Medico Labs, = Inc., Warning Letter

From: Subject: Medico Labs, Inc., Warning Letter Date: Mon, 3 Mar 2008 10:30:30 -0500 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_004A_01C87D19.9AD42D30" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_004A_01C87D19.9AD42D30 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.fda.gov/foi/warning_letters/s6357c.htm Medico Labs, = Inc., Warning Letter

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Department of Health and Human Services

Public Health Service
Food and Drug = Administration

Central Region
Food and Drug Administration
Waterview = Corporate=20 Center
10 Waterview Blvd., 3rd Floor
Parsippany, NJ = 07054

Telephone (973) 331-4910

April 16, 2007

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Venkat E. Kakani
President and COO
Medico Labs, Inc.
1000=20 Nottingham Way
Hamilton, New Jersey 08609

07-NWJ-10

Dear Mr. Kakani:

An inspection of your manufacturing facility located at 1000 = Nottingham Way,=20 Hamilton, NJ was conducted from November 2 through November 16, 2006. = During the=20 inspection, our investigator documented deviations from the Current Good = 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 Food, Drug and Cosmetic Act = (the Act)=20 (21 U.S.C. section 351(a)(2)(B)), and are as follows:

1. Failure to establish and follow procedures prescribing a system = for=20 reprocessing batches to insure that the reprocessed batches will = conform with=20 all established standards, specifications, and characteristics [21 CFR = 211.115(a)]. Specifically, the following batches were reprocessed = without a=20 scientific basis for the reprocessing method or the quantities of = additional=20 excipients or active drug substance charged in during reprocessing. = There is=20 no assurance that the reprocessed batches, which represent new = formulations,=20 are assigned the appropriate expiration dating. The original failing = or low=20 assay values were not investigated and no root cause was = determined.

a) [redacted](Guaifenesin, Dextromethorphan=20 Hydrobromide, Pseudoephedrine HCI) Batch = #[redacted] was=20 reprocessed by adding additional raw materials (Propylene Glycol, = USP,=20 Glycerine,USP and Purified Water, USP) to decrease the = concentrations of=20 Guaifenesin and Dextromethorphan Hydrobromide which exceeded = specification=20 at release testing. Original Guaifenesin assay values ranged between = 110.07%=20 and 111.44%. Original Dextromethorphan assay values ranged between = 111.94%=20 and 114.52%. This reprocessed lot was released to the market and = expires=20 10/07.
b) [redacted] Children's Allergy = Medicine=20 (Diphenhydramine HCI, USP 12.5mg per 5mL) Batch = #[redacted]=20 was reprocessed by adding additional active pharmaceutical = ingredient to the=20 batch after low bulk assay values were obtained from the top of tank = sample=20 (90.88%) and the bottom of the tank sample (90.19%). This lot was = released=20 to the market and expires 12/07.

2. Written records were 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 = 211.192].=20 Specifically out-of-specification assay results for several of your = drug=20 products including [redacted], = [redacted]=20 and [redacted] had no written investigations or = documentation=20 of corrective actions. Although you informed our investigator that = these=20 batches were validation or stability batches and not released to the = market,=20 investigations must be conducted to determine if batches of the same = product=20 on the market have been impacted. Failure to determine the root cause = of=20 out-of-specification results and take appropriate corrective action = undermines=20 any assurance that your manufacturing process is in a state of control = and=20 consistently produces drug products that meet their specifications and = quality=20 attributes.

3. Failure to establish a written testing program designed to = assess the=20 stability characteristics of your drug products [21 CFR 211.166(a)]. = There=20 were no written stability protocols for any of the drug products that = your=20 firm manufactures. Such stability study parameters as sample sizes and = test=20 intervals, storage conditions, test methods and specifications,=20 container-closure system, and number of lots to be placed on stability = to=20 determine appropriate expiration dating were not established in = written=20 stability testing protocols approved by your firm's quality control = unit. In=20 addition,

a) There is no data demonstrating that the methods used for = stability=20 testing of any drug products manufactured by your firm are stability = indicating [211.166(a)(3)]. Consequently, there is no assurance that = stability data generated for each of your firm's drug products is = reliable=20 and that marketed drug products are assigned appropriate expiration = dating.=20
b) Drug products manufactured by your firm have not been = evaluated for=20 the presence of impurities and degradation products [211.160(b)]. =
c)=20 Review of stability data for [redacted] Children's = Allergy=20 Medicine, Batch [redacted], shows that assay and = microbial=20 test data are missing from the one month accelerated test station, = there is=20 no data reported for the two month accelerated test station and = product=20 description, pH and specific gravity data are missing from the three = month=20 accelerated test station [211.166 (a)].

