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
MAR 11 1997
Transcriber Note: This doccument was purged of certain data before we received it.
All missing data is indicated by underlined blanks.
CERTIFIED - RETURN RECEIPT REQUESTED
Robert Myers, D.V.M
Responsible Head
Michigan Biologic Products Institute
3500 North Martin Luther King, Jr., Blvd.
P.O. Box 30035
Lansing, Michigan 48909
Dear Dr. Myers:
The Food and Drug Administration Hereinafter "FDA" or "the agency") conducted an
inspection of Michigan Biologic Products Institute, Lansing, Michigan, between November
18 and 27, 1996. During the inspection, FDA investigators documented numerous significant
deviations from the applicable standards and requirements of Subchapter C and 211, and
Subchapter F, Parts 600-680, Title 21, Code of Federal Regulations, and the applicable
standards in your license. The deviations noted on the Form FDA 483, Inspectional
Observations, issued at the conclusion of the inspection include, but are not limited
to the following:
1. Failure of the quality control unit to approve or reject all components, drug product
containers, closures, in-process materials, packaging material, labeling, and drug
products [21 CFR 211.22(a)] in that the____________________filters and plastic bags
used during production and storage of blood derivatives and the pre-sterilized
foil/plastic bags used as buffer bags in production did not undergo release by the
quality control unit.
2. Failure of the quality control unit to approve or reject all procedures or
specifications impacting on the identity, strength, quality, and purity of drug
products [21 CFR 211 .22(c)]. For example:
a. Validation of loading patterns for the___________________________performed in
June 1995, was not reviewed/approved by Quality Assurance ("QA")
b. Temperature mapping of the Incubator Room_____performed on April 19, 1996 was
not reviewed by QA.
c. Analytical method validation for_______________________was not
reviewed/approved by QA.
d. Eight deviations of the air handling system in the aseptic fill area
identified during the May 1, 1996, requalification of the building____were not
reviewed/approved by QA.
Page 2 - Robert Myers,D.V.M
3. Failure to establish and/or follow written procedures for production and process
controls 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 quality control [21
CFR 211.1OO]. For example:
a. The standard operating procedure ("SOP")_____entitled___________________________
__________________________________________________________________________was not
followed in that there was no qualification for operation of the___________dryer
indicating it can operate as designed and intended.
b. The SOP______entitled_____________________________________________________
______________________________________________________________________________was
not followed in that investigations had not been initiated of continuously
exceeded environmental action limits for nonviable particulates in the____________
_________filling suite.
c. SOP_____entitled__________________________________________________________________
____________________________________________________was not followed in that________
temperature deviations noted on temperature recording charts for walk-in cold
rooms and freezers in building___had not been investigated and notification of
departure was not issued. Additionally, there is no written procedure for the
review of temperature recorder charts.
d. SOP_____entitled___________________________________________________________________
___does not specity the operating temperature ranges for each refrigerator and
freezer in the Blood Derivatives section.
e. SOP_____entitled___________________________________________________________does
not describe the preparation of the sterile_______storage bottle.
f. SOPs for operation of the___________autoclave, used for sterilization of____________
___________________________________for Albumin (Human), Immune Globulin
(Human), and other equipment, do not include load pattern diagrams or
descriptions.
g. SOP_____entitled________________________did not have the correct
load patterns for trays filled with______vials.
4. Failure to establish and follow 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 processes [21 CFR 211.113(b)] in
that:
a. Validation studies to demonstrate microbial retention and compatibility have not
been conducted for sterilizing filters used for Albumin (Human) and Immune
Globulin (Human).
b. The Water For Injection ("WFI") tubing in building___used for final rinse of
__________________, contained pooled water after use. The tubing was not stored
so that the WFI would drain.
Page 3 - Robert Myers,D.V.M
c. There is no written procedure to prevent the flow of personnel between room
(rabies viral lab) and the cell culture laboratory.
5. Failure to establish and follow control procedures to monitor the output and to validate
the performance of those manufacturing processes that may be responsible for causing
variability in the characteristics of in-process material and the drug product [21 CFR
211.110(a)] in that:
a. There was no qualification for operation of the____________________used to produce
the Albumin and Immune Globulin powders as described in SOP______________________
b. All load patterns have not been validated for the__________autoclave in room____
used for sterilization.
