warning letter

warning letter SNBL USA LTD. Public Health Service Food and Drug Department of Health and Human Services Administration Silver Spring, MD 20993 WARNING LETTER CERTIFIED MAIL RETURN RECEIPT REQUESTED Reference No: 10-HFD-45-08-01 Hideshi Tsusaki, D.V.M., Ph.D. President, COO SNBL USA, Ltd. 6605 Merrill Creek Parkway Everett, WA 98203 Dear Dr. Tsusaki: Between July 21 and August 1, 2008, and between November 16 and 20, 2009, representatives of the Food and Drug Administration (FDA) inspected SNBL USA, Ltd. (SNBL) in Everett, WA. These inspections are part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to verify compliance with Title 21 of the Code of Federal Regulations (CFR), Part 58 – Good Laboratory Practice (GLP) regulation. The regulations at 21 CFR 58 apply to nonclinical laboratory studies of products regulated by FDA. We are aware that at the conclusion of both inspections, our investigators presented and discussed with Steven L. Meyer and James K. Klaassen, DVM, Ph.D., Form FDA 483, Inspectional Observations, for the respective inspections in 2008 and 2009. From our review of the establishment inspection reports and the documents submitted with those reports, and your firm’s written responses dated August 20, 2008, October 2, 2008, and December 9, 2009, we conclude that SNBL did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of nonclinical laboratory studies. We wish to emphasize the following: 1. Testing Facility Management failed to ensure that personnel clearly understand the functions they are to perform [21 CFR 58.31(f)]. Specifically, Testing Facility Management did not provide personnel with proper instructions on the preparation of final reports. As a result, Study Directors routinely prepared, and the Quality Assurance Unit audited, final reports based in part on unsigned draft reports of contributing scientists. FDA found numerous examples of this significant deficiency during the inspections conducted in both 2008 (Studies SNBL.118.06, SNBL.210.07, and SNBL.053.06) and 2009 (Studies SNBL.258.10, SNBL.010.27, SNBL.289.03, SNBL.293.01, and SNBL.010.22). We note that the preamble to the 1978 Final Rule emphasized the importance of individually signed and dated contributing scientist reports in establishing the contributing scientists’ individual accountability for accurate reporting.1 Furthermore, the preamble to the 1987 Final Rule stated that “„only the signed and dated final report of the pathologist comprises raw data respecting histopathological evaluation of tissue specimens.”2 Because SNBL Study Directors prepared and submitted final reports to sponsors with draft contributing scientist reports that were not signed and dated, they lacked accountability and confirmation that the contributing scientists’ raw data was accurate. Furthermore, given that SNBL Study Directors invite the study sponsors to comment on and edit both the contributing scientist reports and the final report, bias in data interpretation and reporting cannot be ruled out. Your December 9, 2009, written response claimed that SNBL misunderstood this issue as it was cited on the Form FDA 483, Inspectional Observations, dated August 1, 2008. Your claim has no basis for the following reasons: • Inspectional Observation Item 7 clearly documented the deficiency found during the 2008 inspection thus: “The Study Director prepared the final report using unsigned draft reports of Contributing Scientists.” • The SNBL written responses dated August 20, 2008, and October 2, 2008, stated that “Study Directors will be instructed to ensure that the final versions of contributing scientist reports are utilized during final report preparation.” Consequently, your claim of misunderstanding the issue is not justified and lacks merit. In this regard, SNBL offers no assurance that SNBL will effectively correct this ongoing deficient practice and will adhere to GLP regulatory requirements for reporting nonclinical safety data. 2. Testing Facility Management failed to ensure that test article mixtures were appropriately tested for stability [21 CFR 58.31(d)]. At the 2009 inspection, for Study SNBL.284.01, the final report stated that the test article mixture was considered stable under the conditions of use (i.e., ambient temperature) even though the testing method did not demonstrate stability. Thus, SNBL failed to ensure that test systems were administered with the protocol-required dose of test article. In your response dated December 9, 2009, you indicated that SNBL will conduct appropriate stability testing and amend the final reports for all studies that used the same test article as Study SNBL.284.01. However, because your standard operating procedures (SOPs) failed to require the use of methods appropriate for demonstrating stability, the impact of this deficiency extends beyond the test article used in Study SNBL.284.01. Although you stated that SNBL initiated a review of other studies in which inappropriate methods were used to assess stability, FDA is concerned that Testing Facility Management did not recognize this failure previously or assign qualified staff to address this issue, and that as a result, this deficiency adversely affected multiple safety studies for multiple sponsors. 