Document text
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
1 of 86 TABLE OF CONTENTS
SUMMARY .............................................................................................................................. 1
ADMINISTRATIVE DATA ....................................................................................................... 2
PERSONS INTERVIEWED .................................................................................................... 2
BACKGROUND AND HISTORY ............................................................................................ 2
WALKTHROUGH .................................................................................................................... 3
MANUFACTURING OVERVIEW ........................................................................................... 4
OBSERVATION OF OPERATIONS ...................................................................................... 5
QUALITY SYSTEMS .............................................................................................................. 9
FACILITIES AND EQUIPMENT SYSTEMS ........................................................................ 19
MATERIALS SYSTEM .......................................................................................................... 42
PRODUCTION SYSTE M...................................................................................................... 44
LABORATORY CONTROL SYSTEM .................................................................................. 51
COMPLAINTS ....................................................................................................................... 59
ADVERSE EVENTS ............................................................................................................. 59
RECALL PROCEDURES ..................................................................................................... 60
OBJECTIONABLE CONDITIONS AND MANAGEMENT RESPONSE ............................. 60
REFUSALS............................................................................................................................ 76
GENERAL DISCUSSIONS WITH MANAGEMENT ............................................................ 76
EXHIBITS COLLECTED ....................................................................................................... 80
ATTACHMENTS ................................................................................................................... 84
SUMMARY
(This section w ritten by KRJ)
A pre -license inspection of this drug substance manufacturing facility at Wyeth BioPharma
Division of Wyeth Pharmaceuticals, LLC., in Andover, MA (FEI:1222181), was conducted
July 19 – 23, 2021 under eNSpect assignment #204656. The inspection was led by the
Center for Biologics Evaluation and Research (CBER) Division of Manufacturing and
Product Quality (DMPQ) with assistance from the Office of Vaccines Research and Review
(OVRR) and the Office of Regulatory Affairs ( ORA). The inspection covered BNT162b2
drug substance manufacturing operations for BioNTech Manufacturing GmbH’s Biologics
License Application (BLA 125742/0) for the COVID -19 Vaccine, mRNA [COMIRNATY ]. The
pre-license inspection was based on Inspection of Biological Drug Products (CBER)
7345.848 Compliance Program. This inspection was limited to the operations of the
BNT162b2 drug substance, no other products were covered during this inspection. The profile class covered is Vaccine Bulk Product (VBP).
FDA-CBER-2021-5683-1150528
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
2 of 86 The previous FDA inspection of the facility, a pre-approval inspection in support of BLA
761118/0 for the drug substance of Adalimumab (biosimilar to Humira®) was conducted by
CDER from 4/29/2019-05/03/2019, resulted in the issuance of a three-item Form FDA 483,
List of Inspectional Observations. Deficiencies identified included: (1) Written procedures
are not followed or are inadequate to ensure control over drug substance manufacture and
laboratory operation; (2) Facilities, equipment, and utilities are not adequately maintained; and (3) Corrective action to mitigate an insect incursion into Building and Building has
not been effective. Due to time constraints, the corrective and preventive actions taken by
the firm in response to the Form FDA 483 were not discussed with the firm and should be followed-up on the next surveillance inspection.
The current inspection covered the firm’s Quality, Production, Facilities and Equi pment, and
Laboratory Controls systems, to manufacture the BNT162b2 drug substance (DS). A
thirteen (13) -item Form FDA 483 (Attachment) was issued to the firm at the end of the
inspection on July 23, 2021 for the following observations: (1) There is insufficient data to
support product quality prior to the release of BNT162b2 DS batch manufactured
at Pfizer Andover on ; (2) There is inadequate quality oversight; (3)
Deviation investigations were deficient; (4) Cleaning validati on has not been performed on
(Building ); (5) Cleaning of product -contact parts
using is not validated; (6) Cleaning efficacy studies are inadequate (Building
(7) The ISO - are not monitored to ISO
standards; (8) Routine monitoring of the compressed air of Building does not adequately represent all points of use; (9) The environmental program (EM) program in
is deficient in ensuring that the cleanrooms are operating in a state of environmental
control; (10) Clean status of the room is not verified or documented in the batch record after a preventive maintenance that resulted in a lack of pressure differential; (11) Standard operating procedures are not followed; (12) Facility deficiencies observed; and (13)
Documentation of raw material storage is inadequate.
Verbal observations were also made at the conclusion of the inspection and are found in “General Discussions with Management” Section. The firm’s management stated that they
would provide a response to the inspectional observations within 15 business days. No refusals were encountered, and no samples were collected.
ADMINISTRATIVE DATA
(This section written by KRJ )
Inspected firm: Wyeth BioPharma Division of Wyeth Pharmaceuticals, LLC
FEI:1222181
Location: 1 Burtt Road
Andover, MA 01810
Dates of inspection: 19 - 23 July 2021
Days in the facility: 5
(b) (4)
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2 of 86 Participant s: Kathleen R. Jones, Lead Inspector , CBER /DMPQ (KRJ)
Ekaterina Allen, Inspector CBER /DMPQ (EA)
Anissa Cheung, Product Specialist Inspector , CBER /OVRR
(AC)
Debra M. Emerson, Investigator ORA/ Team Biologics (DME)
The inspection team presented its credentials to Mr. Jo nathan Tucker at the beginning of
the inspection on July 19, 2021. The FDA Form 482, Notice of Inspection (Attachment)
was issued to Mr. Tucker, the most responsible person at the site. Following the
presentation of the credentials , the firm presented an overview of the process, facility, and
organization.
Each inspector wrote her assigned sections of this report, as identified by her initials.
The lists of attendees present at the opening meeting and at the closeout meeting are
provided in Exhibits KRJ -01 and KRJ-02, respectively. During the inspection closeout
meeting on July 23, 2021, a 13-item FDA Form 483 was issued to Mr. Tucker (Attachment).
All FDA personnel were present daily and onsite during the inspection.
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC., which is solely owned by
Pfizer , and will be referred to as the firm, Pfizer, and Wyeth throughout the report.
PERSONS INTERVIEWED
(This section written by KRJ )
A list of attendees for the opening/quality systems meeting ( Exhibit KRJ -01), closeout
meeting ( Exhibit KRJ -02), and subject matter experts and personnel observed during tours
(Exhibit KRJ -03) were provided.
BACKGROUND AND HISTORY
(This section w ritten by KRJ)
The Wyeth Andover, MA site consists o f buildings on
approximately 70 acres. The buildings include the following:
• Building , Clinical Liquid Dose Manufacturing (LDM),
Quality Control (QC) laboratories, and a cell bank
• Building
• Building Central energy plant and cogeneration plant
• Building and warehouse
• Building Analytical research and development (ARD) QC and Pfizer Global
Supply (PGS) laboratories
• Building Research and development
• Building Warehouse
• Building Drug Product (DP) Development
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Business hours are from 8:30 - 17:00, Monday through Friday. Manufacturing operations in
Building are currently performed in from
but can as is needed to meet the manufacturing schedules . Manufacturing
operations in Building are currently performed
There is a that solely performs facility sanitization for and
There are a total of Pfizer employees (both part time and full -time employees)
and contractors on site.
The Andover site is shared between Pfizer Global Supply (PGS) and Pharmaceutical Sciences BioTherapeutics (BT xPS; Pharm Sci), each with distinct quality units. PGS is
responsible for commercial and clinical DS intermediate, DS, and production. PGS consists of QC anal ytical and microbiology laboratories in
Buildings and working cell bank storage in Building Pharm Sci is responsible for
product development, process development, and clinical manufacturing functions. Pharm
Sci consists of Building LDM, ARD laboratories in Building and cell banking in Building
COVID -19 Vaccine-Andover Responsibilities are delineated as follows:
Description Pharm Sci PGS
Working Cell Bank Storage X
Manufacturing* X
Testing (In -process and Release) X X
DS Manufacturing X X
DS Manufacturing * X
DS In -Process Testing X X
DS Release Testing X X
DP Release Testing X X
DS Stability Testing X X
DP Stability Testing X X
Raw Material Testing X X
*Has not been submitted under Emergency Use Authorization (EUA) or commercial BLA
Detailed organization charts were provided for both PGS ( Exhibit KRJ -05) and Pharm Sci
(Exhibit KRJ -06). See Exhibit KRJ -04 for the opening and quality systems presentations.
WALKTHROUGH
(This section written by EA and DME )
Due to COVID -19 related social distancing restrictions and limits on personnel, no
traditional walkthrough for orientation purposes was performed. Instead, inspector(s)
(b) (4)
(b) (4)
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4 of 86 performed walkthroughs of various areas of the facility as they observed different
manufacturing and QC operations. Specifically, the following facility areas and testing
laboratories were inspected:
Building
• areas (refer to Observation #12 for noted concerns) -
wal
kthrough performed by Inspector Emerson on 7/19/2021 and by Inspectors Allen
and Emerson on 7/21/ 2021
•
process for lot and sample - walkthrough
performed by Inspectors Allen , Cheung, and Emerson on 7/21/ 2021
• : DS , and DS - walkthrough performed
by Inspector Jones on 7/21/ 2021
• ARD Micro Laboratory (refer to Laboratory Section below for additional information)
– walkthrough performed by Inspector Emerson on 7/19/2021
• ARD Quality Control (QC) Laboratories (refer to Laboratory Section below for
additional information) – walkthrough performed by Inspector Cheung on 7/19/2021
• Packaging of DS lots for shipment to drug product
manufacturing – walkthrough performed by Inspector Emerson on 7/21/2021
• Warehouse including temperature-controlled units (refer to Warehouse
Section below for additional information and Observation #12 for noted concerns) –
walkthrough performed by Inspector Emerson on 7/19/ 2021
• Dispensing of material used in f orm ulation of
(refer to Observation #13 for
noted conc
erns) – walkthrough performed by Inspector Emerson on 7/22/2021
Buildi
ng
• area - walkthrough performed by Ins pector Allen on 7/19/2021
•
refer to Observation #12 for noted concerns) walkthrough performed by
Inspector Allen on 7/22/ 2021
• PGS Micro Laboratory (refer to Laboratory Section below for additional information)
– walkthrough performed by Inspector Emerson on 7/19/2021 and 7/202/21
MANUFACTURING OVERVIEW
(This section written by AC)
distinct manufacturing buildings are employed for DS manufacture at the Andover site:
and The process at both sites is highly similar and involves the same
process steps as described below ( Exhibit AC -1). All unit operations are performed at
(b) (4)
(b) (4)
(b) (4)
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(b) (4)
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(b) (4)
(b) (4)
(b) (4)
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5 of 86 OBS
ERVATION OF OPERATIONS
in
(This section written by EA)
During a walkthrough of on 7/21/21 performed by EA, AC, and DME, I (EA)
observed reagent lot performed
by an operator in . See Discussion Item EA -3 and Observations 6 and 7
regarding use and environmental monitoring of were passed out of
the facili ty via a passthrough (see Observation 12c regarding state and cleaning of pass
throughs ).
(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-2021-5683-1150533
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Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
6 of 86 (D S
(Written by KRJ)
On 7/21/2021 I observed DS in
Prior to Inspector KRJ exiting explained the rest of the process
operations. Drug substance
See Discussion Item KRJ -1.
area
(This section written by EA)
On 7/19/21, I performed a walkthrough of area which is one of the
areas (another is that support the manufacturing operations in The area is
(b) (4)
(b) (4)
(b) (4), (b) (6), (b) (7)(C)
(b) (4)
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(b)
(4)
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(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150534
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Andover, MA EI End: 07/23/2021
7 of 86
At
the time of the walkthrough, a number of
area. Pfizer explained the staged raw materials are those allocated and pre-
ordered based on the manufacturing schedule, approximately a in advance. Software
program, , is used for inventory management and release of reagents. Reagents are
I requested that
, use the system to locate a recently cleaned . I inspected
which had been cleaned on 7/16/ 2021 and confirmed t he was visually
.
The supporting area associated with is used for cleaning of non-product
contact equipment to support . None of such equipment is .
The is additionally used for cleaning of product -contact part s in support of
other products manufactured in other than Any such parts are cleaned in
are cleaned inside
which was confirmed during walkthrough. No objectionable observations were
noted during walkthrough of area.
