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10.5731/pdajpst.2018.009415Access the most recent version at doi: 213-22874, 2020 PDA J Pharm Sci and Tech
Parag Kolhe, Khurram Sunasara, Lavinia Lewis, et al. Drug ProductControl Strategy Approach for a Well-Characterized Vaccine
on November 8, 2020Downloaded from on November 8, 2020Downloaded from
TECHNOLOGY/APPLICATION
Control Strategy Approach for a Well-Characterized VaccineDrug Product
PARAG KOLHE1,*, KHURRAM SUNASARA1, LAVINIA LEWIS1, MICHELE BAILEY PIATCHEK1,ROBERTO RODRIGUEZ1,†, and KATHERINE ARCH-DOUGLAS1
1BioTherapeutics Pharmaceutical Sciences, Pfizer Inc, Chesterfield, MO 63017 © PDA, Inc. 2020
ABSTRACT: Trumenba (MenB-FHbp; bivalent rLP2086), the first meningococcal serogroup B vaccine approved in the
United States and subsequently approved in Europe, Canada, and Australia, is well-characterized. Pfizer devised a con-
trol strategy approach by using a simplified control strategy wheel for Trumenba based on International Council for
Harmonisation (ICH) Q8 (R2), Q9, Q10, and Q11 guidelines, which provide complementary guidance on pharmaceuti-
cal development, quality risk management, quality systems, and development and manufacture of drug substances,
respectively. These guidelines ensure product quality using a scientific and risk-based approach. Trumenba contains
two factor H binding proteins (FHbps), one from each of the two FHbp subfamilies (A and B), adsorbed onto aluminum
phosphate. Trumenba manufacturing processes are complicated by the recombinant protein expression of Subfamily A
and B proteins and the nature of the drug product (suspension in syringes); the latter also introduces challenges in con-
trolling product critical quality attributes during the development process. In such complex systems, the control strategy
is critical to ensuring consistent desired product quality; it also supports the regulatory requirement of continued
improvement through continuous process verification and aids regulatory filing. This article describes Pfizer’s approach
toward robust control strategy development, built on product and process understanding, and links control strategy to
regulatory document sections and flow of controls. Specifically, an approach is presented on product quality attribute
criticality determination based on safety and efficacy and on an understanding of process parameter criticality. This was
achieved by studying the impact of the approach on product quality attributes to define process parameter and in-pro-
cess controls. This approach is further explained through Trumenba case studies, highlighting specific quality attributes
and the associated controls implemented, and provides a holistic view of controls employed for both drug substance
and drug product.
KEYWORDS: Control strategy, ICH guidelines, Product quality, Trumenba, Drug substance, Drug product.
1. Introduction
A comprehensive control strategy for a pharmaceutical
product is the key to achieving process consistency and
product quality, safety, and efficacy. In addition to serv-
ing as a tool that enables consistent use of a scientific
and risk-based product development approach and the
linking of critical quality attributes (CQAs) to process
parameters or material attributes and associated con-
trols, the control strategy provides the framework for a
defined thought process and superior organization in the
preparation of regulatory documents. The International
Council for Harmonisation (ICH) Q10 guideline defines
control strategy as “[a] planned set of controls, derived
from current product and process understanding, that
assures process performance and product quality. The
controls can include parameters and attributes related to
drug substance (DS) and drug product (DP) materials
and components, facility and equipment operating con-
ditions, in-process controls, finished product specifica-
tions, and the associated methods and frequency of
monitoring and control” (1). The elements that contrib-
ute to control strategy are outlined in ICH guidelines Q8
(R2), Q9, Q10, and Q11 (1–5). These guidelines concep-
tualize a new quality paradigm in which a scientific and
risk-based approach using principles of pharmaceutical
development, quality risk management, and quality sys-
tems is used for quality product development and robust
* Corresponding Author: Pfizer Inc, 1 Burtt Rd., An-
dover, MA, 01810. Telephone: +1-978-247-1168;
e-mail: parag.kolhe@pfizer.com
†Deceased 2019, formally with Pfizer Inc.
doi: 10.5731/pdajpst.2018.009415
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dossier submission, review, inspection, and post-ap-
proval changes to ensure both product quality and pro-
cess consistency (1–3, 6). A robust control strategy not
only ensures process performance and product quality
but is also a regulatory expectation (6).
