THIS DOCUMENT LISTS OBSERVATIONS
MADE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY.
THEY ARE INSPECTIONAL OBSERVATIONS, AND DO NOT REPRESENT A FINAL AGENCY
DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING
AN OBSERVATION, OR HAVE IMPLEMENTED. OR PLAN TO IMPLEMENT. CORRECTIVE
ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS THE OBJECTION
OR ACTION WITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT
THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF YOU HAVE ANY QUESTIONS,
PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.
DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED:
PRODUCTION SYSTEM
1) Regarding control over product bioburden:
A) Per Technical Report
#UKTR/0244 dated August 30th 2006, "During the 2006 commercial campaign
[Redacted] batches of the Filtered Frozen FluMist were
manufactured. Out of these [Redacted] batches there
were 6 in-process bioburden excursions
[Redacted] involving, 8 sub-lots from a total of [Redacted] manufactured".
All of these microbial action level monovalent sub-lots/lots were released
for further manufacturing into the trivalent FluMist drug products. Microbial
organisms such as, Pseudomononas stuizeri, Enterococcus
faecalis, Escherichia coli, Staphylococcus aureus were
isolated. Below are examples of monovalent sub-lots with test results
that are above microbial action levels at the [Redacted] processing
step:
|
[Redacted] Action Level [Handwritten:
Action Level crossed, MSL 3-30-07] |
[Redacted] Action Level [Handwritten:
Action Level crossed, MSL 3-30-07] |
A/Wisconsin |
|
|
Lot 600157 [Redacted] |
12,500cfu/ml |
9,550cfu/ml |
Lot 600157 [Redacted] |
9,400cfu/ml |
9,050cfu/ml |
A/NewCaledonia |
|
|
Lot 600150 [Redacted] |
8,150cfu/ml |
7700cfu/ml |
Specification [Handwritten: Specification crossed
out and replaced with Action Limit: MSL 3-30-07] |
[Redacted] |
[Redacted] |
B) Regarding bioburden control for year 2007 FluMist campaign,
the firm has manufactured [Redacted] monovalent lots.
Of these one was aborted and the last two manufactured lots contained
bioburden levels in excess of the action [Handwritten: insert "or
alert limit" between
action and limit, MSL 3-30-07] limit, as follows:
i) FluMist monovalent lot [Redacted] possessed a bioburden
of 760cfu/ml (Action limit: [Redacted] at the [Redacted]
step
and a bioburden of 14,000 cfu/ml (alert limit [Redacted]
at the [Redacted] step. (Lot disposition has not been made)
ii) FluMist monovalent Lot [Redacted] possessed a
bioburden of 570cfu/ml at the [Redacted] stage (Alert
limits: [Redacted] (Lot disposition has not been made).
C) Examples of excursions during the manufacturing of lot 600157 are
as follows:
i) Per deviation #3089, with discovery date of April 20th 2006
eleven (11) environmental monitoring plates from the
Downstream Processing Room [Redacted] were found to
be contaminated with molds and adverse trend for the isolation of mold
was noted in the processing environment.
ii) Per Deviation # 3258, during microbial environmental monitoring
of lot 600157, action level excursion of too numerous to count (TNTC)
(Action limit [Redacted] [Handwritten: insert
plate MSL 3-29-07] were noted in [Redacted] the
trolley track floor contact on April 21st 2006.
iii) Per Deviation #3455, during [Redacted] in the [Redacted] Room
on April 25th 2006, action level excursion of 13cfu/ml [Handwritten:
cross out ml and insert plate MSL 3-29-07] (Limit [Redacted] [Handwritten:
insert plate MSL 3-29-07] was raised for an operator left hand
plate taken during [Redacted] of lot 600157.
iv) Per Deviation #3456, in the downstream processing room on April
25th 2006 action level excursion of 16cfu/ml [Handwritten:
cross out ml and insert plate MSL 3-29-07] (Limit [Redacted] was
raised for a second operator right hand plate during [Redacted] taken
during [Redacted] [Handwritten: insert plate
MSL 3-29-07] and sampling activities of batch 600157.
v) Per Deviation #3457, during the [Redacted] on April
25th of lot 600157, action level excursion of 252cfu/ml [Handwritten:
cross out ml and insert plate MSL 3-29-07] was raised for the
center of the [Redacted] table #12 in [Redacted] Room
(Limit [Redacted] [Handwritten:
insert plate MSL 3-29-07].
vi) Per Deviation #5043, during QA review, it was noted that pre-cleaning
for [Redacted] and [Redacted] pipette
controllers have not been completed on some equipment used in the harvesting
process for batch 600157.