4. The master production and control records are deficient in that = they=20 lack a justification for the variation in the amount of components = used in the=20 preparation of a dosage form [21 CFR 211.186(b)(4)]. Specifically, = several of=20 your products, including [redacted],=20 [redacted] and [redacted] are = formulated=20 with overages of the active pharmaceutical ingredient ranging from=20 [redacted] however, there is no documented scientific = justification to explain why the overages are necessary.

5. Evaluations were not conducted at least annually to review = records=20 associated with a representative number of batches, whether approved = or=20 rejected [21 CFR 211.180(e)(1)]. Specifically, your firm failed to = conduct=20 annual product reviews for all drug products to evaluate batches = manufactured,=20 rejected, and reprocessed, as well as other issues, including trends = in=20 complaints, investigations, or manufacturing that warrant corrective = actions.=20

6. 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 211.68(b)]. = Specifically,

a) There was a failure to validate the = [redacted]=20 software to assure that all data generated by the system was secure. = This=20 software runs the laboratory HPLC equipment, generates and stores = data, and=20 performs calculations during testing of raw materials, in-process = materials,=20 finished products, and stability samples.

b) User access levels for the [redacted] = software were=20 not established and documented. Currently, laboratory personnel use = a common=20 password to gain access to the system and there are no user access = level=20 restrictions for deleting or modifying data. Furthermore, your = system does=20 not have an audit trail to document changes.

7. Cleaning validation studies for all products manufactured at = this site=20 have not been completed. Your firm has not established specifications = for=20 acceptable levels of active pharmaceutical ingredient residues or = detergent=20 residues in rinse samples [21 CFR 211.67 (b)]. Additionally, method = validation=20 studies for the determination of these residues have not been = completed [21=20 CFR 211.194].

8. Failure to qualify manufacturing equipment such as the liquid = filler,=20 homogenizer and colloidal mill, which were used to manufacture all = liquid=20 finished products at your facility [21 CFR = 211.68(a)].

Neither the list above nor the examples on the FDA-483, List of = Inspectional=20 Observations, which was issued to you firm on November 16, 2006 is = intended to=20 be an all-inclusive list of deficiencies at your firm. It is your = responsibility=20 to ensure adherence to each requirement of the Act and its regulations. =

Also, some of the OTC drug products manufactured by your firm fail to = bear=20 required labeling information, as described below. These deviations = cause your=20 drug products to be misbranded within the meaning of sections 502(a) and = (c) of=20 the Act (21 U.S.C. =A7=A7 352 (a) and (c)) as follows:

The [redacted] Children's Pain Reliever and=20 [redacted] Children's Allergy drug products are = misbranded=20 under section 502(a) of the Act (21 U.S.C. =A7 352(a)) because the = tamper-evident=20 packaging (TEP) labeling statements, "Do not use if tamper evident seal = under=20 cap is broken or missing" and "Packed with tamper evident seal below = bottle cap"=20 each fail to reference the required identifying characteristic in the = feature.=20 (21 C.F.R. =A7 211.132(c))

The [redacted] Tussin DM, = [redacted],=20 Tussin, and [redacted] Tussin DM Syrup drug products = are=20 misbranded under section 502(a) of the Act (21 U.S.C. =A7 352(a)) = because the=20 tamper-evident packaging (TEP) labeling statements, "Do not use if = induction=20 seal is tampered or,destroyed," on each product fail to clearly describe = the=20 placement of the TEP feature so that the consumer will be able to locate = the=20 specific feature. (21 C.F.R. =A7 211.132(c))

The [redacted] Tussin DM, = [redacted]=20 Children's Pain Reliever, [redacted] Tussin DM,=20 [redacted] Tussin DM,[redacted] = Tussin,=20 [redacted] Tussin-DM Syrup, and = [redacted]=20 Children's Allergy product are also misbranded under section 502(c) of = the Act=20 (21 U.S.C. =A7 352(c)) because the labeling fails to fully comply with = the Drug=20 Facts Format regulations in 21 C.F.R. =A7 201.66. Specifically, the = "directions=20 for use" on each of the products is placed on the principal display = panel of the=20 label instead of in the Drug Facts Format box as required by 21 C.F.R. = =A7=20 201.66(c)(6).

