小中大Zhejiang Jiuzhou Pharmaceutical Co., Ltd. 7/9/14
Department of Health and Human Services
Public Health Service
Food and Drug Administration
Silver Spring, MD 20993
Warning Letter
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
WL: 320-14-12
July 9, 2014
Ms. Hua Lirong
CEO
Zhejiang Jiuzhou Pharmaceutical Co., Ltd.
No. 99 Waisha Road, Jiaojiang
Taizhou, Zhejiang Province, 318000
P. R. China
Dear Ms. Hua Lirong:
During our October 21-24, 2013 inspection of your active pharmaceutical ingredient manufacturing facility, Zhejiang Jiuzhou Pharmaceutical Co., Ltd., and your import/export company Zhejiang Zonebanner Jiuzhou Imp. & Exp. Co., Ltd., both located at No. 99 Waisha Road, Taizhou, Zhejiang Province, China, an investigator from the U.S. Food and Drug Administration (FDA) identified deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). These deviations cause your APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We acknowledge receipt of your firm’s correspondences dated November 14, 2013, and January 14, 2014.
Our investigator observed specific violations during the inspection, including, but not limited to, the following:
CGMP VIOLATIONS
CGMP违规情况
Zhejiang Zonebanner Jiuzhou Imp. & Exp. Co., Ltd. (FEI 3010365339)
1. Failure to implement an effective system of managing quality and failure to transfer all quality or regulatory information received from the API manufacturer to your customers.
Your trading company, hereafter referred to as Zonebanner, purchased APIs from an outside supplier and relabeled them without the oversight of a quality unit. The information from the original certificate of analysis, generated by the actual manufacturer, was transferred to a new certificate of analysis on Zhejiang Jiuzhou Pharmaceutical Co. letterhead with no information about the original manufacturer or analytical laboratory performing the analyses. In addition, a new label identifying Zhejiang Jiuzhou Pharmaceutical Co. as the manufacturer was added to drums. In doing so, your firm essentially obscured the supply chain of these APIs.
Zonebanner had no quality system in place for the relabeling operations. In addition, we note that in at least one instance of a lot of gabapentin shipped to the U.S., the retest date from the original manufacturer’s certificate of analysis (November 2013) was changed to an expiration date listed as eleven months later (October 2014) on the new certificate of analysis.
In your response, your firm states that Zonebanner exists as a separate legal entity under Chinese law. However, the FDA considers this entity to be under your control. During the inspection, your employees stated that Zonebanner is a group within Zhejiang Jiuzhou Pharmaceutical Co. Ltd. and provided organizational charts showing that Zonebanner management reports to you as CEO. Zonebanner is located at the same physical address as the inspected manufacturing facility, and the Zonebanner personnel work in the same office space. Moreover, API shipments from Zonebanner are accompanied by a letter stating that Zhejiang Zonebanner and Zhejiang Jiuzhou Pharmaceutical Co. Ltd. are in one group. Despite this close relationship, however, your management has allowed the Zonebanner group to continue to operate outside of your firm’s quality system.
In response to this letter, provide details of the proposed quality system to be implemented at Zonebanner. Describe procedures and provide examples that demonstrate that traceability is maintained for currently distributed APIs and that information sent to customers includes an accurate representation of the manufacturer and analytical testing laboratory. In addition, provide your rationale for the expiry extension of the gabapentin lot described above. If this or other similar extensions were unsupported, then describe your intended actions for the lot(s) in question.
Zhejiang Jiuzhou Pharmaceutical (FEI 3003744377)
2. Failure of the quality unit to review batch production records prior to distribution of an API batch.
Our investigator discovered that your firm shipped finished lots without reviewing the batch records for these lots. Although your firm has procedures requiring the review of batch records prior to their release and distribution, on several occasions your quality unit authorized the shipment of lots prior to their release. Several of your firm’s employees were aware of this practice but took no measures to prevent it.
During the inspection, your firm’s personnel conducted an internal review and found three additional lots that were distributed prior to release by the quality unit. However, we are concerned that your internal review would be unable to detect every instance for which your firm shipped materials whose batch records had not yet been reviewed based on your poor documentation practices described below under #3. We remind you that the quality unit’s approval of batch records should not merely serve as a paperwork exercise but should include a thorough review of all deviations which occurred and any unexpected results which were obtained during the manufacture of the lot being reviewed.
Quality unit review of batch records is a clear expectation of CGMP. Responsible management should ensure that the quality unit performs its assigned functions. In response to this letter, please provide a full accounting of this practice and describe all actions taken to prevent its recurrence. Describe any improvements to ensure that your internal auditing program will detect and correct similar instances in the future.
3. Failure to document manufacturing operations at the time they are performed.
When reviewing the entries in your (b)(4) use, cleaning, and maintenance logbook for the days immediately prior to the inspection, our investigator found missing entries. Your operators stated that lines were left blank to later add information about cleaning events that may have occurred during a previous shift. During the inspection, our investigator found other similar instances of missing data or belated data entry in your manufacturing records. These practices are not consistent with CGMP. Operators acknowledged that there is no system in place to report these lapses in the documentation system; documentation errors of this type did not require deviation investigations or notification to the Quality Unit.