2) Regarding investigations conducted into the above microbial action
levels of monovalent lots with high bioburden levels:
A) There is no documentation of the review of the validation of the
effectiveness of disinfectants used in the cleaning of the facility including
product contact and non-product contact equipment.
B) There is no documentation of the review of Flu Mist manufacturing
equipment cleaning validations, i.e. the [Redacted] Incubators,
Biological and Dispensing Safety Cabinets, Silicon Rubber Housing of
the Candling Lamps and Pipette Controllers.
C) No documentation that the audit of the egg supplier [Redacted] was
conducted to review the farm's sanitation practices and if actions could
be taken to minimize microbial contamination of eggs.
D) There is no documentation of the review of the same manufacturing
processing operator conducting the pre-cleaning of the manufacturing
area followed by manufacturing activities and post clean activities on
the same day. For example:
i) An operator could conduct pre-cleaning activities, harvesting of
eggs and then post-cleaning activities.
ii) An operator could conduct pre-cleaning activities, inoculation
preparation, eggs Inoculation and post clean activities.
E) There is no documentation of literature review in regards to organisms
that were isolated at the [Redacted] step and the effect
that these organisms could have if present in the released FluMist.
3) The following were observed during the set-up, sterile filtration,
and/or aseptic dispensing of A/Wisconsin Monovalent Batch 600163 in the
Dispensing Room (Room [Redacted] on March 28, 2007:
A) Operators working in the ISO Class [Redacted] (Class
[Redacted] area which supports the ISO Class [Redacted] (Class [Redacted] Biological
Safety Cabinet (BSC) (which is used to receive the sterile filtered monovalent
and to dispense the sterile monovalent into [Redacted] bottles) were observed with exposed
skin near the eye area.
B) An operator was observed cleaning his/her personal prescription
glasses in the ISO Class [Redacted] area.
C) An operator was observed to sample his/her fingers onto a touch
plate and then immediately (without re-gloving or sanitizing gloves)
pick up the container within the BSC containing the sterile filtered
monovalent in order to mix it.
4) Regarding disinfectant effectiveness studies:
A) The acceptance criteria of [Redacted] reductions for C.
albicans and A. niger of the diluted [Redacted] used
as a disinfectant in the facility was not met during the disinfectant
effectiveness studies dated November 2003. The [Redacted] disinfectant
effectiveness study that was suppose to demonstrate sporicidal effectiveness
was also found not effective on dried coupon of A. niger,
However, the firm continued the [Redacted] use of [Redacted] to
disinfect its manufacturing facility since the disinfectant validation
of April 2003.
B) There are no assurances that the currently used [Redacted] disinfectant
is effective against fungi and molds. Per Protocol #VF-41283 dated May
2nd 2002, for the disinfectant effectiveness study for [Redacted] the
assay test method validation was for [Redacted] recovery
rate. However, the data obtained during the performance qualification
demonstrated that the minimum of [Redacted] acceptance
criteria established per protocol (VF -41282R) was not consistently obtained
during the positive control recovery studies. As such, the post execution
acceptance criteria of the studies were changed to recovery of within [Redacted] of
the inoculums content.
C) No disinfectant efficacy study has been conducted for the [Redacted] solution
used to decontaminate outer egg shells at time of virus harvest.
5) The FluMist Master Production Record (batch record) lacks specificity.
For example,
A) The validated [Redacted] hold time for the [Redacted] Ultracentifuge
(Equipment #s [Redacted] rotor is not specified as per
the Master Production Record for B/Malaysia Batch 600169.
B) No time limit has been established for the [Redacted] step
as per the Master Production Record for B/Malaysia Batch 600169.
6) Sterile filtered FluMist monovalent bulks are dispensed into [Redacted] bottles
at the following volumes: [Redacted] for storage at [Redacted] Regarding
the [Redacted]study justifying the container closure
integrity of these containers (Study LT-060174 & 060175):
A) The study did not evaluate the effect of the [Redacted] fill
volumes on the integrity of these containers.
