Document text
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
CBE
R CMC BLA Review Memorandum
BL
A STN 125742
CO
VID-19 mRNA Vaccine (nucleoside modified) [ COMIRNATYTM]
CDR Do
nald Ertel, Regulatory Officer , OCBQ/DMPQ/MR B1
Laura Fontan, Consumer Safety Officer , OCBQ/DMPQ/MR B1
Alifiya Ghadiali, C onsumer Safety Officer , OCBQ/DMPQ/MRBII
Kathleen R. Jones, Biologist , OCBQ/DMPQ/MR B1
Nicole Li, Microbiologist , OCBQ/DMPQ/ MRB1
Gregory Price, Biologist , OCBQ/DMPQ/MR B1
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
i 1.BLA#: STN 125742
2.A
PPPLICANT : BioNTech Manufacturing GmbH, US License Number 2229
3.PRO
DUCT NAME/PRODUCT TYPE
CO
VID-19 mRNA Vaccine (nucleoside modified) ; COVID- 19 Vaccine (BNT162, PF-
07302048) ; COMIRNATY
4. G
ENERAL DESCRIPTION OF THE FINAL PRODUCT
a.Pharmacological category
Va
ccine
b.D
osage form
Liquid
c. S
trength/Potency
30 mcg
d.R
oute of administration
Intramuscular
e. I
ndication(s)
Active immunization to prevent COVID -19 caused by SARS -CoV- 2 in individuals
≥16 years of age
5. M
AJOR MILESTONES
Submitted
Roll 1 Submission: May 6, 2021
Roll 2 Submission (final): May 18, 2021
Received: May 18, 2021
First Committee Meeting: June 3, 2021
Filing Meeting: June 29, 2021
Filing Action: July 16, 2021
PDUFA ADD: January 16, 2022
6. CM
C/QUALITY REVIEW TEAM
Reviewer/Affiliation Section/Subject Matter
CDR Donald Ertel, Regulatory Officer,
OCBQ/DMPQ/MRB1 Drug Product and Diluent
(Sections 3.2.P and 3.2.R)
Laura Fontan, CSO,
OCBQ/DMPQ/MRBI Drug Product, Facilities and Equipment
(Puurs), and Executed Batch Records
(Sections 3.2.P and 3.2.A.1)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
ii Reviewer/Affiliation Section/Subject Matter
Alifiya Ghadiali, CSO,
OCBQ/DMPQ/MRBII Facilities and Equipment (Chesterfield)
(Section 3.2.A.1)
Kathleen R. Jones, Biologist,
OCBQ/DMPQ/MRBI DS and Facilities and Equipment
(Chesterfield, ACMF, Andover Suite )
(Sections 3.2.S and 3.2.A.1)
Nicole Li, Microbiolo gist,
OCBQ/DMPQ/MRBI DS and Facilities and Equipment
(Chesterfield, ACMF, Andover Suite )
(Sections 3.2.S and 3.2.A.1)
Gregory Price, Biologist,
OCBQ/DMPQ/MRBI Drug Product, Facilities and Equipment
(Kalamazoo), and Executed Batch
Records
(Sections 3.2.P and 3.2.A.1)
7. SUBM
ISSION(S) REVIEWED
Date Received Submission Comments/ Status
May 6, 2021 STN 125742/0 Original submission
(Part 1 of rolling
submission)
May 18, 2021 STN 125742/0.1 Part 2 of rolling
submission /
Reviewed
May 24, 2021 STN 125742/0.4
(response to May 20, 2021
information request (IR)) Manufacturing
schedule for Pfizer
Andover, Pfizer
Puurs, and Pfizer
Kalamazoo /
Reviewed
July 28, 2021 STN 125742/0.19
(response to July 2, 2021 IR) /
Reviewed
(b)
(4)
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(4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
iii Date Received Submission Comments/ Status
July 30, 2021 STN 125742/0.24
(response to July 26, 2021 IR) P
fizer
Puurs sterilization/
depyrogenation
revalidations and
equipment cleaning
validation; Pfizer
Kalamazoo equipment
qualification,
information, and
cleaning validation;
DP sterilizing filter
validation and
shipping study /
Reviewed
August 3, 2021 STN 125742/0.29
(response to July 26, 2021 IR) DS equipment (due to
file size limitation,
remaining supporting
documentation
provided to Question
10, response received
July 30, 2021) /
Reviewed
August 10, 2021 STN 125742/0.39
(response to August 6, 2021 IR) Pfizer Puurs
step
/ Reviewed
(b)(4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
iv Date Received Submission Comments/ Status
August 11, 2021 STN 125742/0.43 (response to
August 5, 2021 IR) Pfizer Chesterfield
utilities and equipment
information and
cleaning validation;
Pfizer Andover EM ,
equipment hold times,
manufacturing and
equipment
information; Pfizer
Kalamazoo container
closure integrity
testing (CCIT) and
equipment
; Pfiz er
Puurs visual
inspection and CCIT;
Drug product release
and stability testing /
Reviewed
August 13, 2021 STN 125742/0.47
(response to August 11, 2021 IR) Diluent supplier
manufacturer and
shipping procedures /
Reviewed
August 17, 2021 STN 125742/0.56 (response to
August 16, 2021 IR) Diluent suppliers /
Reviewed
August 17, 2021 STN 125742/0.57 (response to
August 13, 2021 IR) Pfizer Andover
computer systems
and equipment
qualifications; Pfizer
Kalamazoo equipment
qualifications, utilities
information,
equipment cleaning
validation, and visual
inspection; Pfizer
Puurs cleaning
validation / Reviewed
August 19, 2021 STN 125742/0.62 (response to
August 17, 2021 IR) Drug substance
hold time / Reviewed
8. A
CRONYM KEY
List of abbreviations and acronyms
(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
v
Abbreviations/Acronyms Description
AAVP active air viable particulates
AC acceptance criteria
ACMF Andover Clinical Manufacturing Facility
AHU air handling units
AOAC Association of Official Analytical Collaboration
AQL acceptance quality limit
ARD Analytical Research and Development
ASTM formerly known as American Society for Testing and
Materials
BI biological indicator
BLA Biologics License Application
BSC biosafety cabinet
BSL biosafety level
CBER Center for Biologics Evaluation and Research
CCIT container closure integrity testing
CEA clean environmental area
CFU colony forming units
CGMP current good manufacturing practice
CHT clean hold time
CIP clean -in-place
CMF Chesterfield Manufacturing Facility
CNC controlled non-classified
COP clean -out-of-place
CPF Chesterfield Pilot Facility
CPP critical process parameter
DBSQC Division of Biological Standards and Quality Control
DHT dirty hold time
DI data integrity
DMPQ Division of Manufacturing and Product Quality
DNA deoxyribonucleic acid
DP Drug product
DS Drug substance
DSPC 1,2-distearoyl -sn-glycero -3-phosphocholine
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(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
vi Abbreviations/Acronyms Description
EIR establishment inspection report
EM environmental monitoring
ERES electronic records and electronic signature
EU endotoxin unit
EUA Emergency Use Authorization
FC flexible container
FDA Food and Drug Administration
FV functional verification
HEPA high efficiency particulate air
HVAC heating, ventilation, and air conditioning
IPT-C in-process test for control
IPT-M in-process tests for monitoring
IOQ installation and operational qualification
IQ installation qualification
IR information request
ISO International Organization for Standardization
KCl potassium chloride
KH2PO4 monobasic potassium phosphate
LNP lipid nanoparticles
MAL material air lock
MCB master cell bank
MCS manufacturing control system
MOC material of construction
MVD maximum valid dilution
MWCO molecular weight cut -off
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
vii
Abbreviations/Acronyms Description
N/A not applicable
Na2HPO4*2 H2O dibasic sodium phosphate, dihydrate
NaCl sodium chloride
NAI No Action Indicated
NaOH sodium hydroxide
NMT no more than
OAI Official Action Indicated
OOS out-of-specification
OQ operation al qualification
OVRR Office of Vaccines Research and Review
PAL personnel air lock
PLC programmable logic controller
PLI pre-license inspection
PP polypropylene
PPQ process performance qualification
PQ performance qualification
PV process validation
PW purified water
q.s quantum satis (as much as may suffice)
QAT quality attributes
RAL residue acceptance limit
RNA ribonucleic acid
SCADA supervisory data and collection
SIP sterilize -in-place
SOP standard operating procedure
SS stainless steel
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
viii Abbreviations/Acronyms Description
TC thermocouple
TCV temperature -controlled vehicle
TNTC too numerous to count
TOC total organic carbon
TYMC total yeast microbial count
v/v volume per volume
VAI Voluntary Action Indicated
VNC validation nonconformances
VRL visual residue limit
WAL waste air lock
WCB working cell bank
WFI water for injection
9. REVI
EWER SUMMARY AND RECOMMENDATION
A.EXECUTIVE SUMMARY
Pf
izer-BioNTech submitted documentation to Biologics License Application (BLA)
125742/0 to support licensure of COMIRNATY™, a COVID -19 vaccine intended for the
prevention of COVID -19 in adults ≥ 16 years of age. DMPQ reviewed and evaluated the
, DS and DP manufacturing process and facilities proposed for use
to manufacture COMIRNATY™ . Coverage of information in this review memo includes
data to validate and support the consistency of the manufacturing process and product
quality; facility information which includes utilities, cross -contamination prevention
measures, and maintenance of controlled environments; and equipment for use in manufacturing including qualification, cleaning and sterilization, and types of equipment used (i.e., dedicated or shared, multi -use or single- use). Note, the facilities proposed for
use to manufacture COMIRNATY™ under the BLA are facilities that are used to
manufacture the Pfizer -BioNTech COVID- 19 Vaccine under Emergency Use
Authorization (EUA), which was originally issued on December 11, 2020. However, not all facilities used to manufacture the Pfizer -BioNTech COVID- 19 Vaccine under EUA
are proposed for use under the BLA.
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
ix A
s part of the BLA review, PLI s were performed to ensure the product meets all
predeterm ined specifications, the production process is validated and controlled, and
the facility and associated systems and equipment are operated with quality oversight
consistent with the CGMP requirements. The PLIs were performed at the DS manufacturing facility at Wyeth BioPharma Division of Wyeth Pharmaceuticals, LLC in Andover, MA (referred to as Pfizer Andover) from July 19 – 23, 2021 and at the DP
manufacturing facility at Pfizer Manufacturing Belgium NV in Puurs, Belgium (referred to as Pfizer Puurs) from June 24 – July 2, 2021. Note, Division of Manufacturing and
Product Quality (DMPQ’s) review and assessment of the Pfizer Andover and Pfizer Puurs facilities are documented in separate establishment inspection reports (EIR). At the conclusion of the Pfizer Andover PLI, a Form FDA 483 was issued on July 23, 2021
with thirteen inspectional observations, which the firm responded to on August 2, 2021. A review of Pfizer Andover’s responses with inspectional follow -up recommendations is
documented in a separate 483 response memo dated August 21, 2021. All inspectional
483 observations were resolved, and the Pfizer Andover PLI was classified as Voluntary Action Indicated (VAI) . No Form FDA 483 was issued at the conclusion of the Pfizer
Puurs PLI, and the PLI was classified as No Action Indicated ( NAI).
I
n addition to the PLIs, facility inspections were waived following an evaluation of the
inspection compliance histories of the and another DP
manufacturer and release testing facilities for Pfizer Inc. in Chesterfield, MO; Pharmacia
& Upjohn Company LLC in Kalamazoo, MI; Pfizer Ireland Pharmaceuticals in Dublin,
Ireland;
, the inspection waivers of the facilities are documented in a
separate inspection waiver memo dated August 9, 2021.
T
he COMIRNATY™ vaccine multi- dose vial requires dilution with 1.8 mL of 0.9%
Sodium Chloride Injection, USP prior to administration of the vacci ne product. Pfizer -
BioNTech will provide the 2 mL or 10 mL vials of 0.9% Sodium Chloride Injection, USP
diluent manufactured by Fresenius Kabi USA , LLC or Hospira, Inc.
in , respectively. The saline diluent will be supplied separately to
healthcare providers shipped in parallel with COMIRNATY™. Both the 2 mL and 10 mL single dose vials of 0.9% Sodium Chloride Injection, USP are packaged in cartons of 25
vials and shipped in a corrugated box with other ancillary supplies (masks, syringes,
gloves, etc.). Cartons of the saline diluent will be clearly labeled to indicate that it is for use with COMIRNATY™.
B
ased on the information submitted to BLA 125742/0 and in conjunction with the PLIs
and inspectional compliance history evaluations, the production process, facilities, equipment, and controls appear acceptable for the licensure of COMIRNATY™ and
approval is recommended.
B. RECO
MMENDATION
I.APPROVAL
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
x Approval is recommended with inspectional follow-u p recommendations below.
C
BER understands the inspectional recommendations may or may not be taken (based
on risk and available resources) and is not requesting documentation to be submitted as
evidence of completion.
P
fizer Inc. i n Chesterfield, MO (known as Pfizer Chesterfield), FEI: 1940118
W
yeth BioPharma Division of Wyeth Pharmaceuticals, LLC in Andover, MA (known as
Pfizer Andover), FEI: 1222181
P
fizer Manufacturing Belgium NV , Puurs, Belgium (known as Pfizer Puurs ), FEI:
1000654629
II.SI
GNATURE BLOCK
Reviewer/Title/Affiliation Concurrence Signature and Date
CDR Donald Ertel, Regulatory Officer,
OCBQ/DMPQ/MRB1 Concur
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(b)(5), (b) (7)(E)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
xi
Reviewer/Title/Affiliation Concurrence Signature and Date
Laura Fontan, CSO,
OCBQ/DMPQ/MRBI Concur
Alifiya Ghadiali, CSO,
OCBQ/DMPQ/MRBII Concur
Kathleen R. Jones, Biologist,
OCBQ/DMPQ/MRBI Concur
Nicole Li, Microbiologist,
OCBQ/DMPQ/MRBI Concur
Gregory Price, Biologist,
OCBQ/DMPQ/MRBI Concur
Lori Peters, Branch Chief,
OCBQ/DMPQ/MRBI Concur
John A. Eltermann, Jr., Division
Director, OCBQ/DMPQ Concur
Mary A. Malarkey , Office Director,
OCBQ Concur
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
1 Module 3
3.
2.S DRUG SUBSTANCE
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
21 3
.2.P DRUG PRODUCT
3.2.P.1 Description and Composition of the Drug Product
The BNT162b2 DP is supplied as a preservative- free, multi -dose concentrate to be
diluted for intramuscular injection, containing six doses. The DP is a sterile dispersion
of RNA- containing lipid nanoparticles (LNPs) in aqueous cryoprotectant buffer. Each
vial, containing 0.45 mL of the DP at is designed to contain a total of six doses
after dilution by the addition of 1.8 mL of sterile 0.9% sodium chloride solution, with
each dose containing 30 μg of RNA in 0.3 mL. There is no manufacturing overage.
