Inspections, Compliance, Enforcement, and Criminal Investigations
Albert Browne Ltd. 5/29/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
May 29, 2012
VIA UNITED PARCEL SERVICE
Albert Browne Ltd.
Chancery House, 190 Waterside Road
Hamilton Industrial Park
Leicester, United Kingdom
Dear Mr. Charlton:
During an inspection of your firm located in Leicester, United Kingdom,on February 27, 2012, through March 1, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures chemical indicators for sterilization processes. 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 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 requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
We received a response from you dated March 20, 2012, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. 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 adequate procedures for validating the device design, as required by 21 CFR 820.30(g). For example, acceptance criteria were not established prior to the performance of validation activities. (b)(4).
The adequacy of your firm’s response cannot be determined at this time. (b)(4). Form 43 (Stability Programme Approval Form), which is required to be used under SOP 12 (Procedure for Evaluation of Shelf Life Study), was completed to indicate approval prior to initiation of testing. A retrospective review of all protocols and reports for design validation activities for projects shared between your firm and (b)(4) for the previous 2 years to ensure that reports meet acceptance criteria defined in the protocols, and that protocols are approved prior to commencement of validation activities, will be performed by June 30, 2012. A (b)(4) corporate procedure to include the establishment of test protocols for design validation activities shared between (b)(4) facilities will be completed by June 30, 2012, and trained to by July 31, 2012. However, no documentation or evidence of implementation of the corrective actions or systemic corrective actions was provided.
2. Failure to establish and maintain adequate procedures for rework, as required by 21 CFR 820.90(b)(2). For example, your firm had no procedure to address the rework of nonconforming products for the following rework activities: Works Order 021351 (rework performed on September 22, 2011) and Works Order 020664 (rework performed on October 19-20, 2011).
The adequacy of your firm’s response cannot be determined at this time. The Control of Nonconformity Procedure (MAI 6) was revised to clearly state rework requirements, and personnel were trained to the revisions. A review of Nonconforming Product Reports for the period of March 1, 2012, to May 31, 2012, to ensure that rework activities are completed in accordance with revised procedural requirements will be conducted. A review of works orders for all FDA-regulated products manufactured in the previous 2 years will be completed by October 31, 2012, to verify that rework activities were appropriately documented. Retention samples will be tested for lots that were reworked to verify product compliance to original specifications. However, no documentation or evidence of implementation of the corrective actions or systemic corrective actions was provided.
3. Failure to establish and maintain adequate acceptance procedures, where appropriate, to ensure that specified requirements for in-process product are met, as required by 21 CFR 820.80(c). For example:
a. Your firm’s Device History Record for LCC016 (QAR LCC016, Rev. 1) requires Pass/Fail testing prior to and after the bottling process to monitor the performance of the product throughout manufacture and to establish stability testing criteria. However, Works Orders 022144 and 022144/1 do not document Pass/Fail testing prior to bottling. Additionally, Works Orders 021936 and 021936/1 do not document Pass/Fail testing after the bottling process.
The adequacy of your firm’s response cannot be determined at this time. A Change Order was completed to implement the (b)(4) Form 93, documenting R&D works orders, was revised to remove the former section where such an event could be documented. Lots 021936, 021936/1, 022144, and 022144/1 were retested in accordance with the currently-documented testing plan and appeared to show compliance with finished product specifications. Training was conducted on March 31, 2012. A retrospective review of works orders for all FDA-regulated products will be performed by October 31, 2012, to ensure compliance with defined sampling and test plans. However, no documentation or evidence of implementation of the corrective actions or systemic corrective actions was provided.
b. SOP 11, Investigating Out of Specification (OOS) Test Results (Rev. 1, effective date April 24, 2005), requires OOS results to be documented using an OOS Worksheet (Form 41) and an OOS Log (Form 42). However, Works Orders 020466 and 021709 contain three OOS results which have not been documented on either an OOS Worksheet or an OOS Log.