As a product is commercialized, it is important to eval-
uate product quality attributes and to monitor process
controls to assess the need for further control mecha-
nisms. This process is called continuous process verifi-
cation (CPV) and the control strategy serves as input
for the CPV plan.
Trumenba (MenB-FHbp; bivalent rLP2086; Pfizer Inc,
Philadelphia, PA) is a vaccine indicated for active
immunization to prevent invasive disease caused by
Neisseria meningitidis serogroup B. This well-
characterized vaccine (7, 8) was first approved in the
United States for individuals 10–25 years of age (9)
under the breakthrough therapy designation and the
accelerated approval process. Since then, it has been
approved in the European Union (individuals ≥10 yearsof age), Canada (10 ± 25 years of age), and Australia(≥10 years of age) (11 ± 13). This article provides Pfizer’sapproach to control strategy and the interconnectionbetween the control strategy and regulatory dossiersubmission. In addition, several Trumenba case studiesof specific examples of quality attributes (QAs) andimplementation of controls are presented.
2. Pfizer’s Approach to Development and
Visualization of the Control Strategy
2.1. Description of Pfizer’s Overall Control Strategy
The control strategy tool developed by Pfizer is used to
identify and systematically document the various ele-
ments of control for the manufacturing processes. Use
of the tool enables ready identification of the elements
being used for each of the CQAs, QAs, critical process
parameters (CPPs), and process parameters.
The control strategy for a given product is developed
using a holistic approach that considers and assesses
several elements of control, ensuring that the control
strategy for DS is linked to the final DP. One common
and key element of most strategies is the distribution of
controls and monitoring across all aspects of manufac-
turing. Thus, control strategy risk assessment involves
the following essential elements:
1. quality target product profile;
2. QA risk assessment;
3. manufacturing process description, process under-
standing of the impact of process parameters and ma-
terial attributes of the CQAs for each unit operation;
4. current good manufacturing practices (cGMPs),
including facility, equipment and procedural elements;
5. failure modes effects and criticality analysis (FMECA)
risk assessment for the DS; and
6. DP manufacturing process and the pharmaceutical
quality system.
2.1.1. Product Quality Attribute Criticality
Assessment: The ICH guidelines define a CQA as “a
physical, chemical, biological or microbiological prop-
erty or characteristic that should be within an appropri-
ate limit, range, or distribution to ensure the desired
product quality” (3). At Pfizer, the assignment of crit-
icality to a quality attribute is based upon the potential
of the quality attribute to impact safety or efficacy.
Flynn and Nyberg (5) have described the background
and philosophy in greater detail for antibodies,
although the same principle can be applied to vaccines.
Risk assessment is performed for product quality attrib-
utes and process parameters to determine criticality
and to understand the relationship between process pa-
rameters and product quality attributes. CQA considers
severity and uncertainty in understanding the attribute,
which can impact safety and efficacy. Table I and Ta-
ble II provide a snapshot of scoring utilized for severity
and uncertainty. A combination of moderate to high
scores of severity and uncertainty would render a given
product quality attribute as critical.
2.1.2. Understanding Impact of Process Parameters
on Product Quality Attributes: Pfizer utilizes a cause-
and-effect matrix approach during the early product de-
velopment where the impact of process parameters on
product quality attributes is assessed to define the pro-
cess parameters that need more understanding; studies
are incorporated during the development. The scoring
guidance used is provided in Table III and Table IV for
product quality attribute score and process parameter
score. The product quality attribute score is based on
the product quality criticality determination exercise
mentioned in the previous section. Table V provides an
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example of a cause-and-effect matrix and how quality
attributes are scored.
From Table V, clearly Process Parameter 1 will
require in-depth experimentation to understand the
impact of this parameter followed by Process Parame-
ter 3. Once these experiments are completed, the
cause-and-effect matrix is revisited and the scores are
confirmed. Process parameter criticality is then estab-
lished based on its impact on CQAs. The risk assess-
ment exercise also determines the strategy for in-
process testing (IPT).
