3.2.P.2.3 Manufacturing Process Development (92 Págs) PDF

MK-8835A PAGE 1 ERTUGLIFLOZIN/SITAGLIPTIN TABLET
3.2.P.2.3 MANUFACTURING PROCESS DEVELOPMENT

Table of Contents
1 MANUFACTURING PROCESS DEVELOPMENT ...................................................6

1.1 Overview of Process Development .......................................................................6
1.1.1 Drug Product Risk Assessment Review ........................................................7
1.1.2 Process Parameter Criticality Assessment ...................................................12
1.1.3 Manufacturing Process Development History .............................................12
1.2 Blending ................................................................................................................16
1.2.1 Blending Summary ......................................................................................16
1.2.2 Blending Risk Assessment...........................................................................17
1.2.3 Blending Prior Knowledge ..........................................................................17
1.2.4 Blending Pilot Scale Development ..............................................................17
1.2.5 Blending Commercial Scale Development..................................................23
1.2.6 Blending Design Space Definition...............................................................33
1.2.7 Blending Conclusions & Control Strategy ..................................................34
1.3 Lubrication ...........................................................................................................34
1.3.1 Lubrication Summary ..................................................................................34
1.3.2 Lubrication Risk Assessment.......................................................................35
1.3.3 Lubrication Prior Knowledge ......................................................................36
1.3.4 Lubrication Pilot Scale Development Summary..........................................36
1.3.5 Lubrication Commercial Scale Development Summary .............................40
1.3.6 Impact of Lubrication Endpoint on Final Blend Tabletability ....................43
1.3.7 Lubrication Design Space Definition...........................................................44
1.3.8 Lubrication Conclusion and Control Strategy .............................................45
1.4 Compression .........................................................................................................46
1.4.1 Compression Overview................................................................................46
1.4.2 Compression Risk Assessment ....................................................................46
1.4.3 Compression Prior Knowledge ....................................................................47
1.4.4 Compression - Image Independent Development Approach .......................47
1.4.5 Compression Pilot Scale Development........................................................49
1.4.6 Compression Commercial Scale Development ...........................................52
1.4.6.1 Compression Commercial Scale Development – Content
Uniformity Results.............................................................................54
1.4.6.2 Compression Commercial Scale Development – Assay Results .......59
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1.4.6.3 Compression Commercial Scale Development – Impact of

Ertugliflozin and Sitagliptin Particle Size and Process Conditions

on Compression Performance ............................................................61
1.4.7 Compression – Establishment of Hardness In-Process Controls Based
on Tablet Friability/ Erosion and Disintegration/Dissolution Responses....64
1.4.7.1 Compression – Establishment of the Lower Hardness In-Process
Control Based on Tablet Friability/Erosion Response.......................64
1.4.7.2 Compression – Justification for No Upper Hardness Limit Based
on Tablet Disintegration/Dissolution Response.................................69
1.4.8 Compression Conclusion and Control Strategy...........................................71
1.5 Film Coating .........................................................................................................72
1.5.1 Film Coating Summary................................................................................72
1.5.2 Film Coating Risk Assessment ....................................................................73
1.5.3 Film Coating Prior Knowledge....................................................................74
1.5.4 Film Coating Development Approach .........................................................74
1.5.5 Film Coating Pilot Scale Development........................................................76
1.5.6 Film Coating Commercial Scale Development ...........................................79
1.5.7 Film Coating Design Space Definition ........................................................88
1.5.8 Film Coating Conclusion and Control Strategy...........................................88
1.6 Batch Size Flexibility ...........................................................................................89
1.7 Environmental and Packaging Controls............................................................90
1.8 Ertugliflozin/Sitagliptin Tablet Control Strategy Summary ...........................90
List of Tables
Table 1 Initial Risk Assessment for Ertugliflozin/Sitagliptin Tablets ........................8
Table 2 Final Risk Assessment for Ertugliflozin/Sitagliptin Tablets .......................10
Table 3 Process Development Manufacturing History for
Ertugliflozin/Sitagliptin Tablets...................................................................................13
Table 4 Process Development Summary by Unit Operation for
Table 5 Summary of Reference Batches and Formal Stability Study Batches for
Table 6 Comparison of Formal Stability Study Process and the Proposed
Commercial Manufacturing Process for Ertugliflozin/Sitagliptin Tablets ..................15
Table 7 Blending Process Development Summary for Ertugliflozin/Sitagliptin
Tablets 16
Table 8 Blending Conditions and Blend Uniformity Results for
Ertugliflozin/Sitagliptin Pilot Scale Batches* ..............................................................19
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Table 9 Blending Conditions and Blend Uniformity Results for

