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DEPARTMENT OF HEALTH & HUMAN SERVICES
Food & Drug Administrat ion
Silver Spring, MD 20993
1
DBSQC/OCBQ ANALYTICAL METHOD REVIEW MEMO
To: The file: STN 125742/0
From :
Reviewer Date
finalized Stamp Supervisor Stamp
Emnet Yitbarek
(Lead reviewer) 8/20/2021 Kori Francis
Hsiaoling Wang 8/19/2021 Tao Pan
Esmeralda
Alvarado-
Facundo 8/20/2021 Muhammad Shahabuddin
Anil Choudhary 8/20/2021
Karla Garcia 8/20/2021 James Kenney
Simleen Kaur
Through: Maryna Eichelberger, Ph.D., Division Director, CBER/OCBQ/DBSQC
Mary A. Malarkey, Director CBER/OCBQ
Applicant : BioNTech Manufacturing GmbH
Subject: Review of Analytical Methods used for the Lot release of COMI RNATY
Drug Substance (DS) and Drug Product (DP)
____________________________________________________________________
Recommendation: Approval
Summary:
The following analytical methods used for lot release of COMIRNATY and the
associated method validation s or qualifications, were reviewed:
1. RNA DP by (Emnet Yitbarek)
2. Identifi cation and quantification of lipids in DP by (Emnet Yitbarek )
3. (Hsiaoling Wang)
4. (Hsiaoling
Wang)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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5. Gener al methods to test DP: Appearanc e, Particu late
Matter , (Hsiaoling Wang)
6. Identi ty of DP by Assay ( Esmeralda Alvarado- Facundo)
7. (Esmeralda Alvara do-Facundo)
8. (Esmerald a Alvarado -Facundo)
9. (Anil Choudhary )
10. (Anil Choudhary )
11. (Anil Chou dhary ).
12. (Karla Garc ia)
13. Endotoxin of DP (Karla Garc ia)
14. Sterility of DP (Karla Garcia)
Conclusion: The analytical methods and their validations and/or qualifications
reviewed for the COMIRNATY drug substance and drug product were found to be
adequate for their inte nded use.
Documents Reviewed
Information in sections of the original BLA (STN125742) and IND 19736 submissions
that descr ibe control of DS and DP (3.2.S.4 and 3.2.P.5, respecti vely) , including
descriptions of DS and DP s pecifica tions, analytical procedures of DS an d DP and
validation of these analytical procedures were reviewed. Additional information in amendmen ts specified by each reviewer were also reviewed.
Background On Ma y 6, 2021, Pfizer/BioNTe ch (sp onsor) submitte d an original r olling BLA, STN
125742, for COMIR NATY (BNT162/PF -07302048), a prophylactic vaccine for the
prevention of COVID -19 which is caused by SARS- CoV-2 virus. COMIRNATY is a
white suspension solution composed of mRNA t hat encodes for the spike protein of
the SARS-C oV-2 virus and is encapsulated i n a lipid nano particle (LNP). The
concentrated suspension is stored at - 60 °C and is diluted with a sterile 0.9% Sodium
Chloride solution , USP, to ad minister intramuscularly to individuals ≥16 years of age.
The proposed dosage is a 30 µg regimen of two 0.3 mL doses given 3 weeks apart.
DBSQC reviews BLAs and their supplements to ensure analytical methods are appropriately described, validated and suitable for the intended purposes. The
following facilities perfor m the methods review ed:
1. Pfizer Biotherapeutics Pharmaceutical Sciences Analytical Rese arch &
Development , Chesterfield, MO ( ARD- STL)
2. Pfizer Biotherapeutics Pharmaceutical Sciences Analytical Rese arch &
Development ,
Andover, MA (ARD- AND)
3. Pfizer Global Supply, Kalamazoo, MI (PGS -KZO)
4. Pfizer Global Supply , Andover , MA ( PGS- AND)
5. Pfizer Global Supply, Puurs, Belgium (PGS -Puurs)
6. Pfizer Global Suppl y, Grange Castle, Ire land ( PGS- GC)
7.
2
(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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3 The following analytical methods used for DS and DP release were reviewed:
1. RNA DP by
Method description
(b) (4)
(b) (4)
(b) (4)
2 pages have been determined to be not releasable: (b)(4)
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Conclusion
The method is adequately validated for the determination of product in
COMIRNATY DP . Th e firm’s test method i ncludes limited instructio ns for
. They have agreed to add the information and submit the updated
procedure to their IND.
2. Identification and quantification of lipids in DP by
Method descri ption
The identi ty and quantit y of the four lipids in the DP , ALC-0 159, c holesterol, DSPC
and ALC- 0315, are determined by . In this method,
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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7 The assay system su itability criteria include:
Assay and DP sample acce ptance criteria include:
Method Validation:
(b) (4)
(b) (4)
(b) (4)
One page has been determined to be not releasable: (b)(4)
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Conc lusion :
The method is adequately described and validated for the
identification and quantitat ion of four lipids (ALC- 0159, cholesterol, DSPC and ALC -
0315) in COMIRNATY DP.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
3 pages have been determined to be not releasable
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4. of DP by
The DP is a sterile of RNA -containi ng lipid nanoparticles (LNPs) in
phosphate buffer contai ning sucrose. The specifications of LNP for DP are
, respectively. The specification for
the .
Method description
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
3 pages have been determined to be not releasable: (b)(4)
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Conclusion
Based on the information provided in the or iginal BLA and t he amendment, the
method has been validated for its intended purpose.
5. General Methods to test DP
methods used for DP analyses are shown in T able 7 below.
Table 7. methods used to tes t DP
These methods do not require validation. Suitability of the methods for this DP was verified as described below.
