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BNT162b2
BLA 125742
Module 1.12.5Request for a Waiver Exceptionto 21CFR 610.15(a) Requirement for a Preservative
PFIZER CONFIDENTIAL
Page 1Request for a Waiver
COVID-19 Vaccine
BNT162
(PF-07302048)
Request for Ex ception
to the
21CFR610.15(a)
Requirement for a Preservative
JULY 2021
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BNT162b2
BLA 125742
Module 1.12.5Request for a Waiver Exceptionto 21CFR 610.15(a) Requirement for a Preservative
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
INTRODUCT ION................................ ................................ ................................ ..................... 3
1. BACKGROUND ................................ ................................ ................................ ................... 4
1.1. Proposed Multi -dose Vial Design and Proposed User Instructions .......................... 4
1.2. Justification for the Unpreserved Multidose Vial ................................ ..................... 4
2. SUMMARY: REQUEST FOR EXCEPTION ................................ ................................ .......5
REFERENCES ................................ ................................ ................................ .......................... 5
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BNT162b2
BLA 125742
Module 1.12.5Request for a Waiver Exceptionto 21CFR 610.15(a) Requirement for a Preservative
PFIZER CONFIDENTIAL
Page 3INTRODUCTION
This submission is a request for an exception to the regulatory requirement under 21 CFR
610.15(a) that a vaccine product in a multi- dose container should contain a preservative. As
discussed more full y below, the requested exception is necessary due to exigent
circumstances resulting from the COVID -19 emergency that would otherwise delay
production of large quantities of the vaccinenecessary for global distribution. The exception
is further justified by the favorable post -authorization experience following distribution of
more than 871,000,000 doses of vaccine in this multi -dose, non- preserved presentation under
the US Emergency Use Authorization ( EUA 27034) and other global authorizations from the
receipt of the first temporary authorization for emergency supply in the UK on 01 December
2020 through 30 June 2021 .
Pfizer and BioNTech havedeveloped avaccineintendedtopreventcoronavirus disease 2019
(COVID-19),whichis caused by the virus SARS-CoV-2. The vaccine , as authorized under
EUA 27034, is a concentrated liquid formulation sto red frozen at - 90 to -60°C in a 2 mL
Type 1 glass vial , with provisions for short -term storage for up to two weeks at -20 ±5°C
and up to 1 month at 2-8°C until administration, as described in Module 3.2 of the BLA .
Due to the urgency of the COVID-19 pandemic andthe immediate and ongoing need to
manufacture large numbers of doses for global use throughout 2021 and 2022 ,a multi-dose,
preservative -free vial presentation remains an important tool to enable sufficient global
supply, even while a single -dose vial is also under development .Therefore, Pfizer and
BioNTech intend to commercialize the current frozenliquidformulation filled into a
multidose vial. After dilution with normal saline, sixdoses would be withdrawn from the
multidose vial . The dosage and administration section onthe label will include detailed
instructions for the health care provider to perform the dilution with 0.9% Sodium Chloride
Injection, USP .
Pfizer and BioNTech acknowledge that 21 CFR 610.15(a) requires that
Products in multiple -dose containers shall contain a preservative ,…
However, 21CFR610.15(d) states that
The Director …may approve an exception or alternative to any requirement in this
section. Requests for such exceptions or alternatives must be in writing.
Pfizer and BioNTech are hereb y makinga written request for an exception to
21CFR610.15(a) for the BNT 162b2vaccine as a multi- dose preservative -free presentation.
The justification for th is exception request is provided herein including details regardi ng
Pfizerand BioNTech’s plans for ensuring that the vaccine will meet the statutory and
regulatory requirements for identity , safety, purity, and potency. Please note, th is exception
has beenrequested and authorized under Emergency Use Authorization 27034 and is
requested to remain in place upon BLA approval.
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BNT162b2
BLA 125742
Module 1.12.5Request for a Waiver Exceptionto 21CFR 610.15(a) Requirement for a Preservative
PFIZER CONFIDENTIAL
Page 41.BACKGROUND
1.1.Proposed M ulti-dose Vial Designand Proposed User Instructions
The BNT162b2 drug product is frozen at - 90 to -60°C for storage and distribution with
provisions for short -term storage forup to two weeks at - 20 ±5°Candup to 1 month at 2-
8°C until administration, as described in Module 3.2 of the BLA . The drug product is
provided as a concentrate that is diluted at point of use prior to administration.
On the day of administration, thethawedvaccine vial is prepared for use . 0.9% Sodium
Chloride I njection, USP (Normal Saline) is added to the vial to increase the volume of the
vaccine solution for dosing to ensure that the injection volumes are appropriate for
administration. The via l islabeled with the time of Normal Saline dilution and must be
discarded within 6 hours after initial dilution. Dose administration of theBNT162b2 vaccine
involves withdrawal of the pre scribeddose from the vial into a delivery system such
asasyringe.