Ertugliflozin/Sitagliptin Commercial Scale Batches ...................................................27

Table 10 Blending Control Strategy for Ertugliflozin/Sitagliptin Tablets..................34
Table 11 Lubrication Conditions and Blend Uniformity Results (Lubrication) for
Ertugliflozin/Sitagliptin Pilot Scale Batches* .............................................................37
Table 12 Lubrication Conditions and Blend Uniformity (Lubrication) Results for
Table 13 Lubrication Control Strategy for Ertugliflozin/Sitagliptin Tablets..............45
Table 14 Summary of Pilot Scale Compression Batches for
Table 15 Content Uniformity Results for Ertugliflozin/Sitagliptin Pilot Scale
Batches 51
Table 16 Summary of Commercial Scale Compression Batches for
Table 17 Content Uniformity Results for Ertugliflozin/Sitagliptin Commercial
Scale Batches ...............................................................................................................55
Table 18 Assay Results for Ertugliflozin/Sitagliptin Commercial Scale Batches ......60
Table 19 Lower Tablet Tensile Strength/Hardness Limits for
Ertugliflozin/Sitagliptin Tablets as Established by Tablet Friability/Erosion .............68
Table 20 Compression Control Strategy for Ertugliflozin/Sitagliptin Tablets ...........71
Table 21 Film Coating Process Development Summary for
Table 22 Film Coat Color and Addition Amount per Ertugliflozin/Sitagliptin
Strength 73
Table 23 Film Coating Conditions for Ertugliflozin/Sitagliptin Pilot Scale
Batches 77
Table 24 Pilot Scale Film Coating Factor Ranges Studied and Factor Ranges with
Passing Elegance for Ertugliflozin/Sitagliptin Tablets ................................................78
Table 25 Commercial Scale Film Coating Study Design Factors and Ranges for
Table 26 Film Coating Conditions and Responses for Ertugliflozin/Sitagliptin
Commercial Scale Batches ..........................................................................................82
Table 27 ANOVA Regression Analysis for the Water Activity Response for the
Ertugliflozin/Sitagliptin Commercial Scale Film Coating Process ............................85
Table 28 Film Coating Control Strategy for Ertugliflozin/Sitagliptin Tablets ...........89
Table 29 Material Control Strategy Summary for Ertugliflozin/Sitagliptin Tablets
Established Through Process Development.................................................................91
Table 30 Process Control Strategy Summary for Ertugliflozin/Sitagliptin Tablets....91
Table 31 Final Risk Assessment for Ertugliflozin/Sitagliptin Tablets .......................92
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List of Figures
Figure 1 Fishbone Diagram for Ertugliflozin/Sitagliptin Tablets ................................9
Figure 2 Pilot Scale Blend Uniformity Sampling Locations for
Figure 3 NIRS Blend Profiles As a Function of Number of Blend Revolutions for
Sitagliptin for Development Batches (Left) and FSS/Reference Batches (Right).......21
Figure 4 NIRS Blend Profiles As a Function of Number of Blend Revolutions for
Ertugliflozin for Development Batches (Left) and FSS/Reference Batches (Right)...22
Figure 5 Commercial Scale Blend Uniformity Sampling Locations for
Figure 6 Commercial Scale Blending Tote Diagrams: 600L (Left) and 1700L
(Right) 24
Figure 7 Commercial Scale Blending Study Design for Ertugliflozin/Sitagliptin
Tablets 26
Figure 8 Commercial Scale Blending Study Design and Blend Uniformity
Results for Ertugliflozin/Sitagliptin Tablets ................................................................30
Figure 9 Blending Efficiency Factor (VHR) and Number of Revolutions versus
Ertugliflozin RSD Blend Uniformity Results for the 15/50 mg
Ertugliflozin/Sitagliptin Dose Strength........................................................................32
Figure 10 NIRS Blend Profiles as a Function of Lubrication Revolutions for the
Reference Batches for Ertugliflozin and Sitagliptin (Left) and Lubricants (Right) ....39
Figure 11 Tabletability Profiles as a Function of Lubrication Endpoint for
Figure 12 Tabletability Profiles for Ertugliflozin/Sitagliptin 5/100 mg, 15/100 mg,
5/50 mg, and 15/50 mg Images Under Similar Compression Conditions ...................48
Figure 13 Content Uniformity Results by Location Adjusted for Tablet Weight for
Ertugliflozin (Left) and Sitagliptin (Right) for Ertugliflozin/Sitagliptin
Figure 14 Ertugliflozin Content Uniformity Results by Kilograms of Material
Processed (1-20 kg) Adjusted for Tablet Weight for Ertugliflozin/Sitagliptin
Figure 15 Tabletability Profiles as a Function of Ertugliflozin and Sitagliptin
Particle Size for Ertugliflozin/Sitagliptin Tablets........................................................62
Figure 16 Tabletability Profiles as a Function of Press Conditions for
Figure 17 Tablet Friability as a Function of Core Tablet Tensile Strength for
Figure 18 Tumbling Trial and Standard Friability Results for % Weight Loss as a
Function of Tablet Tensile Strength for Ertugliflozin/Sitagliptin Tablets...................67
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Figure 19 Tablet Tensile Strength versus Tablet Hardness for the 300 mg and 400
mg Ertugliflozin/Sitagliptin Images.............................................................................68

