Document text
To: F
ile STN BL 125742/0 – COVID -19 mRNA Vaccine
From : Christian D. Lynch, CSO, CBER/O D/BOS
Through: Lori Peters , Branch Chief, CBER/OCBQ/DMPQ /MRBI
John Eltermann, Director, CBER/DMPQ
Mary A. Malarkey, Director, CBER/OCBQ
CC: Ramachandra Naik , Ph.D., RPM , CBER/O VRR/DVRPA/CMC3
Michael Smith, Ph.D., RPM, CBER/OVRR/DVRPA/CMC3
Laura Gottschalk, Ph.D., RPM, CBER/OVRR/DVRPA/CMC3
Kat hleen R. Jones, Ph.D., Biologist, CBER/OCBQ/DMPQ/MRBI
Ek aterina Allen, Ph.D., CSO, CBER/ OCBQ/DMPQ/MRBII
Anissa Cheung, CSO, CBER/OVRR/DVP
Debra M. Emerson, CSO, ORA/OMPTO/OBPO/BPIS
Sponsor : BioNTech Manufacturing GmbH in partnership with
Pfizer, Inc.
Product : COVID -19 mRNA Vaccine (BNT162/ PF-07302048) , COMIRNATY™
Indication: Prevention of COVID -19 in adults ≥16 years of age
Subject : Original Biologics License Application (BLA) STN 125742/0 Review
Memorandum – BioNTech Manufacturing GmbH in partnership with Pfizer,
Inc.: to provide for review of the responses to the 483 Inspectional
Observations issued during the July 19 – 23, 2021, Pre-License Inspection
(PLI) of Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC
(referred to as Pfizer Andover; FEI: 1222181) . Pfizer Andover was
previously authorized for manufacture of BNT162b2 drug substance for
the COVID -19 mRNA vaccine in Building (
) and Building ( under Emergency Use Authorizations
(EUAs ) 27034.0 and 27034.76, respectively .
Review Recommendation
Revi
ew of the firm’s responses (Amendment STN 125742/0.25 and Amendment STN
125742/0.60) to the Form FDA 483 confirmed that the proposed corrective actions for
Observation Nos. 2 – 13 appear to be acceptable and may be evaluated during the next
routine inspection. Regarding Observation No. 1, the firm’s response to this
Observation was evaluated by the Product Office in a sep arate memo randum (dated
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FDA-CBER-2021-5683-1150499
August 12, 2021, from Anissa Cheung) and found to be adequate for follow up during
the next inspection.
Summary
The Center for Biologics Evaluation and Research (CBER) and Office of Regulatory
Affairs conducted a PLI of Pfizer Andover from July 19 – 23, 2021, in support of the
review of original BLA STN 125742/0. Pfizer Andover was previously authorized to
manufactur e BNT162b2 drug substance for the COVI D-19 mRNA vaccine under EU As
27034.0 and amendment 27034.76 for
The inspection team consisted of Kathleen R. Jones (KRJ), Ph.D ., Biologist, Lead
Inspector , CBER/DMPQ/MRBI , Ekaterina Allen (EA), Ph.D., CSO,
CBER/OCBQ/DMPQ/MRBII , Anissa Cheung (AC), CSO, CBER/OVRR/DVP , and Debra
M. Emerson (DME), CSO , ORA/OMPTO/OBPO/BPIS. At the conclusion of the PLI, a
thirteen-item Form FDA 483, List of Inspectional Observations, was issued to the firm.
On July 30, 2021, Pfizer submitted a written response (Amendment STN 125742/0.25)
that outlined the proposed corrective actions to address each inspectional observation.
The firm’s responses to Observation Nos. 2b, 2c, 6, and 9c were also discussed during
a teleconference on August 17, 2021. Additional updates and commitments from the
teleconference were submitted by the firm via email on August 17, 2021 and received
under Am endment STN 125742/0. 60 on August 18, 2021. The information provided in
Amendment s STN 125742/0. 25 and STN 125742/0.60 w as reviewed, summarized, and
assessed in this memorandum by Christian D. Lynch (CDL), CSO, CBER/OD/BOS.
Where applicable, initials of inspection team members were incorporated i f the
inspector/investigator provided comments regarding the appropriateness of the firm’s
response to a specific observation.
Review of the information contained in the preceding respons es revealed that the
corrective actions appear to be acceptable and may be evaluated during the next
routine inspection.
Review of Pfizer’s Responses to the FDA Form 483 Observations
Pfizer ’s response to the FDA Form 483 observations was submitted on August 2, 2021,
in Amendment STN 125742/0.25. A summary of the original 483 Observations (in
italics), Pfizer ’s responses (in regular text), and reviewer (CDL )/inspector/investigator
comments (in bold/italics) is provided below:
Observation No. 1 (written by AC)
1. There is insufficient data to support product quality prior to the release of BN
T162b2 drug substance (DS) batch manufactured at Pfizer
Andover on
was derived from in
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FDA-CBER-2021-5683-1150500
batch , and a deviation ) was initiated due to the multiple
control limit excursions during the of The
were below the control limits and the between
and overall both exceeded the control limits. The
affected batch was manufactured with a process that deviated from the
validated process parameters, and your firm planned to put this batch on stability to further assess product quality. However, DS batch was not put on
stability until July 22, 2021. The affected DS batch was released on
and formulated into drug product (DP) lots
at on . All DP lots were released on
.
Reviewer’s Comments (CDL): The fir
m’s response to this
observation was reviewed by the Product Office in a separate
memorandum and found to be “adequate” with corrective actions
For more
information regarding this assessment, please refer to the August
12, 2021, memorandum from Anissa Cheung.
Observation No. 2 (wri
tten by DME )
2. There is inadequate quality oversight in that:
Pfizer’s Response
The firm’s response acknowledged that manufacture of BNT162b2 DS is
controlled principally by validated computerized systems:
• located in Building of the
Andover Manufacturing Facility
• , located in Building .
For , phase parameters are enter
ed and
per batc
h record instructions . u tilizes the input parameters to
execute phase parameters as designed. The firm also confirmed that
records all entries and actions performed. Per
, the batch summary report, which includes the batch alarm report
and manipulation reports, is reviewed by both Operations and Quality
Assurance (QA) during executed batch record review.