We have received your written response to the FDA-483 observations = dated=20 January 5, 2007; it will be made part of our official files. Our = specific=20 comments are detailed below. In general, however, considering the nature = of the=20 deficiencies, your response is inadequate.

While we acknowledge your commitment to improve your CGMP compliance, = inadequacies in several significant CGMP areas found during the = inspection cause=20 the Agency to question the quality of the drug products released from = your=20 facility. In order to ensure the quality of marketed product, your firm = should=20 promptly initiate a full review of all lots within expiration in the = market to=20 assure that the released drug products have their appropriate identity,=20 strength, quality, and purity. Appropriate action regarding compromised = or=20 questionable product must be taken.

We have reviewed your proposed corrective actions and have the = following=20 comments and questions. These follow the FDA-483 numbering for ease of = review.=20

1. We do not find your response to be satisfactory. Please, explain = and=20 justify what you intend to do about the two product lots cited in the=20 observation. These product lots are both within expiry and were = released to=20 the market. You have not provided any assurance that these reprocessed = batches=20 will remain stable throughout their respective expiry periods. = Furthermore,=20 your Reprocessing SOP QA-067-00, dated November 3, 2006, does not = require an=20 assessment to determine

a. the need to validate the reprocessing procedure and the extent = of the=20 validation

b. the possible impact on long term stability of = the=20 reprocessed lot.

2. Your response was incomplete in that it did not address change = control.=20 The Complaint SOP does not include a time frame for the completion of = the=20 investigation and corrective and preventive action as necessary. = Additionally,=20 your Reprocessing SOP is inadequate as stated above (la & lb). =

Regarding computer validation and security issues, you did not = provide a=20 time frame for writing and implementation of a computer security SOP. = Your=20 response regarding data back-up indicated that a separate server was = being=20 considered and would be implemented by "[redacted]" = We=20 believe this date was to have read [redacted]. Please = explain=20 why this correction cannot be completed in a more timely fashion.

3. The response is incomplete. You stated that Annual Product = Reviews would=20 be completed for all batches manufactured in 2004 and 2005, but you = did not=20 address batches manufactured in 2006. In addition, you did not provide = any=20 written procedures for conducting periodic product reviews.

4. Based upon your response, it appears that investigations of the=20 Out-of-Specification results cited on the FDA-483 have still not been=20 conducted and documented, nor have you assessed whether any of the = failures=20 cited may also affect marketed product lots, for instance, in terms of = the=20 ability of the marketed lots to meet all specifications throughout the = labeled=20 expiry period.

In addition, your response states that your investigation = procedures were=20 "strictly followed" even though the response also states "no formal=20 documentation were finalized." We do not understand your conclusion = that=20 procedures were followed if investigations were not documented.

Furthermore, after reviewing your SOP QC-029-00, Out of = Specification, it=20 appears that your use of the term "retesting" is different than FDA's = meaning=20 of the word. Retesting, as defined by FDA, is a complete repeat of the = entire=20 analysis to include the sample preparation step. During the first = phase of an=20 OOS investigation, i.e., the laboratory investigation, the original = test=20 preparations may be re-analyzed as a means to explore if something = went wrong=20 during the original analysis, but this is not considered retesting. =

Retesting occurs at a later stage of the investigation and involves = an=20 entirely new preparation from the original sample. We are concerned = that your=20 procedure as written will not assure that decisions regarding = retesting and=20 possible release of batches will be appropriate. You did not specify = the=20 maximum number of retests to be performed. This should be specified in = advance=20 in a written standard operating procedure. The number may vary = depending upon=20 the variability of the particular test method employed, but should be = based on=20 scientifically sound principles. The number of retests should not be = adjusted=20 depending on the results obtained. Your procedure should identify the = point at=20 which the additional testing ends and the batch is evaluated.

Also, the issue of averaging results, which is discussed in section = VIII,=20 Reporting, is not clear. FDA does not recommend averaging results = unless the=20 averaging of individual results within a single analysis is called for = as part=20 of the analytical method. Unless the OOS result is due to a confirmed=20 laboratory error, all results, original OOS and retesting results = should be=20 reported.