3. Testing Facility Management failed to implement standard operating procedures (SOPs) in writing setting forth nonclinical laboratory study methods that are adequate to ensure the quality and integrity of the data generated in the course of a study [21 CFR 58.81(a)]. In the 2008 inspection, FDA found that Testing Facility Management failed to maintain an SOP for sterile preparation of dosing solutions, even though SNBL’s workload included studies requiring aseptic preparation (e.g., test article mixtures for intracerebro-ventricular administration). In the 2009 inspection, FDA found continued failure in aseptic preparation. Specifically, an outdated SOP for verification and maintenance of biological safety cabinets in the test article department was not removed and replaced with the current SOP; staff failed to complete required training in biological safety cabinet use; and validation and verification performance of biological safety cabinets was inadequate. Because Testing Facility Management failed to attend to its core responsibilities to remain GLP-compliant, FDA is concerned about the validity of nonclinical safety data generated by SNBL. Your responses following the 2008 inspection stated that SNBL would initiate corrective actions for the identified deficiencies. The 2009 inspection found that, in direct contrast with SNBL’s statement, some of the identified deficiencies had not been corrected, and indeed many had been repeated. Because Testing Facility Management failed for over a year to implement appropriate corrective actions, SNBL’s ability to effectively manage a GLP-compliant testing facility has not been demonstrated. 4. The Study Director failed to ensure that all applicable GLP regulations were followed and all experimental data, including observations of unanticipated responses of the test system, were accurately recorded and verified [21 CFR 58.33(e) and 58.33(b)]. The following examples are provided: a. As described above under Item 1, FDA found in both inspections that Study Directors repeatedly prepared draft final reports without the necessary raw data from contributing scientists. b. At the 2008 inspection, FDA found that the Study Director failed to verify the final toxicokinetics report for Study SNBL.118.06 in that it erroneously contained drug concentrations in dosing solutions, instead of drug concentrations in cerebrospinal fluid. c. FDA found that Study Directors failed to ensure that bioanalytical methods used in nonclinical laboratory studies were accurate. i. At the 2008 inspection, FDA found that SNBL failed to use quality control samples in toxicokinetic assays to ensure quantitative accuracy of the bioanalytical method, and to decide acceptance/rejection of individual runs (e.g., Study SNBL.210.07). ii. At the 2008 inspection, FDA found that SNBL failed to reject bioanalytical runs that exceeded the a priori acceptance limit (e.g., Study SNBL.195.01.BA.1). iii. At the 2009 inspection, FDA found that significant deficiencies in the bioanalytical method for measuring noradrenaline concentrations samples from Study SNBL.200.13 were not addressed (e.g., large degree of assay imprecision, stability following long-term storage was not demonstrated). In your response dated December 9, 2009, you agreed that the method was not valid for use, yet your facility used the invalid method. iv. At the 2009 inspection, FDA found that an aberrant precision result was selectively excluded from method validation SNBL.289.05 in support of Study SNBL.289.03. Although the SNBL responses, dated August 20, 2008 and October 2, 2008, stated that procedures would be revised and additional staff training would be provided to correct deficiencies in bioanalytical study conduct, the 2009 inspection found continuing deficiencies. In this regard, there is no assurance that SNBL is capable of instituting appropriate controls and correcting procedures to ensure that the Study Director records and verifies the accuracy of bioanalytical methods used in nonclinical safety studies. 5. The Quality Assurance Unit failed to maintain an accurate master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director [21 CFR 58.35(b)(1)]. Specifically, at the 2008 inspection, the identity of the Study Director was not listed for several studies. At the 2009 inspection, FDA found that the initial master schedule provided at the start of the inspection contained incorrect entries regarding the current status of several studies which had been archived. 6. The Quality Assurance Unit failed to determine that no deviations from SOPs were made without proper authorization and documentation [21 CFR 58.35(b)(5)]. Specifically, unapproved and undocumented deviations occurred against procedures established by SNBL in the following examples: a. Facility inspections in the 2008-2009 audit plan were not conducted within the required time frame in 14 of the 21 departments involved in GLP work. b. Outdated copies of SOPs related to the facility archive and biological safety cabinets were not removed from workspaces and replaced with the new versions. c. Staff failed to complete required training on SOPs related to the facility archive and biological safety cabinets. d. Staff failed to follow up on and to document the status of materials checked out of the archive in accordance with the required time frame. e. Pipettes’ calibrations were not made in accordance with required time frames, as described in Item 7b below. In your responses dated August 20, 2008, October 2, 2008, and December 9, 2009, SNBL acknowledged these deficiencies and proposed corrective actions. However, you did not provide sufficient information to assess the adequacy of such actions. For example, in your response dated December 9, 2009, you stated that SNBL QAU would closely manage facility inspections in the future without describing how you would achieve timeliness. Furthermore, in light of the overall lack of responsibility of Testing Facility Management to implement basic elements of GLP compliance, FDA is concerned that QAU oversight at SNBL is neither effective nor adequate to ensure data integrity. 7. You failed to adequately inspect, clean, and maintain equipment. Equipment used for the generation, measurement, or assessment of data was not adequately tested, calibrated, and standardized [21 CFR 58.63(a)]. In the 2009 inspection, FDA found that numerous pieces of equipment were not calibrated according to the schedule defined by SNBL procedures. For example: a. The temperature verification for a chromatography column heater had expired in August 2008, yet the apparatus was used through September 2009 in two bioanalytical method validations and sample analyses for Study SNBL.990.40. b. The adequate performance of multiple pipettes in the analytical biology area was not assessed for up to one year, even though SNBL procedures required monthly verification of such active pipettes. Furthermore, multiple pipettes had expired quarterly calibrations, in violation of required SNBL procedures. In your response dated December 9, 2009, SNBL agreed that the equipment records were inadequate and not up to date. Your response indicated that the pertinent SOP was updated to optimize and control documentation practices for pipette maintenance. However, the utility of this change for future studies is not evident, because at the time of the 2009 inspection, when FDA noted the violations above, the SOP in effect clearly defined the necessary documentation and retention of pipette calibration records. 