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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Hi-Tech Pharmacal Co., Inc. 6/28/10


Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 New York District
158-15 Liberty Ave
Jamaica, NY 11433

June 28, 2010



David Seltzer, President/CEO
Hi-Tech Pharmacal Co., Inc.
369 Bayview Avenue
Amityville, NY 11701

Dear Mr. Seltzer:

During our October 21, 2009 through December 3, 2009 inspection of your pharmaceutical manufacturing facility located at 369 Bayview Avenue, Amityville, NY 11701, Investigators 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, Parts 210 and 211. These violations cause your drug products 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.

In addition, your firm manufactures a prescription drug without an approved application. As described below, this drug is an unapproved new drug without an approved application, and by introducing it into interstate commerce, you are in violation of sections 301(d) and 505(a) of the Act  [21 U.S.C. §§ 331(d) and 355(a)]. This unapproved new drug is misbranded pursuant to section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], and by introducing it into interstate commerce you are in violation of section 301(a) of the Act [21 U.S.C. § 331(a)].

Specific violations observed during the inspection include, but are not limited, to the following:

CGMP Violations

1. Your firm failed to establish laboratory control mechanisms to include the detennination of conformance to applicable written specifications for the acceptance of each lot within each shipment of components used in the manufacture, processing, packing, or holding of drug products [21 C.F.R.§ 211.160(b)(1)].

For example, lot 26910 of Prednisolone API failed to meet the acceptance specifications for two unknown impurities and was released. This lot was used to manufacture (b)(4) distributed lots of Prednisolone Oral Solution drug product. Your firm's out of specification (OOS) investigation (b)(4) states the initial samples of this lot yielded OOS results for two unknown impurities. Although the lot was re-sampled and retested as a part of the OOS investigation, results from the retest failed and your firm failed to reject the lot as required by your SOP P-14-04. Your firm continued to resample and retest until test results met the acceptance specifications. Your firm's investigation report attributed the OOS results to probable glassware contamination or instability of the sample solution, even though there was no scientific evidence to support these conclusions. Furthermore, your firm's own laboratory management stated that glassware contamination and instability of solutions did not cause the OOS result in an email dated February 18, 2009.

2. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

For example,

a. Your firm failed to perform residual solvent testing for (b)(4) drug products (including Paregoric Liquid USP and Prednisolone Oral Solution USP) which used API's that were manufactured using solvents that are required to be limited in drug products.

b. Your firm failed to dry in-house reference standards or determine the water content of those standards before use in analyzing your drug products. Your firm uses in-house reference standards on an "as-is" basis without drying or determining water content before use. Your firm then assigns the in-house reference standards an "as-is" purity factor with a one year expiration date as required by your SOP QC-057-05. However, there is no data to demonstrate that these "as-is" purity factors will remain accurate over the one-year expiry period of the standard. Your use of these "as-is" purity factors have resulted in erroneous assay calculations for your drug products.

For example, your firm failed to determine the anhydrous purity factor of Riboflavin 5' Phosphate Sodium (Vitamin B2), Lot 26630 standard as required by your SOP. Your firm used the anhydrous purity factor from the supplier's certificate of analysis (COA), which became the "as-is" reference standard. Because you used this "as-is" purity factor instead of drying the standard or using a loss-on-drying factor, your calculations for the assay of Poly-Vitamin Drops, Lot 602774 resulted in a (b)(4) % error.

c. Your firm failed to confirm the normality factors provided by suppliers for commercially prepared volumetric solutions. Your firm purchases commercially prepared volumetric solutions and uses the normality factors supplied on the certificates of analysis without verification testing to confirm the accuracy of the supplier's results.

3. Your firm has not recorded and justified any deviation from the written specifications, standards, sampling plans, test procedures or other laboratory control mechanisms [21 C.F.R. § 211.160(a)).

For example, your firm failed to follow your SOP QC-057-05 for expiration dating of "in-house" reference standards. Your firm uses Riboflavin 5' Phosphate Sodium (Vitamin B2) raw material as a standard for the analysis of Poly-Vitamin Drop products. It is classified as a non-compendial reference standard and assigned a two-year expiration date, even though this substance is a compendial (USP) product and should be assigned as a "in-house" standard with a one-year expiration date, according to your SOP.

4. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211.165(e)].

