Inspections, Compliance, Enforcement, and Criminal Investigations
Neil Laboratories Inc. 31-May-06
Department of Health and Human Services
Public Health Service
May 31, 2006
RETURN RECEIPT REQUESTED
Mr. Bharat Patel
Neil Laboratories Inc.
55 Lake Drive
East Windsor, NJ 08520-5320
Dear Mr. Patel:
During a December 13 through December 28, 2005, inspection of your drug manufacturing facility located at 55 Lake Drive, East Windsor, New Jersey, an investigator from this office documented deviations from the Current Good Manufacturing Practice (CGMP) regulations in 21 Code of Federal Regulations (CFR), Parts 210 and 211, that cause your finished drug products to be adulterated within the meaning of 21 U.S.C. § 351(a)(2)(B) (section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)). 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(f)(1) (section 502(f)(1) of the Act). Lastly, several of the over-the-counter (OTC) drugs that you manufacture lack required warnings or other information on their labels, making them misbranded drugs under 21 U.S.C. § 352 (section 502 of the Act).
The following are examples of some of the significant CGMP deviations that were found during our inspection of your firm:
1. Failure to establish scientifically sound and appropriate specifications, standards, sampling plans and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity. [21 CFR § 211.160(b)]
For example, the analytical methods used by your firm to determine satisfactory conformance to the final specifications and identity and strength of each active ingredient prior to release have not been validated for the drug products listed below:
Guaifenesin 400 mg Caplets
Guaifenesin/Psuedoephedrine Caplets 600 mg/120 mg and 1200 mg/50mg
Guaifenesin/Psuedoephedrine Sustained Release Caplets 800 mg/90 mg
Guaifenesin/Dextromethorphan Caplets 400 mg/20 mg and 1000 mg/60 mg
Guaifenesin/Psuedoephedrine/Dextromethorphan Caplets 800 mg/90 mg/60 mg
Guaifenesin/Phenylephrine Caplets 1200 mg/40 mg
Bromphenirimine/Psuedoephedrine Caplets 10 mg/120 mg
Isoxsuprine 20 mg Tablets
Sennoside 8.6 mg Tablets
Sennoside/Docusate sodium 8.6 mg/50 mg Tablets
Bisacodyl 15 mg Tablets
Calcium Polycarbophil 625 mg Caplets
Aspirin 800mg Sustained Release Caplets.
This observation also was included on an FDA-483, dated August 10, 2001, and subsequent Warning Letter, issued on October 2, 2001. Regarding Calcium Polycarbophil 625 mg Caplet, your August 30, 2001, response stated that "The method development will take about sixty (60) days." Please explain why you have failed to complete method validation for this product. Also, please submit a schedule for the completion of all method validation work for your existing product line, including the products listed above.
2. Failure to establish a written testing program designed to assess the stability characteristics of drug products, including reliable, meaningful, and specific test methods . [21 CFR § 211.166(a)(3)]
For example, the analytical methods used to test the drug products listed in item # 1 have not been shown to be stability-indicating methods. Regarding justification for the established expiration dates, this observation was also previously brought to your attention in the Warning Letter, dated October 2, 2001. Specifically, the Warning Letter stated that there was "No assurance that the Guaifenesin/Psuedoephedrine 800 mg/45 mg Sustained Release Caplets will meet release and stability requirements through out the two year expiration date." In your October 23, 2001, written response, you stated that "USP 24 does not have any monograph on Psuedoephedrine and Guaifenesin Sustained Release tablets ." Please be advised that the lack of a USP monograph for this product does not absolve your firm of responsibility for developing a reliable, meaningful, and specific test method. Your firm is responsible for assuring that each of your drug products meets its label claims through its expiration date.
3. Failure to employ appropriate controls over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. [21 CFR § 211.68(b)]
For example, your firm has inadequate security measures in place to assure the integrity and reliability of data generated by your laboratory. During the December 2005 inspection, our investigators observed your laboratory analysts operating computers under different analysts' names. Your analysts told our investigators that using other laboratory personnel's names and passwords was a common occurrence in your firm's laboratory while using your Turbochrom laboratory software.
4. Failure to maintain 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 lacked complete and accurate records in that HPLC printouts did not have any record of method parameters, integration parameters, instrument identification, or sample or vial identification.
5. Failure to assure that individuals responsible for supervising the manufacture and processing of a drug product have the education, training and experience to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess. [21 CFR § 211.25(b)].
For example, during the December 2005 inspection of your firm, your laboratory manager and QA personnel stated to our investigator that they were not trained in your [redacted]
Unapproved New Prescription Drugs
You manufacture the following prescription drugs:
Aspirin 800 mg Sustained-Release Tablets
Pseudoephedrine HCI and Guaifenesin 120 mg/600 mg Sustained-Release Tablets
Guaifenesin 1000 mg and Dextromethorphan HBr 60 mg Long-Acting Tablets
Pseudoephedrine HCI 90 mg and Guaifenesin 800 mg Time-Released Tablets
Dextromethorphan HBr 60 mg, Pseudoephedrine 90 mg, and Guaifenesin 800 mg Time-Released Tablets
Guaifenesin 1200 mg and Phenylepherine HCI 40 mg Sustained-Release tablets
Pseudoephedrine HCI 50 mg and Guaifenesin 1200 mg Sustained-Release tablets
Uni-Tex 120/10 (Pseudoephedrine HCI 120 mg/Brompheniramine maleate 10 mg) Extended-Release Capsules.
