[Transcriber Note]: (-WO-) equals areas the FDA whited out. Included here are pages 02 through 12 of the report.
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1. The manufacturing process for Anthrax Vaccine is not validated. For
example,
a. The formulation tank has not been qualified for long term
storage of formulated bulk Anthrax. Storage times have varied from one
week to four months between formulation and filling. Lot FAV033 was
formulated on 8/27/96, however it was not filled until 12/23/96.
b. The formulation tank has not been qualified for mixing time,
demonstrating homogeneity of the suspension. Mixing time is not
specified in the batch record prior to filling and during the filling
operations. The product is (-----WO----) and settles quickly in the
tank.
c. The firm did not perform media fill challenges to validate
aseptic manufacturing after harvest from the holding tank. These
operations include the transfer of the sublots from building (-WO-) to
building (-WO-) for formulation.
Media fills are performed on fermentation and harvest trains, however
not on a scheduled basis.
d. There is no validation of (--WO---) as a sporicide in anthrax
production and potency testing facilities.
e. The analytical methods for determination of and (----WO----) in
Anthrax Vaccine are not validated with respect to accuracy, precision,
linearity, specificity and limit of detection.
f. There is no validation of the length of time sublots are held
until they are used in a lot. Sublots have been held longer than 3
years prior to use. There is no stability data to support this hold
time.
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- - For example, sublot AV370 was produced and placed in coldroom
(-WO-) of building (-WO-) further referred to as (--WO--) in 2/94 until
7/97 at which time it was used to produce lot FAV040
- - Sublot AV450 was produced and placed in (--WO--) 5/95 until 3/97
at which time it was used to produce lot FAV035
- - Sublot AV456 was produced and placed in (--WO--)in 5/95 until
3/97 at which time it was transported to the formulation room of
building (-WO-) with (-WO-) other sublots to make FAV039. Here it was
discovered that AV456 was contaminated with mold, and it was destroyed.
g. The reference standard used for potency testing is lot FAV009,
produced March 1991.
h. There are no expiration dates for the working spore
concentrations (virulent or avirulent strains). For example, the
production strain, (-------WO--------) was used to produce sublot AV216
as early as 3/92 and sublot AV450 as late as 4/95.
i. (--------------WO----------------)testing for Anthrax sublots used
sublot AV462 with a (--WO--) content of 23 ppm. The specification for
(--WO--) in Anthrax vaccine is 15-30 ppm. There is no BF testing at
15ppm or 30ppm.
k. Prior to August 1997, the (----WO---) filters used for harvest of
Anthrax vaccine were neither validated nor integrity tested. This
filter is the only sterile filtration step in the Anthrax manufacturing
process.
l. Validation of microbial retention by the (---WO----)filters used
for harvest of Anthrax vaccine was performed only with (---WO---)media,
which is used in tetanus production. Studies were not performed using
Anthrax product or media.
** "m" is missing inspector may have failed to use that letter, no
indication of white out here**
n. WFI used in the production of Anthrax sublots in
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building (-WO-) transported from building (-WO-) in a stainless steel
tank. There is no validation to assure that the WFI retains it's
critical quality attributes.
o. There is no completed cleaning validation of product contact
equipment.
2. There are no written procedures, including specifications, for the
examination, rejection, and disposition of sublots of Anthrax and
Rabies.
a. Sublots are tested at the time of production, and are not
retested prior to formulation. For example, sublot AV450 was produced
in 5/95 and then used in formulation of lot FAV039 in 3/97.
b. Quarantined materials are held for extended periods.
- - For example, sublot AV216 was placed in (-W0-) on quarantine in
3/92 and was not destroyed, for low antigen content, until 5/97.
- - Sublot AV222 was placed in (--WO-) in 4/92 and was removed and
destroyed in 5/97 due to mold.
- - Sublot AV493 was manufactured in 8/96 and is still in quarantine
in (--WO--) for low antigen content.
3. Potency testing of Anthrax Vaccine requires either testing 1
finished product vial, an aliguot from the formulated bulk tank, or a
pilot bulk sample. There is no data demonstrating that these samples
are representative of the lot.