For example,

a. Your firm failed to validate methods used for the assay analysis of six Poly-Vitamin Drop products, four Tri-Vitamin Drop products, and Sodium Fluoride Drops.

b. Your firm failed to include the following characteristics: accuracy, robustness, ruggedness and specificity in your validation of the UPLC assay method (b)(4) used for the analysis of Pyridoxine Hydrochloride (Vitamin B6), Riboflavin 5' Phosphate Sodium (Vitamin B2) and Thiamine Hydrochloride (Vitamin B1) in Poly-Vitamin Drop products.

c. Your firm failed to generate and document chromatographic data to support the validation of the analytical method (b)(4) used for determination of Urea in Urea Cream 40%. In addition, your firm failed to generate and document chromatographic data to support stress studies for Paregoric Liquid USP to demonstrate that the method is suitable for determining stability.

5. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100].

Your firm failed to complete the process validation studies for the following four prescription drug products:

1. Tri-Vitamin Drops with Iron and Fluoride 0.25mg
2. Poly-Vitamin Drops with Fluoride 0.25mg
3. Tri-Vitamin Drops with Fluoride 0.50mg
4. Tri-Vitamin Drops with Fluoride 0.25mg

For example, there are no batch records with the original data and test results for the validation study of Poly-Vitamin Drops with Fluoride 0.25mg and Tri-Vitamin Drops with Fluoride 0.25mg. In addition, you implemented revisions to your master formula without adequate change control. Evaluation of the data and records associated with the manufacture of Poly-Vitamin Drops with Fluoride 0.25mg and Tri-Vitamin Drops with Fluoride 0.50mg was not available to assure that the changes made to the batch records (revisions to the master formula) do not impact the product quality.

6. Your firm does not have, for each batch of drug product, an appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release [21 C.F.R. § 211.165(a)].

For example, your firm failed to perform analytical testing for the following active ingredients to determine conformance to their assay specifications:

1. Vitamin D in Poly-Vitamin Drops with Iron and Poly-Vitamin Drops with Iron and Fluoride 0.25mg
2. Vitamin D and B12 in Poly-Vitamin Drops with Fluoride 0.50mg and Poly-Vitamin Drops with Fluoride 0.25mg

7. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)].

For example, your firm failed to establish the reliability of your suppliers' test results. Specifically, verification of a supplier's residual solvent test results for excipients is limited to testing of only one lot of material to confirm the accuracy of the supplier's test results.

Unapproved and Misbranded Prescription Drug

In addition to the CGMP violations, discussed above, you manufacture and market an unapproved new drug in violation of the Act at your facility. Based on the information your firm submitted to FDA's Drug Registration and Listing System and the information collected during the inspection, you manufacture the following prescription drug:

• Paregoric Liquid, USP (Anhydrous Morphine 2 mg, Alcohol 47.7%)


The above product is a drug within the meaning of Section 201 (g) ofthe Act, [21 U.S.C. 321(g)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, it is a "new drug" within the meaning of Section 201(P) of the Act [21 U.S.C. § 321(P)] because it is not generally recognized as safe and effective for its 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, you do not have any FDA-approved applications on file for this drug product.

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 product is misbranded because, as a prescription drug, adequate directions cannot be written for it so that a layman can use this product safely for its intended uses. Consequently, its labeling fails to bear adequate directions for use as required under Sections 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)] and because it lacks a required approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115.

The introduction or delivery for introduction into interstate commerce of adulterated and misbranded drugs or products without approved new drug applications violates Sections 301(a) and (d) of the Act [21 U.S.C. §§ 331(a) and (d)]. Therefore, you should discontinue manufacturing and distributing all of your unapproved drugs at all facilities immediately. We acknowledge the letter from your consultant, (b)(4) dated November 5, 2009, who provided your firm an opinion on the regulatory analysis of your products. Based on our information, you do not have any FDA-approved applications on file for those drug products.

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.

As stated above, you must cease manufacturing and distributing all your unapproved new drug products. Within fifteen working days of receipt of this letter, you should notify this office to arrange for a meeting to discuss the specific steps you have taken to correct the noted 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. We also request that you outline the action you are taking to discontinue the marketing of the unapproved drug product at your facility, or any other applicable drugs which you may market. Additionally, your response should state if you no longer manufacture or distribute products, and provide the date(s) and reason(s) you ceased production. Please note that if you are no longer marketing this (these) product(s), you must update the Drug Listing files in accordance with 21 C.F.R. § 207.30(a)(2).

Your reply should be sent to the following address: Compliance Branch, Food and Drug Administration, 158-15 Liberty Avenue, Jamaica, NY 11433. Attention: Lillian C. Aveta, Compliance Officer.



Ronald M. Pace
District Director
New York District


Enclosure: Fonn FDA 483 dated December 3,2009