Document text
COVID-19 Vaccine (BNT162, PF -07302048)
BLA 125742/0
Response to 02 Jul 2021FDA queries -CMC information and categorical exclusion for an environment analysis
PFIZER CONFIDENTIAL
Page 1TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 4
REGARDING THE MANUFACTURING OF DRUG SUBS TANCE (DS) ............................ 5
QUERY 1 ................................ ................................ ................................ ................................ ...5
RESPONSE 1 ................................ ................................ ................................ ................... 5
SUPPORTING DOCUMENTATION ................................ ................................ ....6
New or Replaced Supporting Documentation................................ ..........6
Previously submitted supporting documentation ................................ .....6
QUERY 2 ................................ ................................ ................................ ................................ ...7
RESPONSE 2 ................................ ................................ ................................ ................... 7
SUPPORTING DOCUMENTATION ................................ ................................ ..24
New or Replaced Supporting Documentation................................ ........24
Previously submitted supporting documentation ................................ ...24
QUERY 3 ................................ ................................ ................................ ................................ .25
RESPONSE 3 ................................ ................................ ................................ ................. 25
SUPPORTING DOCUMENTATI ON................................ ................................ ..25
New or Replaced Supporting Documentation................................ ........25
Previously submitted supporting documentation ................................ ...25
QUERY 4 ................................ ................................ ................................ ................................ .26
RESPONSE 4 ................................ ................................ ................................ ................. 26
SUPPORTING DOCUMENTATION ................................ ................................ ..26
New or Replaced Supporting Documentation................................ ........26
Previously submitted supporting documentation ................................ ...26
REGARDING THE FILL A ND FINISH MANUFACTUR ING PROCESS .......................... 27
QUERY 5 ................................ ................................ ................................ ................................ .27
RESPONSE 5 ................................ ................................ ................................ ................. 27
SUPPORTING DOCUMENTATI ON................................ ................................ ..27
New or Replaced Supporting Documentation................................ ........27
Previously submitted supporting documentation ................................ ...27
QUERY 6 ................................ ................................ ................................ ................................ .28
RESPONSE 6 ................................ ................................ ................................ ................. 28
SUPPORTING DOCUMENTATION ................................ ................................ ..28
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FDA-CBER-2021-5683-1149357
COVID-19 Vaccine (BNT162, PF -07302048)
BLA 125742/0
Response to 02 Jul 2021FDA queries -CMC information and categorical exclusion for an environment analysis
PFIZER CONFIDENTIAL
Page 2New or Replaced Supporting Documentation................................ ........28
Previously submitted supporting documentation ................................ ...28
QUERY 7 ................................ ................................ ................................ ................................ .29
RESPONSE 7 ................................ ................................ ................................ ................. 29
SUPPORTING DOCUMENTATION ................................ ................................ ..29
New or R eplaced Supporting Documentation ................................ ........29
Previously submitted supporting documentation ................................ ...29
QUERY 8 ................................ ................................ ................................ ................................ .30
RESPONSE 8 ................................ ................................ ................................ ................. 30
SUPPORTING DOCUMENTATI ON................................ ................................ ..30
New or Replaced Supporting Documentation................................ ........30
Previously submitted supporting documentation ................................ ...30
QUERY 9 ................................ ................................ ................................ ................................ .31
RESPONSE 9 ................................ ................................ ................................ ................. 31
SUPPORTING DOCUMENTATION ................................ ................................ ..31
New or Replaced Supporting Documentation................................ ........31
Previously submitted supporting documentation ................................ ...31
QUERY 10 ................................ ................................ ................................ ............................... 32
RESPONSE 10 ................................ ................................ ................................ ...............32
SUPPORTING DOCUMENTATION ................................ ................................ ..32
New or R eplaced Supporting Documentation ................................ ........32
Previously submitted supporting documentation ................................ ...32
QUERY 11 ................................ ................................ ................................ ............................... 33
RESPONSE 11 ................................ ................................ ................................ ...............33
SUPPORTING DOCUMENTATI ON................................ ................................ ..33
New or Replaced Supporting Documentation................................ ........33
Previously submitted supporting documentation ................................ ...33
REGARDING THE ANALYT ICAL PROCEDURES ................................ ........................... 34