Figure 1 depicts a control wheel containing the control
elements. Both “control” and “monitoring” aspects of
IPTs and process parameters are described in each of
the individual elements as necessary.
For IPTs, the control and monitor are defined as
follows:
1. In-Process Test for Control (IPT-C): IPT-C is
used to control a QA/CQA to within a specified
value so that it meets desired DS/DP quality. IPT-
C has an associated acceptance criterion (e.g., pro-
tein concentration).
2. In-Process Test for Monitor (IPT-M): IPT-M is
used to measure a QA/CQA (1) to ensure that it is
consistent with respect to previous process history or
(2) for forward processing. The monitoring tests may
have action limits (e.g., in-process impurity).
For process parameters, control indicates that a
given parameter and specified ranges are actively
maintained within the process. Almost all of the
process parameters fit into this category. However,
process parameter monitoring indicates that a
given parameter is observed but that no decisions
or process adjustments are made based on these
observations.
2.2. Elements of the Control Strategy
As described in the control wheel (Figure 1), each indi-
vidual element of the control strategy does not neces-
sarily ensure the elimination of risk. Rather, the
elements in entirety work in combination to ensure
TABLE I
Severity Score Definitions for Product Quality Attribute Criticality
Severity Score Ranking Definition
10 Major Potentially serious impact to patient, may be life-threatening or irreversible
7 Moderate Moderate impact on patient – treatable AEa, no permanent harm
5 Minor Low impact on patient – temporary inconvenience/impairment
1 Negligible No patient harmaAE is adverse event.
TABLE II
Uncertainty Score Definitions for Product Quality Attribute Criticality
Uncertainty
Score Ranking Definition
10 Low confidence or no
information
Limited data to support newly detected product variant or impurity
6 Medium confidence Published relevant literature data for an equivalent variant in a
similar product
4 High confidence Product-specific in-vitro or non-clinical data available for the
attribute or data (in-vitro, non-clinical, or clinical) available for
another product of the same platform that is directly relevant
2 Prior knowledge (well
established understanding)
Product-specific clinical data available for the attribute. In case of an
impurity, some non-clinical or clinical data are available
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the quality, safety, efficacy, and potency of the prod-
uct. As each element of control is constructed, the corre-
sponding results are reviewed to ensure that the control
strategy contains the appropriate components (control or
monitor), and if not, to identify and correct any gaps in the
strategy. Additionally, although elements of control are
identified for the entire process, the final control strategy
includes a life cycle approach to continued process verifica-
tion and a continuous monitoring strategy, so that shift or
drift of the process relative to the control limits is detected.
The contribution of each element toward the overall
control strategy is provided in further detail in Table VI.
2.3. Compilation of the Proposed Controls
Once all the controls are identified, an attribute-oriented
view can be applied to show which elements of control
support the delivery of a given quality attribute. The ele-
ments presented in Table VII are specific to each attribute;
hence, only the elements that contribute to the control of
that attribute are highlighted. The compiled view allows
the ready identification of the control strategy elements.
The case studies provide more details regarding the devel-
opment of the compiled view.
3. Case Study: Trumenba
Trumenba, a meningococcal serogroup B vaccine, is indi-
cated for active immunization to prevent invasive disease
caused by N. meningitidis serogroup B. Trumenba is a
sterile suspension consisting of two recombinant lipidated
factor H binding protein (FHbp) variants, one each from
Subfamily A and Subfamily B, which are individually
produced in Escherichia coli and subsequently purified.
The purified lipoproteins are combined in a DP manufac-
turing process, which also requires aseptic addition of alu-
minum phosphate (AlPO4), with the final sterile
suspension placed into prefilled syringes for the deliver-
able form of the drug. The manufacturing process for the
FHbp proteins is complex and challenging. Additionally,
the mixing of the two lipoproteins during the DP manufac-
turing process presents specific challenges for product
consistency, which must be closely controlled to obtain
the desired product quality.
This section describes the control strategy approach that
was taken for Trumenba DP. The assessment began with
the product quality attributes criticality assessment. The
following were identified as CQAs:
1. protein concentration;
2. bound protein;
3. purity; and
4. sterility.
