| Public Health Service Food and Drug Administration |
| Chicago District 550 West Jackson Blvd., 15th Floor Chicago, Illinois 60661 Telephone: 312-353-5863 |
Department of Health and Human Services
September 1, 2011
WARNING LETTER
CHI-16-11
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Charles T. Deibel
President and Chief Operating Officer
Deibel Laboratories of Illinois, Inc.
7120 N. Ridgeway Avenue
Lincolnwood, IL 60712
Dear Mr. Deibel:
During our February 23 to April 21, 2011 inspection of your firm, Deibel Laboratories of Illinois, Inc., located at 7120 N. Ridgeway Avenue in Lincolnwood, Illinois, 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 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.
We have reviewed your firm's response of May 12, 2011, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has failed to conduct appropriate laboratory testing of each batch of drug product required to be free of objectionable microorganisms [21 C.F.R. § 211.165(b)].
For example, your firm has not conducted microbiological method suitability testing, as per USP Chapters <61> and<62>, for all drug products to establish that your test method can detect microorganisms. Examples of drug products tested without evidence that microorganisms can be recovered include the following: (1) 0.12% Chlorhexidine Gluconate prescription oral rinse; (2) Levothyroxine Sodium raw material; (3) 1.5% Chlorhexidine Gluconate scrub; (4) 1% Furosemide syrup; (5) Benzalkonium Chloride solution; (6) Piperazine Adiptate paste, and; (7) Gentamicin Sulfate USP raw material.
In your response, your firm states that Standard Operating Procedure DLI-QM-SOP-034 will be updated to include a section on validations in which clients will be asked if they would like validation of the methods performed for the formulation. Your response is not adequate because it does not indicate whether you intend to validate all of the microbiological methods for each of the marketed and tested drug products. For commercially marketed drug products, you should determine if the laboratory method used is actually validated, reliable, and adequate to support microbial growth. It should not be left to the client's discretion. Failure to test marketed drug products in accordance with CGMP renders these drug products adulterated and your firm bears the responsibility of this adulteration even if the client fails to request the additional work in determining the suitability of the test method.
2. Your firm has failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211.165(e)]. For example:
a. Your firm has not conducted validation studies for analytical methods routinely used for assay determination of the drug products. Some examples of the methods without validation studies include: (1) PCMX Assay by HPLC, and; (2) Capsaicin Assay for gel sample by HPLC.
b. Your firm's method validation studies for multiple methods used in the testing of drug products are incomplete and are not validated. Some examples of these methods include: (1) Hydroquinone raw material Assay by HPLC; (2) Hydroquinone USP Assay by HPLC as applied to finished drug products; (3) Lidocaine Hydrochloride USP Assay by HPLC; (4) Triclosan USP Assay by HPLC as applied to finished drug products; (5) Hydrous Benzoyl Peroxide by titration; (6) Sulfur by Titration, and; (7) Tartartic Acid by Titration.
In your response, your firm states that the expected completion date for the validation of all analytical methods is June 2012. Your response, however, is not adequate since you have not provided interim actions to ensure the reliability of data until the analytical methods are validated.
In addition, your response states that the standardization of the volumetric solutions used in the above referenced titration methods will be addressed as part of this overall revalidation plan. All volumetric solutions should be standardized prior to use in order to obtain accurate assay results. This is a corrective action that can, and should be, implemented immediately.
3. Your firm has failed to verify the suitability of all testing methods under actual condition of use [21 C.F.R. § 211.194(a)(2)].
For example, your firm has not verified the suitability of the following USP test methods: (1) Tolnaftate USP Assay by HPLC, and; (2) Zinc Pyrithione by Atomic Absorption (AA).
In your response, your firm states that the expected completion date for the validation of all analytical methods is June 2012. Your response is not adequate since you have not provided interim actions to ensure the reliability of data until the analytical methods are validated in 2012.
4. Your firm has not thoroughly investigated 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:
a. Your firm failed to conduct an investigation when you were made aware on March 15, 2011, that a lot of Butterfield Phosphate Buffer (Lot (b)(4) was Out-of-Specification (OOS) for pH. Your firm continued to use this buffer until March 30, 2011, to test approximately (b)(4) drug products.
Your response is not adequate because you did not provide copies of the investigation or the pH test results. Your response also minimizes and attempts to justify the failure to initiate an investigation by indicating that the buffer's pH was within 5% of the target value. In accordance with 21 C.F.R. § 211.192, any deviations from the specification are considered to be discrepancies and must be investigated.
b. Your firm has failed to conduct an investigation for numerous OOS results (e.g., for colony forming units, conductivity, assay, etc.). Many of these OOS results were not reported to your client.
In your response, your firm indicates that you will revise your procedure for nonconformances to state that investigations for raw materials, water, swabs, and stability samples will only be initiated upon client request. As discussed above, when your laboratory obtains out-of-specification results, it is imperative that you promptly initiate an investigation to determine whether your laboratory's practices led to the failure (analysts error, equipment failure, etc.) or the results are valid. Your firm is responsible for fully meeting CGMP for operations that you conduct. Accordingly, your firm is responsible for investigating all non-conformances associated with your laboratory and testing.
