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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Kirk Pharmaceuticals, LLC 2/4/10


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  555 Winderley Pl., Ste. 200
Maitland, FL 32751




February 4, 2010

Gerald F. Price
Interim Chief Executive Officer
Kirk Pharmaceuticals, LLC
5360 NW 35th Ave.
Fort Lauderdale, FL 33309

Dear Mr. Price:

This is regarding our June 17 through July 2, 2009 inspection of your pharmaceutical manufacturing facility, Kirk Pharmaceuticals, LLC, located at 5352 NW 35th Ave., Fort Lauderdale, Florida, conducted by Investigators Ileana Barreto-Pettit and Raymond A. Lyn, Jr. The inspection identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), 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.

We reviewed your firm's response of August 12,2009, 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 not rejected drug products failing to meet established standards or specifications and any other relevant quality control criteria [21 CFR 211.165(f)].

For example, your firm did not reject Isoxsuprine Hydrochloride 20 mg tablets, lot (b)(4) which had an Out-of-Specification (OOS) assay result of (b)(4) (Specification (b)(4) This OOS assay result was documented on the certificate of analysis and was overlooked by your Quality Control Unit (QCU). Your firm released this lot for distribution on December 11, 2008.

Your response states that you revised the OOS and change control Standard Operating Procedures (SOP), trained appropriate personnel, and made organizational and personnel changes within your Quality Control Unit. You initiated an investigation, LIR-2009-0003, six months after the distribution of lot (b)(4) and determined the OOS result was due to an analyst error. Your response, however, is not adequate because it is not clear how you attributed the OOS result to an analyst error, nor have you addressed the failure of your QCU to properly verify and evaluate the certificates of analysis upon distribution.

2. 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, and has not extended the investigation to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 CFR 211.192].

For example,

a. You failed to investigate dissolution failures (between November 20, 2008 and June 19, 2009) for validation lots of Ephedrine Hydrochloride 12.5 mg/Guaifenesin 200 mg hard gelatin capsules. Specifically, validation lots (b)(4) and (b)(4) did not meet the dissolution specification of not less than (NLT) (b)(4) at the three month long-term stability conditions. Validation lot (b)(4) also did not meet the dissolution specification at the six month intermediate stability conditions.

We acknowledge your response stating an investigation, LIR-2008-0019, was initiated and found "the original dissolution method was not appropriate for this product." You state that a new dissolution method has been validated, which will be used to retest the three validation lots once the revised method is approved. However, your response is not adequate because you have not provided the results of this retesting, the complete validation package, or your reevaluation of all distributed batches that passed dissolution testing using the approved, final method.

b. You failed to conduct a timely investigation of the blend uniformity failures for lots (b)(4) and (b)(4) of Diphenhydramin Heroichiloride 25 mg blend. Both lots had OOS blend uniformity results, (b)(4) for lot (b)(4) and (b)(4) for lot (b)(4) (Specification (b)(4) and were released for distribution on January 30, 2009. An investigation was not initiated until after this issue was brought to the attention of your Director of Quality and Regulatory and your Quality Control Supervisor during the recent FDA inspection.

In your response, you provided a table of blend results for Diphenhydramine Hydrophloride 25 mg capsules lots manufactured before and after lots (b)(4) and (b)(4) Your firm indicates that you were unable to retest the blends for lot (b)(4) and (b)(4) because there was no material left. Subsequently, you conducted a documentation review [that] did not uncover evidence of analyst error," but you "believe that the error may have been caused by improper sampling." Your response is not adequate because you hf1ve not provided justification to demonstrate whether improper sampling is the root cause or described an action plan to prevent future recurrence.