Regarding ,
the firm confirmed that all recipes within this recipe-based
system are reviewed and approved by Subject Matter Experts (SMEs) and Q A in
accordance with
Operators are responsible for loading
approved recipes per batch record instructions . Per
,
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FDA-CBER-2021-5683-1150501
Operations personnel are required to review manipulations
(such as temporary changes to running batch active steps as per
), the event log, and the batch alarm report.
The firm also noted t hat
requires that QA review
the associated manipulations, the event log, and the
batch alarm report as part of the executed batch recor d review process . The firm
acknowledged that QA does not review the Batch Summary Report as
part of its executed batch record review “in all instances ”; however, QA does
review the Batch Summary Report in certain scenarios (e.g., when the report is
linked to an investigation or during impact assessment reviews ).
a. The electronic data/reports from associated with the ,
and process used in the manufacture of BNT162b2
drug substance are not reviewed by Quality during batch record review or
prior to batch release.
Pfizer’s Response
The firm’s response reiterated that governs QA review of
batch related operating parameters and monitoring data. The firm also
confirmed that the batch alarm report for each batch is attached to
the executed batch record. As noted above, any manipulation, the event log, and the batch alarm report that is generated
during batch processing must also be documented in the executed batch
record for QA review. Additionally, the firm reiterated that QA is part of the
review and approval process for the recipe build, which includes the review and approval of alarm setpoints and alarm criticality. Although t he firm
claimed that the established batch recor d review pr ocess described above
ensures full QA oversight of batch execution and any associated eventful
operations (such as deviations and alarms), they committed to revise (and
enhance) to include additional instructions for
system review (which includes the Batch Summary Report) as part of
the executed batch record review process . The due date for this action item
is September 30, 2021.
Reviewer’s Response (CDL and DME): The
firm’s commitment to
revise to include additional instructions for
system review (which includes the Batch
Summary Report) is considered an acceptable response for enhancement of their executed batch record review process.
b. Duri
ng processing of BNT162b2 drug substance lot , the
were , and the operator
switched from for . The
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FDA-CBER-2021-5683-1150502
operators performed a calculation for , and this calculation is
not recorded in the batch record. The printout from the
system documents yet the batch
record documents were performed . The record
was reviewed and approved by QA on .
Pfizer’s Response
The firm’s response confirmed that during processing of BNT162b2 DS l ot
were performed via . As values
were the oper
ators switc hed from
(in accordance with ,
in To account for the the
operators and engineering determined an appropriate amount for
however, the firm acknowledged that t his calculation was not documented
in the batch record. On , investigation was initiated
to address the documentation di screpancy. Although not documented in the
batch record, the calculation that was missing from the batch
record was reconstructed using data documented in
and the executed batch record at the time of execution. During Operations
and Quality Assurance batch record review (per ), the correct
was confirmed using the data and the executed
batch record for . The firm also confirmed (as part of batch
record review) that met all acceptance criteria as
documented in the executed batch record.
The fir
m’s response noted that the process for
was documented in the executed batch record. The firm also clarified
that during continues to run in the background (though
it is not controlling the additions ). Consequently, continued to log
data for additions during this event; however, the firm noted that
this “ data is rendered ex traneous data in The firm also confirmed that
after operators take manual control of the , the primary source
data is the executed batch record.
In response to this Observation, the firm committed to revise to
include clarified instructions for implementing operations and
documenting calculations within the batch record. The firm also committed to revise , to include
clarification that after operations are switched to , only the
data captured in the batch record should be used for evaluation against established acceptance criteria. The due date for both action items i s
September 15, 2021.
Reviewer’s Comments (CDL a nd
DME) : Initial review of this
response found it to be deficient in that it failed to address that
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FDA-CBER-2021-5683-1150503
can: (1) display that a was when it was
performed ; and (2) generate extraneous data (a potential
data integrity issue) after operators switch from to
control for . During the teleconference on
August 17, 2021, FDA discussed these concerns with the firm and
asked what actions would be taken to correct the concerns prior to
the next inspection. The firm acknowledged our concerns and
agreed to submit an updated response for this observation. In
Amendment STN 125742/0.60, the firm committed to conduct an
evaluation to determine whether can document (internally) any
change from mode and cease recording of data
(following a change to mode ). The firm’s updated response
is considered acceptable and the Agency recommends
.
c. BNT162b2 drug substance lot was manufactured in
The record was reviewed by Operations in and by
Quality on . All were . There was no
notation in the batch record until that
exceeded the allowable .
Pfizer’s Response
The firm’s response indicated that DS Batch No. , the first batch
of BNT162b2 produced in , was manufactured in per master
batch record 513AM , version 2.0. The executed batch record was reviewed
by Operations in and by Q A in . The firm noted
that at the time of batch execution, the was a target and not a
control limit per the batch record, and therefore, no further action was taken
for the exceeded value.
To provide assurance that
the routine production process remains in a state
of control, the was changed to a control limit (per
in
mas
ter batch record 513AM , version 3.0 (Effective date:
). As part of the process verification monitoring outlined in
, the for batch No. was noted as
On , investigation was initiated to assess and
document the impact to batch No. . The firm confirmed that on
, a notation was made (in the executed batch record for
) referencing this investigation. The firm’s response also noted
that th is investigation was closed on ; however, no information
was provided regarding the outcome of the investigation.
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FDA-CBER-2021-5683-1150504
The firm’s response confirmed that they will continue to monitor the
BNT162b2 DS manufacturing process via the process
manufact
uring verification program and the change control process (for
management of validated parameter changes ).
No additi
onal action items were reported for this observation.
