| Public Health Service Food and Drug Administration |
Waterview Corporate Center Telephone (973) 331-4905 |
Department of Health and Human Services
Warning Letter
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
WL: #10-NWJ-07
February 23, 2010
Mr. Robert E. Caliari
President
Tri-Med Laboratories, Inc.
68 Veronica Avenue, Suite #1
Somerset, NJ 07607
Dear Mr. Caliari:
During our September 9-25, 2009 inspection of your pharmaceutical manufacturing facility, Tri-Med laboratories, Inc., located at 68 Veronica Avenue, Suite #1, Somerset, New Jersey, investigator(s) 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 (CPR), 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 October 15, 2008,1 and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
CGMP Violations
1. Your firm failed to reject a lot of material that does not meet appropriate written specifications of identity, strength, quality, and purity [21 C.F.R. § 211.84(e)]. For example,
a. Your Quality Control Unit (QCU) did not reject the Active Pharmaceutical Ingredient (API) Guaifenesin USP, control number 034233, when it failed to meet established specifications for the potency assay. Specifically, the laboratory assay results for this lot were 102.5% and 102.7% outside the specification range of (b)(4). These results were subsequently invalidated by your QCD even though your investigation was unable to confirm a laboratory error as the root cause of the failure. Your QCD selectively used passing results from a different analysis to approve the lot.
We reviewed your written response dated October 15,2008 and you do not provide justification for invalidating the original results and utilizing retest results to approve product.
b. Your QCD failed to reject purified water that did not pass your acceptance limit for Coliform (b)(4). Specifically, the Coliform result of the water sample tested by your contract microbiological testing facility on May 14, 2009, was 4 cfu/100ml. Although the investigation, Laboratory (O.O.S.) Failure Investigation Report (LOOSIR), LOOSI #072808-I, did not identify a root cause for the failing test result, your firm continued to use this water to manufacture drug products.
In your response, you state the investigation results concluded that the original sample was contaminated. Your response is inadequate because you have not described how your firm's investigation determined that the sample was contaminated, the root cause of the sample contamination, or what corrective actions have been implemented to prevent sampling errors in the future.
2. Your firm failed to thoroughly investigate unexplained discrepancies of a batch or any of its components to meet any of its specifications and failed to establish a written record, including conclusions and followup, of that investigation [21 C.P.R. § 211.192]. For example,
a. Your firm's Nonconformance / Discrepancy Investigation Report (NDIR), NDI # 061808-1, failed to thoroughly investigate the aerobic plate count failure of a purified water sample. The results of your firm's purified water sample (collected on June 4, 2008) resulted in an 120 cfu/ml aerobic plate count, which exceeds your action level of (b)(4) Based upon acceptable results from the retain sample and retesting of additional water samples, your QCD invalidated the above microbiological test result. The QCD concluded that the failure was a result of a sample contamination, but failed to describe how that conclusion was determined or the root cause of the sample contamination.
In your response, you state that the tests from additional samples were within specification and that your investigation concluded that the original sample was contaminated. Your response is inadequate because regardless of subsequent microbiological results, It is your responsibility to Investigate and determine the cause of the initial failing results. Your response does not describe how your firm's investigation determined that the sample was contaminated, the root cause of the sample contamination, or what corrective actions have been implemented to prevent sample contamination in the future.
b. Your firm failed to perform an investigation or determine the root cause of humidity excursions in your Controlled Room stability chamber #5 for the weeks of May 6 to 13, 2009, and July 28 to August 5, 2009 and in your Accelerated Room stability chamber #4 for the week of January 7 to 14, 2009. Humidity charts for your Accelerated Room stability chamber #4 were also missing for the time periods of February 11 to 18, 2009, and March 11 to 18, 2009.
In your response, you state that your firm has contacted the chamber manufacturer in order to obtain a maintenance contract with a 48-hour response time; however; your response is inadequate in that it failed to identify the root cause of the humidity excursions during the time periods listed above. In addition, your corrective action fails to identify measures to prevent recurrence of these problems in the future.
This is a repeat violation from the 2008 Untitled Letter.
3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)]. For example,
a. Your firm changed the upper specification range of the final pH for Ferrous Sulfate Infant Drops from (b)(4) without written justification in response to Nonconformance/Discrepancy Investigation Report (NDR) 052609. In addition, your firm's QCU changed the pH release and the specific gravity specifications for all your products on May 28, 2009, without scientific justification or an assessment of how these changes may impact finished products. Specifically, your release and stability specification for pH and specific gravity were widened on May 5, 2008 without appropriate justification.
