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BNT162b2
2.3 Introduction
PFIZER CONFIDENTIAL
Page 1TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 1
2.3. INTRODUCTION ................................ ................................ ................................ .............. 4
2.3.1. General Information ................................ ................................ ............................... 4
2.3.2. Module 3 Lay out ................................ ................................ ................................ ....5
2.3.3. Control Strategy ................................ ................................ ................................ .....5
2.3.3.1. S election of Critical Qualit y Attributes ................................ ..................... 6
2.3.3.2. Process Risk Assessment Approach and Parameter Designation .............. 6
2.3.3.3. Presentation of Control Strategy in the Drug Substance Sections ............. 7
2.3.3.4. Presentation of Control Strategy in the Drug Product Sections ................ 9
LIST OF TABLES
Table 2.3-1. General Information................................ ................................ .................... 5
Table 2.3-2. Module 3 Drug Substance Control Strategy Information ........................... 8
Table 2.3-3. Module 3 Control Strategy Information for Drug Product ....................... 10
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Page 2ABBREVIATIONS
Abbreviation Definition
ALC -0159 (2-[(polyethylene glycol) -2000] -N,N-ditetradecylacetamide)
ALC -0315 ((4-hydroxybutyl)azanediyl)bis(hexane -6,1-diyl)bis(2 -hexyldecanoate)
A260 Absorbance at 260 nm
ADRM Animal derived raw material
AOF Animal origin free
ATM Animal trial material
ATP Adenosine triphosphate
BNT BioNTech
cDNA Com plimentary DNA
CFU Colony forming units
CI Confiden ceInterval
CMC chemistry, manufacturing, and controls
CoV Coronavirus
COVID -19 Coronavirus Disease 2019
CRP C-reactive protein
CPP Critical process param eter
CQA Critical quality attribute
CTD Common technical document
CTP Cytidine triphosphate
DART developmental and reproductive toxicology (study)
DS Drug substance
dsRNA Double stranded RNA
DSPC 1,2-distearoyl -sn-glycero -3-phosphocholine
EDTA Ethylenediaminetetraacetic acid
ELISA Enzyme -linked Immunosorbent Assay
EU Endotoxin unit
FMEA Failure mode and effect analysis
GMP Good manufacturing practice
GLP Good Laboratory Practice
GTP Guanosine triphosphate
HEPES Hydroxyethyl piperazine ethanesulfonic ac id
hcDNA Host cell DNA
hcP Host cell proteins
HPLC High performance liquid chromatography
IgG Immunoglobulin G
ICH International Council for Harmonization
IPC In-process control
IPT In-process test
IPT-C In-process test for control
IPT-M In-process test for monitoring
IVT In vitro transcription
LNP lipid nanoparticle
modRNA nucleoside modified messenger RNA
mRNA messenger RNA
MCB Master cell bank
NAAT nucleic acid amplification test
NaCl Sodium chloride
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Page 3Abbreviation Definition
NaOH Sodium hydroxide
NMR Nuclear magnetic resonance
nt(s) Nucleotide(s)
NTPs Nucleotide triphosphates
NTU Nephelometric turbidity unit
NOR Normal operating range
PAR Proven acceptable range
PV Process validation
QA Quality attribute
QC Quality Control
RPN Risk priority number
RNA -LNP RNA lipid nanoparticle
saRNA self-amplifying messenger RNA
SARS severe acute respiratory syndrome
SARS -CoV -2 SARS Coronavirus -2; virus causing the disease COVID -19
WCB Working cell bank
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Page 42.3.INTRODUCTION
2.3.1. General Information
Pfizer and BioNTech continue to develop a vaccine intended to prevent Coronavirus Disease
2019 (COVID -19) caused by the virus, SARS -CoV -2. The vaccine is based on SARS -CoV -2
spike (S) glycoprotein antigens encoded in RNA and formulated in lipid nanoparticles
(LNPs), referred to as COVID -19 Vacci ne (BioNTech code number BNT162, Pfizer code
number PF -07302048). The goal of the global development program is to rapidly develop
and license a vaccine for use in participants ≥12years of age, followed b y a pediatric
indication. I nitiall y, four different clinical candidates were considered based on evaluation of
emerging preclinical and clinical data. A single vaccine candidate , BNT162b2, was selected
to proceed into the Phase 2/3 of Study C4591001 and anticipated licensure at a 30µg dose
level . An Emergency Use Authorization (EUA 27034) for emergency use of the
Pfizer -BioNTech COVID-19 Vaccine in individuals > 16 years of age was issued on
December 11, 2021, under section 564 of the Federal Food, Drug, and Cosmetic Act (FDCA)
(21 U.S.C. 360bbb -3).
This n ucleoside modified messenger RNA (modRNA), BNT162b2 (RBP020.2) modRNA ,
encod ingP2 S (V9) , expresses a prefusion stabilized full -length variant of the SARS -CoV -2
S-glycoprotein. The candidate platform has blunted innate immune sensor activating capacit y
and thus augmented antigen expression. The RNA -based vaccine isformulated in L NPs.
The vaccine candidate will be released as a concentrated multi- dose liquid formulation stored
frozen at - 90 to -60°C in a 2 mL Type 1 glass vial to be thawed and subsequen tly diluted
with sterile 0.9% sodium chloride Solution for Injection, USP (saline diluent) , and stored at
2-8 °C until administration. The Applicant intends to commercialize the current formulation
and initially plans to provide a single vial which is desi gned to provide six 30µg vaccine
doses . The multi -dose vial presentation will be preservative -free.
