Concord = Laboratories, Inc., Warning Letter

From: Subject: Concord Laboratories, Inc., Warning Letter Date: Mon, 3 Mar 2008 10:54:39 -0500 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_005D_01C87D1C.FA6CF4E0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_005D_01C87D1C.FA6CF4E0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.fda.gov/foi/warning_letters/archive/g5973d.htm Concord = Laboratories, Inc., Warning Letter

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Department of Health and Human = Services	Public Health Service Food and Drug = Administration
	Central Region New Jersey District Waterview Corporate=20 Center 10 Waterview Blvd., 3rd Floor Parsippany, NJ=20 07054 Telephone (973) = 526-6010

July 11, 2006

WARNING = LETTER
06-NWJ-14

CERTIFIED MAIL
RETURN RECEIPT = REQUESTED

Mr. N.K. Rao Ramanadham, R.Ph.
President
Concord = Laboratories,=20 Inc.
140 New Dutch Lane
Fairfield, New Jersey 07004

Dear Mr. Ramanadham:

An inspection of your manufacturing facility located at 140 New Dutch = Lane,=20 Fairfield, NJ, was conducted from February 23 through March 22, 2006. = During the=20 inspection our investigator documented deviations from the Current Good=20 Manufacturing Practice (CGMP) Regulations, Title 21 Code of Federal = Regulations,=20 Parts 210 and 211 (21 CFR 210 and 211) for drug products manufactured = and tested=20 at this site. These deviations cause your drug products to be = adulterated within=20 the meaning of Section 501(a)(2)(B) of the Federal Food, Drug and = Cosmetic Act=20 (the Act) (21 U.S.C. =A7 351 (a)(2)(13)).

1) Written records are not always made of investigations into = unexplained=20 discrepancies, nor did investigations of unexplained discrepancies = extend to=20 other batches of the same drug product or other drug products that may = have=20 been associated with the specific failure or discrepancy [21 CFR =A7 = 211.192].=20 Specifically:

a) Product samples tested in conjunction with a complaint = regarding loose=20 caps on Nitroglycerin tablets, lot 201105, produced = out-of-specification=20 results for assay and content uniformity. There was no examination = of=20 product retains or a review of the batch record. The sample results = were=20 invalidated due to product damage from environmental exposure = although there=20 was no provision for this in your firm's written procedures.
b) = Product=20 samples tested in conjunction with complaints regarding tablets not=20 dissolving for Nitroglycerin tablets, lots 201105 and 214605, were = tested=20 for all release specifications except assay. There was no = justification for=20 omission of this test, nor was there any evidence of an examination = of=20 stability lots, retained samples, or a review of the batch = records.
c)=20 The reference standard injection following assay and content = uniformity=20 testing of Hyoscyamine Sulfate Tablets, lot P3274, failed to show = any peaks=20 due to a leaking column. There was no documented investigation of = this=20 deviation, there was no assessment of the impact of the leaking = column on=20 the Hyoscyamine Sulfate analysis or any other analysis conducted = with the=20 same column, and the
observation was made during the previous=20 inspection, yet no investigation was conducted.
d) There was no=20 documented investigation regarding HPLC malfunctions requiring = external=20 repair. Both HPLC [redacted]and = [redacted]=20 required repair in June 2005; however there is no documentation = regarding=20 whether the malfunctions impacted any analyses, and if so, what the=20 corrective actions were regarding those analyses.
e) The = investigation=20 into an out-of=3Dspecification assay result for Diphenhydramine = Tablets=20 concluded the cause to be a dilution error as a result of the use of = incorrect glassware. This conclusion could not be supported as the = actual=20 glassware used was not documented and laboratory procedures do not = require=20 that glassware be maintained until the analysis is complete.
f) = Power=20 failures occurred during analyses of Nitroglycerin, lot 101005, and = Senna S,=20 lot 204103. Investigations did not document the impact on the = analyses, any=20 re-testing or resampling, or if the power outage impacted any other=20 analyses.