Your response has failed to provide the data to support a change of pH and specific gravity specifications.
b. On June 18, 2008, your firm tested purified water samples that were originally collected on June 11, 2008, and on May 19, 2009, your firm tested purified water samples collected on May 13, 2009. Samples were tested six days after the samples were obtained. Your firm has no written justification for the adequacy of bacterial recovery when holding and retesting water samples. In addition, your firm has no justification for retesting microbial samples. Product manufactured using the purified water on these dates was released for distribution on June 23, 2008, and May 26, 2009, respectively.
This is a repeat violation from the 2004 Warning Letter and the 2008 Untitled Letter.
4. Your firm failed to follow written procedures describing the receipt, identification, storage, handling, sampling, testing, and approval or rejection of drug components and drug product containers and closures [21 C.F.R. § 211.80(a)]. For example,
a. Your firm failed to follow SOP-02-007-05, Purified Water, which requires an investigation to include an identification of the microorganism to at least the species level and initiating procedures to sanitize the water system whenever Coliforms are identified. However, neither step was performed as part of the investigation 072808-I.
b. Your firm failed to follow SOP-02-007-05 for NDIR # 061808-I, which requires identification of the microorganism to at least the species level when the aerobic plate count exceeds the action level.
5. Your firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, or quality of the drug product [21 C.F.R. § 211.67(a)].
For example, you have not provided any evidence to support your firm's (b)(4) dirty hold time for equipment (e.g., mixing tanks) used in production. Also, there is no data to support the use of a (b)(4) maximum clean equipment hold time.
Please provide information to support your use of this specific hold time.
This is a repeat violation from the 2008 Untitled Letter.
Unapproved and Misbranded Prescription Drugs Violations
In addition to the CGMP violations, you manufacture unapproved new drugs in violation of the Act. Based on the information collected during the inspection, you manufacture the following prescription drugs, including but not limited to:
• Pseudo DM GG Syrup (Dextromethorphan Hydrobromide 15 mg, Pseudoephedrine HCI 40 mg, guaifenesin 100 mg)
• Triall Syrup (Phenylephrine Hydrobromide 8mg, Chlorpheniramine Maleate 2mg, Metscopolamine Nitrate 6.75 mg)
• Triplex DM Liquid (Dextromethorphan Hydrobromide 15 mg, Pytamine Maleate 12.5 mg, Phenylephrine HCI 7.5 mg)
• Tenar PSE (Pseudoephedrine HCI, guaifenesin 200 mg)
• Tenar DM (Dextromethorphan Hydrobromide 15 mg, Pseudoephedrine HCI 32 mg, guaifenesin 200 mg)
• Guiatex PE Syrup (guaifenesin 200 mg, Phenylephrine HCI)
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 diseases. 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, under section 301(a) of the Act [21 U.S.C. § 331(a)] it is prohibited to introduce into or deliver for introduction into interstate commerce a misbranded drug. The above products are misbranded because, as prescription drugs, 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 they lack required approved applications, they are not exempt from this requirement under 21 C.F.R. § 201.115. The introduction or delivery for introduction into interstate commerce of these products without approved new drug applications violates section 301(a) and (d) of the Act [21 U.S.C. §§ 331(a) and (d)]. Also, your response to this letter should include if you no longer manufacture or distribute any other drug product(s), and provide the date(s) and reason(s) you ceased production.
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.
Repeat citations from prior inspections indicate that your quality control unit is either not exercising its responsibilities, or may not have the appropriate authority to carry out its responsibilities. Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant having appropriate CGMP expertise to assess your firm's facility, procedures, processes, and systems to ensure that your drug products have their appropriate identity, strength, quality, and purity.
Finally, we note that the CGMP violations listed in this letter include similar violations to those cited in the 2004 Warning Letter and the 2008 Untitled Letter. It is apparent that
Tri-Med is not implementing global and sustainable corrective actions. We remind you that you are responsible for ensuring that you firm's drug manufacturing operations comply with applicable requirements, including the CGMP regulations. FDA expects Tri-Med to undertake a comprehensive and global assessment of your manufacturing operations to ensure that drug products conform to FDA requirements.
Please contact Mr. Joe McGinnis at the FDA, New Jersey District Office, to schedule a meeting to discuss your proposed corrective actions and your projected timeframes. Mr. McGinnis can be reached at (973)-331-4905.
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.
Your reply should be sent to the following address: U.S. Food and Drug Administration, 10 Waterview Blvd., Parsippany, New Jersey 07054, Attn: Joseph F. McGinnis, R.Ph, Compliance Officer.
Sincerely,
/S/
Diana Amador-Toro
District Director
New Jersey District
________________________________________
1 Responses were inadvertently dated October 15, 2008 and we believe that the correct date is October 15, 2009.
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