The DP
is supplied in a 2 mL glass vial sealed with a bromobutyl rubber stopper and an
aluminum seal with flip -off plastic cap.
The c
omposition of the DP, including amount per vial and function and quality
standard applicable to each component, is given in the table below .
C
omposition of BNT162b2 Drug Product, multi- dose vial (225 µg/vial)
Name of
Ingredients Reference
to Standard Function Concentration
(mg/mL) Amount
per vial Amount
per dose
BNT162b2 DS In-house
specification Active
ingredient 0.5 225 µg 30 µg
ALC-0315 In-house
specification Functional lipid 7.17 3.23 mg 0.43 mg
ALC-0159 In-house
specification Functional lipid 0.89 0.4 mg 0.05 mg
DSPC In-house
specification Structural lipid 1.56 0.7 mg 0.09 mg
Cholesterol Ph. Eur. and/or
USP-NF Structural lipid 3.1b 1.4 mg 0.2 mg
Sucrose USP-NF and
Ph. Eur. Cryoprotectant 103b 46 mg 6 mg
Sodium chloride USP-NF and
Ph. Eur. Buffer
component 6 2.7 mg 0.36 mge
Potassium
chloride USP-NF and/or
Ph. Eur.a Buffer
component 0.15 0.07 mg 0.01 mg
Dibasic sodium
phosphate,
dihydratecUSP-NF and
Ph. Eur. Buffer
component 1.08 0.49 mg 0.07 mg
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
22 Name of
Ingredients Reference
to Standard Function Concentration
(mg/mL) Amount
per vial Amount
per dose
Monobasic
potassium
phosphated USP-NF and/or
Ph. Eur.a Buffer
component 0.15 0.07 mg 0.01 mg
Water for Injection USP-NF and
Ph. Eur. Solvent/vehicle q.s. q.s. q.s.
a.Supplier Certificate of Analysis confirms compliance to both USP- NF and Ph. Eur., however incoming testing may be
performed only in accordance with a site’s local compendia.
b.Values are rounded to maintain the same level of precision as the label claim, with trailing zeros not shown, where
applicable. For example, 46 mg sucrose is rounded from mg (103 mg/mL).
c.Dibasic sodium phosphate, dihydrate ( Na2HPO4*2 H2O ) is named as
d.Monobasic potassium phosphate (KH2PO4) is named as
e.The diluent (0.9% sodium chloride Injection) contributes an additional 2.16 mg per dose.
Abbreviations:
ALC-0315 = ((4-hydroxybutyl)azanediyl)bis(hexane-6,1- diyl)bis(2 -hexyldecanoate)
ALC-0159 = 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide DSPC = 1,2-distearoyl- sn-glycero-3-phosphocholine
q.s. = quantum satis (as much as may suffice)
3.2.
P.2 Pharmaceutical Development
3.2.P.2.1 Components of the Drug Product
3.2.P.2.1.1 DS
The RNA component of the DS is the only active ingredient in the BNT162b2 DP. The
DS is a single -stranded, 5’ -capped mRNA produced by in and provided for DP
manufacture as a aqueous solution in
3.2.
P.2.4 Container Closure System
The container closure system for the commercial BNT162b2 DP is a 2 mL Type I
borosilicate glass vial and a 13 mm bromobutyl stopper. Multiple vendors of the glass
vial are utilized on a global basis.
The glas
s vial meets requirements
for chemical testing for Type I glass containers. The elastomeric stoppers meet
chemical testing requirements for
elastomeric closures.
Ref
erence Section 3.2.P.7 Container Closure System for description of container
closure and stopper functional testing; reference Section 3.2.P. 5.3 for CCIT evaluation.
Review
er’s comment : The evaluation of suitability, chemical compatibility &
resistance, extractables/leachables, safety of the materials of c onstruction,
biological activity, and photostability is deferred to the OVRR reviewer .
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
23 3.2.P.2.5 Microbiological Attributes
The manufacturing process utilizes pre- sterilized raw materials and supplies, HEPA-
filtered, classified production areas, and personnel gowning controls. During
manufacturing, the formulated bulk DP is sterile filtered prior to being aseptically
filled into vials. T he sterilizing filter is integrity tested.
The fi
nal product storage conditions do not support microbial growth, as the product is
stored frozen at - 90°C to - 60°C. The container closure system and its components
were selected based on their ability to protect the quality of the product over its shelf life
and have been qualified for use.
The BN
T162b2 container closure system has been tested by both
CCIT methods. Both studies have produced acceptable data and
verify that the stopper/vial/cap combination maintains integrity when challenged with a
. Container closure integrity testing is covered in Section 3.2.P.5.3.
3.2
.P.2.6 Compatibility
The initial in -use period for the thawed, undiluted vial is room temperature for not more
than 2 hours. Pfizer initiated formal thermal cycling stability studies on both emergency use lots and PPQ lots in order to further support the in- use period.
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
24 Reviewer’s comment : The in- use period of 6 hours is supported by the results
of the microbial in- use study, which demonstrates safe use of the multi -dose vials
over 6 hours at ambient temperatures.
3.
2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
Table P.3.1 -2 in the submission (recreated with additional information below) lists the
manufacturing and testing facilities for BNT162b2 DP manufacturing and release
testing.
Site FEI/DUNS
Number Responsibility
Pfizer Manufacturing
Belgium NV
Rijksweg 12
Puurs, 2870
Belgium FEI:
1000654629
DUNS:
370156507 LNP production and bulk DP formulation
Fill and finish
Primary packaging
Secondary packaging
Release and stability testing: Sterility (including
sterility), Endotoxin, Appearance,
Appearance (Visible Particulates), ,
Container Content, LNP , LNP ,
RNA , RNA Content, ALC- 0315
Content, ALC -0159 Content, DSPC Content,
Cholesterol Content, Lipid Identities, RNA
Pharmac ia & Upjohn
Company LLCc
7000 Portage Road
Kalamazoo, MI 49001
United States FEI:
1810189
DUNS:
618054084 LNP production and bulk DP formulation
Fill and finish
Primary packaging
Secondary packaging
Release and stability testing: Sterility (including
sterility), Endotoxin, Appearance,
Appearance (Visible Particulates), ,
Subvisible Particles, Container Content, LNP ,
LNP , RNA Content, RNA
, ALC-0315 Content, ALC-0159
Content, DSPC Content, Cholesterol Content,
Lipid Identities, RNA , Container Closure
Integrity
Wyeth BioPharma
Division of Wyeth
Pharmaceuticals LLCa
1 Burtt Road
Andover, MA 01810
United States FEI:
1222181
DUNS:
174350868 Release and stability testing: Identity of encoded
RNA sequence,
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
25 Site FEI/DUNS
Number Responsibility
(Analytical Research &
Development) Wyeth
BioPharma Division of
Wyeth Pharmaceuticals
LLC a
1 Burtt Road
Andover, MA 01810
United States FEI:
1222181
DUNS:
174350868 Drug Product release and stability testing:
Appearance, Appearance
(Visible Particulates),
, Container Content, LNP , LNP
, RNA , RNA Content,
ALC-0315 Content, ALC-0159 Content, DSPC
Content, Cholesterol Content, Lipid Identities,
Identity of encoded RNA sequence,
, RNA , Container Closure
Integrity
In-process testing
Pfizer Inc.
875 Chesterfield Parkway
West
Chesterfield, MO 63017
United States FEI:
1940118
DUNS:
004954111 Release and stability testing: Appearance,
Appearance (Visible Particulates),
, Container Content, LNP ,
LNP , RNA , RNA
Content, ALC -0315 Content, ALC-0159 Content,
DSPC Content, Cholesterol Content, Lipid
Identities, Identity of encoded RNA sequence,
, RNA , Container Closure
Integrity
Pfizer Ireland
Pharmaceutical
Grange Castle
Grange Castle Business
Park
Clondalkin, Dublin 22
Ireland FEI:
3004145594
DUNS:
985586408 Release and stability testing: ,
Identity of Encoded RNA Sequence,
FEI:
DUNS
:
Release testing: Sterility
FEI:
DUNS
:
Release testing: Sterility
Fresenius Kabi USA, LLC
FEI:
DUNS:
Diluent Manufacturer
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
26 Site FEI/DUNS
Number Responsibility
Hospira, Inc. FEI:
DUNS: Diluent Manufacturer
a The legal entity name change from Wyeth BioPharma Division of Wyeth Pharmaceuticals was changed at the acquisition by Pfizer
in 2009, since then the Wyeth Pharmaceuticals manufacturing site in Andover, Massachusetts belongs to Pfizer’s production sites
and is part of Pfizer´s GMP system.
b is a wholly owned subsidiary of Pfizer Inc.
c Pharmacia & Upjohn Company LLC is a wholly owned subsidiary of Pfizer Inc.
3.2.
P.3.3 Description of Manufacturing Process
The following paragraphs describe the DP manufacturing process, which occurs at both
the Pfizer Kalamazoo and Pfizer Puurs locations:
The manuf
acturing process for BNT162b2 DP includes LNP production and bulk DP
formulation followed by fill and finish activities .
(b)(4)
(b)(4)
(b)(4)
(b) (4)
(b) (4)
2 pages have been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
29 Fill/Finish Operations
Two locations, Pfizer Kalamazoo and Pfizer Puurs, each with multiple filling lines , are
used for fill and finish manufacturing operations. Process controls are the same for both
sites unless otherwise described. Please refer to 3.2. A.1 for a description of the facilities
and equipment.
Sterile Filtration
The pr
ocess parameters for sterile filtration are summarized in Table P.3.3- 1 and IPT- C
tests are summarized in Table P.3.3- 2. Tests for monitoring (IPT- M) are sum marized in
Table P.3.3 -3. The tables are reproduced below.
The fol
lowing two tables describe the in- process acceptance criteria for sterile filtration.
(b) (4)
(b)(4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
30 Preparation of Vials and Stoppers
The vials are processed through the vial washer, where they are rinsed with . After
washing, the vials are depyrogenated by means of application.
Bulk stoppers are washed and depyrogenated with .
Aseptic Filling
The
DP is aseptically filled into vials. Prior to filling,
All non-conforming vials are
rejected.
The process parameters for aseptic filling are summarized in Table P.3.3- 4 and IPT- C
tests are summarized in Table P.3.3-5 , both reproduced below .
Process Parameters for Aseptic Filling
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
31
Stoppering and Capping
At the end of aseptic filling, a stopper is seated onto each filled vial. Vials are
subsequently transferred to the capping station. The stoppered vials are transferred to the capper. A 100% check on the presence and position of the stopper is performed.
The capper automatically rejects vials unless the stopper is seated. The stoppered vials are capped with aluminum overseals under airflow and crimped onto each vial.
Visual Inspection
Vials are 100% inspected for defects either through automated visual inspection or manual visual inspection.
D
uring the 100% automated inspection process the vials are fed to the inspection
machine. The vials undergo a check for product
defects. The rejected vials are segregated in prelabeled reject trays. The
acceptable vials are transferred to tr ays.
For
automated inspection, prior to each batch,
If r
equired, vials may undergo 100% manual visual inspection. Vials are manually
inspected for product defects. The
stoppers and caps are inspected for
. All rejected vials are segregated into prelabeled reject trays.
The remaining acceptable vials are placed into trays.
V
ials passing automated or manual inspection are statistically sampled to meet
Acceptance Quality Limit (AQL). Throughout the inspection process, samples are taken
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
32 for AQL testing . Defects are classified as Critical, Major or Minor and are addressed
according to site procedures.
Labeling, Packaging, and Freezing
The labeling and packaging of the BNT162b2 vaccine vials for commercial distribution is
performed on a fully automated or semi -automated packaging line. Inspected vials are
individually labeled with a vial label. A printer on the vial labeler is used to print batch-specific information on the vial labels. The labeler has
After labeling, the vials are placed into trayboxes using an automated trayer or a manual traying process. After filling of the boxes, vial quantities are verified, an insert may be added, and the boxes are manually closed and labeled.
A sample for identity testing is taken after labeling operations are completed.
Packaged BNT162b2 vials are frozen and stored in a freezer at - 90°C to - 60°C pending
shipment for commercial distribution.
Storage, Packaging and Shipment of BNT162b2 Drug Product
Drug product (DP) vials are stored according to conditions supported by Section
3.2.P.8.1 Stability Summary and Conclusions (modRNA).
DP is shipped under qualified conditions as supported by Section 3.2. P.3.5 Shipping
Validation, validating shipping conditions of - 90°C to -15°C including a maximum
cumulative time of at . The final packaged products are
transported by established transportation routes to point of use.
When DP is shipped at - 90°C to -60°C, the trayboxes containing the vials are moved
from the freezer and placed into validated shippers that use dry ice for temperature
control. Temperature monitoring devices are inserted and activated for all shipping
containers. Temperatures during shipment are verified to ensure that the product
maintains -90°C to -60°C. The product can be warmed up to a maximum of to
perform transfers and redistribution during shipping with multiple transfers allowed within that timeframe. The product temperature in the shipper can be maintained by adding additional dry ice. Alternative qualified insulated thermal conveyances may be used following appropriate qualification.
When DP is shipped at - 20±5°C, the trayboxes containing the vials are moved from the
freezer and may be shipped using a temperature- contr olled vehicle (TCV). All TCV
shipments are monitored for temperature during shipment to ensure that the temperature within the TCV remains within - 20±5°C, and temperatures during transport
are verified. Upon arrival at a qualified distribution center or logistics service provider,
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
33 the trayboxes containing the vials are transferred to a freezer for storage at - 90°C to -
60°C.
The DP
shipment may also be shipped directly at - 20±5°C in thermal conveyances that
use material for temperature control or following
deconsolidation at a qualified distribution center or logistics service provider into smaller
bundles or quantities. Temperature monitoring devices are inserted and activated for all shipping containers. Temperatures during shipment are verified to ensure that the
product is maintained at - 90°C to -15°C. Alternative qualified insulated thermal
conveyances may be used following appropriate qualification.
A
maximum cumulative time of is allowed at during shipping and
deconsolidation of the DP until arrival at point of use. Process parameters for storage
and shipping are summarized in Table 3.2.P.3.3-8 , reproduced below .
Revi
ewer’s comment: The description of the manufacturing process is
complete and sufficiently detailed. Please refer to 3.2.P.3.5 for review of the validation studies supporting these processes .
H
old Times
The hold times of the DP in-process materials during are
provided in Table 3.2.P.3.3-9 of the submission and are reproduced below. All hold
times following are in alignment with the validated media fill times,
ensuring acceptable microbial control during the DP manufacturing process. The
processing steps are performed within the maximum times determined by the
validation.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
34 Material or In-
Process Hold
Description Process Steps Target Hold
Time
3.