In addition, expiration dates are assigned based on the latest valid
potency test. There is no correlation between this date and formulation
of bulk or filling of the finished product.
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4. There is no written justification for redating lots of Anthrax
vaccine that have expired. "Redating" testing consists only of a
potency test. There is no documentation of testing for
container/closure integrity or container/closure compatibility for
periods up to 7 years. In addition there is no analytical testing
identifying and demonstrating the absence of degradants.
There is no written SOP for redating, including when redating will be
performed in order to extend the expiration period.
- -Lot FAV023 was tested for redating 2 times in 1997 and failed. It
also failed twice on stability in 1997. It is scheduled to be retested
for redating on 4/21/98.
Anthrax lots that are submitted for redating are released by CBER with
alternate lot numbers to indicate the redate. However product is not
labeled with the alternate lot number.
- -Lot FAV020 (initial date of potency 4/13/93) was submitted for
redating as FAV020-1 and labeled on 2/6/98 as FAV020
For Anthrax Vaccine lots #FAV008 through #FAV016, the firm unpacked the
vials from the cartons and removed the labels (the labels were removed
by soaking in alcohol). The firm does not have a written procedure for
performing unpackaging of vials and removal of labels. Also, the firm
does not have documentation of performing reconciliation of the vials
before and after this operation.
5. Regarding the firm's stability program for Anthrax:
a The firm's stability program did not start until 1997. Stability
testing consists only of performing release tests at various intervals
and does not address product degradation. There is no justification for
placing lots manufactured as early as 1991 into the stability program.
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b. The firm does not have a system in place to investigate and
report stability failures. (All results noted below are from samples
stored at 2 - 8 degrees C. Accelerated stability test results are not
included.) For example,
- - Lot FAV010 was filled on 7/1/91 and submitted for redating on
10/11/94, having passed all potency testing. It was placed in the
stability program (zero time) on 10/7/97 and tested for potency. The
"zero time" potency for this lot is recorded as "unsatisfactory". There
is no investigation into this result nor is there any additional potency
testing.
- - Lot FAV011 was filled on 10/17/91 and submitted for redating on
10/11/94, having passed all potency testing. It was placed in the
stability program (zero time) on 10/27/97, and tested for potency. The
"zero time" potency for this lot is recorded as "No Test" having not met
the (-WO-) dilution criteria. Test records indicate it was tested for
potency 11/24/97. There is no investigation into this result nor is
there any additional potency testing. In addition, the test result for
(---------------WO------------------), dated 10/30/97 is 11 ppm.
(Specification is 15-30ppm.) This lot was not rejected nor placed in
quarantine.
- - Lot FAV013 was filled on 10/25/91 and submitted for redating on
11/22/94, having passed all potency testing. It was placed in the
stability program (zero time) on 11/12/97, and is recorded as "No test",
having an invalid test. Test records indicate it was tested for potency
on 12/5/97. There is no investigation into this result nor is there any
additional potency testing.
- - Lot FAV18 was filled on 7/28/92 and submitted for redating on
6/11/96, having passed all potency testing. It was placed in the
stability program (zero time) on 6/10/97, and is recorded as
"Unsatisfactory". Test results dated 7/7/97 indicate it failed potency
specifications. There is no investigation into
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this result nor is there any additional potency testing
- - Lot FAV022 was filled on 2/9/93 and submitted for redating on
10/15/96, having passed all potency testing. It was placed in the
stability program (zero time) on 10/7/97, and is recorded as having an
"Unsatisfactory valid test". Test results dated 10/31/97 indicate it
failed potency specifications. There is no investigation into this
result nor is there any additional potency testing.
- - Lot FAV023 was filled on 12/13/93 and passed a potency test on
3/29/94. It was submitted for redating on 4/2/97 and was placed in the
stability program (zero time) at the same time. It is reported as
failing potency on 4/2/97. It was tested again on 8/12/97 and is
reported as failing potency. A fourth potency test conducted on 10/6/97
is listed as passing by 0.01. There is no investigation into the
original result and justifying the additional testing.