The control strategy used was based on extensive prod-
uct and process knowledge, including detailed molecu-
lar characterization of the antigens.
TABLE III
Criteria for Product Quality Attribute Score in Cause and Effect Matrix
Product Quality Attribute Score Definition
10 Established or expect a direct impact on safety and/or efficacy of product.
7 Moderate or indirect impact on safety and/or efficacy.
5 Low or unlikely impact on product safety and/or efficacy.
1 No impact on product safety and/or efficacy.
TABLE IV
Criteria for Scoring Process Parameter Impact on Product Quality Attribute in Cause and Effect Matrix
Scoring for Process Parameter Impact on
Product Quality Attribute Definition
10 Know there is a strong relationship based on data in hand or experience
9 Don not know but expect there is a strong relationship
5 Medium relationship
1 Know that there is not a relationship
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Figure 2 illustrates the overall process for Trumenba DP
manufacturing. Briefly, AlPO4 is added aseptically to
a formulation tank, followed by filtered Subfamily A pro-
tein, buffer, Subfamily B protein, and additional buffer.
The contents of the formulation tank are mixed to achieve
homogeneity. The formulation tank is then connected to an
intermediate vessel to which formulated material is trans-
ferred in a batchwise fashion with continuous mixing.
Finally, the intermediate vessel is connected to a filling
pump, nozzles, and syringes for filling.
Table VIII provides the final cause-and-effect matrix,
which describes the relationship between process parame-
ters and CQAs. Data are presented in this section for the
parameters that had potential impact on CQAs and how
process capability is tested by using wider ranges of pro-
cess parameters. Information from this assessment was
used to derive Element 2 for the control strategy wheel.
Table VII presents a holistic compiled view for five
QAs (protein concentration, bound protein, purity,
TABLE V
Example of a Cause and Effect Matrix Scoring
Process Parameter
Quality
Attribute 1
(QAa Score - 10)
Quality
Attribute 2
(QA Score - 7)
Quality
Attribute 3
(QA Score - 5)
Final Score
(Sum of QA
Score� Process
Parameter
Score)
Experimentation
Priority to
Understand
Impact of
Process
Parameter
Process Parameter 1 9 6 9 177 High
Process Parameter 2 1 5 1 49 Low
Process Parameter 3 5 5 5 110 MediumaQA is Quality attribute.
Figure 1
Elements of control depicted as a “control wheel.”
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TABLE VI
Pfizer’s Interpretation of Control Strategy Definition and Representation in the Form of the Control Wheel
Element Description
Element 1: Direct In-Process
Monitoring or Control of
Product QAsa
Element 1 involves identifying direct in-process monitoring and/or control that is
applied throughout the DSb and DPc manufacturing process. This monitoring and/
or control relates to attributes that are specifically tested during processing. This
element of control is described by the IPTd applied in the process.
Element 2: Monitoring or
Control of Process
Parameters and Material
Attributes Functionally
Linked to Product QAs
Element 2 involves identifying monitoring and/or control of process parameters
functionally linked to QAs. Sources of information to populate this element
include upstream and downstream DS process characterization studies, DP
manufacturing process characterization studies, and related risk assessments.
Monitoring and/or controls for process parameters and material attributes in each
unit operation are identified through the risk assessment process described earlier,
and any existing functional relationships between those process parameters or
material attributes and corresponding QAs are documented.
Element 3: Direct In-Process
Monitoring or Control of
PPAse
Element 3 is similar to Element 1 but differs in that it involves documenting direct
monitoring and control of PPAs rather than QAs. As the current discussion
focuses on QAs, this element is not explicitly discussed here; however, its
documentation ensures appropriate monitoring and controls are in place to ensure
consistency of process performance.
Element 4: Monitoring or
Control of Process
Parameters or Material
Attributes Functionally
Linked to PPAs
Element 4 is similar to the Element 2 but differs in that it involves documenting
monitoring or control of process parameters and material attributes that are
functionally linked to PPAs rather than QAs. As for Element 3, this element is not
explicitly discussed here but is documented and updated to ensure that any
modifications in the control strategy do not have a deleterious impact on process
performance.
