Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire Avenue|
Silver Spring, MD 20993-0002
June 11, 2013
VIA UNITED PARCEL SERVICE
Richard J. Yarwood
Chief Executive Officer
Penn Pharmaceuticals Services, Ltd.
23-24 Tafarnaubach Estate
Tredegar, Gwent, Wales
Dear Mr. Yarwood:
During an inspection of your firm located in Gwent, Wales, United Kingdom, on February 4, 2013, through February 07, 2013, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures synthetic bone filler material, β-TCP (Beta Tricalcium Phosphate). Under Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), this product is a device because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.
The inspection revealed that the device is 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, its 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.
We received a response from you dated February 28, 2013, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm on February 07, 2013. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. Failure to establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met, as required by 21 CFR 820.75(b).
For example, the Product Release Check Sheet for Batch # (b)(4), manufactured on (b)(4), reports that there was a deviation: (b)(4). As a result, your firm opened Deviation DR-1063 and concluded that the apparent reason for the damage was (b)(4). As a result, your firm (b)(4). However, there was no documentation provided by your firm to confirm that the (b)(4).
The adequacy of the response cannot be determined at this time. Your firm noted that it will amend the Batch Record to allow for the operator to document the result (b)(4). Additionally, your firm noted that Deviation DR-1532 will confirm the results of the (b)(4). DR-1532 will be completed by (b)(4). However, your firm did not include documentation or evidence of the corrections and/or corrective actions and your firm did not provide evidence of implementation. Therefore, FDA cannot make an assessment with respect to adequacy.
2. Failure to review and evaluate the process and perform revalidation, where appropriate, when changes or process deviations occur and to document these activities, as required by 21 CFR 820.75(c). For example, as part of the Performance Qualification to qualify a (b)(4). Furthermore, your firm’s Experimental Progress Report for the (b)(4). However, the (b)(4) Test Report, approved on June 19, 2012, reveals that (b)(4). There was no proper investigation of the reported seal delamination by your firm and revalidation was conducted by your firm in order to demonstrate that the (b)(4).
The adequacy of the response cannot be determined at this time. Your firm noted that there was insufficient documentation to support the actions that were carried out following the receipt of the (b)(4) Test Report, approved on June 19, 2012. Your firm noted that it will open a new deviation, DR-1532, in order to confirm that an assessment was performed and concluded that the potential cause was determined and that remedial work was completed. In addition, your firm plans to conduct a further study of the materials and equipment in order to identify possible process improvements to (b)(4). However, your firm did not include documentation or evidence of the corrections and/or corrective actions and your firm did not provide evidence of implementation. Therefore, FDA cannot make an assessment with respect to adequacy.
3. Failure to establish and maintain procedures to include requirements for investigating the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR 820.100(a)(2). For example, your firm’s SOP 3-09-0037, Deviations, Corrective Action and Preventive Action (CAPA) Reporting, Revision No. 19, states that investigation should be (b)(4). Additionally, the deviation should be recorded in the (b)(4). However, as part of the investigation for DR-1063, created on April 20, 2012, the firm documented an incident that occurred on April 16, 2012, when the (b)(4) drifted out of specification. It was reported that the (b)(4). The out-of-specification measurement resulted in rejected material due to the (b)(4). There was no investigation for the cause of the incident and there was no determination of what corrective action may have been necessary to prevent recurrence.
We reviewed your firm’s response and conclude that it is not adequate. Your firm noted that it will update SOP 3-13-0010, Deviations, Corrective and Preventive Actions (CAPA) Reporting, to include instruction for consideration of analytical testing of any potential contaminants discovered during manufacture or testing of products. In addition, your firm noted that it will update SOP 4-10-0105, (b)(4), in order to clarify the escalation procedure following any failures found during the inspection of the (b)(4). However, your firm did not provide a plan and evidence of the corrective action including retroactive review of CAPA reports for proper investigation. In addition, your firm did not include the updated procedures for review.
4. Failure to establish and maintain data that clearly describe or reference the specified requirements, including quality requirements, for purchased or otherwise received product and services, as required by 21 CFR 820.50(b). For example, during the inspection, the investigator noted that the ownership of the PMA for the GEM21S had changed from Biomemidics to Luitpold Pharmaceuticals, Inc., in 2008. However, there are no purchasing documents between your firm and Luitpold Pharmaceuticals, Inc., for identifying the necessary responsibilities and quality controls for manufacturing the β-TCP 0.5 CC Perio Cups.
The adequacy of the response cannot be determined at this time. Your firm noted that the (b)(4). Also, your firm noted that (b)(4). However, your firm did not include documentation or evidence of the corrections and/or corrective actions and your firm did not provide evidence of implementation. Therefore, FDA cannot make an assessment with respect to adequacy.
5. Failure to establish and maintain procedures for quality audits and conduct such 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. For example, your firm’s standard operating procedure No. 3-17-0005, GMP Self Inspections, Revision 11, defines how self inspections are applied and performed at Penn Pharmaceuticals. Additionally, Section 7.3 states that each Process Stream and Department is formally inspected (b)(4), unless otherwise stated. However, review of the firm’s Self Inspection Schedule for (b)(4), revealed that the audit activities for Quality Assurance, Project Management (CTS), CTS Packaging, and Logistics ((b)(4)) departments were not completed.
The adequacy of the response cannot be determined at this time. Your firm stated that all open reports for Quality Assurance, Project Management (CTS), CTS Packaging, found in the Self Inspection Schedule for (b)(4) were previously closed out with CAPA actions in the (b)(4) system. The reports were not signed off and identified as closed on the schedule due to an oversight. Your firm noted that it has subsequently closed all these reports. Additionally, your firm noted that no critical or major observations were raised during the (b)(4) audit for the logistics department. The report was subsequently closed. Finally, your firm noted that it will conduct a full review of all internal quality reports from (b)(4) in order to identify any incomplete actions and open reports. In addition, any open action will be mitigated and closed or escalated to CAPA in the (b)(4) System. However, your firm did not submit for review documentation demonstrating that the full review of quality reports audit was completed. Additionally, your firm did not include documentation or evidence of the corrections and/or corrective actions and your firm did not provide evidence of implementation. Therefore, FDA cannot make an assessment with respect to adequacy.
The U.S. federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the awarding of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation violations 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 business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective actions (including any systemic corrective actions) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Please provide a translation of documentation not in English to facilitate our review.
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Operations Branch, White Oak Building 66, Rm 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #396210 when replying. If you have any questions about the contents of this letter, please contact: Ronald L. Swann at 301-796-5770.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance.
Steven D. Silverman
Office of Compliance
Center for Devices and