| Public Health Service Food and Drug Administration |
| Los Angeles District Pacific Region 19701 Fairchild Irvine, CA 92612-2506 Telephone: 949-608-2900 FAX: 949-608-4415 |
Department of Health and Human Services
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
December 6, 2010
W/L 15-11
Mr. Thomas M. Raffy
President and Owner
GAR Laboratories, Inc.
1844 Massachusetts Avenue
Riverside, CA 92507
Dear Mr. Raffy:
During our July 13 - 29, 2010 inspection of your pharmaceutical manufacturing facility, GAR Laboratories, Inc., located at 1844 Massachusetts Avenue, Riverside, California, 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 CGMP 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.
In addition, this inspection also revealed that your drug product (b)(4) is labeled using a phrase that appears to cause confusion to the user who may believe that the term herpes simplex would include genital herpes. As described below, this causes the product to be misleading and misbranded under section 502(a) of the Act.
We have reviewed your firm’s response, dated August 13, 2010, and note that this response lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited to, the following:
CGMP Violations
1. Your firm has 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 [21 C.F.R. § 211.22(a)].
For example, your firm failed to comply with recommendations by your Quality Control Unit (QCU) to destroy drug products used to treat acne because of failing assay results in three separate instances (i.e., (b)(4) (lot (b)(4)) and (b)(4) (lots (b)(4) and (b)(4)). At the direction of your firm’s Plant manager, the affected lots were reworked to pass testing without a documented justification.
In your response, you stated that your firm would draft a new Standard Operation Procedure (SOP) addressing the QCU’s roles and responsibilities by September, 2010. Your response, however, is inadequate because you have not yet provided this SOP (b)(4) detailing the QCU’s authority to approve and reject all in-process materials and drug products.
2. Your quality control unit has not approved or rejected all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product [21 C.F.R. § 211.22(c)].
For example, the following changes were made to formulations and specifications by your Research and Development Department without QCU review and approval:
• A material consisting of (b)(4) benzoyl peroxide was substituted for (b)(4) in the manufacturing of the (b)(4)
• The specification for in-process bulk and finished product assay for benzoyl peroxide was changed from (b)(4) of the labeled strength to (b)(4) of the labeled strength for the (b)(4) and the (b)(4) products.
In your response, your firm stated that your QCU shall review and approve written procedures that are drafted, reviewed, and approved by the appropriate organizational unit. However, your response is inadequate because you have not provided any documentation to demonstrate that QCU review and approval of daily production and control record is being performed.
3. Your firm’s quality control unit has failed to review and approve all drug product production and control records to determine compliance with all established and approved written procedures before a batch is released or distributed; and your firm does not maintain a written record of investigations including conclusions and follow-up [21 C.F.R. § 211.192]. For example,
a. Your firm’s QCU has failed to review batch production records prior to release and distribution of the batch. The batch record for (b)(4) (lot (b)(4)) was observed without a signature for final release by the QCU.
In your response, your firm states that the QCU will be required to review and approve all production records to determine compliance with procedures prior to release or distribution, effective August 2010. However, your response is inadequate because you have not provided any documentation to demonstrate that your QCU has started this review of batch production records.
b. Your firm did not perform and document investigations into Out-of-Specification (OOS) results on topical drug products that included (b)(4) and (b)(4). Your firm did not perform and document investigations into conflicting OOS microbiological results obtained from in-house testing and testing performed by a third party contract laboratory.
c. Your firm failed to investigate the cause of at least twenty-five (25) out-of-limit results for the deionized water system.
In your response concerning example (b) and (c) above, you state that you will revise your current SOP (b)(4) to include a more detailed procedure of investigation. Your response, however, is inadequate because you have not provided your revised procedure or any documentation to show that it has been appropriately implemented.
4. Your firm does not have adequate written procedures, and does not follow those procedures, for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100].
For example, your firm has failed to validate a number of procedures and processes used in the manufacture of your drug products. Specifically, your firm does not have data to verify that the mixing times used for bulk drug products are adequate to produce homogeneity. Further, you have not provided any data to demonstrate that your bulk drug products, such as the (b)(4) can be stored for extended periods of time under ambient conditions without altering their identity, strength, quality, and purity.
In your response, you state that you are “fielding expert individuals” to establish proper process controls. Your response, however, is inadequate because you fail to: (1) provide timelines for implementing your corrective actions; (2) reference the specific processes you intend to validate, or; (3) provide the validation protocols or plans you intend to implement.