Please refer to FDA's "Guidance for Industry Investigating=20 Out-of-Specification (OOS) Test Results for Pharmaceutical Production" = published in October 2006 to assist you in revising your SOP. This = Guidance=20 can be found at http://www.fda.gov/= cder/guidance/3634fnl.htm=20

5. The response is not satisfactory. You have produced no evidence, = either=20 in the response or during the inspection, to show that the analytical = methods=20 are stability indicating. You referred to the USP; however, not all = USP=20 methods are stability indicating. You must evaluate your specific = products for=20 potential impurities or degradation products and determine if = specifications=20 for them need to be established.

Regardless of whether your products are equivalents of national = brands, the=20 stability of your specific products, including impurities and = degradation=20 products, must be demonstrated by validated methods. Stability studies = are=20 incomplete and insufficient if the methods used therein are not = stability=20 indicating.

6. Your response discusses future stability studies, but there has = been no=20 commitment to review completed or on-going studies to determine if = they were=20 adequate, especially since your SOP RD-003-00, Protocol for Stability = Testing,=20 does not appear to have been followed.

Your response states that you have taken action to maintain a = consistent=20 temperature throughout the stability chamber, but you did not provide = a=20 description of the specific actions taken. Please elaborate on these=20 corrective actions.

We note that you have committed to monitoring the humidity in the = stability=20 room; however, the time frame for implementing this action was given = as=20 [redacted]. Please explain why this correction cannot = be=20 completed in a more timely fashion.

7. See the comments under #2 above.

8. Although you state that the "error in judgment" regarding lot=20 [redacted] will not be repeated, you have provided no = details=20 on any changes in procedures that are designed to preclude this type = of error=20 in the future.

9. The response to this observation is not = satisfactory.=20 You have provided no scientific justification for the overages in = existing=20 products. Your response suggests that you will determine overages = based on=20 patterns of degradation. Overages for stability purposes are not = recommended.=20 If an overage of active is needed so that the product remains within=20 specification at the end of the expiry period, it raises a potential = clinical=20 concern. With a [redacted] or = [redacted]=20 overage in a product, there is potentially 15% or 20% degradant(s) in = the=20 product at the end of the expiry period. Your firm has not evaluated = the=20 possible degradants or impurities in your drug products.

10. The response is not satisfactory. Please provide us with = details on the=20 actions you are taking to address all of the specific issues in the = FDA-483=20 observation as well as a specific time frame for the completion of = those=20 specific actions.

11. Your cleaning program and procedures will = be=20 evaluated at the next inspection.

12. You did not include a = time frame=20 for completing equipment qualification studies. Your qualification = studies=20 will be evaluated during the next inspection.

We remain concerned that the underlying system problems resulting in = the=20 violations have not been fully addressed. Given the serious nature of = the=20 violations, more information about your actions is necessary before we = can=20 consider your response adequate.

The issues and violations cited in this letter are not intended to be = an=20 all-inclusive statement of violations that exist at your facility. You = are=20 responsible for investigating and determining the causes of the = violations=20 identified above and for preventing their recurrence or the occurrence = of other=20 violations. It is your responsibility to conduct a comprehensive audit = of your=20 facility and operations and assure compliance with all requirements of = federal=20 law and FDA regulations.

You should take prompt action to correct the violations cited in this = letter.=20 Failure to promptly correct these violations may result in legal action = without=20 further notice, including, without limitation, seizure and injunction. = Other=20 federal agencies may take this Warning Letter into account when = considering the=20 award of contracts. Additionally, FDA may withhold approval of requests = for=20 export certificates, or approval of pending new drug applications = listing your=20 facility as a manufacturer until the above violations are corrected. A=20 reinspection may be necessary.

Within fifteen working days of receipt of this letter, please notify = this=20 office in writing of the specific steps that you have taken to correct=20 violations. Include an explanation of each step being taken to prevent = the=20 recurrence of violations, as well as copies of related documentation. If = you=20 cannot complete corrective action within fifteen working days, state the = reason=20 for the delay and the time within which you will complete the = correction. If you=20 no longer manufacture or market any products, your response should so = indicate,=20 including the reasons for, and the date on which, you ceased production. =

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 yours,

/S/

Douglas I. Ellsworth
District Director
New Jersey District = Office=20

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FDA/Freedom=20 of Information

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