Inspections, Compliance, Enforcement, and Criminal Investigations
Time-Cap Labs 4-10-2009
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|New York District
158-15 Liberty Ave.
Jamaica, NY 11433
April 10, 2009
VIA FED EX
Ref NYK 2009-11
Mr. Joseph Errigo
Time-Cap Laboratories, Inc.
7 Michael Avenue
Farmingdale, NY 11735-3921
Dear Mr. Errigo:
An inspection of your facility located at 7 Michael Avenue, Farmingdale, New York, in which you manufacture prescription and over-the-counter (OTC) drug products for human use as well as a prescription drug for veterinary use, was conducted on October 28, 2008, through December 5, 2008, by investigators of the U.S. Food and Drug Administration (FDA). The inspection revealed that your drug products are adulterated within the meaning of Section 501(a)(2)(B) [21 U.S.C. § 351 (a)(2)(B)] of the Federal Food, Drug, and Cosmetic Act (Act) 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 Current Good Manufacturing Practice (CGMP) regulations for drugs, Title 21, Code of Federal Regulations (CFR), Part 211.
In addition, you manufacture a number of prescription drugs without approved applications. As described below, these drugs are unapproved new drugs, and by introducing them into interstate commerce you are in violation of 21 U.S.C. § 355(a) (section 505(a) of the Act). These drugs are also misbranded under 21 U.S.C. § 352(0(1) (section 502(f)(1) of the Act).
We acknowledge receipt of your letter dated December 18, 2008, as well as your updated responses dated January 7 and 26, 2009 and March 13, 2009. The violations we observed, along with comments regarding your responses to FDA Form 483 include, but are not limited to, the following:
1. Failure to establish reliable, meaningful and specific test methods as part of a written testing program designed to assess the stability characteristics of your firm's drug products to determine appropriate storage conditions and expiration dates [21 CFR § 211.166(a)(3)]. For example, your firm's analytical methods have not been validated to demonstrate that they are stability indicating. Review of validation results for your analytical methods noted that forced degradation studies had been performed, but at the time the validation work was conducted, your firm did not have the analytical instrumentation capable of evaluating the data to determine if co-elution between potential degradants and analytes was present. Therefore, these methods were not shown to be stability indicating. Equipment was subsequently purchased and additional data was generated. However, review of the data generated confirmed that significant degradation was not present and that the additional work did not establish the methods as stability indicating.
Your response stated that your firm is reviewing all of your analytical methods to assess their validation status and suitability for determining the stability of your drug products. You committed to complete this assessment within thirty (30) days of the date of your correspondence (February 26, 2009). In addition, you committed to conduct any validation studies necessary to demonstrate that your analytical methods are stability indicating. However, the proposed validation studies do not have specific timeframes for completion. The adequacy of the implemented corrective actions will be reviewed at the next inspection.
This is a repeat observation from the October 2006 inspection.
2. Failure to establish scientifically sound and appropriate specifications, standards, sampling plans and test procedures that are designed to assure each drug product satisfactorily conforms to appropriate standards of identity, strength, quality, and purity. [21 CFR § 211.160(b)] For example, your firm failed to perform residual solvent testing on drug products that were manufactured using solvents that are required to be limited in drug products. At the time of inspection, (b)(4) drug products required residual solvent testing.
Your response stated that your firm intends to complete the residual solvent testing within the next nine months (or when the product is manufactured for infrequently manufactured products). However our response does not include any plans for future periodic residual solvent (RS) testing of these (b)(4) drug products to ensure the RS specifications of these drug products remains below the required levels. Further, your corrective action did not address products that have been distributed that were not tested for RS. Finally, please note that any analytical method you select to test for RS must be suitable for its intended use.
3. Failure to establish time limits for completion of each phase of production to assure the quality of the drug product. [21 CFR § 211.111] Time limits have not been established in a written procedure or in master production records for all drug products. For example, investigators noted that Thyroid Tablets 65mg, lot GO 15U, was blended on May 13, 2008. However, tablet compression for the finished product was not started until September 17, 2008.
Regarding this issue, your response states in part that your firm has stability data extending to 48 months. However, you have not established a correlation between the extended stability data test results and the extended product hold times. In addition, regarding testing of this specific lot, your response states "Our finished product testing of all Thyroid Tablets includes both chemical and microbiological analysis. The finished product release testing of Thyroid Tablets, 65 mg (lot D013U/G015U) confirmed the potency, purity and integrity of the lot of product." Finished product release testing is not a substitute for CGMP controls. Further, although not provided, your response indicates that a procedure establishing time limitations for each phase of the production process will be created and implemented by February 26, 2009. Please ensure that you establish hold times for all your firm's drug products. The adequacy of the implemented corrective actions will be reviewed at the next inspection.