2.P Diluent
The COMIRNATY™ vaccine requires dilution with 0.9% S odium Chloride Injection, USP
diluent prior to administration of the vaccine product. Pfizer did not include information
in the BLA, Module 3, regarding the suppliers for this diluent. The original labeling proposal (in Module 1) provides a description of the plan as follows:
For
the licensed commercial vaccine, a similar approach will be used as was done
under EUA. Pfizer -BioNTech will provide the same 0.9% Sodium Chloride Injection,
USP diluent manufactured by Fresenius Kabi LLC or the Hospira, Inc. saline diluent (if
needed). The saline diluent will be supplied separately to healthcare providers (shipped
in parallel with shipments of the COMIRNATY™, with arrivals synchronized so that diluent is delivered before the vaccine is delivered). Cartons of the saline diluent will be clearly labeled to indicate that it is for use with COMI RNATY™ , specifically: cartons of
the 0.9% Sodium Chloride Injection, USP diluent supplied by Fresenius Kabi LLC will be ink print stamped on the side of the carton opposite the Fresenius Kabi diluent label with the following text: “For Use with COMIRNATY™ [COVID- 19 mRNA Vaccine (nucleoside
modified)] ”. The information is printed from a printer in dot matrix font in a
default font size of 7 in black ink. No physical label can be applied, as the packaging
line is fully automated and does not have this capability. Cartons of the 0.9% Sodium
(b) (4)
(b)(4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
35 Chloride Injection, USP diluent supplied by Hospira, Inc., will be labeled , same text as
mentioned, on the side of the carton opposite the Hospira diluent label.
I
mages of the cartons and relevant stamps were supplied as attachments.
R
eviewer’s Comment : Per amendment 125742/0.47, the manufacturers table
and FDA Form 356h have been updated with the diluent manufacturers. Pfizer
provided a description of the diluent shipping and controls in Module 3. Pfizer identified three manufacturers of diluents. It was found that one of the three manufacturers, . (FEI# ), currently
has a pending Warning Letter (reference WL issued ) and
Official Action Indicated status. An IR was issued and, per amendment 125742/0.56, Pfizer has removed all references to this supplier from the BLA, including in the recently added Diluent Manufacturers table. All diluents have been verified as approved under ANDA / NDA as follows:
Proprietary
Name NDC
Package
Code Appl. #. Labeler Name Product
NDC Package
Description
Sodium
Chloride 63323-
186-02ANDA
088912 Fresenius Kabi
USA, LLC
FEI: 63323-
186 25 VIAL, SINGLE -
DOSE in 1 TRAY
(63323-186-02)
> 2 m
L in 1 VIA L,
S
INGLE -DOSE
(
63323-186-04)
Sodium
Chloride 0409-
4888-10 NDA
018803 Hospira, Inc.
FEI: 0409-
4888 25 VIAL, SINGLE -
DOSE in 1 TRAY
(0409-4888-10)
> 10 m
L in 1 VIA L,
S
INGLE -DOSE
(
0409-4888-02)
The i
nformation provided appears acceptable.
3.
2.P.3.4 Controls of Critical Steps and Intermediates ( Pfizer Puurs and Pfizer
Kalamazoo)
In-Process Monitoring and Control of Fill and Finish
Sterile filtration process controls and target range/acceptance criteria, and microbial
process controls and acceptance criteria are provided in Table 3.2.P.3.4.1 and Table 3.2.P.3.4.2 in the submission and are reproduced below.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
One page has been determined to be not releasabe: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
37 Aseptic Filling
During production, an in- process fill test is performed at
The
filling process controls and target ranges/acceptance criteria are provided in Table
3.2.P.3.4 -5 in the submission, and are reproduced below.
Capping
Capping process controls and acceptable ranges are provided in Table 3.2.P.3.4-6 and
are reproduced below .
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
38 Process Step Hold Times –
The table below provides the hold times of the DP in-process materials during
. All hold times following were verified and are
consistent with the validated media fill times, ensuring acceptable microbial control
during the DP manufacturing process. The processing steps are within
the maximum times d etermined by the validation which is
reviewed below in Section 3.2.P.3.5.
Freez
ing process controls and acceptable ranges are provided in Table 3.2.P.3.4 -7.
The acceptable range for freezing is - 90°C to -60°C and is defined as a critical process
parameter (CPP) .
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
39 Reviewer’s comment : In process monitoring and controls were defined for the
BNT162b2 manufacturing fill finish steps. The parameters defined are supported
by the process validation provided and appear acceptable. The controls defined
for sterile filtration agree with the parameters established from the
studies discussed in the validation for
(3.2.P.3.5). The integrity test parameters and wetting agents defined
also agree with the integrity test limits defined in 3.2.P.3.5. The
filters from will be used for the sterile filtration
of the DP bulk in the commercial operations. The information appears acceptable.
The t
ime limit defined for aseptic processing agrees with the parameters
established during the media fills for each line (3.2.P.3.5). The media fills on the
filling line support up to filling t ime; however , the
production limit has been set at . The media fills on the filling line
support up to filling time; however , a production limit
has been set at .
The pr
ocess controls set for capping on filling lines are within the
validation parameters defined in the capping process validation provided in 3.2.P.3.5. In process monitoring and controls appear acceptable.
3.
2.P.3.4.2 Time Out of Freezing
The BNT162b2 DP has an allowable time out of freezing during movement from
freezers to packagi ng and into shippers of each for transfer and limited to
total transfers. is used to ensure the product
temperature in the secondary packaging material does not exceed .
The
BNT162b2 DP has allowable out of condition post freezing at - 90°C to -60°C during
manufacture, packaging and transport of up to cycles reaching a
maximum of
Table 3.2.P.3.4-2 , reproduced below, shows the time allowed out of
freezing for the BNT162b2 DP.
N
ote: The same acceptable ranges are listed in the manufacturing process description
in Table 3.3- 8 Process Parameters for Storage and Shipping.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
40 Revi
ewer’s comment : The allowable times out of freezing are supported by
stability data for DP. Container closure integrity testing was performed on
samples that were exposed to worst case shipping hazards. All lots tested were
integral .
I
n addition, transfers of DP to freezers, into , and into shipping
containers w ere observed during the recent inspection f rom June 24 to July 2,
2021. Each of these transfers was timed and was far less than .
The information provided appears acceptable.
3.
2.P.3.5 Process Validation and Evaluation
MANUFACTURING PROCESS
3.2.P.3.5 Process Performance Qualification ( PPQ ) Data
The PPQ data from the LNP production and bulk DP formulation and fill/finish locations
(Pfizer Puurs, Pfizer Kalamazoo) w ere provided. An overview of the process validation
phases is described below.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
7 pages have been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
48 Visual Inspection
During inspection of the BNT162b2 filled vials, 100% automated or manual inspection of
the validation batches was performed, followed by Acceptable Quality Level (AQL)
sampling of the inspected vials. The requirement for the inspection process is that the
vials for AQL inspection must not exceed the acceptance criteria for critical ( ) ,
major ( ) and minor defects ( ). For each process validation lot,
(b)(4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
49 the number of filled vials that were inspected along with the total rejection percentages
are presented in the table below.
Drug Product
Lot Number of
Vials
Inspected Number of
Vials
Accepted Number of
Vials
Rejected Vials Rejected
(%)
A
n IR was submitted for clarification on the visual inspection process and a response
was received under STN 125742/0.57. According to Pfizer all PV lots above were
inspected via automated visual inspection. The allowable alert limit of rejects for visual inspection is (critical), (major), and (minor). All PV lots passed this acceptance criteria.
All v
alidation lots were AQL sampled following inspection ( ) and met the AQL
acceptance criteria for critical ( ), major ( ) and minor ( ) defects .
R
eviewer’s comment : Pfizer did not provide adequate information regarding the
visual inspection validation including which lots were inspected by automated methods and which were inspected visually as well as the acceptance criteria for
the allowable limit of rejects. The information provided appears acceptable.
Labeling and Packaging
The validation of integrated labeling and secondary packaging operations for commercial distribution involved running of product -filled vials through the
automated labeling and packaging equipment. This validation run included
testing.
The pr
ocess validation run included enhanced inspection to established Acceptable
Quality Level (AQL) limits for critical, major, and minor defects. The results complied
with the acceptance criteria which demonstrates suitable validation of the labeling and
packaging operations.
R
eviewer’s comment : Labeling and packaging of the BNT162b2 DP were
reviewed during the recent surveillance inspection conducted by OBPO in May 2021. No major issues were identified. Labeling and packaging appear acceptable.
Freezing
After the labeling and secondary packaging process, the packaged DP was frozen for
storage and distribution. The freezing of the product was monitored to ensure that the
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
50 process performs within the established limits. The process parameter for freezing of
the BNT162b2 DP is a freezing temperature of - 90 to - 60oC. All PV lots passed this
acceptance criteria.
R
eviewer’s comment : Freezing operations of the BNT162b2 DP were reviewed
during the recent surveillance inspection conducted by OBPO in May of 2021.
No issues were identified regarding this operation. The information appears acceptable.
H
old Times Pfizer Kalamazoo
The routine in- process hold times for the BNT162b2 DP manufacturing process were
confirmed during the manufacture of the process validation lots. Process validation lots
were subjected to a cumulative hold time study. The study
evaluated the cumulative effect of the maximum process hold times for each process
step, from , on the
microbiological and physicochemical quality of the DP. The maximum hold times are
established based on the hold times of the cumulative hold process validation lot .
Microbial testing was performed for held , or as
otherwise deemed appropriate. Hold time relevant to operations (
) are within those qualified by media fill which will be
presented in its own section below. The processing steps are within the
maximum time determined by validation. Additional
information is presented below.
The i
n-process hold times for each step in the manufacturing train were provided for
each PV lot, and will be deferred to OVRR for review.
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
One page has been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
52 H
old Times Pfizer Puurs
The routine in- process hold times for the BNT162b2 DP manufacturing process were
confirmed during process validation lot manufacture.
P
rocess validation lots were subjected to cumulative hold times to
evaluate the maximum process hold times for each process step, from
, on the microbiological and
physicochemical quality of the DP. The maximum hold times are established based on
the hold times of the cumulative hold process validation lot.
I
n addition, microbial testing was performed for held
or as otherwise deemed appropriate.
The ev
aluated in- process hold times for the process validation lots are listed in
Table 3.2.P.3.5-1 , which includes hold time data from DP lots
. The following table incorporates the
hold time data from Table 3.2.P.3.5- 1 and process hold times defined in Table
3.2.P.3.4 -1 for manufacturing activities.
(b) (4)
(b)(4)
(b)(4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
One page has been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
54 Val
idation of at Kalamazoo
(b)(4)
(b) (4)
(b) (4)
(b)(4)
(b)(4)
8 pages have been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
63 V
alidation of Aseptic Filling Process by Media Fills (Pfizer Kalamazoo)
Media fills were conducted for Lines to validate of the aseptic processing
steps for consistent manufacture of sterile products. Media fills are conducted
with all shifts included in the routine media fill schedule. Environmental and
personnel monitoring are also performed for each media fill .
(b)(4)
(b) (4)
(b) (4)
(b)(4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
64 Acceptance criterion .
R
eviewer’s comment : Lines are existing fill lines used to fill FDA
approved products and have been validated for filling other products. The media
fill studies included in this application appear acceptable with no issues identified and the filling line and environment appear to be in a state of control.
V
alidation of Aseptic Filling Process by Media Fills (Pfizer Puurs)
Media fills were performed to validate the aseptic process at Puurs for 2mL components on the filling line and vial line. Media fill re -qualification is required
for each filling line. All personnel that enter the filling area including process control
technicians, maintenance personnel, and quality assurance must take part in at least
.
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
6 pages have been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
71 S
terilization Processes for Product -Contact Equipment and Components (Pfizer
Kalamazoo)
(b)(4)
(b)(4)
11 pages have been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
83 S
hipping Validation
Pfizer’s facilities in Kalamazoo, MI and Puurs, Belgium perform DP manufacturing,
primary packaging, labeling, and secondary packaging operations for BNT162b2 DP.
Following these activities, BNT162b2 DP is shipped in its final packaging to US
receiving agencies and dosing sites directly or via the Pfizer US logistics center in Pleasant Prairie, WI (PPLC).
The f
ollowing shipping methods are used (or planned):
•Tr
ansport to Logistics Centers and distribution sites occur at shipping conditions
of -90 to - 60°C via passive thermal conveyance or at shipping conditions of -
20±5°C via active or passive shipping conveyances. Shipments at -90 to - 60°C
occur within thermal shipping conveyances that passively maintain temperatureconditions of - 90 to - 60°C using dry ice.
•S
hipments at - 20±5°C may occur under active control via t emperature- controlled
vehicle (TCV). All TCV shipments are monitored for temperature duringshipment to ensure that the temperature within the TCV remains within - 20±5°C,
and temperatures during transport are verified.
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
84
•
Planned for future implementation (estimated
November 2021) .
All shipments of BNT162b2 DP are continuously temperature monitored to confirm that
the appropriate temperatures are maintained. The worst -case location identified during
the OQ of the thermal shipper, i.e., , is identified for
placing temperature monitor during routine shipments .
Shipment Methods
Method Temperature
requirements Qualification status Controls used/
comments
Softbox -90°C to -60°C
using dry ice.
OQ completed:
-Minimum and maximum chamber
studies (worst case temperature
conditions for )
PQ completed:
- shipments using
representative
(average transit time of
) from Puurs, Belgium, to
Kalamazoo, Michigan, US
-Simulated transportation hazards
such as Continuously
temperature
monitored in worst
case location with
GPS
Temperature
Controlled
Vehicle -20°C ±5°C OQ completed
PQ ongoing Continuously
temperature
monitored and
active control in
Vehicle
OQ ongoing
PQ ongoing Currently not in use
Qualification of Passive Thermal Conveyance with Dry Ice
The r esults from the three OQ tests for the temperature conditions are
presented in Table 3.2.P.3.5-1 (Maximum temperature recorded was for a
duration).
Summary results from the performance qualification are shown in Table 3.2.P.3.5- 2.
The monitor data demonstrated that the shippers performed within the - 90°C to - 60°C
temperature range. The lowest recorded temperature between the three shipments was
and the highest was .
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
85
OQ of the Passive Thermal Conveyance with Phase Change Material
A chamber test performed with a minimum load and maximum volume strategy
simulating worst -case temperature conditions and shipping durations demonstrated the
thermal conveyance is capable of maintaining . Results for the temperature conditions are presented in Table 3.2.P.3.5- 3. Additional OQ studies and
PQ studies are planned.
Qualification of the Frozen Temperature Controlled Vehicle (TCV)
DP manufacturing facilities may ship BNT162b2 DP in its final packaging to Logistics
Centers and distribution sites for temporary storage and deconsolidation via - 20°C ±5°C
TCV). OQ testing was performed
Qualification of TCVs for transport from manufacturing sites in the US to Logistics Centers and distribution sites in the US and for transport from manufacturing sites in the EU to Logistics Centers and distribution sites in the EU are ongoing.