Reviewer’s Comments (CDL and DM E): Initial review of the firm’s
response found it to be deficient in tha t no corrective actions were
noted regarding the failure of Operations and QA to identify that the
exceeded the target ) during production
of batch No. . During the teleconference on August 17,
2021, the firm was asked if any corrective actions had been initiated
regarding QA oversight of the batch record review process. The firm initially reiterated much of the information regarding the
target and the subsequent switch to a control limit ; however, after
FDA clarified that our general concern with this response was the
lack of corrective actions regarding QA oversight of batch record review, the firm acknowledged that no corrective actions had been
initiated. FDA recommended that the firm consider w ays to enhance
their process verification monitoring and batch record
review process. The firm acknowledged our recommendation and
agreed to evaluate potential enhancement of these processes prior
to the next routine inspection.
Observation No. 3 (wri
tten by EA)
3. The following deviation investigations were found deficient. Deviation
, (COVID): ) and ,
(COVID): : was found in
during its visual inspection
. On both occasions the was cleaned and released into manufacture.
No sampling of and no cleaning verification was
performed or is required after re-cleaning.
Pfizer’s Response
The firm ’s response indicated that
, defines the visual inspection process to evaluat e
wetted process equipment surfaces for cleanliness. In brief, all visual inspection
outcomes are assessed as described to include identification of
observed in equipment” (which results in a failed visual inspection). If the visual
inspection fails due to the presence of , an investigation is initiated
per , and a team of Subjec t
Matter Experts (SMEs) co mprised of QA, Engineering, Maintenance, and Utilities
(EMU), and Operations is notified. The SME team then conducts a preliminary
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FDA-CBER-2021-5683-1150505
assessment , which typically includes a review to: (1) confirm that the qualified
cleaning cycle ran as expected; (2) determine if any mechanical failures
occurred; (3) determine the duration between the completion of t he cleaning
cycle and identification of the ; and (4) qualitatively determine the
Based on the review of data collected above, QA will
then document in the investigation whether operations can proceed or not.
According to the firm’s response, inves tigations and
(initiated on and , respectively ) were both initiated in accordance
with following detection of . As part of these
investigations, the firm reviewed t he dirty hold time established as part of the
cleaning performance qualification (CPQ). In both events , the amount of time the
was in the system was t
han the maximum dirty hold time.
Consequent
ly, sampling of the was not deemed to be a
requirement by the SME team. Regarding investigation , recleaning
of the was performed as the amount of time the was present
in the system was . The firm noted that per
, stored is given a
expiration from the date it is dispensed. While this instruction is specific
to dispensed , the SME team that performed the
preliminary assessment leveraged this instruction and directed Operations to
reclean the . A cleaning verification was not performed as the amount of
time the was in the was than the qualified maximum
dirty hold time established for the . For investigation ,
recleaning of the was not performed as the amount of time the
was present in the system was . was again
leveraged by the SME team to make this determination. The firm also reported
that a (approximately was observed in (and
subsequently ) the prior to commencement of manufacturing
operations .
The SME pr
eliminary assessments performed for these investigations result ed in
QA endorsement to proceed with manufacturing operations ; however, the firm
acknowledged that documentation of these assessm ents was deficient and
committed to revise procedure to include a more standardized
approach for performing and documenting the SME preliminary assessment of
the potential impact to manufacturing equipment following a
. Specific revisions to the SOP will include the requirement to
assess and document the following:
The due date for this action item is August 31, 2021.
A study will also be conducted to determine which conditions will trigger cleaning
verification following identification of This study will include an
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FDA-CBER-2021-5683-1150506
evaluation of the potential impact of
and the requirement for cleaning verification. Based on the outcome of the
study, the revision of will also include additional instructions for
utilizing key factors when performing and documenting risk assessment. The
due date for this action item is November 30, 2021.
Reviewer’s Comments (CDL): The f ir m’s commitment to revise
to include a more standardized approach for assessing and
documenting the potential impact to manufacturing equipment
following a appears to be an
adequate enhancement of their investigational procedures.
Observation No. 4 (wri
tten by KRJ)
4. Per , cleaning
validation has not been performed on the (Building
). The is stored in a and as a result, a
trend occurred in ( ); noted by identification of
Pfizer’s Response
The firm’s response indicated that the design and use of the Building
requires storage of both the
between manufacturing batches. Consequentl
y, the opportunity to collect
samples for
i
s limited. The firm also noted that the ability to collect
from the surface of the is impractical as the
would need to be dismantled. As a result, the system is subject to cleaning
verification via in-process monitoring rather than the cleaning cycle being
validated (via execution of a cleaning performance qualification protocol ).
The firm confirmed that i s subject to routine process
monitoring controls which ensure, among other things, detection of
. The trend referenced in the observation was
detected with these controls and subsequently evaluated as part of investigation
(initiated on ). The investigation determined that
the most probable root cause for the trend was certain areas
of the not being
. The root cause for the inadequate of the
was identified as an , which resulted in a
being unexposed to the
The firm also reported that as the was
subjected (per procedure) to a
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FDA-CBER-2021-5683-1150507
. Based on the findings of this investigation, the following corrective and
preventive actions were implemented:
The preceding actions were implemented on , as outlined in
change control . A supplemental validation protocol,
, was then executed by the firm to demonstrate the
effectiveness of the corrective and preventive actions. As part of this protocol ,
the firm monitored the BNT162b2 DS batches that were manufactured
post-remediation. Results of the monitoring for all samples from these
batches were reported as (per validati on report
). Based on these results, the firm concluded that the
manufacturing process steps within the scope of the study effectively maintained
control with no additional mitigation warranted.
The firm also reported that an effectiveness check (child action record to
)
was initiated on July 28, 2021, to document the effectiveness of the
mitigation strategy implemented per change control . For
this evaluation, the firm reviewed s ample results from operations in
for batches of BNT162b2 DS manufactured from
. F
ollow ing review of these data, the firm concluded
that the equipment continues to operate as expected and no indication of a
trend has been observed since implementation of the corrective and
preventive actions.
Reviewer
’s Comments (CDL and KRJ ): Although the results from the
effectiveness check appear to confirm that the corrective actions
implemented in response to the trend have been
effective in maintaining control of ,
Observation No. 5 (wri tten by EA and KRJ )
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FDA-CBER-2021-5683-1150508
5. Cleaning of reusable product -contact parts using is not validated.
Cleaning verification of such parts is inadequate as it is limited to testing of
. Verification of surface and
tes
ting is not performed routinely.
