Source: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm330431.htm
Timestamp: 2017-09-24 23:12:02
Document Index: 191211832

Matched Legal Cases: ['arts 210', '§ 351', '§ 211', '§ 211', '§ 211', '§211', '§ 211', '§ 211', '§ 211', '§ 211', '§ 355', '§ 352', '§ 352', '§ 321', '§ 201', '§ 321', '§ 355', '§ 381', '§ 351']

Shanghai Huhui Daily Use Chemical Products Co., Ltd. 11/14/12
VIA UPS MAIL
WL: 320-13-02
Mr. HuaFeng Jiang
No. 8 Luda Road
Liuzao Town
Pudong District New Area
Shanghai, China 201322
Dear Mr. Jiang:
During our February 6-10, 2012 inspection of your over-the-counter (OTC) drug manufacturing facility, Shanghai Huhui Daily Use Chemical Products Co., Ltd. located at No. 8 Luda Road, Liuzao Town, Shanghai, China, an investigator from the 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 products 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 correspondence dated March 11, 2012.
1. Component test records specifically associated with batches of drug product manufactured at your facility were not readily available for an authorized inspection during their retention period. [21 C.F.R. § 211.180(c)]
a. Your firm refused to provide the test records of (b)(4), an active pharmaceutical ingredient (API) used to manufacture the drug products, (b)(4) Skin Protectant and (b)(4) Skin Protectant. Your firm refused to provide the results of tests performed on (b)(4) and instead redacted the test methods and acceptance criteria in your (b)(4) raw material specification sheet prior to providing a copy of this document to the investigator.
b. Your firm also refused to provide the test records for (b)(4), an API used in your (b)(4) Skin Protectant Cream, by redacting this data before providing a copy of (b)(4) raw material specification sheet to the investigator.
These documents are component test records that must be retained and are subject to review and photocopy during an inspection. The above examples constitute unreasonable denials in permitting FDA to assess the manufacturing conditions at your facility. In your response to this letter, please provide your testing requirements and results for the (b)(4) and (b)(4) APIs used in your drug products. Specifically, include information regarding the drug products shipped to the US and that remain within expiration.
2. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. [21 C.F.R. § 211.22(a)]
Four examples of violations of § 211.22(a) are as follows:
a. Your quality control unit (QCU) failed to adequately review the batch production record for your product (b)(4) Skin Protectant Cream, bulk batch # (b)(4). Our inspection documented discrepancies between your batch production and cleaning records. For example, your batch product record indicated that on August 31, 2011, your firm began processing bulk batch #(b)(4) in (b)(4) at 7:20 A.M., and that the production ended at (b)(4) A.M. of the same day. However, your cleaning record showed that the same (b)(4) #3 had been cleaned between 8:00 to (b)(4) A.M. on the same day of August 31, 2011. The information collected indicates that two different operations were being performed during the same period of time.
b. Your QCU did not notice the contradictory yields obtained between your batch production record and raw data record sheet for the same batch of the drug product (b)(4) Skin Protectant Cream. Your production records for bulk batch (b)(4) document the size of this batch as (b)(4). Your raw data record sheets for finished product batch #(b)(4) showed that a total of (b)(4) of final product were packed from the bulk batch lot #(b)(4). Your firm’s management could not explain and justify the origins of the extra (b)(4) of finished product. Similarly, the investigator found that the quantity of bulk batch # (b)(4) produced was (b)(4), whereas your raw data records show that the quantity of finished product (batch #(b)(4)) produced from this bulk batch was (b)(4).
c. Your QCU failed to ensure the traceability of the batch lot number used in the production of (b)(4) Skin Protectant Cream. Your firm’s QCU was unable to determine the final finished product lot produced from the two bulk lots #(b)(4) (batch size: (b)(4)) and #(b)(4) (batch size: (b)(4)).
d. The investigator also observed the presence of opaque correction fluid in many of your production records of (b)(4) Skin Protectant Cream. For instance, your firm used opaque correction fluid to change lot numbers of two raw materials in the bulk batch lot #(b)(4), signatures in bulk lot #(b)(4), and process temperature and viscosity readings in lot #(b)(4). In each instance, there was no notation of who made the change or when and why the change was made. Please note that batch records are to document accurately the production and control activities associated with each lot. A QCU cannot reasonably rely on records containing unexplained corrections to make batch release decisions.
The above four examples raise serious concerns regarding the integrity, reliability and traceability of the data generated and documented in your batch production records. Your QCU failed to adequately review and verify the accuracy of these production records prior to releasing the products. In your response to this letter, describe your comprehensive evaluation and remediation of your firm’s documentation systems used in both manufacturing and laboratory operations. Provide a detailed corrective action plan that describes the steps you have taken to prevent recurrence of similar events. Include in your response a retrospective review and assessment of the extent of the problem and potential risks involved (e.g., other products, systems and data). Also provide a detailed description of the responsibilities of your QCU.