We acknowledge that these two lots met assay, dissolution, and content uniformity specifications when final Quality Control (QC) testing was conducted on a small lot sample. We also acknowledge that (b)(4) of the (b)(4) lots, provided in your table found in your August 12, 2009 response, passed blend uniformity testing. However, the data for this product indicates that a high degree of variation is inherent in the current process. Your response is not adequate because you do not address this apparent variability or provide justification for concluding your blending and overall manufacturing process results in a homogenous product.

c. You failed to conduct adequate investigations of the dissolution failures for lot (b)(4) and (b)(4) of Diphenhydramine Hydrochloride 25 mg capsules at the two and three month accelerated stability conditions. Failing dissolution results included (b)(4) for lot (b)(4) and (b)(4) and (b)(4) for lot (b)(4) (Specification (b)(4) Two investigations LIER-2008- 0001 and LIR-2008-0010 were initiated on January 8, 2008 and June 3, 2008, respectively, and concluded that the failures were attributed to the inability of the hard gelatin capsules to tolerate the accelerated stability conditions. Your firm then discontinued the accelerated stability study without adequate justification. In addition, you did not extend the investigation to your contract manufacturer (of the bulk Diphenhydramine Hydrochloride capsules) or packaging operations to determine the root cause and to confirm your firm's belief that the dissolution failures were due to the hard gelatin capsules at accelerated conditions rather than the quality of the drug product.

Your response indicates that the failures at accelerated conditions were due to the inability of your packaging components to provide sufficient protection at accelerated conditions. You also provided the 18 month stability results at controlled room temperature (CRT) showing lot (b)(4) and (b)(4) met assay and dissolution specifications. However, the assay are on the low side, closer to (b)(4) The product has an expiration date of 24 months, but you have only provided results up to 18 months. Your response is not adequate because you do not provide the stability data to support your 24-month expiration date. We note it appears that placing further lots in distribution on the stability program to assure shelf-life stability is needed.

d. You failed to extend the investigation, LIR-2008-0012, of the assay failure obtained after retesting a portion of lot (b)(4) of Diphenhydramine Hydrochloride 25 mg capsules, to other shipments of the same lot that were distributed to (b)(4) different customers. On August 11, 2008, your Quality Control Unit (QCD) obtained an OOS assay result of (b)(4) (Specification (b)(4) while retesting the portion of the lot that was returned due to an accidental double shipment. Although you identified a root cause and rejected a portion of the lot, you did not extend the investigation to the remainder of the lot.

Your response states that an investigation, LIR-2009-0004, was conducted in which samples from each of the (b)(4) sub-lots that comprise lot (b)(4) were tested in-house (by Kirk and (b)(4) and by an independent lab (b)(4) All results were found to be OOS. We your issuance of a Field Alert Report on July 16, 2009, and your initiation of a recall for lot BK549. We also acknowledge your extension of this investigation to (b)(4) other lots of Diphenhydramine Hydrochloride 25 mg capsules, all of which: were retested and met specification. However, your response is not adequate because you have not addressed how you ensure prior investigations were extended and future investigations are extended to sub-lots and associated lots when appropriate.

This is a repeat observation from the August 2007 and July 2006 inspections. 

3. Your firm has not established and documented the accuracy, sensitivity, specificity, and reproducibility of test methods employed [21 CFR 211.165(e)].

For example, your dissolution method (b)(4) "Ephedrine HCl 12.5/25 mg and Guaifenesin 200 mg Hard Gelatin Capsules Testing Methods for Assay, Blend Uniformity, Content "Uniformity and Dissolution," was not validated prior to implementation. After encountering multiple dissolution failures during the stability studies of process validation for lots (b)(4) and (b)(4) (between November 20, 2008 and June 19, 2009), your firm concluded that the method may not be appropriate for testing this product. These validation lots were tested and released between October 31, 2008 and November 26, 2008, prior to the approval of (b)(4) The dissolution method (b)(4) was first made effective on December 24, 2008.

Your response states: 1) "this is a personnel issue;" 2) Kirk's procedures require approval of methods prior to use; and 3) failure of your personnel to follow these procedures will result in their suspension or termination. Your response is not adequate. There is a fundamental failure of top management to ensure and support adequate authority of the QCU, and that these duties are discharged independently and fully. It is your responsibility to ensure that your personnel have the necessary training to enable them to perform their assigned functions. You have not addressed the changes to your management systems, procedures, or the training of your personnel to ensure methods are not used and lots are not released prior to method validation and approval. In addition, we note that the dissolution results using the new method are approximately (b)(4) higher than previous results for the same lots using the inappropriate method. You have (b)(4) not provided your risk analysis of the lots that were analyzed with the current method, or your determination of the acceptability of product analyzed using the former apparently inappropriate method.