8. Study Directors failed to sign and date final reports [21 CFR 58.185(b)]. For example, in the 2008 inspection, FDA found that draft reports for Studies SNBL.223.07, SNBL.109.01, and SNBL.053.04 were unsigned for three to five years. The SNBL responses dated August 20, 2008 and October 2, 2008 stated that these reports would be finalized. In contrast to those statements, FDA found during the 2009 inspection that Study SNBL.053.04 still lacked appropriate finalization, in that the Study Director signed and dated the final report without adequate information. Specifically, the Study Director relied on a peer review pathology statement (dated June 1, 2005) that preceded the study pathologist’s actual report (dated April 25, 2009) by about four years. 9. You failed to make corrections or additions to a final report in the form of an amendment by the Study Director [21 CFR 58.185(c)]. In the 2008 inspection, FDA found that toxicokinetic assays in Study SNBL.210.07 lacked quality control samples to determine assay performance, and that the ECG report failed to include relevant data tables. Your responses dated August 20, 2008 and October 2, 2008 stated that SNBL would establish appropriate procedures to address these deficiencies. However, FDA found during the 2009 inspection that the Study Director had not made the necessary corrections or additions to the final report in the form of an amendment. This letter is not intended to be an all-inclusive list of deficiencies at your facility. As evidenced by FDA’s inspectional findings, SNBL Testing Facility Management failed to fulfill its primary responsibility to establish appropriate policies and procedures intended to ensure the quality and integrity of nonclinical safety data for FDA submission. Furthermore, the serious deficiencies found in oversight by the Study Director and the Quality Assurance Unit can be attributed to the lack of responsibility of Testing Facility Management to establish core elements necessary for GLP compliance. SNBL responses, dated August 20, 2008 and October 2, 2008, promised corrective action following the 2008 inspection. However, during the 2009 follow-up inspection, FDA found that Testing Facility Management failed to correct the deficiencies that SNBL had agreed upon after the 2008 inspection, thus leading to the problems found during the recent inspection and resulting in a continued lack of GLP compliance. For this reason, SNBL’s written response, dated December 9, 2009, does not inspire confidence or provide sufficient convincing evidence that compliance will be achieved. It is your responsibility to ensure that SNBL’s practices and procedures comply fully with all applicable statutes and regulations. Within fifteen (15) business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Your written response should include any documentation necessary to show that full and adequate correction will be achieved. Please include the projected completion dates for each action to be accomplished. Failure to respond satisfactorily to this letter and take appropriate corrective action could result in FDA taking regulatory action including disqualification in accordance with 21 CFR 58.204. We acknowledge receipt of your written responses dated January 25, 2010, April 15, 2010, and July 20, 2010, to Form FDA 483, but note that these responses were received more than fifteen (15) business days from close of the inspection. Thus, while we have reviewed these responses, we have not included a discussion of them in this letter as per the Commissioner’s Enforcement Initiative announced August 11, 2009. If you believe these written responses to the Form FDA 483 fully explain the actions you have taken to prevent similar violations in the future, please communicate that to us in writing within fifteen (15) business days. You may reference the written responses dated January 25, 2010, April 15, 2010, and July 20, 2010, in your response to this letter. We appreciate the cooperation shown to the FDA Investigators during the inspections. If you have any questions, please contact Sam H. Haidar, Ph.D., R.Ph., at 301-796-4777; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to: Sam H. Haidar, Ph.D., R.Ph. Acting Branch Chief GLP and Bioequivalence Investigations Branch Division of Scientific Investigations Office of Compliance Center for Drug Evaluation and Research Food and Drug Administration Bldg 51, Room 5210 10903 New Hampshire Avenue Silver Spring, MD 20993 Sincerely, /S/ Leslie K. Ball, M.D. Director Division of Scientific Investigations Office of Compliance Center for Drug Evaluation and Research Food and Drug Administration ________________________________________ 1 43 Fed. Reg. 60009 (December 22, 1978) 2 52 Fed. Reg. 33770 (September 4, 1987) --------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------- /s/ ---------------------------------------------------- LESLIE K BALL 08/09/2010 Laboratorios L.O., Oftalmi, C.A. 5/12/10 Public Health Service Food and Drug Department of Health and Human Services Administration Silver Spring MD 20993 Warning Letter VIA UPS MAIL WL: 320-10-004 May 12, 2010 Mr. Jose Ruscica, Plant Director Laboratorios L.O., Oftalmi, C.A. Calle 6, Centro Empresarial RS Zona Industrial de La Urbina Caracas 1061 – A Venezuela Dear Mr. Ruscica: During our February 22 – 26 and March 1 – 2, 2010 inspection of your pharmaceutical manufacturing facility, Laboratorios L.O., Oftalmi, C.A. located at Calle 6, Centro Empresarial RS, Zona Industrial de La Urbina, Caracas 1061-A, Venezuela, 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. Specific violations observed during the inspection include, but are not limited, to the following: 1. Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. ? 211.113(b)]. For example, a. Your media fill studies suggest that your manufacturing process is not under control. The presence of contaminated units found in four of the six media fills conducted during 2008 and 2009 is an indication of serious breaches to assure sterility of the ophthalmic drug products manufactured at your facility. Your failure to document the evaluation of media fill units after 14 days of incubation, and to identify the organisms in contaminated media fill units, is also unacceptable. Adequate records of media fill unit examinations and identification of the contaminating microbes are essential to any investigation into the origin of the media fill failures. b. Operators involved in the filling operations for the sterile ophthalmic drug products manufactured at your facility do not practice adequate aseptic techniques to prevent product contamination. Deficient practices include, but are not limited, to: operators that directly contacted sterile bottles with their gloved hands during filling operations, improper movements and actions, and operators who reach over sterilized open bottles and (b)(4) on the filling line. These practices are unacceptable. We expect that operators who conduct operations within aseptic processing areas be properly trained and monitored to ensure that proper aseptic techniques are utilized during all operations, especially filling operations. c. Your environmental monitoring program does not give assurance that environmental contaminants are reliably detected. Your deficient procedures and practices include, but are not limited, to: failure to collect active (viable) air samples during filling operations, failure to collect non-viable particulate samples during filling operations, collecting non-viable particulate samples near the HEPA-filter unit, and inadequate sampling frequency for other classified areas. An adequate environmental monitoring program needs to be established by your firm. It should capture meaningful data and act as an early warning system to detect possible environmental contaminants that may impact the sterility of the ophthalmic drug products manufactured at your facility that purport to be sterile. 2. Your firm does not thoroughly investigate the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. ? 211.192]. For example, you do not conduct adequate evaluation of out-of-specification (OOS) test results during investigations. Specifically, your practice of invalidating initial OOS results without justification is unacceptable. Under CGMP, your firm must perform an adequate investigation into the OOS results. The investigation should include an appropriate evaluation of events associated with the laboratory analysis that scientifically supports any determination that the OOS result is caused by laboratory error. Strong evidence and science-based justification is necessary for your quality unit to permit invalidation of an initial OOS result. 3. Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R. ? 211.42(c)]. For example, a) Your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potentially hazardous compounds (e.g., beta lactam antibiotic and steroid products) at your facility. Deficiencies were observed in the shared manufacturing areas where you manufacture potentially hazardous compounds and sterile ophthalmic drug products intended for the U.S. market. You should ensure that a documented justification and a well-designed contamination prevention strategy has been put in place to minimize the possibility of contamination. FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination. To achieve an acceptable level of risk requires sound and risk-based assurance that one drug does not contaminate another drug. b) There was no documentary evidence of in-situ air pattern analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Please note that proper design and control prevents turbulence and stagnant air in the critical area. It is crucial that airflow patterns be evaluated for turbulence that can act as a channel for air contamination. The studies should be well documented with written conclusions, and evaluate impact of aseptic manipulations (e.g., interventions) and equipment design. c) You do not have a procedure or documentation for monitoring differential pressure within the aseptic processing areas. It is vital for rooms of higher air cleanliness to have an appropriate and substantial pressure differential relative to adjacent rooms of lower air cleanliness. Pressure differentials between cleanrooms should be monitored continuously throughout each shift and frequently recorded. All alarms should be documented and deviations from established limits should be investigated. In addition to the items listed above, the results of this inspection include other deficiencies that increase our serious concerns regarding the quality of the sterile ophthalmic drug products manufactured at your facility. These deficiencies include, but are not limited, to: inadequate procedures for deviation investigations, lack of an ongoing stability program, and failure to validate (b)(4) procedures and (b)(4) cycles intended to sterilize equipment and utensils used in the aseptic processing operations. 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. If you wish to continue to ship your 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. 