QUERY 12 ................................ ................................ ................................ ............................... 34
RESPONSE 12 ................................ ................................ ................................ ...............34
SUPPORTING DOCUMENTATION ................................ ................................ ..34
New or R eplaced Supporting Documentation ................................ ........34
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PFIZER CONFIDENTIAL
Page 3Previously submitted supporting documentation ................................ ...36
REGARDING THE REFERENCE STANDARDS USED I N THE ANALYTI CAL
ASSAYS ................................ ................................ ................................ ............................. 37
QUERY 13 ................................ ................................ ................................ ............................... 37
RESPONSE 13 ................................ ................................ ................................ ...............37
SUPPORTING DOCUMENTATION ................................ ................................ ..38
New or Replaced Supporting Documentation................................ ........38
Previously submitted supporting documentation ................................ ...38
QUERY 14 ................................ ................................ ................................ ............................... 39
RESPON SE 14................................ ................................ ................................ ...............39
SUPPORTING DOCUMENTATION ................................ ................................ ..39
New or Replaced Supporting Documentation................................ ........39
Previously submitted supporting documentation ................................ ...39
QUERY 15 ................................ ................................ ................................ ............................... 40
RESPONSE 15 ................................ ................................ ................................ ...............40
SUPPORTING DOCUMENTATI ON................................ ................................ ..40
New or Replaced Supporting Documentation................................ ........40
Previously submitted supporting documentation ................................ ...40
REGARDING THE CLINI CAL ASSAYS ................................ ................................ .............41
QUERY 16 ................................ ................................ ................................ ............................... 41
RESPONSE 16 ................................ ................................ ................................ ...............41
SUPPORTING DOCUMENTATION ................................ ................................ ..41
New or Replaced Supporting Documentation................................ ........41
Previously submitted supporting documentation ................................ ...41
QUERY17................................ ................................ ................................ ............................... 42
RESPONSE 17................................ ................................ ................................ ...............42
SUPPORTING DOCUMENTATION ................................ ................................ ..42
New or R eplaced Supporting Documentation ................................ ........42
Previously submitted supporting documentation ................................ ...42
REGARDING THE CATEGO RICAL EXCLUSION FOR AN ENVIRONMENT
ANALYSIS ................................ ................................ ................................ ......................... 43
QUERY 18 ................................ ................................ ................................ ............................... 43
RESPONSE 18 ................................ ................................ ................................ ...............43
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PFIZER CONFIDENTIAL
Page 4SUPPORTING DOCUMENTATION ................................ ................................ ..45
New or Replaced Supporting Documentation................................ ........45
Previously submitted supporting documentation ................................ ...45
LIST OF TABLES
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PFIZER CONFIDENTIAL
Page 5REGARDING THE MANUFACTURING OF DRU G SUBSTANCE (DS)
QUERY 1
The was listed as one of the process parameters
under IND/EUA. In your BLA 125742 submission, this process paramete r was removed as
shown in Table 3.2.S.2.2- 3 Parameters. Please specify the acceptable
range of the
RESPONSE 1
The
and was initially evaluated at based on BioNTech platform knowledge. As
stated in 3.2.S.2.6 Process Development and Characterization section, the low er range of
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PFIZER CONFIDENTIAL
Page 6Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
3.2.S.2.2 Manufacturing Process [Andover] Replaced
Previously submitted supporting documentation
3.2.S.2.5 Manufacturing Process [Andover -
3.2.S.2.5 Manufacturing Process [Andover- ]
3.2.S.2.6 Risk Assessment of Process Related Impurities
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Page 7QUERY 2
In Section 3.2.S.2.5, you stated that the for UFDF at
commercial scale is . Please provide the performance test results for the commercial -scale
, including the data and
evaluation of the performance during .
RESPONSE 2
The is evaluated based on
parameters evaluated for as stated in
Section 3.2.S.2.5 Process Validation and/or Evaluation -Additional Process Evaluation
[Andover] are listed below in Table 2.
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PFIZER CONFIDENTIAL
Page 8
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PFIZER CONFIDENTIAL
Page 23Conclusion:
Based on the acceptable criteria, the is acceptable with
the exception of the residual DNA template result for batch which is being
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Page 24investigated for root cause, all other results that exceeded monitoring
limits have been determined to be unrelated to .
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 25QUERY 3
In Figure 3.2.S.2.2 -1 RNA Manufacturing Process, step y ield is designated as a process
performance attribute throughout the manufacturing process. Please specify the acceptable
range/control limit at each manufacturing step (i.e.,
) to ensure appropriate monitoring and controls during the manufacture of DS.