B) The lowest torque documented as applied to the test container caps
in the study was [Redacted] The allowable range in actual
use as per the Master Production record for B/Malaysia Batch 600169 is [Redacted]
7) Regarding warehousing activities:
A) There is no written procedure for the control of keys in the warehouse
area (Room [Redacted] On 3/21/2007 a secure storage
area (caged area) in Room [Redacted] containing process
material was observed secured with a padlock. In order to open this lock
an employee was observed obtaining a key to a nearby key lock box (located
in Room [Redacted] fiom another employee. The key to
the secure storage area padlock was retrieved fiom this lock box. There
is no written procedure governing this process.
B) There is no written procedure governing the control of access to
a MedImmune warehouse area used for the receipt and storage of raw materials
located at the [Redacted] The [Redacted] facility
is not owned or operated by MedImmune.
C) On March 21st 2007, rejected products were observed in reject bin
commingled with released and unreleased products in the QC liquid media
storage area in the warehouse room [Redacted]
FACILITIES AND EQUIPMENT SYSTEM
8) Regarding Product Contact Cleaning validations, there is no documentation
of cleaning validations for the following product contact equipment in
accordance with the associated SOPS. For example:
A) Cleaning validation of the silicone rubber housing per SOP #UKP0154
dated March 27th 2007. Technical Report study of R/0264/10/00 dated December
6th 2000 note that the highest level of contamination was recovered from
the silicon rubber housing candling lamps.
B) Cleaning validation for the [Redacted] per SOP
#UKP0143 dated November 11th 2006. The [Redacted] is
used to score the specific pathogen free (SPF) eggs prior to harvest.
C) Cleaning validation of the [Redacted] Pipette Controllers
per SOP #UK0142 dated October 25th 2006. The pipette is used in the dilution
of inoculum and to extract the allantoic fluid fiom the eggs.
D) Cleaning validation of the [Redacted] Filter Integrity
Tester per SOP #UK0144 dated March 22nd 2007. The integrity tester was
noted as the root cause of the source of 11 microbial plate mold excursions
during the manufacturing of lot 600157.
E) No validation studies were conducted to the support cleaning of the [Redacted]
9) Not all manufacturing ISO Class [Redacted] rooms,
Biological Safety Cabinets and manufacturing equipment have documentation
of cleaning validations. Per Validation Report #VL-400003-PQP-AI-R1 dated
March 20th 2007 provided as cleaning validation documentation for the
above ISO Class [Redacted] Biological Safety Cabinets
states: "this validation was to demonstrate that the Production
Process Rooms Heating Ventilation & Air Conditioning (HVAC) System,
Identification Number [Redacted] located in the floor
utility area of MedImmune's [Redacted] Bulk FluMist
Production Facility, in Speke UK continues to operate in a safe and effective
manner in association with MedImmune procedures for material, personnel
and equipment flow following the modifications performed to the [Redacted] facility".
However, the number of microbial surface samples taken during the above
Validation (#VL-400003-PQP-AI-R1) were the same number of samples taken
under normal monitoring process of these areas per SOP #UK0192, Environmental
Monitoring Program for MedImmune [Redacted] Manufacturing
Facility. The following areas were covered by Validation Report #VL-400003-PQP-AI-R1:
A) ISO Class [Redacted] (Class [Redacted] Dispensing
Room
B) [Redacted] ISO [Redacted] (class [Redacted] Downstream
Microbiological/Dispensing Safety Cabinets and [Redacted] Laminar
Flow units
C) [Redacted] and [Redacted] Incubator
Units
D) [Redacted] Eggs Chiller Rooms
10) Regarding the Purified Water System:
The firm discontinued the microbial sampling of [Redacted] sampling
points for the Purified Water System on November 2006 even though the
microbial levels at these sample points were higher than the prior site
incoming water sampling point microbial level. Per Technical Report #UKTR/0203
dated March 6th 2006, "During the performance qualification of the
purified water system it was evident that the limits that had been set
for points [Redacted] were not achievable and therefore
no limits were applied". (Set limit of [Redacted] Microbial
sample results of the discontinued valves compared to the prior incoming
city water valve [Redacted] with microbial limit of [Redacted] are
as follows:
|
2005 max CFU/ml |