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, FDA will be refusing admission of articles manufactured at Laboratorios L.O., Oftalmi, C.A., Calle 6, Centro Empresarial RS, Zona Industrial de La Urbina, Caracas, Venezuela 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 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. Please identify your response with FEI # 3003571292. If you have questions or concerns regarding this letter, contact Douglas Campbell, 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, Room 4224 10903 New Hampshire Ave Silver Spring, MD 20993 Tel: (301) 796-3201 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 Chiron Corporation 09-Dec-04 Public Health Service Food and Drug Department of Health and Human Services Administration Center for Biologics Evaluation and Research 1401 Rockville Pike Rockville MD 20852-1448 CBER-05-006 December 9, 2004 WARNING LETTER CERTIFIED MAIL RETURN RECEIPT REQUESTED Howard Pien President and Chief Executive Officer Chiron Corporation 4560 Horton Street Emeryville, California 944608-2916 Dear Mr. Pien: The Food and Drug Administration (FDA) conducted an inspection of Evans Vaccines, an affiliate of Chiron Corporation, Gaskill Road, Speke, Liverpool L24 9GR, United Kingdom, between October 10 and October 15, 2004. During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) in the manufacture of Influenza Virus Vaccine, Fluvirin? (Fluvirin), including the bulk monovalent blend pools and trivalent bulk batches. These deviations from CGMP include the applicable requirements of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and Title 21, Code of Federal Regulations, (21 CFR) Parts 210, 211, and 600-680. These violations of CGMP render your product adulterated under Section 501(a)(2)(B) of the FD&C Act and not safe, pure, and potent under Section 351 (a) of the Public Health Service Act (PHS Act). At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations, that described a number of significant objectionable conditions relating to the facility’s compliance with CGMP. Significant deviations in the manufacture of Fluvirin observed during the inspection include, but are not limited to, the following: 1. Your facility’s quality control unit failed to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated; the quality control unit also failed to investigate thoroughly any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR 211.22 and 211.192] For example: a) The quality control unit’s investigation of Fluvirin sterility failures (Fluvirin Sterility Failure Investigation Report #R/0198/04, October 9, 2004) concluded that [redacted] fumigation of your facility’s formulation areas on May 17, 2004 “was successful” as confirmed by your ongoing environmental monitoring program. Yet environmental data from April 2004 through September 2004 for formulation rooms [redacted] and [redacted] indicate continued alert and action level excursions for gram negative organisms, including but not limited to Serratia spp. b) The Fluvirin sterility failure investigation conducted by the quality control unit failed to include and address the bulk sterility failure of B/Jiangsu monovalent blend pool # [redacted]. c) The Fluvirin sterility failure investigation conducted by the quality control unit failed to address the fact that numerous monovalent blend pools (over 50%) used from March 2004 through October 2004 exceeded your firm’s bioburden alert level ([redacted] cfu/ml). The quality control unit did not thoroughly investigate the environmental monitoring excursions during filling for Fluvirin lots [redacted] and [redacted]. The non-conformance reports were limited to review of the filling activity for each specified lot. There was no investigation in these non-conformance reports of aseptic filling area environmental monitoring excursions that occurred for other lots between September 2004 and October 2004, and which subsequently resulted in the rejection of the lots. 2. Your firm failed to follow written procedures applicable to the function of the quality control unit. [21 CFR 211.22(d)] For example: a) Your km’s standard operating procedure (SOP) M198 “Sterility Investigation Reports” requires that the facility initiate a Non-Conformance Report (NCR) upon the determination of a valid positive sterility test (sterility test failure). Your firm’s SOP SCP009 “Non Conformance Reporting” requires that “the identifier of a Non-Conformance must initiate a Non-Conformance report form as soon as reasonably possible, [redacted] where detection of the Non-Conformance was highlighted” (emphasis in original). These SOPs were not followed in that: i) Individual NCR reports were not initiated, completed and approved for the nine lots of Fluvirin [redacted] that failed sterility testing. ii) The non-conforming events associated with the nine lots of Fluvirin that failed sterility testing were not investigated using an NCR in a thorough and timely manner with corrective and preventive actions assigned and implemented. b) Your firm’s SOP MDP-0024 “Routine Monitoring and Review of Adverse Events to Identify Safety Signals” requires that the facility conduct a batch review if certain criteria relating to adverse drug experiences are satisfied. This SOP was not followed in that there is no documentation that batch record reviews were conducted by the quality control unit for adverse event reports received for at least twenty-two batches of Fluvirin manufactured in the 2004 campaign, where one or more criteria for review were satisfied. 3. Your firm failed to establish and follow 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 CFR 211.160(a) and (b)]. For example, the facility did not present an established, scientifically sound justification, rationale, and/or procedure for the sampling and testing of additional filled vials to confirm the extent of the unsatisfactory sterility test results on batches of Fluvirin. 4. Your firm failed to establish and follow appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile and to assure that such procedures include validation of any sterilization process. [21 CFR 211.113(b)] For example, the process simulation media fills performed to demonstrate aseptic processing during Fluvirin production are inappropriate in that your procedures simulate separately the [redacted] final vial filling, which is not representative of the entire aseptic process. In addition, SOP SCP029 “General Procedure for Routine Monitoring of Aseptic Manufacturing Processes by Process Simulation Utilizing Sterile Media Fills” requires performance and documentation, during media fills, of all interventions performed during actual aseptic filling operations. Your facility did not follow this SOP in that all interventions were not documented for the simulation fills of monovalent and trivalent blending. 