Element 5: DS and DP Testing
(Release Testing)
Element 5 encompasses the DS and DP release testing and specifications.
Element 6: DS and DP
Stability Monitoring or
Control
Element 6 encompasses the attributes selected to be monitored on stability and the
associated acceptance criteria. This element is continually managed in accordance
with stability protocols.
Element 7: Control of Raw
Materials
Element 7 encompasses control of raw materials linked to QAs and/or PPAs. In
addition, any raw material controls that are linked to process performance and/or
product QAs are documented.
Element 8: Facility and
Equipment Controls
(cGMPfand Procedural)
It is noted that cGMPs mitigate some of the specific risks associated with the
manufacture and delivery of particular attributes associated with product.
Development of the product-specific control strategy is predicated on the
existence of prerequisite programs, including cGMPs and pharmaceutical quality
systems for the manufacturing facilities. In documenting Element 8, reliance on
cGMPs is noted for specific attributes where relevant.aQAs is Quality attributes.bDS is drug substance.cDP is drug product.d IPT is in-process testing.e PPAs is process performance attributes.f cGMP is current good manufacturing practice.
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bioburden, and sterility) within the control strategy for
Trumenba. The details of these controls are provided in
Table IX in accordance with the control strategy wheel.
The next section explains the details of these elements
and how they were determined.
3.1. Control Strategy for Protein Concentration across
DS and DP Manufacturing
Protein concentration is the CQA for the Trumenba DP.
The DS process employs the following four elements of control:
1. Element 1: in-process control;
2. Element 2: fill consistency in container;
3. Element 5: DS protein concentration release; and
4. Element 6: DS protein concentration stability.
In-process control consists of a combination of IPT-
M and IPT-C. During the final ultrafiltration and dia-
filtration step, the purified protein is introduced into
the final DS buffer by diafiltration. To meet DS
release specification, the diafiltered retentate is then
concentrated using the IPT-C for protein concentra-
tion. A dilution step is utilized if the protein concen-
tration is outside of monitored acceptance criteria
for IPT.
Although the fill amount in the DS container does not
affect the protein concentration for DS release, it can affect
the DP concentration substantially because the entire con-
tainer contents are used during DP manufacturing. DP
protein concentration is therefore controlled through fill
TABLE VII
Summary of the Control Elements for Various Quality Attributes
aElement 1: Direct in-process monitoring or control of product quality attributes.bElement 2: Monitoring or control of process parameters or material attributes functionally linked to product quality
attributes.cElement 3: Direct in-process monitoring or control of process performance attributes.dElement 4: Monitoring or control of process parameters or material attributes functionally linked to process performance
attributes.eElement 5: DS and DP testing specifications.fElement 6: DS and DP stability monitoring or control.gElement 7: Control of raw materials.hElement 8: Facility and equipment controls (current good manufacturing practices and procedural).iDS is drug substance.jDP is drug product.kAsterisk (*) indicates data not provided in article. Controls are shown for illustrative purposes to demonstrate how this
map can provide a snapshot of the control across DS and DP process for a given quality attribute. Yellow indicates the
element is controlled.lBlue indicates the element is monitored.
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amount in DS containers during DS processing. The fill
weight tolerance of DS containers is subjected to a strin-
gent criterion; this ensures that the DS container is
adequately filled to obtain the target DP concentrations.
Figure 3 and Figure 4 demonstrate the fill weight accuracy
and precision of the process for various batches. It was
determined that the process can reliably fill the target
amounts within an acceptable range. The target
Figure 2
Trumenba DP manufacturing process flow. AlPO4 is aluminum phosphate; DP is drug product.