FDA regards descriptions such as "sustained-release," "extended release," and "long acting" as timed release dosage forms. Prescription products marketed in timed release dosage form are not generally recognized as safe and effective under 21 U.S.C § 321(p) (section 201(p) of the Act). Further, the agency has, through rule making procedures, codified the new drug status of timed release drugs at 21 CFR § 310.502(a)(14). Thus, the above products manufactured by your firm are new drugs.
Section 505(a) (21 U.S.C. § 355(a)) of the Act requires that any new drug be the subject of an FDA-approved new drug application before it is introduced into interstate commerce. There are no approved applications on file for the above products and their continued marketing is in violation of 21 U.S.C. § 355(a) (section 505(a) of the Act).
In addition, these drugs are misbranded. 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 21 U.S.C. § 352(f)(1) (section 502(f)(1) of the Act) and, lacking required approved applications, they are not exempt from this requirement under 21 CFR § 201.115.
Misbranded Over-the-Counter Drugs
You also manufacture numerous drug products for over-the-counter use. Some of these are misbranded. Specifically, several aspirin products that you manufacture fail to bear the complete Reye's Syndrome warning and the specific pregnancy warning required for products that contain aspirin. Further, certain of your products fail to bear an adequate labeling statement regarding the tamper-evident packaging (TEP) feature used. These drug products are identified below:
The Health Care America Aspirin 325 mg film coated tablets, the Health Care America Enteric Coated Aspirin 325 mg tablets, Health Care America 81 mg. Low Dose Aspirin tablets, and NC Low Dose EC Aspirin 81 mg: tablets, are misbranded under 21 U.S.C. § 352(f)(2) (section 502(f)(2) of the Act) because they fail to bear the complete Reye's Syndrome warning required by 21 C.F.R. § 201.314(h)(1) and they fail to bear a complete warning regarding the use of aspirin in the third trimester of pregnancy (21 C.F.R. § 201.63(e)).
The Preferred Plus Pharmacy Enteric Coated Aspirin 500 mg tablets product is also misbranded under 21 U.S.C. § 352(f)(2) (section 502(f)(2) of the Act) because it fails to bear the complete Reye's Syndrome warning required by 21 C.F.R. § 201.314(h)(1) and it also fails to bear the alcohol warning for aspirin products required by 21 C.F.R. § 201.322(a)(2).
The Health Care America Total Allergy Medicine (25 mg diphenhydramine hydrochloride) two-piece banded capsules packaged in bottles and the NL Diphenhydramine Hydrochloride (25 mg and 50 mg) two-piece banded capsules packaged in bottles fail to reference the second TEP feature, i.e., capsule band, in the TEP labeling statement as required by 21 C.F.R. § 211.132(c)(1). Therefore, the products are misbranded under 21 U.S.C. § 352(a) (section 502(a) of the Act ).
The URL Guaifenesin 400 mg tablets and the NL Guaifenesin 400 mg tablets TEP labeling statement, "Do not use if seal is broken," fails to identify the specific TEP feature and also fails to reference any identifying characteristic that is used (21 C.F.R. § 211 .132(c)(1)). Thus, the product is misbranded under 21 U.S.C. § 352(a) (section 502(a) of the Act).
You should take prompt action to correct these deviations and violations. Failure to promptly correct these deviations and violations may result in additional regulatory action without further notice. These actions include, but are not limited to, seizure of your products or injunction. Federal agencies are advised of warning letters issued so that they may take this information into account when considering the award of government contracts.
Regarding your Sennoside product, your January 24, 2006 written response to our December 2005 inspectional observation states that, to calculate the total potency of this finished drug product: "In the past, (the) method was considered and reviewed to incorporate Sennoside D." However, you further stated, the "USP reference standard is available for Sennoside A and B only. Also, we have tried to get more information on Sennoside A, B and D from other available sources (internet and other publications). All information was available for Sennoside A and B only, but no information was available for Sennoside D. By reviewing all the available information it looks like Sennoside D was calculated in method of analysis for finished product and stability sample was on the basis of an assumption only." Please explain what you mean by "on the basis of an assumption only." During the next inspection, the Agency will review: 1) the performance of this method, including adequate documentation; and 2) the change control procedure for changes made to established methods."
During the inspection, we noted that identification testing of Active Pharmaceutical Ingredients by your firm using Infrared Spectroscopy (IR) was not performed in accordance with compendial methods. For example, sample preparations were not made concomitantly or using the same IR instrument as the standard preparations. We acknowledge your response which states that you will now analyze samples concomitantly with standard preparation. However, we are not clear if you will be using the same IR instrument to analyze your standards and samples. Please indicate whether you will use the same IR instrument to analyze a standard and a sample. If you use different IR instruments, please provide evidence demonstrating that the equipment is comparable.
Please notify this office in writing within 15 working days of receipt of this letter: 1) of the additional specific steps that you will take to correct these violations, including an explanation of each step being taken to prevent the recurrence of the violations; and 2) how you plan to assure that each of the systems at your firm is in an overall state of control. If corrective actions cannot be completed within 15 working days, please state the reason for the delay and the time frame within which corrective actions will be completed. Your response should be addressed to: U.S. Food & Drug Administration, 10 Waterview Boulevard, 3rd Floor, Parsippany, New Jersey 07054, Attn: Andrew Ciaccia.
Douglas I . Ellsworth
New Jersey District