2006 Max CFU/ml |
[Redacted] |
18,400cfu/ml |
790cfu/ml |
[Redacted] |
10,000cfu/ml |
2,100cfu/ml |
[Redacted] |
10,000cfu/ml |
2,400cfu/ml |
[Redacted] |
194cfu/ml |
160cfu/ml |
QUALITY SYSTEM
11. Per SOP #MSP-QA-0056 dated September 6th 2006, titled: Deviation
Reporting and Management, manufacturing deviations are to be closed within
a defined period of [Redacted] calendar days of initiation
unless otherwise noted through documentation requests. However, there
is no defined period for the closure of corrective and preventive actions
that are implemented as the result of deviations that are to be closed
within [Redacted] calendar
days. It was noted that from March 2006 to March 2007 that the firm had
261 deviations. The Corrective and Preventive Actions (CAPA) associated
with and [Handwritten: cross out "and" MSL 3-29-07] 66
(25%) of these were closed within [Redacted] days. For
the remaining 195 (75%), some remained open for up to 8 months. For example:
i) Deviation #4953 discovered June 28th 2006 regarding batch #300639
showing scanning errors on SAP for bottle [Redacted] which
was identified as [Redacted] should have read [Redacted] Similarly, [Handwritten: insert
comma after Similarly MSL 3-29-07] bottle of [Redacted] the
same batch identified as [Redacted] should have read [Redacted] The
deviation was created on June 29th 2006 and the deviation portion of the
investigation was closed on July 10th 2006. However, the CAPA portion
remained opened for 8 months and was not closed until February 9th 2007.
ii) Deviation #3234 with discovery date of April 27th 2006 regarding
three objectionable organism excursions for hand plates from one operator
was created on April 27th 2006. The deviation portion was closed on July [Handwritten: cross
out July MSL 3-29-07] May 24th 2006. However, the CAPA portion
remained open for 6 months and was not closed until October 6th 2006. [Handwritten:
MSL 3-29-07]
iii) Deviation #5028 with discovery date of July 3rd 2006, regarding
three microbial excursions raised for environmental monitoring of the
Disinfectant makeup Room was created on July 5th 2006. The deviation portion
was closed on August 14th 2006. However, the CAPA portion remained open
for 6 months and was not closed until February 6th 2007.
LABORATORY CONTROL SYSTEM
12) Raw data generated in the Quality Control Laboratory is recorded
onto uncontrolled data sheets. For example QC release test data for B/Malaysia
Monovalent Batch 600169 was recorded onto forms with no tracking or serial
number or other apparent means of control other than a date stamp showing
the date the forms were generated.
13) SOPs used in the testing of FluMist Monovalents lack specificity.
For example:
A) SOP UKC0220 Version 2.0 entitled "Response to Central Chart
Recorder Alarms by Quality Control Department" does not specify
the amount of time Quality Control Laboratory incubators, refrigerators,
and freezers may be out of specification for temperature or humidity
before a deviation must be written for expected alarm conditions.
B) Growth promotion testing of microbiological media is not necessarily
performed under conditions consistent with the actual use of the media.
For example, SOP UKC0043 Version 10.0 entitled "Growth Promotion
and Sterility Testing of Microbiological Media" indicates that [Redacted]
Media (used for water testing) and [Redacted] Media
(used for environmental monitoring) are incubated for [Redacted] depending
on organism. SOP UKC0167 Version 6.0 entitled "Microbiological Analysis
of Water" indicates
that [Redacted] agar cassettes are to be incubated [Redacted] SOP
UKC0004 Version 14.0 entitled "Receipt and Testing of Viable Environmental
Monitoring Samples and Reporting of the Monitoring Results" indicates
that [Redacted]
14) Regarding Aseptic Processing Simulation of Sterile filtration of
CAIV-T (Cold Adapted Influenza Virus-Trivalent):
A) There is no documentation in the [Handwritten: line
to insert "media fill" between the and batch, MSL 3-29-07] batch
records or SOP #UKC0278 dated February 2nd 2007 titled: Performance
and Evaluation of Aseptic Processing Simulation of Sterile Filtration
of CAIV-T, regarding the performance of planned, unplanned and or worst
case interventions during any of the aseptic media fills that has been
simulated.
B) There is no documentation of batch records review for unusual occurrences
during normal aseptic processing for consideration/incorporation into
media fill simulations as interventions.
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