Review of Appearance Methods and Method Verifications :
The appearanc e of includes the tests for . The appearance
tests described in TM100010539 for ARD labs and in LAB - for PGS -AND lab are
equivalent.
DP Test Specification
method
DP Appearance: Visual
and particles White to off -white suspension; May
contain white to off-white opaque,
amorphous particles
DP
DP
DP
DP Container content Not less than
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
3 pages have been determined to be not releasable: (b)(4)
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21 Review of Container Content and Method Verifications :
The container content is an adaption of the for DP. Analytical
procedures in TM100011129 for ARD labs, LAB- for PGS -Puurs and TM9106A
for PGS -KZO are equivalent. DP vials are used and
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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The contai
ner content is calculated to decimal places and every one of the vials
should have a volume of no less than to be reported as “No Less Than
”.
Infor
mation Request and Reviews :
The following IR was sent to the firm on August 2, 2021:
a.You calculate volume of each vial based on . Please
describe how was determined.
b.In the verification report [
] from PG S-KZO lab, DP container content was
determined by measuring the total volume after 1.8 mL of sterile 0.9% sodium
chloride solution was added. Please confirm that this method will be used for lot release testing by the PG S-KZO laboratory and that the container volume
specification “Not less than ” is the same regardless of test site/method.
Review of the response: The response was received on August 9, 2021 in amendment 35.
a.The firm stated that the
was obtained by
b.The firm confirmed that the container con tent specification of Not less than
is the same regardless of test site/method. Container content for
was used as a DP specification under EUA, which was replaced by
22
(b) (4)
(b)
(4)
(b) (4)
(b)
(4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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vial container content in BLA. PGS -KZO will perform DP container cont ent test
as other labs described in analytical procedure TM9106A.
The responses are acceptable. Re -verification from PGS -KZO is not necessary
because the analytical steps are equivalent.
23 Conclusion
Based on the information provided in the original BLA and the amendment, these
methods have been verified for their intended purposes.
6. Identi ty of DP by Assay
The assay is a release test to verify the identity of DP by
demonstrating the presence of the mRNA target. The test is performed at Pfizer
facilities PGS -GC, PGS -AND, A RD a nd . The spec ificatio n for DP is
“Identity confir med”.
Method description
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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24 The assay validity criteria are:
If the assay fails to meet predefined acceptance criteria, then the assay is invalid and
must be repeated. If the DP assay acceptance crit eria fail, the sample is re -
processed f rom th e beginning .
The sample acceptance criteria are:
If the assay acceptance criteria and sample acceptance criteria are met, the result is
reported as “ Identity C onfirme d” for the presence of target mRNA or “Identity not
confirmed” for the absence of target mRNA.
Method Va lidatio n
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Conclusion:
The method to confirm the identity of DP mRNA was adequately
descri bed and the validation data demons trate the assay is suitabl e for its intended
use.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
10 pages have been determined to be not releasable: (b)(4)
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10. Total RNA by
The principle of the method t o quantify RNA is
Method De
scription
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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A
ssay acceptanc e criteria are as f ollows :
Sample accepta nce criteria are as follow:
Reporting of the Results : The total RNA content is reported for each test sample in
; the RNA is reported as a whole
number. The current specifications for DP are:
.
Method Qualification
(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)
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Overall Conclusion
The RNA method is adequately described and demonstrated to be
suitable for measuring total RNA and .
(b) (4)
(b) (4)
(b) (4)
(b) (4)
5 pages have been determined to be not releasable: (b)(4)
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45 13 . Bacter ial Endotoxin Test (BET)
Pfizer qualified the BET m ethod at the ARD -AND a nd PGS-
AND facilities for testing of BNT162b2 mRNA . In addition, t he
method was also qualified at the PGS -AND facility. The -BET
method was performed usin g a and -BET method was performed
using the
the BET for Drug Product (DP), which also uses a
. The BNT162 b2 DP
is a single -stranded, 5 ’-capped mRNA that is translated into a protein. Lipids are later
added to form lipid nanopartic les (LNP);
the DP BET is perfor med.
Method des c ription
-BET Me thod Qualif ication for
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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BET Qualification for D rug Produc t
Pfizer qualified the -BET method for DP at the Pfizer Global Supply in Puurs,
Belgiu m (PGS- Puurs ) and Pfizer Global Supply in Kalamazoo, MI ( PGS- KZO)
facilities .
-BET Method Qualification for BNT162b2 mRNA DP:
The -BET is performed to dete ct or quantitate bacterial endoto xins present in test
samples .
The original submiss ion d id not include qualification data from the PGS -Puurs and
PGS- KZO laboratories. CBER sent an i nformation request (IR) to Pfizer on July16,
2021, regar ding their t est for interfering factors at the PGS -Puurs and P GS-KZO
facilities. Respons e to this IR w as received on July 30, 2021 in amendment num ber
21. Pfizer submitted supplemental verification report s performed on DP at each
requested facility . These verification tests were performed with
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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The c urrent DP bacterial endotoxin test method involves sample preparation in which
Pfizer performed a bacterial endotoxin test to
demonstrate the
. This test is described below:
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
One page has been determined to be not releasable: (b)(4)
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Conc lusion
The endotoxin ( ) test meth od was qualified
appropriately and demonstrated to be suita ble unde r the actual c ondit ions of use .
Pfizer has committed to
and wi ll sub mit the verification study result s
with a proposed updated lot release protocol template a s a supplement to this file on
or before December 6 , 2021.
14. Sterility T est
Method descripti on
The is used t est DP sterility.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
2 pages have been determined to be not releasable: (b)(4)
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Conclusion : The Sterility Test method was validated in
accordance with and was found t o provi de detec tion results equival ent
sterility test method. The data provided
show that the method is suitable for its intended use.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)