Pfiz
er’s Response
The firm’s response indicated that the Andover Cleaning Master plan (
) takes into consideration that operator
dependent processes like are less controllable and repeatable when
compared with equipment syst em parameter dependent processes (and thus are
to be verified and not validated as a cleaning procedure). The Cleaning Master
Plan also highlights that when cleaning by is required, the strength of
the process requires a combination of stringent development studies, specific
procedural instructions including disassembly of equipment, operator training and
assessment, and inclusion of analytical and visual verification of acceptable
cleanliness.
According to the firm, a development cleanability assessment was executed
using the BNT162b2 vaccine process residues to understand both the
characteristics of the process residues that are intended to be cleaned and determine the cleaning capabilities of the procedure used by operations personnel. The firm’s assessment concluded that the
operation can clean the process residues from equipment surfaces and that the
BNT162b2 vaccine process residues can be visually detected on processing
equipment within the . The development cleanability
assessment included representative materials of construction (MOCs) for
equipment used to manufacture BNT162b2 vaccine and used worst -case
cleaning conditions to appropriately challenge the procedure (
) used by operations personnel.
The firm also noted that verification of the effectiveness of the
operation (to include testing) is
performed on a basis. Additionally, periodic monitoring is performed
on equipment cleaned via under the formal cleaning monitoring program . This program is governed by
Cleaning monitoring provides ongoing assurance that t he cleaning
process is operating as expected in accordance with predetermined acceptance
criteria. Cleaning Monitoring includes
, as well as visual inspection. The acceptance
criteria are pre-established and include the following:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150509
The
firm confirmed that the most recent c leaning monitoring of the
operation was executed in March 2021. Although all results obtained from
this monitoring activit y (including were within specified
acceptance criteria, the firm committed to execut e a pre-approved protocol to
generate a larger data set (inclusive of sampling) to
further support verification of the operation performed in This
protocol will verify cleaning operations performed on dirty
equipment utilized in using all testing required in the
verification. The results obtained from the executed protocol will be summarized in a formal summary report by November 30, 2021. Per the firm, if the data from the study indicate that a change in cleaning monitoring is needed, a subsequent
commitment will be initiated.
Reviewer’s Comments (CDL): Execu
tion of a pre-approved protocol
to compile a larger data set (inclusive of
sampling) to further support verification of the operation
performed in appears to be an acceptable response for this
observation. It is recomm ended that
Observation No. 6 (w
ritten by KRJ)
6. Cleaning efficacy studies are inadequate (Building ), in that the firm has not demonstrated consistent efficacy with and a contact time of
. ;
(Building ) demonstrates efficacy on all surfaces, however,
(Building demonstrates
a lack of efficacy on all surfaces except with a contact time of
Pfizer’s Respo nse
The firm indicated that disinfectant efficacy studies were performed to qualify
disinfectants for use in facilities (including ).
These studies are summarized in report
The firm also confirmed that the
efficacy studies included surfaces and that are representative of
Building and support the contact times applied to Building .
Per the firm, r esults from the independent studies, which included different
surfaces and challenged different , showed that a greater
than reduction could be achieved with a contact time for
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
) )
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) ( )
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4), (b) (5), (b) (7)(E)
(b) (4), (b) (5), (b) (7)(E)
FDA-CBER-2021-5683-1150510
The firm also acknowledged that a comprehensive review of the Building
disinfectant efficacy program (including was conducted over the last
several years. Following this review, a contemporaneous study employing
improved study design and methodologies was executed and summarized in
. Per the firm, results
from this study “also demonstrated efficacy of a contact time for
consistent with studies supporting the same for Building .” The
firm concluded that the combined data from the multiple studies/reports support a
contact time for in both facilities . Consequently, no
corrective actions were reported for this observation.
Reviewer’s Comments (CDL and KRJ): During t he teleconference on
August 17, 2021, CBER reported that discrepancies were noted
between
(approved on April 28, 2021), and
effective
April 30, 2015. Specifically, the report indicated that
was effective with a contact time of
while noted that was not effective
with a contact time of (except on . The firm
acknowledged these discrepancies; however, they also noted that
the study was performed by on
the coupons (versus of the coupons as per ).
The fir
m that the on the coupons
allowed for evaporation and appeared to be the preferred method for conducting thes e studies (when compared with . The
firm also referenced an additional study that was
performed with improved design and methodologies for Building
(including by on the coupons . As
noted above, results f rom this study demonstrated that
is effective with a contact time (which is consistent with
the studies supporting the same for Building ).
It should be noted that an additional discrepancy was di
scovered
(post -inspection) regarding the effectiveness of
against on flooring and wa
ll
surfaces.
Specifically, reported that
demonstrated effectiveness with a contact time of , while
noted that was not effective with a
contact time of . During the August 17, 2021,
teleconference, FDA confirmed that the contradictory information
regarding was also due to study methodology
Based on the clarified information regarding
studies , the firm’s response is
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150511
considered acceptable
Observation No. 7 (wri tten by KRJ)
7. The ISO - are not monitored to ISO
standards. Specifically,
a. monitoring is not routinely performed.
b. monitoring limit is set a instead of .
c. (Building ; is within an ISO room.
Pfizer’s Response
The firm’s response indi cated that the Building were classified
and qualified as ISO during the execution of the Environmental Monitoring
Qualification (EMQ) per validation protocol . The objective of this
EMQ was to demonstrate that each of the current Clean Environmental Areas
(CEAs) in could meet and maintain the air and surface environmental
quality levels for Good Manufacturing Practice (GMP) based on use for a
DS fa
cility. The EM Q was also designed to demonstrate that the
facility met United States Pharmacopeia (USP) and International Organization for
Standardization (ISO) requirements. Per the firm , results from the
EMQ showed that the ISO- in met air quality level requirement s
(per ISO for
monitored under conditions. Regarding
levels, t he firm stated that quality levels are not specified per
ISO quality levels for are not
applicable to a drug substance facility. ” The firm also reported
that “ the are routinely monitored for and meet
the air quality levels of ISO requirements. ”
Despite t
he above referenced ISO qualification and routine monitoring of the
, the firm acknowledged that all ISO - in will have the ISO
designation removed and be re-classified as Additionally,
and
will be revised to reflect the new
classification of these units for a DS facility. The due date
for the preceding action items is September 15, 2021. Affected individuals will
also be retrained in accordance with site procedures.
