| Public Health Service Food and Drug Administration |
| Silver Spring MD 20993 |
Department of Health and Human ServicesWarning Letter
VIA UPS MAIL
WL: 320-10-07
July 20, 2010
Ms. Goh Bee Leong
General Manager
Haw Par Healthcare Limited
2 Chia Ping Road
#09-00 Haw Par Tiger Balm Building
Singapore 619968
Dear Ms. Leong:
During our October 26-29, 2009 inspection of your over-the-counter (OTC) drug manufacturing facility, Haw Par Healthcare Limited, located at 2 Chia Ping Road #09-00, Haw Par Tiger Balm Building, Singapore, investigators 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.
In addition, this inspection revealed that TIGER BALM® Pain Relieving PATCH (Tiger Balm) is misbranded and in violation of section 502(a) of the Act [21 U.S.C. § 352(a)].
We acknowledge your written response, dated November 30, 2009, to the Form FDA 483. We plan to evaluate the response, along with any other written material provided, as a direct response to this Warning Letter.
Specific violations observed during the inspection include, but are not limited, to the following:
1. 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)]. For example,
a) The specificity test, included in the method validation reports for KWAN LOONG OIL® PAIN RELIEVING AROMATIC OIL (Kwan Loong) (active ingredients: methyl salicylate, and menthol) and Tiger Balm (active ingredients: camphor, menthol, and capsicum extract), is inadequate. It has not been shown to be capable of detecting potential impurities. In addition, no forced degradation studies were conducted for the validation of these two methods. The analytical methods used for release and stability (for batches (b)(4) and (b)(4) of Kwan Loong and (b)(4) and (b)(4) of Tiger Balm) have not been determined as appropriate for determining and monitoring the impurity profile. We are concerned that several unknown peaks were observed at the time of release and during the stability studies for Tiger Balm, but no attempt was made to identify these peaks. The inspection also reported that the instruments and method parameters used are not documented.
In your response to this letter, provide the updated validation reports of both assay methods, including the specificity studies performed to demonstrate that both assay methods are stability indicating and appropriate for determining and monitoring impurity profiles.
b) Your firm failed to assess the (b)(4) in your finished products for both Kwan Loong and Tiger Balm, which are marketed in the United States. In addition, the certificate of analysis for methyl salicylate API (Active Pharmaceutical Ingredient) provided by your supplier lacks a residual solvents test result.
Your firm has a memo from the API manufacturer assuring you that the API (methyl salicylate) does not contain any solvents included in the USP residual solvent tables, except (b)(4), of which the concentration is very low. Subsequently, there is no assurance that your manufacturer tested or confirmed that the level that may be present is within the (b)(4) USP limit.
Please provide corrective actions to this issue with supportive documents, including testing criteria for (b)(4) in your Certificate of Analysis, for both of your finished products and methyl salicylate API.
c) Your assay method validation of methyl salicylate API by gas chromatography (GC) analysis is inadequate in that it lacks a specificity determination. During the inspection, your laboratory supervisor indicated that a (b)(4) standard was injected. However, no evidence or documentation confirming that this standard was injected during the chromatographic run was available. As explained by your laboratory supervisor, (b)(4) was identified as a possible impurity present in the API.
Please provide a completed validation report for the GC assay method as part of your response to this letter. It should include the specificity studies performed to demonstrate that the assay method is capable of analyzing methyl salicylate without interference from other impurities, including (b)(4).
The inspection also reported that the syringe used during your GC analysis is a 10.0 μL syringe. However, the current method injection volume is 0.2 μL. Please provide supportive data to justify whether the 10.0 μL syringe used in the method for GC injection can precisely and accurately measure 0.2 μL of the methyl salicylate API sample solution.
d) Your GC and high performance liquid chromatography (HPLC) analyses for both finished products and raw materials lack appropriate system suitability determinations. Your SOP TMA-KLOF2/02, “Method of Analysis of Kwan Loong” and SOP MA/TBPW/10, “Tiger Balm Plaster - RD/Tiger Balm Medicated Plaster - RD/Tiger Balm Patch,” each specify three standard solution injections. Both methods are used for testing of drug products at batch release and during stability study. In addition, your assay test of methyl salicylate API (lot (b)(4)) by GC analysis was conducted with a single injection of pure standard, and a single injection of sample.