The dilution scheme for vaccine dosed under the EUA is representative of the proposed dose
administration instructions for planned commercial supply under an approved BLA.
1.2.Justification for the Unpreserved Multidose Vial
The BNT162b2 drug product is fil led into2 mL vials at a concentration of 0.5 mg/mL RNA
contained in lipid nanoparticles (LNPs). Formulation development studies conducted to date
do not support long -term storage of formulations at lower RNA orLNP concentrations
without a change to the formulation. A new formulation to enable lower strengths of RNA
LNP will require additional time togainglobalregulatory authorization and build additional
production capacity to supply global demand .
In addition to the formulat ion limitations, the drug product manufacturing sites have
limitations on the lowest volume that can be filled in tothe vial in a reliable and consistent
manner. This has been determined to be 0.3 mL for many of the drug product manufacturing
linesthat have been qualified for this vaccine drug product. Due to these constraints, the final
filled vial will contain enough concentrated active vaccine to suppl y 6 doses. Normal Saline
must be added to the vial in order to achieve an adequate injection volume reg ardless of
whether the vial is used as a single dose or a multi dose vial. If used as a single dose vial, 5
additional doses would be discarded after removal of a single dose. The use of this product as
a multi dose vial therefore provide s 6times more doses than if used as a single dose vial and
preventswastage of a critically needed vaccine.
Pfizer and BioNTech ha veassessed the risks of this approach b y taking into consideration
formulation factors including, but not limited to, pH, solvent sy stem, osm olality, drug
product storage temperature, and solution properties, which may impact the ability of the
finished drug product to support or inhibit microbial growth. Additionally , prior knowledge
from extensive experience with other products and data from platform formulations and
commonly used infusion fluid studies have been used to evaluate dilution and administration
risks.
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BNT162b2
BLA 125742
Module 1.12.5Request for a Waiver Exceptionto 21CFR 610.15(a) Requirement for a Preservative
PFIZER CONFIDENTIAL
Page 5Pfizer performed the microbial challenge assessments based on Dr. Metcalfe’s paper1which
included the panel of microbes in USP <5 1> and used prepared vaccine dosing solutions. I n
the study, samples werespiked with a low level inoculum (<100 cfu/mL) of S.aureus, E. coli,
Ps. aeruginosa, A. niger (name changed to A. brasiliensis ), and C. albicans, held at 20-25 ° C,
and then assessed for growth at time points up to 16 hours. Testing revealed no significant
growth for an y of the organisms within 12 hours of inoculation with storage at 20 -25 °C
which is defined as not more than 0.5 log 10unit higher than the previous value measured cfu.
The results of this study are provided in Section 3.2.P. 2.6 Compatibility andprovide
assurance for the microbial integrit y of the product over 6 hours. The in-use period of 6 hours
is necessary to ensure adequate time is provided to prepare and administer 6dosesand is in
alignment with WHO policy on the use of opened multi -dose vaccine vials2.
The exception is further justified by the favorable post -authorization experience following
distribution of more than 871,000,000 doses of vaccine in this multi -dose, non- preserved
presentation under the US Emergency Use Authorization (EUA 27034) and other global
authorizations from the receipt of the first temporary authorization for emergency supply in
the UK on 01 December 2020 through 30 June 2021.
As noted in 21 CFR 610.15, “ Any preservative used … shall not denature the specific
substances in the product to result in a decrease below the minimum acceptable potency
within the dating period when stored at the recommended temperature. ” Given the lipidic
nature of the lipid nanoparticles, compatibility with common preservatives is not expected.
As the microbial growth assessment study results support an in-use period of up to 6 hours,
the exclusion of a preservative which may otherwise compromise potency is prudent.
2.SUMMARY: REQUEST FOR EX CEPTION
Pfizerand BioNTech hereby request an exception from 21 CFR 610.15(a) regarding the
requirement for using a preservative in a M ulti-Dose Vial for commercial supply of the
candidate vaccine under BLA 125742.
REFERENC ES
1Metcalfe JW .Microbiological quality of drug products after penetration
of the container sy stem for dose preparation prior to patient
administration. American Pharmaceutical Review 2009 ;(Jan/Feb):84 -9.
2WHO Policy Statement: Multi -Dose Vial Policy (MDVP) – Handling of
Multi-Dose Vaccine Vials After Opening, Revisi on 2014.
WHO/IVB/14.07. Available at
https://apps.who.int/iris/bitstream/handle/10665/135972/WHO_I VB_14.
07_eng.pdf
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