Company: Lake Erie Medical and Surgical, Inc.
Subject: Current Good Manufacturing Practices for Finished Pharmaceuticals/Adulterated
Issuer: Detroit District Office
Issued: June 21, 2005 Closed:
Not applicable.
Source ucm075454 Archive Code:

Lake Erie Medical and Surgical, Inc. 21-Jun-05

Department of Health and Human Services

Public Health Service
Food and Drug Administration

Detroit District
300 River Place
Suite 5900
Detroit, MI 48207
Telephone: 313-393-8100
Fax: 313-393-813


JUNE 21, 2005


Michael W. Holmes
Lake Erie Medical and Surgical, Inc.
7560 Lewis Avenue
Temperance, MI 48182

Dear Mr. Holmes:

A January 25 - February 14, 2005 inspection of your Quality Care Products drug repackaging operations found your firm is operating in violation of the Federal Food, Drug, and Cosmetic Act (the Act). Your repackaged drug products are adulterated within the meaning of section 501(a)(2)(B) of the Act [ 21 U.S.C. ยง 351(a)(1)]. Your products are also misbranded within the meaning of sections 502(f)(1) [21 U.S.C. 352(f)(1)] and 502(o) [21 U.S.C. 352(o)] of the Act.

At the conclusion of the inspection, Investigator Patsy J. Domingo issued to you a Form FDA:-483, List of Inspection Observations (copy enclosed). The deviations from the current Good Manufacturing Practices Regulations, Title 21 of the Code of Federal Regulations Part 211 (21 CFR 211), listed on the Form FDA-483, cause your drug products to be adulterated. For example:

1. Failure to assure that the repackaging of penicillin products is performed in facilities separate from those used for other drug products for human use [21 CFR 211.42(d)]. Specifically:

a. The magnahelic gauge installed in [redacted] (penicillin) to monitor whether the room pressure differential is maintained negative to the hallway connecting to the main building has not been calibrated or certified as working properly in accordance with written procedures and, thus, there is no assurance that air from the room does not intermingle with the air in the non-penicillin production areas (See Form FDA-483 # 1.C.].

b. Employees performing repackaging of penicillin drugs are allowed to return on the same day to perform repackaging operations of non penicillin drugs without adequate controls in place to prevent cross contamination by personnel (See Form FDA-483 #-1.A.].s

c. [redacted} is not completely separate from the main building because the only exit from room is via a hallway to the main building. Thus, all personnel involved in repackaging of penicillin drug products, all finished products, and all gowns and other penicillin-contaminated waste must exit the room by traversing at least part of the main building, and there are no procedures to prevent cross contamination.

2. Failure to establish separate or defined areas or other such control systems "as are necessary to prevent contamination or mixups in the course of manufacturing and processing operations [21 CFR 211.42(c)(5)]. Specifically, the magnahelic gauge installed in [redacted] (cephalosporin) to monitor whether the room pressure differential is maintained negative to the hallway connecting to the main building had not been calibrated or certified as working properly in accordance with written procedures and, thus, there is no assurance that air from the room does not intermingle with the air in the non-cephalosporin production areas [See Form FDA-483 #,1,C.].

3. Failure to test non-penicillin drug products for the presence of penicillin if a reasonable possibility exists that non-penicillin drug products have been exposed to cross-contamination with penicillin [21 CFR 211.176]. Specifically, no testing of the non-penicillin drug products for penicillin is performed. The only testing done is for the presence of beta-lactams in the non-betalactarn production areas but the methods used, as described in SOP 01.18, have not been qualified for their intended purpose [See Form FDA-483 # 1,D.].

4. Adequate written procedures applicable to the quality control unit have not been established and followed [21 CFR 211.22(d)]. Specifically:

a. Written procedures do not assure that correct package inserts are included with repackaged product [See Form FDA-483 #2.B.1].

b. Written procedures specifying double counting of tablets or capsules during production and requiring installation and annual calibration of magnahelic, pressure, gauges by a certified HVAC company are not followed [See Form FDA-483 #2.A.,B.4,].

5. Failure to include in the batch production and control records, complete labeling control records, including specimens of all labeling used for each drug product [21 CFR 211.188(b)(8)]. Specifically, there is no assurance that package inserts attached to batch records are the same version shipped with the repackaged product. Inserts are not included with each with each container of repackaged product and those that are available for inclusion have revision dates that are different from that of the insert attached to the batch record [See Form FDA-483 # 3.B.] .