6. 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 specifications have not been established for pressure differential
readings taken from magnehelic gauges in the capper, filling, and gowning rooms.
7. Failure to establish and/or follow written testing programs designed to assess the stability
characteristics of drug products [21 CFR 211.166(a)] in that there is no documentation
available to support acceptable storage temperature excursion time frames for samples of
Immune Globulin (Human) and Rabies Vaccine.
8. Failure to follow the stability program for the rabies vaccine [21 CFR 211.166(a)(2)] to
assure valid estimate of stability in that there is limited control over storage conditions
of samples prior to time zero which can be as long as three months.
9. Failure to establish separate or defined areas or other control systems for manufacturing
and processing operations to prevent contamination or mixups [21 CFR 211.42(c) and
600.11(a)] in that:
a. The door to the powder harvest room_____which is a controlled Class
area, was propped open to roon_____which is an uncontrolled area, during
powder harvest.
b. There is no separate airlock for degowning after working with live rabies virus.
c. There is no segregation of quality control raw material testing for____________
______and research activities in room____
d. The gowning room was open to the_______________and open to the__________
______________simultaneously.
Page 4 - Robert Myers,D.V.M
10. Failure to clean, maintain, and sanitize equipment and utensils at appropriate intervals to
prevent malfunction or contamination that would alter the safety, identity, strength,
quality, or purity of the drug product [21 CFR 211.67(a)] in that:
a. Cleaning validation studies have not been completed for routine cleaning
procedures on multi-use equipment.
b. Rust was observed on the__________freezer used to store intermediate products.
11. Failure to maintain or follow written procedures for cleaning and maintenance of equipment
including utensils, used in the manufacture, processing, packing, or holding of a drug
product [21 CFR 211.67(b)] in that the SOP_______entitled_____________________________
________________________________________________________a does not list the parts to
be washed and does not describe the procedure used to clean the parts.
12. Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic
equipment used in the manufacture, processing, packaging, and holding of a drug product
according to a written program designed to assure performance [21 CFR 211.68(a)] in that
the temperature control system of the manifold loading area of the____________has not been
calibrated. The________________s used to produce the Albumin and Immune Globulin powders.
13. Failure to Store and handle components and drug product containers and closures in a
manner to prevent contamination [21 CFR 211.80(b)] in that chemicals tested and
released as in compliance with good manufacturing practices were not segregated from
chemicals not tested and released.
14. Failure to identify and control rejected components, drug product containers, and closures
under a quarantine system designed to prevent their use in manufacturing or processing
operations for which they are unsuitable [21 CFR 211.89] in that materials rejected by
quality control are not clearly labeled "rejected."
15. Failure to calibrate instruments, apparatus, gauges, and recording devices at suitable
intervals [21 CFR 211.160(b)(4)) in accordance with an established written program, in
that:
a. The conductivity meter for distillate in the WFI system in building____was past
due for calibration and had not been calibrated.
b. The chart recorder on_____________the used to store________________at_______or
colder, was past due for calibration on November 14, 1996, and was reading______
__Review of the chart recorder records indicated that the temperature of the
freezer was out of specification__________________since April 1996.
c. All chart recorders and temperature probes which monitor the product temperature
in the reaction tanks and the jacket temperatures were past due for calibration.
Page 5 - Robert Myers,D.V.M
16. Failure to maintain buildings used in the manufacture, processing, packing, or holding of
a drug product in a clean and sanitary condition [21 CFR 211.56(a)] and 600.11(a)] in that:
a. There is no spill clean-up or periodic floor cleanmg when plasma spills onto the
floor during the several hour plasma pool/thaw process.
b. Dead insects were present in room
c. A live insect was observed in capping room
17. Failure to establish written procedures describing the cleaning schedules, methods,
equipment, and materials to be used in cleaning the buildings and facilities [21 CFR
2ll.56(b)] in that:
a. There is no SOP for the clean-up of live rabies virus spills in room______
b. The floors, walls, and ceilings of the production area were not cleaned at the
prescribed frequency as required by SOP__________entitled____________
18. Failure to maintain buildings used in the manufacture, processing, packing, or holding of
a drug product in a good state of repair [21 CFR 211.58] in that:
a. Condensate was observed dripping from tank piping onto open tanks
filled with_______________________
b. Standing water was observed underneath the pasteurizer in room_____and_____
underneath the________________
c. Rust and chipped paint were observed on the banister and around the centrifuges
in room_____and on the transfer cage in the capping room.
d. Chipped paint was observed on the walls of room______
e. A leak was observed in the ceiling of room_______
f. In cold room_____the lights were inoperable, stains and flaking paint were
observed on the walls, and the thermostat was iced over.
