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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Accumed Inc. 6/24/09

   

hhsbluebirdDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 

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

 

Telephone (973) 331-4905

 

 


June 24, 2009


WARNING LETTER


CERTIFIED MAIL

RETURN RECEIPT REQUESTED


Mr. Burgise F. Palkhiwala
President
AccuMed Inc.
2572 Brunswick Pike
Lawrenceville, NJ 08648


File # 09-NWJ-05


Dear Mr. Palkhiwala:


From January 15 to February 5 and March 11 to March 12,2009, the Food and Drug Administration (FDA) conducted two inspections of your manufacturing facility located at 2572 US Highway 1, Lawrenceville, New Jersey. The inspections revealed significant deviations from current Good Manufacturing Practice (CGMP) regulations [Title 21 Code of Federal Regulations (CFR), Parts 210 and 211] in the manufacture of drug products. These CGMP deviations were listed on Inspectional Observations (FDA-483) forms issued to you at the close of the inspections. These CGMP deviations cause your drug products to be adulterated within the meaning of section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)] of the Federal Food, Drug, and Cosmetic Act (the Act).


We have completed review of your March 22, April 1, and May 26, 2009 responses to the FDA-483 observations. The CGMP deficiencies need more comprehensive corrections than the actions you have proposed or taken.


The CGMP deviations observed during the inspection include, but are not limited to, the following:


1. Failure to follow the written responsibilities and procedures applicable to the quality control unit [21 CFR § 211.22(d)]. Your Quality' Control Unit (QCD) did not follow your firm's applicable written procedures and controls, as set forth in your Standard Operating Procedures (SOPs) (e.g. SOP# QC-024-02, Responsibility of the Quality Unit; SOP #QA-022-01, Product Recalls; SOP #QA-005-02, Reprocessing of Products; SOP #QA-023-01, Investigation of Product Failure). Specifically, the QCU failed to:


a. review production and control records to ensure the correct packaging unit cartons are used to package Cough Formula DM, lot #106295 (incorrectly packaged into Tussin Chest Congestion Formula unit cartons);
b. conduct thorough out-of-specifications (OOS) investigations;
c. ensure the stability program is followed;
d. review and approve reprocessing procedures for non-conforming batches;
e. ensure batch records are accurate and complete;
f. notify the agency of the recall concerning the Cough Formula DM labeling mixup; and
g. reject drug products failing to meet stability specifications.


Your March 22, 2009 response regarding the failure of your QCU to fulfill its responsibilities states in part, "management has decided to change the leadership of Quality unit that includes QC and QA." Please provide full details of the organizational changes to the QCU, along with the qualifications of relevant personnel. In addition, explain how the new leadership will ensure that the QCU will identify and correct the deficiencies in this letter and prevent recurrences.


Your April 1, 2009 response regarding the failure to follow labeling and packaging materials procedures states in part, "The only open issue is the collection, confirmation and disposition of Lot # 106295...." (i.e., Cough Formula DM). Your response is inadequate because it does not include corrective actions regarding the violative product (which was incorrectly packaged and mislabeled) that may have been purchased by consumers. In your response, you also need to investigate other lots or products that were handled and inspected by the personnel responsible for the Cough Formula DM labeling mix-up and the training of your QCU and its managers.


In addition, please provide an explanation as to why your firm waited approximately four months to notify the New Jersey District Recall Coordinator of the packaging error regarding Cough Formula DM, and why a recall that was initiated in November 2008 has yet to be completed as of the date of your April 2009 response. Please provide an update regarding the status of the recall, including whether any other products have been similarly recalled, withdrawn, or returned by customers due to discrepancies in your firm's products.


2. Failure to thoroughly investigate and document unexplained discrepancies or a batch or any of its components not meeting any of its specifications; failure to extend investigations to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy; and failure to ensure that written records of the investigation include conclusions and follow-up [21 CFR § 211.192]. Specifically, your QCD did not conduct thorough investigations to identify the root cause of what may have caused the following OOS results, extend the investigation to the production system, include an evaluation of other lots of the same and other products, and include any corrective actions, final conclusion, and follow up.