1. Failure to establish test procedures or other laboratory control mechanisms that are designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity and to assure that any deviation from the written test procedures or laboratory control mechanisms are recorded and justified. [21 CFR 211.160(a)]. For example:
a) Investigators observed that analysts did not follow your firm's established method on four dissolution drug release tests for Aspirin Delayed Release Tablets, lots C116U and RD H017U. There was no documented justification for these deviations from the established procedures.
b) Your firm failed to follow your written procedures for qualification of raw materials as in-house reference standards. Specifically, raw materials (e.g. Phenylephrine HC1, Chlorpheniramine Maleate) are not always (b)(4) prior to determining their potency as required by your procedure. This step is necessary to correctly determine the standard's potency.
c) Your firm's laboratory assay testing method for preparing Thyroid Tablets USP does not include instructions to protect standard laboratory solutions from light exposure, per USP requirement. Your QC laboratory supervisor told our investigator that any laboratory glassware could be used in preparing standard solutions for Thyroid Tablets USP without precautions to protect the solution from light exposure.
Your January 26, 2009 response to these observations [FDA-483 item # 8(subparagraphs 3 & 4) and FDA-483 item #9] included revised procedures, eliminating inadequate sampling methods and use of glassware by your firm's analysts. Please provide your rationale for the distribution of products with standards that were characterized incorrectly. Finally, please include justification regarding the use of test results obtained using inadequate glassware for standard solutions sensitive to light.
5. Failure to maintain complete laboratory records with complete data from all tests necessary to assure compliance with established specifications and standards, including a complete record of all data secured in the course of each test. [21 CFR § 211.194(a)]
For example, your firm's system suitability testing under the nine-month time point for the CRT stability assay and dissolution analysis of Nitroglycerin Extended Release Capsules Lot M041S is inadequate. Your firm's analyst discarded data from a total of seven standard injections for system suitability and standard average calculations. The analyst failed to provide any justification for discarding the selected data. Further, the analyst and supervisor failed to review this discarded data, as required by SOP 3.194. Inclusion of this discarded data would have resulted in the failure to meet both system suitability and standard average specifications as required by your firm's method, AP 121(A) and SOP 3.194.
Your response stated in part, "Although it was not documented, the data were legitimately discarded because they did not meet system suitability requirements." Not meeting system suitability requirements alone it is not adequate justification to discard data. In addition, your response indicates that you reviewed every case over the prior 12 months where analytical data were disqualified and no similar cases of not following the procedure were noted.
Please note that SOP 3.194 is inadequate because it only requires the analyst to explain why an injection was eliminated from a calculation.
A decision to discard data should be based on a detailed assessment of the steps taken during the test. If laboratory or calculation errors are not identified in the first test, there is no scientific basis for invalidating initial out-of-specification (OOS) results in favor of passing test results. All test results, both passing and suspect, should be reported in accordance with 21 CFR § 211.188 and 21 CFR § 211.192 and considered in batch release decisions.
In addition, adequate corrective action should include training for the analysts and supervisor on the proper handling of OOS results.
6. Failure to conduct calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used. [21 CFR § 211.160(b)(4) For example:
a) The investigators observed the following deficiencies:
• The baskets used for dissolution testing were severely warped, resulting in significant wobble. The Director of Quality Control (QC) concurred with this visual observation. In addition, all available baskets used for dissolution testing were examined by both our investigator and the Director of QC and found to be in the same warped condition. Wobbling is not checked during apparatus calibration and set up.
• Our investigator estimated that the distance from the inside bottom of the dissolution vessel and the bottom of the basket was different than the USP specification (25mm (± 2mm)) to assure adequate instrument conditions prior and during testing. This deviation was also confirmed by the Director of QC.
Your response stated: "There were approximately a dozen baskets stored in a cabinet that were in very good condition and available for use." However, during the inspection, the Director of QC identified to our investigator additional dissolution baskets that were stored in a laboratory drawer, and were in the same warped condition. We acknowledge your corrective action to replace unacceptable baskets.
In addition, the revised SOP 3.181(A), (b)(4) dated January 9, 2009, is inadequate due to the following reasons: 1) The SOP fails to describe how to use a wobble meter, 2) The SOP fails to define what is considered unacceptable wobbling; and, 3) The SOP fails to describe what is considered a physical defect for baskets and paddles.
b) You failed to follow SOP 3.159(A), (b)(4) for annual calibration of your QC laboratory's (b)(4) HPLC units. This equipment calibration was performed between May and July 2008. However, to determine HPLC instrument carryover, the analyst failed to (b)(4) per the SOP, but instead re-injected a standard solution and proceeded to calculate the carryover incorrectly. In addition, three different analysts, including the Director of QC, reviewed and approved these final calibration test results.
Your response stated that your firm conducted a training session with the analyst involved with the Calibration Protocol (b)(4) for HPLC Unit. However, review of this training record, dated November 13, 2008, revealed training for two analysts . You did not include training documentation for the additional analysts and the Director of QC that reviewed and approved these incorrect test results.