- - Lot FAV040 was filled on 11/13/97 and placed in the stability
program (zero time) on 11/19/97. It is reported as having an "invalid"
potency test on 11/19/97. There is no investigation into this result
nor is there any additional potency testing.
c. The firm's SOP(s) for handling manufacturing
deviations/departures does not address when a lot should be monitored on
stability.
6. There has been no investigation into numerous "invalid" potency test
results for lots. For example:
- - Lot FAV021 was filled on 11/24/92, having a passing potency test.
It was tested again on 10/15/96 and failed potency. It was tested again
on 1/28/97 for redating and passed. There is no investigation into the
test failure nor justification for
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retesting the lot.
- -Lot FAV025 was filled on 4/24/94, having a passing potency test. It
was tested again on 4/22/97 and failed potency testing. There is no
investigation into the test failure.
- -Lot FAV028 was filled on 6/2/95. It was not tested for potency
until 7/9/96 when it failed the test. It was tested again on 8/27/96 and
passed. There is no investigation into the test failure nor
justification for retesting the lot.
- - Lot FAV041 was filed on 11/18/97. It had an "invalid" potency
test on 9/30/97. There is no investigation into this invalid test.
- - Lot FAV042 was filled on 11/21/97. It had an "invalid" potency
test on 10/29/97.
- - Lot FAV043 was filled on 12/25/97. It had an "invalid" potency
test on 11/18/97. There is no investigation into this invalid test.
- - Lot FAV044 was filled on 1/7/98. It had an "invalid" potency test
on 12/8/97. There is no investigation into this invalid test.
7. The firm's SOP (---WO--- 36 spaces of WO!----------)dated 9/3/96,
requires that vials discarded as rejects be counted, however, it does
not specify limits for when a lot should be investigated or rejected as
a result of this lot reconciliation. For example:
-- Lot FAV016 had 6579 vials rejected due to particulates
during post filling inspection. These particulates were not
identified, nor was an investigation conducted. The batch was
released.
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- - Lots FAV028, FAV031, FAV033, and FAV038 had 3323, 2441, 2509,
1347 vials rejected respectively for low volume during post filling
inspection. There was no investigation conducted.
- - Lot FAV035 had 409 vials rejected for faulty closure during
post filling inspection. There was no investigation conducted.
8. The firm does not have specifications for time limits at which the
product can be exposed to room temperature conditions during filling,
labeling and packaging operations (repeat observation).
- - Lot PAV036 was at room temperature for (-WO-) hours and then
the filling operation was aborted, it was placed back in the
refrigerator (deviation report #97DAV34).
In addition, there is no stability information regarding product
exposure to room temperature. Prior to 1996 the firm did not monitor
the length of time at which the product was exposed to room temperature
conditions during the filling operations (FAV009-FAV015).
9. The firm's procedures for Environmental Monitoring of critical
production areas do not require that additional cleaning and increased
sampling be performed when environmental action limits are exceeded.
When environmental monitoring action limits are exceeded during filling,
investigations do not consider environmental monitoring results during
production of sublots, sterility test results of sublots and sterility
test results of final product. In addition, when a sterility retest is
performed during stability testing, no investigation is performed. For
example:
- - Lot FAV029 was filled on 8/11/95 and passed sterility testing.
On 9/23/97, during stability testing (--WO?)
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it required a sterility retest. The contaminant was identified as
Penicillium species. The product passed a retest. Production records
for sublots used to produce FAV029 indicate (----WO----) were bulked to
produce the lot. Sublot AV383 had an initial sterility failure on
5/17/94 (Rhodocoddus species); Sublot AV390 had an initial sterility
failure on 7/19/94 (Propionibacterium acnes). Both sublots passed
sterility retest. There is no environmental monitoring data from
preparation of the sublots. On 8/11/95, during filling of lot FAV029,
environmental monitoring testing found the following on critical
surfaces: Cladosporium species, Alternaria species, Micrococcus
species. Bacillus subtilis, Staphylococcus saprophyticus,
Staphylococcus epidermidis, and Staphylococcus capitis.
