Inspections, Compliance, Enforcement, and Criminal Investigations
Provident Pharmaceuticals LLC, 11/9/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Denver District Office
Building 20- Denver Federal Center
P.O. Box 25087
Denver, Colorado 80255-0087
November 09, 2009
RETURN RECEIPT REQUESTED
Brian A. Crook, DVM, President
Provident Pharmaceuticals, LLC
4831 Centennial Blvd.
Colorado Springs, CO 80919-3308
Reference No.: DEN-10-03
Dear Dr. Crook:
This letter regards a June 1 through June 19, 2009 inspection of your pharmaceutical, contract manufacturing facility, Provident Pharmaceuticals, LLC, located at 4831 Centennial Blvd., Colorado Springs, Colorado, conducted by investigators from the United States Food and Drug Administration (FDA). The inspection identified significant violations from the Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations Parts 210 and 211 (21 CFR 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 regulations.
In addition, you manufacture prescription drugs without an approved application. As described below, these drugs are unapproved new drugs, and by introducing them into interstate commerce you are in violation of sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 33l(d) and 355(a)]. These unapproved new drugs are also misbranded pursuant to section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], and by introducing them into interstate commerce you are in violation of section 301(a) of the Act [21 U.S.C. § 331 (a)].
We have received your firm's responses of June 19, 2009 and July 20, 2009, and note that they lack sufficient corrective actions.
Specific violations observed during inspection include, but are not limited, to:
1. Your firm has failed to ensure that the responsibilities and procedures applicable to the quality control unit (QCD) are followed [21 CFR 211.22(d)]. For example, your quality procedure (i.e., Responsibility of the Quality Group at Provident Pharmaceuticals, LLC) states that the Quality Group shall have the responsibility and authority to direct all operational groups with respect to compliance with all CGMP requirements. However, your Quality Group (i.e., QCU):
a. failed to establish valid test methods for raw materials and drug products that assure components and drug products conform to appropriate standards of identity and strength prior to release;
b. approved the validation of test method (b)(4) even though the ruggedness (b)(4) and robustness (b)(4) elements do not meet the acceptance criteria. The intended purpose of method (b)(4) includes finished product testing (b)(4)
c. approved the validation of analytical method (b)(4) even though the specificity element (b)(4) does not meet the acceptance criteria. The test method is intended for the testing of the (b)(4) product;
d. failed to ensure that stability samples are tested at their scheduled time points, pursuant to (b)(4) Stability Program);
e. failed to conduct annual product reviews, pursuant to (b)(4) (Annual Product Reviews);
f. failed to ensure OOS results are thoroughly investigated pursuant to (b)(4) (Investigating Out-of-Specification (OOS) Test Results). Confirmed OOS results (original and retest) are invalidated without justification; and
g. failed to conduct an internal audit to verify the completion and effectiveness of corrective actions.
We have concerns regarding your commitment to ensure compliance with the CGMP regulations. We recommend that you hire a qualified consultant to provide comprehensive CGMP training that focuses on the responsibilities and procedures applicable to the QCD. We also recommend that you develop or revise your internal audit program and all procedures applicable to the QCD that will assist you in identifying and correcting similar deviations. Further, we recommend that once the training is completed, you conduct a comprehensive evaluation of all of your written procedures to ensure they are adequate, complete, and in compliance with the CGMP regulations.
2. Your firm has not established and documented the accuracy, sensitivity specificity, and reproducibility of test methods employed by your firm [21 CFR 211.165(e)]. For example:
a. The assay test methods (b)(4) for your components have not been validated.
b. The dissolution test method, included in (b)(4) in the drug product (b)(4) has not been validated.
c. The assay, blend uniformity, and uniformity of dosage units test methods included in (b)(4) in the drug products have not been validated.
Your July 2009 response to Observation 1, part 1A, concerning the failure to validate test methods, states that your firm takes seriously its responsibility to establish scientifically sound and appropriate laboratory controls. You also state that (b)(4) prior to the inspection. Note that (b)(4) by your firm should have no bearing on the development and validation of your test methods. The validation of test methods should precede the manufacture for release and distribution of any of your drug products. It is your responsibility to ensure that all of your test methods, for the testing of raw materials, in-process samples, intermediates, stability samples, and finished products are validated to demonstrate that the test methods are adequate, accurate, complete, and reliable to assure the identity, strength, and quality of your drug products before they are released for distribution to the public.
