Inspections, Compliance, Enforcement, and Criminal Investigations

Transcription

1 Page 1 of 8 HomeInspections, Compliance, Enforcement, and Criminal InvestigationsEnforcement ActionsWarning Letters Inspections, Compliance, Enforcement, and Criminal Investigations Capco Custom Packaging Inc 2/20/13 Department of Health and Human Services Public Health Service Food and Drug Administration Los Angeles District Fairchild Irvine, CA Telephone: FAX: WARNING LETTER VIA UNITED PARCEL SERVICE SIGNATURE REQUIRED February 20, 2013 Mr. Albert Licciardo President & CEO Capco Custom Packaging Inc Greenleaf Ave Santa Fe Springs, CA WL # Dear Mr. Licciardo: The United States Food and Drug Administration (FDA) inspected your firm located at Greenleaf Ave, Santa Fe Springs, California, from May 4-18, Our investigation revealed significant violations of the Current Good Manufacturing Practice (CGMP) regulation for dietary supplements, Title 21, Code of Federal Regulations, Part 111 (21 CFR Part 111). These violations cause your dietary supplement products to be adulterated under Section 402(g)(1) of the Federal Food, Drug and Cosmetic Act (the Act), 21 U.S.C. 343(g)(1), because they have been prepared, packed, or held under conditions that do not meet the CGMP regulations for dietary supplements. In addition, our investigation 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. You may find the Act and FDA regulations through links at FDA s home page at 1. These observations were presented to you in an FDA-483 at the conclusion of our inspection on May 18, We have reviewed your responses dated June 11, 2012 and July 7, 2012, and specifically address your June 11, 2012 response below as it addresses violations of 21 CFR Parts 111 and 211.

2 Page 2 of 8 Specific violations observed during the inspection include, but are not limited, to the following: Dietary supplement Violations 1. You failed to establish and follow laboratory control processes that are reviewed and approved by quality control personnel, for use of criteria for selecting standard reference materials used in performing tests and examinations, as required by 21 CFR (d). Specifically, you use the first shipment of raw materials received as the standard for subsequent incoming shipments. However, you failed to establish any criteria to establish a reference standard. In addition, you failed to identify the reference standard used for your identity testing, including the certification of accuracy of the known reference standard and a history of recertification of accuracy, as required by 21 CFR (b)(3)(iii). response to be inadequate. You state in your letter that you commit to perform a comprehensive assessment of the controls necessary for all standards and sampling plans currently incorporated into the laboratory to ensure compliance with current standards. However, you have not specified when you will establish and follow laboratory control processes that are reviewed and approved by quality control personnel for use of criteria for selecting standard reference materials used in performing tests and examinations, as required by 21 CFR (d). You also state in your letter that you are committed to acquiring primary reference standards from a recognized reference standard supplier, or to otherwise purifying a batch of raw materials such that it would meet the requirements of a reference standard. You provided a completion date of August 30, However, you have not provided FDA with the new protocols as of November 1, Therefore we could not evaluate the adequacy of your modified protocols. 2. You failed to determine whether the specifications you established for limits on contamination that may adulterate or may lead to adulteration of the finished batch of dietary supplement were met, as required by 21 CFR For example, your laboratory does not follow the USP Microbial Limits Method for Total Plate Count and Yeast and Molds as referenced in your batch records. Your total aerobic counts are not performed in duplicate in accordance with the USP. Additionally, your sample volumes for total aerobic count were 1mL and not 10mL as indicated in the USP. response to be inadequate because you did not provide documentation to show that you have amended your protocols. You state in your letter that you commit to following the procedures in USP <61> for the Microbial Limits Method for Total Plate Count and Yeast and Molds, and to changing your protocols to be consistent with the USP procedure, including correct sample volumes and the performance of the analytical experiments in duplicate. You also state in your letter that you commit to completing the amendment of your protocols for the Microbial Limits Method for Total Plate Count and Yeast and Molds by the end of the third quarter of However, as of November 1, 2012, we had not received a copy of your proposed new protocols. Therefore we could not evaluate the adequacy of your modified protocols. 3. Your batch production records failed to include complete information relating to the production and control of each batch, as required by 21 CFR (b) and Specifically, your batch records failed to include the following: Baby's DHA liquid lot (b)(4):