Reviewer’s comment : In BLA 125742/0.24 Pfizer stated that all shipments of
BNT162b2 DP will be continuously temperature monitored to confirm that the
appropriate temperatures are maintained via passive thermal conveyance in the TCV.
In addition, Pfizer clarified that they have not yet started shipping using the
controlled shipping method from either Pfizer Puurs or Pfizer Kalamazoo
and qualification studies are expected to be completed by November 2021.
Pfizer also stated they will provide results of these studies prior to implementation.
The studies supporting the
shipping method and transport were on- going at the time of BLA approval.
The shipping information appears acceptable.
Simulated Shipping Study (exposure to )
A simulated shipping study was performed to simulate realistic shipping conditions that expose representative product to concurrent shipping hazards based on
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (5), (b) (7)(E)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
86 standards. Af ter exposure to simulated distribution hazard
conditions, samples were evaluated for CCI and DP quality to determine the physical
and chemical stability of the product in its primary container.
The s
imulation included
Results
are shown in Table 3.2.P.3.5 -11 in the BLA. and indicate that container closure integrity
was maintained during shipping simulations.
R
eviewer’s comment: Container closure integrity testing is performed on
samples that were exposed to worst case shipping hazards. All samples tested
were integral. Therefore, the hazards of routine shipping do not appear to impact
the integrity of the container closure system. The shipping hazards were performed to mimic the global supply chain shipping logistics as a worst -case
scenario. The information appears acceptable.
3.
2.P.5 Control of Drug Product
3.2.P.5.1 and 3.2.P.5.6 Specification(s) and Justification of Specification(s)
Pfizer lists quality attributes (QATs) as specifications for BNT162b2 DP (tested at
release and throughout shelf life). DMPQ performs primary review of CCIT. The analytical methods used by Pfizer are analysis. Refer to
3.2.P.5.3 for more information.
3.
2.P.5.3 Validation of Analytical Procedures (Container Closure Integrity Testing)
is Pfizer’s standard CCIT method for routine testing (at T 0,
months) on stability lots. Separate 3.2.P.2 Microbiological Attributes documents
were provided for both the Puurs and Kalamazoo sites.
A
ccording to Pfizer, the original validation of the test method verified
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
87 A
t Kalamazoo, Pfizer performs the
A
t Puurs, Pfizer performs the
A
cceptance criteria for the test method consist of the following:
For
the test method, the challenge consisted of
R
eviewer’s comment : CCIT validation incorporated worst -case capping and
shipping conditions . The CCIT method at Pfizer Kalamazoo appears consistent
with standard industry methods. Pfizer reports that the CCIT method at Pfizer
Puurs is validated, but the method appears less than optimal with the
positive control and analysis. An IR was sent
for further evaluation of the method validation protocol, summary
(b)(4)
(b)(4)
(b)(4)
(b) (4)
(b)(4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
88 report and assay performance procedure that is followed at Pfizer Puurs and
Pfizer Kalamazoo. In amendment 125742/0.43, Pfizer states that Pfizer Puurs is not currently registered as a site for CCIT for DP stability. Protocol #CCT -
052421- R0-JJB provides documented evidence of the transfer of the CCIT
Test (Test Method TM100010635) from the Pfizer Andover, MA site to the
Pfizer Kalamazoo, MI site. The test method at the Pfizer Kalamazoo, MI site is now identified as TM -01-9305A / MCD -086951. TM100010635 was evaluated,
see section 3.2.R. The information appears acceptable.
3.2.P.5.4 Batch Analyses
The Batch Analysis section reflects the global development effort and the DP lots
included are not limited to those produced in market -specific registered manufacturing
facilities. In the submission, in Table 3.2.P.5.4- 1, Pfizer listed batches that were
identified as non- clinical (the first batch produced in March 2020), clinical or emergency
supply. Of those batches, batches support either stabili ty, PPQ, or both. From
that list, Pfizer identified the following batches (total of at the respective DP facilities)
that support PPQ (or process validation) and/or stability, as indicated, for the BLA:
DP Lot # Manufacture
Date LNP Site DP Fill / Finish
Site # Vials On
Stability
(yes/no)
Puurs Puurs Yes
Puurs Puurs Yes
Kalamazoo Kalamazoo Yes
Puurs Puurs Yes
Puurs Puurs No
Puurs Puurs Yes
Kalamazoo Kalamazoo Yes
Puurs Puurs No
Kalamazoo Kalamazoo No
Kalamazoo Kalamazoo No
Kalamazoo Kalamazoo Yes
Puurs Puurs No
The analytical testing strategy applied to BNT162b2 DP has evolved throughout the
development history. Pfizer reports that all of the PPQ batches were tested against quality attributes, including, those tests under DMPQ purview with acceptance criteria defined the same as in 3.2.P.5.1 Specifications, appearance, appearance (visible particulates), , vial content (volume), bacterial endotoxin, and
sterility.
Pfizer provided summaries of the results in tables in the submission for all prementioned batches. Pfizer reports that all results met the acceptance criteria (AC)
at the time of release.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
89 Reviewer’s comment : Pfizer reports no out -of-specification (OOS) results for
appearance, appearance (visible particulates), , vial content
(volume), bacterial endotoxin, or sterility at release for any of the PV or
additional PPQ batches. All the PV batches ( for Kalamazoo and for Puurs) are accounted for in the batch analysis. The AC for the quality attributes, under DMPQ purview, did not change from the reported commercial AC (specification). Evaluation of the results and AC, including analytical met hod
evolution, for the other quality attributes is deferred to the OVRR reviewer. Pfizer did not include CCIT results in the batch analysis ; however, Pfizer reports
that CCIT is tested at release and stability at months. No CCIT failures were reported. The information provided appears acceptable.
3.
2.P.7 Container Closure System
Pfizer provided separate 3.2.P.7. Container Closure System documents for the Puurs
and Kalamazoo facilities, respectively.
The pr
imary container closure system for the BNT162b2 vaccine consists of the
following components:
Component Description
Vial 2 mL Type I borosilicate glass vial, 13 mm finish
Vial Stopper 13mm vial stopper composed of gray elastomer (bromobutyl rubber) coated with
Vial Seal 13 mm aluminum vial seal with tamper -evident PP flip off cap
Vial (Product Container)
The vial consists of a clear and colorless Type I borosilicate glass vial with a 2 mL nominal fill volume and 13 mm finish (lip/flange) diameter. Pfizer reports the following vial manufacturers (suppliers):
Vial Manufacturer Vial used at Pfizer site:
Puurs
Puurs
Puurs
Puurs
Puurs
Kalamazoo
Kalamazoo
Kalamazoo
Kalamazoo
Kalamazoo
P
fizer reports that the vials from all the manufacturers have the same materials of
construction and critical dimensions, and the vials from each supplier are considered
equivalent in terms of processability, container closure integrity and DP interaction. The
(b) (4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
90 vial meets requirements for Type I glass
containers. The vials are sterilized by by Pfizer at each DP facility.
Pfizer reports the same dimensions for vials from all suppliers as follows:
Measurements Limits
Finish Outside Diameter
Finish Inside Diameter
Finish Lip Height
Body Outside Diameter
Overall Height
The testing performed on the vials at the DP manufacturing sites is as follows:
Test Requirements
Visual Inspection Performed per
Physical Inspection Performed per
Type I Glass tests Manufacturer’s certification per
Vial Stopper
The elastomeric closure is a vial stopper composed of gray bromobutyl
rubber that is not manufactured from dry natural rubber (latex). The vial stopper meets the requirements of requirements for functional
tests of . Vial stoppers are
sterilized by depyrogenated by Pfizer at each DP facility. Both facilities, Puurs and Kalamazoo, use the same stopper suppliers,
.
The dimensions of the vial stoppers:
Measurements Limits
Height
Plug Outside Diameter
Flange Thickness
Stopper Functional Properties :
For functional properties, Pfizer performed testing as follows:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
91 The t
esting performed per on the vial stoppers is:
•Visual Inspection
•Dimensional testing
•Identification of
Vial Seal (Cap)
The vial seal is a 13 mm flip- off design constructed of aluminum with a PP tamper -
evident flip- off vial seal that has no embossing. For both facilities, Pfizer Puurs and
Pfizer Kalamazoo, the cap is supplied by
and, for Kalamazoo only,
is included as an additional supplier.
P
fizer reports the dimensions for seals as follows:
Description Limits
Flip-Off Cap Diameter
Seal Inner Diameter
Overall Height
The testing performed per on the vial seal is visual and physical inspection.
(b)(4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
92 Secondary Packaging Components
DP vials are placed into corrugated boxes with lids.
3
.2.A APPENDICES
3.2.A.1 Facilities and Equipment
PFIZER, INC., CHESTERFIELD, MO (USA):
MANUFACTURING AND DS/DP RELEASE AND STABILITY TESTING
(b) (4)
(b)(4)
(b) (4)
One page has been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
94 U
tilities Pfizer Chesterfield
Critical utilities include purified water (PW), clean steam, compressed air,
. The water system has been qualified to meet
requirements; furthermore, the PW is routinely sampled and tested to meet
chemistry and microbial limits of .
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
95 Reviewer’s comment : Pfizer Chesterfiel d PW is routinely sampled and tested
to meet standards.
The information appears acceptable.
Heating, Ventilation, and Air Conditioning Pfizer Chesterfield
There are air handling units that supply conditioned air to the BNT162b2
production areas. Air handling units (AHU) provide
100% filtered outside air with to (ISO -), wher e
the were manufactured and the
is performed. provides 100% filtered outside air with
and clean preparation areas (non- classifie d).
provides 100% filtered outside air with
manufacturing suite for BNT162b2. While the manufacturing area is classified as ,
the supply air is high efficiency particulate air (HEPA) filtered to minimize the
introduction of environmental contaminants. Qualified
provide additional environmental control.
Reviewer’s comment: Pfizer provided the AHUs that service all BNT162b2
manufacturing areas, and there is within these rooms. Pfizer
Chesterfield has updated the level of control by of supply
air to the manufacturing areas. The step is the beginning of the BNT162b2 manufacturing process with
steps in the subsequent DS and DP manufacturing
operations. This information appears acceptable.
Environmental Monitoring Pfizer Chesterfield
The Suite environmental monitoring (EM) qualification served as justification for the routine EM program, EM frequencies, acceptance criteria (alert and action levels), and facility environmental control procedures. EM parameters were conducted both at rest and in operations.
Controlled, classified areas ( , ISO , and ISO ) are monitored for
. Applicable
standard operating procedures (SOPs) contain summaries of the EM tests performed,
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
96 frequencies, and alert/action levels. EM trend reports are generated on a
basis to evaluate adequacy of environmental controls and quality levels.
action levels are provided in Table 3.2.A.1- 2 in the
submission, and action levels are provided in Table
3.2.A.1 -3 in the submission (combined below).
monitoring action levels are provided in Table 3.2.A.1- 4 in the submission
(duplicated below).
ISO Class Action Level
air and personnel monitoring action levels are provided in Table 3.2.A.1- 5
in the submission (duplicated below).
Sample Type Action Level
Reviewer’s Comment: EM is performed routinely. The acceptance criteria
appear appropriate for upstream production. The information appears
acceptable.
Contamination and Cross Contamination Controls Pfizer Chesterfield
General contamination controls include:
Additional microbial controls include:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
97 R
eviewer’s comment: Cross -contamination and microbial controls designed to
minimize contamination from multiple sources including people, product,
equipment, waste, and environment appear acceptable.
E
quipment Summary Pfizer Chesterfield
This section contains an overview of the process equipment, equipment qualifications, and the equipment cleaning and sanitization (if applicable) for the equipment used to manufacture the at Pfizer Chesterfield. Prior to use for BNT162b2
manufacturing, all critical equipment underwent an equipment
verification process to verify that equipment is properly calibrated, maintained, and deemed fit for use in manufacturing.
(b)(4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
One page has been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
99 The inf
ormation appears acceptable.
E
quipment Cleaning Validation Pfizer Chesterfield
All equipment utilized in the CMF for manufacturing is either single-
use or dedicated. All dedicated equipment undergoes a complete
to use, is thoroughly cleaned and sampled to ensure no product carryover prior to
use. Components on each piece of equipment that control parameters that could
potentially impact product quality are calibrated prior to use and maintained on a calibration schedule.
The pr
oduction equipment is regularly cleaned per site procedures. Fixed equipment is
cleaned using the or per the appropriate SOP (
). Portable equipment, such as
in a parts or glass washer. In general,
procedures consist of
are used as cleaning agents. All final rinse steps utilize .
E
quipment cleaning validation was performed during routine processing. Samples were
collected in accordance with approved site procedures. The results of the cleaning validation (Table 3.2.A.1- 3 through Table 3.2.A.1- 12) were provided in the submission
(summarized below).
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b)(4)
(b) (4)
(b)(4)
One page has been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
101 Reviewer’s comment: Acceptance criteria were met for all equipment for which
cleaning validation results were provided.
The i
nformation provided appears acceptable. However, during the execution of
the cleaning validation, fifteen deviations were encountered,
Disinfectant Effectiveness Pfizer Chesterfield
The effectiveness of the various disinfectant agents used against microbial isolates
recovered from the manufacturing areas, as well as test organisms have been evaluated following guidance. The effectiveness of general and sporicidal
disinfectants was determined using a m inimum reduction for vegetative bacteria
and yeast and effectiveness of sporicidal disinfectants was determined using a minimum reduction for spore- forming bacteria and mold.
R
eviewer’s Comment: The sponsor stated that the disinfectant efficac y study
was performed using methodology and with microorganisms.
The study was not provided as part of the BLA. The study INX100155064, a general summary report of disinfectant efficacy study performed at other FDA approved/licensed buildings was reviewed as part of the EUA and found acceptable. Additionally, facility cleaning SOP -MG-05206 was reviewed as part
of the EUA and found acceptable. The qualification of the cleaning efficacy study for CPF appears to be low risk given the operations performed and the compliance history of the site. The information provided appears acceptable.
W
YETH PHARMACEUTICALS LLC, ANDOVER, MA (USA): DRUG SUBSTANCE
MANUFACTURING AND DS/DP RELEASE AND STABILITY TESTING
Pfizer Andover Clinical Manufacturing Facility (ACMF)
ACMF, located in Building is a new multi -product building that commenced
manufacturing operations in March 2019 and is intended to manufacture DSs for
(b) (4)
(b) (5), (b) (7)(E)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
102 various clinical products. Building is part of the Pfizer Andover campus that includes
other production facilities and laboratories that have been inspected numerous times by the FDA. ACMF is managed by Pfizer Biotherapeutics Pharmaceutical Sciences and is operated under Pfizer Global Quality Standards and Pharmaceutical Sc iences Quality
procedures. ACMF has experience with similar routine manufacturing operations (including ) for other biological
products.
ACMF has separate cleanroom production suites. Production suites consists of suites ( ) and suites ( ). Suite is
dedicated for the manufacturing of BNT162b2. Suite is located on the floor and solutions preparation and support are also located on the floor.
