Inspections, Compliance, Enforcement, and Criminal Investigations
Scientific Laboratories, Inc. 16-Nov-05
Department of Health and Human Services
Public Health Service
Baltimore District Office
November 16, 2005
RETURN RECEIPT REQUESTED
Mr. Amit Roy, CEO
Scientific Laboratories, Inc.
10150 Old Columbia Rd.
Columbia, MD 21046
Dear Mr. Roy:
During a May 9 to June 30, 2005 inspection of your pharmaceutical manufacturing facility located at 9701 C Philadelphia Way, Lanham, Maryland, our investigator documented serious deviations from current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals delineated in Title 21, Code of Federal Regulations (CFR), Parts 210 and 211.
The inspection revealed that your firm's Quality, Production, Facilities and Equipment, Materials, and Laboratory Controls systems employed during the manufacturing, processing, packing and holding of your firm's drug products do not conform to cGMP requirements. These violations cause the drug products manufactured at your facility 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)).
At the close of the inspection, you were issued a Form FDA-483, Inspectional Observations, which contained a number of significant cGMP deviations. The following are examples of the significant deficiencies regarding your firm's operating systems:
1. Failure to establish and follow appropriate written procedures designed to prevent objectionable microorganisms in drug products not required to be sterile [21 CFR 211.113(a)].
For example, your firm failed to perform antimicrobial effectiveness testing for any of the preservatives used in the drug products made at your firm.
2. Failure to perform appropriate laboratory testing, as necessary, for each batch of drug product required to be free of objectionable microorganisms [21 CFR 211.165(b)].
For example, there was no microbial limits testing performed on oral liquid and suspension drug products for potentially harmful gram negative organisms such as E. coli and Pseudomonas species.
3. Failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 CFR 211.165(e)].
For example, your firm employs a microbial limits test for Total Aerobic Count (TAC) and Total Yeast and Mold (TYM) that differs from the compendial procedure outlined in USP<61> and has not validated the altered method.
4. Failure to establish scientifically sound and appropriate specifications, standards, sampling plans, and test procedures, designed to assure that components and drug products conform to appropriate standards of identity, strength, quality and purity [21 CFR 211.160(b)].
For example, microbial limits testing was performed on both finished drug products and purified water used in the drug products, using commercial growth media that was beyond its expiration date. In addition, sampling of lots of oral liquid and suspension drug products was not representative and the firm's SOP 0-009 "Submitting Liquid Product Samples, Stability Studies, Finishing Product Testing & Retains," which requires more extensive testing than is actually performed, was not followed.
5. Failure to follow written procedures for issuance of labeling and packaging materials and for reconciliation of the quantities of labeling issued, used, and returned [21 CFR 211.125(c) and (f)].
For example, your [redacted] which requires documentation of packaging and labeling issued and returned, was not followed. There were no records of the number of labels or inserts issued for any of the lots of drug products produced at your firm.
6. Failure to limit access to label storage areas to authorized personnel [21CFR 211.122(d)].
For example, labels and packaging material were stored on open shelves in an unsecured area of your firm's warehouse.
7. Failure to follow written procedures for the receipt, identification, storage, handling, sampling, and examination of labeling and packaging materials [21 CFR 211.122(a)].
For example, your firm failed to assign receiving numbers to packaging and printed materials, and hold such materials under quarantine until released by the quality control unit, as is required by SOP [redacted]. In addition, sampling and examination of labels, inserts, outserts, and packaging materials was not performed in accordance with SOP [redacted] and SOP.
8. Failure to establish written procedures designed to insure that correct labels, labeling and packaging are used for drug products [21 CFR 211.130(d)].
For example, your firm failed to establish procedures for conducting examinations of packaging and labeling materials for suitability and correctness prior to packaging operations.
9. Failure to establish and follow written procedures for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product [21 CFR 211.67(b)].
For example, your firm failed to establish written cleaning procedures for major production equipment such as the [redacted] Automated Filling Machine or the [redacted] Tablet Press. In addition, [redacted] was not followed.
10. Failure to keep records of maintenance, cleaning, sanitizing and inspection of equipment as specified in 21 CFR 211.180 and 21 CFR 211.182 [21 CFR 211.67(c)] .
For example, your firm does not maintain written records for the documentation of maintenance, cleaning, and inspection of major equipment used in drug manufacture, such as tablet presses, counting machines and blenders.
11. Failure to maintain written records of calibration checks and inspections of automated, mechanical or electronic equipment used in the manufacture, processing, packing or holding of a drug product [21 CFR 211.68(a)].