The adequacy of your firm’s response cannot be determined at this time. The OOS results obtained for Works Orders 020466 and 021709 were documented per SOP 11. Personnel were retrained on SOP 11 on March 31, 2012. A review of OOS records generated from April 1, 2012, to May 31, 2012, to ensure that all such OOS results were appropriately documented and resolved in accordance with procedural requirements will be conducted. A retrospective review of in-process and product release testing results obtained on all FDA-regulated products during the previous 2 years to ensure that any OOS outcomes were appropriately documented and resolved will be performed by October 31, 2012. However, no documentation or evidence of implementation of the corrective actions or systemic corrective actions was provided.
4. Failure to establish and maintain adequate schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met, as required by 21 CFR 820.70(g)(1). For example, the procedure (b)(4) these maintenance requirements are not always documented (b)(4).
The adequacy of your firm’s response cannot be determined at this time. Maintenance Procedure PR 25 and associated forms were revised to identify that all maintenance activities will be documented at time of completion, including signatures and dates of individuals who conducted them. Review of maintenance schedules and records was incorporated into the Internal Audit Schedule. Training was completed on April 30, 2012. A review of all maintenance schedules against the equipment manufacturers’ recommended maintenance guidelines will be performed by October 31, 2012. Maintenance activity logs will be created by October 31, 2012, for each piece of critical equipment to document required activities and their performance. However, no documentation or evidence of implementation of the corrective actions or systemic corrective actions was provided.
5. Failure to establish and maintain adequate procedures to control documents, as required by 21 CFR 820.40. For example, Change Order 2287, which documents the revision change for QAR LCC016 from Rev. 1 to Rev. 2, does not address the removal of the Pass/Fail test for (b)(4).There was no documented justification for the removal of this test requirement. At least one batch (Works Order 022378) has been manufactured under QAR LCC015, Rev. 2, with this test requirement removed.
The adequacy of your firm’s response cannot be determined at this time. A Change Order was completed to implement the enhanced in-process inspection technique for LCC016. Retained samples of product from Works Order 022378 were retested to demonstrate product compliance to specifications. A retrospective review of the previous 2 years of Change Orders relevant to all FDA-regulated products will be completed by October 31, 2012. (b)(4). However, no documentation or evidence of implementation of the corrective actions or systemic corrective actions was provided.
6. Failure to establish adequate procedures for quality audits, as required by 21 CFR 820.22. For example, individuals who conduct quality audits have direct responsibility for the matters being audited. An internal audit of your firm’s Quality System Requirements, including CAPA (MAI 8) and Control of Nonconformity (MAI 6), was conducted in January, 2012, by (b)(4) your firm’s General Manager. (b)(4) stated that he is responsible for sign-off on all CAPA closures. Additionally, (b)(4) stated that he reviews all Nonconforming Product Reports (NCPRs) and completes sign-off on all NCPRs that involve scrapped material.
Your firm’s response to this observation appears to be adequate.
7. Failure to establish adequate procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b). For example, your firm’s training procedure (“Training” RES3, Issue 5, effective date September 19, 2008) requires training to be documented on a Training Event Record (Form 39). However, training provided to warehouse personnel on September 14, 2010, to address problems raised in CAPA 0074 and subsequent changes to SWP002 – Step 7 (Rev. 2, signed off September 13, 2010) was not documented using the Training Event Record.
Your firm’s response to this observation appears to be adequate.
A follow-up inspection will be required to assure that corrections and/or corrective actions are adequate.
Given the serious nature of the violations of the Act, chemical indicators manufactured by your firm 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 "detention without physical examination," until these violations are corrected. In order to remove the devices from detention, your firm 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 firm’s response appears to be adequate, and we may need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.
Also, 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 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 business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, including 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 #306459 when replying. If you have any questions about the contents of this letter, please contact Carl Fischer at 301-796-5770 or 301-847-8137 (fax).
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
Cc: Walter M. Rosebrough, Jr.
President and Chief Executive Officer
5960 Heisley Road
Mentor, Ohio 44060
Kathleen L. Bardwell
Vice President, Chief Compliance Officer
5960 Heisley Road
Mentor, Ohio 44060