The facility layouts for the floor were provided in Section 3.2.A.1: Andover ACMF General Facility Layout Building . Both Suites are equipped with
personnel air locks (PAL), material air locks (MAL), and waste air locks (WAL). Suite
includes an
Suite contains a
. Between the suites is a
suites contain (ISO -). Solution preparation is performed on the floor
(ISO- ) and weighing and dispensing (ISO -) is on the floor.
The production suites are supported by process operations support, validated utilities, controlled warehousing for receiving and storage of raw materials and supplies, and shipping of materials. Critical utilities (compressed air, clean steam, and PW) are generated in Building . However, are supplied from bulk
.
The ACMF facility, equipment, and utility systems are supported by preventive maintenance and calibration programs. It is also designed for segregation and unidirectional flow of personnel, equipment, materials, samples, product, and waste. Heating, ventilation, and air conditioning (HVAC) air filtration and pressurization create different zones (classification), and the EM system ensures that the appropriate cleanliness and segregation is maintained for manufacturing. Temperature is set at
for manufacturing areas and is monitored and alarmed.
is monitored in the manufacturing areas. To mitigate cross -contamination risks,
all open processes are performed in , and most operations are
performed using systems.
Additionally, ACMF associated Analytical Research and Development (ARD) labs will be used for DS and DP release and stability testing. The ARD laboratories located in Building consists of newly designated BNT162b2 mRNA vaccine laboratory spaces, located within and alongside the pre- existing ARD laboratory areas and systems. Pfizer
ARD laboratories in Andover and Chesterfield operate as one organization under one
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(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) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
103 set of procedures, documentation systems and following the same Pfizer Quality
standards.
Facil
ity Flows
Procedures ensure appropriate flows, personnel gowning, and sanitization of the facility and equipment. Flows within the facility are described below.
A
ccess Control and Personnel Flow: All facilities are access -controlled and gowning
procedures are supported by defined hygienic measures and guidelines. Increased gowning is required based on operations performed in the manufacturing areas. To reduce the risk of product contamination and provide personnel protection, personnel and material entry into separate manufacturing areas are segregated.
P
roduct Flow: All raw materials are released by the Quality group and are weighed and
dispensed into closed, labeled containers. Solution preparation occurs in classified processing areas where solutions are batched and packaged according to master records. Prepared solutions are transported to Suite
.
M
aterial and Equipment Flow: Fixed, stainless steel (SS) equipment is
per validated automation control and approved instructions. Clean and soiled mobile equipment is staged in separate designated areas within ACMF. Mobile equipment is transferred to and from the production suites and support areas via Controlled Not -
Classified corridors and elevator, and non- classified service corridors per approved
instruction. Separate paths exist for the flow of clean and soiled equipment.
A
ll process equipment utilized in the BNT162b2 DS process is
and introduced into Suites via the MALs. Once in the suite, the equipment is prepared for processing through final cleaning and set up with disposable components. After manufacturing is complete, the single use equipment is disconnected and discarded as waste. Any non- disposable product contact equipment is .
W
aste Flow: Waste is placed into closed containers prior to transfer. Hazardous waste
is appropriately labeled and transferred through the area’s waste airlocks.
R
eviewer’s comment: A general overview of BNT162b2 DS manufacturing
areas was provided. The facility appears suitable sized and adequately designed to manufacture BNT162b2 DS. All manufacturing areas are access controlled, and diagrams for personnel, samples, product and product intermediate, consumable materials, equipment, and waste flows were provided. Flow patterns do not appear to present unnecessary challenges that could potentially introduce contaminants during manufacturing.
M
edia and Buffer Preparation Area:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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104
Reviewer’s Comment: From the descriptions provided, the buffer and
equipment preparation areas appear acceptable.
Utilities ACMF
Critical utilities include WFI, clean steam, and compressed air. The WFI storage
Clean steam is generated via
Compressed air is generated by
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
105 R
eviewer’s comment: The critical utilities of WFI, clean steam, and
compressed air were described in general terms. The qualification of the utilities
for ACMF appear acceptable.
Heating, Ventilation, and Air Conditioning ACMF
Building HVAC systems are designed to provide air volume, air flow, HEPA filteredair, and room pressurization. The supply air processed by the HVAC units is deliveredthrough HEPA filtration. The manufacturing areas were designed to minimize thepossibility of product contamination by using separate air handling units, pressuredifferential zones, air locks, gowning rooms, and defined flows for personnel,equipment, materials, and waste.
Tem
perature is set at for manufacturing areas and is monitored and alarmed.
is monitored in the manufacturing areas. To mitigate
cross- contamination risks, all open processes are performed in , and most
operations are performed using systems.
The ai
r handling units supporting BNT162b2 DS manufacture are listed in Table
3.2.A.1 -2 in the submission (duplicated below).
The HV
AC system has been qualified, demonstrating that the system operates to
design specifications and maintains the facility within design parameters. Qualification tests the system’s ability to provide required air changes, pressurization, temperature,
and relative humidity in the production areas. Rooms were monitored for
. The integrity of the HEPA / f
ilters were verif ied
and certified.
D
ifferential pressures are maintained and monitored between adjacent spaces, and
. Additionally, temperature is
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b)(4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
106 monitored and alarmed throughout the facilities and relative humidity is monitored within
the ISO Class manufacturing areas.
R
eviewer’s comment: The HVAC system has been qualified and maintains
ISO- and ISO - manufacturing areas. Pfizer clarified that each manufacturing
suite and buffer preparation area has a dedicated air handling unit to mitigate any risk of cross contamination, and provided the diagrams showing the different air
handling units for Level and Level . The room classifications, temperature, relative humidity, and gowning are appropriate for the operations performed i n
each area. While the qualification of the HVAC system in Building was not provided in the BLA, qualification of the HVAC system in approved/licensed buildings at the Andover site have been observed/assessed during previous FDA inspections. The HVAC systems appear acceptable.
Environmental Monitoring ACMF
ACMF EM qualification of classified areas served as justification for the routine EM program, EM frequencies, acceptance criteria (alert and action quality levels), media types, incubation, maximum personnel room capacity and facility environmental control procedures. EM was conducted both at rest and in operation, and included
. At rest is
defined as the status of the facility with all services functioning, standard processing
equipment installed, and with no personnel or manufacturing activities being performed other than EM. Unlike at rest, the definition of in operation includes routine personnel and production- related activities being performed or simulated. A facility is in operation
status from the time of the
.
Co
ntrolled, classified (ISO -, ISO- , and ISO-) areas are monitored for
. Summaries of the
EM tests performed, frequencies, and alert/action levels are found in the applicable SOPs. Trending of EM is generated to evaluate adequacy of
environmental controls and quality levels.
(b) (4)
(b)
(4)
(b)
(4)
(b)
(4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4)
(b)
(4)
(b)
(4)
(b)
(4)
(b) (4)
(b) (4)
(b)(4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
107 R
eviewer’s Comment: EM is performed routinely. In Amendment 125742/0.43,
Pfizer clarified the definition of at rest and in operation, which have been
incorporated into the EM narrative above, and that the limits
are applicable for both at rest and in operation monitoring. The EM program appears acceptable.
Contamination and Cross- Contamination Controls ACMF
Suites are campaign dedicated to manufacture BNT162b2. Cross contamination controls include use of
. All
equipment are cleaned, and nondedicated product contact equipment are changed over
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
108 between uses for different products. In campaign dedicated areas, a clearance of
product, components, documentation, and equipment must be performed with an area inspection at the end of the campaign. Surfaces and equipment exteriors are cleaned according to approved procedures, and procedures are in place for special sanitization activities in response to EM excursions or breaches in normal environmental controls. Routine EM is performed to ensure that room classifications are maintained.
Environmental controls are maintained via HVAC design and control, procedural controls for gowning and flow, and facility and equipment surface sanitization.
are used for non- critical operations (sample aliquoting) and critical operations,
such as making .
Procedures for labeling, flow, storage, and use of materials and equipment are established to avoid potential mix -ups or cross -contamination in manufacturing areas.
Product processing takes place in areas that are product dedicated on a campaign basis. In campaign dedicated areas, a clearance of product, components, documentation, and equipment together with an area inspection at the end of the campaign provides assurance that no batch specific materials or documents remain, and that the area may be used for the manufacture of a different product.
Control and Cross -Contamination Controls are summarized below.
Contamination from other products : Operations take place in areas that are dedicated
for use with a single product on a campaign basis, with a documented changeover cleaning verification and clearance between uses for different products. All solutions and materials required for operations are specified in approved procedures and production records. Product and non- product solutions are transferred in portable
bioprocess containers. All product and non- product solution containers are identified
according to description, batch number, and storage conditions.
Contamination from equipment: Status of fixed equipment is indicated and tracked by
validated automation control, and the status of non- fixed equipment is indicated in
accordance with approved labeling procedures. Clean and soiled equipment are stored closed, in separate designated areas within the manufacturing suites, and have separate flow paths. Procedural and validated automation controls exist to ensure that equipment is only used with its designated product. In addition, single use technology is utilized within the facility for many product processing operations.
Contamination from people: Gowning procedures are designed to minimize
contamination and cross -contamination. Gowning is appropriate for the operations.
Gowns are changed when damaged or soiled, and discarded upon exiting each production area. Gloves are changed between working with different products within the facility. Fresh, pre -sterile, single use gowning is required prior to performing open
operations in the bulk fill room. Personnel monitoring is conducted per site procedures. Contamination from system failures: Environmental controls for parameters such as
differential pressure, temperature, and relative humidity controls are continuously
(b) (4)
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109 monitored and alarmed. Critical equipment and systems are powered by emergency
back -up power systems. Critical control systems are on uninterrupted power supply to
allow continuous operation during power outages. Site procedures exist for disaster recovery and response to unplanned system failures of monitoring systems and environmental control systems.
Contamination from Waste: Liquid process waste is disposed through the facility waste system, which is equipped with . Liquid
waste is treated and discharged in accordance with local and state regulations. All solid waste is removed from the facility on a routine basis. Procedures exist for handling and disposal of biohazardous waste in dedicated, single- use containers. Hazardous
chemical waste is removed from the manufacturing areas on a regular basis in accordance with approved procedures. Procedures exist for routine facility cleaning, sanitization, and spill response for containment and remediation of process spills. The product changeover program is a procedural approach for providing assurance that potential cross -product contamination from one manufacturing process to the next does
not occur. The Quality group reviews and approves the changeover documentation.
All product processing areas or systems undergo a product clearance after completion of a product campaign. These area product clearances are performed and documented by trained personnel in accordance with approved procedures and physical inspection of the area. Execution of product clearance is documented in cGMP records, which are
reviewed and approved by manufacturing and quality as part of the changeover approval process.
Reviewer’s comment: Cross -contamination controls are designed to minimize
contamination from multiple sources including people, product, equipment, waste, and environment and appear acceptable. EM is performed in all classified areas, and action and alert limits appear acceptable. In Amendment 125742/0.43, Pfizer clarified the ACMF suites ( ) are segregated manufacturing suites that were not used for any product prior to BNT162b2 DS manufacturing. The suites and product contact equipment used for BNT162b2 are dedicated to the production of BNT162b2. No other product is manufactured in the ACMF suites or used with the dedicated equipment, and production of BNT162b2 in ACMF is ongoing with no plans to change- over to
another product.
Equipment Summary ACMF
This section contains an overview of the process equipment, equipment qualifications, and the equipment cleaning and sanitization (if applicable) for the equipment used to manufacture the DS at Pfizer Andover.
Critical Process Equipment:
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111 E
quipment Qualification ACMF
All equipment used in the manufacturing process and equipment preparation meet
specific requirements and are qualified for their intended use. Equipment qualification is
performed for new equipment or changes to existing equipment. Installation qualification (IQ) and OQ provide evidence that the equipment/systems are installed and consistently operate in accordance with design and pre- defined acceptance
requirements. The routine calibration frequency is defined in the qualification report. The PQ demonstrates that equipment or systems will consistently perform per pre-determined acceptance criteria.
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112 Equipment Cleaning Overview ACMF
The product contact equipment and parts used for BNT162b2 are single use or
campaign dedicated and cleaned using validated procedures.
C
leaning Proc edures:
The production equipment is regularly cleaned by (fixed equipment) or (portable equipment, hoses, etc.). Both consist of
Monitoring of the
cleaning processes during routine production is performed via testing for
C
leaning Validation Overview:
Cleaning validation is performed to demonstrate that the intended cleaning procedure is
efficient and can consistently remove residual product,
. of equipment and is applied during
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113 cleaning validation, where appropriate. Sample plan and locations (based on most
difficult to clean and representative locations) are defined in the cleaning validation protocol and procedures and specific to equipment being cleaned. Cleaning verification is performed when cleaning validation is in process or is not in place. Cleaning verification sampling will be performed on any batches not being sampled for cleaning validation.
C
leaning validation will be performed for the . No product
contact parts are washed in the parts washer. Product contact small parts (
) are cleaned via
cleaning procedure in suite. The procedure includes a
.
C
leaning validation consists of the following:
P
ost cleaning validation, periodic cleaning verification (based on risk approach) is
performed to provide ongoing assurance regarding the state of control of validated cleaning procedures.
R
eviewer’s comment: A description of the BNT162b2 manufacturing
equipment was provided. Cleaning verification is performed if cleaning validation is not performed, as in the case of small product contact items and hoses cleaned manually via . The cleaning validation plan appears acceptable.
C
leaning Validation information
Cleaning validation was performed on only the is
product dedicated, and the
The acceptance criteria are found in the
table below
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117 Disinfectant Effectiveness ACMF
The effectiveness of the various disinfectant agents used against microbial isolates
recovered from the manufacturing areas, as well as test organisms have been evaluated following information chapter. The effectiveness of general and
sporicidal disinfectants was determined using a minimum reduction for vegetative bacteria and yeast and effectiveness of sporicidal disinfectants was determined using a minimum reduction for spore- forming bacteria and mold.
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118 R
eviewer’s Comment: The sponsor stated that the disinfectant efficacy study
was performed using methodology and with microorganisms.
The disinfectant efficacy study appears acceptable.
Computer Systems A CMF
The critical steps in BNT162b2 drug manufacturing include ,
which use equipment with automated control by computer systems that are identified in
the table below.
The sy
stems have local control using programmable logic controllers (PLCs) that are
part of the overall automation strategy. The Supervisory Data and Collection (SCADA) component of the automation provides an operator interface and a means to collect and archive data in the .
A
CMF uses to control and monitor equipment. The
validation activities of and associated PLCs included installation/operational qualification (IOQ), which were completed and approved by quality assurance and summarized in Qualification Report. An electronic records and electronic
signature (ERES) and Data Integrity (DI) assessment of the computerized system was carried out in accordance with Pfizer’s DI and Data Lifecycle Controls policy associated with data and operations. recipes for specific to BNT162b2 were
approved and implemented in accordance with the change management procedure to create and modify recipes in ACMF. A summary of the critical steps controlled by the computer systems are described below.
