| Public Health Service Food and Drug Administration |
| Rockville MD 20857 |
Department of Health and Human ServicesJUN 22 2010
WARNING LETTER
Via UPS
Ms. Li Qing, Plant Manager
Nanjing Pharmaceutical Factory Company Limited
Nanjing Chemical Industry Park
No.9, Fangshui East Road
Nanjing, China (Mainland) 210047
Dear Ms. Li Qing:
This letter is regarding the U.S. Food and Drug Administration (FDA) inspection of your active pharmaceutical ingredient (API) manufacturing facility located at Nanjing Chemical Industry Park, No.9, Fangshui East Road, Nanjing Chemical Industry Park, Nanjing, China, conducted by FDA Investigators, Jose Hernandez and Chemist Felix Maldonado, on September 21 - 25, 2009. A pre-approval/current Good Manufacturing Practice (cGMP) inspection of your API manufacturing facility was performed covering the processing of the API Praziquantel intended for animal drug use. Due to the significant observations uncovered, the inspection was expanded to also cover the API Sucralfate, intended for human drug use only.
We have completed our review of the Establishment Inspection Report (EIR) for the inspection. The inspection revealed significant deviations from the cGMPs in the manufacture of APIs. These deviations were listed on an Inspectional Observations form (Form FDA483) issued to you at the conclusion of the inspection.
These cGMP deviations cause your APIs 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). This section of the Act states that drugs, as defined in the Act, are adulterated when they are not manufactured, processed, packed, and held in conformity with current good manufacturing practices. You can find the Act and its associated regulations on the internet through links on the FDA's web page at www.fda.gov. No distinction is made between animal and human drugs, and the failure of either to comply with cGMP constitutes a failure to comply with the requirements of the Act.
We have also received your written responses to the Form FDA 483 inspectional observations, dated January 18, 2010 and April 20, 2010. We note that you state that many corrections have been, or soon will be implemented. However, your responses do not adequately address some of the deficiencies as further discussed below. Specific areas of concern include, but are not limited to:
Current Inspectional Findings:
1. Failure of your firm's Quality Unit to complete its essential responsibilities.
For example,
a. Your quality unit failed to discover, document, and investigate the data altering practices and lack of adequate cGMP documentation practices at your facility.
Specifically, the practice of scraping off or erasing original data from production batch records is pervasive throughout your facility. Our investigators documented over 30 production batch records (approximately 80% of the records reviewed) that contained evidence of original data such as dates, signatures, temperatures, test results, weights, volumes, and times being removed, and new data written. This data alteration was done without an explanation of why the data was changed, or the signature or initials of the person making the changes. Interviews conducted with an operator revealed that this practice is so common that the operator made a special tool to scrape off entries in production batch records, so that new data or information can be recorded in its place.
Additionally, you acknowledged during the inspection that the GMP Controller makes entries into the production batch records associated with the manufacturing steps. However, there is no documentation of his/her signature to acknowledge the entries recorded. The operator responsible for conducting the manufacturing step includes only his or her signature or initials to information completed by the GMP Controller.
During an interview with the Quality Assurance (QA) Manager, he stated that management has been aware of the data alteration practices since September 2007. Your quality unit failed to document, investigate, and prevent the recurrence of these deviations. Provide in your response, the actions taken to correct these deviations and prevent their recurrence.
b. Your quality unit failed to ensure that effective systems are in place for the calibration and maintenance of critical equipment and instrumentation.
Specifically, there was no chromatography data (chromatograms) for the calibrations of High Pressure Liquid Chromatography (HPLC) and Gas Chromatography (GC) systems completed by the (b)(4). Also, your firm had no record of the procedure that the (b)(4) used to complete the yearly qualifications of your HPLC and GC instrumentation. In addition, there was no chromatography data (chromatograms) for the qualification of the Headspace GC completed by (b)(4), who was used as a contract service vendor.
Additionally, not all of your analytical laboratory instrumentation had written and approved calibration procedures. There were no calibration procedures for melting point apparatus (b)(4)), analytical balances (b)(4)), or (b)(4)
Furthermore, you had no records of the calibration of the vacuum drier's (b)(4)) chamber thermometer and the actual parameters used during the qualification of this vacuum drier (b)(4) was incomplete).