 

Product  Lot OOS assay results (%) Specification (%)

Accusen Extra Strength Tabs (Sennoside 25mg)

 

TK-70716 (b)(4) (b)(4)


Accudryl Spray (Diphenhydramine HCI 2%/Zinc Acetate 0.1 %)

 

LK-71890

 

(b)(4) (finished)

(b)(4) (bulk)

(b)(4)


Surely White Gel Night Time (Hydrogen Peroxide 9%)

 

LK-70537 (b)(4) not less than (b)(4)*

Peptaid Regular Strength Suspension 

(Bismuth Subsalicylate 262mg/15ml)

 

70522 (b)(4) (b)(4)
Accusen Plus Coated Tabs (stability) 70640 6m = (b)(4) 9m = (b)(4) (b)(4)

Sinus Relief Nasal Spray
70862 18M = (b)(4) (b)(4)

* - Although the specification does not have an upper limit, the QC Manager rejected the batch based on historical data because the concentration was too high.

Your March 22, 2009 response regarding the failure to adequately investigate OOS results states in part that the "SOP on Investigation of Product failure will be reviewed and audited.... " Your response is inadequate because this violation is not due to a failure of your written SOP. Rather, this is a failure of your QCD to follow and enforce the proper procedures. Please explain why your firm failed to investigate these OOS results, and also provide an explanation of how you will prevent recurrence of this violation.


Your May 26, 2009 response regarding the Peptaid Regular Strength Suspension OOS result (see table above) states in part, "The high assay value in Lot # 70522 may be due to the non-uniformity of the suspension...." Please clarify your response. The response is unclear because the OOS result is not a high assay value. In addition, any non-uniformity issues in the suspension formulation of the product need to be addressed and corrected.


Your May 26, 2009 response regarding stability failures states in part that retention samples as well as samples from subsequent stability time points were tested and found to be within product specifications. The response regarding OOS results that exceeds the specifications also states in part, "The published literature on the safety data of the products has been verified. The dose delivered by the stated to be super potent product (as per the results of stability study) is within the safe therapeutic zone." Regardless of the apparent, passing, test results on retain and stability samples and the aforementioned safety literature that you have included in your response, we want to remind you that it is your responsibility to ensure that your firm's personnel conduct timely and thorough investigations, establish adequate product specifications,and ensure that product complies with such specifications.


3. Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products; and failure to evaluate the results of stability testing to determine appropriate storage conditions and expiration dates [21 CFR § 211.166(a)]. Specifically,


a. Your QCD failed to thoroughly evaluate five laboratory-confirmed, stability, OOS assay results in order to determine adequate storage conditions and expiration dates (see table below).


b. Your QCD failed to follow SOP-QC-010-02, "Stability Study Guidelines," which provides stability testing requirements for drug products. Specifically, your QCD failed to ensure that:


i. products placed under long term stability are tested at their scheduled time points (see table below);

 

 

Product

Lot

 

OOS test station(s)

(months)

test station(s) skipped 

(months)

 

Sinus Relief Ultra Fine Mist 71142 12 18
Accusen Plus Coated Tabs 70640 3, 6*, and 9* 12 and 18
Sinus Relief Ultra Mist Pump 70498 9 12 and 18
Sinus Relief Nasal Spray

80001

70862

9

9 and 18*

3

N/A

* - 008 investigation was not conducted (see item 2 of this letter)


ii. samples with a new blister packaging from the first three production batches (i.e. Fast Acting Dairy Relief Caplets) are placed on accelerated and long term stability;
iii. microbial testing for liquid and powder stability samples are performed at 12 month and 24-month stability time points; and
iv. batches manufactured after approved process changes (e.g. formulation changes) had approved stability protocols or stability testing.


This is a repeat violation of the February 2007 inspection.


c. Your QCU failed to establish an adequate stability testing program designed to evaluate the integrity of the container-closure system. Specifically, SOP-QC-010-02 does not include the storage orientation for liquid products. The stability samples for liquid products should be stored in an upright or inverted orientation in order to test and evaluate the integrity of the bottle seal.


Your March 22, 2009 response states in part, "the management has decided to change the leadership of Quality control laboratory." Please provide full details of the organizational changes to the Quality Control laboratory, along with the qualifications of relevant personnel. In addition, explain how the new leadership will ensure that the Laboratory System procedures and controls will identify and correct deficiencies and prevent them from recurring.