Figure 20 Disintegration Time as a Function of Tablet Hardness (Left) and Tablet
Tensile Strength (Right) for Ertugliflozin/Sitagliptin Tablets .....................................70
Figure 21 Film Coating Process Diagram ....................................................................75
Figure 22 Water Activity Response as a Function of Time for the
Ertugliflozin/Sitagliptin Pilot Scale Batches ...............................................................79
Figure 23 Commercial Scale Film Coating Study Design for
Figure 24 Water Activity Response as a Function of Time for
Figure 25 Perturbation Responses of Ertugliflozin/Sitagliptin Tablet Water
Activity to Commercial Scale Film Coating Inputs.....................................................86
Figure 26 Contour Plot Response of Ertugliflozin/Sitagliptin Tablet Moisture to
Air:Spray Ratio and Bed Temperature at the Commercial Scale ................................87
Figure 27 Overlay Plot Response of Bed Temperature and Air:Spray Ratio
Resulting in Tablet Water Activity Below 0.45 for Ertugliflozin/Sitagliptin
Tablets at the Commercial Scale..................................................................................87
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1 MANUFACTURING PROCESS DEVELOPMENT

This section outlines the manufacturing process development of Ertugliflozin/Sitagliptin
Tablets for the 5/100 mg 15/100 mg, 5/50 mg, and 15/50 mg ertugliflozin/sitagliptin
strengths. The experimental approach and evaluation of the data generated during process
development is presented in order of processing step. Information is also provided
concerning the scale up of the process for the film coated tablet as well as establishment of
control strategies for each unit operation.
1.1 Overview of Process Development
A robust drug product manufacturing process has been developed for Ertugliflozin/Sitagliptin
Tablets through systematic risk-based development. A risk-based approach was taken during
development of the manufacturing process to consistently provide a final drug product of
acceptable quality and stability for patient safety and efficacy. The manufacturing process
has been demonstrated through various development scales, including the commercial scale
at the intended commercial manufacturing site. The manufacturing process has been deemed
robust and is suitable for manufacture of the intended commercial drug product.
The objective of manufacturing process development was to develop a process to produce

drug product that reproducibly meets the predetermined acceptance criteria established in the
quality target product profile (QTPP) and the drug product critical quality attributes (CQAs)
of assay, content uniformity, impurities and degradation products, appearance/elegance,
dissolution/disintegration, and elemental impurities.
The development objectives were accomplished through experimentation to identify linkages