(b) (4)
(b) (4)
(b) (4)
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The parameters controlled and/or monitored by the automated control systems in BNT162b manufacturing process include:
Reviewer’s Comment: In Amendment 125742/0.57, Pfizer provided a list of the
critical BNT162b2 DS manufacturing steps that are computer -controlled with a
brief description of the validation process and parameters monitored, which have been incorporated into the narrative above. IOQ was performed according to site procedures and documented, which appears acceptable.
Pfizer Andover Suite
Pfizer Andover is currently licensed for manufacturing recombinant DNA derived protein DS intermediates and DSs using
. There is no manufacturing of
products containing penicillin, cephalosporins, live viruses, spore- forming organisms, or
cytotoxic drugs. The categories of DS are found in Table 3.2.A.1- 1 in the submission
(duplicated below).
(b) (4)
(b) (4)
(b)
(4)
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120 Fac
ility Overview
Building is a -story building containing manufacturing suites , and now
Suite . Suites are multiproduct suites, and Building allows for
concurrent multiproduct manufacturing, with programs and operating procedures for
gowning and segregation/directional control of flows of personnel, equipment, tools, instruments, materials, samples, and waste to mitigate contamination/cross
contamination. BNT162b2 DS manufacturing operations occur within Suite .
• Suite is a new segregated manufacturing suite dedicated to the
production of BNT162b2 created from existing Suite . Suite of Building has
been inspected by the FDA (January 2019; Voluntary Action Indicated (VAI)) and is used to manufacture other FDA approved products
).
• Suite has dedicated personnel, equipment and material entrances and exits, serviced by a dedicated HVAC system.
• Suite design, construction, and materials of construction details are consistent with existing suites.
• All support services and utilities utilized in Suite are utilized by existing suites.
• All raw materials, supplies, and shipping of materials utilize the same controlled warehousing, receiving and storage as other suites.
• All facilities, process equipment, and utility systems are supported by procedure-
based preventive maintenance and calibration programs utilized by the existing
suites.
• All current operations in Suite will be consistent with the general operational and quality policies and procedures as the existing suites.
Quality Control laboratories associated with COVID -19 are located in Building and
Building .
The process flow diagram indicates that any open operations, consisting of aseptic connections, are performed in the and no open operations occur outside of the
. All components in the , and final filtration and
dispensing are . The equipment used in the are dedicated and
.
Area Classifications
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121 Areas in Suite used for the manufacturing of BNT162b2 are classified based on the
manufacturing operations occurring in those areas. Area classifications are found in Table 3 in the submission (duplicated below).
A
rea Classification and Biosafety Level (BSL) for the COVID -19 Vaccine Drug
Substance Manuf acturing Facility
Temperature and Relative Humidity
Temperature is monitored and alarmed in the raw material and solution storage areas, and manufacturing suites. The processing areas, Suite , and solution preparation area are set to and monitored and alarmed at . The raw materials warehouse is monitored and alarmed at . All ISO - and ISO - manufacturing areas are
operated and monitored within a relative humidity range of .
Flows
Personnel Flow: Personnel flow is controlled through restricted access and signage. Personnel may not move between these areas freely but must de- gown and exit one
area and enter another through the designated gowning rooms.
P
roduct, Material, and Waste Flow: All raw materials used in Suite are released by the
Quality group. The exterior surfaces of instruments and supplies are
Suite . The exterior surfaces of material containers are
into the controlled areas of Suite through designated
equipment and MALs. There are no transfers of process intermediates from Suite , and in-process samples are transported in . Drug substance is dispensed
into within the designated areas of Suite .
BNT162b2 DS exits Suite for via the MALs and
corridor. Waste is placed into closed containers prior to transfer. Hazardous waste is appropriately labeled and transferred to the suite out -lock. Waste is transferred through
the area’s equipment and material in/out -lock.
E
quipment Flow: Process equipment is labeled with status. Fixed equipment is
. Clean and soiled, product contact mobile equipment and parts are
staged in a contained fashion in separately designated areas within Suite and are cleaned within the suite. Non- product contact mobile equipment and small parts may be
transferred to and from the Product Services Equipment Processing areas. Separate paths exist for the flow of clean and soiled equipment. All process equipment utilized in the BNT162b2 DS process are . The equipment are introduced into Suite via the materials airlocks associated with each suite where the equipment are
. Once in the suite the equipment are prepared for processing through final
(b)
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(b)
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(b) (4)
(b) (4)
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(b)
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(b)
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(b)
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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122 cleaning and set up with disposable components. After manufacturing is complete the
single use equipment are disconnected and discarded as waste.
R
eviewer’s Comment: A general overview of BNT162b2 DS manufacturing
areas in Suite is provided. All manufacturing areas are access controlled, and gowning is progressive. Diagrams for personnel, product, consumable mat erials,
equipment, and waste flows were provided. There are different flows for clean and soiled equipment. Flow patterns do not appear to present unnecessary challenges that could potentially introduce contaminants during manufacturing. The information appears acceptable.
D
rug substance is manufactured in ISO - areas with DS in a . The
area classification appears acceptable, as the majority of the process is closed and performed in systems. Additionally, all o pen manipulations
occur in the .
Description of Buffer Preparation Area
Buffer preparation for BNT162b2 is performed within a dedicated suite. The suite consists of preparation rooms ( ) that are separated by airlocks.
Solutions ar e formulated in
R
eviewer’s Comment: From the descriptions provided, the buffer and
equipment preparation areas appear acceptable.
Utilities Suite
Critical utilities such as WFI, clean steam, and compressed air are existing utility systems in Building . The utilities for Building , including Suite , have been evaluated during multiple past FDA inspections. Suite was made from space in Suite
and the utilities for Suite were reviewed during the recent PLI of Pfizer Andover .
Ther
e were no changes to the WFI, including no additional WFI drops, or clean steam
points of use due to the addition of Suite . The WFI system has been installed, validated, and is operational for use in manufacturing commercial products in Building
. Routine sampling is performed to verify bioburden (action limit: )
and endotoxin (action limit: ). The system is monitored, alarmed, and
trended for
to verify the system is i n a state of chemical control.
The c
lean steam system has been installed, validated, and is operational for use in
manufacturing commercial products in Building . Routine sampling is performed to verify that the system is in a state of control for chemical ( )
(b)
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(b)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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123 and and
. Steam quality testing for the clean steam distribution system is performed for
R
eviewer’s Comment : The critical utilities of WFI and clean steam were
described in general terms and appear acceptable.
Compressed Air System
The compressed air system provides compressed air to various process and instrument
use points in Building . Compressed air is produced by
Points -of-use are equipped with a in product contact
applications including, but not limited to,
The compressed air distribution piping was modified to add
additional points of use within Suite . The new compressed air distribution points of use were validated for
C
ompressed air is sampled from representative points and routinely tested for the
are continuously
moni
tored and alarmed at the compressed air sources.
R
eviewer’s Comment: Compressed air was described in general terms.
Validation data were not provided for the compressed air but monitoring data from July to December 2020 were provided in the EUA (27034.76). new points of use were added to the compressed air in Suite . All samples met acceptance criteria. The information provided appears acceptable.
Heating, Ventilation and Air Conditioning Suite
The HVAC systems supplying the air to the manufacturing areas in Building are designed to provide air volumes, air flows, HEPA filtered air, and room pressurization appropriate for the required environmental classification.
S
uite has its own dedicated HVAC unit (HVAC ; Drawing A -8034902 in section
3.2.A.1). Construction of Suite involved
All the make- up air consists of air drawn from outside and
conditioned resulting in . The supply air is delivered to manufacturing
areas through HEPA filters. A gowning room or air lock is located between all corridors of lower and higher classification.
The H
VAC systems were designed and qualified to maintain pressure- controlled
environments that are based on manufacturing operations performed in that area that
(b)(4)
(b) (4)
(b)(4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b)
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(b)
(4)
(b) (4)
(b)
(4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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124 are monitored between adjacent spaces. Temperature is monitored and alarmed in the
raw materia l and solution storage areas as well as throughout the manufacturing suites.
Additionally, relative humidity in classified manufacturing areas is monitored.
HVAC Validation
The HVAC system for Building production areas has been validated. As part of the performance validation, all classified production areas are tested under
conditions. Rooms were monitored for
.
The integrity of the HEPA/ filters was verified and certified.
R
eviewer’s Comment: The HVAC system has been validated and maintains
ISO manufacturing areas. The HVAC system for Suite was reviewed as part of the January 2019 FDA inspection. Manufacturing suites, Suites , each have dedicated air handling units. The HVAC controls and segregation for each suite appears acceptable.
E
nvironmental Monitoring Suite
The existing EM program used in the classified areas within Building was applied to include Suite .
EM Qualification
Area classification served as justification for routine EM program, EM frequencies, acceptance criteria (alert and action limits), media types, incubation, and facility environment control procedures. EM testing was conducted at
Routine EM
Suite has been assigned an environmental classification of ISO - with (ISO -
air supply). are used for non- critical operations (
) and critical operations (
). Buffer preparation and autoclaving used for BNT162b2
manufacturing is performed in product service areas of Suite and Suite . Theseareas are controlled classified manufacturing spaces with established routine EMprograms. Additionally, periodic monitoring for mold and fungi is conducted withspecialized media and incubation conditions for areas. The routine EM tests and actionlimits are found in the Table 3.2.A.1- 4 in the submission (duplicated below):
(b) (4
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b)
(4)
(b)
(4)
(b)
(4)
(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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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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125 Revi
ewer’s Comment: All alert and action limits appear acceptable. Action
limits are appropriate for the operations performed in the .
I
n Amendment 125742/0.43, Pfizer clarified the definition of at rest and in
operation, which have been incorporated into the ACMF EM narrative above and
apply to Suite , and that the limits are applicable for
monitoring. The EM information appears acceptable.
Contamination and Cross- Contamination Controls Suite
Suite is dedicated to manufacturing of BNT162b2 and has dedicated personnel. Product contact equipment are either single use (i.e., disposable) or multi -use (i.e.,
reusable stainless -steel equipment) but dedicated to BNT162b2. Cross contamination
contr ols include
Procedures for
labeling, flow, storage, and use of materials and equipment are established to avoid mix-ups and cross contamination. Batch records include a specific product code
designation.
C
ontamination and cross -contamination controls are summarized below:
C
ontamination from equipment: Status of fixed equipment is indicated and tracked by
validated automation control, and the status of non- fixed equipment is indicated in
accordance with approved labeling procedures. Clean and soiled equipment is stored closed, in separate designated areas within the manufacturing suites, and have separate flow paths. Procedural and validated automation controls exist to ensure that equipment is only used with its designated product. In addition, single use technology is
utilized within the facility for many product processing operations.
C
ontamination from people: Gowning procedures are designed to minimize
contamination and cross -contamination. Gowning is appropriate for the operations.
Gowns are changed when damaged or soiled, and discarded upon exiting each production area. Gloves are changed between working with different products within the facility.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
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126
Contamination from system failures: Environmental controls for parameters such as
differential pressure, temperature, and relative humidity controls are continuously monitored and alarmed. Critical equipment and systems are powered by emergency back -up power systems. Critical control systems are on uninterrupted power supply to
allow continuous operation during power outages. Site procedures exist for disaster recovery and response to unplanned system failures of monitoring systems and environmental control systems.
Contamination from waste: Liquid process waste is disposed through the facility waste
system, which is equipped with . Liquid
waste is treated and discharged in accordance with local and state regulations. All solid waste is removed from the facility on a routine basis. Procedures exist for handling and disposal of biohazardous waste in dedicated, single- use containers. Hazardous
chemical waste is removed from the manufacturing areas on a regular basis in accordance with approved procedures. Procedures exist for routine facility cleaning, sanitization, and spill response for containment and remediation of process spills.
Reviewer’s comment: Cross -contamination controls are designed to minimize
contamination from multiple sources including people, product, equipment, waste, and environment. EM is performed in all classified areas, and action and alert limits appear acceptable (see EM section). The information provided appears acceptable.
In Amendment 125742/0.74, Pfizer clarified Suite is a segregated manufacturing suite that was not used for any product prior to BNT162b2 DS manufacturing. The suite and product contact equipment used for BNT162b2 are dedication to the production of BNT162b2. No other product is manufactured in Suite or used with the dedicated equipment, and production of BNT162b2 in Suite is ongoing with no plans to change- over to another product.
Equipment Summary Suite
This section contains an overview of the process equipment, equipment qualification, and the equipment cleaning and sanitization (if applicable) for the equipment used to manufacture the DS at Pfizer Andover Suite .
Critical Process Equipment:
(b) (4)
(b)
(4)
(b)
(4)
(b)
(4)
(b)
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(b)
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134
The parameters controlled and/or monitored by the automated control systems in BNT162b manufacturing process in Suite are the same parameters in ACMF. For additional details about the controlled and monitored parameters, refer above to the ACMF Computer Systems section.
Reviewer’s Comment: In Amendment 125742/0.57, Pfizer provided a list of the
critical BNT162b2 DS manufacturing steps that are computer -controlled with a
brief description of the validation process and parameters monitored, which have been incorporated into the narrative above. IOQ was performed according to site procedures and documented in reports. The information appears acceptable.
DRUG PRODUCT MANUFACTURING FACILITY, PFIZER, KALAMAZOO, MICHIGAN
The Pharmacia & Upjohn Company LLC site located at 7000 Portage Road,
Kalamazoo, MI 49001- 1099, (referred to as Pfizer Kalamazoo) is a DP manufacturing
site for sterile injectable products, including biological medicinal products such as
human vaccines. This site has an acceptable compliance history with the FDA and
recently underwent a Level 1 surveillance inspection in May 2021 which included Building which houses the BNT162b2 manufacturing areas. Within Building , the
areas are used for
LNP formulation and filling of the BNT162b2 DP, respectively. The May 2021
surveillance inspection covered the licensed biological products manufactured at the site and also included the observation of t he BNT162b2 DP manufacturing operations
(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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135 and review of associated quality documentation. The inspection did not identify
significant deficiencies and was classified as Voluntary Action Indicated (VAI).
Heating, Ventilation, and Air Conditioning Pfizer Kalamazoo
The HVAC systems are designed to provide properly filtered air with volumes, air velocities and room pressurization schemes commensurate with the required room
classifications for each respective area. The manufacturing rooms with their respective
grades are listed below.
Differential pressure is maintained and monitored between adjacent rooms. Room
pressures are set up in
All fresh air is taken from outside,
AHUs that supply the cleanrooms.
HVAC systems have been qualified, demonstrating adherence to the parameters
required for each respective area classification designation. Monitoring is performed for
pressures, temperature, and humidity as appropriate.
(b) (4)
(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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136 • The operating temperature specification is in all G rade areas.
• R elative humidity measurements are continuously monitored in critical rooms if
required ( ) .
