Inspections, Compliance, Enforcement, and Criminal Investigations
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
RETURN RECEIPT REQUESTED
January 14, 2002
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
Alonza E. Cruse