(DS
(This section written by EA)
On 7/22/2021, I (EA) gowned in to observe the following operations in DS
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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(b) )
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(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150535
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(b) (4)
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9 of 86 QUALITY SYSTEMS
Quality Unit
(This section wr itten by KRJ)
I reviewed the , effective 02/24/2021
(PGS). The quality systems elements are as follows:
1.) Process Performance and Product Quality Monitoring System
2.) Investigations and Corrective and Preventive Action (CAPA) System
3.) Change Management System
4.) Management Review of Process Performance and Product Quality
5.) Management of Outsourced Activities and Purchased Materials
6.) Management of Change in Product Ownership
7.) Additional Quality System Elements and Processes
I also reviewed the Pharmaceutical Science Quality Plan: Pharmaceutical Science Small Molecule (PSSM), BioTherapeutics (BTx), Global Clinical Supplies (GCS), and Quality Assurance Pharmaceutical Sciences, approved on 04/02/2020. The quality sys tems
elements are as follows:
1.) Quality:
Management Controls: QA roles and responsibilities, governance, and
notification to management
Regulatory: Regulatory inspections, internal audit program, regulatory
submissions, and recall/stock recovery
Change Management : Change management/control
Vendor/Supplier Management: Third party management
Disposition: Batch Record Review/Release
Knowledge Management: Quality system manual, document control, records
management, and data integrity
Deviations: Deviations/investigations and complaint/adverse event
management
Personnel: Training/learning system
Risk Management: Quality risk management and medical device quality risk
management
2.) Facilities and Equipment: Design and construction, maintenance, calibration,
environment controls, pest control, security, and cleaning/sanitation/
contamination control .
3.) Laboratory: Stability testing and monitoring, expiry/use by testing, laboratory test
methods/testing, sample management, reference standards, and specifications .
4.) Validation: Validation life cycle management, qualification/requalification,
validation/revalidation, and computer systems .
(b) (4)
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10 of 86 5.) Materials: Materials control, receipt and sampling, supply chain security, returned
goods, retention samples, and warehousing/distribution/logistics .
6.) Production: Master/production batch records, manufacturing, aseptic processing
controls, environmental moni toring, and rework/reprocessing.
7.) Packaging/Labeling: Master/executable batch records, packaging, labeling, and
repackaging/relabeling.
8.) Development: Formulation development, process development/design control,
specification development, analytical method development, packaging
development, labeling development, technology transfer, and medical device
design controls .
No objectionable o bservations were identified.
Deviation/CAPA Management
(This section written by KRJ)
On 07/20/2021, I discussed deviation management with the following people:
•
•
•
•
•
•
We discussed , ,
effective
02/24/2021 (PGS); ,
Effective 08/05/2020 (PGS); and
, effective 01/28/2021 (Pharm Sci). The process is the
same, but timings are slightly longer in Pharm Sci . Non-conformance events that occur in
manufacturing, testing, packaging, labelling, handling, or disposition of drug substance are classified as MIRs. MIRs are document ed in s
ystem. Incidents need to
be docum
ented in QTS within one business day. If the root cause and scope are known
and no product impact is confirmed, then an Event Report (ER) is created. ERs have the
primary document completed, and further analysis may not be required. CAPAs may not
be required as well. If the root cause or scope are unknown, or if there is any product
impact , the incident needs to be classified as a Quality Action Report (QAR). QAR s require
process mapping and thorough evaluation, historical review, in-depth root cause analysis,
and CAPAs. CAPA effectiveness is governed by
, , effective 02/26/2021 (PGS) and
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
FDA-CBER-2021-5683-1150538
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11 of 86
,
effective 05/08/2020 (Pharm Sci). QARs also include final impact
assessments and Quality Assurance (QA) product disposition decisions. Events must be
classified within business days, and QTS records must be closed within calendar
days. Extensions are allowed with QA approval based on an interim report. Additionally, a Notification to Management (NTM) is generated for significant product quality or regulatory compliance issues. I was told that in practice that any BNT162b2 related QAR generates
an NTM.
On 07/20/2021, I spoke with
and about
NTM. We discussed , , effective
11/04/2020 (PGS) and
, , effective 12/21/2020. NTM is a
mechanism to escalate an event to management and broader as events are then evaluated
by quality review teams. Quality review teams can be site specific or can be global for any Pfizer facility performing similar operations. Pharm Sci will coordinate with PGS leadership if the need for a quality review team is warranted. Quality review teams are governed by
, ,
effective 09/16/2020. No objectionable observations were identified.
Deviation Review
(This section written by AC)
Ten deviations related to the during the reaction
in and were reviewed by Inspector Debra Emerson and I. I focused only on
deviation , and Inspector Emerson covered all of the deviations . Deviation (
) was initiated on due to the multiple control limit excursions during
the of DS batch . The
Not compiling the control limits for
could have an impact on quality for the affected DS lot. Therefore,
the firm decided to enroll this affected DS batch on stability because of the potential impact
on product quality. CAPA was opened to facilitate the enrollment of this batch into
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
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12 of 86 the stability program per Protocol ; howev er, this batch has not been placed
on stability as of . The CAPA was only executed on after we
discussed this deviation with the firm. See FDA Observation #1 for additional details. See
the “Computerized Systems” section below for details surrounding the deviations.
(This section written by KRJ)
I reviewed QAR / P F-07305885 / batch / DS ,
opened on 04/12/2021. On 04/09/2021 during execution of batch (
the failed the test. Per
, , effective 01/27/2021, the
can be tested a maximum of times . The failed to have an acceptable
result times. The batch was per
and became batch
The root cause was determined to be
material, as this lot of used had a rate than previous lots. A
complaint was opened with the vendor and the will be sent to the vendor for further analysis. Addi tionally, this lot is put on stability per , and the
feasibility of using
will be updated as appropriate. No objectionable observations were identified.
Change C
ontrol Management
(This section written by KRJ)
On 07/20/2021, I discussed change control procedures with
. We
discussed , , effective
12/16/2020. I was told that Pharm Sci defaults to PGS’s change control SOP. Change
controls are documented and tracked in Quality Tracking System (QTS) for both Pharm Sci
and PGS. Change control consists of the following steps:
• Change Identification Phase: Includes the business process steps to identify a
change control .
• Change Development Phase: Includes recommended business process steps to plan and consult with stakeholders .
• Change Creation Phase: Includes determining scope of the change along with creating a draft change record.
• Change Assessment and Pre-Approval Phase: Includes evaluation of the change by the functional area impact assessors and quality. Change i mplementation cannot
occur until QA has pre-approved the change control.
• Change Implementation Phase: Includes executing and documenting
implementation activities including releasing for GMP use with a phased release
approach.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (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)
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13 of 86 • Change Post Approval and Closure Phase: QA approver verifies that all
actions/deliverables have been successfully completed. The change is closed once
any remaining activities have been verified as complete.
Temporary and permanent change controls are treated the same. Temporary change controls can incorporate multiple line items for such items as updated procedures, interim reports, or to reevaluate risk assessments. A temporary change control can operate in an
implement/approval state and is considered closed when everything is reverted back to the
original state. Any changes with potential multi -site impact are escalated to the Biotech
Change Review Board (BCRB). The BCRB meets , and all Pfizer affected sites are
present and discuss the change. The implementation timing is decided during this meeting
and is coordinated so that any lot manufactured in one area with the change will not be released until the change is implemented at both “sites”. However, each individual “site” is responsible for their individual change control. No objectionable observations were
identified.
Biotech Change Review Board (BCRB)
(This section written by KRJ)
I discussed the Biotech Change Review Board (BCRB) with
on 7/21/2021. There is only one
, effective
02/14/2017) that governs the BCRB as it is a Pfizer global board. Section 7.1 Background
point B4 defines membership into the BCRB. This includes Quality Operations Product Leader(s) for product(s) covered, site(s) change control chairpersons, Global Chemistry,
Manufacturing and Control personnel, Operations personnel, and a chairperson. This
ensures that any change that would affect product manufactured in one Andover “site” would be communicated to and implemented by the other Andover “site”. No objectionable observations were identified.
Change Control Review
(This section written by KRJ)
I discussed the temporary change control and risk assessment to manufacture BNT162b2 in with on 7/19/2021
and 7/20/2021, as well as
and on 7/19/2021. The temporary
change control ( ) contained 43-line items that include but not limited to
updating standard operating procedures, implementation of cleaning validation, adding
quality agreements. The line items associated with mitigated the risks
identified in , ,
effective 03/02/2021 in order to bring BNT162b2 into No object ionable
observations were identified.
Document Control Management
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Andover, MA EI End: 07/23/2021
14 of 86 (This section written by KRJ)
On 07/20/2021 and 07/21/2021, I discussed document control with
and
We discussed
, , effective 03/01/2021
(PGS) and
, 06/22/2021. I was told that the processes are nearly identical,
but the systems used in document control are different. In general, documents are created,
reviewed, approved, effective, superseded, and obsoleted . Any document that impacts
functional areas, has to be assessed if a regulatory affairs review is required. If so, then it
would be reviewed by the BCRB. Documents are periodically reviewed every
If a control print is required, then a reconciliation is also completed and reviewed at least
. If there is a red lined version as part of a temporary change control, Pfizer Global
can see both documents in the system but it is clearly delineated. No objectionable
observations were identified.
QA Batch Numbering (This section written by KRJ)
On 7/21/2021, from Pharm Sci and I
discussed
, ,
Effective 04/23/2021. Batch numbering for is generated. Batch numbers
are a combination of letters and numbers and the formula is
are the last of the production year.
is the Suite Identifier (for BNT162b2 it is for are the product
c
ode. identifies the process step. is the batch number for campaign, and
would be sequential process steps (e.g., three sequential see lab records for scale up).
is used for multiple .
I
spoke with from PGS on 7/21/2021 regarding
batch number. We discussed
, effective 11/25/2020. Batch number can be
generated batch number s are created similarly as in
assignment of batch records/batch number is performed Pfizer wide, so
sequential batches may not have sequential batch numbers. No objectionable
observations were identified.
QA Batch Release (This section written by KRJ)
On 7/21 /2021, I discussed batch release with
We discussed
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (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)
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15 of 86 effec tive date 06/03/2021 (PGS), and
,
effective 12/21/2020. Batch disposition starts with review of all batch records by QA ,
including raw material s and equipment status compliance. A check for open investigations,
change controls, and CAPAs is performed. Open change controls are acceptable if they
are implemented with restriction (QA approved). QA is responsible for providing final sign-
off on the DS batch records to permit release for DP manufacture. No objectionable
observations were identified.
Quality Agreements (This section written by KRJ)
I reviewed
, , effective 0202/2021 (Pharm Sci);
, effective 06/30/2021 (PGS); and
, effective 04/14/2021 (PGS).
The general process is to determine if a quality agreement is required, determine the
appropriate quality agreement template or form, customize the template, complete a cross -
functional stakeholder review, negotiate responsibilities (may involve Quality), and
sign/archive. Quality agreements are good for the lifetime of the product; however, the agreements undergo an review. Typical services covered in a quality agreement include, but are not limited to:
• Partial or full product manufacture
• Primary/Secondary Packaging
• Warehousing, Distribution
• Cell bank production and storage
• Testing associated with manufacture, product release, and stability
• Testing to support investigations or v alidations
• Sterilization
I discussed the quality agreement between the Pharm Sci and PGS quality units with
on 07/20/2021. The quality
agreement between the quality units indicates that equipment validation, maintenance, calibration, change control systems, pest control, and cleaning validation (revalidation) are the responsibility of PGS system. It also denotes required cross talk between the
quality units. Additionally, I reviewed the following quality agreements:
• Pharm Sci and PGS: delineating responsibilities between the Quality units
• Wyeth BioPharma Division LLC ( Andover , MA) and Pfizer Manufacturing Belgium
NV (Puurs, Belgium; drug product manufacturer)
• Wyeth BioPharma Division LLC ( Andover , MA) and Pharmacia & Upjohn Company
LLC (Kalamazoo, MI; drug product manufacturer)
No objectionable observations were identified.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(
(b) (4)
(b) (4)
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16 of 86 Vender Qualification
(This section written by KRJ)
I spoke with and on
7/19/2021 both from PGS ( , and and
from Pharm Sci ( on 7/21/2021 and 7/23/2021 about supplier
qualification. We discussed the following documents:
Document
number Title Version Effective
Date Pharm
Sci or
PGS
12/02/2020 PGS
12/09/2020 PGS
12/16/2020 PGS
12/05/2019 PGS
11/09/2020 Pharm Sci
11/10/2020 Pharm Sci
New suppliers are selected via a change control and a cross functional team determi nes
the criticality of material or service. The risk assessment and criticality of material
determines the frequency of audits. Qualification of material includes establishing the
material specifications and the testing requirements. The risk assessment s are established
at the time of supplier qualification, and all risk assessments are reviewed on a three-year schedule. However, individual supplier qualification reassessment is performed at a minimum of every , w
ith high-risk suppliers requiri ng reassessment every .
Pfizer can request a for -cause audit at any time. provided the gap
assessment performed as part of the change control ( and child action
). The differences between the Pharm Sci and PGS groups was in the
frequency of audit for different types of suppliers. All suppliers for Pharm Sci were also qualified for PGS, meaning all the suppliers had been qualified at the frequency of PGS
(commercial standards). I reviewed the supplier qualifications for all bag suppliers:
No objectionable observations were
identified.