Your laboratory supervisor indicated that you do not perform system suitability because the analysis consists of an injection of pure methyl salicylate standard without dilution. He also indicated that the potency is determined using the total percent peak area results. Please note that the system suitability test is an integral part of a chromatographic method, regardless of the drug product or API being tested. It is your responsibility to have appropriate specifications and acceptance limits as part of your system suitability determination. You are required to ensure that the chromatographic system is adequate for its intended analysis prior to use. Otherwise, the accuracy and precision of HPLC data collected are potentially compromised. Please provide corrective actions with supportive documentation to address this issue.
2. Your firm fails to thoroughly investigate unexplained discrepancies or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 C.F.R. § 211.192].
For example, the stability assay test chromatograms for Tiger Balm, lot (3 and 6 months stability at temperature of 30°C), contained co-eluting peaks. These tests and results were approved without investigation by your quality control unit. Specifically, during the HPLC analysis, the capsaicin peak (peak of interest) was observed co-eluting with an unknown peak, while a second large unknown peak was also present in front of the capsaicin peak. Additionally, the system suitability was performed using only three standard solution injections at the end of the run and was not performed before the sample injections. Therefore, there is no assurance that the instrument was running properly prior to the sample analysis. In your response to this letter, please provide corrective actions with supportive data to address this issue.
3. Representative samples are not taken of each shipment of each lot of components for testing or examination [21 C.F.R. § 211.84(b)].
For example, your sampling plan of incoming components was not representative. Your SOP QC10/SOP/004.08 contains an exception for menthol API that states, “Collect four samples if the raw material comes directly from the manufacturer with dedicated production,” regardless of the lot size of incoming material your firm received. Menthol API lot (b)(4) consisted of (b)(4) drums, but only 4 drums were sampled for testing. In addition, your quality control unit demonstrated that SOPs were not followed [21 C.F.R. § 211.80(a)]. The same SOP requires the collection of (b)(4) API samples, if between (b)(4)containers are received. Your quality control unit collected only 4 samples from (b)(4) drums of methyl salicylate (lot (b)(4)).
Please provide scientific rationale for your current sampling procedure and any revised SOPs with supportive documents.
4. There is no assurance that your firm establishes 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)(2)].
For example, your vendor qualification has not provided adequate evidence that the manufacturer can consistently supply raw materials that meet appropriate quality attributes. Suppliers are not monitored and regularly scrutinized to ensure ongoing reliability. Specifically, your firm has not adequately qualified the supplier of methyl salicylate API. There is no assurance that the API suppliers are in compliance with CGMPs, without supplier qualification by your firm and knowing how APIs have been manufactured, tested, and if quality is consistently assured. There is also no assurance that your firm has established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.
Provide related corrective actions with supportive documents and procedures for qualifying your suppliers.
5. Your firm does not follow written production and process control procedures in the execution of various production and process control functions, or record and justify deviations from the written procedures. [21 C.F.R. § 211.100(b)]. For example,
a) Your performance qualification protocol planned for the manufacture of a (b)(4) batch size of Kwan Loong. However, your three conformance batches (process validation lots) for Kwan Loong consisted of a (b)(4) (lot (b)(4)), and two (b)(4) (lots (b)(4) and (b)(4)) lots. These lot sizes differed from your (b)(4) commercial batch size for the U.S. market (e.g., lot (b)(4)).
b) Your three conformance batches were (b)(4) Your process has not been qualified to manufacture the (b)(4) batch size because your process validation batches were not prepared using your routine process parameters and production batch size.
Please provide corrective actions with supportive documents to demonstrate that your manufacturing process of Kwan Loong has been validated.
6. Your employees engaged in the manufacture, processing, packing, holding of a drug product lack the training required to perform their assigned functions [21 C.F.R. § 211.25(a)].
For example, your SOP and batch (b)(4) instructions are in English (the official language in Singapore). However, one operator who works in the processing of the plaster line for the finished product of Tiger Balm cannot read English. The investigator asked the operator to read step #(b)(4) of the batch production record (BPR) for processing the plaster (batch (b)(4)) and show what item is listed in the step. This step reads in part, "Use a (b)(4).” However, the operator pointed to the panel that displayed values of temperature and RPM for the control for the (b)(4).
In response to this letter, provide corrective actions with supportive documents, including training records, to address this issue.
7. Your laboratory records are deficient in that they do not include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays [21 C.F.R. § 211.194(a)]. For example,
a) Samples and standard weights are written by the analysts in their personal notebook and then transferred to the analytical worksheet, as reported by an analyst during the inspection. These notebooks are not controlled documents. They are not referred to on the analytical worksheet, or reviewed as part of the analytical worksheet review process by your quality control unit.
b) The laboratory instruments and method parameters used are not documented on the analytical worksheets. Analysts write the %RSD results with pencil on the chromatograms and do not explain how the result was obtained - no example calculation is included.