We acknowledge your July 2009 response and commitment to develop a (b)(4). Please provide a copy of your (b)(4). In addition, if not included in the (b)(4) provide corrective actions to prevent similar deviations from recurring. Note that failure to have an adequate number of qualified personnel is not justification to circumvent your adherence to CGMP requirements.
3. Your firm has not followed written procedures to evaluate, 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 211.180(e)]. For example, despite the requirements in your written procedures, (b)(4) Annual Product Reviews, your QCD has not completed annual product reviews (APRs) that include a review of approved and rejected batch records, complaints, recalls, returns, and investigations conducted on any of the products manufactured in 2008.
We acknowledge your July 2009 response that indicates the (b)(4) in the completion of your APRs and your commitment to (b)(4) to complete APRs. Please provide timeframes for the completion of the (b)(4). In addition, please provide corrective actions to prevent similar deviations regarding your failure to follow your APR procedure. Note that failure to have an adequate number of qualified personnel is not justification to circumvent your adherence to CGMP requirements.
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 CFR 211.192]. Specifically, OOS investigation (b)(4) invalidated the initial OOS assay results without justification (b)(4) for (b)(4) in a tablet formulation containing (b)(4) at the (b)(4) time point for accelerated ("ALS") and ('AMB") stability conditions, respectively. In addition, you failed to investigate the root cause that lead to the OOS results and reject the product, and inform the responsible authorities of the stability failures, per your OOS SOP (b)(4). Further, the OOS investigation disregarded a (b)(4) results from the same composite sample (b)(4) that confirmed the original OOS results. Instead, the OOS investigation report concluded (b)(4). In an update to the OOS investigation, your QCU continued stability testing at the (b)(4) time points and obtained an OOS result (b)(4) at the (b)(4) time point that was also disregarded.
We have concerns about your firm's fundamental understanding of the regulatory expectations and requirements when conducting OOS investigations. Please review the FDA Guidance entitled, "Investigating Out-of-Specification Test Results for Pharmaceutical Production," which explains FDA's policy on how to evaluate chemistry-based, laboratory, OOS test results. This guidance can be found on FDA's webpage at
Please provide corrective actions to address this violation.
5. Your firm failed to comply with its written stability testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates [21 CFR § 211.166(a)]. Although your procedure, SOP (b)(4) Stability Program, requires stability samples to be tested (b)(4) your QCD exceeded the established timeframes. For example there are no stability data, or the data do not include all required testing, for the following products:
We acknowledge your July 2009 response and commitment to complete stability testing, (b)(4) to ensure adherence to the stability procedure. However, we believe your response does not provide adequate preventive actions because (b)(4) do not address the failure of the QCD to ensure your procedures are followed and training is effective. Please provide corrective action to prevent recurrence of similar deviations. For example, you may develop a contingency plan to send your stability samples for testing to a qualified contract laboratory, or you may reduce your product line to reduce the laboratory workload.
Unapproved and Misbranded Prescription Drugs
• Based on the information collected during the inspection, you manufacture the following prescription drugs including but not limited to:
The above products are drugs within the meaning of section 201(g) of the Act [21 U.S.C. § 321(g)] because, as demonstrated by their labeling, they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Further, they are "new drugs" within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses. Under sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)], a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under either section 505(b) or (j) of the Act [21 U.S.C. §§ 355(b) or (j)] is in effect for the drug. Based on our information, there are no FDA-approved applications on file for these drug products.
Additionally, because the above prescription drug products are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for use as required under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)]; and because the products lack required approved applications, they are not exempt from this requirement under 21 CFR 201.115. The introduction or delivery for introduction into interstate commerce of these products without approved new drug applications violates sections 301(a) and (d) of the Act [21 U.S.C. §§ 331 (a) and (d)].
Please be advised your June 19, 2009 and July 20, 2009 responses to the FDA 483 are not adequate. The responses identified the following drug production as being discontinued: (b)(4) Partial discontinuation of your marketed unapproved drugs is not sufficient. You must discontinue manufacturing and distributing all of your drug products that require FDA approval. Also please note that if you are no longer marketing these products, you must update the Drug Listing files in accordance with 21 CFR 207.30(a)(2).
You may reference your June 19, 2009 and July 20, 2009 responses in responding to this letter, as appropriate.
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 reinspect to verify corrective actions have been completed.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute the drug products manufactured at this facility, and provide the dates and reasons you ceased production.
Your reply should be sent to the attention of Nancy G. Schmidt, Compliance Officer, at the address on the above letterhead:
If you have questions, please contact Ms. Schmidt at (303) 236-3046.
H. Thomas Warwick, Jr.
Denver District Director