conforms to defined user needs and intended uses, per 21 C.F.R. § 820.30(g).

Specifically, there is a requirement that the product be kept at a temperature of 2-8°C. The DiaPharma Factor X test kit was cleared for diagnostic use in July 2004 and has been sold and distributed as a diagnostic test kit since then, with no documentation that testing was done to verify that the product was held within the specified temperature range during shipment.

4. Failure to establish adequate procedures to ensure that all purchased or otherwise received product and services conform to specified requirements per 21 C.F.R. § 820.50.

Specifically, your Factor X Design and Development Procedure states that "development work was performed by a qualified outside source, (b)(4)." Your firm was unable to produce any documentation that the process was fully validated by the contract manufacturer. In addition, that document also states that "The manufacturer's SOPs for the manufacture and assembly of the DiaPharma Factor X assay is adequate for our needs." Your firm stated that these documents were reviewed during the on site audit conducted in July of 2007. No documentation was available that describes the manufacture or final testing process of the kits prior to leaving the contract manufacturer. Your firm conducts an incoming inspection that is limited to labeling, shipping damage, and proper paperwork. No final testing is done by your firm to ensure the devices are manufactured to your specifications.

5. Failure to establish and maintain procedures for validating the device design, including documentation of the appropriate risk analysis, as required by 21 C.F.R. § 820.30(g).

Specifically, the risk analysis of the DiaPharma Factor X kit does not include possible failures or justification for rankings provided. The risk analysis is found in the DiaPharma Factor X Development and Design Procedure, dated 8/2/2007. The risk analysis provides a rank number associated with the following categories: severity, likelihood of occurrence, likelihood of Detection/Verification.  No justification was provided for the severity value given. The only justification for likelihood of occurrence value was that no record of hazard was found in the predicate device history.   

6. Failure to perform quality audits at sufficient frequency to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system per 21 C.F.R. § 820.22.

Specifically, your firm has never conducted a formal quality audit to ensure the effectiveness of the quality system.

7. Failure of management with executive responsibility to review the suitability and effectiveness of the quality system at defined intervals per 21 C.F.R. § 820.20(c).

Specifically, your firm's Quality System Procedure, SOP 820.20, Rev. 1, dated 05/15/2007, states that a management review should take place on an annual basis. The last management review took place on 5/12/2010, the management review prior to that was conducted on 5/17/2007.

8. Failure to have personnel with the necessary background, training, and experience to perform their jobs, as required by 21 C.F.R. § 820.25(a). 

Specifically, your Technical & Regulatory Affairs Manager does not have the necessary background, training and experience to manage the quality system. The responsibilities of the Technical & Regulatory Affairs manager include verifying that the company and its products are in compliance with all regulations. However:

a. This individual has never attended formal training on the FDA's regulations, particularly the Quality System Regulations, 21 C.F.R § 820.

b. This individual stated to our investigator that she didn't understand risk analysis.

9. Failure to establish adequate procedures for acceptance activities per 21 C.F.R. § 820.80(a).

Specifically, your firm uses SOP# 820.80 "Product Inspection Instructions" to inspect all incoming products. Three lots from the past year required re-labeling due to package indicating diagnostic use, when they are not approved for diagnostic use in the USA. The Receiving Inspection, form 820.80-1, was reviewed for all three lots, with discrepancies noted under the "Is Labeling Correct?" question. The labeling question on the inspection sheet was marked “yes” on two of the forms, and “no” on the third, even though all three required the same action to be completed after initial inspection. Upon review of the procedure it was noted that the procedure was not clear on how the form was supposed to be filled out for this question.

You should take prompt action to correct the violation(s) addressed in this letter. Failure to promptly correct these violation(s) 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 money penalties. Also, 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, premarket 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 violation(s), or similar violation(s), 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.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) 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 violation(s), and take prompt actions to correct the violation(s) and to bring your products into compliance.

Your written response should be sent to Mark E. Parmon, Compliance Officer, U.S. Food and Drug Administration, 6751 Steger Drive, Cincinnati, OH 45237. If you have any questions about this letter please contact Mr. Parmon at 513-679-2700 ext. 162.  



Teresa C. Thompson
District Director
Cincinnati District