3. Your firm failed to establish and follow adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and your QCU also did not review and approve those procedures. [21 C.F.R. §211.100(a) and (b)]
a. At the time of the inspection, your firm had not conducted any process validation, or equipment qualification for your (b)(4) Skin Protectant Cream manufacturing process. Additionally, your QCU had not approved the batch production records for this product. The inspection documented that your firm relied on your import/export company’s batch production record for producing the (b)(4) Skin Protectant Cream bulk without on-site validation of the process. Moreover, your personnel were not following the transferred batch production record.
b. At the time of the inspection, your firm had not conducted validation studies for your drug product packaging processes, including container cap or tube sealing, fill volumes, and labeling.
In response to this letter, provide a detailed corrective action plan to address the lack of process validation and equipment qualification issues for the drug products exported to the U.S. market. Please note that each drug product’s manufacturing process must be adequately validated. The critical controls and processing parameters must be known and shown to be in control. You should also demonstrate that your manufacturing process is reproducible.
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 lacked data to support the (b)(4) expiration date established for (b)(4) Skin Protectant Cream. During the inspection, FDA’s investigator was informed that accelerated stability data was generated. Nonetheless, such data was never made available for review. In addition, the investigator documented that your firm has not established a written testing program and is not equipped with appropriately-qualified stability chambers to conduct the necessary stability studies.
b. Our investigator found that your finished products, (b)(4) Skin Protectant Cream, (b)(4) Skin Protectant, and (b)(4) Skin Protectant, have been stored in a warehouse with no temperature control. Your firm lacks stability data to support your labeling claim, “Store at room temperature (b)(4) – (b)(4) ˚C.”
In your response to this letter, include a statement regarding what your firm intends to do with products currently on the market for which you have no supporting stability data. Please provide details of your stability study program, including, but not limited to, products tested, analytical test methods, qualification of the stability chambers, specific tests performed, stability specifications, and testing location. In addition, please provide your summary validation report for your stability-indicating analytical methods used in the assessment of your stability studies.
5. Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit. [21 C.F.R. § 211.84(a)] Specifically, your firm failed to conduct at least one specific identity test on a component and failed to establish the reliability of the supplier’s analyses, through appropriate validation of the supplier’s test results at appropriate intervals, when relying on that component supplier’s analysis. [21 C.F.R. § 211.84(d)(2)]
a. Your firm has not adequately qualified your drug component suppliers used in the manufacture of (b)(4) Skin Protectant Cream. Your firm received (b)(4) from your import/export company. However, your import/export company’s Certificate of Analysis (CoA) for (b)(4) batch #(b)(4) did not disclose the name of the (b)(4) manufacturer or the laboratory that conducted the testing of the batch. Moreover, you did not conduct a specific identity test nor did you establish the reliability of the supplier’s analyses.
b. Your firm failed to appropriately test the component, (b)(4) (API), because your specification did not meet the requirements of the USP monograph. Your current raw material specification does not include testing of impurities, specific gravity, consistency, and (b)(4) as required by the USP monograph. Also, your firm did not provide any justification for not conducting these required tests. In addition, your firm’s QCU relied solely on the supplier’s analysis without adequately verifying the accuracy of the supplier’s testing results for this material.
In your response to this letter, provide a detailed plan to qualify your suppliers of raw materials and the scientific justification for your decision to rely on your suppliers test results. Also, describe the routine identity testing you will conduct for each shipment of raw materials received and used to manufacture your drug products. Additionally, clarify the relationship and responsibilities between your firm and your import/export company. Please note that adequate qualification of suppliers is critical in assuring that your drug products are of the quality intended.
6. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity. [21 C.F.R. § 211.160(b)]
a. Your firm failed to conduct identity and assay tests of (b)(4) (API) and identity test of (b)(4) (API) in your finished product, (b)(4) Skin Protectant Cream (batch #(b)(4)). Your firm was not able to provide the investigator any testing results to support your product label’s ingredient claims.
b. Your firm failed to conduct assay testing of (b)(4) (API) in your finished product of (b)(4) Skin Protectant (lot #(b)(4)). Your firm was not able to provide the investigator any testing results to support your product label’s ingredient claims.
In your response, provide information regarding any voluntary corrective actions you intend to initiate to correct this deficiency and your rationale for taking those actions. Describe your testing methodology for each of the products described above. Summarize the relevant analytical method validation protocols and provide timelines for execution of these protocols.
Unapproved and Misbranded Over-the-Counter (OTC) Drugs
(b)(4) Skin Protectant Cream and (b)(4) Skin Protectant as presently formulated, labeled, and promoted, are OTC products that violate provisions of the Act. As described in more detail below, these products are unapproved “new drugs” in violation of section 505(a) of the Act [21 U.S.C. § 355(a)]. In addition, (b)(4) Skin Protectant Cream and (b)(4) Skin Protectant are misbranded under section 502(e)(1)(A)(ii) of the Act [21 U.S.C. § 352 (e)(1)(A)(ii)] and (b)(4) Skin Protectant Cream is further misbranded under Section 502(a) of the Act [21 U.S.C: § 352(a)].