Please provide training records and related procedures to demonstrate that analysts have been adequately trained on how to record and document the laboratory data to comply with CGMP requirements.
In addition to the issues referenced above in this letter, the inspection found that your stability samples are not properly controlled, stored, and maintained. 21 C.F.R. § 166(a)(2) requires that a written testing program include appropriate storage conditions for samples retained for testing. The investigator observed that the temperature and relative humidity of the room where the stability samples are stored were not being monitored or controlled. The investigator also noted that your stability room was established three weeks prior to the inspection and consisted of a standard office. The room lacked the appropriate controls and was used to store samples from the floor to the ceiling. A control box connected to three home humidifiers is used to monitor the humidity, while a small home heater is used to control the room’s temperature. Additionally, the door and roof of this stability room were not sealed, and no temperature and humidity mapping had been performed. We are concerned that the data generated from your stability studies, and used to establish drug products' expiration dates, may not be reliable because of the inadequate storage conditions. Provide the supporting data to demonstrate that the storage conditions for samples retained for testing are appropriate (e.g., mapping studies). Also, provide a copy of your stability protocol.
Misbranded Drug
Your firm is the manufacturer of TIGER BALM® Pain Relieving PATCH (Tiger Balm), an over-the-counter (OTC) drug that your firm labels as a topical analgesic for the temporary relief of minor aches and pains associated with arthritis, backaches, stiffness, and muscle strains. Tiger Balm meets the definition of a drug as defined in section 201(g) of the Act [21 U.S.C. § 321(g)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of a disease.
Drug products intended for the above indications are being evaluated under the Tentative Final Monograph (TFM) for OTC External Analgesics. The TFM was published in the Federal Register on February 8, 1983 [External Analgesic Drug Products for Over-the-Counter Human Use; Tentative Final Monograph, 48 Fed. Reg. 5852 (Feb. 8, 1983)]. The label for Tiger Balm declares its active ingredients, camphor, menthol, and capsicum, in milligrams. Active ingredients that are proposed as generally recognized as safe and effective for external analgesic indications are to be declared, in section 348.12 of this TFM, in percentages not milligrams. This causes Tiger Balm to be misbranded under section 502(a) of the Act [21 U.S.C. § 352(a)].
The label for Tiger Balm includes the additional statement, "its ingredients penetrate the skin and are absorbed, thus stimulating blood circulation around the area of pain." The TFM does not include the terms, "ingredients penetrate the skin and are absorbed," and, "stimulating blood circulation," as allowable indications and we are not aware of any OTC product formulated and labeled like Tiger Balm having been available in the U.S. market, at the inception of the OTC Drug Review. While the TFM allows for statements describing pain relief as "penetrating," it does not propose that any of its "ingredients penetrate the skin and are absorbed." Nor does the TFM propose any language regarding, "stimulating the blood circulation." Such language suggests a novel delivery system causing Tiger Balm to be a new drug requiring NDA approval [21 C.F.R. § 310.3(h)(5)]. Since Tiger Balm is not the subject of an approved new drug application, its marketing in the United States violates section 505(a) of the Act [21 U.S.C. § 355(a)]. Accordingly, Tiger Balm is a new drug as defined by section 201(p) of the Act [21 U.S.C. § 321(p)].
A description of the new drug approval process can be found on FDA's internet website at http://www.fda.gov/cder/regulatory/applications/default.htm. Any questions you may have regarding this process should be directed to the Food and Drug Administration, Division of Drug Information (HFD-240), Center for Drug Evaluation and Research, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993-0002.
The issues and violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility or in connection with your product. 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. If you wish to continue to ship your drug products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Failure to correct these violations may result in FDA refusing admission of articles manufactured at Haw Par Healthcare Limited, 2 Chia Ping Road #09-00, Haw Par Tiger Balm Building, Singapore, into the United States. 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 Current Good Manufacturing Practice 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 violations. Include an explanation of each step being taken to prevent the recurrence of violations and 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 correction. Additionally, your response should state if you no longer manufacture or distribute Tiger Balm and Kwan Loong at this facility, and provide the dates and reasons you ceased production. Please identify your response with FEI #3001432470.
If you have questions or concerns regarding this letter, contact Yanyan (Jenny) Qin, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3207
Fax: (301) 847-8741
Sincerely,
/Richard L. Friedman/
Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
No comments:
Post a Comment