- - Lot FAV032 was filled on 10/26/95. On 7/28/97, during stability
testing (-WO-) it required a sterility retest. The contaminant was
identified as Penicillium species. The product passes a retest. The
lot was formulated on 9/21/95. Two operators performing the formulation
exceeded action limits on viable monitoring. Four CFU were sampled from
one of the operator's gloves and identified as Penicillium species.
- - Lot FAV035 was filled on 2/5/97. On 8/11/97, during stability
testing (--WO--) it required a sterility retest. The contaminant was
identified as Bacilius cereus. The product passed a retest. The lot
was formulated on 1/9/97. Environmental monitoring exceeded action
limits in the gowning area prior to formulation identifying the
following: Staphylococcus capitis, Micrococcus species, Bacillus
coagulans, and Corynepacterium species. In addition, photohelic gauges
were out of range during this time indicating insufficient air pressure
in critical areas.
--The firm does not trend multiple contaminations with
microorganisms in sublots. For example, between 4/94 and 2/95,
(----WO---) were produced of which 23 were discarded due to some kind of
microbial contamination. Lots FAV029, FAV030 and FAV031
Begin page 11:
were whole or partially formulated from those sublots not discarded in
this time period. In January and February 1997 of 12 consecutive
sublots produced, 5 were discarded for microbial contamination. The
others were included in lot FAV039. In September and October 1997, of
(---WO---) produced, 6 had contamination and two of those were retested
and released for formulation. The remaining sublots were formulated
into FAV045 or FAV046.
10. Recording of data in building (-WO-) from room (--WO--) log books
in room (-WO-) is accomplished by viewing the results through the UV
pass box and is not checked for accuracy prior to discarding the
original data.
11. Specifications for the release of sublots were not formally
established until 1995.
12. The firm does not have a current SOP for environmental monitoring
in the Anthrax production facility. The firm has replaced it's previous
environmental monitoring SOP with a centralized procedure that
references area specific monitoring plans. However, the Anthrax
specific plan has not been finalized.
Anthrax Building Facilities Conditions:
13. In room(s??) (------WO--------) of the Anthrax production facility,
we observed peeling paint, exposed duct and pipe work, insulation
peeling off the pipes, and rusty steam and gas lines.
14. Compressed air used to perform positive pressure transfers of sterile
products (Anthrax and Rabies) is central plant air and ?? is not
monitored. The (-WO-)micron filters used at the point of use are not
integrity tested.
15. Rooms (-------WO------) are not environmentally controlled. There
was no active environmental monitoring of aseptic
Begin page 12:
manufacturing activities until 1996. During the 1996 production of
sublots, more than half of the sublots had environmental monitoring
excursions. There was no tracking of these events and no significant
corrective action taken until 10/96.
16. Plant steam is used for sterilizing production vessels and
glassware in buildings (---WO----) and is not monitored or controlled.
17. Poor facility arrangements exist for aseptic processes in building
(-WO-) room (-WO-) in that media is made, dishes washed, equipment and
glassware autoclaved, as well as the production processes of
fermentation, inoculation, and harvest all occur in this one room
simultaneously.
18. Regarding cold storage of critical seed stock:
a. In the Anthrax production suite the logs for
refrigerator/freezer(--------------------------------
--------WO---------------------------------) are incomplete. The logs
do not match the refrigerator/freezer contents. The Anthrax
refrigerator/freezer contained unlabeled vials.
b. There is no segregation of the master spore concentrations and
the working spore concentrations of both the virulent and old (---WO---)
strains in (----WO---) Anthrax production and potency testing
facilities.
c. The keys for all refrigerator/freezers in building
(-----WO------) and building (-WO-) were found on top.
19. There is no SOP for change over in building (-WO-) Anthrax
Biosafety Cabinets (BSC). Both inoculum preparations and aseptic sublot
formulation occur in these hoods.
(-----------------------WO----------------)
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