Annual Pr
oduct Review
(This section written by KRJ)
I discussed the annual product quality review (APQR) with
on 7/20/2021. As the APQR is standard
practice for manufacturing commercial products, Pharm Sci uses PGS’s
, , effective 07/14/2021). The annual product
) )
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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17 of 86 review contains summaries from both Pharm Sci and PGS. This document is reviewed and
signed by both the Pharm Sci and PGS’s site heads and quality heads. The SOP defines roles and responsibilities , content for each chapter, and computer instructions to properly
create, format, and enter the APQR into the QTS system. No objectionable observations were identified.
Biological Product Deviation Reporting (This section written by DME)
The firm’s document: ,
,
, effective 6/24/2020, was reviewed without comment. The procedure requires a
Biological Product Deviation Report ( BPDR ) to be submitted to FDA within with
regards to any event associated with the manufacturing, to include testing, processing,
packing, labeling, storage, or holding of a licensed biological product in which the safety, purity, or potency of a distributed product may be affected. Per
, there have been no BPDR’s submitted for commercial products since the
last inspection. The COVID -19 vaccine is authorized under an EUA and as such not
subject to BPD Reporting at this time. Pfizer submitted a notification to FDA on 7/14/2021
about a st
ability failure of BNT162b2 drug substance batch which was
manuf
actured in for a confirmed out -of-specification ( OOS ) for at the
stability interval result: . The specification for was initially
and in May 2021 was revised to The BNT162b2 drug substance stability is currently . The BNT162b2 drug substance lot was used in drug
product lots: drug product lots were manufactured at Pfizer
Kalamazoo. Drug product lot has been distributed to the US Market and the lot
has also been placed on the stability program for drug product. Drug product lot has been distributed to Japan. The investigation into the DS stability failure is in-progress.
Repr
ocessing/Rework
(This section written by AC)
establishes the requirements for reworking and reprocessing clinical and commercial
current GMP materials manufactured in P GS. Any reworking or reprocessing shall be
approved through the change control process per . All reworked or reprocessed
materials shall meet all specifications and acceptance criteria prior to release and must
have unique traceable batch numbers, be segregated, identified with the appropriate
status, and controlled to prevent mix -ups.
A laboratory scale validation study was performed to demonstrate that a
of the DS through the step has no adverse effects on the quality of
DS. A step may be performed using a new and identical if
a technical issue occurs that compromises the integrity of the system. This
(b) (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) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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18 of 86 validation study supports the process of DS lot under QAR report
# .
A separate DS batch that went through several reprocessed steps were discussed
under the section of Deviation Review.
Training Program
(This section written by KRJ)
I spoke with
from PGS and
from
Pharm Sci on 07/19/2021 and 07/20/2021 about training. We discussed the following
documents:
Document number Title Version Effective
Date Pharm
Sci or
PGS
08/05/2020 PGS
12/16/2019 Pharm Sci
05/27/2021 Pharm Sci
The personnel explained the main difference in training between Pharm Sci and PGS are
the systems that document the training. Training consists of
. There are general trainings, such as GMP training or
GMP refresher, and job specific trainings. Job roles and subsequent trainings are
reviewed . Employees and managers can view training statuses at any time, and there are metrics that allow managers view outstanding training records. There is also an review of training status of all employees.
I reviewed the task related training records of employees performing operations in ( ), and employees
performing testing ( ) and operations in
( ). All training was complete. No objectionable
observations were identified.
Returns/Salvage
(This section written by DME)
The procedure:
, effective 12/16/2020, was reviewed without comment. Per
, the firm has received two shipments of Pfizer manufactured material
under Returns. The first was for multiple lot s of which
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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19 of 86 were returned from Puurs, Belgium. The was shipped back to Pfizer Andover using
the same qualified shipper and Pfizer Andover provided training to Pfizer Puurs staff on how to properly pack the shipper. The second was for product Adalimumab which was
made at Andover and sent to for “special projects” manufacturing. There were no
shipping
excursions for either return. Through records provided, Pfizer was able to confirm
the storage temperatures of the material when at both facilities.
FACILITIES
AND EQUIPM ENT SYSTEMS
Environment Monitoring
(This section written by EA)
Room , for manufacture of DS , was
implemented in December 2020 by partitioning it from the existing manufacturing area
( Some walls w ere removed to enlarge room . Within room , there are
existing (relocated together with its utilities
during the remodel to S outhwest wall) and a new installed next to entry/exit to
Gowning Room in Spring 2021. Supporting rooms remained the
same and were not remodeled.
I discussed the Environmental Monitoring ( EM) program with
, and . The Subject Matter
Experts ( SMEs) explained that EM sites were assessed for and during
the construction phase. The site selection was documented in initial
which was modified to
include after it was installed ( effective 04/30/2021). The assessment
covered room (ISO and the only , as the rest of the adjacent rooms were not
remodeled. Risk assessment considered difficulty to clean, personnel fl ow/presence/
activity, material flow, proximity of open product or product contact material, and known risk for bacteriological host cell containment. Each risk factor was rated as
for each of the areas being assessed was divided across in
of similar area, each with a The total risk score (multiplication of all individual
risk factor scores) was used to determine minimum sampling sites, e.g.,
sample for lower risk areas, no less than samples,
for medium risk areas and no less than samples,
for high-risk areas. were determined “high risk” and
both were evaluated as critical non-aseptic processing area.
Based on the risk assessment, the routine EM sampling plan for includes
si
tes, . I (EA) reviewed the
locations and they appeared acceptable (however see Discussion Item EA -2 regarding
lack of sample location reevaluation post -commissioning of action
limits were in line with ISO sample is collected); l imits are
except floor samples
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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20 of 86 sample. Sampling of ISO areas is performed on a basis. sampling
using is performed . EM frequency and sample size
are insufficient to ensure cleanrooms operate in the state of control given the
room size and frequency of use in manufacture See
Observation 9b and Discussion Item EA -2 for more details .
are monitored for for
ar
e not monitored during or post -operation. Action limits are
. According
to Paige Persky, Manager DP Manufacturing, and ,
monitoring in operation is not proceduralized and is MBR -driven instead. It is limited to
sampling during activities per
effective 06/30/2021. No personnel monitoring or
monitoring post -operations is performed.
EM i
s proceduralized in
effective 05/12/2021. The sampling sites/types described in this
document match those determined in the risk assessment and described above.
Additionally, samples are collected in Gown/Degown room and
. No routine EM is performed for other areas adjacent to
, including Control Room/Storage (see Observation 9c).
According to , growth promotion testing is performed on every lot of
used for sampling upon receipt and thereafter. Media
qualif
ication is proceduralized in
. The firm uses with as disinfectant
neutralizers.
All
EM excursions above alert level and any mold growth are identified. Isolate identification
is performed to aid with root cause analysis, and to identify any unusual recoveries. EM
data is trended along with changes in percent recovery . Limits are established
statistically once sufficient data is acquired and trends can trigger investigation if alarm
level excursions repeat . evaluation of isolate identification is also performed. Mold
recoveries at any level trigger an investigation initiation (also required for any
recoveries) and CAPA (facility sanitization with a sporicidal and visual inspection).
Recoveries over alert level are identified and assessed for trends (mold and spore
formers). For recoveries over action level QTS record is required, including product -impact
analysis. Isolates are not retained past the amount of time required for identification;
therefore, no facility isolates are available if trends emerge that require additional
disinfectant effectiveness studies to be performed.
I reviewed the following EM trending reports covering
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
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21 of 86 •
effective 03/31/2021
•
effective 05/27/2021
No above action level recoveries were reported for Isolated mold recoveries
were reported in December 2020 and January 2021, none in the
EMPQ of was performed after of the facility and equipment with a
sporicidal in December 2020 following
effective 11/04/2020 (see). Per my (EA) discussion with
, EMPQ consisted of of sampling, followed by
of sampling, at which point the facility was released for operations.
Increased sampling continued over at which point sampling
switched to routine schedule. Sampling locati ons and volumes used for EMPQ were the
same as those used for routine EM and described above. was included in
EMPQ. EMPQ results were provided to me in a form of EM Trend Detail Report printout for rooms (including the for the period of
sampling) and for (including the only for the
period of 12/28/ 2020-01/02/2021 (extended sampling). was qualified upon its
installation by performing sampling only on . All results met the
acceptance criteria. See also Observation 9a and Discussion Item EA-2 regarding
EMPQ design and qualification.
I reviewed environmental alarm configuration and an alarm data report for for the
period from 01/01/2021 to 12/31/2021 (data only provided through inspection dates) and
alarms with . Alarm
limits for and adjacent rooms were defined during HVAC IOQ and are set as foll ows:
• Room temperature: outside of min delay.
• Humidity: outside of range; delay.
• Pressure differentials (relative to non-controlled corridor):
Foyer: outside of
Gown/Degown: outside of
outside of
: outside of
Sample Pass Through: outside of
Pressure differential alarms are on delay.
If an alarm is triggered, personnel from an appropriate call list will be contacted by central
monitoring system; however, routine EM data is not reviewed. The alarm response staff 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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (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)
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22 of 86 dedicated and is on call . For the pressure differentials , there is also a local alarm (light
and audible), which is on delay to ensure the doors are not propped open for
example, delay on the alarm was set to ensure it is only triggered in case of an
HVAC failure. Alarm monitoring and response is proceduralized in the following SOPs:
•
effective 07/21/2021
•
effective 04/14/2021
During review of the alarm dat a report for I (EA) noticed a number of pressure
differential alarms on 03/31/2021 (status in rooms and
on 03/18/2021 (status in room . See Observation 10 for further details.
EMPQ and Routine Monitoring. used for the DS manufacture is located on
Level of Building facility also includes , all accessed from clean
corridor, and a return corridor. All classified areas were qualified under the same EMPQ documented in
effective 09/04/2019. My assessment focused on (
I reviewed the study report and discussed it with .
EMPQ of the facility was performed following the baseline EM study (for information only)
followed by cleaning using . EMPQ consisted of of monitoring followed by monitoring completed on and
; the scope of the study included used for reagent
in , ISO see Observation 7c) and in
Activities during sampling included various representative in operation activities, including downstream manufacturing activities in Maximum personnel capacity
was challenged for only. Sampling included
, and . All sampling was performed after
completion of operations using and only) with
Cleanrooms were oversampled during EMPQ ( e.g., number of
samples was based on ISO recommendation).
Action limits (EMPQ and routine EM) for were per ISO ( , ISO
f
or ISO ISO and ISO areas, respectively.
(b) (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) (6), (b) (7)(C)
(b) (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)
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23 of 86 action limit was
s
ampling; see Observation 7b ). action limits were
surface-dependent (in (ISO (ISO and
(ISO
There was a trend identified for excursions (both
conditions; all results within the limit). However, a root cause of failures in
most cases was found to be spraying or similar activities. The counter was purged,
and a second sample was collected immediately with a passing result in all cases.
excursions were observed under conditions only:
and , . Per
the
SME, acceptance criterion for the study was out of of passing results.
There was no additional extended sampling as a follow up to the EMPQ excursions, instead all sampling locations with results over the action limit were
incorporated into routine monitoring program. All growth over action limit and in was
identified; of
(entire facility).
Hazard/critical control point analysis of microbial control in the facility was performed and
high hazards were determined to be critical and open critical processes/additions
(include final activities, to be performed “in critical ISO per p.22 of the report ). Monitoring of critical ISO to include EM of
and and personnel monitoring. Non-critical
ISO were deemed low hazard; their sampling is to exclude and
personnel monitoring (see Observation 7a).
Upon completion of EMPQ sampling sites for routine EM were reduced by a cross -
functional group based on the evaluation of EMPQ outcomes and location of potential
hazard points to the manufacturing environment, process, and product. Contributing
factors to sample site elimination were the size of the room, other sampling sites being
more representative, historically low bioburden levels for similar surfaces ( i.e., walls) at
other sites. Routine EM sites in small non-production areas (airlocks and In-Process Lab)
were reduced to samples.
sampling was reduced to
samples. sampling was reduced to
. sampling was reduced to
samples. routine monitoring sites include
samples
of the worksurface).
Frequency of routine sampling is for critical ISO areas (except
and personnel monitoring which are performed per batch record), for ISO
(b) (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)
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24 of 86 and non-critical ISO areas, and for ISO areas. All excursions over the action
limit and all ISO recoveries are identified to . Per the SME, bioburden
recovered from ISO areas is saved until completion of next trending report. Routine EM
program, including sampling locations, frequencies, methods, action limits, notifications and
incidence reporting, etc. is proceduralized in
effective
12/31/2020.
Routine EM results and isolates identified are trended
contami nation recovery rates action levels to be established as more data becomes
available. I (EA) reviewed the following EM trending data covering DS manufacturing areas
within
• Printout of Environmental Monitoring Summary – Andover Rooms
for the period from
07/01/2020 to 08/31/2020
• Printout of Environmental Monitoring Summary – Andover Rooms
for the period from
04/01/2021 to 07/23/2021
•
approved on 05/27/2021
No objectionable observations were noted.
Water System
(This section written by EA)
Water System .