3 Page 3 of 8 The identity of the scale used for weighing of the raw materials was not recorded [21 CFR (b)] Documentation that the finished dietary supplement meets specifications established in accordance with (e) and (g) was not recorded [21 CFR (i)] Documentation of the mixing time and net weight of the final blend was not recorded [21 CFR (j)] Initials of the person responsible for adding the component to the batch for mixing and verifying this step was not documented [21 CFR (j)(2)(iii)] Documentation at the time of performance that quality control personnel approved and released the batch for distribution, including any reprocessed batch was not recorded [21 CFR (l)(3)] Baby's DHA liquid, batch (b)(4) continued: Documentation at the time of performance that quality control personnel reviewed the results of any tests and examinations conducted on in-process materials was not recorded [21 CFR (l)(1)(ii)] A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing were not recorded [21 CFR (f)] Pro DHA Infant liquid, batch (b)(4): The initials of the person responsible for weighing or measuring each component used in the batch was not documented [21 CFR (j)(2)(i)] The minimum fill weight was not documented [21 CFR (e)] Documentation at the time of performance that quality control personnel reviewed the results of any tests and examinations conducted on in-process materials was not recorded [21 CFR (l)(1)(ii)] Documentation at the time of performance that quality control personnel approved and released the batch for distribution, including any reprocessed batch was not recorded [21 CFR (l)(3)] response to be inadequate. You state in your letter that you will correct the deficiencies by the end of the third quarter of 2012 to complete these corrections. However, as of November 1, 2012, we had not received a copy of your proposed new protocols. Therefore we could not evaluate the adequacy of your modified protocols. 4. You failed to prepare and follow a written master manufacturing record for each unique formulation of a dietary supplement that you manufacture to ensure uniformity in the finished batch from batch to batch, as required by 21 CFR Specifically, although your SOP (b)(4) titled Master Manufacturing Records requires your firm to create an MMR for each formula and for each batch size that is manufactured, you stated at the time of inspection your firm uses a working batch record for each unique formula. response to be inadequate. You state in your letter that SOP (b)(4), Master Manufacturing Records will be reviewed and revised to ensure that the content is accurate and current with CAPCO manufacturing activities, and that Master Manufacturing Records (MMRs) will be issued for dietary supplements according to SOP (b)(4): Master Manufacturing Records. You also state that completed MMRs are attached with this response (Attachment 14). Based on our review, we found the MMRs to be deficient, because the MMRs did not contain the information required in 21 CFR , including the specifications required under (h) (1) and the specific actions required under 21 CFR (h)(3). 5. Your firm did not confirm the identity of other components (not including dietary ingredients) and determine whether other applicable component specifications established

4 Page 4 of 8 in accordance with 21 CFR are met by conducting appropriate tests or examinations; or relying on a certificate of analysis (COA) from the supplier of the component that you receive, provided that, among other requirements, you first qualify your component suppliers by establishing the reliability of the suppliers COA through confirmation of the results of the suppliers tests or examinations, as required by 21 CFR (a)(2)(ii)(A). Specifically, your firm accepts Certificates of Analysis without establishing the reliability of the supplier s test results by independent testing or confirmation. Furthermore, you stated at the time of inspection you did not know it was a requirement to establish the reliability of the supplier's test results. response to be inadequate because you have not provided evidence of implementation of your proposed corrective actions nor have you provided a quarterly update as mentioned in your response demonstrating your components are from qualified suppliers. You state in your letter that CAPCO commits to perform a comprehensive assessment of the controls necessary for component, raw material, and active ingredient acceptance activities currently incorporated in the laboratory to ensure compliance with USP and regulatory requirements. We would first like to emphasize that there are no USP requirements with which you have to comply. The exceptions are only if you claim that a dietary ingredient, component or dietary supplement product meets USP compendial requirements, or that you are using a specific USP analytical protocol, in which case you have to meet the USP compendial requirements or the USP protocol, which you have set for yourself. The latter requirement is true for any standard or specification you set for your dietary ingredients, components or dietary supplement product; the established standards or specifications that you set must be met. Drug CGMP Violations 6. Your firm failed to thoroughly investigate any unexplained discrepancy or 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 CFR ]. For example, your firm failed to conduct investigations of out-of-specification (OOS) test results, as required per your written procedure, (b)(4), Out-of-Specification Result Investigation, obtained for the melting point of Camphor raw material, lot (b)(4) and for in-process capsule weight averages for Guaifenesin Capsules, (b)(4). We have reviewed your written response dated June 11, 2012, and determined it to be inadequate. We acknowledge your firm s commitments in this response to re-open the Campho investigation and retest all products containing this ingredient by end of third quarter 2012, as well as the commitment to modify your written procedure for weight checks. However, as of November 1, 2012, you provided no evidence that you implemented these corrective actions nor have you provided the promised quarterly updates indicating your progress toward their implementation. In your response to this letter, please provide documentation that your written procedure for handling OOS investigations does not permit invalidation of an OOS result on the basis of retest results alone. The fact that a retest generates a passing result, by itself, is not a scientifically sound reason for invalidating an OOS result. Due to lack of uniformity in the material analyzed or in the particular sample or sample portion, the OOS result may still be the correct result for that particular test. It cannot be automatically assumed that the OOS result was due to laboratory error. Such a determination is supportable when there is clear evidence of assignable cause. Also, your OOS SOPs should be corrected to clearly reflect that an OOS result cannot be invalidated on the basis of a statistical outlier test. An outlier test is a statistical analysis of the test results. It will not identify the cause of an extreme observation and does not invalidate a suspect result. For more information, see FDA s Guidance on Investigating Out-of-Specification Test Results for Pharmaceutical Production. 7. Your firm failed to establish laboratory controls that include 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