RESPONSE 3
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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Page 26QUERY 4
Regarding the action limits for bioburden and endotoxin testing listed in document 3.2.S.2.2
Manufacturing Process Andover, it appears that there are multiple ty pographical errors (“ ≤”
instead of “>”) in Table 3.2.S.2.2- 4 In-Process Tests (Monitoring) for
Control and in Table 3.2.S.2.2- 7 In-Process Tests (Monitoring) for Control.
Please confirm and correct the errors.
RESPONSE 4
The Bioburden and Endotoxin limits listed in Table 3.2.S.2.2 -4 and 3.2.S.2.2 -7 are
designated as Action limits that would require an action when the limits are exceeded. In
Pfizer’s quality system, a test result greater than the action limit requires an investigation and
therefore t he symbols are accurate as depicted.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 27REGARDING THE FILL A ND FINISH MANUFACTURING PROCESS
QUERY 5
Please update the documents 3.2.P.3.3 Description of Manufacturing Process and Process
Controls – LNP Production and Bulk Drug Product Formulation [Puurs] to include a brief
description for the primary areas and equipment involved in BNT162b2 LNP production and
bulk DP formulation.
RESPONSE 5
An updated Section 3.2.P.3.3 Description of Manufacturing Process and Process Controls –
LNP Production and Bulk Drug Product Formulation [Puurs] is provided to include the
primary areas and their classifications.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
3.2.P.3.3 Description of Manufacturing Process and Process Controls – LNP Production and
Bulk Drug Product Formulation [Puurs] , replaced
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 28QUERY 6
You stated that
Please provide relevant
supportive data (e.g., stability of the ) to demonstrate that this
step has no significant impact on the qualit y of the .
RESPONSE 6
As described in previously provided Section 3.2.P.2.3 Process Development and
Characterization, subsection 3.2.P.2.3.3.2 Characterization of
Operations, a study was performed with BNT162b2 using batch
.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
Section 3.2.P.2.3 Process Development and Characterization
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PFIZER CONFIDENTIAL
Page 29QUERY 7
You stated that between lots.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
Section 3.2.P.3.5 Process Validation and/or Evaluation – [Puurs] , new
Section 3.2.P.3.5 Process Validation and/or Evaluation –
[Kalamazoo] , new
Previousl y submitted supporting documentation
None
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Page 30QUERY 8
Please clarify whether the
steps) at
Pfizer Kalamazoo submitted to IND/EUA will also be implemented under the BLA. Please
update the relevant documents if y ou intend to include for the
manufacture of the DP at Pfizer Kalamazoo.
RESPONSE 8
Pfizer Kalamazoo intends to implement under the BLA. The
will be submitted to the BL A as a post -approval
change.
Literature References
None
SUPPORTING DOCUMENTATION
Newor Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 31QUERY 9
Regarding the process control/parameters, please address the following at each
manufacturing site (Puurs and Kalamazoo):
Please specify the for DS
Please specify the .
RESPONSE 9
Puurs
Kalamazoo
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
Section 3.2.P.3.3 L NP Production and Bulk Drug Product Formulation [Puurs] , replaced
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 32QUERY 10
Please update the documents 3.2.P.3.3 Description of Manufacturing Process and Process
Controls – Fill and Finis h [Puurs] to include a brief description for the primary areas and
equipment involved in BNT162b2 DP fill and finish operations.
RESPONSE 10
An updated Section 3.2.P.3.3 Fill and Finish [Puurs] is provided to include the primary areas
and their classifications. Additionally , Table3.2.P.3.3-6Process Parameters for Capping is
updated to correct inverted values between the
(typographical error).
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
Section 3.2.P.3.3 Fill and Finish [Puurs] , replaced
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 33QUERY 11
Please update the Table 3.2.P.3.3 -8 Process Parameters for Storage Shipping to define the
maximum allowable numbers of
EUA 27034 in amendment 176 on May 17, 2021.
RESPONSE 11
Footnote d (in Table 3.2.P.3.3-8 Process Parameters for Storage andShipping and
Table3.2.P.3.4-2 Time Out of Storage Condition for BNT162b2 Drug Product ) has been
updated to include a maximum of A
representative table, as updated in the relevant sections for both Puurs and Kalamazoo, is
shown below.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
Section 3.2.P.3.3 Fill and Finish [Puurs] , replaced
Section 3.2.P.3.3 Fill and Finish [ Kalamazoo] , replaced
Section 3.2.P.3.4 Process Step Hold Times – Fill and Finish [Puurs] , replaced
Section 3.2.P.3.4 Process Step Hold Times – Fill and Finish [ Kalamazoo] , replaced
Previously submitted supporting documentation
None
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PFIZER CONFIDENTIAL
Page 34REGARDING THE ANALYT ICAL PROCEDURES
QUERY 12
Please identify all the test sites that will be used for the release and stability testing of the
BNT162b2 DS and DP under the BLA submission and include listings for anal ytical
procedures performed at each site. Please note that site -specific validation studies for
analytical procedures or the demonstration of comparable assay performance of the receiving
site to the transfer site that completed the validation are required for BLA submissio n.