2) Laboratory records fail to include the initials or signature of = the=20 person who performs each laboratory test [21 CFR =A7 211.194(a)(7)].=20 Specifically, laboratory analysis records for analyses performed on = HPLC=20 [redacted] and [redacted] do not = indicate=20 which analyst performed the injections.

3) Failure to maintain complete records of any modification of an=20 established method employed in testing [21 CFR =A7 211.194(b)]. = Specifically,=20 the records of laboratory methods stored in the [redacted]=20 computer system do not include the identity of the person = initiating=20 method changes.

4) Appropriate controls are not exercised over computers or related = systems=20 to assure that changes in analytical methods or other control records = are=20 instituted only by authorized personnel [21 CFR =A7 211.68(b)].=20 Specifically:

a) Laboratory managers (QC and R&D) gained access to the=20 [redacted] computer system through a common = password.=20 Analysts were not required to use individual passwords; they = operated the=20 system following the login by the laboratory managers.
b) Due to = the=20 common password and lack of varying security levels, any analyst or = manager=20 has access to, and can modify any HPLC analytical method or record.=20 Furthermore, review of audit trails is not = required.

5) Failure to follow written procedures applicable to the quality = control,=20 unit [21 CFR =A7 211.22(d)]. Specifically, the contracted laboratories = responsible for performing analyses on Active Pharmaceutical = Ingredients and=20 other drug components, used in the finished drug products, such as = LOD,=20 nitrogen content; microbial limits, and specific rotation, have not = been=20 qualified by the quality unit as per your firm's written = procedures.

6) Failure to maintain separate or defined areas or other such = control=20 systems as are necessary to prevent contamination and mix-ups in the = course of=20 manufacturing and processing operations [21 CFR =A7 211.42(c)(5)]. = Specifically,=20 no monitoring of the system is conducted to demonstrate that the = volume of air=20 supplied is sufficient to maintain appropriate air pressure = differentials=20 between manufacturing rooms, corridors, and pharmacy rooms.

7) Failure to provide adequate measures.to control air = contamination and=20 recirculation of dust from production areas where air is recirculated = [21 CFR=20 =A7 211. 46(c)]. Specifically:

a) No studies have been conducted to assure that the system = removes=20 contaminants from the production area and that cross-contamination = does not=20 occur.
b) Modifications made to the air handling systems of = production=20 rooms 6 and 8, to add exhaust ventilation, were not qualified to = show their=20 effectiveness at the time of installation.

8) Failure to establish master production and control records for = each drug=20 product including a statement of the maximum and minimum percentages = of=20 theoretical yield beyond which investigation is required [21 CFR =A7=20 211.186(b)(7)]. Specifically, actual and theoretical yields are = calculated=20 after tablet compression but your firm has not established appropriate = specifications for acceptable yields.

9) Test devices are deficient in that apparatus not meeting = established=20 specifications are used [21 CFR =A7 211.160(b)(4)]. Qualification = studies for=20 the [redacted] room temperature stability chamber = were=20 deficient in that they did not always include specifications, = acceptance=20 criteria, or raw data. Specifically:

a) There was no data to demonstrate that the chamber alarm would = perform=20 as required in the event of a humidity excursion.
b) There were = no=20 specifications or acceptance criteria for the water pressure or = water=20 quality to the chamber. There are specific requirements for these = outlined=20 in the operating manual for the chamber.

10) Failure to maintain equipment at appropriate intervals to = prevent=20 malfunctions or contamination that would alter the safety, identity, = strength,=20 quality or purity of the drug product [21 CFR =A7 211.67(a)]. = Specifically, the=20 [redacted] Packaging Hopper was found to be cracked. = Cracked=20 equipment cannot be easily cleaned to prevent cross-contamination = between=20 products.

