Peking Medicine Manufactory 3/25/13
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||Silver Spring, MD 20993 |
CERTIFIED MAIL WL: 320-13-12
RETURN RECEIPT REQUIRED
March 25, 2013
Mr. Martin Chow
Peking Medicine Manufactory
Flat B. 7/F, Phase 1, Leader Industrial Centre
188-202 Texaco Road
Tsuen Wan, New Territories, Hong Kong, SAR
Dear Mr. Chow:
During our April 30 through May 4 2012inspection of your pharmaceutical manufacturing facility, Peking Medicine Manufactory, located at Unit B.7/F, Phase 1, Leader Industrial Centre, 188-202 Texaco Road, Tsuen Wan, New Territories, Hong Kong, an investigator from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) 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.
Our investigator observed specific violations during the inspection, including, but not limited to, the following:
1. Your quality control unit failed to approve procedures and specifications impacting the identity, strength, quality and purity of the drug product. Secondly, your quality control unit failed to exercise its authority to approve or reject drug product components, containers, closures, in-process materials, packaging material, labeling and finished products. This responsibility includes the requirement to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated, and approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. Finally, there are no written procedures describing the responsibilities and procedures applicable to the quality unit. [21 C.F.R. § 211.22].
Your firm failed to have a functioning quality control unit (QCU). Several examples of the violation are as follows:
a) Your quality unit has not approved procedures and specifications impacting the quality of finished drug products imported to the U.S. market.
(i) During the inspection, our investigator found that your current procedures have not been reviewed and approved by the QCU. Examples of these unapproved procedures include: Finished Product Release, Storage, and Distribution (SOP-01-05); Stability Testing of Finished Product (SMP-QC-016-00); Change Control and Validation (PS-10); Material Receipt Management Procedure (RM-02); Product Recall Management (SMP-11-02); and Complaint and Adverse reactions (SMP-12-01).
(ii) Additionally, our investigator also found that your QCU failed to establish and approve standard operating procedures (SOPs) as follows: cleaning validation; finished product release and control; change control; labeling and packaging operations; annual product review; and procedure for writing, reviewing, and approving standard operating procedures.
b) Your finished drug products have been released by your warehouse manager, not signed off by your QCU. In addition, your unapproved procedure, SOP-01-05 “Finished Product Release, Storage and Distribution” addresses how your warehouse releases materials for shipping, not how your finished product is examined, and approved by your QCU.
c) Your QCU failed to establish SOPs to examine and ensure the suitability of incoming raw materials, components, container, closures, or labels.
d) Your firm contracted out the manufacturer of STRONG WOO LOK GAO to an external party. Your firm is the owner of this drug product, but did not adequately evaluate whether the CMO (contract manufacturing organization), which is an extension of your operations, can consistently produce product that is suitable for distribution. For example, your quality unit did not evaluate the quality of each batch of drug product produced by the CMO in order to make an appropriate disposition decision (approval or rejection).
e) There is no written procedure or program to address the validation of processes used to produce any of the finished drug products manufactured by your firm.
f) Your firm has not established an SOP describing the specific responsibilities of the QCU.
In response to this letter, provide the written procedures developed and applicable to your QCU, including defining its roles and responsibilities. When preparing your written procedure, please note that a CGMP-compliant quality system supports a sustainable state of control. This includes, but is not limited to, systems to use suitable raw materials and components, reliable manufacturing processes, vigilant quality monitoring throughout drug manufacturing, and a robust program for corrective and preventive actions. We recommend that you seek the advice of a third-party consultant for assistance with a comprehensive evaluation to determine the improvements that you will need to make to meet CGMP requirements for the manufacture of drug products.
2. The establishment of specifications, standards, sampling plans, test procedures, laboratory control mechanisms including any changes thereto, are not drafted by the appropriate organizational unit, reviewed and approved by your quality control unit. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. [21 C.F.R. § 211.160]
Three examples of the violation are as follows:
a. There are no specifications, standards, sampling plans, test procedures, and laboratory control mechanisms approved by your QCU.
b. Your firm has not established finished product specifications for STRONG WOO LOK GAO.
c. Your firm lacks a written program for calibration of your laboratory instruments or equipment. All of your instruments or equipment in your laboratory are not calibrated.
In response to this letter, provide copies of your drug product specifications, as well as sampling plans and all test methods including the identity and assay for STRONG WOO LOK GAO. Provide a written plan how your laboratory instruments will be adequately calibrated and suitable for their intended use.
3. Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications and identity and strength of each active ingredient prior to release. [21 C.F.R. § 211.165(a)]
a. Your finished product, STRONG WOO LOK GAO (lot#II18A) was not tested for conformance to the labeled amount of active ingredients. Your firm contracted out the STRONG WOO LOK GAO product. Your firm accepted and relied on the Certificate of Analysis (COA) from your contract manufacturer (CMO) and failed to verify the accuracy and completeness of testing results in the COA. For example, STRONG WOO LOK GAO contains six active ingredients. The COA for this lot showed that only identity testing for two of the six active ingredients was conducted. No assay testing was conducted.