19. Failure to provide adequate space for the orderly placement of equipment and materials to
prevent mixups between different components, drug product containers, closures,
labeling, in-process materials, or drug products, and to prevent contamination [21 CFR
211.42(b)] in that:
a. Plastic bags, used to cover the___________________________________after product
freezing, were stored without protection on top of the freezer in the wash room.
b. Boxes of packaged gowning supplies were on the floor in the hallway outside of
the second floor gowning room for the post virus inactivation area.
c. A tipped box containing an opened plastic bag with pre-sterilized foil/plastic bags
was on the floor in the hallway outside of_____________________
d. In Rooms_____and______there was no segregation and labeling of clean and dirty
glassware.
Page 6 - RobertMyers,D.V.M
20. Failure to assure that the equipment used in the manufacture, processing, packing, or
holding of a drug product is of appropriate design and of adequate size for its intended
use and for its cleaning and maintenance [21 CFR 211.63) in that an indoor/outdoor
thermometer, which can not be calibrated, monitors the temperature in freezer______
used to store retention samples of pastes and powders.
21. Failure to concurrently record the performance of each step in the manufacture and
distribution of products [21 CFR 600.12(a)] in that the temperature recorder chart times
did not agree with manually recorded log book times for sterilization.
22. Failure to assure that equipment with surfaces that contact components, in-process
materials, or drug products is not reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of a drug product [21 CFR 211.65 and
600.11(b)] that a cutting board constructed of plywood, which is not a sanitary or easily
cleaned surface, is used in room_____for______________________
23. Failure to properly identify storage containers and their contents as well as major
equipment used during the production of a batch of a drug product [21 CER 21 l.105(a)].
For example, the label on the cartridge filter housing stored inside
indicating the status and contents was not readable.
While these deviations were documented in the most recent inspection, we note that significant
deviations have been documented during previous FDA inspections of May 4 through May 7,
1993; May 31 through June 3, 1994; and April 24 through May 5, 1995. The seriousness of these
deficiencies was emphasized to you in a letter dated December 22,1993, and a Warning Letter
dated August 31, 1995.
Based on the nature and number of the deficiencies identified during the recent inspection, it is
the agency's judgment that management of the Michigan Biologic Products Institute has not
fulfilled its responsibilities to exercise control in all matters relating to compliance with
federal regulations and the applicable standards of your establishment and product licenses,
or to assure that personnel are adequately trained and supervised and have a thorough
understanding of the procedures that they perform, as required by 21 CFR 600.10(a) and (b), and
21 CFR 211.25(a) and (b).
The above identified deviations are not intended to be an all-inclusive list of deficiencies at
your establishment. It is your responsibility as Responsible Head to assure compliance with all
requirements of the federal regulations and the standards in your license.
We have reviewed your letter dated January 16, 1997, regarding the corrective actions which you
proposed to the observations of the most recent inspection. We note that your firm has
Page 7 - Robert Myers,D.V.M
repeatedly promised corrective actions in the past, but follow-up inspections continue to show
that adequate, effective, and long term corrective action has not been taken. Accordingly, we
have no assurance that the corrective actions will be properly implemented to correct the
deficiencies noted during the most recent inspection.
Pursuant to 21 CFR 601.5(b)], this letter is to provide you with notice that, unless you
demonstratd or achieve compliance with the applicable standards and regulations, it is the intent
of the FDA to institute proceedings to revoke U.S. license 0099-001, issued to Michigan
Biologic Products Institute, 3500 North Martin Luther King, Jr., Blvd., Lansing, Michigan, for
the manufacture of Diphtheria Toxoid Adsorbed, Tetanus Toxoid Adsorbed, Rabies Vaccine
Adsorbed, Antihemophilic Factor (Human), Immune Globulin (Human), Albumin (Human),
Anthrax Vaccine Adsorbed, Pertussis Vaccine Adsorbed, Diphtheria & Tetanus Toxoids
Adsorbed, and Diphtheria & Tetanus Toxoids & Pertussis Vaccine Adsorbed, and to issue a
notice of opportunity for hearing on the proposed revocation pursuant to 21 CFR 12.21(b). The
agency will proceed with the revocation of U.S. license 0099-001 unless you do the following:
1. Within ten (10) days of receipt of this letter, advise FDA in writing of your commitment
to correct the noted deficiencies, explaining the approach by which compliance will be
achieved in an expeditious manner.