TABLE VIII
Final Cause and Effect Matrix Showing Relationship Between Process Parameters and Product Quality Attributes
Protein
Concentration
Bound
Protein Purity Sterility
Process Parameters
QAa
Criticality
Score -10
QA
Criticality
Score -10
QA
Criticality
Score -10
QA
Criticality
Score -10
Formulation process
Mixing times and speeds in the formulation
tank after addition of Subfamily A and
Subfamily B proteins
5 10 1 1
Filling process
Mixing times and speeds for the formulation tank and
intermediate vessel
10 5 1 1
Transfer rate from the formulation tank to the
intermediate vessel
10 5 1 1
Filling operation parameter controls 10 5 1 1
Overall process
Ambient temperature exposure and time through the
filling, shipping, and packaging operations
1 1 10 1
Hold time and temperature during formulation and filling 1 1 5 10aQA is Quality attribute.
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amounts vary based on the actual protein concentra-
tion of the DS.
The Trumenba vaccine DP process employs the follow-
ing three elements of control:
1. Element 2: Mixing times and speeds for the formula-
tion tank and intermediate vessel, transfer rate from
the formulation tank to the intermediate vessel, and
various filling operation parameter controls;
2. Element 5: DP protein concentration release; and
3. Element 6: DP protein concentration stability.
Manufacture of the Trumenba vaccine DP (Figure 2)
requires several considerations from a protein concen-
tration perspective. A series of considerations are
warranted to define controls on account of the bulk vac-
cine DP being formulated as a suspension.
Establishing functional relationships among process
parameters that affect protein concentration through-
out DP manufacturing during product and process
development is critical to determining Element 2
controls. Specific examples with experimental data
are provided here that demonstrate the relationship
and corresponding implemented controls.
3.1.1. Mixing Speed and Time in the Formulation
Tank: The formulated bulk product can be held for a
certain period of time before initiation of the filling
operation. Because the formulated DP is a suspension, it
is critical that the suspension is homogeneous before
syringes are filled, as a nonhomo-geneous suspension
will affect the protein concentration considerably.
TABLE IX
Detailed Control Strategy Map for Quality Attributes
CQAa
Control
Element Control Implemented
Total protein
concentration
Element 2 Mixing speed and time in formulation tank, mixing speed and time in
intermediate vessel, stoppage times during filling
Element 5 Incoming DSb release testing
Total protein concentration release testing
Element 6 Total protein concentration stability testing
Bound protein Element 2 Mixing speed and time in formulation tank after addition of Subfamily A and B
Element 5 Bound protein release testing
Element 6 Bound protein stability testing
Purity Element 2 Ambient temperature exposure and time through the filling, shipping, and
packaging operations
Element 5 Incoming DS purity release testing
Purity release testing
Element 6 Purity stability testing
Sterility Element 1 Prefiltration bioburden of buffer (IPT-C)c
Pre- and post-filtration filter integrity test (IPT-C)
Pressure decay testing of AlPO4d cans (IPT-C)
Element 2 Hold time and temperature during formulation and filling
Element 5 Incoming DS bioburden release testing
Sterility release testing
Element 6 Sterility stability testingaCQA is critical quality attribute.bDS is drug substance.c IPT-C is in-process test for control.dAlPO4 is aluminum phosphate.
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Therefore, both the optimum minimum mixing speed
and mixing time at that speed needed to obtain a homo-
geneous suspension are important parameters that must be
assessed and controlled.
Mixing studies were performed in the formulation
tank to evaluate mixing parameter ranges (time and
speed) needed to achieve a homogenous bulk. This
was achieved by allowing the formulated bulk DP sus-
pension to settle overnight in the formulation tank
with no mixing after the formulation operation was
complete. Mixing studies at scale were performed at
80 and 120 revolutions per minute (rpm). The homo-
geneity of the suspension was assessed by testing
samples from the top and bottom of the tank. Percent-
age transmittance (%T) at the two mixing speeds was
Figure 3
Fill accuracy of (A) Subfamily A and (B) Subfamily B proteins.
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used as a surrogate assay for determination of suspen-
sion homogeneity. The %T is calculated by meas-
uring absorbance at a wavelength of 645 nm. The
formulated bulk was considered to be homogenous
when %T values for sample turbidity between the top
and bottom samples were within three %T units. The
transmittance results of samples from the top and bottom
of the formulated bulk at mixing times of 0, 5, and 10
min are shown in Figure 5, which demonstrates that the
formulated bulk could be mixed well at 5 min even at
the lower mixing speed of 80 rpm after addition of
AlPO4, Subfamily A protein, and Subfamily B protein,
respectively.
