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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Neil Laboratories, Inc. 02-Oct-01

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Central Region
Food and Drug Administration
Waterview Corporate Center
10 Waterview Blvd., 3rd Floor
Parsippany, NJ 07054
Telephone (973) 526-6004

October 2, 2001
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
FILE NO.: 02-NWJ-02

Bharat Patel, President and CEO
Neil Laboratories, Inc.
55 Lake Drive
East Windsor, New Jersey 08520

Dear Mr. Patel:

On July 31 through August 10, 2001, the U.S. Food and Drug Administration conducted an inspection of your facility located at 55 Lake Drive, East Windsor, New Jersey. During the inspection our investigators documented significant deviations from the Current Good Manufacturing Practices Regulations (cGMPs) Title 21, Code of Federal Regulations, Part 210 and 211, in conjunction with your firm?s manufacture of Prescription and Over-the-Counter (OTC) drug products.

The inspection revealed that drug products manufactured at your facility are adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (the Act), in that the methods used in, or the facilities or controls used for their manufacture, processing packing or holding do not conform with cGMPs, to assure that such drug products meet the requirements of the Act The deviations were presented to you on a FDA-483, List of Inspectional Observations, at the close of the inspection on August 10, 2001.

The significant observations are as follows:

1. No assurance that the product Guaifensin/Pseudoephedrine HCl 800/45 mg Sustained Release (S/R) Caplets will meet the release and stability requirements throughout the two-year expiration date. Lot #102013 (Validation Batch) manufactured on March 7, 2001, did not meet dissolution specifications [redacted]) during 4-week accelerated stability analysis; Lot #103003 (Validation Batch) manufactured on March 16, 2001, did not meet dissolution stability specifications;

Lot #103002 manufactured on March 8,2001, did not meet dissolution stability specifications; and Lot #105023 manufactured on May 22, 2001, did not meet dissolution release specifications.

Your firm averages Out-of-Specification (OOS) dissolution results with test data results that are within specification. The average of six caplets is used to determine if the results are within the acceptable range. The four referenced lots were all distributed. No investigation was performed into the OOS results.

2. Failure to adequately validate the product Aspirin 81 mg Enteric Coated (E/C) Tablets. Validation Batch #008009 failed dissolution at 3-month accelerated stability on November 21, 2000. The batch record shows the validation of the coating process is invalidated and the batch was rejected. Validation Batch #008010 manufactured using the same process is being stored in your reject area, due to the stability failure of batch #008009. Validation Batch #008008 manufactured using the same process was released on October 13, 2000 and distributed on October 31, 2000.

There is no assurance that Batch #008008 would meet dissolution specifications throughout its two-year labeled expiration date.

3.Your firm does not have adequate data to support changes made to the Master Formula for the product Diphenhydramine HCl 25 mg Film Coated (F/C) Caplets.

The changes include the addition of an excipient change in specifications, and the increase in batch size. Additionally, your Change Control Procedure, SOP 5.5 Change Control, is incomplete in that it does not specify when a process requires Revalidation.

4.Your procedures for laboratory instrumentation calibration are incomplete.

For example:

a. Procedure for HPLC Calibration Method 013 has no predetermined acceptance criteria for the auto sampler calibration The auto sampler calibration does not demonstrate that the instrument is capable of accurately assessing linearity.

b. Procedure for UV/VIS Spectrophotometer only assesses linearity using alkaline potassium chromate solution atone wavelength when analytical tests are performed at various wavelengths. The procedure does not include functional tests, such as wavelength accuracy, photometric accuracy, and reproducibility within ranges of intended use for the instrument

c. Procedure for Dissolution Apparatus Calibration Method 002A does not require testing for physical attributes of the bath. The procedure does not assess wobble during calibration

5. Investigation Reports into Out-of-Specification test results are inadequate.

For example, Investigation Report 00-001 dated November 27, 2000, concerning 3-month accelerated stability failure for Aspirin 81 mg Enteric Coated (E/C) Tablets, Batch 008009, did not indicate if manufacturing records were reviewed, corrective and/or preventive measures were identified, assessment of all possible causes for the failure were evaluated and review of additional batches possibly affected.

6. The analytical method used for the product Calcium Polycarbophil 625 mg F/C Caplets is not validated in that there is no data to show that the method is rugged, robust, and is capable of sustaining minor challenges, such as mobile phase adjustments.

7. The analytical methods used for the release of raw materials and finished products during stability testing are inadequate. For example:

  1. There is no assurance that the Acetaminophen 325/500 mg Tablets/Caplets Stability Method is stability indicating in that the method does not contain predetermined dissolution specifications.

b. Raw Material Acetaminophen DC 90% Method does not contain predetermined specifications for the assay analysis.

c. Aspirin E/C 325 mg Tablets Method does not have predetermined specifications for percentage of Acid during the Acid Stage dissolution.

8. Failure to maintain stability storage temperature within the specified ranges of [redacted] ?F to [redacted]?F. The stability monitoring charts were observed to reach levels of 90 ?F to 100 ?F for several days during the week of May 3, 2000. No investigation was performed into the Out-of-Specifications ranges.

We received your response letter dated August 30,2001 regarding the inspectional observations noted on the FDA-483. We recommend you conduct a comprehensive evaluation of your facility to determine cGMP compliance. We will review the implementation and the adequacy of your corrective actions during our follow-up inspection of your firm.

The above identification of violations is not intended to bean all-inclusive list of deficiencies at your facility. It is your responsibility to assure adherence with each requirement of the Good Manufacturing Practices Regulations. Federal agencies are advised of the issuance of all Warning Letters about drugs and devices so that they may take this information into account when considering the award of contracts. You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action without further notice. This includes seizure and/or injunction.

You should notify this office in writing within 15 working days of receipt of this letter, of any additional corrective actions, including an explanation of each step being taken to prevent the recurrence of similar conditions. If corrective action cm-not be completed within 15 working days, state the reason for the delay and the timeframe within which corrections will be completed. Your reply should be sent to the Food and Drug Administration New Jersey District Office, 10 Waterview Blvd, 3rd Floor, Parsippany, New Jersey 07054, Attention: Andrew Ciaccia, Compliance Officer.

Very truly yours,
DOUGLAS L. ELLSWORTH
District Director
New Jersey District Office