5. Your firm has not established or followed written procedures for the cleaning and maintenance of equipment [21 C.F.R. § 211.67(b)].
For example, your firm does not have data to demonstrate your cleaning processes for non-dedicated manufacturing equipment (i.e., blending tanks, storage totes, fillers, and transfer piping) and utensils are adequate.
In your response, your firm states that you will draft procedures for the cleaning of manufacturing equipment by October 2010, and that these will be effective November 2010. Your firm is responsible for assuring the adequacy and robustness of these procedures, and we will evaluate this issue during the next inspection.
6. Your firm has not established scientifically sound appropriate specifications, standards, sampling plans, and test procedures designed to assure that in-process materials and drug products conform to appropriate standards of identity, strength, quality and purity [21 C.F.R. § 211.160(b)]. For example,
a. Your firm does not use reference standards obtained from an official source for the (b)(4) testing of APIs (i.e., (b)(4) USP and (b)(4) USP) that are used in your firm’s OTC drug products.
b. Your firm does not ensure that the samples taken for release testing are representative of the entire batch. There is no data to show that the samples taken for assay and microbiological analyses from the top and bottom of your compounding tanks are sufficient to demonstrate batch uniformity. Additionally, there is no statistical rationale for the number of samples collected for finished product sampling.
c. Your firm has not validated your testing procedures. Your laboratory methods for microbiological analysis of purified water used in the manufacture of your drug products have not been validated to demonstrate accuracy and equivalence to compendial methods.
d. Your firm has not performed or documented system suitability tests for the (b)(4) assays to verify that the resolution and reproducibility of your (b)(4) system are adequate prior to your analysis of product samples.
In your response, you state that you will (1) draft new sampling procedures, (2) begin using USP reference standards for (b)(4) analysis, and (3) begin top, middle and bottom sampling to evaluate blend uniformity. Your response, however, is inadequate because you have not provided documentation to demonstrate that you are using USP standards as the reference standards for (b)(4) testing. In addition, you have not provided any documentation of the new sampling procedures to evaluate blend uniformity or your new (b)(4) that describes how sampling will be based on “the quantity produced.” Further, your response does not address the validation of the methods used for the microbiological analysis of purified water samples.
7. Your firm has failed to use equipment in the manufacture, processing, packing, or holding of drug products that are of appropriate design, of adequate size, and suitably located to facilitate operations for its intended use [21 C.F.R. § 211.63].
For example, your firm has failed to validate the deionized water system that supplies the process water used in all drug products manufactured at your facility. Further, your firm has not established a maintenance program for your water system or validated the biweekly sanitization process to ensure that it extends to all areas of the recirculation loop and that the deionized water meets specifications.
In your response, your firm plans to include additional sampling points for your water system to qualify the water quality of the holding tank. Your response is inadequate because you fail to specify where these sampling sites are located. In addition, your response does not include any details describing the following: (1) the 12-month study to determine whether an increase in sanitization frequency is required; (2) the monitoring of conductivity and Total Organic Carbon (TOC), or; (3) documentation for revising the Piping & Instrumentation Diagram (P&ID). Also, the minimum acceptable quality standard for water used in drug product manufacture is found in the United States Pharmacopeia. Please see the Purified Water, USP, monograph. Also, see FDA’s Guide to Inspections of High Purity Water Systems (1993) for discussion of appropriate microbial action levels and water system validation approaches.
8. Your firm has failed to follow your written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expirations dates [21 C.F.R. § 211.166(a)].
For example, your procedures require the first three lots of each product “to be placed on stability testing,” and for stability studies to be performed on the first lot of each product produced in subsequent calendar years. These procedures were not followed in that the first lot of each product was not placed on stability in subsequent years. You do not have stability data for any of your drug products to demonstrate these products will meet the intended finished product specifications for the shelf life of the product. In addition, your bulk lot (b)(4) and bulk Lots (b)(4) and (b)(4) of (b)(4) were found to be out of specifications after 7-9 months in storage.
In your response, your firm states that you will be finalizing your stability program procedure by October 2010. However, your response is inadequate because you do not provide any details concerning the stability program or any specific information or documentation to demonstrate that your products will meet specifications at expiration.
9. Your firm has not established or followed written procedures prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to assure that the reprocessed batches will conform with all established standards and performs reprocessing of batches without review and approval of the quality control unit [21 C.F.R. § 211.115(a) and (b)]. For example,
a. Your firm has failed to establish any written procedures for reprocessing bulk drug products.
b. Your QCU did not review and approve the reprocessing of two bulk lots of (b)(4) and one bulk lot of (b)(4).