I (EA) discussed water monitoring with .,
who explained that the routine monitoring is performed per
effective 11/25/2020.
sampling is performed for all within for
ambient return, and for ambient supply. Source water prior to is
monitored 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) (6), (b) (7)(C)
(b) (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)
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25 of 86
(b) (4)
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26 of 86
No
objectionable observations were made. There appeared to be a decrease in frequency
of excursions compared to 2019. It was noted that predominant in 2019 were those indicative of . However, their recoveries reduced dramatically
in 2020:
Note that the manufacture of
BNT162b2 was initiated in 2020 following the reduction in the .
Compressed Air
(This section written by KRJ)
On 07/23/2021, I discussed compressed air qualification and monitoring of
manufacturing areas with the following people:
•
•
•
•
•
We discussed ,
approved on 08/28/ 2018 ( Exhibit
KRJ-14) and the report ,
approved on
04/23/2019 (Exhibit KRJ -15). The acceptance criteria are as follows:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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27 of 86 ISO
Class Water/Oil
Detection Total Air Particulates
≥ 0.5 µm
(particles/m3) Total Air
Particulates ≥ 0.5 µm (particles/m
3) Active Air Viable
Particulates (CFU/m
3)
Facility Cleaning
(This section written by KRJ)
I discussed the facility cleaning of with
on 7/22/2021. We discussed
effective 06/26/2021. is Area and BNT162b2 buffer prep is Area The floors and glass items are cleaned , and the disinfectant between
Walls, external equipment, and are cleaned with
Surfaces are wiped down with after contact time with
Cleaning is performed during . Rooms are cleaned
starting at the . Cleaning is
document in logbooks. Frequency deficiencies were identified, see Observation 12a.
(This section written by EA)
facility cleaning is performed per
effective
06/09/2021. The SOP addresses cleaning frequency, methodology, agents, their preparation, rotation, expiry, and contact time, as well as documentation, suite status, and special sanitization requests. I discussed cleaning wit h
. He explained that facility cleaning occurs
during the shift, regardless of whether the was used. is used for manufacturing operations It was noted that clean status of the room is not
documented in batch record or verified prior to start of manufacture (see Observation 10).
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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28 of 86 Disinfectants, , are used for cleaning
is used on basis. is performed in foyer,
gowning, and pass -through room. is used in all areas prior to scrubbing with
and as needed). Otherwise, method is used.
logbook is used to document room status, sanitization agent preparation (including lot and
expiration date), cleaning type, method, agent used, and areas sanitized.
Training of cleaning personnel consists of a of reading SOPs followed by assessment
of the following skills by a qualified trainer: sanitization, log, use and handling of
, gowning (no gowning qualification is performed). I reviewed Facility
Sanitization Summary reports from 12/31/2020 to 2/28/2021. No objectionable observations were noted.
Periodic cleaning of outside surfaces of major equipm ent and cleaning/breaking down of
is performed by operators using or down, respectivel y
per . See Observation 11b regarding outside cleaning of major equipment .
Disinfectant Efficacy (This section written by KRJ)
I discussed disinfectant efficacy with
on 7/22/2021. We discussed
effective 04/30/2015 (PGS; Exhibit KRJ -11)
and , approved on
04/28/2021 (Pharm Sci; Exhibit KRJ -10).
PGS: The surfaces tested in include
. The
organisms tested include
The disinfectants tested and the validated contact
times include
against all
organisms tested with the exception of
The surfaces tested in a include
The disinfectants tested and the validated
(b) (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) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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29 of 86 contact times include
See Observation 6 regarding confl icting efficacy data in the two studies for
with a contact time of .
Security
(This section written by EA)
Only authorized personnel are allowed in the manufacturing area, which is
controlled via access . During the walkthrough (see “Walk
through” section), I verified that the door to Foyer could not be opened with the of , who does not have access to
the area. No concerns were noted regarding security.
Containment
(This section written by EA)
I reviewed the following procedures governing personnel, material, equipment, and waste
flows in
•
effective 06/02/2021
•
effective 04/07/2021
Both and airlocks have interlocking doors; the functionality of personnel
airlocks was verified during the walkthrough.
Material, equipment, DS, and waste exits the suite via , which
is operated as a
During the walkthrough of I discussed waste handling procedures with Haroon Beg.
Mr. Beg explained that there are types of solid waste generated within the suite,
respective waste containers were observed within the
suite. container was (allowed per
for solid waste). Mr. Beg explained that operators r emove waste at 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) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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30 of 86 Per , waste is removed from , during the shift as well as
by operators and placed into a with a , where it is picked
up from . See Discussion Item EA -5.
I explained that SOPs should be clear and specific enough to allow for consistent execution. There is also an increased risk of cross -contamination due to the waste handling
procedures, such as not using or not temporally segregating waste from DS and
materials that are transferred via the same
Pest Control (This section written by DME )
The procedure Effective 7/7/ 2021, was
reviewed without comm ent. The procedure provides the requirement for pest control of all
Pfizer buildings at this location. Pfizer uses located in
to provide and inspection and pest treatment for all
buildings. The pest contr ol includes inspection of
inspection of inspection of , and
replacement of . Pfizer staff inspect the external areas of all buildings for
areas where bugs/rodents may enter, and work orders are opened to repair these facility
concerns. Pfizer compiles a review of all pest control documents and an
review of all pest control records that includes all buildings. The following reports were
reviewed without comment:
•
effective 3/31/2021
•
eff
ective 5/25/2021
Equipment Qualification (This section written by KRJ)
(b) (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) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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31 of 86
(b) (4), (b) (6), (b) (7)(C)
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32 of 86
(b) (4), (b) (6), (b) (7)(C)
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33 of 86
(b) (4), (b) (6), (b) (7)(C)
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34 of 86 Equipme
nt Maintenance/Calibration
(This section written by KRJ)
I reviewed Work order 1452715 for calibration of used
during DS in This is calibrated every
. The passed
calibration without adjustment. This work order was completed on 01/26/2021. No
objectionable observations were identified.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4), (b) (6), (b) (7)(C)
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35 of 86 Calibration Program
(This section written by KRJ)
On 07/20/2021, I discussed calibration out of tolerance (OOT) procedures with
. Per
the Quality Agreement PGS is responsible for oversight of calibration and validation in
We discussed
effective 03/10/2021 (PGS);
effective 04/16/2021(Pharm Sci); and
, effective 07/15/2020 (Global Workplace Solutions (laboratories)). Calibration
OOT investigation process for GMP critical instruments is documented on the EAMS wor k
order when the condition is first identified. The responsible person documents the
investigation and sends it to Quality. Quality will either approve the investigation or will
initiate a deviation. Laboratory calibration OOT are documented in the work order. The
equipment owner is notified, corrective actions are implemented and recorded in the work order, work order is approved by a secondary reviewer, and equipment owner performs an
impact assessment and routes for quality approval. No objectionable observations were
identified.
Equipment Cleaning Validation
(This section written by KRJ)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4), (b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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36 of 86
(b) (4), (b) (6), (b) (7)(C)
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37 of 86
(b) (4), (b) (6), (b) (7)(C)
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38 of 86
(b) (4), (b) (6), (b) (7)(C)
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39 of 86
(b) (4), (b) (6), (b) (7)(C)
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(b) (4), (b) (6), (b) (7)(C)
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41 of 86 Wast
e
(This section written by DME)
The procedure for the flow and removal of waste in Building ( was reviewed
without comment. The procedure:
, effective 6/25/2021, was reviewed along with
schematics for the flow of waste without comment. Building is a multi -product/multi -host
GMP clinical manufacturing building. The following waste products exist in Building
S
pecific waste from
The procedure for the flow and removal of waste in Building (including was
reviewed without comment. Procedure:
effective 4/7/2021, was reviewed along with
schematics for the flow of waste without comment. Building is a multi -product
commercial manufacturing building.
(b) (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)
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42 of 86 MATERIALS SYSTEM
Material Control
(This section written by EA)
I discussed single use material management as it relates to DS manufacture with
, and . Receiving of raw
materials is proceduralized in
effective 07/21/2021. Briefly, before materials are
See
Discussion Item EA -7 regarding lack of periodic sampling of incoming lots of product -
contact materials suppliers.
Warehouse (
(This section written by DME )
I reviewed the procedure:
, effective 12/21/2020,
(Exhibit DME 1 ) without comment. The procedure speaks to transfer of materials into the
warehouse, storage of materials in the warehouse, the issuance of materials to process
areas, handling of damaged or defective materials and incl udes a floor diagram for the
warehouse ( Exhibit DME 1 p. 8) and a diagram of the room used for drug
substance and shipping of materials and the associated walk -in units used for
storage of drug substance ( Exhibit DME 1 p. 9).
On 7/19/2021, I met
, and he walked me through the receipt of materials, storage of incoming
materials, and shipping out of drug substance. I observed a gap along the side of the
mobile platform at the overhead shipping door, see FDA Observation 12d below for
additional information.
Raw Materials (This section written by DME )
On 7/22/2021, I observed operator
, performing operations for solutions that will be
used in the manufacture of the BNT162b 2 drug substance. was observed
opening a new container of . He the material into a
. The is connected to the system that contains the
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
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43 of 86 . explained that he calculates the amount of
explained the
calculation is . brought in a container with the wrong lot code
and , retrieved another container with the
same lot code. The container that retrieved was partially opened.
took the cover off the container, opened the and began adding
There was no documentation on
the container to identify that it had been opened or when, see FDA Observation #13 for
additional details.
I looked into the large pass thru on the wall of the area and residue
was observed along the sided and bottom of the pass thru, see FDA Observation 12c for
additional details.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4), (b) (7)(C)
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44 of 86
(b) (4)
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45 of 86
Ch
angeover
(This section written by KRJ)
I discussed
effective 03/31/2021 with
on 07/20/2021. I was told that an area can be
(b) (4)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4), (b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
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46 of 86
N
o objectionable observations were identified.
I discussed shutdown and new product introduction on 7/22/2021 with
and
. We broadly discussed
effective 03/23/2020;
effective 03/04/2021; and
, effective
12/16/2020. I was told that an area can be
No objectionable observations were
identified.
(This section written by EA)
I discussed line clearance and changeover procedures for with Paige Persky. Ms.
Persky stated that changeover was only required for multiproduct manufacture and line clearance was not proceduralized, but rather MBR -driven. I reviewed line clearance
documentation in the following batch records:
I
t was noted that does not document area clearance. Ms. Persky explained
that
. Other MBRs document removal of previous batch-specific
documentation, samples, and solutions prior to the respective operations, but not upon their completion. Verification of waste removal is not documented. I (EA) explained that it is
typical and advisable to perform line clearance before and after the operation to provide additional assurance.
Computerized Systems (This section written by DME)
Pfizer utilizes systems in the manufacture of BNT162b2 drug substance which
includes (but not limited to) the and the processes. In
the is used to perform these operations. In Bui lding ( ), the
system is used to perform these operations.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
FDA-CBER-2021-5683-1150574
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47 of 86 It was explained that for the process, there are which can be
performed either . The target for each
. It was explained that if
process to account for the
discrepancy. Pfizer staff provided a list of all deviations associated with the
(Exhibit DME 7 ). There were 7 deviations in Building ( ) and 3 deviations
in It was explained by Pfizer staff that the process validation batches included
Some of the deviations are discussed bel ow:
Building ( ):
• Deviation (Exhibit DME 8 ) was opened for lot , when the
volume of the
It
was explained by , that there was a download which
created a glitch in the system and the w
as not connecting to the logic
comm
unication. As the was above the control limits, the decision was
made to change from When I
reviewed the batch record, there is documentation for
(Exhibit DME 9 p. 17 ). There is no printout in the batch
record from to document that the was given through
. There is no documentation in the batch record that the
was given via . I asked
why the operators did not document the events in the batch record, and he said
because it is documented in the deviation ( Exhibit DME 8 p. 4). I asked how
Quality would be aware that the even though the
batch record has listed and stated that Quality
would be aware from the deviation. Release testing indicated no impact to
. The batch record was reviewed by manufacturing and quality
(Exhibit DME 9 p. 21 -22).
• Deviat
ion (Exhibit DME 10 ) was opened for lot when the
did not begin as planned because the .
When the operator realized the issue, the operator switched the
began. However, due to timing for the
The issue was found to
be the mode and should have been set
on when running on the When I reviewed the batch
record, there is documentation 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) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
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48 of 86 (Exhibit DME 11 p. 12 ). There is no printout in the batch record from
to document that the was given through . There
is no documentation in the batch record that the was given via
. As a corrective action, they added a step
in the batch record to ensure that the operators program the correctly. The
batch record was reviewed by manufacturing and quality ( Exhibit DME 11 p. 16 -17).
• Deviation (Exhibit DME 12 ) was opened for lot when
was and an was given. The
time frame. I asked if the
process validation exceeded the timeframe for and he said
no. I asked if the process validation included and he said no.