RESPONSE 12
All test sites used for release and stability testing of the BNT162b2 DS and DP under BLA
submission are included in Section 3.2.S.2.1 Manufacturer(s) and Section 3.2.P.3.1
Manufacturer(s).
Section 3.2.R Standard Operating Procedures, Meth od Validation and Transfer Reports
includes listings for analytical procedures performed at each site and has been updated to
include additional DS and DP testing sites filed to the EUA on June 30, 2021 and to be filed
to the EUA b y July 30,2021.
Due to these additions, anal ytical procedures are
updated wit h minor edits and included (see Supporting Documentation below).
The appropriate supportive documentation (anal ytical procedures and validation/transfer) for
each testing site which is referenced in Section 3.2.R Standard Operating Procedures,
Method Vali dation and Transfer Reports is also available within the 3.2.R section.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
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Page 37REGARDING THE REFERENCE STANDARDS USED IN THE ANALYTIC AL
ASSAYS
QUERY 13
We acknowledge that qualifications of the analy tical assay s were originally conducted to
support vaccine distribution under the EUA. However, validation of the analy tical release
assays for DS and DP is required for the BLA submission and pre -established a cceptance
criteria should be based on y our previous qualification studies. Please provide the full
validation reports for the following analy tical procedures:
a.Quantification of Poly (A) tail in BNT162b2 DS by ddPCR
b.Quantification of residual DNA template content in BNT162b2 DS by qPCR
c.Quantification of total RNA concentration and the relative percentage of encapsulated
RNA in BNT162b2 DP by fluorescence assay
d.Determination of the in -vitro expression of the BNT162b2 DP by cell-based flow
cytometry
RESPONSE 13
The following sections are updated with validation and/or transfer data supporting multiple
testing sites:
3.2.S.4.3 Validation of Analy tical Procedure – qPCR
3.2.S.4.3 Validation of Analy tical Procedure – ddPCR
3.2.P.5.3 Validation of Analy tical Procedure – Fluorescence
3.2.P.5.3 Validation of Analy tical Procedure – Cell-based Flow C ytometry
In addition, the 3.2.R Standard Operating Procedures, Method Validation and Transfer
Reports is updated with all references to supporting documentation (M ethod SOP’s and full
validation and/or transfer reports for each site). The 3.2.S.4.2 Analy tical Procedures –qPCR
and 3.2.P.5.2 Analytical Procedures –Fluorescence is also updated to outline method
changes addressed in the EUA submitted on 30 June 2021 and to be filed to the EUA b y 30
July2021respectivel y.
Literature References
None
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Page 38SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
3.2.S.4.3 Validation of Analy tical Procedure – qPCR-Replaced
3.2.S.4.3 Validation of Analy tical Procedur e –ddPCR-Replaced
3.2.P.5.3 Validation of Analy tical Procedure – Fluorescence -Replaced
3.2.P.5.3 Validation of Analy tical Procedure – Cell-based Flow C ytometry-Replaced
3.2.R Standard Operating Procedures, Method Validation and Transfer Reports -
Replaced
3.2.S.4.2 Analy tical Procedures –qPCR-Replaced
3.2.P.5.2 Analytical Procedures –Fluorescence -Replaced
Previously submitted supporting documentation
None
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Page 39QUERY 14
Please confirm that the BNT162b2 DS assay control used in multiple DS analytical
procedures (i.e., CGE for RNA integrit y, RP-HPLC for 5’ -cap, ddPCR for poly (A) tail, and
immunoblot for dsRNA) is the same one ( ) as described in Section
3.2.S.5 Reference Standards or Materials .
RESPONSE 14
The drug substanc e (DS) anal ytical procedures do not require the use of DS reference
material ). Any DS batch that meets the release criteria (3.2.S.4.1
Specification) at the time of manufacture is suitable as a control . DSmaterial will be used as
an internal control representative of the sample tested.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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Page 40QUERY 15
Please update the document 3.2.P.6 Reference Standards and Materials to describe the
BNT162b2 DP assay control(s) used in multiple DP analy tical procedures (e.g., CGE for
RNA integrit y, in vitro expression potency assay , fluorescence assay for RNA content and
RNA encapsulation, and DL S for LNP size and poly dispersity), including the DP lot number,
the lot-release testing results, the qualification data to support its intended use as a reference
standard, and an y available stability data.