In your response, you state that you will draft a written procedure that defines the roles and responsibilities of the QCU by October 2010. However, your response is inadequate because you do not address the QCU’s review of batch reprocessing or the establishment of any written procedures pertaining to that review and approval.
10. Your firm has failed to maintain all production and control records associated with a batch of drug product for least one (1) year after the expiration date of the batch [21 C.F.R. § 211.180(a)]. For example,
a. Your firm failed to maintain records regarding the adjustments made to the bulk product for (b)(4) (lot (b)(4)) prior to the filling and distribution of the bulk material.
b. Your firm failed to maintain records for the reprocessing or reworking of drug product batches, specifically when the drug product failed to meet specifications after long-term storage in plastic totes. The remaining portion of Lot (b)(4) of (b)(4) was found to be OOS for assay and pH when re-tested seven months after manufacture. Representatives of your firm stated this lot was reworked by adjusting the bulk material prior to filling. However, there is no documentation of this occurrence.
11. Your firm’s laboratory records failed to include complete data derived from all tests, examinations, and assays necessary to assure compliance with established specifications and standards [21 C.F.R. § 211.194(a)].
For example, your firm failed to maintain records derived from the (b)(4) analyses of in-process bulk and finished drug products. Laboratory notebooks containing sample information such as analytical dates, sample weights, calculations, and analytical results for all your products analyzed from August 2009 to February 2010 were not maintained.
In your response, you indicate that you will implement corrective actions, including necessary documentation in your laboratory notebooks. Your response, however, is inadequate because you have not demonstrated how or when you will implement these changes.
12. Your firm failed to store drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity are not affected [21 C.F.R. § 211.142(b)].
For example, your storage warehouse area (Building (b)(4)) is not temperature-controlled when storing raw materials, in-process bulk product, and finished drug products. On July 19, 2010, temperatures in this warehouse area were observed to range from 88.7º F to 93.5º F.
In addition, your firm has not performed temperature or humidity mapping studies in the in-process bulk and finished products area to determine if the warehouse is capable of consistently providing conditions that meet the storage requirements.
In your response, you state that you will be “fielding expert individuals” to assess temperature and humidity controls. Your response is inadequate because you do not provide definitive corrections or a corrective action plan.
13. Your firm failed to establish written procedures to evaluate, at least annually, the quality standards, including provisions for a review of complaints, recalls, returned or salvaged drug products, and investigations conducted for each drug product [21 C.F.R. § 211.180(e)(2)].
For example, your firm has failed to establish written procedures for annual product reviews. To date, your firm has not conducted any annual product reviews for any manufactured drug products.
In your response, your firm states that you are currently conducting an annual review of your drug products with a completion date of December 2010. Your response, however, is inadequate because you have not provided any documentation as evidence of this review. In addition, your timeframe for completion (i.e., December 2010) is unacceptable.
Misbranded Over-the-Counter (OTC) Drugs
During the inspection noted above, the investigators collected your labeling for the product (b)(4) As presently labeled and promoted, this product is a misbranded drug in violation of section 502(a) of the Act. This violation is described in more detail below.
Your labeling, which includes the Internet Web site (b)(4) for (b)(4) states, (b)(4) herpes simplex infection. (b)(4) This statement represents and suggests that your product can be used to treat herpes simplex infections; however, this indication is unacceptable. FDA has described how the term “herpes” is too broad, may be misleading to the consumer who may associate the term with the genital form of herpes, and is not acceptable for use in OTC labeling in the External Analgesic Drug Products for Over-The-Counter Human Use; Proposed Rulemaking for Fever Blister and Cold Sore Treatment Drug Products, 55 Fed. Reg. 3370 (Jan. 31, 1990). Therefore, the above quoted statement, because it is misleading, causes the product to be misbranded under section 502(a) of the Act [21 U.S.C. § 352(a)].
The violations cited in this letter are not intended to be an all-inclusive statement 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. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant having appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that your drug products have their appropriate identity, strength, quality, and purity.
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 products, and provide the date(s) and reason(s) you ceased production.
Your reply should be sent to the attention of William Vitale, Compliance Officer, at the following address: Food and Drug Administration, Los Angeles District Office, 19701 Fairchild, Irvine, California 92612.
Sincerely,
Alonza E. Cruse
District Director
Los Angeles District
(b)(4)
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