5. Your firm failed to establish and follow written procedures, and to justify any deviation from written 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 CFR 211.100(a) and (b)] For example, SOP M201 “Identification of a Micro-organism” requires that all microorganisms be speciated upon isolation. Between January and September 2004, only 20% of the microbial isolates had been identified and speciated. 6. Your firm failed to establish an adequate system for monitoring environmental , conditions of aseptic processing areas. [21 CFR 211.42(c)(10)(iv)] For example, routine viable air sampling does not encompass aseptic activities including the times and locations where the critical operations are performed. 7. Your firm failed to establish separate or defined areas or other control systems for aseptic processing operations to prevent contamination or mixups. [21 CFR 211.42(c) (10) and 600.11 (a)] For example, formulation rooms [redacted] and [redacted] do not meet manufacturing needs and prevent contamination, due to the equipment configurations within the Class [redacted] area, in that the airflow, above the critical area where multiple aseptic connections are made, is obstructed by the operators when making the connections. 8. Your firm failed to establish and follow written procedures to assure the cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product. [21 CFR 211.67(b) and 600.11(b)] For example, cleaning validation for the clean-in-place (CIP) process Vessel [redacted] which is utilized in the aseptic formulation of trivalent bulk influenza vaccine, did not include an assessment of the spray ball coverage for the vessel. The spray ball is used for cleaning product contact equipment. In addition, the study did not include swab sampling of the product transfer lines. Additionally, significant deviations in manufacture of your bulk drug substance were observed during the inspection. These deviations cause your bulk drug substance to be adulterated within the meaning of Section 502(a)(2)(B) of the FD&C Act and not safe pure, and potent under Section 351 (a) of the PHS Act. Specific areas of concern include, but are not limited to: INVESTIGATION OF FAILURES 1. There is no indication that failures are fully investigated or that you extended investigations to other batches as appropriate. For example: a) Numerous Fluvirin monovalent blend pools (over 50%) manufactured between March 2004 and October 2004 and used in the formulation of trivalent batches manufactured for the 2004 Fluvirin Campaign, greatly exceeded the bioburden alert level of [redacted] cfu/ml. Although non-conformance reports were completed, your firm did not conduct a thorough investigation into the root cause of the increased bioburden levels. Your firm failed to implement corrective and preventive actions. b) Your firm used numerous cultures of live virus inoculum that exceeded the bioburden alert level of less than [redacted] cfu/ml in the inoculation of eggs during the 2004 Fluvirin campaign. A thorough investigation into the root cause of the increased bioburden levels was not conducted. In addition, corrective and preventive actions were not implemented. CLEANING AND MAINTENANCE OF EQUIPMENT 2. Appropriate validation studies have not been conducted for critical processes. For example, validation for the manual cleaning of the upper and lower rotor assemblies of equipment used for zonal centrifugation operations have not been performed. 3. There is no indication that prior to August 2004 there were periodic preventive maintenance programs or procedures to prevent malfunctions or contamination for the [redacted] tanks, In addition, the cleaning validation did not include an assessment of the spray ball coverage for the tanks. PRODUCTION AND PROCESS CONTROLS 4. Batch production records are inadequate in that many of the-tanks are not traceable throughout manufacturing operations for specific lots of product. All of the above deficiencies are indicative of your quality control unit’s inability to fulfill its responsibility to assure the identity, strength, quality, and purity of your drug product [21 CFR 211.22]. We acknowledge receipt of your written response dated November 13, 2004, regarding the inspectional observations listed on the Form FDA 483. Corrective actions addressed in your response may be referenced in your response to this letter; however, we believe that your response did not provide sufficient detail to allow FDA to assess fully the adequacy of the corrective actions. Our evaluation of your response follows, and is numbered to correspond to the items listed on the Form FDA 483: Observations 1, 4, 5 and 7 We acknowledge your commitments to enhance your Quality System Improvement Program to develop more robust processes in your Quality Systems and to strengthen the organizational structure of your quality control unit. As described in the FDA Form 483 and this letter, however, Chiron has not performed adequate investigations into deviations as required by applicable FDA regulations. Please describe in detail how Chiron will attain GMP compliance: with regard to deviation investigations by, among other things, taking into account other failures or discrepancies that may be related, and then using all of the relevant information to conduct a root cause analysis to ensure that adequate steps are taken for the evaluation of product impact, deviation investigations, and the implementation of effective corrective and preventive actions. Observation 1H We acknowledge your commitment to hire a Chief Microbiologist in order to improve the scientific basis in the design of studies to aid in your investigations. Please describe in detail how Chiron will ensure that the studies you conduct are scientifically sound and justified and conducted according to appropriate procedures, specifications, standards, and sampling plans. Neither this letter nor the list of inspectional observations (Form FDA 483) is meant to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility as management to assure that your establishment is in compliance with the provisions of the FD&C Act, PHS Act, and applicable federal regulations. Federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when considering the award of contracts. Please notify us in writing, within 15 working days of receipt of this letter, of the steps you have taken or will take to correct the noted violations and to prevent their recurrence. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to correct these deviations promptly may result in regulatory action without further notice. Such actions may include license suspension and/or revocation. Your reply should be sent to James S. Cohen, J.D., Acting Director, Office of Compliance and Biologics Quality, U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200 N, Rockville, Maryland 20852-1448. If you have any questions regarding this letter, please contact Ms. Mary Malarkey, Director, Division of Case Management, at (301) 827-6201. Sincerely, /s/ David K. Elder Director Office of Enforcement K.C. Pharmaceuticals Inc. 6/21/10 Public Health Service Food and Drug Department of Health and Human Services Administration Los Angeles District Pacific Region 19701 Fairchild Irvine, CA 92612-2506 Telephone: 949-608-2900 FAX: 949-608-4415 WARNING LETTER CERTIFIED MAIL RETURN RECEIPT REQUESTED W/L 23-10 May 21, 2010 Mr. Joseph Sutedjo, President K.C. Pharmaceuticals Inc. 3201 Producer Way Pomona, CA 91768 Dear Mr. Sutedjo, During our December 14 - 30, 2009 inspection of your medical device and pharmaceutical manufacturing facility, KC Pharmaceuticals, Inc., located at 3201 Producer Way, Pamona, California, investigators from the United States Food and Drug Administration (FDA) identified significant violations of Quality System Regulations for Medical Devices, Title 21, Code of Federal Regulations, Part 820, and 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 medical device(s) and drug product(s) to be adulterated within the meaning of section 501(h) and section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (the Act) [21 U.S.C. ?? 351(h) and 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, holding, or installation do not conform to, or are not operated or administered in conformity with the Quality System Regulation or CGMP. On February 3, 2010, your firm attended a meeting in the Los Angeles District Office to address serious concerns regarding the results of the December 14 to December 30, 2009 inspection. Subsequently, a teleconference was held on March 1, 2010, to discuss your proposed corrective actions. We reviewed your written response dated January 18 and have considered this information in our evaluation and have included our comments as they pertain to each item below. Specific violations observed during the inspection include, but are not limited, to the following: 1. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process shall be validated with a high degree of assurance and approved according to established procedure [21 C.F.R. ? 820.75(a)]. Specifically, the procedure "Validation of the Aseptic Filling Process Utilizing the Media Fill Method," (b)(4), states that initial validations should be conducted consecutively and prior to routine production fills and subsequent re-qualifications should be performed (b)(4) as appropriate. In addition, the procedure states that routine production may not resume until acceptable qualification or validation runs are achieved or until all appropriate investigations and/or repeat media fills have been performed with acceptable results. However, validation of the aseptic filling process in filling suite (b)(4) for (b)(4) bottles was inadequate in that the (b)(4) re-qualification of the (b)(4) Aseptic Filling Process utilizing the Media Fill Method (b)(4) performed on March 23, 2009 failed. The failure produced (b)(4) contaminated units out of approximately (b)(4) units inspected. In addition, the subsequent validation of (b)(4) for filling (b)(4) and (b)(4) bottle (b)(4) performed on May 20, 2009 also failed. This failure produced (b)(4) contaminated units out of approximately (b)(4) units inspected. (b)(4) lots of Sterile Saline Solution preserved in (b)(4) bottles were filled on March 31, 2009 and April 2, 2009 in (b)(4) filling suite. The (b)(4) lots were filled in between the two failed media fills. We have reviewed your response and have concluded that it is inadequate. Your firm indicated that the (b)(4) lots (b)(4) were aseptically filled, met all their respective release criteria (i.e., (b)(4) and therefore were deemed safe to release for marketing. Your firm did not provide a reason why they manufactured and released the (b)(4) lots of products before the (b)(4) filling suite was re-qualified as indicated in the procedure. In addition, you did not provide evidence of implementation of the correction and corrective action. 2. Your firm has not extended investigations of an unexplained discrepancy to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 C.F.R. ? 