In addition, the inspection revealed that certain drug products = manufactured=20 by your firm are in violation of sections 505(a) and 502(f)(1) [21 = U.S.C. =A7=20 355(a) and =A7 352(f)(1)]of the Act, for the following reasons:

You manufacture the following prescription products:

Colchicine Tablets

Hyoscyamine Sulfate Tablets

Nitroglycerin Sublingual Tablets

These products are drugs within the meaning of section 201(g) of the = Act [21=20 U.S.C. =A7 321(g)] because they are intended for use in the diagnosis, = cure,=20 mitigation, treatment, or prevention of disease. FDA is unaware of = substantial=20 scientific evidence that any of these products as manufactured by your = firm are=20 generally recognized by qualified experts as safe and effective for = their=20 labeled indications. Therefore, they are "new drugs" within the meaning = of=20 section 201(p) of the Act [21 U.S.C. =A7 321(p)].

Section 505(a) of the Act [21 U.S.C. =A7 355(a)] requires that any = new drug be=20 the subject of an FDA-approved new drug application before it is = introduced into=20 interstate commerce. There are no approved applications on file for the = above=20 products and their continued marketing violates section 505(a) [21 = U.S.C. =A7=20 355(a)].

In addition, these drugs are misbranded. As prescription drugs, = adequate=20 directions cannot be written for them so that a layman can use these = products=20 safely for their intended uses. Consequently, their labeling fails to = bear=20 adequate directions for use as required under section 502(f)(1) of the = Act [21=20 U.S.C. =A7 352(f)(1)] and, lacking required approved applications, they = are not=20 exempt from this requirement under 21 CFR =A7 201.115.

We have received your written response to the FDA-483, dated May 3, = 2006.=20 This response will be added to our official files. For the reasons = below, we do=20 not find this response to be sufficient. Please note that the comments = below=20 pertain only to the CGMP observations; the exclusion of a discussion of = the=20 responses to the observations made about the drug products subject to = ANDAs does=20 not mean that the responses were adequate. An assessment of the = responses to the=20 ANDA-related observations will be sent under separate cover.

The response does not include documentation to show that the = corrective=20 actions have been implemented (see FDA-483 items 3, 4, 6, 8, 9, 11, and = 12). For=20 example you did not submit the revised calibration procedures referenced = in your=20 response to FDA-483 item # 4. In addition, some of the responses to the = FDA-483=20 items (1 and 6) do not include timeframes for completion of the = corrective=20 action. For example, your response to item #1 states that a new password = system=20 will be implemented but does not specify a completion date. Also, some = of the=20 responses fail to address the underlying issues inherent in the noted=20 deficiencies. For example, the response to item # 2 states that the=20 in-specification test results obtained for products tested before and = after=20 various failures of the analytical instruments show that the reliability = of the=20 analyses was not impacted by the failures. However, obtaining = in-specification=20 test results from a product analysis does not, by itself, indicate the=20 suitability of the analytical system used or the reliability of the = results=20 .

The above identification of violations is not intended to be an = all-inclusive=20 list of deficiencies at your facility. It does not include observations = of=20 deficiencies related to ANDA products which have not yet been approved = and=20 marketed. It is your responsibility to ensure that drug products your = firm=20 manufactures are in compliance with the Act and the regulations = promulgated=20 under it. Federal agencies are advised of the issuance of all warning = letters=20 about drug products so that they may take this information into account = when=20 considering the award of contracts. Until FDA can confirm correction of = the=20 deficiencies observed during the most recent inspection, this office can = recommend disapproval of any new applications listing this site as a=20 manufacturer of drugs.

You should take prompt action to correct deficiencies at your = facility.=20 Failure to do so may result in further regulatory action without notice = . These=20 actions may include seizure of your products or injunction.

You should notify this office within 15 working days of receipt of = this=20 letter of the additional corrective actions you plan to implement to = address the=20 deficiencies at your firm. If corrective actions cannot be completed = within 15=20 working days, please state the reason for the delay and the time frame = within=20 which corrective actions will be completed.

Your response should be addressed to: U.S. Food & Drug = Administration, 10=20 Waterview Boulevard, 3rd Floor, Parsippany, New Jersey 07054, Attn: = Sarah A.=20 Della Fave, Compliance Officer.

Sincerely,

/S/

Douglas I . Ellsworth
District Director
New Jersey = District.

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FDA/Freedom=20 of Information

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