Reviewer’s Comments (CDL and KRJ): Given that the in
are utilized for DS (upstream) operations in ISO areas, the firm’s
commitment to remove the ISO designation and re-classify these
units as ” is considered acceptable.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (5), (b) (7)(E)
(b) (5), (b) (7)(E)
FDA-CBER-2021-5683-1150512
Observation No. 8 (wri tten by KRJ)
8. Routine monitoring of the compressed air of Building does not adequately represent all points of use. Only , specifically
listed in
are routinely
monitored.
Pfizer’s Response
The firm’s response noted that at the present time, no specific regulatory
guidance documents ( or requirements ) exist regarding the number of
compressed air points of use (POUs) to be sampled or the frequency of
sampling. However, the firm did referenc e recommendations such as the ISPE
Good Practice Guide, which recommends testing every on a
rotating basis from representative sample locations.
The firm also indic
ated that
outlines the routine monitoring
program for the compressed air system. As part of this program,
were designated as representative sample locations with
a sampling frequency of (based on Validation Protocol
:
. Per (Section 5.1), the sample site selection followed a
approach that was based on
T
he fir
m also confirmed that
Following the compressed air PQ, the firm implemented routine monitoring at
sample . Monitoring results are
compared against the following quality levels:
Table 1: Quality Levels for Compressed Air
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150513
ISO Class Water / Oil
Detection TAP Action
Level
0.5 µm
Particles / m3 TAP Action
Level
5.0 µm
Particles / m3 Active Air
Action Level
cfu/m3
Resul
ts from routine monitoring of sample valve locations
showed that all samples met quality levels for the period from
March 7, 2019 – May 7, 2021. Based on these results, the firm concluded that
the compressed air system in Building is operating in a state of control
(based on only sample locations); however, they also acknowledged that
will be revised to include a requirement that all
locations be tested each The due date for this action item is August 31,
2021. Relevant individuals will also be trained in accordance with site
procedures.
Reviewer’s Comments (CDL): The f ir m’s commitment to revise
t o include a require ment for sampling of all
is con sidered an acceptable response for
enhancement of their monitoring program.
Observation No. 9 (wri
tten by EA)
9. The environmental program (EM) program in is deficient in ensuring that
the cleanrooms are operating in a state of environmental control:
a. No prospective EM performance qualification (PQ) of classified areas or PQ of was performed to ensure EM specifications in operation are met.
Pfizer’s Response
The firm’s response indicated that the envir onmental monitoring
performance qualification (EMPQ) of was performed in accordance with
The EMPQ
included days of sampling ( ) in
Room and under conditions. This was followed
by days of sampling ( ) in Room
and under conditions . All sampling was
performed per , Environmental Monitoring Program for
Building which includes sample locations, action levels, and required ident
ifications. The fi rm also
confirmed that the conditions referenced above were achieved in
production Room (ISO by allowing personnel into the room to
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
) )
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150514
operat
ional equipment.
Results from the EMPQ (captured on
) showed that all samples met acceptance criteria (with no action
level excursions and only one result above the alert level ) and were
approved by Q A on December 24, 2020 (prior to performing operations ).
Additional sampling of Room and was performed from
December 28, 2020 – January 2, 2021, under conditions (and in
accordance with site procedure ). Release of for use
was documented in change control .
Although it was reported that the EMPQ included , and
additional sampling of , the firm acknowledged that the EMPQ
of the was not performed under true conditions as there was
no activity in the at the time of sampling. The firm also
acknowledged that during review of change control , it was
revealed that the EMPQ was not executed with a pre-approved protocol
(as required per ) or summarized in a final report . On June 30,
2021, investigation was initiated to document and investigat e
the deviation from . The root cause for this event was
identified as an isolated human error with no impact to the EMPQ or product quality (as all sampling was performed in accordance with
established procedures). A summary report,
was
written and approved on July 23, 2021.
In response to the observ
ation, the firm committed to revise to
include defined c
onditions that should be
executed
during the portion of an EMPQ. will also
be revised to include appropriate documentation requirements to capture
activities within the EMPQ protocol and final
report. The action due date for the revisions to is August 31,
2021. The firm also committed to perform an EMPQ of and
(in under predefined conditions by September
15, 2021.
Reviewer
’s Comments (CDL): The f ir m’s commitment to revise
and per form an EMPQ of
(in under predefined conditions appear s to
be acceptable response for this observation.
b. Routine m
onitoring of ISO area is performed on a basis.
Pfizer’s Response
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150515
The firm’s response indicated that the EMPQ for controlled
classified production areas was executed from December 16 – 21, 2020
(with increased sampling conducted from December 28, 2020 – June 2,
2021). The firm also confirmed that routine EM was initiated on January
4, 2021, at a frequency defined in
Analysis of the routine EM data from January 4 – June 30, 2021, revealed
that all samples total) had results within quality levels (below alert or
action levels) for all test types
collected from ISO areas .
In response to the observation, the firm committed to implement a protocol
for increased sampling (at a frequency of ) for a
period in the ISO areas. Results from this study will be
evaluated to determine an appropriate sampling frequency for the ISO areas. The target date for completion of this study is December 15, 2021. Relevant individuals will also be trained on any sampling changes
in accordance with established site procedures.
Reviewer’s Comments (CDL): The fir
m’s commitment to
conduct an increased sampling study in the ISO
areas is considered an acceptable response to address the
concern s regarding EM in these areas. It is recommended that
c. Duri
ng a walkthrough on 7/22/2021, the door to the Control Room
was observed opened to manufacturing (ISO through the duration of the walkthrough. Room is classified as controlled not
classified and is not monitored.
Pfizer’s Response
The firm’s response acknowledged that a communication error occurred
during the inspection regarding classification of c ontrol room
Specifically, it was communicated (in error) that control room
is a Controlled Not Classified (CNC) area. The firm’s response
clarified that c ontrol room is actually classified as an ISO area.