2. Within thirty (30) days of receipt of this letter, submit a comprehensive report and
detailed approach supplementing your January 16, 1997, response addressing the methods
which will be used to bring your facility into compliance, including a proposed
completion date for correction of the noted deficiencies. Your plan should include
corrective actions regarding all noted deficiencies, and should specifically emphasize
your firm's plan for:
a. ensuring that the QA Section functions in an adequate, effective, and timely
manner, including addressing all QA oversight deficiencies;
b. conducting a thorough review of all standard operating procedures to achieve
compliance with good manufacturing practices as specified in 21 CFR 210 and
211;
c. establishing a system of training and evaluation to ensure that personnel have
capabilities commensurate with their assigned functions and a thorough
understanding of the manufacturing operations which they perform;
d. conducting a review of all observations listed on the Form FDA 483 issued
November 27, 1996, to determine whether or not product quality has been
affected, including addressing the need for possible recall of product if deemed
necessary.
Page 8 - Robert Myers, D.V.M
These submissions should be sent to Mr. James C. Simmons, Director, Office of Compliance,
HFM-600, Center for Biologics Evaluation and Research, 1401 Rockville Pike, Suite 200N,
Rockville, Maryland, 20852-1448. Mr. Simmons may be reached at (301)594-2066.
Additionally, a copy of all submissions should be sent to the FDA's Detroit district office,
1560 B. Jefferson Avenue, Detroit Michigan, 48207-3179, to the attention of Ms. Brenda Holman.
In addition, we request a meeting with you at your earliest convenience to discuss the compliance
status of your firm. We suggest that you also invite representatives from the State of Michigan
and the Department of Defense to attend the meeting. Please telephone Mr. Simmons to discuss
an appropriate date and time for the meeting.
If we do not receive an adequate response within the prescribed time, or if subsequent inspection
of your firm fmds your corrective actions to be inadequate, we shall proceed pursuant to the
regulations governing formal evidentiary public hearings, as found in 21 CFR 12.21(b), and
publish in the Federal Register a notice of opportunity for hearing on a proposal to revoke U.S
license 0099-001 and your product licenses for the manufacture and sale of Diphtheria Toxoid
Adsorbed, Tetanus Toxoid Adsorbed, Rabies Vaccine Adsorbed, Antihemophilic Factor
qiuman), Immune Globulin (Human), Albumin (Human), Anthrax Vaccine Adsorbed, Pertussis
Vaccine Adsorbed, Diphtheria & Tetanus Toxoids Adsorbed, and Diphtheria & Tetanus Toxoids
& Pertussis Vaccine Adsorbed.
If you choose not to bring your establishment into compliance and wish to waive the opportunity
for a hearing, you must contact Mr. Simmons within ten (10) days of receipt of this letter. The
waiver must be confirmed in writing and may be accomplished by your voluntary request that
U.S. license 0099-001 be revoked.
Copies of this letter have been sent to members of the Michigan Biologic Products Commission.
In addition, the appropriate state officials will be notified of this administrative action.
Sincerely yours,
/signed/
Kathryn C. Zoon, Ph.D.
Center for Biologics
Evaluation and Research
cc: The Honorable John R. Engler
Governor, State of Michigan
P.O. Box 30013
Lansing, Michigan 48909
Page 9 - Robert Myers, D.V.M
Dennis L. Schornack
Chairman, Michigan Biologic Products Commission
3500 North Martin Luther King, Jn, Blvd.
P.O. Box 30035
Lansing, Michigan 48909
James Haveman
Commission Member, Michigan Biologic Product Commission
3500 North Martin Luther King, 3n, Blvd.
P.O. Box 30035
Lansing, Michigan 48909
Mary Lannoye
Commission Member, Michigan Biologic Product Commission
3500 North Martin Luther King, Jr., Blvd.
P.O. Box 30035
Lansing, Michigan 48909
