DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Services
__________________________________________________________________________
Food and Drug Administration
Center for Biologics Evaluation And Research
1401 Rockville Pike
Rockville, MD 20852-1448
August 31, 1995
WARNING LETTER
Certified-Return Receipt Requested
Robert Myers, D.V.M
Responsible Head
Michigan Department of Public Health
3500 North Logan
Lansing, Michigan 48909
Dear Dr. Myers:
During an inspection of the Michigan Department of Public Health,
3500 North
Logan, Lansing, Michigan, conducted on April 28 to May 5, 1995,
FDA inspectors
Lyn D. Olson, Ph.D., Florence A. Kaltovich, Kelley L. Clark, and
Scott D.
Barlow documented significant deviations from Title 21, Code of
Federal
Regulations (21 CFR), Parts 600-610 and Part 211 with respect
to the
manufacture of your products as follows:
1. Failure to notify the Director, Center for Biologics Evaluation
and
Research (CBER), of proposed changes in location, equipment, responsible
personnel, and manufacturing methods in accordance with 21 CFR
601.12(b)
in that:
a. Beginning with the manufacture of Immune Globulin lot 1G107,
an open reaction tank has been used instead of a shaker tank
as described in your Establishment License Application. As
a result, mixing of the product and the size and arrangement
of the clarifying filters have been modified.
b. New master cell banks for Rabies vaccine production were
obtained and utilized for manufacturing.
2. Failure to assure that the cell lines used for manufacturing
biological
products are genetically stable and free of contaminants (21 CFR
610.18(c)] in that all tests necessary to characterize and qualify
the
new master cell banks have not been performed.
Organization and Personnel
1. Failure of the personnel engaged in the manufacture, processing,
packaging, or holding of a drug product to be adequately trained
in
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current good manufacturing practice (CGMP) including the CGMP
regulations and written procedures required by these regulations
as they
relate to the employee's functions [21 CFR 211.25). Employees
of the
Divisions of General Services and Laboratory Services do not receive
CGMP training on a continuous basis to assure they remain familiar
with
applicable CGMP requirements.
2. Failure of the quality control unit to have written procedures
delineating its authority to approve or reject all components,
drug
product containers, closures, in-process material, labeling, and
drug
products, and to review production records to assure that either
no
errors have occurred or that they have been fully investigated
[21 CFR
211.22].
Buildings and Facilities
1. Failure to provide separate or defined areas or such control
system for
the firm's manufacturing and processing operations to prevent
contamination or mixups [21 CFR 211.42(c)] in that:
a. Access to the blood derivative manufacturing and rabies
manufacturing buildings is not controlled.
b. There is no separate air lock for degowning in the rabies
manufacture building.
c. Unlocked cold rooms are use to store__________________
__________________________
2. Failure to establish a system for monitoring environmental
conditions
[21 CFR 211.42(c)(1O)(iv)] in that:
a. The bacterial vaccine gowning room is not monitored during
periods of activity.
b. Monitoring is not performed during rabies vaccine
manufacture.
3. Failure to maintain any building used in the manufacture, processing,
packing, or holding of a drug product in a good state of repair
[21 CFR
211.58] in that water from the cooling unit in cold room ____
drips onto
boxes of stored final product; the leak has not been fixed after
several
informal reports to maintenance.
Control of Components and & Drug Product Container & and
Closures
1. Failure to have written procedures describing in sufficient
detail the
receipt, identification, storage, handling, sampling, testing,
and
approval or rejection of components and drug product containers
and
closures [21 CFR 211.80(a)] in that SOP_____ for receipt and release
of
raw material does not include the flow of raw material containers
from
receiving (building ____ to the warehouse (building ___ ), and
Quality
Control (building ____ to prevent contamination or mixups.
Page 3 - Michigan Department of Public Health
2. Failure to open, sample, and reseal containers in a manner
designed to
prevent contamination of their contents and contamination of other
components, drug product containers or closures [21 CFR 211.84(c)(2)]
in
that there is no sampling area for large containers of raw material.
Production and Process Control
1. Failure to establish and/or follow written procedures for production
and
process control designed to assure that the drug products have
the
identity, strength, quality, and purity they purport or are represented
to possess and to assure that such procedures, including any changes,
are drafted, reviewed, and approved by the appropriate organizational
units and reviewed and approved by the quality control unit [21
CFR
211.100] in that:
a. Two employees were observed entering room____to charge the
fermenter without hair covers.
b. Expired____________ medium lot 1635 was used in the
manufacture of______________________
c. There is no written procedure for the following:
1) The qualification of new lots of media used
during rabies and bacterial vaccine manufacture.
2) The production of fraction II+III and fraction
II+IIIw intermediates.
3) The formulation of fraction II+III rework lots
and fraction V rework lots from plasma run lots.
4) The formulation of albumin or immune globulin
lots from fraction V and fraction II+IIIw rework
lots.
5) Sampling of large containers of raw materials.