When I reviewed the batch record, there is documentation for the
(Exhibit DME 13 p. 126 ). However, there is no
documentation in the batch record for the time taken to administer . I
asked why and , stated that it can
be seen in the . This data for is not on the printout
provided by ( Exhibit DME 13 p. 126 ). In addition, when the operator
changes from , they need to set the .
This information is not documented in the batch record. In talking with , I
stated that there are insufficient details in the batch record for the critical process parameters defined by the firm. The batch record was reviewed by manufacturing
and quality ( Exhibit DME 13 p. 99 -100). The batch met release specifications. The
lot was released for use under the EUA on 3/18/2021 (Exhibit DME 14 ).
• Deviation (Exhibit DME 15 ) was opened on after staff realized
that the time for the was incorrect in the batch record. The parameter in the batch record was documented as (Exhibit DME 16 p. 75 ). A
review of all batch records was performed and , was found
to have a deviation in the time. All
(Exhibit DME 16 p. 75 ). This record was
reviewed by Operations and QA (Exhibit DME 16 p. 97 -98). See Observation #2c
for additional details.
• Deviation was opened for (which became DS lot
as did not meet the control
limits. The operators added a
into the control limit, but this addition did not account 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) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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49 of 86 the that was missing between . I
asked why the operators did not add the as and no
answer was provided. It was explained that as the did not
meet the target because the with the was
The corrective action was to the
. I asked if there was an investigation with documented
impact and said no. The lot was interim released on to
and the full release occurred . When I asked if the
lot was placed on stability, she explained that stability is not part of the release
program. The lot was placed on stability on 7/22/2021. The firm determined no
product impact as all data is within acceptance criteria. The batch is only allowed to
be distributed in the US and Canada. See FDA Observat ion #1 for additional
details.
• Deviation was opened when the
was exceeded. The was within the control limits. It was
determined that the was because the system had not been
cleared from the deviation discussed above (where too little of a was
given for An emergency change control
was opened to correct the code in the system to reset the parameters for eac h
new batch. I asked if they notified the staff working in the building about the code issue with and I was told no. , checked
the system and confirmed that the is set to clear before beginning a new batch, therefore this error would not occur in the building.
• Deviation (Exhibit DME 18 ) was opened for BNT162b2 drug substance lot
(Exhibit DME 19 ), as the
, and the operator switched from
. The operators performed a calculation for
and this calculation is not recorded in the batch record. I asked Paige Persky, Manager of Drug Product Manufacturing, why the calculation for is not
in the batch record and she stated that per their documentation procedures, the
operators should have recorded the calculation for the . The
printout from the system documents
(Exhibit DME 19 p. 54 -56) yet the batch record documents
(Exhibit DME 19 p. 22 -33). I asked Ms. Persky why there are
recorded under the as well as
and she said that she cannot speak to this. The record was reviewed and
approved by QA on ( Exhibit DME 19 p. 47 ). See Observation 2b for
additional details.
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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50 of 86 Gowning
(This section written by DME)
Building
The procedure:
effective 12/30/2020, was reviewed without
comment. This procedure provides gowning and de-gowning requirements for all
personnel and visitors entering and exiting Manufacturing Areas at the Pfizer
Andover, MA facility; and it describes the pathways for personnel, equipment, and materials
that are entering moving through, and exiting manufacturing area at the Pf izer
Andover, MA facility. Personnel are to wear safety glasses, hair cover, beard cover (if
applicable), face mask, plant shoes or shoe covers, high density polyester (HDP) coverall is
worn over street clothes, gloves with sanitization, and a bump cap. I spoke with
about the gowning process on 7/22/2021. She
confirmed that there is training for gowning which includes a performance assessment by a
qualified trainer. She explained that the operators are qualified by ensuring that the staff
can perform the gowning independently and this is documented in skills check.
Building
The document:
effective 1/4/2019, was revi ewed without comment. This
procedure defines the process for gowning required of personnel flowing into, out of, and
throughout the Clean Environmental Areas (CEA) within the
during production and facility non-production periods. All personnel
enter either the Women’s or Men’s locker room, wash their hands and apply covers over
their street shoes. Then they remove all outer street clothes and change into plant
provided blue scrubs. Staff wear plant dedicated shoes (which are changed and
visitors wear their shoes with covers. Then safety glasses, masks, head covers, beard
covers (if applicable), and disinfection of hands occurs. This gowning allows access to the controlled non classified areas. To enter media prep or buffer prep (where
BNT162b2 is manufactured), a frock is added with shoe covers, and gloves with sanitization. The gowning was confirmed upon entry into the areas. I spoke with
, about the gowning process on 7/22/2021. She
confirmed that there is training for gowning which includes a performance assessment by a
qualified trainer. She explained that the operators are qualified by ensuring that the staff
can perform the gowning independently and this is documented in a skills check.
(b) (4)
(b) (4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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51 of 86 LABORATORY CONTROL SYSTEM
Laboratory Investigation (Out of Specification (OOS), Out of Limit (OOL), and
Questionable Result (QR))
(This section written by KRJ)
On 07/20/2021 I discussed compressed laboratory investigations with the following people:
•
•
•
•
•
•
•
Laboratory investigations (LIR) include out of specification (OOS), out of limit (OOL), and questionable results (QR). OOS applies to release specifications excursions in PGS and any filed specification, including in-process action limit excursions in Pharm Sci. OOL
includes alert limit excursion in PGS or target limit excursion in Pharm Sci. QRs applies to
any questionable result, especially in comparison to historical data. We discussed
effective 03/24/2021 (PGS), and
effective
04/20/2020 (Pharm Sci). All OOS, OOL, or QRs must be documented and notification to management needs to be initiated if applicable within of discovery. Records should be closed within days from date of discovery, and if records exceed
timeline, an interim report shall be issued prior to the due date. PGS has a
category for Readily Apparent Assignable Cause (RAAC). Examples of RAAC are incorrectly executed test method, instrument failure during a r un, or standard curve failure.
In the case of a RAAC, the original result is invalidated, and a repeat test is performed. QTS RAAC -LIR are approved by the lab manager and site quality authority. LIR workflow
include initial investigation, investigation measurements protocol (IMP), further analysis,
retest, and conclusion. Retesting can be performed once QA concurs. Retest protocol followed per procedures replicates for PGS and replicates for Pharm Sci). During the LIR conclusion, the scope is reassessed following determination of root cause,
review for trends, and any applicable CAPAs are implemented. If the assignable cause is not lab related, a MIR/QAR must be opened. A MIR/QAR may be opened with QA concurrence at any stage of the LIR if there is concern the assignable cause is not a laboratory error. LIR and RAAC -LIRs are trended at least . No objectionable
observations were identified.
Review of OOS Investigations
(This section written by AC)
More than 40 product - or process -related deviations were reviewed by Inspector Cheung.
Majority of them were adequately addressed and appropriate CAPA s were implemented if
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
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52 of 86 necessary. A few deviations were discussed more extensively with the firm and are
described below.
1. QAR was created on regarding to a batch that
had a at
the stage. The recorded
concentration was and the acceptable range is
. The operator escalated the problem to area management and final decision was
made to further process to . However, the
of the final DS batch was which was outside the
specification of , but the other DS release attributes including
were all within specifications. The root cause of this deviation was due to
the sam
ple collection. The firm created a
Change Request
(6093257) to reprocess the DS batch and was governed
per
. As part of the reprocessing, they re-execute the
of the DS lot. To perform these reprocessed steps,
was documented
to ensure that it was within the recommended time duration. During the inspecti on,
only a portion of the release tests for this reprocessed batch were
completed and the was within specification at . The
reprocessed batch will have the original batch expiration date. The reprocessed DS batch and the corresponding formulated DP batches will be placed on stability to monitor product quality during long-term storage. The firm already enrolled on stability with a base date on July 19, 2021 and the first pull date will be on
that is also the expiry date for . Pfizer put this
reprocessed lot under quarantine in their warehouse and will wait for the full release results before making further decision. I did not identify issues of concerns for this deviation.
2. A total of four dev iations related to the OOS of the in DS lots
were created between May 24, 2021 and June 30, 2021. Two deviations (QAR
and QAR ) associated with DS batches
( and ( had confirmed OOS results, therefore the DS batches
were discarded. No root cause was identified for the
for the above investigations. After about a , another two
deviations for the OOS (LIR and LIR
) associated with DS batches (
( and ( were raised, and the firm has an ongoing
investigation. During the review on these deviations with
they shared that the
was first observed in by the Process
Verif
ication program prior to any OOS results. Pfizer started a proactive meeting on
May 26, 2021 to establish a clear problem definition and have a better
(b) (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)
)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (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)
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53 of 86 understanding on the process. As more data from the raw materials, operation
parameters, and stability/validation data were collected, in addition, more deviations were created due to the OOS, the was confirmed,
and the investigation was escalated to for further analysis and root cause
identification. During the inspection, the firm has not identified any root cause, but they believe the raw materials may be the potential root cause. They are expediting the investigation effects to identify the root cause and implement solutions and
control plan if necessary.
Sample Handling
(This section written by KRJ)
I reviewed a sampling handling presentation of samples from and to ARD
laboratories. The general flow for chemical analysis samples is as follows:
S
ample flow from to ARD -MS T (microbiology lab) is similar ; only samples are
delivered to sample port , and either Sample Handling or MST lab personnel
inspect the samples and retrieves the sample from the
Samples from
to P
GS laboratories is as follows:
T
he microbiology laboratory personnel run queries at least
for time sensitive assays
I spoke with PGS) and
PGS) on 7/22/2021 about sampling handling of DP samples. I
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
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54 of 86 was told that Andover is not performing testing on drug product from Pfizer Manufacturing
Belgium NV. ,
, effective 05/26/2021 defines what drug product testing will be performed from
samples from Pharmacia & Upjohn Company LLC and Hospira Inc. Quality Control Biological Shipping and Receiving (QCBSR) receives shipment and examines it for damage. The container is opened, and the temperature monitoring device is stopped. The contents are compared against the invoice, packing list, and internal Pfizer form
. The temperature monitoring data reviewed and QSM is notified. QSM reviews
and temperature monitoring data. QSM creates a lot in LIMS, gener ates
labels, inspect vials, affix LIMS labs, transfer samples to appropriate laboratory chambers, and changes the location of samples in LIMS . No objectionable observations were
identified.
Review of Analytical Methods for Drug Substance
(This section wr itten by AC)
Currently, all release and stability testing of DS lots manufactured at and are performed at either PharmSci or PGS analytical laboratory at Andover except the
for DS lots manufactured at ( Exhibit AC -6). However, the firm stated
that all these analytical assays will be performed only at PGS -Andover eventually and the
transition date will be in the of this year. The approach of transferring the
analytical assays from PharmSci to PGS is based on data generated either from the co-validation/qualification studies or method transfer exercise.
During review of the assay validation report, I found that no data was
generated to validate the assay range. reminded me that is a limit
test, and the specification is , so the assay range is not
required to be validated. However, an absolute percentage of was reported on
the CoA of each DP batch. I discussed with SMEs that if a quantitative % is being reported
rather than a positive/negative result, data to validate the assay range is needed to support that the quantitative % reported on the CoA is accurate. explained that this
assay had been validated for multiple times and they may have data to define the linear
range. On July 21, 2021 presented validation reports for the assay from
different analytical laboratories: ,
and the data from these studies support that concentrations at
is the lowest concentration that meets linearity criteria.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4), (b) (6), (b) (7)(C)
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55 of 86
(b) (4)
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56 of 86
(b) (4)
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57 of 86
Tour
of the QC Chemical Laboratory
(This section written by AC)
accompanied me on the tour of the
Bioassay laboratory located in Building room on July 19, 2021. The analytical
assay that I observed was assay. This is an assay to
for BNT162b2 DP. The entire assay
takes to complete, and I only observed the initial sample preparation step. The
operator
.
s
howed me the raw data generated by the
and demonstrated how
the software performing the data analysis. The negative control , positive control
( and test samples were run . For a
The technician is responsible to create the assay record under
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
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58 of 86
.
I did not identify issues of concerns
regarding the execution of the assay and analyses of the raw data.
Tour of Microbiology Laboratories
ARD Micro Laboratory:
(This section written by DME)
On 7/19/2021, I inspected the ARD microbiology laboratory. I inspected the storage area
for
incoming samples. There are one is used for bioburden
testing of and one is used for bioburden testing of product samples.
The firm uses a to test samples for . This
laboratory has areas identified for . During the inspection,
stations were empty, and an operator was obser ved to be
in an area marked ”. I asked why the operator was
in the area marked ” and ,
stated that the other stations were being used earlier today so the analyst
used a different area. I observed
. These were for new lots of
Env
ironmental are
. explained that the is the primary
equipment used for identification of organisms. If the is unsuccessful in
generating an identification, then the is used. The is currently out of
service as it is being upgraded to
GMP Micro Laboratory
(This section written by DME)
On 7/19/2021, I inspected the GMP microbiology laboratory. I inspected the refrigerated
storage area for incoming samples. There is a refrigerator in the laboratory that
is used
, explained the are
stored in case an investigation is needed. The laboratory is currently qualifying a
identification. Freezer is used to store reagents.
