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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Enforcement Actions

Bachem California, Inc 14-Jan-02

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration

19900 MacArthur Blvd., Ste 300

Irvine, California 92612-2445

Telephone (714) 798-7600

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

January 14, 2002

WARNING LETTER

WL-24-02

Philip Ottiger

President and CEO

Bachem California, Inc.

3132 Kashiwa Street

Torrance, CA 90505

Dear Mr. Ottiger:

During an inspection of your pharmaceutical manufacturing facility conducted from

November 13 to 27, 2001 our investigators found significant deviations from the current

Good Manufacturing Practice (cGMP) for Finished Pharmaceuticals Regulations (Title 21, Code of Federal Regulation (CFR), Parts 210 and 211). These deviations cause your

drug products to be adulterated within the meeting of Section 501(a)(2)(B) of the Federal

Food, Drug and Cosmetic Act (the Act) as follows:

1. Failure to ensure that cleaning methods used in cleaning production equipment will

sufficiently prevent contamination that would alter the safety, identity, strength,

quality, or purity of drug products [21 CFR 211.67]. Specifically, no documented

evidence exists to demonstrate the effectiveness of cleaning methods and agents used

in cleaning of all production equipment and utensils to ensure that residues have been

reduced to acceptable levels. Cleaning validation is limited to only glassware.

Additionally, your firm failed to conduct investigation(s) of out of specification

results obtained during the cleaning validation for lyophilization trays. ?There is no

cleaning validation for screens or wire electrodes that have product contact during

lyophilization. Our investigators also observed foreign substances on production

screens and trays.

2. Failure to establish implement and control procedures for maintenance, including

utensils, used in the manufacture, processing or holding of drug products [21 CFR 211.67]. Specifically, our investigators observed that tape is used to hold your production trays and screens together and tape residues were also observed on the frames of the trays; the ties were also frayed. Our investigators also observed that the wire metal electrodes used for monitoring the temperature of product were frayed. There is no preventative maintenance for the electric wires that are placed in product solutions during tray lyophilization to determine product temperature.

The nitrogen filters in the lyophilizers have not been changed since 1998. The filters

are to be changed annually per the labeling instructions on the filter housing. Also,

there is no routine maintenance program for these filters. Our investigators

determined that a tray lyophilizer was not fictional and the equipment maintenance

log did not document that status.

3. Failure to ensure that written production and process controls are designed to assure

that drug products have the identity, strength-quality and purity they purport or are

represented to possess [21 CFR 210.100]. Specifically, no eutectic temperature or

sublimation temperatures have been established for any of your drug products. There

is no documented evidence to assure that the vacuum and condenser temperatures are

maintained throughout your routine manufacturing lyophilization cycle. There is no

documented evidence to ensure that the product is completely frozen in an acetone

bath with dry ice prior to lyophilization. There is no scientific rationale that assures

that in-process lyophilization drying is complete. In addition, no maximum drying

time has been established.

4. Failure to ensure that laboratory controls include the establishment of scientifically

sound and appropriate test procedures designed to assure that drug products conform

to appropriate standards of identity, strength quality and purity [21 CFR 211.160(b)(1)]. Specifically, there are no requirements for HPLC column system suitability that are applicable to the purification process of your drug products.

5. Failure to ensure that batch production record and control records include complete

information relating to the production and control of each batch of drug product [21

CFR 211.188]. Specifically, tray lyophilization charts in batch records are not set up

to accurately assess if running parameters are maintained throughout the cycle.

Storage conditions for sidecuts are not specified. No tray lyophilization parameters

are specific for s performed after purification for each step except [redacted].

We acknowledge that you have submitted to this office written responses to the form

FDA-483. We have reviewed your responses and while these responses address several

of our concerns, there still remain several issues that could not be completely-evaluated

because the supporting documentation was not submitted with those responses, or the

responses were inadequate. Detail comments are listed on Attachment A to this letter.

The above identification of violations is not intended to be an all-inclusive list of

deficiencies at your facility. A list of observations (FDA-483) was issued and discussed

with you at the conclusion of the inspection It is your responsibility to assure adherence

with each requirement of the Good Manufacturing Practice regulations and other

applicable regulations. Federal agencies are advised of the issuance of all warning letters

about drugs and devices so that they may take this information into account when

considering the award of contracts.

You should take prompt action to correct these deviations. Failure to do so may result in

regulatory action without further notice, including seizure and/or injunction. You should

notify this office in writing, within fifteen (15) working days of receipt of this letter, of

the specific steps you have taken to correct the noted violation including an explanation

of each step taken to prevent the recurrence of similar violations. If corrective action

can not be completed within (15) working days, state the reason for the delay and time

within which the confections will be completed.

Your reply should be addressed to:

Thomas Sawyer, Director of Compliance

U.S. Food and Drug Administration

19900 MacArthur Blvd., Suite. 300

Irvine, CA 92612

Sincerely,

Alonza E. Cruse

District Director