For example, our firm does not maintain records of any inspections or maintenance on the [redacted] or [redacted] balances used to weigh pharmaceutical ingredients for production.
12. Failure to establish and follow written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing and approval or rejection of drug product containers and closures [21 CFR 211.80(a)].
For example, your firm has not established written procedures for the receipt, examination, and acceptance of containers and closures used for prescription solid oral dosage form, oral liquid, and oral suspension drug products.
13. Failure to follow written procedures for the preparation of master production and control records [21 CFR 211.186(a)].
For example, master batch records were not signed by the preparer and reviewed and signed by a second person, as is required by your SOP [redacted]. In addition, document control procedures for approved master batch records in this SOP were not followed.
14. Master production and control records are incomplete [21 CFR 211.186(b)(7), (8), and (9)].
For example, master production and control records did not include statements of theoretical yield, including acceptable maximum and minimum percentages. In addition, they failed to include specimens of the drug product's approved label and labeling or descriptions of the product's containers and closures. They also failed to include special instructions concerning the handling of DEA-controlled active ingredients.
15. Failure to prepare batch production and control records for each batch of drug product containing complete information relating to the production and control of the batch, including documentation that each significant step in the manufacture, processing, packing or holding of the batch was accomplished [21 CFR 211.188(b)(2),(6),(7),(8), (9) and (11)].
For example, batch production records for your firm's oral liquid and oral suspension drug products were found that failed to include label control information or specimens or copies of all labeling used, a full description of all containers or closures, and results from inspection of packaging and labeling areas before and after use. In addition, batch production records for your firm's solid oral dosage form drugs failed to include identification of major equipment used, a description of containers and closures used, specimens of inserts used, identification of persons checking each significant step in production, and statements of actual yield.
16. Failure to follow written procedures for conducting, at least annually, an evaluation of the quality standards of each drug product to determine the need for changes in specifications or in manufacturing and control procedures [21 CFR 211.180(e)].
For example, batch records associated with a representative number of batches have not been reviewed, as is required by SOP [redacted]. In addition, annual reviews of complaints, recalls and drug product returns have not been conducted as specified in this SOP.
All of the cGMP deficiencies are indicative of your Quality Control Unit's failure to meet requirements impacting the identity, strength, quality, and purity of your drug products [21 CFR 211.22].
In addition, the inspection revealed that certain drug products manufactured by your firm are in violation of sections 502(c), 502(f)(1), 503(b)(4)(B) and 505(a) [ 21 U.S.C. § 352(c), § 352(f)(1), § 353(b)(4)(B), and § 355(a)] of the Act for the following reasons:
Benn-Tann Suspension, D-Tann CT Suspension, D-Tann Suspension, Duotan PD Suspension, Duotan Suspension, Exratuss Suspension, Quad Tann Pediatric Suspension, Quad Tann Tablets, Rentamine Tablets, Trionate Suspension, V-Tann Suspension B.I.D., Coldcough PD Syrup, Coldcough Syrup, Guiadex DM Liquid, and Histacol LA Tablets are drugs within the meaning of 21 U.S.C. § 321 (g).
Further, they are "new drugs" within the meaning of 21 U.S.C. § 321(p) and lack approved applications filed pursuant to section 21 U.S.C. § 355, they are also misbranded pursuant to 21 U.S.C. § 352(f)(1) because they do not bear adequate directions for use.
The drug products Carbihist Antihistamine and Carbinoxaime PD are similar or related to the carbinoxamine containing drug products reviewed under the agency's Drug Efficacy Study Implementation (DESI) program, March 19, 1973 (38 FR 7265-7266). All drug products evaluated under the DESI program are new drugs and, since FDA determined that these products were not effective, they require a new approved application pursuant to 21 U.S.C. § 355 before they may be legally marketed. All drug products that are identical, similar, or related to the products described in the Federal Register Notice cited above are also new drugs and require an approved application before marketing, 21 CFR § 310.6.
Carbihist Antihistamine and Carbinoxaime PD are similar or related to the carbinoxamine products reviewed under the DESI program and, therefore, are new drugs subject to the provisions of 21 U.S.C. § 355(a) and are misbranded pursuant to 21 U.S.C. § 352(f)(1), in that they lack adequate directions for use. No approval of an application filed pursuant to 21 U.S.C. § 355(a) is in effect for these drugs. The interstate distribution of these products violates 21 U.S.C. § 331(a) and (d).