The firm also noted that as control room and adjacent room
have the same ISO classification and a neutral pressure
differential , the room air cascade and air quality should not be
impacted. The firm also acknowledged that the doors to ancillary room s
should not be left open.
(b) (4
(b) (4
(b) (4)
(b) (4)
(b) (4)
(b) (4
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (5), (b) (7)(E)
FDA-CBER-2021-5683-1150516
In response to the observation, the firm committed t o implement a protocol
for increased sampling (at a frequency of for a
period in the control room . Results from this study
will be evaluated to determine an appropriate sampling frequency for the
ISO areas. The target date for completion of this study is
December 15, 2021.
will also be
revised to ensure that all doors to ancillary rooms (including are
not left open. Attention activators will also be applied to doors within
to remind personnel to close doors behind them. The due date for the
SOP revision and application of attention activators is August 31, 2021.
Relevant individuals will be trained on the preceding revisions in
accordance with established site procedures.
Reviewer’s Comments (CDL and EA): The f irm’s commitment
to conduct an increased sampling study in the
control room is considered an acceptable response to address
the concerns regarding the EM program in this area. It is
During
the teleconference on August 17, 2021, the firm was
asked about their EM strategy for the ancillary ISO rooms in
(including the control room). The firm indicated
that an updated response would be submitted for this
observation. In Amendment STN 125742/0.60, the firm
committed to implement a protocol for increased sampling (at
a frequency of ) for a period in
the ISO ancillary rooms. The compiled data will be
evaluated to determine an appropriate routine EM strategy (to
include sample types and frequency) for all the ancillary ISO
rooms in (including the control room ). The due
date for completion of the increased sampling study is Decem ber 15, 2021.
The firm’s updated response is
considered acceptable to address the observation
Observation No. 10 (w ritten by EA)
10. On the HVAC supplying was shut down for preventive
maintenance, which resulted in pressure differential of room to drop to
relative to the outside non-controlled non-classified
corridor at 2:25 AM. The room was not cleaned until and
environmental monitoring (EM) of the room was not performed to ensure that the
(b) (4)
(b) (4)
(b) (4)
) )
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (5), (b) (7)(E)
(b) (5), (b) (7)(E)
(b) (5), (b) (7)(E)
FDA-CBER-2021-5683-1150517
room returned to ISO state until . Between
the room was used for processing of drug substance batches
all of which were processed into drug product and
released to US and international markets.
Clean status of the room is not verified or documented in the batch record. The firm allows up to of HVAC shutdown time until an additional cleaning
needs to be performed. There is no data to support that room
continuously meets its EM specification for any time after HVAC shutdown. No product impact assessment was performed.
Pfizer’s Response
The firm’s response c onfirmed that the heating, ventilation, and air conditioning
(HVAC) systems that supply the manufacturing areas are qualified per
During initial qualification, each HVAC unit is required to
undergo multiple tests per ISO -
. This includes a test, which is designed to
identify the time frame required for each HVAC unit to reduce the
concentration by after being exposed to a source of
challenge. The firm reported that HVAC , which serves
passed particulate t
esting (in under as well as all other
HVAC
qualification tests, thus demonstrating that ISO standards were
achieved.
The firm al
so noted that
, includes an allowance for a loss of air flow for up
to prior to requiring an additional facility sanitization. The firm
confirmed that this allowance is based on historical data documented i n
A Closure Risk Assessment (CRA) was also per formed (and became effective on
December 31, 2020) per
to document and understand the operational details and
environmental controls around the unit operations
(and related processing steps performed within The assessment noted
that i n-process monitoring is employed to detect the entry of
cont
aminants into the manufacturing process. During the production of each
batch, samples are also taken at pre-defined points from
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
) )
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150518
R
egarding the events surrounding the observation, the firm noted that a facility
sanitization was performed at on , per ,
Scheduling, Frequency and Order of Sanitizing for
. No personnel were present within the suite
and no manufacturing operations occurred during the HVAC shutdown. The
HVAC unit serving was then shutdown at approximately
to perform planned maintenance. The planned
maintenance was performed to and of terminal HEPA
filters. Temperature and relative humidity inside stayed within
specification throughout this period. The HVAC unit was returned to service and
all pressure cascades and air change rates were re-established at
Closed operations within were initiated at approximately . The
firm noted that this event did not require additional sanitization as the loss of
airflow did not exceed the allowance outlined in . The firm
also confirmed that the subsequent facility sanitization was performed on
.
According to , audi ble HVAC alarm s that occur during manufacturing
operations require a comment to be entered in the Manufacturing Batch Record
(MBR) that is in process at the time of the alarm. Regarding batch Nos.
, the firm noted the QA review of the MBRs (per
) revealed that no comments
were entered in the respective MBRs as no operations were being conducted at
the time of the loss of air flow . The firm also noted that DS batch Nos.
met all in process and release specifications
(including as outlined in
and were
subsequently dispositioned with a status of released. Based on the preceding
information, the firm concluded that there was no product impact to batch Nos.
following the .
In
response to the observation, the firm com mitted to initiat e a study (by October
28, 2021) to assess the return to environmental control specification(s) per
Depending on the results of the study, may be revised to include
specific actions, such as facility sanitization and/or EM, that will be required in
response to future alarm events. An interim control to assess product impact
following an HVAC shutdown greater than in duration was also
approved on July 30, 2021 and will be documented per planned temporary change . Additionally, MBRs will be revised by September
15, 2021, to capture confirmation of cleaning status in this suite.
(b) (4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150519
Reviewer’s Comments (CDL): The firm’s commitment to revise
to include specific actions for future alarm events is
consi dered an acceptable response for this observation.
Observation No. 11 (wr itten by EA)
11. Standard operating procedures are not followed. For example,
a. On 7/22/2021 during observation of operations, cleaning of
, and dispensing of drug substance, the following was
observed in deviation from
,
and
:
i. An alarm went off due to operator to
introduce a . prohibits work
in a if it is in alarm condition.
ii. operators were over the of the
blocking the .
iii. did not cover all surfaces of the and was
contact time required per .