• Supply HEPA f ilters installation measurements show no leakage of of
the measured upstream concentration.
• testing ( testing)
for Grade processing areas are performed.
• / Area Classifications were executed to monitor and
evaluate the under ’ and ’ conditions
in classified areas.
• Environmental Qualifications were also performed. As part of the qualification, all
classified production areas were tested under conditions.
Rooms were monitored for
.
Environmental Monitoring Pfizer Kalamazoo
A facility EM program is in place to sample air, surfaces , and equipment for the
presence of microorganisms. The cleaning and sanitization program is evaluated by
performing microbiological surveys and reviewing and trending data to ensure the
program is effective. The routine EM program is in place to detect an adverse change
in microbiological conditions. Specifications for each room grade are defined as follows:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
138
All personnel entering the cleanrooms are trained and certified for the work required.
The personnel monitoring program is to provide information on the type and possible
sources of microorganisms that are isolated from and potentially transmitted by
cleanroom personnel. Personnel aseptic technique and behavior as well as the
adequacy of gowning procedures are monitored using this approach. A total of
sites per operator are monitored including
the sites were chosen because
Routi ne personnel monitoring is
conducted for all personnel who have entered the aseptic area under operational conditions at least per shift.
Reviewer’s comment : The HVAC system was qualified, and EM is in place for
. The recent surveillance inspection conducted
by ORA/OBPO in May 2021 covered the HVAC and EM trends in Building
from May 1, 2019 to May 11, 2021 and no trends were noted. The information
provided in the BLA appears acceptable.
Purified Water and W ater for injection Pfizer Kalamazoo
Purified water is generated from
Microbial control is achieved by
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
139 through looped distribution piping at a rate that ensures turbulent flow and positive
distribution loop return pressure during normal operating conditions. Hoses used to
dispense PW and WFI are drained after use. WFI and PW are stored and distributed at
temperatures. WFI system temperature is
and PW syst
em is . The w ater is delivered at the use points based on user-defined
temperatures.
WFI and PW water quality criteria are provided below:
WFI
PW
For microb al control the systems are routinely tested for
. Testing is conducted to ensure the water quality meets current
requirements.
(b) (4)
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(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
140 C
lean Steam Pfizer Kalamazoo
grade clean/ pure steam is prepared from
The c
lean steam are continuously monitored in- line. Clean
steam is tested at representative test stations tested at least . Clean steam
meets the minimum quality requirements for . Additionally ,
the following thermodynamic properties of clean steam are tested at least at
representative use points:
W
ater are continuously monitored in- line.
Water quality is also monitored by physical, chemical, and microbiological tests in
conformance with applicable compendial requirements.
R
eviewer’s comment : The water systems and clean steam systems were
reviewed during the recent surveillance inspection conducted by ORA/OBPO in
May 2021 and no trends were noted.
A
n information request was s ent to Pfizer to request more information about the
water quality criteria for WFI and PW as well as the water monitoring programs at Kalamazoo (STN 125742/0.57 The information is presented in the water systems
sections above. The information provided appears acceptable.
(b)(4)
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(b) (4)
(b) (4)
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(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
141 C
ompressed Air Pfizer Kalamazoo
grade compressed air is prepared from
Com
pressed air for BNT162b2 manufacture at Kalamazoo is used during the
. The compressed air alert limit is
. An action level is reached following an investigation of an alert
limit where follow- up testing also meets or exceeds alert limits. All organisms are
identified following positive tests and an action level is also reached if there is a tr end
identified (i.e., the organism has been identified at that sample location in the last
). The compressed air is at the POU.
Reviewer’s comment : The compressed air is a qualified utility and undergoes
routine sampling. An information request was s ent to Pfizer to obtain more
information regarding air and usage in BNT162b2 manufacture as well
as the monitoring limits which were also not provided in the original submission
(STN 125742/0.57) . Pfizer con firmed is not used in the manufacture of
BNT162b2. The information for the compressed air appears acceptable.
E
quipment Summary Pfizer Kalamazoo
New equipment for manufacturing BNT162b2 (i.e., ), freezers and
ultra-low temperature storage freezers, etc.) were installed within the existing footprint
of the main DP production building (Building ). The critical equipment used in the
manufacture of BNT162b2 along with the description of product contact status is
presented in the table below.
C
ritical Equipment Used in Manufacturing of BNT162b2 at Pfizer -Kalamazoo
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
143 Al
l equipment w as qualified prior to use according to Pfizer. It should be noted that all
product -contact equipment is either BNT162b2 dedicated or single- use.
A
n IR was submitted to Pfizer regarding any new product contact equipment that may
have been added to BNT162b2 manufacture that was not included in the original EUA
27034 submission and to confirm all equipment is BNT162b2- dedicated (STN
125742/0.2 4. Pfiz er provided a list of equipment and the qualification status. All
equipment has been qualified and is dedicated to BNT162b2 manufacture.
A
n additional IR was sent to Pfizer to obtain the qualification summary documents for
the operational and performance qualification (OQ/PQ) of the new equipment at Pfizer
Kalamazoo (STN 125742/0.57) .
P
fizer provided the release report COVID Vaccine
Summary System Acceptance which was provided to confirm that verification
testing was conducted on all equipment and equipment software/hardware utilized for
BNT162b2 manufacture.
P
fizer stated all verification documentation was reviewed by the qualified subject matter
experts and any non- conformances during qualification were addressed and resolved.
All testing for each piece of equipment was provided along with whether the testing
passed acceptance criteria, or a non- conformance occurred. Pfizer provided an
explanation of all non- conformances and these were reviewed. Following an
investigation all non- conformances were resolved.
I
n addition, Pfizer provided the Release Report and the COVID Vaccine
Formulation System Acceptance and Release Report which they state is
representative of all groupings of in terms of testing. This testing included installation and functional verification (FV). For this report was
provided. All non- conformances were investigated and resolved.
R
eviewer’s comment (Equipment Qualifications) : From the data provided, it
appears all new pieces of equipment have been qualified for their intended use
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
144 which included installation, software/hardware, and FV . Pfizer listed all non -
conformances during the various qualifications and according to Pfizer all were
resolved. The information provided appears acceptable.
E
quipment Cleaning Validation Pfizer Kalamazoo
All product contact equipment is
, with an automated system that uses cleaning recipes or is manually cleaned
with appropriate cleaning agents. The DP stoppering parts and tank change parts are
disassembled and in a qualified washer.
The c
leaning procedure consists of the following s teps:
The f
inal rinse steps use and the wash steps in some cases
employ the use of cleaning additives.
C
leaning validations (CV) were performed on all BNT162b2 produ ct contact equipment.
Each CV consisted of 3 consecutive successful runs using a representative or challenge material held for a defined extended DHT . Sample locations were defined as the most
difficult to clean and representative of product contact locations.
Pf
izer Kalamazoo provided the cleaning validation sample requirements for the various
pieces of equipment used in the manufacture of BNT162b2. All equipment has a validated soiled hold time of except for the which have a
soiled hold time of . The following bullets summarize the cleaning validation
for the major manufacturing equipment:
The m
aximum validated CHT s for each piece of equipment are as follows:
BNT162b2 CV Results
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(b)(4)
2 pages have been determined to be not releasable: (b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
147
Contamination and Cross- Contamination Controls Pfizer Kalamazoo
The Building facility is designed as a multi -product facility and is used in the
manufacture of aseptically processed DPs. All new products are evaluated for potential
impact to existing products prior to introduction into the area. There is no manufacture
of products containing penicillin, cephalosporin, live viruses, spore forming organisms or
cytotoxic drugs. The Pfizer Kalamazoo B uilding facility is licensed as a multi -product
facility.
Contamination Controls Pfizer Kalamazoo
The Building facility has been designed to minimize the potential of product
contamination and personnel exposure using a combination of controls including pressure differential zones, airlocks, gowning rooms and defined pathways for the flow
of personnel, equipment, materials and waste. Manufacturing areas are classified as
Grade and Grade controlled environments and are appropriate to the operations
that take place within each area. Air pressure cascades are maintained from areas of
. A gowning room or airlock is
located between all areas of lower and higher classification. A Grade environment is
used in the aseptic filling area. Room finishes are durable, smooth and cleanable.
Site standard operating procedures (SOPs) describe the flow of materials, equipment and personnel through the facility to prevent contamination and mix -up. Procedures
also ensure that appropriate storage conditions are met throughout the manufacturing
process. Routine EM is performed in the aseptic area to ensure that microbial and
particulate levels remain in control.
Cross -contamination Controls Pfizer Kalamazoo
Introductions of new product families, updat es to manufacturing processes, and
changes to the facility design or equipment are assessed via the site change
management process.
(b) (4)
(b) (4)
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(b)
(4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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148
The general principles to prevent cross -contamination within the Aseptic Manufacturing
facility include:
• A controlled utilities system
• Validated cleaning and sanitization procedures for equipment
• Material, personnel, and waste flow controls through air locks with access
controls
• Different pressure zones
• Gowning requirements
• A documented EM program for classified rooms
Contamination from other p roducts Pfizer Kalamazoo
The following are the strategies applied to mitigate cross -contamination from other
products:
• Only one lot of product is filled at a time.
• The facility is fully dedicated to formulation of the BNT162b2 DP.
• Production and formulation areas are regularly cleaned and sanitized as per site
procedures.
• Clean and clearance procedures are in place for formulation and filling lines
according to site procedures.
Contamination from Equipment Pfizer Kalamazoo
The following are the strategies applied to mitigate cross -contamination from
equipment:
• Equipment is cleaned per site procedures. Cleaned and soiled equipment are
identified and segregated.
• Product contact equipment and components are cleaned and either
depyrogenated or sterilized via validated processes prior to use for each batch.
• Product contact tubing and hoses are either one time use and discarded after each process order or prepared for re- use using site procedures.
• Equipment is properly maintained through a preventive maintenance program.
Contamination from People Pfizer Kalamazoo
The following are the mitigation strategies:
• Personnel entering production areas require gowning training or a trained escort
per site procedures.
• Site procedures adhere with C GMPs and are used for production activities.
• Personnel monitoring is conducted per site procedures.
Contamination from System Failures Pfizer Kalamazoo
The following are the mitigation strat egies:
• Classified production areas and cold rooms are monitored for temperature
through automated control systems, with appropriate warnings and alarms, and are maintained as per site procedures.
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
149 • Differential pressure between rooms of the same and different classifications are
monitored and maintained as per site procedures.
• Recovery from a disruption to a controlled area is performed as per site
procedures.
Contamination from Waste Pfizer Kalamazoo
• Production waste is disposed according to site procedures.
• Production waste receptacles are emptied and sanitized as applicable per site procedures.
Product Changeover Operations Pfizer Kalamazoo
Product changeover procedures provide a high level of assurance that potential cross -
product contamination from one manufacturing process to the next does not occur. The
product changeover process is executed and documented according to approved
procedures that are designed to ensure that cross -product contamination risks are
minimized.
Product Clearance Pfizer Kalam azoo
Product processing areas undergo a clearance process after completion of a product lot. These product clearances are performed and documented by trained personnel in
accordance with approved site procedures. Successful completion of these activities
provides documented evidence of control over product, product specific components,
product specific documentation, and equipment between uses for processing of different
products.
Disinfectant Effectiveness Pfizer Kalamazoo
The effectiveness of the various disinfectant agents used against microbial isolates
recovered from the manufacturing areas, as well as test organisms, have been
evaluated following guidance and
methodology and their effectiveness of disinfection has been
demonstrated on representative surfaces in the facility. The effectiveness of general
and sporicidal disinfectants was determined using a minimum reduction for
vegetative bacteria and yeast and effectiveness of sporicidal disinfectants was
determined using a minimum reduction for spore -forming bacteria and mold.
Reviewer’s comment: Pfizer provided flow and air classification diagrams
which appear acceptable. An EM system is in place and was reviewed above.
The Building contamination controls, cleaning and disinfectant efficacy studies were reviewed during the recent surveillance inspection conducted by ORA/OBPO in May 2021 and no issues were noted. The information provided appears acceptable to support the cross -contamination measures .
DRUG PRODUCT MANUFACTURING FACILITY, PFIZER, PUURS, BELGIUM
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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150 The Pfizer Manufacturing Belgium NV site, located at Rijksweg 12, 2870 Puurs, Belgium
(also known as Pfizer Puurs) , will produce BNT162b2 Drug Product (DP), including the
steps of LNP formation/Formulation Bulk DP, Fill/Finish, and Labeling and Pack aging.
Manufacturing areas for the commercial supply at Pfizer Puurs are located in several
buildings across the campus , including:
•
Building (which includes the
and , stopper processors and the area used
for BNT162b2 production) is an existing building. The building is approved as
multiproduct. is an existing suite that is used to formulate multiple
products; however, these products are not approved in the US.
and the area are existing suites that are respectively used to
formulate and multiple US licensed products.
•
Building consisting of areas , which includes
the Vial Filling Line used for filling BNT162b2 DP . Vial Filling Line is an
existing suite that is used to fill multiple products; however, these products are
not approved in the US.
•
Building consisting of and
includes the and the filling line.
are new suites inside the licensed facility. The
vaccine building has been inspected by FDA and other regulatory agencies. The building is licensed/approved as multiproduct. and the
Filling Line have been recently inspected by FDA. are used for
LNP and sterile filtration of the BNT162b2 product . vial filling line
is used for filling BNT162b2 DP.
The
Pfizer Puurs facility, equipment, and utility systems are supported by preventive
maintenance and calibration programs. Procedures ensure appropriate flows, personnel gowning, and sanitization of the facility and equipment. The Heating, Ventilation, and
Air Conditioning (HVAC) system air filtration and pressurization create different
classification zones coupled with EM to ensure appropriate cleanliness and segregation
are maintained for manufacturing. To additionally mitigate cross -contamination risks,
process steps are performed under in a Grade environment, in
either a .
Faci
lity Description Pfizer Puurs
The DS is in the Building in R oom which is
. LNP/Formulation activities of BNT162b2 are conducted in
the Facility. The Facility is a -story structure, divided into a
manufacturing area on the floor with a technical area (i.e., area used for
, etc.) and offices on the floor. On the
floor , , (Room ), (Room ) and
(Rooms ) are used for LNP /Formulation Bulk DP and
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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(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)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
151 filtration of BNT162b2 DP. are in Grade classified
areas.
The BNT162b2 DP filling takes place in a Grade filling line (Room ),
surrounded by Grade environment . Visual inspection of the filled product is also
conducted on the floor in R oom (Grade environment ).
Buffer formulation activities and DS are conducted in the
Building. The Building is a -story structure,
divided into a manufacturing area on the floor and a technical area on the floor. On the floor , are used for buffer formulation.
Also, BNT162b2 DS is area on the
floor.
Filling and inspection are also conducted in the Building (Filling L ine ).