Please see FDA's Guidance for Industry entitled, "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production" (October 2006).1
5. Your firm has failed to follow and document, at the time of performance, established test procedures and laboratory control mechanisms. Any deviation from the written test procedures and laboratory control mechanisms shall be recorded and justified [21 C.F.R. § 211.160(a)]. For example:
a. Your firm has failed to follow the procedures related to the preparation and use of Butterfield Buffer Solution, SOP-DLI-2030, entitled "Media Receipt, Makeup and Testing Procedure for PharmCo Media," and "Medium No MB119." Specifically, your firm failed to test (b)(4) batches of Butterfield Buffer Solution (Lots (b)(4) for toxicity or growth enhancement in accordance with your procedure. Approximately (b)(4) drug products and (b)(4) swabs for environmental surface sampling were tested using these (b)(4) batches. In addition, the procedure for preparing Butterfield Phosphate Buffer (BUT buffer), "Medium No. MB 119," has not been followed since 2007. Specifically, your firm has been preparing the BUT buffer with a final concentration of (b)(4)mg/mL, instead of (b)(4)mg/mL as per the procedure, at least since the FDA's July 2007 inspection.
Your response in inadequate because it is unclear as to what measures your firm plans to take to prevent future deviations.
b. Your firm has failed to follow SOP-DLI-2090, entitled "Purified Water Requirements and Recording for PharmCo." This is evidenced by your firm's failure to perform total organic carbon (TOC) testing on the purified water system for a period of four months in 2010.
Although you list the completion of training of new personnel and added checklists for Quality Control personnel responsibilities, your response is not adequate because your firm has not provided specific details of the corrective actions or documentation to show the effectiveness of the corrective actions.
c. Your firm has failed to follow SOP-DLI-2550, entitled "Good Documentation Practices." It is common practice in your firm to have another employee record the test results and/or the initials/signatures of the analyst who actually performed the testing on raw data worksheets. Your firm's management was aware of this practice.
Although you firm has revised your procedure to state that writing another analyst's initials or signature is considered "forgery", your response is inadequate because there is no evidence to show that the revisions will be effectively implemented. In addition, your revised procedure still allows for employees to enter data on each others' paperwork, which is a practice that continues to undermine your data integrity and increases the possibility of errors in the laboratory record.
d. Your firm has failed to follow High-Pressure Liquid Chromatograph (HPLC) procedures. Your firm does not inject a check standard at the end of each HPLC run to confirm system suitability throughout an entire sample run sequence as per procedure.
In your response, your firm states that all HPLC procedures will be revised to include a requirement for a standard to be injected at the end of the run; however, this was not the issue noted during the inspection. The inspection found that your firm was not following procedures, such as SOP DLI-4702, "Capsaicin USP by HPLC" and SOP DLI-4711 "PCMX assay" which already included this requirement.
e. Your firm has failed to follow your procedure SOP DLI-2550, "Non-Conformance Reporting." Specifically, your firm has failed to either document a deviation for OOS investigations or failed to review the OOS results within the required timeframes.
f. Your firm failed to meet the (b)(4) day review timeframe set forth in SOP DLI-2090, entitled "Purified Water Requirements and Recording." When your firm discovered in February 2011 that the Total Organic Carbon (TOC) testing on the purified water system was not performed or reviewed for the months of September, November and December of 2010 a deviation was not initiated.
In your response, your firm indicates that a deviation will be written and the lack of TOC testing for February 2010 will be investigated in the deviation((b)(4))for September, November, and December 2010. Your response, however, is incomplete in that it lacks information to demonstrate that your firm has addressed the cause and will prevent recurrence of these significant CGMP deviations.
The inspection identified a pattern of your firm failing to follow procedures. In your response to this letter please indicate how you will ensure that procedures will be followed in the future.
6. Your firm has failed to ensure that the laboratory records include the initials or signatures of the person(s) performing the test and the initials and signatures of a second person showing that the original record(s) were reviewed for accuracy, completeness, and compliance with established standards [21 C.F.R. § 211.194 (7) and (8)].
a. Your firm failed to have a second person review the laboratory records for completeness and accuracy including the forms for media preparation, aerobic plate count testing of purified water, and total organic carbon/conductivity testing of purified water.
In your response, your firm proposes a corrective action to hire (b)(4) additional quality personnel. Your response is inadequate because it is unclear that the hiring of (b)(4) additional employees ((b)(4)), will ensure timely completion of the tasks required by CGMP that were not performed previously.
b. Your firm failed to ensure that the initials or signature of the original analysts were included as part of their chromatogram reviews. Approximately 95% of chromatograms reviewed during the inspection did not include the signature of the original analyst or date, or the signature of a second analyst and date indicating that the chromatograms had been reviewed for accuracy.
In your response, your firm indicates that the corrective action is a procedural revision requiring signatures and dates of the original and reviewing analyst. Your response, however, is inadequate because the procedure has not yet been revised.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction.
Your response should be sent to: Carrie Ann Plucinski, Compliance Officer, Food and Drug Administration, 550 W. Jackson Blvd., 15th floor, Chicago, IL 60661. If you have any questions about the content of this letter, please contact Ms. Plucinski at 312-596-4224.
Sincerely,
/S/
Scott J. MacIntire
District Director
1Available at:
http://www.fda.gov/downloadslDrugs/GuidanceComplianceRegulatorylnfonnation/Guidances/UCM070287.pdf
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