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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

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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: [email protected]

†Deceased 2019, formally with Pfizer Inc.

doi: 10.5731/pdajpst.2018.009415

Vol. 74, No. 2, March--April 2020 213

on November 8, 2020Downloaded from

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

214 PDA Journal of Pharmaceutical Science and Technology


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



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



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.”



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.



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.



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.



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.



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.



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.



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.



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.



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.



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.



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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