The drug products Detuss Liquid, Dynatuss HC Syrup, Dynatuss HCG Syrup, Rindal HD Plus Syrup, and Rindal HPD Syrup are similar or related to the hydrocodone containing drug products reviewed under DESI program (47 FR 23809) June 1, 1982, and are new drugs subject to the provisions of 21 U.S.C. § 355(a). No approval of an application filed pursuant to 21 U.S.C. § 355(a) is in effect for these drugs. These drugs are also misbranded pursuant to 21 U.S.C. § 352(f)(1) because they lack adequate directions for use. The interstate distribution of these products without approved new drug applications violates 21 U.S.C. § 331(a) and (d).
Your firm manufactures two products, Bromdec DM Syrup and Rondamine DM Syrup, that bear the"Rx only" legend, yet they contain combinations and amounts of ingredients that are covered under the final regulations on over-the-counter (OTC) cough/cold drug products found at 21 CFR § 341.40. The Bromdec DM Syrup and Rondamine DM Syrup contain 4 mg brompheniramine maleate, 45 mg pseudoephedrine hydrochloride, and 15 mg dextromethorphan hydrobromide per 5 ml. Both products are offered for use as antihistamines, decongestants, and antitussives. The active ingredients and claims for these products are covered under the OTC drug regulation cited above. These products are not entitled to bear the "Rx only" legend because they are OTC drugs. Therefore, the products are misbranded under 21 U.S.C. § 353 (b)(4)(B).
Bromdec DM Syrup and Rondamine DM Syrup are also misbranded under 21 U.S.C. § 352(f)(1) because they do not bear adequate directions for use as required by 21 CFR § 341.72(d)(1) for antihistamines, 21 CFR § 34.74(d)(1)(iii) for antitussives, and 21 CFR § 341.80(d)(1) for nasal decongestants. The products are further misbranded under 21 U.S.C. § 352(f)(2) because they do not bear the complete warnings in the wording required by 21 CFR § 341.72(c) for antihistamines, 21 CFR § 341.74(c) for antitussives, and 21 CFR § 34.80(c) for nasal decongestants, the pregnancy/breast-feeding warning required by 21 CFR § 201.63, and the accidental ingestion warning required by 21 CFR § 330.1(g).
Because Bromdec DM Syrup and Rondamine DM Syrup deviate from the OTC final rule as cited above, they are not generally recognized as safe and effective for their labeled indications. Accordingly, the products are new drugs under 21 U.S.C. § 321(p) that are marketed without an approved application in violation of 21 U.S.C. § 355(a) and 331(d).
Bromdec DM Syrup and Rondamine DM Syrup are also misbranded under 21 U.S.C. § 352(c) because they are not labeled in compliance with the Drug Facts Format labeling regulations found at 21 CFR § 201.66. Introduction or delivery for introduction into interstate commerce of these products violates 21 U.S.C. § 331(a).
We are in receipt of your written response, dated July 21, 2005, to the Form FDA-483 issued at the close of the inspection. The promised corrective actions for observations 6, 9-11, 15, 16, 21, 33, and 38 appear to be adequate to correct the violations noted on the FDA-483 upon their full implementation. However, the remaining corrective actions do not appear to be adequate to correct all the deviations. Many of the responses to the FDA-483 items do not include a timeframe for completion of the corrective action. For example, your response to FDA 483 item #14 states that product hold times are being validated but gives no date for completion or any indication of whether or not production will continue without the validation. In addition, the documentation submitted to show implementation of the corrective actions your firm claims to have completed is inadequate. For example, your response to item #2 includes results from your revised test procedure for TAC but did not include the revised procedure.
This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to assure that your firm adheres to all requirements of the Act and implementing regulations.
We also request that you outline the action you are taking to discontinue the marketing of the unapproved drug products or any other applicable drug which you may market. Also please note that if you are no longer marketing this (these) product(s), you must update the Drug Listing files in accordance with 21 CFR 207.30(a)(2).
You should take prompt action to correct these deviations. Failure to promptly correct these violations may result in regulatory action without further notice. Such actions include, but are not limited to, seizure and/or a court injunction against further marketing of your drug products. In addition, Federal Agencies are advised of the issuance of all Warning Letters so that they may consider this information when awarding government contracts.
Please notify this office in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct the noted violations and to prevent recurrence. Your response should outline the specific things that you are doing to correct these deviations. You should include in your response documentation and written verification procedures or other useful information that would assist us in evaluating your corrections. If the corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Your reply should be sent to the Food and Drug Administration, 6000 Metro Drive, Suite 101, Baltimore, Maryland 21215, Attention: Steven B. Barber, Compliance Officer. If you have any questions concerning the stated matters, you may contact Mr. Barber at 410-779-5134.