In response to this letter, you should include a commitment to test all products according to appropriate finished product release specification. Your firm should also include a plan to address the quality of the lots already on the U.S. market. At minimum, your firm should promptly provide testing results for retain samples of all drug product lots within expiry and distributed to the U.S. market.
4. Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates. [21 C.F.R. § 211.166(a)]
a. Your firm does not have a written testing program to assess stability characteristics of your drug product, STRONG WOO LOK GAO. In addition, your stability procedure (SMP-QC-01600) designed for new products is still a draft and not reviewed and approved by your QCU.
b. Your firm has not conducted any stability studies for STRONG WOO LOK GAO. Your firm accepted and relied on the expiration date provided by your plaster manufacturer.
c. Your QCU did not adequately ensure that the drug products released to the market were supported by appropriate stability data.
In your response to this letter, provide documentation to support the current expiration dates assigned to your drug products currently in U.S. distribution, as well as a commitment to ensure that each of your drug products is routinely tested according to a stability program that has been approved by your QCU.
5. Written procedures are lacking that describe in sufficient detail the receipt, identification, storage, handling, sampling, testing, approval, rejection of components, drug product containers, and closures. Bagged or boxed components of drug product containers and closures are not stored off the floor and are not suitably spaced to allow cleaning and inspection. [21 C.F.R. § 211.80 (a) and (c)]
a. Your written procedure “Material Receipt Management Procedures” (document#RM-02) has been in draft for two (2) years and never approved by your QCU. In addition, this procedure only requires an examination of the purchase order for correctness and verification that the components are not damaged.
b. Our investigator found that many boxes are stored on the floor in the warehouse. Your warehouse was not able to provide adequate space to allow cleaning and inspection.
In response to this letter, provide a detailed corrective action plan for the receipt, sampling, testing, and release or rejection of drug components, containers, and closures.
6. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals [21 C.F.R. § 211.84 (d) (1)]
a. Our investigator found that your firm did not perform identity testing of incoming materials, instead only microbiological testing was performed.
In response to this letter, provide a detailed corrective action plan to address this deficiency.
7. Your firm failed to ensure that employees received training in current good manufacturing practices, as well as in particular operations assigned to the employees [21 C.F.R. § 211.25(a)].
a. The inspection documented that your firm lacks a training program and that none of your employees has received CGMP training.
In your response to this letter, provide a plan to develop an ongoing and robust CGMP training program for your personnel, including an explanation of how you will assess training effectiveness.
UNAPPROVED AND MISBRANDED OVER-THE-COUNTER (OTC) DRUGS
In addition to the CGMP violations, your firm manufactures and/or distributes STRONG WOO LOK GAO. Based on the labeling statements for this product, STRONG OO LOK GAO is a drug, as defined by section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 321(g)(1)], because it is intended for use in the prevention, mitigation, treatment, or cure of disease, and/or intended to affect the structure or any function of the body. Examples of labeling statements documenting the intended uses of your product include, but are not limited to, the following:
- “For temporary relieve (sic) of pains, sprains, injuries, sore shoulders and backs, lumbago and pains in sinews and bones”
Ingredients declared on product label:
- “Active Ingredients: . . . Semen momordicae 1.5% . . . Semen Ricini 5% . . . Myrrha 2% . . . Olibanum 2% . . . Mentholum 5% . . . Methyl Salicylate 1%”
STRONG WOO LOK GAO is a “new drug,” as defined in section 201(p) of the Act [21 U.S.C. § 321(p)], because this product is not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling. Under sections 301(d) and 505 of the Act, a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. Your distribution of the above-mentioned product without an approved application violates these provisions of the Act.
We note, drug products intended for topical administration for OTC indications related to pain are being evaluated under the OTC Drug Review. The Tentative Final Monograph (TFM) issued on February 8, 1983, for OTC External Analgesics (48 FR 5852) is part of this evaluation. STRONG WOO LOK GAO is not covered under this TFM because its formulation includes the active ingredients “semen momordicae,” “semen ricini,” “myrrha,” “olibanum,” and “mentholum,” none of which are included in the OTC Drug Review for any indication. In addition, “bone” pain is not included in the external analgesic TFM. Thus, STRONG WOO LOK GAO is not eligible for inclusion in the OTC Drug Review.
On April 5, 2012 a Warning Letter (#300-12-007) was issued for failing to register and list as required under 21 CFR Part 207.40. Please include in your response the steps taken to comply with this requirement.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at, Peking Medicine manufactory, Unit B, 7/F, Phase 1, Leader Industrial Centre, 188-202 Texaco Road, Tsuen Wan, New Territories, Hong Kong SAR, into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles are subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3004186759.
Please send your reply to the following address:
Yanyan (Jenny) Qin
Senior Policy Advisor
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51, Room 4235
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3207
Fax: (301) 847-8741
Richard L. Friedman
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research