The multi- dose vial is supplied as a white to off -white sterile frozen liquid, packaged in a
clear glass 2 mL vial with a bromobuty l rubber stopper, aluminum overseal and flip off cap.
A 1.8 mL volume of saline diluent is added directly to the vaccine concentrate in the
multi- dose vial. After dilution, the vials contain a sufficient volume to supply 6 doses, where
each 0.3 mL dose contains 30 µg of vaccine for IM injection.
The vaccine will be a dministered intramuscularl y (IM) in the upper arm (deltoid muscle) as a
series of two 30 µgdoses of the diluted vaccine solution (0.3 mL each) according to the
following schedule: asingle 0.3 mL dose followed by a second 0.3mL dose 21 day s later
(prime/boost regimen).
A summary of the General I nformation is provided in Table 2.3-1.
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Page 5Table 2.3-1.General Information
Item
Proprietary Name of Drug Product To be determined
Non-proprietary or Common Name of Drug Product COVID -19Vaccine
Com pound Nam e BioNTech code number BNT162 b2
Dosage Form(s) Liquid Concentrated Form ulation in a 2mL vial
Strength(s) 225 µg/vial
Route of Administration Intramuscular injection
2.3.2. Module 3 Layout
Module 3 of the dossier is structured with:
one drug substance (DS) section,
one drug product (DP) section,
fiveA.1 Facilities and Equipment section s,
three A.2 Adventitious Agents Safet y Evaluation section s,
two A. 3 Excipients sections to describe two novel lipid excipients , and
one R Regional section.
Aspecific document is provided to describe the plasmid (3.2.S. 2.3 Control of Materials -
Source, History and Generation of Plasmids ).
2.3.3. Control Strategy
A control strategy has been designed to ensure that a product of required quality will be
consistently produced. Elements of the control strategy as defined in ICH Q10 may include
the parameters and attributes related to the drug substance and drug produc t, facility and
equipment operating conditions, in- process controls, finished product specifications, and the
associated methods and frequency of monitoring and control.
The approach to developing a control strategy for the v accine manufacturing process
The control strategies are described in further detail
Sections 3.2.S.2.6 Control Strategy and Section 3.2.P.2.3 Control Strategy .
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Page 62.3.3.1. Selection of Critical Quality Attributes
The assignment of criticality to a quality attribute is based upon the potential of the quality
attribute to impact safet y or efficacy . Critical quality attributes ( CQAs )are distinguished
from quality attributes (QAs) by an iterative process of quality risk management and
experimentation that is assessed totheextent to which their variation has an impact on the
quality of the product. Additional information is provided in Section 3.2.S.2.6 Quality
Attributes and Section 3.2.P.2.3 Quality Attributes.
2.3.3.2. Process Risk Assessment Approach and Parameter Designation
A structured quality risk management program is utilized for all new products, which
includes Cause and Effect Matrices (C&E) and Failure Modes and Effects Analy sis (FMEA).
The Cause and Effects (C&E) risk assessment was used to assess each process parame ter for
potential impact on quality attributes. C ritical process parameters (CPPs) were
conservativel y defined after the C&E risk assessment by evaluating the parameters which
had a strong functional relationship to a quality attribute as supported by data available from
the process characterization studies, established scientific rationale or platform knowledge.
For the PPQ (process validation) campaigns, all CPPs will be included to confirm consistent
process performance. Parameter criticality and assoc iated range and settings may be
reassessed throughout the product ’s lifecy cle.
In addition to evaluation of process parameters, for both drug substance and drug product, in
process test s for control (IPT- C) and in process test s for monitor ing(IPT- M) are used to
ensure a consistent manufacturing process. In process test sfor control (I PT-C) are in- process
tests used to control a QA/CQA to within a specified value so that it meets desired DS/DP
quality . The IPT-Cs have an associated acceptance criterion. IPT -Ms are in -process tests
used to measure a QA/CQA to either ensure that it is consistent with respect to previous
process history or for forward processing. The monitoring tests may have action limits.
Refer to Section 3.2.S.2.6 Manufacturing Process Development and Section 3.2.P.2.3
Manufacturing Process Development for additional information .
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Page 72.3.3.3. Presentation of Control Strategy in the Drug Substance Sections
Provided in Table 2.3-2is a schematic which summarizes where control informat ion is
presented in the drug substance sections of Module 3. Studied and evaluated parameters are
discussed in Section 3.2.S.2.6 Process Development and Characterization .
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Page 8Table 2.3-2. Module 3 Drug Substance Control Strategy Information
Category 3.2.S.2.6
Manufacturing Process
Developm ent3.2.S.2.2
Description of
Manufacturing Process and
Process Controls3.2.S.2.4
Control of Critical S teps
and Intermediates3.2.S.2.5
Process Validation and/or
Evaluation
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Page 92.3.3.4. Presentation of Control Strategy in the Drug Product Sections
Provided in Table 2.3-3is a schematic which summarizes where control information is
presented in the drug product sections of Module 3. Studied and evaluated parameters are
discussed in Section 3.2.P.2.3 Process De velopment and Characterization.
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Page 10Table 2.3-3. Module 3 Control Strategy Information for Drug Product
Category 3.2.P.2.3
Manufacturing Process
Developm ent3.2.P.3.3 Description of
Manufacturing Process and
Process Controls3.2.P.3.4 Control of Critical
Steps and Intermediates3.2.P.3.5 Process Validation
and/or Evaluation
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