6. Failure to establish written procedures to prevent objectionable microbiological organisms in drug products not required to be sterile [21 CFR 211.113(a)]: Specifically, written procedures do not address or require the use of gloves or other protective equipment by personnel during manual tablet counter interventions. Personnel were observed using bare hands to dislodge tablets in a counting machine [See Form FDA-483 # 4.].

7. Failure to establish and follow adequate written procedures to assure routine calibration of mechanical equipment [21 CFR 211.68(a)]. Specifically, SOP 02.07 is inadequate in that it does not require that the counting machine be challenged with an overage to verify proper operation of the diversion mechanism that switches the flow of tablets to another bottle when the specified count has been reached [See Form FDA-483 # 5.1].

Furthermore, your drug products appear to be misbranded within the meaning of section 502(f)(1) of the Act [21 U.S.C. 352(f)(1)] in that the product labeling does not bear adequate directions for use. Your firm fails to include a copy of the package insert or a reference to the package insert on the product label with each unit of product distributed. Although 21 CFR 201.100 outlines certain exemptions to this requirement, your firm does not qualify for these exemptions because the product's labeling fails to bear information required by regulation section 201.100, i.e., adequate directions for use under which a practitioner licensed by law can use the drug safely and for the
purposes for which it is intended.

Also, your drug products appear to be misbranded under section 502(o) of the Act [21 U.S.C.352(o) in that they do not appear to be adequately listed as required by 21 U.S.C. 360(j). Our review of FDA's Drug Registration and Listing System revealed that the drugs listed reflect a "pending" status. This "pending" status signifies that your firm has failed to supply complete listing information to the agency. Registration and listing information can be found at http:/ listing.htm .

The above list of violations is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to assure adherence to each requirement of the Good Manufacturing Practice Regulations. Other Federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when considering the award of contracts.;

Additionally, pending NDA, ANDA, or export approval requests may not be approved until the above violations are corrected.

We acknowledge your letter of April 1, 2005, responding to the Form FDA-483 but find this response to be unsatisfactory for several reasons. Regarding your response to Form FDA-483 item #1.A., for example, a new exit door permitting employees to leave the beta-lactam rooms without returning to the main facility would be an appropriate step toward controlling personnel flow but your response does not clearly indicate the location of this door in relation to the main building. Also, your proposed. ban on employee re-entry to the main facility on the same day must be strictly enforced through carefully drafted and implemented control procedures for this corrective action to be an effective step toward reducing the possibility of cross contamination of the non beta-lactam areas. Your response does not provide any details on implementation. Your proposal, in your response to item 1.B., to supplement your use of [redacted] Isopropyl Alcohol to clean the cephalosporin and penicillin rooms with "disinfecting" wipes seems to indicate a fundamental misunderstanding of the nature of the contamination that must be controlled. Beta-lactarns are chemical substances and these antibiotic drug residues that can cause cross-contamination are not due to viable mold spores. Your statement that you are working on implementing "RESIDUE clean testing does not provide any details on the nature of the testing you plan to perform. Scientifically based test procedures for antibiotic residues must be validated by showing the test(s) can identify contamination in the production rooms and connecting passageways from the specific repackaged antibiotic(s) at levels, that would indicate that the possibility of such contamination in the non beta-lactam drug products, was minimal. Your responses to items # 1.C. and # 2.A., only address the lack of calibration of the magnahelic gauges and do not address the issue of proper installation in accordance with your firm's written procedures. Finally, while many of the corrective actions outlined in your letter for the remaining FDA-483 items appear to address the specific objectionable observations, no documentation, such as revised SOPs, was provided to support these assertions.

We request that you take prompt action to correct these violations. Failure to promptly correct these without further notice, such as seizure and/or injunction.

Please notify this office in writing, within fifteen (15) working days of receipt of this letter, as to any steps you have taken to correct these violations, including an explanation of each step being taken to identify and make corrections to assure that similar violations will not recur.

If corrective action cannot be completed within 15 working days, state the reason for the delay and the time frame within which the corrections will be implemented.

Your reply should be directed to Judith A. Putz, Compliance Officer, at the above address.



Joann M. Givens
District Director
Detroit District