5 Page 5 of 8 purity [ 21 CFR (b)]. For example, your laboratory does not follow the USP microbial limits method for total plate count and yeast and mold testing as referenced in batch records for your over-the- counter (OTC) drug products, Guaifenesin Capsules, pain relieving liquid (Menthol 1.25% and Camphor 0.20%), and antifungal solution (1% Clotrimazole). In addition, your firm failed to use qualified reference standards for your identification testing of the raw materials used in the above referenced products by FT-IR. Also, your firm has not conducted any preparatory studies on these products to evaluate the products for inhibitory properties that may interfere with microbial limits testing. We have reviewed your June 11, 2012 response and have determined it to be inadequate. We acknowledge the corrective action commitments outlined in the responses, including your commitments to acquire new standard reference material for raw material identity testing by FT -IR, retest all lots of the three products and their associated active ingredients still in inventory by end of 3 rd quarter 2012, establish new procedures for microbial limits testing by end of 3 rd quarter 2012, and complete inhibition studies and validation of new test methods by end of 4 th quarter However, as of November 1, 2012, you did not provide any evidence that these corrective actions were implemented. You also have not provided the quarterly updates on corrective actions as promised in the response. 8. Your firm failed to follow required laboratory control mechanisms [21 CFR (a)]. For example, your written procedure, (b)(4) Water Testing, requires that the purified water you use as a component in drug manufacture be tested for conductivity and total organic carbon (TOC). Your firm failed to follow this procedure. We have reviewed your written response and acknowledge your firm s commitments to identify an outside testing lab for the testing, revise (b)(4) to better conform with USP requirements, and initiate testing of the purified water for the above referenced parameters by end of 3 rd quarter However, apart from a single document showing that you requested these analyses from an outside testing laboratory, you have not provided any evidence that these corrective actions have been implemented. 9. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use the results of such stability testing to determine appropriate storage conditions and expiration dates [21 CFR (a)]. For example, your firm failed to conduct stability studies to support the (b)(4) expiration dates assigned to the OTC finished drug products pain relieving liquid (Menthol 1.25% and Camphor 0.02%) and Guaifenesin Capsules as required by your written procedure (b)(4) Stability Testing and its revision, (b)(4) Stability Testing. In addition, your firm failed to perform antimicrobial effectiveness testing on 3 lots of the OTC finished drug product antifungal solution (1% Clotrimazole) as required by the revised procedure. We acknowledge the corrective revisions to your firm s written procedure and the commitments made in your responses to initiate new stability studies for the three referenced products using the services of an outside testing laboratory. However, you have not provided the quarterly updates that were promised in the responses. 10. Your firm failed to establish the reliability of the component supplier s analyses through appropriate validation of the supplier s test results at appropriate intervals [21 CFR (d)(2)]. For example, your firm accepts the test results from certificates of analysis provided by your component suppliers without establishing the reliability of the supplier s tests. We have reviewed your written response, including your revised written procedures, (b)(4) Raw Material Identity Testing and (b)(4) Raw Material Supplier Qualification Program, and acknowledge your commitments to conduct a product impact assessment and develop an action plan for further corrections by end of 4 th quarter However, your revised procedure for vendor qualification is inadequate because it contains no provision for periodic verification of a