Your response also states that your firm will investigate all OOS results reported during stability testing, and that samples of the products listed in the observations will be tested for missed, as well as current, stability time points. You should ensure that all stability products that skipped their scheduled time points are included in your investigation. Provide copies of your investigation and test results.


Your response further states that SOPs on stability and on handling of OOS results will be reviewed and revised. Although procedures should always be reviewed for improvement and compliance, we note that this violation is primarily a failure of your QCU to follow and enforce your written procedures, and not necessarily a problem with the SOPs.


Please note that if your firm's failing stability results cannot be adequately explained or justified, your QCU is expected to remove the violative product from the marketplace (e.g. Sinus Relief Nasal Spray Lot #80001, expiry January 2010).


4. Failure to prepare batch production and control records for each batch of drug product produced, including complete information relating to the production and control of each batch [21 CFR § 211.188]. For example:


a. The batch record for Natural Fiber Laxative Smooth Texture Orange Flavor, lot PK-72190, does not contain complete information documenting that each significant step in the manufacture of the batch was accomplished, per 21 CFR § 211.188(b). For example, the batch record includes information that indicates citric acid was added during the initial manufacture of the batch; however, an investigation report conducted by the firm alleges that citric acid was not initially added to this batch. In addition, there is no indication within the batch record that the batch was reprocessed and the citric acid added at a later time.


b. The batch record for Hydrogen Peroxide Gel 9%, lot LK-70537, does not document that an investigation was conducted according to 21 CFR § 211.192, per the requirements of21 CFR § 211.188(b)(12), albeit the lot was rejected because the concentration was too high.


This is a repeat violation of the February 2007 inspection.


In the August 2007 Untitled Letter sent to you, we informed you that information (e.g. weighing records, equipment identification) was missing from your batch records, per 21 CFR § 211.188. Please be advised that your batch manufacturing records continue to be inadequate in that they do not contain complete information relating to the production and control of each batch of products.


5. Failure to follow written procedures prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics; and failure to conduct reprocessing with the review and approval of the QCD [21 CFR § 211.115(a) and (b)].


Rather than following SOP # SOP-QA-005-02, "Reprocessing of Products," which defines the steps to follow when a product does not meet its approved specifications, your manufacturing personnel and QCD failed to initiate and approve, respectively, a reprocessing procedure for the addition of a missing component (i.e., citric acid) and reblending of the Natural Fiber Laxative Smooth Texture Orange Flavor, lot PK72190, powder for oral suspension, which failed the pH test. In addition, your QCD failed to ensure the lot was placed on stability, per your written procedures.


Your March 22, 2009 response regarding the failure to follow the procedure for reprocessing of products states in part that "The Formulation Development manager, Production manager, and QA manager will be notified in writing to follow the compliance guidelines and prepare all the required documentation...." Note that your firm's procedure, in conjunction with an adequate training program and the monitoring of your operations for compliance by the QCD, should include the necessary CGMP fundamentals to ensure your personnel adequately follow procedures. Your response suggests that: 1) your training is ineffective; 2) the procedure(s) is not readily available in your immediate areas; 3) the procedure(s) is not understood; or 4) your personnel are not qualified to perform their functions. Please comment on how your leadership will ensure that your firm's procedures are fully followed to achieve an acceptable level of compliance.


In addition, we want to note the importance of maintaining your buildings in a good state of repair. During the February 5,2009 inspection, our investigator observed the following: peeling epoxy paint on your blending room and packaging room #1 floors; deep scratches and grooves in the plywood floor housing your ribbon blender and sifter; and several holes in the walls throughout your manufacturing and warehouse areas. Similar issues were also observed during the February 2007 inspection. It is your responsibility to provide sustainable corrective actions to maintain your manufacturing facility in a good state of repair.


The issues and 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 or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations and to implement global corrections to all of the facilities under your control.

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 new drug applications listing your facility as a manufacturer, until the above violations are corrected. A reinspection may be necessary.


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


Your reply should be sent to the address listed above and to the attention of Joseph F. McGinnis, Compliance Officer. If you have any questions regarding this letter, please contact Joseph F. McGinnis at (973) 331-4905.


Sincerely, 

/S/

Diana Amador-Toro
District Director
New Jersey District