RESPONSE 15
The DPassay controls used within multiple DP analy tical procedures (CGE for RNA
integrity, in vitro expression potency assay, fluorescence assay for RNA content and RNA
encapsulation, and DL S for LNP size and poly dispersity ) are not considered reference
standards since the final sample results do not rely on quantitation of this material in the
method. They are used as an internal control representative of the sample tested. An y DP
batch that meets the release criteria (3.2.P.5.1 Specification) at the time of manufacture is
suitable as a control.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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Page 41REGARDING THE CLINICAL ASSAYS
QUERY 16
Please submit the SOP VR -TM-10295 for the Cepheid Xpert Xpress SARS- CoV-2 RT-PCR
assay.
RESPONSE 16
SOP VR-TM-10295 for the Cepheid Xpert Xpress SARS- CoV-2 RT-PCR is attached.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
VR-TM-10295
Previously submitted supporting documentation
None
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Page 42QUERY 17
Please provide the method validation report(s) for the Single- plex Direct Luminex assay
(dLIA) for quantification of IgG antibodies to SARS -CoV-2S1and RBD proteins in human
serum.
RESPONSE 17
VR-MVR-10077, themethod validation report for the Single -plex Direct Luminex assay
(dLIA) for quantification of IgG antibodies to SARS -CoV-2S1and RBD proteins in human
serumis attached.
Literature References
None
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
VR-MVR-10077
Previously submitted supporting documentation
None
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Page 43REGARDING THE CATEGO RICAL EXCLUSION FOR AN ENVIRONMENT
ANALYSIS
QUERY 18
Please provide background information for the lipids in the L NP to support the claim that
each of the lipids is naturally occurring and does not alter significantly the concentration or
distribution of the substance, its metabolites, or degradation product s in the environment.
RESPONSE 18
As per the FDA July 1998 Guidance for Industry , submissions to CDER or CBER that
ordinarily are excluded categoricall y under the regulations include actions on the use of an
active moiety or drug substance. The pharmacolo gically active moiet y or drug substance in
COMIRNATY is messenger RNA (mRNA), which is recognized as naturally occurring.
Therapeutic use of COMIRNATY will not significantly alter the concentration or distribution
of mRNA, its metabolites, or degradation products in the environment.
COMIRNATY contains four pharmacologicall y inactive lipid excipients, each with a
functional or structural purpose in the lipid nanoparticle (LNP) component of the drug
product, as summarized in Table 15:
Table 15.Lipid Components of COMIRNATY Lipid Nanoparticles
Lipid Description Chemical Name Amount per
dose (mg)
ALC-0315 Novel cationic lipid ((4-hydroxybutyl)azanediyl)bis(hexane -
6,1-diyl)bis(2 -hexyldecanoate)
ALC-0159 Novel PEGylated
lipid2-[(polyethylene glycol) -2000]-N,N-
ditetradecylacetamide
DSPC Phospholipid 1,2-Distearoyl -sn-glycero-3-
phosphocholine
Cholesterol Sterol lipid Cholesterol
The phospholipid (DSPC) and the sterol lipid (cholesterol) are both recognized as naturall y
occurring membrane lipids. Therapeutic use of COMI RNATY will not alter significantl y the
concentration or distribution of these lipids, their metabolites, or degradation products in the
environment.
ALC-0315 and ALC -0159 are novel lipids and therefore not recognized as naturally
occurring. However, the presence of these lipids in the drug product is not expected to have
an impact on the en vironment, as the very conservatively estimated concentrations of each
lipid at the point of entry into the aquatic environment will be significantly below 1 part per
billion, as presented below.
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Page 45Literature References
US Food and Drug Administration . Guidance for Industry : Environmental Assessment of
HumanDrug and Biologics Applications. Rockville, MD: Center for Drug Evaluation and
Research, Center for Biologics Evaluation and Research; July 1998.
The United States Census Bureau. U.S. and World Population Clock. Available from:
https://www.census.gov/popclock . Accessed: 06 J uly 2021.
SUPPORTING DOCUMENTATION
New or Replaced Supporting Documentation
None
Previously submitted supporting documentation
None
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