7. Failure to establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture of drug products. [21 CFR § 211.67(b)] Specifically, your firm's Disintegration apparatus was observed in the following condition:
• Basket-rack assemblies were observed unclean and containing excessive residue from previous analysis.
• Disks that were available for use did not all have smooth surfaces free from chips as required by the USP. Further, the disks were discolored.
Your response for the above two examples indicates that your firm revised your procedure for the Disintegration apparatus. Your response is inadequate in that your revised SOP 3.205(A) (b)(4) fails to indicate if these physical defects and unclean basket-racks or disks are discarded or removed from use when observed. Further, your response failed to indicate if: a) the unclean basket-racks noted in the above observation were subsequently cleaned or discarded or b) the disks noted in the above observation that did not have smooth surfaces were discarded.
8. Failure to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. [21 CFR § 211.100 (a)] For example, your firm failed to complete the process validation study report for Thyroid Tablets, USP. Data were collected for this product in July 1999 and July 2004, but the documentation was not evaluated to show that product performance is consistent and reproducible from batch-to-batch.
Your response stated, in part: ". . .; however, a study report was not written. Therefore, we will review the process validation study obtained for Thyroid Tablets, USP in July 1999 and July 2004, and issue a summary report on each of these validation studies within sixty (60) days of the date of this correspondence [March 26, 2009]." The adequacy of the implemented corrective actions will be reviewed at the next inspection.
In addition, note that assuring that a manufacturing process produces the outcome that it was designed to produce is considered an ongoing process. It is necessary to conduct additional periodic process verification.
9. Failure to maintain separate or defined areas necessary to prevent mix-ups during manufacturing and processing operations. [21 CFR § 211.42(c)(5)] Specifically, (b)(4) adjacent tablet compression areas are separated by pass-through clear plastic curtains with interleaved strips from the top of the door to the floor. Different formulated solid oral drug products are tableted in these various compression areas, separated by the pass-through plastic curtains. Your Regulatory Affairs Manager stated the plastic curtains were set up to allow operators to move freely through the curtains that are between the various compression areas to perform operations on different batches.
Your response for this item stated: "The interleaved six (6) inch strips act as a solid barrier. As a result, the curtain imparts what is tantamount to a solid wall between the adjacent compression suites, thus preventing any cross-contamination." FDA disagrees with this assessment in that pass-through plastic curtains are not considered the same as solid walls. Current industry practice includes a well-defined system of control of separate areas in a drug manufacturing facility.
Unapproved New Prescription Drugs
In addition to the CGMP violations discussed above, this inspection also revealed that your firm manufactures and markets unapproved new drugs in violation of Section 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)]. Based on the information your firm submitted to FDA's Drug Registration and Listing System and information collected during the inspection of your facility, your firm manufactures the following prescription drugs:
• Thyroid 1/2 gr. (32.5 mg) Tablets
• Thyroid.l gr. (65 mg) Tablet s
• Thyroid 2 gr. (130 mg) Tablets
• Thyroid 3 gr. (195 mg) Tablets
The above products are drugs within the meaning of Section 201(g) of the Act, [21 U.S.C. § 321(g)] because 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(a), (d) and 355(a)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for the drug. Based on our information, you do not have any FDA-approved applications on file for these drug products.
Additionally, 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 CFR § 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)].
We acknowledge your commitment to discontinue manufacturing the following unapproved drugs and other unapproved extended release products, in your written response to the Form FDA 483, dated January 26, 2009:
• Papaverine HCl 150 mg / Chlorpheniramine Maleate 8 mg E.R. capsules
• Chlorpheniramine Maleate 4 mg / Phenylephrine 20 mg capsule
• Chlorpheniramine Maleate 8 mg / Pseudoephedrine HCl 120 mg capsule
• Chlorpheniramine Maleate 12 mg / Pseudoephedrine HCl 100 mg capsule
We also request that you outline the actions you are taking to cease distribution of these or any other unapproved drug products from your facility. Please provide the following information in your response: 1) an inventory of all unapproved drugs at your firm and 2) disposition of these unapproved drugs by your firm. 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).
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 or the occurrence of other violations.
It is your responsibility to assure that your firm complies 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 new drug applications, listing your facility as a supplier or manufacturer until the above violations are corrected. A reinspection may be necessary.
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 the violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. In addition to the drugs you committed to cease manufacturing, if you no longer manufacture any other drugs, your response should so indicate, including the reasons that, and the date on which, you ceased production.
Your reply should be sent to Compliance Branch, Food and Drug Administration, 158-15 Liberty Avenue, Jamaica, NY 11433 Attention: Lillian C. Aveta, Compliance Officer.
Otto D. Vitillo
New York District
Enclosure: Form FDA 483 dated December 5, 2008