Instrument and equipment calibrations should be conducted according to approved, written procedures and established frequencies. All raw data and associated records, such as procedures, standard certificates, etc., should be maintained. An assessment of all current calibration of equipment and instrumentation should be done to ensure required information is available, and adequate corrective actions have been implemented.
c. Your QCD failed to review and approve all quality related documentation.
For example, blank production batch records are printed by an outside company. These printed production batch records are not reviewed by the QCU prior to being issued. Your Standard Operating Procedure (b)(4) effective date July 1, 2009) includes the instructions for the printing and issuance of batch production records, but does not include instructions on reviewing and approving the blank batch production records. Provide updated procedures for the quality review and approval of all quality related documentation.
2. Failure of the operator to document all quality related activities at the time they are performed.
For example, review of batch records (specifically (b)(4) and (b)(4)) and interviews with operators revealed that operators are not recording their own observations (batch record required entries) into production batch records. The entries (including observations) are being entered by the "GMP Controller" and not by the operator at the time they are performed. This is a cGMP deviation and is inconsistent with your written procedures, specifically (b)(4), effective date July 1, 2009).
A comprehensive investigation into this deviation should be conducted, including why this behavior was not discovered by the quality unit during production batch record review.
3. Failure to have an adequate stability testing program designed to monitor the stability characteristics of APIs.
For example, at the time of the inspection, you did not have an approved stability protocol for the two APIs manufactured for the U.S. market, Praziquantel and Sucralfate. You should establish an ongoing testing program of APIs to monitor its stability characteristics.
Your stability testing protocols should include as a minimum, representative sampling, storage conditions, testing time-points, adequate analytical testing methods, and specifications. You should review all available stability data to determine if the testing is adequate, timely, and includes a representative number of samples. If any inconsistencies are discovered, a justification or explanation should be included.
4. Failure to appropriately store stability. samples under controlled conditions to evaluate the thermal stability and moisture sensitivity of the API.
You do not store the stability samples under controlled conditions. The stability room currently in use for long term stability conditions is not designed to control temperature and humidity adequately. The room's temperature is controlled by a (b)(4) unit located on one side of the room. The back-up cooling and heating unit in use is not capable of controlling relative humidity. This room also contains a large, clear glass window that is not completely sealed, and a standard office type entry door that is not sealed. The temperature and relative humidity is not continuously recorded.
Provide with your response, the corrective actions to ensure stability samples are stored at the required controlled conditions. Also, provide justification of current retest or expiry dates assigned to your APIs using data from this stability room.
5. Failure to have an adequate number of personnel qualified by education, training, experience, or a combination thereof, to ensure the APIs are manufactured in accordance with cGMP.
Complete training records are not maintained for operators. The training records associated with operators do not identify the SOPs the operators were trained on. As a result, there is no way to confirm if operators were trained on SOPs concerning raw data and batch record documentation (b)(4), effective date July 1,2009) that are a required part of their responsibilities.
Additionally, the QA Manager stated that numerous temporary employees were used in 2007 for the manufacture of APls that were inadequately trained. The QA Manager admitted to knowing about the errors the temporary employees had made, but did not document, investigate, or prevent the recurrence of these errors via training.
Please indicate in your response when the employees will receive external cGMP or Q7A "Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients" training.
6. Failure to completely validate analytical equipment used for quality testing of APIs, such as in-process, release, and stability.
For example, the electronic formulas used to calculate results for assay, related compounds, and residual solvents associated with HPLC and GC tests for Praziquantel and Sucralfate USP APls, have not been verified for accuracy. This observation is considered a repeat of an observation made during the October 2005 inspection of your facility when your laboratory was cited for the failure to validate calculations used in the laboratory.
All electronic formulas used at your facility during testing should be verified for accuracy as a part of a validation. Please provide documentation of these efforts and include how the security of these calculations will be controlled to ensure these formulas are not altered.
Please specify in your response how your firm will improve procedures and training, and all actions you are taking to ensure raw materials are sampled in a manner to prevent their contamination and contamination of other materials.