211.192]. For example, your investigation regarding the media fill failures for eye wash aseptic filling suite (b)(4) is inadequate because it was attributed solely to improper aseptic techniques during the filling operation without scientific justification to support this conclusion. Further, your film's investigation did not include re-validation of the (b)(4) filling operations prior to resuming aseptic filling operations. Your firm has not conducted a thorough investigation regarding the media fill failures in your (b)(4) filling suite. The Non-Conformance Report (b)(4) dated July 2, 2009), indicated that the microorganisms identified in your investigation are considered waterborne and are prevalent within the water system. Your firm did not conduct an adequate investigation to ensure that microbiological contamination sources were eliminated from the (b)(4) water system and the manufacturing process before it was returned to operation. FDA does not believe your water system has been adequately designed and qualified to ensure the prevention of microbial contamination. It is unclear if your firm has determined the root cause of the problem or has attempted to resolve it. Due to the microbial contamination identified in your water system, please explain the appropriate interim measures your film plans to take including but not limited to passivation, routine sanitization, and additional representative sampling. The water system used to produce your sterile drug products should be properly designed, controlled, monitored, tested, sampled and maintained to ensure a continuous state of control. It is essential that pharmaceutical water routinely and reproducibly meet appropriate specifications. Please provide your firm's short and longer term (e.g., design modifications) corrective actions, and timeframe for completion. 3. There is a failure of the equipment used in the manufacture, processing, packing, or holding of drug products to be 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's (b)(4) water system is deficient in that unused portions of piping (dead-legs) were observed in the (b)(4) piping of the (b)(4) water system. Biofilm may form in the unused portions of piping. Dead-legs are not acceptable in water systems used for the manufacture of sterile drug products. Please provide appropriate corrective actions to address the dead-legs in your water system, including an explanation of design modifications that would address the issue. In addition, please provide the following: 1) additional cleaning/sanitization data to support that bacteria are effectively removed from the water system; 2) documentation for qualification of the water system that demonstrates the water system is capable of consistently producing the desired water quality; and 3) the timeframe for completion. 4. Your firm does not have an adequate system for monitoring environmental conditions in aseptic processing areas [21 C.F.R. ? 211.42 (c)(10)(iv)]. For example, environmental monitoring is inadequate in the (b)(4) eye wash aseptic filling suite (b)(4). Your procedure (b)(4) "Environmental Monitoring Program" (February 08, 2008) is inadequate because (b)(4) air monitoring is limited to (b)(4) We disagree with your analysis that a (b)(4) cannot be used for (b)(4) monitoring: It can be integrated into a (b)(4) process monitoring system using related software. Please provide a corrective action(s) which will ensure that (b)(4) monitoring of non-viable particulates is conducted at your firm and that appropriate environmental conditions are maintained. 5. Failure to establish and maintain an adequate procedure for implementing corrective and preventive action to include requirements for investigating the cause of nonconformities relating to product, processes, and the quality system [21 C.F.R. ? 820. 100(a)(2)]. Specifically, your firm's procedure (b)(4) "Corrective Action/Preventive Action (CAPA) Management System" was not adequately implemented. Your film's CAPA #CP-09-001 (dated July 1, 2009) was created for media failures on (b)(4) filling suite and the Quality Risk Assessment part states that "a review of all batch records using the (b)(4) filling suite reveals no suspect results, all sterility passed." However, on January 14, 2009, Non-conformance Report (b)(4) was initiated for a sterility failure on Sterile Saline Solution Preserved (SALP) Lot (b)(4) filled in (b)(4) filling suite on December 29, 2008. The entire lot was rejected and removed from inventory on March 3, 2009 because it was considered potentially contaminated. We have reviewed your response and have concluded that it is inadequate. Your firm stated that a specific section to address any potentially affected lot will be added to (b)(4) Quality Risk Assessment section. In addition, the firm stated that it will update the (b)(4) procedure to include a requirement to review all potentially affected lots. However, your firm did not provide the revised procedure (b)(4) and the updated (b)(4) for review and therefore its adequacy could not be determined at this time. In addition, your firm did not provide any discussion or evidence of a systemic corrective action, such as a retrospective review of CAPAs to ensure there are no other CAPA discrepancies with regard to product potentially impacted. We acknowledge your commitment to cease manufacturing until additional testing is conducted on your water system and in your clean rooms as verbally stated in the February 19, 2010 teleconference with FDA. However, you should evaluate the design of your water system to ensure that it meets its intended use and is designed to prevent microbial contamination. It is essential that you demonstrate that your manufacturing facility and your (b)(4) water system are operating in an appropriate state of control before resumption of operations and commercial distribution. You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about drugs and medical devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected. This letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance. Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Additionally, your response should state if you no longer manufacture or distribute medical device or drug products, and provide the date(s) and reason(s) you ceased production. Your response should be sent to: Daniel Cline Acting Director, Compliance Branch Food and Drug Administration 19701 Fairchild Irvine, CA 92612-2506 If you have any questions about the content of this letter please contact Marco S. Esteves, Compliance Officer at 949-608-4439. Sincerely, /S/ Alonza E. Cruse District Director Los Angeles District Sacramento, CA 95899-7413