Pfizer’s Response
The firm’s response confirmed that at the time of the alarm conditions on July 22, 2021,
no work was being performed in . The firm also noted
that all aseptic connections required for the were
completed by the operator within prior to the alarm event. In
accordance with
,
the were
with prior to transfer into the . The
firm acknowledged that the alarm condition was triggered by the operator
to introduce the into the however, once
the were in the and the was , the alarm
cleared. The firm also noted that the introduced items remained undisturbed for the required within the (per
) before the operator attached the
.
On July
26, 2021, investigation was initiated for the alarm
condition observed within . The root cause for this event was identified as a lack of instructions (in ) regarding how to proceed
when the needs to be to add or remove items from a . As a corrective action, the firm committed to revise (Section 9.1.6
regarding alarm condition) to include instructions for what to do if the needs to be when adding or removing items from a The fir m also
committed to assess the procedure for final to determine whether the
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FDA-CBER-2021-5683-1150520
number of items transferred into the can be minimized to only those
required for open product manipulation.
will be revised (as appropriate) based on t he results of the
assessment. The due date for the preceding action items is September 15,
2021.
The firm indicated that an additional investigation was initiated
on July 27, 2021, to document the deviations to regarding aseptic
technique and insufficient work surface sanitization of . The
operator that performed the work surface sanitization of and
operations within the for this event was trained on the
appropriate SOPs ( and at the time of the deviation.
The affected operator was also interviewed and confirmed that he was aware of the requirement to not the of the (per
; however, as the was running, he
As a corrective action for this event, will be
reviewed to ensure that all key aseptic technique elements from
are included. will also be revised to include
instructions to not the of the as part
of the proper aseptic technique demonstration. Additional aseptic technique
elements will be added, as needed, based on the firm’s review. The due date
for these revisions is September 30, 2021.
Regarding work surface sanitization of the , specifies that
unit surfaces be saturated with and remain undisturbed for
however, this SOP does not require that the work surface remain
wet for the full contact time. Additionally, as a control for batch-to -
batch processing, requires a work
surface sanitization of the . The operator involved in the work surface
sanitization event was interviewed and confirmed that was
followed and that all surfaces of the were covered with . As
a corrective action for this event, the affected operator was re-trained on
on July 29, 2021, prior to performing any additional operations
within the
The firm also noted that samples from the
product for batch No. (in-process at the time of the deviation
event) met all specifications. Based on these results and the investigations,
the firm concluded that there was no product impact for batch No.
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FDA-CBER-2021-5683-1150521
Reviewer’s Comments (CDL): The firm’s commitment to revise
t o include updated instructions for
demonstration of proper aseptic technique in is considered an
acceptable response to address the aseptic behavior and events
noted in this observation.
b. c
leaning of the in was
not performed in the of July 2021 in deviation from .
Pfizer’s Response
The firm’s response indicated that investigation was initiated on
July 22, 2021, to document the deviation to regarding failure to
perfor m the cleaning of the outside surfaces of the equipment in
during in July 2021. Following identification of this
deviation, all equipment surfaces in were cleaned (on July 22, 2021)
in accordance with . also requires review of
the log sheet for completeness and accuracy (“as needed”). A retrospective
review of the sanitization logbook confirmed that no other cleanings
for had been missed. The firm also conf irmed that no environmental
or HVAC alarm excursions were reported for during the
timefram e. Based on this information, the firm concluded that there was no
impact to product quality as all in-process controls and environmental
monitoring samples were within limits.
In response to this observation, the firm committed to revise to
include remov al of the terminology “as needed” and change the requirement
for review of the sanitization log sheets from . The due date
for this action item is August 31, 2021.
Reviewer’s Comments (CDL): The firm’s commitment to revise
to include a n updat ed requirement for review of
sanitization log sheets is considered an acceptable response fo r this
observation.
Observation No. 12 ( a, c, and d written by DME ; b written by EA)
12. The following deficiencies were observed within buildings used to produce BNT162b2 drug substance as noted below :
Pfizer’s Response
The firm indicated that the Andover site is committed to ensuring facilities,
equipment , and utilities are well maintained. Site
– Maintenance Procedure,
describes the procedures used to perform preventive and corrective
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FDA-CBER-2021-5683-1150522
maintenance activities and manage and document these activities within CMMS.
The firm noted that this procedure also covers the requirements for
establishing and executing equipment maintenance tasks and schedules
applicable to equipment, instruments, utilities, facilities and systems, and the
documentation, review, and approval of maintenance records in CMMS (in
accordance with
).
The firm also confirmed that periodic self -inspection programs are in place for the
manufacturing areas and associated mechanical spaces as described in the
responses for 12a and 12b below . These inspection programs include the
identification of facility defects on walls and floors. Defects identified
during the inspection process are repaired using corrective maintenance procedures . Corrective work orders to repair surface defects are evaluated and
prioritized based on risk.
a. In Building preparation area:
i. was observed on
multiple walls.
ii. was observed in the
hallway.
iii. were observed with dust and debris on the
and streaking/raised residue down the sides and bottom of
multiple .
Pfizer’s Response
The firm indicated that
,
provides standard expectations for quarterly self-inspections of the external
condition of the equipment, general physical appearance inside manufacturing spaces , and associated mechanical spaces. According to the
firm, the last self -inspection of was performed on June 7, 2021, and
documented in report
The firm also confirmed that
, requires
cleaning of all equipment exterior s with disinfectant . After the
disinfectant contact time is achieved, the exterior of piece of equipment is
wiped with ethanol to remove any residual cleaning agent.
, Section 5.8, instructs operators to perform workspace
clearance formulation. Workspace clearance
)
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FDA-CBER-2021-5683-1150523
R
emediation
of the observed residues on the exterior surfaces of
was completed on July 28, 2021, and documented as
part of work order Nos. 1593895, 15593897, 1593908, and 1593910,
respectively. The firm also committed to revise , to include
more robust instructions for cleaning of equipment exteriors and remov al of
residual disinfectant. Additionally, the firm committed to revise
to include the following:
• Requirement for workspace clearance upon
formulation.