7. Failure to evaluate all changes that may affect the production and control of manufactured APls, specifically, assuring current analytical methods are used to test USP APIs.
For example, you used an obsolete USPINF (ASIAN edition) version from 2005 for the testing of the two USP products (Praziquantel and Sucralfate) manufactured at your facility.
In your response, provide a complete assessment of the adequacy of the methods used to test the APIs you manufacture. The differences between the current USP methods and that of the 2005 version used at your site should be identified, and their potential impact evaluated.
The violations cited in this letter or on the Form FDA 483 issued to your firm are not intended to be an all-inclusive list 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 ship APIs to the United States, it is the responsibility of your firm to ensure compliance with all FDA standards for cGMP and all other applicable U.S. laws and regulations.
Please respond in English to this letter within thirty (30) days of receipt and identify your response with FEI # 3004674350. Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm's compliance with cGMP, these offices may recommend withholding approval of any new applications or supplements listing your firm as an API manufacturer. Until these deviations are corrected and a FDA inspection confirms your facilities to be compliant with the cGMP, FDA will continue to deny entry of articles manufactured at Nanjing Chemical Industry Park, No.9, Fangshui East Road, Nanjing, China 210047 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). Additionally, you should consider obtaining the services of an organization or person known by FDA to have knowledge and experience in FDA rules and regulations to certify the firm as in compliance prior to any future inspection by FDA personnel. You should also consider obtaining the services of an organization or individual known to possess keen knowledge in cGMP or Q7 "Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients" to provide training to all employees and management.
We remind you that your firm shall comply with the drug establishment registration and drug listing requirements as codified in Title 21, Code of Federal Regulations, section 207.40 (21 C.F.R. 207.40). in order to export drugs to the U.S.A. You can find pertinent information on-line at the following internet website: http://www.fda.gov/cder/drls/registration_listing.htm.
Please note that a guidance document entitled "Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients" (ICH CGMP Guidance), prepared under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), describes current good manufacturing practice (cGMP) for the manufacturing of APIs. The guidance is intended to help ensure that all APIs meet the standards for quality and purity they purport or are represented to possess. Although the ICH CGMP guidance does not impose requirements, FDA considers its recommendations, as well as alternatives intended to accomplish the same goals and provide an equivalent level of quality assurance, in determining whether a firm's APIs have been manufactured, processed, packed, and held according to current good manufacturing practice under section 501 (a)(2)(B) [21 U.S.C. 351(a)(2)(B)] of the Act. To obtain the ICH CGMP guidance document for your reference, please refer to the following website: http://www.fda.gov/cder/guidance/4286fnl.htm.
Please contact Jonathan R. Bray, Compliance Officer, at the following address and telephone number if you have any questions related to animal drugs:
U.S. Food & Drug Administration
Center for Veterinary Medicine (CVM)
Office of Surveillance & Compliance
Division of Compliance
Enforcement & Regulatory Policy Team (HFV-232)
7519 Standish Place
Rockville, MD 20855 U.S.A.
Phone: (240) 276-9228
Fax: (240) 276-9241
Or, please contact Brian L. Belz, Compliance Officer, at the following address and telephone number if you have any questions related to human drugs:
U.S. Food & Drug Administration
Center for Drug Evaluation and Research (CDER)
Division of Manufacturing and Product Quality
International Compliance Branch (HFD-325)
10903 New Hampshire Avenue
Silver Spring, MD 20993 U.S.A.
Tel: (301) 796-4279
Fax: (301) 847-8743
To schedule are-inspection of your facility, after corrections have been implemented and your firm is in compliance with cGMP requirements, send your written request to:
Director
U.S. Food & Drug Administration
Office of Regulatory Affairs
Office of Regional Operations
Division of Field Investigations (HFC-130)
5600 Fishers Lane
Rockville, MD 20857 U.S.A.
You can also contact that office by telephone at (301) 827-5655 or by fax at (301) 443-6919.
Sincerely yours,
/S/
Neal Bataller, ME, DVM,
Director,
Division of Compliance
Office of Surveillance & Compliance
Center for Veterinary Medicine
/S/
Richard L. Friedman MS
Director,
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation & Research
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