Below is an analysis of the regulatory status of (b)(4) Skin Protectant Cream and (b)(4) Skin Protectant which includes excerpts of the violative labeling and the specific new drug and misbranding charges. Note that this is not an all-inclusive description of violative labeling for your OTC drug products.
(b)(4) Skin Protectant Cream
The package labeling for (b)(4) Skin Protectant Cream includes the claims that establish the intended use of the product as a drug. Specific examples of claims are as follows:
“Skin Protectant”
“ACTIVE INGREDIENT:…(b)(4)% and (b)(4)%”
“PURPOSE: Occlusive Skin Protectant Cream with (b)(4).”
“USES: Aids in the prevention and treatment of diaper dermatitis (rash). Helps protect skin from moisture and wetness.”
The above statements demonstrate that (b)(4) Skin Protectant Cream is a “drug” as defined by section 201(g)(1) of the Act [21 U.S.C. § 321(g)(1)] because it is intended to prevent disease or to affect the structure or function of the body of man. Although the labeling clearly lists (b)(4) and (b)(4) as active ingredients, (b)(4) and (b)(4) are also “active ingredients” under 21 C.F.R. § 201.66(b)(2) because, based on representations on the product label (e.g., the juxtaposition of “(b)(4)” to the label claims “PURPOSE: Occlusive Skin Protectant”), they are intended to furnish pharmacological activity or other direct effect in the mitigation and treatment of diaper rash.
Under FDA’s OTC monograph system (also referred to as the “OTC Drug Review”), the agency is evaluating the safety and effectiveness of active ingredients in OTC skin protectants offered for the treatment or prevention of diaper rash. Pending a final rule or monograph for such products, FDA does not object to the marketing of such diaper rash products as long as they meet both the formulation AND labeling requirements described in the tentative final monograph (TFM) for these products or the product is otherwise eligible for consideration under the ongoing rulemaking. The TFM was published in the Federal Register of June 20, 1990 (55 FR 25204). See:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm091669.pdf
However, (b)(4) Skin Protectant Cream is neither labeled nor formulated in accordance with the TFM. Specifically, the ongoing rulemaking does not propose or otherwise include a skin protectant product with (b)(4) as an active ingredient. In addition, we are unaware of any evidence that a product so formulated and labeled was marketed in the United States on or before the inception of the OTC Drug Review and therefore such a product would not be eligible for consideration under the ongoing review. Therefore, (b)(4) Skin Protectant Cream does not qualify for evaluation and marketing under the OTC Drug Review. Furthermore, we are not aware of any evidence establishing that (b)(4) Skin Protectant Cream, as formulated and labeled, is generally recognized as safe and effective. Therefore, it is a “new drug” under section 201(p) of the Act [21 U.S.C. § 321 (p)] and may not be legally marketed in the United States without an approved application under section 505(a) of the Act [21 U.S.C. § 355(a)].
DRUG REGISTRATION VIOLATIONS
Your firm failed to fulfill its registration obligations under Section 510(i)(1) of the Act and its listing obligations under Sections 510(i)(2) and 510(j), which is prohibited under Section 301(p). 21 U.S.C. [360(i)(1) and (2), 360(j), and 331(p)]
For example, from 2009 through 2012, your firm offered for import into the United States drugs that you manufactured or otherwise processed at the above-referenced establishment. During that same time period, however, your firm did not maintain a current establishment registration and complete and accurate drug product listing with the FDA.
Please note that a drug offered for import into the United States may be refused admission under Section 801(o) of the Act if the importer, owner, or consignee is not able to provide a statement of the registration of the establishment that manufactured it. In addition, if a drug is not listed in accordance with Section 510 of the Act, including if the listing for the drug references a manufacturing establishment that does not maintain a current establishment registration, the drug appears to be misbranded under Section 502(o) and subject to refusal of admission under Section 801(a)(3). [21 U.S.C. 352(o)]
The FDA investigator(s) discussed this issue with you during the inspection. Your response did not address this issue. Information on how to register and list is available at the following internet website: http://www.fda.gov/cder/drls/registration_listing.htm. If you continue to produce drugs that are offered for import into the United States, you must complete the required registration and listing. You should provide evidence that you have fulfilled these requirements in your response to this letter.
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 Shanghai Huhui Daily Use Chemical Products Co., Ltd, in Liuzao Town, Shanghai, 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 CGM P 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 action 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 (b)(4) Skin Protectant Cream, (b)(4) Skin Protectant, or (b)(4) Skin Protectant, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI #3003271254.
Yanyan (Jenny) Qin
Tel: (301) 796-3207