between process inputs (material attributes, in-process attributes, process parameters) and
process outputs (material attributes, critical quality attributes). The knowledge gained was
used to develop an effective control strategy which is comprised of controls for material
attributes, in-process controls, process parameter design spaces, and environmental controls.
These controls along with finished product specifications ensure the drug product meets all
critical quality attributes. The relationship between the input parameters/attributes, the
process parameters, and the output responses/attributes for the unit operations are discussed
in each development section along with the resulting control strategy.
Principles consistent with ICH Q8, Q9, and Q10 were used during development, including a
quality target product profile (QTPP) to guide development, the use of quality risk
management, process analytical technology tools, and risk-based development studies across
scales. The proposed control strategy for Ertugliflozin/Sitagliptin Tablets consists of process
parameter design space ranges and in-process controls. Development of an effective risk-
based control strategy requires a foundation of strong scientific understanding of both the
formulation and the process.
To achieve the level of scientific understanding required and to also gain a better
understanding of the linkages between process inputs and outputs, product development
focused on factors that potentially posed a moderate to high risk to achieving the product
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critical quality attributes. This evaluation was based on a risk assessment which was
leveraged to develop study designs across scales of development. Studies employed the use

of both multi-factor/multivariate designs as well as one factor at a time studies when
appropriate. The development of the Ertugliflozin/Sitagliptin Tablets manufacturing process
also used scale independent and image independent material properties and process
parameters, allowing for understanding across the dose strengths, images, and scales of
development. The understanding resulting from this development work established design
space ranges for the control of process parameters as well as in-process controls for the
control strategy.
A control strategy has been established at the intended commercial site to ensure the product
consistently meets all CQAs. The control strategy for each unit operation is intended to
apply to all dose strengths and scales. The understanding gained through process
development and the resulting control strategies will be used to manage the product lifecycle
across various scales and batch sizes, including continuous improvement in process
robustness that will ensure product supply, quality, and performance. Flexible approaches to
the final proposed control strategy such as operational flexibility within design space ranges
established with multivariate studies are being proposed.
As described in Sec. 3.2.P.2.1, ertugliflozin is a cocrystal with L-PGA (L-pyroglutamic acid).

For the commercial process, the ertugliflozin L-PGA and sitagliptin undergo a conventional
compression process. The manufacturing process for Ertugliflozin/Sitagliptin Tablets
includes a blending and lubrication step where the two active ingredients and excipients are
blended in a diffusion mixer. The blending step takes place with the active ingredients and
all the excipients with the exception of the lubricants (sodium stearyl fumarate and
magnesium stearate). After the blending step, the lubricants are added to the diffusion mixer
and blended for additional revolutions. The lubricated blend is fed to a rotary tablet press
and compressed into the appropriate image size/shape based on the dose strength of the
tablet. Tablet cores undergo a film coating step to an appropriate weight gain based on the
surface area of the core image and a subsequent waxing step. A process flow schematic is
shown in Sec. 3.2.P.3.3 (Description of Manufacturing Process and Process Controls) for the
manufacturing process proposed at the commercial scale.
In the following sections, the unit operations are reviewed sequentially, describing the studies
performed to establish the design space ranges and the resulting control strategy. Presented
is a summary of the experimental approach and evaluation of the data generated during the
development and optimization of the manufacturing process for Ertugliflozin/Sitagliptin
Tablets, 5/100 mg, 15/100 mg, 5/50 mg, and 15/50 mg. The information provided is
intended to provide the reviewer with an understanding of the manufacturing process as well
as the establishment of the control strategy for each unit operation.
1.1.1 Drug Product Risk Assessment Review
A risk based approach was used to identify the process inputs to be evaluated during
manufacturing process development. The assessment was based on available process and
scale-up knowledge at the time of the risk assessment and resulted in identification of
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linkages between the process inputs and the drug product critical quality attributes. The
initial risk assessment was conducted with pilot scale data in hand and limited experience at