The Building is a -story structure, divided into a packaging area on the
floor, a filling and preparation area on the floor and a formulation and
preparation area on the floor. The BNT162b2 DP filling takes place in a Grade
filling line ( Room ), surrounded by a Grade environment . Inspection
of the filled product is also conducted on the floor in R oom (Grade ).
Area classification drawings and f lows were provided in Section 3.2.A.1 for the
Building, Building and the Building. The production suites
are supported by technical support, validated utilities, controlled warehousing for receiving and storage of raw materials and supplies, and shipping of materials. Critical utilities (clean steam, WFI, and purified water) are generated in mechanical areas and supplied to the Building, Building and the
Building. Compressed air and systems are installed in the Building,
Building and in the Building. The and
are also located in the mechanical areas.
The Pfizer Puurs facility, equipment, and utility systems are supported by preventive maintenance and calibration programs. It is also designed for segregation and directional flow of personnel, equipment, materials, samples, product, and waste. Procedures ensure appropriate flows, personnel gowning, and sanitization of the facility and equipment. HVAC air filtration and pressurization create different zones
(classification), and the EM system ensure that the appropriate cleanliness and
segregation are maintained for manufacturing.
Reviewer’s comment: A general overview of BNT162b2 DP manufacturing
areas was provided. The room classifications appear appropriate for the operations performed in each area. All diagrams for personnel, product,
consumable materials, and waste flows were provided. The flow patterns appear acceptable.
Formulation, filtration, filling and capping Pfizer Puurs
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
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(b)
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(b)
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(b) (4)
(b)
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(b) (4)
(b)
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(b) (4)
(b) (4)
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
152 The BNT162b2 DP solution is manufactured in .
Manufacturing are disassembled and cleaned using manual and/or
procedures. The manual method is considered a back -up method to the .
P
roduct is dispensed into
containers by volume and periodically checked for fill .
A
septic processing is conducted using technology. The main function of the
is the protection of the aseptic filling process against
contamination by creating a Grade environment. This is achieved by
P
rior to capping, stopper detection systems are set -up and verified to
ensure rejection of improperly seated stoppers. The c apping station is set -up with
parameters specific to the BNT162b2 DP stopper used for the 2 mL presentation.
R
eviewer’s comment: The overview of the formulation, filtration , filling, and
capping appears acceptable. See Section 3.2.P.3.5 for evaluation of individual sterilization validations .
U
tilities Pfizer Puurs
Clean Steam System
The clean steam system serving the Building, Building as well as the
Building consists of several Clean Steam Generators (CSG). The
CSG process feed water ( ) to produce clean steam. The clean steam is delivered to clean steam headers and distributed to the points of
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
153 use located in the clean rooms and technical areas. The CSG uses
to prevent cross contamination from the industrial steam.
The clean steam systems serving the Building, and the
Building have been validated. The validation demonstrated that the
system operates according to design specifications and maintains the system within the design parameters.
The clean steam system for the commercial manufacturing areas was designed and qualified to meet the criteria for the following attributes as specified in
(as appr opriate):
The clean steam quality is monitored by routine sampling of the clean steam
at least
. Representative user points are tested on a basis for
.
Water for injection System
A WFI system is installed in the Building, Building and
Building. The water system serving the Building, Building
and Building consists of a
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(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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(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
154 The f
ollowing test functions have been met for the WFI system:
•All critical controls, alarms, and indicators operate according to design
specification.
The W
FI distribution system is sampled and tested for
analysis and every for analysis. Each WFI system has inline
measurements for . All WFI points of use are
routinely sampled and tested at least every for analysis. The testing is performed to current WFI requirements for
analysis.
C ompressed Air
A compressed air system is installed in the Building,
Building as well as in the Building. The systems comply with the
description and requirements described hereafter.
The c
ompressed air system consists of
The v
alidation demonstrated that the system operates according to design
specifications.
The following test functions have been met during validation of the compressed air
system:
(b)(4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b)(4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
155 •All of the critical controls, alarms and indicators operate per design
specifications.
•System critical points of use meet the following acceptance criteria:
Rout
ine sampling is performed for
are monitored continuously at the .
Revi
ewer’s comment: Descriptions and the respective qualification/validation
overviews were provided for Clean Steam, WFI, PW, compressed air, and
. The descriptions provided were applicable to the Building,
Building and the Building and supplied adequate
detail. The acceptance criteria provided for the systems appear acceptable.
Heat
ing, Ventilation, and Air Conditioning Pfizer Puurs
Several HVAC systems serve the Building, Building and
Building. Each clean room has its own recirculation unit.
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b)(4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
156 The H
VAC Systems serving the building, Building and
Building consist of an arrangement of AHUs and a number of
recirculation AHUs. The Qualified Building Information System monitors temperature,
RH, and pressurization of each clean room.
A
ll fresh air is taken from outside
air is supplied either directly to the cleanroom or indirectly via
the recirculation AHUs.
The s
upply air is delivered to the manufacturing areas through HEPA filters for the
Building, Building and Building. All HEPA filters
are included in an existing routine program for performance testing. The return air from
the rooms is removed through return air grids. The installation is equipped with necessary airflow measuring stations; sensors. All classified areas are equipped with terminal HEPA filters.
The HVAC systems were designed and qualified to meet criteria that include the
following :
A
s part of the qualification, all classified production areas were tested under
conditions. Rooms were monitored for
.
I
n addition, the room pressure, temperature, and RH are continuously monitored, with
control elements in the HVAC system modulated to maintain the desired parameters.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b)(4)
(b) (4)
(b) (4)
(b) (4)
CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
(nucleoside modified)
157 Reviewer’s comment : The HVAC system s serving the buildings used for
BNT162b2 manufacturing have been qualified and maintain Grade
manufacturing areas. The utilities appear acceptable. Also refer to the EM (EM)
review below.
Manufacturing Rooms Used for BNT162b2 Manufacturing Pfizer Puurs
Tables 3.2.A.1 -1 through 3 summarize room locations and classification for the
formulation area, buffer preparation area and support areas for equipment such as parts
washers, autoclaves and stopper processors, filling lines and inspection areas used for the manufacture of BNT162b2 DP. The tables are reproduced below.
(b) (4)
(b) (4)
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158 Equi
pment Summary Pfizer Puurs
This section contains an overview of the process equipment, equipment qualifications,
and the equipment cleaning and sanitization (if applicable) for the equipment used to manufacture the BNT162b2 DP at Pfizer Puurs.
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ualified equipment is cleaned and dried prior to use and sterilized or sanitized when
necessary. The equipment detailed in Table 3.2.A.1- 4 and Table 3.2.A.1- 5 (reproduced
below) support s the BNT162b2 manufacturing process. The BNT162b2 manufacturing
process equipment is qualified for use through installation, operational, and
performance qualification (IQ, OQ, PQ) activities to demonstrate that the equipment operates according to design specifications and is maintained within its design parameters.
Pr
oduct Contact Equipment/ Material s Pfizer Puurs
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160 R
eviewer’s comment: The building locations of the major equipment to be used
in manufacturing were provided for reference. The BNT162b2 manufacturing
process equipment has been qualified and performance qualifications performed.
The product contact equipment/materials were also provided, including the materials of construction, cleaning and sterilization/sanitization method. Most of the direct product contact equipment is dedicated or single use.
Sterilization/depyrogenation performance qualification summaries for the product
contact equipment were submitted under 3.2.P.3.5 and appear acceptable. In addition, the capper qualification summary was submitted in 3.2.P.3.5 and appears acceptable. A cleaning validation summary was submitted in 3.2.A .1
and is discussed in the cleaning validation section.
The equipment qualification and cleaning/sterilization validation studies were reviewed and appear acceptable. Further details regarding the equipment cleaning can be referenced in the cleaning validation section of this review memo.
Preparation of Equipment and Components Pfizer Puurs
Equipment is cleaned and dried prior to use and sterilized or sanitized when necessary.
Cleaned and/or sterilized equipment is stored in order to prevent contamination before
use.
All equipment and primary packaging components (i.e., vials and stoppers) used in the production of parenteral products, such as BNT162b2, are sterilized/ depyrogenated
according to approved, validated cycles. Equipment that cannot be sterilized by these two methods is and enter through
dedicated airlocks.
Vials
Vials are processed through
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Stoppers
The preparation of sterile stoppers is performed in the preparation areas of the
Building or the B uilding.
Stopper validation
Product contact equipment Pfizer Puurs
Product contact line equipment parts are assembled from
. Accessories, such as filters, etc., are
assembled and .
Validation of
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Reviewer’s comment: The overview of the equipment preparation, cleaning,
sterilization and depyrogenation provided, appears acceptable. Refere nce memo
Section 3.2.P.3.5 for evaluation of individual sterilization validations.
Visual Inspection Pfizer Puurs
The BNT162b2 DP vials are one hundred percent inspected for cosmetic, particulate,
and other product defects using manual inspection techniques in the inspection
department, an in- line automated visual inspection machine, or an off -line automated
inspection line.
The automated inspection vial lines are qualified to
inspect BNT162b2 DP vials for cosmetic, fill level and particulate defects.
The automated visual inspection lines are fully automated systems that inspect filled
vials for cosmetic, fill level and particulate defects. Equipment verification and performance qualification were performed to qualify the system for inspection of
BNT162b2 vials.
The Installation Verification verified that the Automated Inspection Lines were installed in accordance with specifications and the intended use of the system.
The Operational Verification verified that the Automated Inspection Lines operate as defined and that the system is fit for its intended us e.
The Performance Qualification (PQ) verified that the Automated Inspection Lines perform in accordance with expected quality attributes when inspecting BNT162b2 vials. The PQ consisted of the following parts:
A verification run is performed at the in routine production
(mode) to verify that the system, the set -up and the BNT162b2 Inspection Program is
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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163 capable of rejecting defective samples at 100% on the right camera. It also check s the
functioning of the reject system. The purpose of this test was to verify that all samples
of the verification set were rejected correctly.
PQs verified that the automated visual inspection systems could detect the following:
The results are summarized in Table 3.2.A.1- 6, Table 3.2.A.1- 7 and Table 3.2.A.1-8 of
the submission.
Reviewer’s comment: The overview of the automated visual inspection system
qualification appears acceptable. The goal of the phase 1 testing was to identify
. Phase 2 PQ testing focuses on
batch quality control by increased AQL testing and
defect trending to assess process variability at batch scale. The qualif ication
documents reviewed appear acceptable. No concerns were noted.
Contamination and Cross- Contamination Controls Pfizer Puurs
The Building is a multi -product facility dedicated for vaccine manufacturing.
Formulation and filling of BNT162b2 DP is performed in the Building.
The Building and Building are multi -product facilities and
are used in the manufacture of aseptically processed DPs. Filling of BNT162b2 is
performed in the Building. The introduction of new product families, updates to manufacturing processes, and
changes to the facility design or equipment are assessed via the site change
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164 management process. Site Standard Operating Procedures describe the flow of
materials, equipment and personnel through the facility to prevent contamination and mix-up. Procedures also ensure that appropriate storage condi tions are met throughout
the manufacturing process.
Cross contamination controls include use of
Reviewer’s comment: Cross -contamination controls are designed to minimize
contamination from multiple sources including people, product, equipment, waste, and environment. EM is performed in all classified areas, and action and
alert limits appear acceptable. Performing the aseptic filling of BNT162b2
Grade greatly mitigates potential microbiological contamination.
Product contact (mRNA and LNP) BTN162b2 formulation and filling equipment is
not shared with other products and is currently dedicated. The filling line is used for BNT162b2 DP filling activities only .
Environmental Monitoring Pfizer Puurs
Classified areas in the manufacturing buildings are routinely monitored for
. Summaries of
the action levels for Grade , Grade and Grade areas are detailed in Table 3.2.A.1-
8.
levels on in the are monitored according
to site procedures. During operation, are monitored at the completion of
the batch or campaign (if applicable) prior to .
Reviewer’s comment: EM is performed in all classified areas, and action and
alert limits appear acceptable per review of the information in the BLA .
The procedures describe the types of EM , sampling locations, frequency and the
alert and action limits for the classified rooms. The firm performs
. The
Grade monitoring includes
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monitoring which is managed under an SOP.
is also described per SOP. Both filling lines
are equipped with a consisting of
that are controlled per line by a .
Equipment Cleani ng Overview Pfizer Puurs
All the equipment and parts used in the manufacture of BNT162b2 will be cleaned using
validated processes before use. Large equipment, such as tanks, are cleaned by
methods. Small, removable, easy to disassemble equipment, may alternatively be
cleaned by method.
The cleaning process generally consists of
Routine monitoring of the cleaning process is performed by
The results are held to the same requirements as those established during the cleaning validation for each applicable cleaning process and any excursions over action limits would be investigated.
Equipment Cleaning Validation Pfizer Puurs
There are two approaches taken for cleaning: 1) cleaning validation and 2) cleaning verification. A cleaning validation approach is currently being implemented for the BNT162b2 DP manufacturing process .
The equipment used for BNT162b2 is cleaned manually or automatically by trained
operators. Dirty and cleaned equipment are stored in separate clean rooms to prevent cross contamination.
Prior to cleaning validation, commissioning, qualification and cleanability/development studies are performed to demonstrate, through testing, that the equipment/systems perform as designed and are able to reduce challenge material to within the predefined acceptance criteria. Cleaning validation studies consist of three c onsecutive, successful
cleaning validation runs using a representative or challenge material.
Sample plans and sample locations are clearly defined in the cleaning validation protocols and are dependent on the equipment being cleaned. Sample locations are selected based on the most difficult to clean and representative product -contact
locations. Sampling and testing are performed to demonstrate that the intended
cleaning is effective, robust and consistently meets the cleaning validation
requirements.
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CBER CMC BLA Review Memo, STN 125742, COVID -19 mRNA Vaccine
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166 The cleaning validation execution includes the following evaluations:
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lity Cleaning Overview Pfizer Puurs
Cleaning and sanitization of the facilit ies are performed on a regular and routine basis
according to established procedures. Maximum time intervals for cleaning are
established for production lines. Additionally, complete sanitizations are performed at regularly scheduled intervals. During these sanit izations, all ceilings, walls, cabinets,
tabletops, partitions, etc., are cleaned and sanitized. Floors are also cleaned and sanitized. Monitoring is performed to verify the efficacy of the sanitization.
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eviewer’s comment: An overview of the facility cleaning was provided,
however, the validation demonstrating the efficacy of the cleaning agents was not provided in the BLA.
3.
2.R Regional Information (USA)
E
xecuted Batch Records
Executed batch records were provided with this submission for filling and inspection of
Lot , LNP formulation for Lot , and Packaging for Lot . This information appears acceptable.
M
ethod Validation Package
Pfizer provided Test Method TM100010635, Test for Container Closure Integrity Testing of Stoppered, Capped and Crimped Vials for PF- 07302048 COVID -19
Drug Product.
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eviewer’s comment : This method was reviewed. The method appears to be
consistent with the summary provided in section 3.2.P.2 Microbiological Attributes and appears acceptable.
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