4. Your firm has not established valid in-process specifications that are consistent with drug product final specifications [21 CFR 211.110(b)].

For example, your QCU approved two specification changes for the in-process blend of Isoxsuprine Hydrochloride 20 mg tablets. The specifications were changed from (b)(4) to (b)(4) (Change Control CC08-l002 on October 27, 2008). The justification was documented as "...changed specification from (b)(4) to (b)(4) otherwise tablet might not pass assay." The specification was then changed back to (b)(4) (Change Control CC08-1039 on November 21, 2008) as a corrective action for blend uniformity failures of (b)(4) batches investigated under LIR-2008-0017. Neither change was based on scientific data.

Your response states that your blend results "do not correlate perfectly with the finished tablet results" and that you believe the current discrepancy between these results may derive from problems with blend sampling. As such, you are evaluating your blend sampling and sampling processing procedures. Be advised that adequate in-process controls are required to assure final product quality. Your response is not adequate because you have not provided the scientific justification for the multiple changes to the in-process blend specification and why you believe a specification of is the most appropriate range.

5. Your firm does not ensure that the responsibilities and procedures applicable to the quality control Ul1it are followed [21 CFR 211.22(d)]. This is a repeat observation from the August 2007 inspection.

For example, your firm's QCD failed to follow SOP QA-002, "Change Control System." The test method for assay and dissolution of Isoxsuprine Hydrochloride 20 mg tablets was changed from (b)(4) to (b)(4) and implemented prior to completion of method validation. Change Control CC09-0181 was initiated on April 15, 2009, approved by the QCU on April 27, 2009, and the new method implemented on April 30, 2009. However, the method validation protocol was not approved until June 17, 2009, and the method validation report was not completed until June 23, 2009, during the inspection.

Your response states "this is a personnel issue" and that you have evaluated your laboratory procedures. It is your responsibility to ensure that your personnel have the training to enable them to their assigned functions. Your response states that your review of the test method, (b)(4) determined that "some additional work is required." Your response is not adequate because you have neither provided any supporting documentation indicating the necessary revisions to this method are appropriate for analyzing your products nor your evaluation of all of your tests methods demonstrating that they are appropriate for analyzing your products. You also state that you intend to retest the affected lots with the revised dissolution method to confirm they meet any revised specifications. Please provide a summary of these retest results.

6. 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, your firm failed to conduct annual product reviews for 2008 by March 2009, as required by section 7.4.2 of SOP QA-029, "Annual Product Review," (APR) for the following drug products:

a. Acetaminophen 325 mg and 500 mg tablets; 325 mg and 500 mg caplets
b. Ephedrine 12.5 mg/Guaifenesin 200 mg tablets and gel capsules
c. Diphenhydramine Hydrochloride 25 mg capsules and tablets
d. Isoxsuprine Hydrochloride tablets
e. Sennosides tablets
f. Acetaminophen 500 mg/Diphenhydramine 25 mg tablets

Although you commit to revising SOP QA-029 and completing the APRs, your response is not adequate because it does not address necessary changes in the quality system including, but not limited, to the training of personnel and the specific changes to your SOP. Your firm also does not describe why your APRs continued to not be completed within the timeframe
established in your SOP.

This is a repeat observation from the August 2007 inspection.

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 violation 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 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. Additionally, your response should state if you no longer manufacture or distribute the drug product(s) manufactured at this facility, and provide the date(s) and reason(s) you ceased production.

Your reply should be sent to the attention of Winston R. Alejo, Compliance Officer, U.S. Food and Drug Administration, 555 Winderley Place, Suite 200, Maitland, Florida 32751.

Emma R. Singleton
Director, Florida District