These data provided the basis for the mixing speed
process parameter control of ≥80 rpm for ≥5 min mix-ing time as a proven and acceptable range from a ho-mogeneity perspective. The actual manufacturingprocess implemented tighter controls by extending thenormal operating range for mixing time.
3.1.2. Mixing Speed and Time in the Intermediate
Vessel: Studies in the intermediate vessel evaluated the
mixing parameter ranges (i.e., time and speed) needed to
achieve a homogenous bulk. To evaluate mixture homo-
geneity, %T of samples from the top and bottom of the
intermediate vessel were evaluated at different mixing
Figure 4
Precision analysis for filling of (A) Subfamily A and (B) Subfamily B proteins.
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speeds and bulk weights (i.e., high, medium, and low).
Formulated bulk was allowed to settle in the intermedi-
ate vessel for at least 1 h between each mixing speed,
and the contents were allowed to settle overnight for the
bulk weight studies. The bulk weight represents the vali-
dated lot size of 150 kg. The %T results of samples taken
from the top and bottom of the intermediate vessel after
mixing times of 1, 3, 5, 8, and 10 min are shown in Fig-
ure 6. Values of 36.5% to 38% were not considered sig-
nificant. Based on experiments performed at aluminum
and protein concentration limits for approved specifica-
tions, the criteria for significance was a change in %T
value of >3%. A homogenous bulk was achieved after 1
min of mixing for the high-formulated bulk mass at
130 rpm (worst-case scenario for product homogeneity).
On the basis of this study, syringe filling is initiated af-
ter the formulated bulk has been mixed for ≥20 min (anadditional 19 min provided for added robustness).
3.1.3. Filling Parameters: Because the Trumenba DP
is a suspension, it is critical to establish fill parameters
to ensure homogeneity. These include purge volume
after stoppages at the fill line and maximum stoppage
time at the fill line.
A study of fill line stoppage time was carried out to es-
tablish a maximum stoppage time without recirculation
before the restart of filling. Stoppage times of 2, 3, 5,
and 10 min, without recirculation (representing worst-
case scenario), were evaluated. The first four syringe
tubs (each holding 100 syringes) were collected for
testing after each stoppage time. For filled syringes, the
%T was performed for single data points by pooling 15
syringes and diluting them with water.
The turbidity data showed, in general, that the longer
the stoppage time, the larger the difference between
minimum and maximum %T (Figure 7). The %T
ranges for stoppage times up to 5 min fell within the
control range of65 %T for bulk sample to syringe
sample comparisons, and ≤5 %T for syringe sampleto syringe sample comparisons. Thus, a maximumstoppage time of 5 min without recirculation and with-out the need to eject any tubs was established.
3.2. Control Strategy for Bound Protein
Percentage binding of Subfamily A and Subfamily B pro-
tein to AlPO4 is a CQA for Trumenba DP. The following
controls are implemented to control this attribute:
Figure 5
Percentage transmittance (%T) as a function of mix-
ing time at two speeds (low and high) in the formu-
lation tank after (A) addition of AlPO4 in buffer, (B)
addition of Subfamily A proteins, and (C) addition
of Subfamily B proteins. AlPO4 is aluminum phos-
phate; rpm is revolutions per minute.
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1. Element 2: Mixing times and speeds in the formula-
tion tank after addition of Subfamily A and Subfam-
ily B proteins;
2. Element 5: Bound protein release testing; and
3. Element 6: Bound protein stability testing.
To define Element 2 controls, it was important to under-
stand and incorporate binding kinetics in the process
design. The most important parameters relevant to this are
Figure 6
Percentage transmittance (%T) as a function of mixing time at two speeds (low and high) in the intermediate ves-
sel. rpm is revolutions per minute.
Figure 7
Syringe turbidity as a function of stoppage time. %T is percentage transmittance.