6 Page 6 of 8 supplier s test results after the initial qualification. In addition, your firm has not provided the promised quarterly updates on the other corrective actions. 11. Your firm failed to establish adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of the in-process material and the drug product [21 CFR (a)]. For example: a. b. Your firm has conducted no blend uniformity testing on Guaifenesin Capsules to show adequacy of blending. Additionally, there is no data to show that the mixing time is adequate for all batch sizes. Your firm has not established a mixing time for the bulk pain relieving liquid (Menthol 1.25% and Camphor 0.02%). Additionally, there is no data to show that the resulting blend remains uniform during the maximum length of time allowed for the filling operation. We acknowledge the commitment made in your response to complete process validation activities, including confirmation of blend uniformity, establishment of blending times, and IO, OQ and PQ of equipment, for the above referenced products among others by the end of 4 th quarter However, your firm has not provided any documentation to show completion of these actions. 12. Your firm failed to establish and follow adequate written procedures for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures (21 CFR (e)). For example, since April 2011 your firm has not performed annual product reviews fo manufactured drug products as required by (b)(4) Annual Product Review. We acknowledge the commitment made in your responses to complete an annual review by the end of 3 rd quarter However, as of November 1, 2012, you had not provided any evidence of the completion of this review. 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. In addition to the violations cited above, we have the following comment: Your firm includes expiration dates on the labels for your dietary supplement products, including DHA, Pro DHA Infant, and Children s DHA products. During the inspection, you informed our investigators that you did not have any data supporting the expiration dates listed on your product labels. Any expiration date you place on a product label should be supported by data that demonstrates the product s shelf life [See 72 Fed. Reg , (Jun. 25, 2007). 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 these violations. Your response should include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete these corrective actions within fifteen

7 Page 7 of 8 working days, state the reason for the delay and the date by which you will have completed the correction. Section 743 of the Act (21 U.S.C. 379j-31) authorizes FDA to assess and collect fees to cover FDA s costs for certain activities, including re-inspection-related costs. A re-inspection is one or more inspections conducted subsequent to an inspection that identified noncompliance materially related to a food safety requirement of the Act, specifically to determine whether compliance has been achieved. Re-inspection-related costs means all expenses, including administrative expenses, incurred in connection with FDA s arranging, conducting, and evaluating the results of the re-inspection and assessing and collecting the re-inspection fees (21 U.S.C. 379j-31(a)(2)(B)). For a domestic facility, FDA will assess and collect fees for reinspection-related costs from the responsible party for the domestic facility. The inspection noted in this letter identified noncompliance materially related to a food safety requirement of the Act. Accordingly, FDA may assess fees to cover any re-inspection-related costs. Your reply should be sent to: Blake Bevill Director, Compliance Branch US Food & Drug Administration Fairchild, Irvine, CA If you have any questions about the content of this letter, please contact Dr. Raymond W. Brullo, Compliance Officer, at or raymond.brullo@fda.hhs.gov. Include the case identification number of # on all correspondence. Sincerely, /S/ Alonza E. Cruse, Director Los Angeles District Cc: Patrick Kennelly, Acting Chief California Department of Public Health Food and Drug Branch PO Box Capitol Avenue, MS-7602 Sacramento, CA Attn: FDA Correspondence Page Last Updated: 02/25/2013 Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players. AccessibilityContact FDACareersFDA BasicsFOIANo Fear ActSite MapTransparencyWebsite Policies U.S. Food and Drug Administration New Hampshire Avenue Silver Spring, MD Ph INFO-FDA ( ) FDA For GovernmentFor Press Combination ProductsAdvisory CommitteesScience & ResearchRegulatory InformationSafetyEmergency PreparednessInternational ProgramsNews & EventsTraining

8 Page 8 of 8 and Continuing EducationInspections/ComplianceState & Local OfficialsConsumersIndustryHealth ProfessionalsFDA Archive Links on this page: 1.