• More robust instructions for and surrounding
surfaces .
• Requirement for inspection of and surrounding areas to
ensure they are free of dust, debris, and residual raw material
formulation.
The firm reported that repairs to the observed in the
Building Preparation Area were completed on July 22,
2021 and documented as part of work order Nos. 1592463 and 1592462 . The
firm also confirmed that no defects were observed in DS manufacturing
and Repairs to the in the Clean Not Classified corridors
were completed on July 28, 2021 and documented as
part of work order Nos. 1593616 and 1593622.
The firm also committed to revise
, to
include instructions for personnel to identify any defects/damage that occur or
are observed between routine inspections and escalate facility maintenance
issues. The due date for this action item is September 10, 2021.
Reviewer’s Comments (CDL): As the facility was repair ed and the
firm committed to revise relevant SOPs to include updated
instructions for identifying and escalating facility maintenance
issues, the response to this observation is considered acceptable.
b. In Building
i. was observed on multiple walls inside room
ii. was observed in room
Pfizer’s Response
The firm ’s response indicated that
, provides the standard expectations
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FDA-CBER-2021-5683-1150524
for self-inspections that are required to ensure that issues are
escalated and resolved when observed. According to the firm, the last self -
inspection of was performed on July 14, 2021 and documented as
part of work order No. 1528780. The firm claimed that Operations personnel
are performing self -inspections as required per .
The firm confirmed that r epair of the in was
completed on July 23, 2021 and documented as part of work order No.
1592483. The firm also committed to revise to include an update
of the Operations responsibility section to clarify that Manufacturing personnel are responsible for escalating facility/equipment issues when observed to
ensure that these issues are resolved between GMP100 inspections .
Preventive maintenance (PM) plans will be also implemented in the site
maintenance system to assess , on a basis , the need to repair
wall and floor surface defects in suites. The f requency of this assessme nt will
be re-assessed at . The due date for the preceding action items is
September 8, 2021.
Reviewer’s Comments (CDL): A
s the facility was repaired and the
firm committed to revis e to include updated
responsibilities for escalating facility/equipment is sues, the
response to this observation is considered acceptable.
c. Residue was observed on the sides and base of multiple sample pass throughs to include , and
Pfizer’s Response
The firm ’s response indicated that
, Sections
9.1.3 and 11.9, requires disinfection of all sample pass throughs.
The firm acknowledged that the residue observed on the inside surface of the
sample pass throughs was determined to be residual disinfectant .
In response to this observation, a special sanitization request (SSR) was
issued and completed on July 27, 2021, (
) to remov e the residual disinfectant. The firm also committed to revise
, to include more robust instructions for sanitization of
sample pass through interior surfaces and removal of residual disinfectant.
The due date for this action item is September 30, 2021.
Reviewer’s Comments (CDL): Th
e firm’s response is acceptable.
d. A gap to the outside was observed on the side of the mobile platform at
the receiving dock in Building
Pfizer’s Response
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FDA-CBER-2021-5683-1150525
The firm ’s response indicated that , outlines
the procedures for control of insect, bird, rodent, vermin, and wildlife at the
Pfizer Andover, MA facilities. As noted in Section 5.11 (Pest Control Device
Inspections and Locations) , the pest control provider is responsible, in sub-
sections 5, 6, 7, 8 and 9, to “note any adverse conditions observed in the
vicinity of the device.” Section 5.11, sub-section 10, also states that “ any
conditions and observations are noted on the inspection report. The
Integrated Facilities Management (IFM) QA Pest Control Specialist, or
designee, will initiate and track work orders to address any deficiencies.”
The firm noted that the last inspection for the control devices
associated with location was completed on June 28, 2021.
According to the firm, no adverse conditions (or pest control issues) were
noted with respect to the loading dock door at location . A review
of previous inspections was also conducted and revealed no adverse trends
associated with site pest control .
The firm confirmed that the gap identified on the loading dock door at location
was repaired on July 23, 2021 and documented as part of work
order No. 1591632. The firm also committed to revise to include
addition of a step in Section 5.11 (Pest Control Device Inspections and Locations) that requires th e pest control provider to inspect doors and similar
openings for adverse conditions that could lead to pest infiltration. All
adverse conditions will continue to be documented in the pest control report.
Additionally, t he Pest Control Specialist or designee will continue to initiate
work orders to address any deficiencies. The due date for revision of
is August 31, 2021.
Reviewer’s Comments (CDL): As the doc
k door was repaired and the
firm committed to revise to include addition of a step for
inspection of doors (and other openings ), the response to this
observation is considered acceptable.
Observation No. 13 (wr
itten by DME )
13. During activities observed on 7/22/2021, an operator was
obser
ved to and subsequently material from a full and previously
opened container of . The previously opened container of
had a lid which was not fully closed, the within the
contai
ner was not closed, and there was no documentation as to when the
container had been initially opened.
Pfi
zer’s Response
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FDA-CBER-2021-5683-1150526
The firm ’s response noted that per
, partial containers
returned to the warehouse after sub-division must be closed, sealed, and
contained.
The firm also noted that
, requires that each received container be assigned a unique
reference number ( sub-batch) , which allows the Inventory and
system to provide full a transaction history (and report) for each sub-
batch. The firm noted that the transaction history report includes information
such as open date (and operator ) and negates the need for labeling of
containers. Regarding the event noted in the observation, r eview of the
transaction history report for the container of (Batch
, Sub-batch ) observed on July 22, 2021, re vealed that
this container was initially opened for subdivision on July 21, 2021.
On July 27, 2021, the fi
rm inspected 23 partial containers stored in the
warehouse for compliance with . Results from the
inspection showed that all containers were closed and all were
. T
he f
irm also committed to revise
, to include clear instructions for acceptable container
closure (following sub-division or sampling) and escalating observations of
unexpected conditions. The due date for this action item is August 31, 2021.
Reviewer
’s Comments (CDL and DME): The f ir m’s commitment to
revise to include clear instructions for acceptable
container closure and escalation of unexpected conditions is
considered a n acceptable response for enhanc ement of their raw
material management program .
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