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mixing speed and time after addition of Subfamily A and
B proteins in the formulation vessel. A small-scale study
carried out to evaluate binding kinetics demonstrated that
binding occurred quickly and that almost all proteins from
subfamilies A and B are bound at the initial time point
(Figure 8). The small-scale experiments were performed
using a 0.5 kg scale and by scaling down the vessel and
mixers that were used in the manufacturing environment.
The mixing time chosen was based on the specification for
binding of >90%.
Furthermore, at-scale mixing experiments were carried
out at mixing speeds that were lower and higher than the
target to confirm that the mixing time was adequate to
achieve the desired binding of Subfamily A and B proteins
(Figure 9). Greater than 90% binding was observed within
10 min at both the lower and higher mixing speeds.
3.3. Control Strategy for Purity
Purity of DP was controlled through the following three
controls:
1. Element 2: Ambient temperature exposure and time
through the filling, shipping, and packaging operations;
2. Element 5: DP purity release testing and incoming
DS purity release testing; and
3. Element 6: Purity stability testing.
Because purity has a direct relationship with tempera-
ture, exposure to ambient temperature and time was
controlled as a process parameter for Element 2. No
changes in purity were observed when the effect of
shear forces on purity was assessed.
3.4. Control Strategy for Sterility
Sterility is a critical aspect of a parenteral DP and is
an obligatory CQA from a regulatory standpoint. Sev-
eral control elements are used to ensure the sterility of
Trumenba:
� Element 1: IPT employed for prefiltration bioburden,
pre- and post-filter integrity testing, and pressure
decay testing for AlPO4 cans;
� Element 2: hold time and temperature during formu-
lation and filling;
� Element 5: incoming DS bioburden, sterility release
testing;
� Element 6: sterility stability testing; and
� Element 7: AlPO4 sterility release testing.
Figure 8
Small-scale binding kinetics of Subfamily A and Subfamily B proteins.
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This specific example demonstrates the broader use of con-
trols (Element 8 is not mentioned but is implicit in the
design of the process). In-process bioburden control, filter
integrity testing, and integrity testing of AlPO4 cans are crit-
ical to ensure that the process is running as intended. Hold
time and temperature have functional relationships from a
microbiological perspective; these were therefore controlled
as well. In addition to DP sterility release testing, bioburden
on incoming DS is tightly controlled through release testing.
Because AlPO4 is used as a raw material and formulation is
a closed process, sterility of incoming AlPO4 is of the
utmost importance to the sterility of the final product.
4. Summary
We have described the control strategy approach that
was taken for Trumenba vaccine from a DP manufac-
turing perspective based on our interpretation of ICH
guidelines and our general approach to control strat-
egy development. The eight-wheel approach devel-
oped by Pfizer simplifies the understanding and
implementation of control strategy. This provides a
clear roadmap for understanding the controls needed
for manufacturing product with consistent product
quality attributes that can impact safety and efficacy.
It is critical that product is developed with the con-
trol strategy in mind and that appropriate
experimentation is performed to demonstrate proper
control of process parameters, in addition to other
control elements.
Acknowledgments
Editorial support was provided by Judith Kandel, PhD, at
Complete Healthcare Communications, LLC (North
Wales, PA), a CHC Group company, and was funded by
Pfizer Inc. The authors thank Manasa Kandakatla for
support with the figures.
Conflict of Interest Declaration
All authors are current or former employees of Pfizer
Inc and may hold stock and/or stock options. This
study was sponsored by Pfizer Inc.
Abbreviations
AlPO4, Aluminum phosphate; cGMPs, current Good Man-
ufacturing Practices; CPPs, critical process parameters;
CQAs, critical quality attributes; CTD, Common Technical
Document; CPV, Continuous Process Verification; DP,
drug product; DS, drug substance; FMECA, failure modes
effects and criticality analysis; FHbps, factor H binding
proteins; ICH, International Council for Harmonisation;
Figure 9
Mixing efficiency and protein binding at scale. rpm is revolutions per minute.
Vol. 74, No. 2, March--April 2020 227
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IPT, in-process testing; IPT-C, In-Process Test for Control;
IPT-M, In-Process Test for Monitor; PPAs, process per-
formance attributes; QAs, quality attributes; rpm, revolu-
tions per minute; %T, Percentage transmittance.
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