2. Failure to establish appropriate written procedures designed
to prevent
microbiological contamination of drug products purporting to be
sterile
and to assure that such procedures include validation of any
sterilization process [21 CFR 211.113(b)] in that:
a. There is no written procedure relating to sterile media
fills
b. There is no written procedure relating to the flow of
personnel between room____(hot laboratory) and the cell
culture laboratory.
Packaging and Labeling Control
Failure to have written procedures describing in detail the receipt,
identification, storage, handling, sampling, examination, and/or
testing
of labeling and packaging material [21 CFR 211.130(a)].
Holding and Distribution
Failure to have written procedures describing the distribution
of drug
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products including a system by which the distribution of each
lot of
drug product can be readily determined and whereby the oldest
approved
stock of drug product is distributed first [21 CFR 211.150] in
that
there is no written procedure for interstate distribution of Immune
Globulin (Human) vaccine.
Laboratory Controls
1. Failure to establish laboratory controls that include scientifically
sound and appropriate specifications, standards, sampling plans,
and
test procedures designed to assure that components, drug product
containers, closures, in-process materials, labeling, and drug
products
conform to appropriate standards of identity, strength, quality,
and
purity [21 CFR 211.160(b)] in that:
a. Release of media used in the manufacture of rabies and
diphtheria vaccines is based on satisfactory growth during
production.
b. Endotoxin specifications for intermediate blood derived
products after the drying run have not been established.
2. Failure to establish and/or follow written testing program
designed to
assess the stability characteristics of drug products [21 CFR
211.166(a)] in that:
a. There is no program in place for__________________________
____________________________________
b. There is no evidence that samples are randomly selected for
final product testing for the Diphtheria and Tetanus Toxoids
and Pertussis Vaccine, Adsorbed, (DTP) stability program.
3. Failure to follow the stability program for the rabies vaccine
[21 CFR
211.166(a)] to assure valid estimates of stability in that:
a. The sample size collected and tested is inadequate.
b. Test intervals are inadequate.
c. The storage temperature is not always recorded.
d. Stability samples are removed prior testing.
Records and Reports
1. Failure to maintain adequate and complete batch production
and control
records for each batch of drug product produced [21 CFR 211.188(b)]
in
that:
a. The batch record for Immune Globulin (Human) lot 1G106 did
not contain the written deviation report describing changes
in the procedure.
b. Batch records for diphtheria toxin lots DTN74 and DTN5l and
tetanus toxin lots TT3448, TT3449, and TT3450 did not
include all manufacturing procedures, equipment
identification, and storage sites of in-process and final
material.
c. The batch record for plasma run lot PR2811 did not include
Page 5 - Michigan Department of Public Health
the expiration date of_________ the section for individual
container weights was incomplete; the buffer was not
prepared according to the specified procedure; and a
difference between the documented centrifugation stop time
on the tank record and the batch record was noted.
2. Failure to investigate and document the failure of a batch
or components
to meet specifications [21 CFR 211.192] in that since January
1995 at
least one cell culture batch per month was contaminated, and no
investigation has been done.
3. Failure to have complete laboratory records [21 CFR 211.194(a)]
in that
sterilization records for the autoclaves used by the Quality Control
laboratory do not always include the sterilization time, person
operating the autoclaves, and review signature.
The above identified deviations are not intended to be an all
inclusive list
of deficiencies at your facility. 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 awards of contracts.
In
accordance with 21 CFR 600.10(a), it is your responsibility, as
Responsible
Head, to exercise control of the establishment in all matters
relating to
compliance with all pertinent regulations. You are also responsible
for the
training of employees in manufacturing methods and for their being
informed
concerning the application of the regulations pertinent to their
respective
functions.
We acknowledge your June 9, 1995, response to the Form FDA 483
issued at the
close of the inspection. We view the response to items 1, 2, 3,
6, 11, and 14
of the form FDA 483 as incomplete because it does not include
supportive
documentation indicating in detail how and when corrective actions
will be
taken and the approximate dates by which they will be completed.
The kind of
supportive documentation necessary includes, but is not limited
to,
appropriate license supplements, standard operating procedures,
copies of
revised master batch production records, training records, and
monitoring
data. In addition, you may refer to and need not repeat in detail
the
corrective actions mentioned during the April 12 and July 5, 1995,
meetings
with CBER in response to this Warning Letter.
You should notify this office in writing within 15 working days
of receipt of
this letter of any additional steps you have taken to correct
the noted
violations and to prevent their recurrence. If corrective action
cannot be
completed within 15 working days, state the reason for the delay
and the time
within which the corrections will be completed. Failure to promptly
correct
these deviations may result in regulatory action without further
notice.
These actions include license suspension and/or revocation, seizure,
and/or
injunction.
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Your reply should be sent to my attention in the Office of Compliance,
Center
for Biologics Evaluation and Research, 1401 Rockville Pike, Suite
200N, HFM-
600, Rockville, Maryland, 20852.
Director, Office of Compliance Center for Biologics Evaluation
and Research
Last revised: March 2000