Freezer ) is used to store reagents. The stability samples for
drug substance are stored in Pfizer Kalamazoo is responsible for the
stability samples and stability program for drug product. However, some samples are sent
to Pfizer Andover for stability testing.
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
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59 of 86
I observed performing a
It w
as explained that the method was being concurrently validated. I
observed the analyst touch the
. I asked why the analyst was touching the
and
, explained that this is a
, explained that the
analyst is and that the analysts implemented
this type of to
allow the material to . I was provided a
printout
for the samples processed by the analyst on 7/19/2021 ( Exhibit DME
3). I reviewed the following procedures:
effective 6/9/2021 ( Exhibit DME 4 ); and
effective 6/23/2021 ( Exhibit DME 5 ) and both were silent as to the by the
analyst observed on 7/19/2021. explained later during the inspection that she
has spoken with the analysts performing the testing and they will revise the
method to have the analyst consult management for issues during testing, see
Discussion Points with Management .
COMPLAI
NTS
(This section written by DME)
The firm’s document: ,
effective 5/19/2021 was reviewed without comment. I discussed the
complaint process with . Complaints are
received by Pfizer US Drug Safety Unit at 100 Route 206 N, Peapack, NJ 07977, and sent
to Andover through the Pfizer Quality Tracking System (QTS). stated that since
the last FDA inspection, Pfizer has received one request to perform an investigation as the
result of a complaint.
Complaint parent document in QTS was received on 12/21/2020 for COVID drug
product lot drug substance lot . A child record was opened
for Pfizer Andover to perform a batch record review for COVID drug substance lot
This investigation was reviewed and was uploaded into QTS once complete. No
concerns noted.
ADVERSE EVENTS
(This section written by DME )
The firm’s document: ,
, effective 5/19/2021 was reviewed without comment. I discussed the adverse
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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60 of 86 event process with . Adverse events are received by Pfizer US Drug Safety Unit
at 100 Route 206 N, Peapack, NJ 07977, and sent to Andover through the Pfizer Quality
Tracking System (QTS). stated that since the last FDA inspect ion, Pfizer has
not received any request to perform an investigation as the result of an adverse event.
stated that this includes the COVID -19 vaccine (which is authorized under an EUA)
as well as other commercial drug products manufactured onsi te.
Reports of complaints and/or adverse events can be received through:
E-mail: [email protected]
Phone: 1(866) 635-8337 or 1(800) 438-1985 Website: https://www.pfizersafetyreporting.com
RECALL PROCEDURES
(This section written by DME )
The firm’s procedure: , effective 7/10/2019, was
reviewed without comment. This document describes the process and procedures to be
followed in determining and acting on a decision to execute a Market Action for distr ibuted
commercial product. The Market Action Coordination Committee (MACC) is responsible for
determining the need for and executing a Market Action. A Market Action is a general reference embracing a potential product recall, market withdrawal, field correction, or Dear
Healthcare Provider Letter. A Market Action also includes notification to authorities
regarding remedial actions, urgent public health threats, corrective actions, and field safety notices. As part of the Market Action Procedure, a mock Market Action will be tested annually to confirm effectiveness of the program. If a Market Action has occurred in the
past 12 months for the Pfizer Andover site, a mock Market Action is not required. There
have been no Market Actions of biologic product to date.
OBJECTIONABLE CONDITIONS AND MANAGEMENT RESPONSE
Observations listed on form FDA 483
Below in bold type are the inspectional observations as they appear on the Form FDA 483.
Beneath each observation is a discussion of the supporting evidence and relevance.
Relevant discussions with Management are also included.
OBSERVATION 1
There is insufficient data to support product quality prior to the release of BNT162b2 drug subs
tance (DS) batch manufactured at Pfizer Andover on
was derived from batch , and a
devia
tion ( ) was initiated due to the multiple control limit excursions
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
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61 of 86 during the of . The were below the
control limits and the between and overall
bot h 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 w as 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 three DP lots
were released on .
Supporting Evidence, Relevance, and Discussion with Management:
(Written by AC)
Deviation ) was initiated on due to the multiple control limit
excursions during the of DS batch ran on . The
. CAPA
was opened on to facilitate the enrollment of this batch into the
stability program per Protocol ; however, has not been placed on
stability as of July 22. CAPA was only executed on July 23, 2021 after the inspectors discussed the deviation with the firm ( Exhibit AC -8). It is acceptable for the firm
to release the affected DS batch for formulation based on the DS release data;
however, the firm should place the affected batch on stability in a timely manner, so they
will have data to support the degradation profile of the affected DS batch is not significantly different from the regular DS batches prior to the release of final DP batches
on (Exhibit AC -9).
(b) (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)
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62 of 86 OBSERVATION 2
There is inadequate quality oversight in that:
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.
b. During processing of BNT162b2 drug substance lot , the
were , and the operator switched from
The operators
performed a calculation for , and this calculation is not
recorded in the batch record. The printout from the
system documents per yet the batch record
documents were performed . The record was
reviewed and approved by QA on .
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 .
Supporting Evidence, Relevance, and Discussion with Management:
(Written by DME )
a. It was explained by , that the reports
associated with the and the process are not reviewed by
QA as they do not have access to the system to review this data. In addition, these
reports are not always part of the batch record.
It was explained by Paige Persky, Manager of Drug Product Manufacturing, that the
printouts are not required to be part of the batch record.
, stated that QA staff will access a computer terminal the
manufacturing to review the data in . I did not go to the terminal to
confirm that QA does review this data. It is not known if this electronic review by QA
is documented.
b. During processing of BNT162b2 drug substance lot , the
, Exhibit DME 19 p. 54 -56),
and the operator switched from
(Exhibit DME 19 p. 22 -33). Th e operators performed a calculation for
and this calculation is not recorded in the batch record. I asked Paige Persky,
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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63 of 86 Manager of Drug Product Manufacturing, why the calculation for is not
in the batch record and she stated that per their documentation procedures, the
operators should have recorded the calculation for the . The
printout from the system documents
(Exhibit DME 19 p. 54 -56) yet the batch record document s were
performed ( Exhibit DME 19 p. 22 -33). I asked Ms. Persky why there are
recorded under the as well as for
and she said that she cannot speak to this. I spoke with
, who stated that the system was running in the
background while the were added. It was not fully explained why the
documents (Exhibit DME 19 p. 54 -56) and the
(Exhibit DME 19 p. 22 -33). The record was
reviewed and approved by QA on 7/15/2021 ( Exhibit DME 19 p. 47 ).
c. BNT162b2 drug substance lot was manufactured in . The
record was reviewed by Operations in (Exhibit DME 16 p. 97 ) and by
Quality on ( Exhibit DME 16 p. 98 ). All were
(Exhibit DME 16 p. 75 ). There was no notation in the batch record until
that exceeded the allowable of (Exhibit
DME 16 p. 75). The batch record target was and the
added was over ( Exhibit DME 16 p. 75). I explained to Mr. Tucker and
other management in the room that during the batch record review it should identify
when allowable parameters have been exceeded. The batch was released by QA on ( Exhibit DME 17 ). A memo dated 3/4/ 2021, was added to the
deviation that there is no product impact as the batch met release specifications (Exhibit DME 15 p. 5 ).
During review of the deviations it was explained that the systems are
validated. The validations associated with these systems was not reviewed. I asked if the
data has been restored from the system to ensure it is accurate and it was explained that this was done as part of validation of the system but no restore has been performed since.
OBSERVATION 3
The following deviation investigations were found deficient. Deviation ,
(COVID): ) and , (COVID):
: was found in
(b) (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) (6), (b) (7)(C)
(b) (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)
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64 of 86 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.
Supporting Evidence, Relevance, and Discussion with Management:
(Written by EA)
There were two deviations opened for
post cleaning
• “ (COVID): ” created
(Exhibit EA-32)
• “ (COVID): ” created
(Exhibit EA-32)
Investigations of these deviations were limited to to determine whether the
; no sampling was performed to ensure
Per the deviation reports and my discussion with
, and , the was
recleaned, visually inspected with passing results, and released for manufac ture. Visual
inspection of the is performed per
effecti ve 04/23/2021 ( Exhibit EA-33; also see
Discussion Item EA -1). No cleaning verification (i.e.,
or product impact assessment was performed or is required for
deviations.
OBSERVATION 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
Supporting Evidence, Relevance, and Discussion with Management:
(Written by KRJ )
Per , effective 04/15/2021
(Exhibit KRJ -07), cleaning validation was not performed on the
trend (seven incidences) in commissioning,
samples occurred prior to the results of
in October. The results for batches led
the rejection of the batches ( Exhibit KRJ -08).
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (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)
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65 of 86 I explained my observations to Mr. Tucker and other management in the room at the time.
There were no additional discussions during the close.
OBSERVATION 5
Cleaning of reusable product -cont act parts using is not validated.
Cleaning verification of such parts is inadequate as it is limited to testing of
. Ve
rification of surface and final rinse
t
esting is not performed routinely.
Supporting
Evidence, Relevance, and Discussion with Management:
(Written by EA) In is used for cleaning of a range of miscellaneous small product -
contact parts ( Exhibit EA-36). According to , and
as confirmed by others (see SMEs below), validation of process was not performed. Instead, cleaning verification on sample (visual inspection and
per specification) is performed for each load per
effective 07/14/2021 ( Exhibit EA-37).
testing of sample is performed per
effective 03/31/2021 ( Exhibit EA-38). No sampling was performed
to verify cleaning effectiveness.
According to
the rationale for not validating
was the nature of the process and associated high variability of the
outcome. Developmental coupon studies were performed using the same materials,
as soil and worst -case process parameters
to determine dirty hold time for . Flat surface coupons do not present the same level of challenge for the cleaning process, and although cleaning verification rather than
validation could be more suitable for a process, it is insufficient to perform
testing only as it does not inform of or
(Written by KRJ)
, effective 07/16/2021 is used to clean small parts and hoses
via in This SOP only requires visual inspection and testing for
, and not . There is no cleaning validation
performed on small parts and hoses in as this is a process and can be operator dependent. There are direct product contact small parts and hoses, that could
contribute contamination to the drug substance if not appropriately monitored.
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (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)
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66 of 86
I explained my observations to Mr. Tucker and other management in the room at the time.
There were no additional discussions during the close.
OBSERVATION 6
Cleaning efficacy studies are inadequate (Building in that the firm has not demon
strat ed 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 wi
th a contact time of .
Supporting Evidence, Relevance, and Discussion with Management:
(Written by KRJ)
, approved on
04/28/2021 ( Exhibit KRJ -10) demonstrates that a is effective with
a contact time of . ,
, effective 04/30/2015 ( Exhibit KRJ -11) demonstrates that is not effective
with a contact time of except on A
ll disinfectants used are the same
between PG
S and These studies overlap on
The that overlap
between the studies include .
I explai
ned my observations to Mr. Tucker and other management in the room at the time.
There were no additional discussions during the close.
OBSERVATION 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.
Supporting Evidence, Relevance, and Discussion with Management:
(Written by KRJ )
I reviewed BLA section 3.2.A.1 for ( Exhibit KRJ -12). It states that meet ISO
standards and are used for critical operations. It includes and room
backgrounds. On 7/22/2021, I was told by
(b) (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) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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67 of 86 that
monit
oring during critical operations did not include monitoring.
informed me on 7/23/2021 that
effective 02/10/2021 is the
only SOP governing monitoring of during critical operations. does
not require monitoring.
I explained my observations to Mr. Tucker and other management in the room at the time.
There were no additional discussions during the close.
OBSERVATION 8
Routine monitoring of the compressed air of Building , does not adequately represen
t all points of use. Only , specifically
l
isted in
,
are routinely
monitored.
Supporting
Evidence, Relevance, and Discussion with Management:
(Written by KRJ )
On 07/23/2021, I was told by
that
testing of the compressed air has never been
performed on all . That only were qualified and
monitored, as these points are the of
distribution and therefore
represent
ative. However, there is no data to support that these points are
representative of all the . Additionally, qualified and monitored are in ISO -
rooms ( Exhibit KRJ -16). There are located in ISO rooms ( Exhibits
KRJ-14 and KRJ-15), which has different acceptance criteria based on the room
classification .
I explai
ned my observations to Mr. Tucker and other management in the room at the time.
There were no additional discussions during the close.
OBSERVATION 9
The environmental program (EM) program in is deficient in ensuring that the
cleanrooms are operating in a state of environmental control:
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
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68 of 86 a. No prospective EM performance qualification (PQ) of classified areas or PQ
of was performed to ensure EM specifications in operation are met.
b. Routine monitoring of ISO area is performed on a basis.
c. During a walkthrough on 7/22/2021 , the door to the Control Room
was observed opened to manufacturing (ISO through the
duration of the w alkthrough. Room is classified as controlled not
classified and is not monitored.
Supporting Evidence, Relevance, and Discussion with Management:
(Written by EA)
No prospective EMPQ protocol or EMPQ report for was provided by the firm
immed iately upon request. According to , and
, instead of following such protocol,
EMPQ was performed based on
effective
11/04/2020 (Exhibit EA-14). The SOP does not contain sufficient detail and provides only
general EMPQ requirements. Furthermore, section 4.1.3.1 of the SOP states that EMPQ
activities following suite modifications and new construction “will be run per protocol”. The study report
effective 07/23/2021 ( Exhibit EA-15) was provided to me during
the close -out of the inspection (see Discussion Item EA -2).
The initial EMPQ study summarized in the report was performed in December 2020, prior
to installation of , which was qualified upon its installation by performing
sampling on . Qualification of this under was not
performed and no PQ report was generated. Instead, a printout of EM Trend Detail Report
for this sampling location for the dates stated above was provided ( Exhibit EA-16).
Routine environmental monitoring of is described in
effectiv e 05/12/2021 ( Exhibit
EA-12). Sampling of ISO areas are performed on a basis, which can fail to
detect excursions impacting multiple lots of product manufactured in which is
currently operating days a (see Discussion Item EA -2).
The SMEs referred to Table 2 of (Exhibit EA -11) to support sampling
frequency. However, it is stated in the footnote of the table that “these recommendations do
not apply to production areas for non-sterile products or other classified environments in
which fully aseptic gowns are not donned”. Aseptic gowning is not used in it was
observed during the walkthrough on 7/22/2021 and confirmed by
, that street clothes are allowed underneath overalls in
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (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)
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Andover, MA EI End: 07/23/2021
69 of 86 Per
effective 05/12/2021 ( Exhibit EA-12), no routine EM is performed in Control
Room/Storage . , and
, explained that the room is not monitored because it is
Controlled Not Classified (CNC). Door between and (ISO was observed
opened (i.e., not alarmed and with no pressure differential as would be required between
rooms of different classification) throughout the walkthrough of the
OBSERVATION 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 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.
Supporting Evidence, Relevance, and Discussion with Management:
(Written by EA)
According to the alarm data report for for the period from 01/01/2021 to 12/31/2021
(Exhibit EA-18), the pressure in room on was relative to the
non-controlled corridor, while rooms adjacent to remained over pressurized relative
to the same corridor (no alarm was recorded). Given that the pressure differential alarms are setup with delay ( Exhibit EA-17) and the time of the alarm (
), duration of the pressure differential excursion was approximately
. According to the work orders 1500905 and 1523038 (Exhibit EA-20), the cause of
the alarm was a planned HVAC shut down for maintenance. P ost-HVAC sh utdown cleaning
requirements are proceduralized in
(b) (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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (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)
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Andover, MA EI End: 07/23/2021
70 of 86 effective 07/21/2021 ( Exhibit EA-19), which
does not require additional cleaning unless loss of airflow duration exceeds .
I also reviewed facility sanitization log reports ( Exhibit EA-21), EM trend detail report
(Exhibit EA-22) and manufacturing schedule for Exhibit EA-23) c overing the
event and established the following sequence of events:
: sanitization of performed : HVAC shut down, pressure differential in below the
limit
: HVAC alarm triggered; pressure differential is
: HVAC alarm off; pressure differential returned to normal
: of batch
: sanitization of performed
No EM of the suite was perfor med from the time of the event until only)
and (Room . Batches were processed in between
DS batches (manufactured from
(manufactured from ), and
(manufactured from ) processed within the timeframe when the
EM status could not be assured were manufactured into DP batches and released
between to the US and the international market ( Exhibit EA-
24). No impact assessment on the product was performed.
According to
, no study
had been performed to determine room recovery rate after HVAC shutdown with respect to
air and surface viables. There is also no procedure to ensure that any required additional or
routine cleaning was performed as clean status of the room is not verified prior to start of manufacture in
The SMEs brought up the following documents to support the existing procedure for the
HVAC shutdown response:
• effective
03/29/2021 ( Exhibit EA-25)
•
effective 04/07/2021 ( Exhibit EA-26)
As part of HVAC qualification, a room recovery test was performed on 12/11/2020.
Recovery t ime for was determined to be as determined by
(b) (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) (6), (b) (7)(C)
(b) (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)
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71 of 86 reduction of . The study included a and does not
address room recovery with respect to contamination.
The risk assessment justifies the time window based on the lack of EM incidents,
events, and deviations with HVAC air loss as a root cause. There were HVAC
outages ranging from , including event of a sitewide outage
with alarm durations of . Lack of such deviations is not
informative given lack of EM sampling requirement -HVAC shutdown and the
infrequent and limited EM sampling in see Observation 9 and Discussion Item
EA-2 ).
OBSE RVATION 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
• An alarm went off due to operator to
introduc
e . prohibits work in
a if it is in alarm condition.
•
operators were over the of the
blocking the .
• did not cover all surfaces of the and was
set contact time required per .
b. cleaning of the in was
not performed in the of July 2021 in deviation from .
Supporting Evidence, Relevance, and Discussion with Management:
(Written by EA)
During the walkthrough of on 7/22/2021, I observed the following:
During the setup for operations the were brought
into
. The items were too large to fit under the , which had to be each
time triggering an alarm.
effective 02/24/2021 ( Exhibit EA-4 )
states “never work in a …if it is in alarm condition”.
(b) (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)
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72 of 86 The operator was observed on the while monitoring the
filtration. This is in violation of (Exhibit EA-4 ) section 9.6.1 General Behaviors
stating “In , do not the Same operator behavior was
observed dur
ing walkthrough (see Discussion Item EA -3).
During cleaning of the operator used in a to
cover
surfac
es of the , including the . Approximately area along the bottom of
the was not completely covered and streaking of could be observed. Surfaces
out before timer was up; some portions of surfaces were
. Similarly, during setup surfaces of the , which was
with left undisturbed inside the for contact time, out
before the timer was up. On both occasions , the disinfectant was not reapplied to
maintain the contact time. Contact time is specified in Section 9.1.4 Disinfectant Guidance
of (Exhibit EA-4 ).
During t
he walkthrough of on 7/22/2021, the outside of major equipment appeared
dusty, streaky, and had dried out residue ( i.e., , Exhibit EA-5 ). Periodic
cleaning of outside surfaces of major equipment and cleaning/breaking down of is performed by operators using down, respectively per
effective 06/09/2021 ( Exhibit EA-6 ). According to
Section 17.2 of the procedure, sanitizations are to be performed “within each of the following dates of the month:
Upon review of effective
03/05/2018 for equipment sanitization ( Exhibit EA-8) , it was noted that in deviation
from the , surface sanitization was not performed on .
OBSERVATION 12
The following deficiencies were observed within buildings used to produce
BNT162b2 drug substance:
a. In Building preparation area:
• was observed on
multiple wa lls.
• was observed in the hallway.
• were observed with dust and debris on the
and streaking/raised residue down the sides and bottom of multiple
b. In Building
• was observed on multiple walls inside room
(b) (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)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Establishment Inspection Report FEI: 1222181
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Andover, MA EI End: 07/23/2021
73 of 86 • was observed in room
c. Residue was observed on the sides and base of multiple sample pass
throughs to include preparation, and .
d. A gap to the outside was observed on the side of the mobile platform at the
receiving dock in Building
Supporting Evidence, Relevance, and Discussion with Management:
(Written by DME)
a. On 7/19/2021, while looking through the hallway windows into the
production rooms in Building I observed streaking residue on the
outside of multiple .
On 7/21/2021, I observed dust and debris on . The
status of was clean. I observed streaking down the outside of
. The status of was clean. It was explained that the exteriors of
the are cleaned , and they were last cleaned in June 2021. A picture was taken which shows the streaking down the side of the ( Exhibit DME 2 p.
7).
On 7/21/2021, I observed areas of that were in excess of 6
inches i
n length on multiple walls which included the wall behind , t
he base
of the
wall near the floor scale, on the wall near the shower, the wall by
the sink, and the wall above the outlets. Pictures were taken to show the concern (Exhibit DME 2 p. 1 to 6 ) however the pictures do not clearly show the
In additi
on, I observed a ring around the inside of the at about
and a ring around the inside of the at about up . I was later
provided a technical report for the ring:
, , effective 1/6/2017, which stat es that the ring is due
to the slip agents inside the of some raw materials. It was explained that Pfizer has a process for monitoring the with these rings and will remediate the
residue from the when appropriate. Due to the time constraints, I was unable
to assess if this is being done for the in
I observed white residue streaking down the inside of the at 10 and
11 o’clock positions through the site glass. The was in a clean status. I asked
about the residue, but no information was provided before the close of the
inspection.
On 7/23/2021, I was provided with pictures ( Exhibit DME 20 ) which demonstrate
corrective actions to walls in preparation in
(b) (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)
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74 of 86 I spoke with Mr. Tucker and other management staff in the room and explained my
concerns and I showed him the photos which were taken. Mr. Tucker stated that
they have a robust program where the facility is inspected for damage,
equipment issues, leaks, or areas of concern. During the close,
, stated that the facility is an operational/working facility.
There were no additional discussions during the close.
(Written by EA)
b. During the walk through of I observed on walls inside room
(behind equipment, from the floor) and in
Control Room/Storage ( Exhibit EA-7 ), by the entrance (see Observation
12b).
(Written by DME)
c. On 7/19/2021, w hile looking through the hallway windows into the
production rooms in Building I observed residue on the base of the
pass through into .
On 7/22/2021, while inside the room, I looked into the large
pass through, and residue was observed. I went with to the hallway
where the pass-through exits and explained that the pass through is
used for the transfer of samples out of . I looked into the pass
through and residue, some of which was raised and dark in color, was observed on
multiple sides and the base of the pass through. I asked the firm to take pictures of
the residue observed. Pictures were provided by the firm of this pass through, but
the pictures were not clear ( Exhibit DME 2 p. 10 -13).
(Written by EA)
During walkthrough I observed dried up residue (splatter and pools of liquid)
on the bottom surface of the sample pass through. No cleaning of the pass through was performed (or is required) before or after its use by the operator
effective 08/25/2020 ( Exhibit EA-2 )]. Per
effective 06/26/2019 ( Exhibit EA-3 ), pass throughs are cleaned by
“saturating” interior and exterior surfaces with disinfectant. The SOP does not
instruct to wipe the surfaces after the contact time is achieved.
(Written by DME)
I explained my observations to Mr. Tucker and other management in the room at the
time. No response was provided by the firm as to what the material was inside any
of the pass throughs. There were no additional discussions during the close.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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75 of 86 (Written by DME)
d. On 7/19/2021, while walking through the warehouse in Building I observed a gap
(approximately ½ to 1 inch in size) to the outside, on the side of the mobile platform
at the receiving dock. I explained to Mr. Tucker and other staff in the room that the
gap on the side of the mobile platform is large enough to allow bugs and possibly small rodents into the facility. There were no additional discussions during the close.
OBSERVATION 13
During activities observed on 7/22/2021, an operator was
observed 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 container was not
closed, and there was no documentation as to when the container had been initially opened. Supporting Evidence, Relevance, and Discussion with Management:
(Written by DME )
On 7/22/2021, I observed operator
,
performing operations for solutions that will be
used in the manufacture of the BNT162B2 drug substance. He brought in one container with the wrong lot code in error and the system would not allow him to proceed with the
oper
ation.
, retrieved a different another container
with the same lot code. The container that retrieved was partially open.
took the cover off the container, opened the and began adding
to the that was being . There was no documentation on
the container to identify that it had been opened or when. It was explained by
that they are not required to make note on the containers when they are initially
opened or by whom. explained that he retrieved this container from a
specific area of the warehouse for partial containers. took me to a storage
area in the warehouse which is labeled “In-Process Materials Only Below This Sign”. A picture was of the sign and to show the two pallets of materials which were stored in this
area ( Exhibit DME 2 p. 14 ). None of the containers stored on either pallet had a date
on the container to identify when the material had been opened. In review of procedure:
Warehouse Storage and Movement of Mat erials in the
effective 12/21/2020, ( Exhibit DME 1 p. 3 )
provides some instruction for partial containers as far as checking the expiration date and
down prior to entry into the . The procedure does state “ensure
all partial containers are appropriately closed, sealed, and contained before moving back 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) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (6), (b) (7)(C)
(b) (4)
(b) (4)
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76 of 86 Warehouse” ( Ex hibit DME 1 p. 3 ). There were no additional instructions for
sealing/closing the containers.
I explained to Mr. Tucker and other management in the room that at a minimum, the
containers should be dated so that staff know when the container had been opened. I
explained that some materials are sensitive to moisture and if not properly closed it could
impact the potency and/or stability of the raw material. There were no additional
discussions during the close.
REFUSALS
(Written by DME )
We encountered no refusals during the current inspection.
GENERAL DISCUSSIONS WITH MANAGEMENT
We discussed various issues with Management during the inspection which may require
their attention including the following:
(Written by K RJ)
Discussion Item KRJ -1
On 7/21/2021, I di
scussed with management the crowded appearance of the
with the in the room and the spatial area for the
analysts to maneuver. I also discussed the set -up for the testing, as there is
substantial empty space in . By not being able to place the on the cart
completely, there is a risk that the c
ould fall off the cart and crack.
(Written by E A)
Discussion Item EA -1
Visual Inspection of Process Equipment – I discussed the following issues related to
visual inspection of process equipment:
• Procedure
effective 04/23/2021 ( Exhibit EA-33) is deficient in that residue sample
retrieval is not described. During investigation of (COVID):
(Exhibit EA-31)
used (
clean room brand towel) attached to a
to avoid scratching
the . As a result, the sample was contaminated with adhesive (presumed to
originate from tape used for tool wrapping).
• Per
(Exhibit EA-33) opening deviations/investigations is not required for
particulate deemed to be “native to the process”, such as . During
(b) (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) (6), (b) (7)(C)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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77 of 86 (Exhibit EA-31) investigation the residue was identified as and
deviation was closed without further follow -up. Per list of parts used in with
(Exhibit EA-34),
Solution incompatibility with material was not considered or investigated as a
potential root cause of shedding.
Discu ssion Item EA -2
EMPQ and Routine EM – I discussed the following issues related to design of EMPQ and
routine EM of
• It could not be confirmed that EMPQ was performed under conditions. Per
, and
, there is no requirement that any manufacturing activities are
performed during sampling; presence of personnel at the time of sampling
could not be confirmed.
• EMPQ was not performed under the worst conditions. Specifically, the firm did not
define or challenge maximum occupancy during EMPQ.
• EMPQ/routine EM sampling is deficient in sample size and locations. First, locat ions
of EM sample sites determined per risk assessment
(Exhibit EA-9) and implemented per
(Exhibit EA-12) were selected during construction phase and were not reevaluated
after the was commissioned based on the actual personnel traffic. It was observed during the walkthrough that certain areas of the suite (i.e. around
have unexpectedly high traffic, which had not been considered by the initial
risk assessment. Second, the air sample volume (i.e.
, would not be representative of given the room size (
, especially given that only air samples of each type are collected on
a bas i
s (see Observation 9b) . and referred
to ISO standard ( Exhibit EA-10) to support the sample size. However,
ISO requires collection of samples rather than samples based on the
size of
- I discussed the following issues related to use:
• During walkthrough the operator was observed
the of the impeding the . (Exhibit EA-
1) prohibits placing items on the .
• During a walkthrough of was observed crowded with
various items during of reagent. For
example, a , an opened set of were
observed stacked on top of each other inside the
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FDA-CBER-2021-5683-1150605
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
78 of 86 ef fective 08/23/2019 ( Exhibit EA-1 ) prohibits piling items on top of
each other inside of a .
• During walkthrough the operator was observed and
using the for multiple strokes across surfaces. This is
in violation of Attachment 7 Methodology” of
(Exhibit EA-6)
• Utility of was discussed given that the equipment was not adequately qualified
(see Observation 9a), monitored, or used (see also Observation 11a). According to
Paige Persky, Manager DP Manufacturing, and ,
monitoring in operation is limited to
activities per
effective 06/30/2021 ( Exhibit EA-13). No personnel monitoring or monitoring
post-operations is performed.
Facility and Equipment Design - I discussed the following issues related to the facility
and equipment design:
• As a result of s tationary and mobile equipment /cart placement in and spatial
limitations that it created, operators were observed kneeling on the floor and reaching under a cart to plug a into an electrical outlet, placing paper MBRs,
printed SOPs and pens on top of SUMs being used in manufacture.
• The in appeared to have insufficient size for the operations being
performed: during DS the entire space was occupied with a
The operator had to rearrange the items inside the
to bring in necessary equipment. The newer is used interchangeably
and is smaller than .
• testing was setup in the corner of the behind a mobile
stairc
ase adjacent to (Exhibit EA-5 ). During the setup, one of the
operators was observed attaching a hose to the in the utility panel located
on the wall behind the staircase while the other operator was assembling tubing on
the surface of a cart located in front of the staircase. To help with the tubing assembly, the operator had to initially hold the hose over the rail of the staircase and eventually let it hang over the rail. Then operators squeezed past each other between the wall and the staircase to the utility panel where they proceeded to setup
the filter on for .
Discussion
Item EA -5
Containment – The following issues related to containment were discussed:
• Per Haroon Beg and , operators close biohazardous waste
by
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FDA-CBER-2021-5683-1150606
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
79 of 86 •
(Exhibit EA-27) governing transfer of solid waste is not
detailed or specific enough to allow for consistent execution. For example,
waste glov e sanitization after waste handling, or placing waste into a
secondary container inside is not described. The SOP appears to require
of solid process waste, a practice that is not in place at the facility.
• Waste
flow is not temporally segregated from flow of DS, materials, and equipment
through . It is typically placed in the at the end of each production
shift and picked up from the (not on schedule) by
Environmental Health & Safety (Exhibit s EA -28 and EA-29).
Discussion Item EA -6
D
iscussion Item EA -7
Material Management - I discussed the following issues related to management of single
use product -contact materials:
• status of product -contact materials sterilized by suppliers is
not verified through periodic sampling of incoming lots. According to the SMEs, no
testing is required for release of any product -contact single use materials, all of
which are released solely based on suppliers’ CofC/CofA and their
claims.
• According to the provided lists of product -contact materials ( Exhibits
• EA-39 and EA-40) there are several direct product -contact materials for which no
claim is provided by supplier.
(Written by AC)
Discussion Item AC -1
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FDA-CBER-2021-5683-1150607
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
80 of 86
Dis
cussion Item AC -2
PPQ Lots Stability -
• To demonstrate manufacturing process consistency at PPQ lots were
executed. Nevertheless, only one PPQ lot, , was put on stability, and this DS
lot failed the specification at time point at real -time storage
conditions ( Exhibit AC -3). I strongly recommended the firm to put at least
PPQ lots on stability to assure that sufficient data will be available to support the
proposed shelf life. The firm acknowledged the recommendation and stated that at least PPQ lots will be placed on stability for the size DS
manufacturing process.
(Written by DME)
Discussion Item DME -1
EXH
IBITS COLLECTED
Exhibits collected by Inspector Jones are identified by “K RJ”, Inspector Allen are identified
by “EA”, Inspector Cheung are identified by “AC”, and Inspector Emerson are identified by
“DME”.
KRJ Exhibits
KRJ-01 Opening Meeting Attendees/Quality Oversight Presentation Attendees (3
pages)
KRJ-02 Close -out Meeting Attendees (1 page)
KRJ-03 Subject Matter Experts Interviewed (22 pages)
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FDA-CBER-2021-5683-1150608
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
81 of 86 KRJ-04 Opening Meeting/Quality Meeting Presentations (51 pages)
KRJ-05 Quality Organization Charts (5 pages)
KRJ-06 Quality Organization (16 pages)
KRJ-07 (62 pages)
KRJ-08 trend deviation and deviation
(7 pages)
KRJ-09
3 pages
)
KRJ-10
appr
oved on 04/28/2021 (9 pages)
KRJ-11 , ,
effective 04/30/2015 (PGS) (26 pages)
KRJ-12 Section 3.2.A.1 (28 pages)
KRJ-13
(40 pages)
KRJ-14
(Plan) (6 pages)
KRJ-15
(Executed) (10 pages)
KRJ-16
(12 pages)
EA Exhibits
EA-1
eff
ective 08/23/2019 (12 pages)
EA-2
ef
fective 08/25/2020 (12 pages)
EA-3
effective 06/26/2019 (20 pages)
EA-4
effective 02/24/2021 (65 pages)
EA-5 Photos of , front view and surface (2 pages)
EA-6
effective 06/09/2021 (66
pages)
EA-7 Photos of in (3 pages)
EA-8 Sanitization Log pages 32 and 37 (2 pages)
EA-9
effective 04/30/2021 (24 pages)
EA-10 International Standard ISO (44 pages)
EA-11
, official on 07/14/2021 (12 pages)
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FDA-CBER-2021-5683-1150609
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
82 of 86 EA-12
effect ive 05/12/2021 (28 pages)
EA-13 effective 06/30/2021
(49 pages)
EA-14
effective
11/04/2020 (10 pages)
EA-15
effective 07/23/2021 (11 pages)
EA-16 EM Trend Detail Report printout for room location for the
period of 05/12-14/2021 (5 pages)
EA-17 Environmental alarm configuration in (11 pages)
EA-18 Environmental alarm data report for for the period from 01/01/2021 to
12/31/2021 (6 pages)
EA-19
ffective 07/21/2021 (26 pages)
EA-20 Pfizer maintenance work orders 1500905 and 1523038 (10 pages)
EA-21 sanitization log report for (2 pages)
EA-22 EM Trend Detail Report from 2/18/2021 to 05/12/2021 (8 pages)
EA-23 Manufacturing Schedule from 03/17/2021 to 04/01/2021 (1 page)
EA-24 Disposition declaration for DS and associated DP batches (1 page)
EA-25
effective 03/29/2021 (108 pages)
EA-26
effective 04/07/2021 (12
pages)
EA-27
effective 06/02/2021 (42 pages)
EA-28
effective 04/07/2021 (27 pages)
EA-29 EH&S Memorandum: Frequency of Waste Removal (1 page)
EA-30 Major manufacture equipment summary table (5 pages)
EA-31 (COVID): created
(11 pages)
EA-32 (COVID): created
; COVID):
created (63 pages)
EA-33
effective 04/23/2021 (32 pages)
EA-34 Lists of items and parts used in (2 pages)
EA-35
effective 05/18/2021 (13 pages)
EA-36 List of product -contact equipment cleaned via (1 page)
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) 4)
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FDA-CBER-2021-5683-1150610
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
83 of 86 EA-37 effective 07/14/2021
(30 pages)
EA-38
effectiv e
03/31/2021. (74 pages)
EA-39 List of product -contact materials (2 pages)
EA-40 List of product -contact materials (with supplier claims);
List of Stock Room Supplied Parts (with supplier
claims) (16 pages)
EA-41 List of Direct Contact/Indirect Contact Parts (1 page)
AC Exhibits
AC-1 RNA Manufacturing Process Flow Diagram, 1 page
AC-2
, 22 pages
AC-3 Stability Data (Long-term and Accelerated Storages) for Drug Substance PPQ batches at Andover and 12 pages
AC-4 Additional DS Batches from enrolled on Stability Program, 1 page
AC-5 Product Quality Data for Validation of C OVID -19 Vaccine Drug Substance
Shipping, 3 pages
AC-6 Analytical Testing Lab for the Release of COVID -19 Vaccine Drug Substance
and Drug Product, 3 pages
AC-7 Manufacturing Batch Record for Reprocessed DS Lot
AC-8 Manufacturing Investigations -Action Item Detail Report , 3 pages
AC-9 Release Dates of COVID -19 Drug Product Associated with DS Batch
, 1 page
DME Exhibits
DME 1
effective 12/21/2020,
10 pages
DME 2 Pictures from the facility, 14 pages
DME 3 Printout of the samples tested on 7/19/2021, 5 pages
DME 4 Procedure: , effective 6/9/2021,
57 pages
DME 5 Procedure:
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FDA-CBER-2021-5683-1150611
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
84 of 86 ,
ef
fective 6/23/2021, 13 pages
DME 6 List of BNT162b2 drug substance ,
13
pages
DME 7 List of deviations. 3 pages
DME 8 QAR deviation, 7 pages
DME 9 Pages from batch record lot , 26 pages
DME 10 QAR deviation, 13 pages
DME 11 Pages from batch record lot , 22 pages
DME 12 QAR deviation, 6 pages
DME 13 Pages from batch record lot , 126 pages
DME 14 Release packet and Certificate of Analysis for batch , 5 pages
DME 15 PR ID , 6 pages
DME 16 Batch record for lot , 105 pages
DME 17 Release packet for lot , 5 pages
DME 18 QAR , 29 pages
DME 19 Batch record , 56 pages
DME 20 Pictures of repaired areas, 13 pages
ATTACHMENTS
Form FDA 482, Notice of Inspection Dated 07-19-2021
Form FDA 483, Inspectional Observations Dated 07-23-2021
The signatures of the FDA representatives are on the following page.
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FDA-CBER-2021-5683-1150612
Establishment Inspection Report FEI: 1222181
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC. EI Start: 07/19 /2021
Andover, MA EI End: 07/23/2021
85 of 86
Signature Page
Kathleen R. Jones , Biologist , CBER/OCBQ/DMPQ/ MRB1
Ekaterina Allen, CSO, CBER/OCBQ/DMPQ/MRB2
Anissa Cheung, CSO, CBER/OVRR/DVP
Debra M. Emerson, CSO, Team Biologics
FDA-CBER-2021-5683-1150613