the commercial scale. An initial process risk assessment was conducted for
Ertugliflozin/Sitagliptin Tablets in order to determine risk areas for commercial scale
development and the results from the initial risk assessment are summarized in Table 1. In
addition to the unit operations, the materials of ertugliflozin and sitagliptin are included in
Table 1 in order to highlight the interaction between the material properties, unit operations,
and the CQAs. In addition to the CQAs presented, all unit operations were assessed in terms
of risk of introducing elemental impurities to the drug product and were determined to have a
low risk with respect to the CQA of elemental impurities.
Table 1 Initial Risk Assessment for Ertugliflozin/Sitagliptin Tablets
Handling/Environmental
Film Coating
Compression
Ertugliflozin
Lubrication
Sitagliptin
Exposure
Blending
Material
CQA
Assay ● ○ ● ● ○ ● ●
Content Uniformity ● ○ ● ○ ○
Impurities and Degradation Products ○ ○ ● ○ ● ○
Appearance/Elegance ○ ● ● ● ○ ○ ○
Dissolution/Disintegration ○ ○ ○ ○ ○
Legend
No impact to CQA
○ Suspected / Confirmed impact to CQA.
Existing Controls Adequate to meet CQA
● Suspected / Confirmed impact to CQA.
Existing controls or understanding not adequate to meet CQA
Based on the risk assessment, development work was conducted at the pilot and commercial
scales to establish the necessary in-process controls and parameter ranges for key processing
inputs. A fishbone diagram showing the relationship between the process inputs studied in
development and the drug product CQAs identified in the initial risk assessment is presented
in Figure 1.
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Figure 1 Fishbone Diagram for Ertugliflozin/Sitagliptin Tablets
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The process inputs outlined in the fishbone diagram were assessed during development for
impact to the drug product CQAs. Based on the development data, in-process controls and
parameter design space ranges were then developed. The development data along with the
resulting control strategy were then used to re-visit the risk assessment which resulted in all
risks being successfully mitigated as shown in Table 2. In addition, some suspected
relationships between the unit operations and the CQAs were not confirmed with the
development data and thus were removed from Table 2.
Table 2 Final Risk Assessment for Ertugliflozin/Sitagliptin Tablets
Handling/Environmental
Film Coating
Compression
Ertugliflozin
Lubrication
Sitaglptin
Exposure
Blending
Material
CQA
Assay ○ ○ ○ ○ ○ ○
Content Uniformity ○ ○ ○ ○
Impurities and Degradation Products ○ ○ ○ ○
Appearance/Elegance ○ ○ ○ ○ ○ ○
Dissolution/Disintegration ○ ○ ○
Legend
No impact to CQA
○ Confirmed impact to CQA.
● Confirmed impact to CQA.
The majority of the risks identified by the risk assessment were associated with ertugliflozin
losses or the segregation potential of the blend and the resulting impact on assay and content
uniformity. Due to the low ertugliflozin drug loadings and the selected process, the impact
of ertugliflozin and sitagliptin particle size on assay and content uniformity was also
identified. Ertugliflozin and sitagliptin were identified as having assay risks due to the
potential for segregation as well as the potential loss of either active due to preferential
adherence to processing equipment; the potential impact of the active properties on content
uniformity was deemed to be a lower risk based on pilot scale data demonstrating results
within the specifications. The risk assessment therefore highlighted assay and content
uniformity as risks for the blending and compression unit operations with potential
interactions with ertugliflozin and sitagliptin properties.
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Elegance was identified as a CQA with risk from the lubrication, compression, and film
coating unit operations. The impact of lubrication on elegance was related to the potential

for over-lubrication to impact the ability to meet the minimum hardness required to ensure
tablet robustness through the film coating step. The elegance risk highlighted for
compression was based on the need to establish an appropriate lower hardness limit to ensure
robustness. The impact of film coating conditions on tablet appearance and elegance was
recognized during the risk assessment and plans were put in place to study elegance as a
function of processing conditions across scales. Assay was also highlighted for film coating
which was intended to cover the risk of broken tablets; this risk was covered in development
through elegance evaluation.
The impurities and degradation products CQA was also identified as having a risk in the film
coating unit operation. This risk is related to the film coating step introducing moisture to
the tablet which would impact chemical stability of the drug product. Ertugliflozin was also
highlighted as having a chemical stability risk related to the risk of smaller particle size
material impacting chemical stability. This risk was studied both in early development
stability studies (Sec. 3.2.P.2.2) with a range of ertugliflozin particle sizes as well as in the
formal stability studies (FSS).
Details of the process development studies to address these risks and the process interactions
will be presented in sections 1.2 to 1.5. Based on the risk assessment, process development
work was conducted for the following items:
1. The impact of ertugliflozin particle size and sitagliptin particle size on blend uniformity,
content uniformity, and assay was studied across scales. Blend uniformity was measured
both by traditional thief sampling and HPLC analysis and also through NIR monitoring at
the pilot scale for development purposes. The intention behind studying the blend
uniformity, content uniformity, and assay data as a function of the ertugliflozin particle
size was to aid in establishment of the ertugliflozin particle size specification of NMT 52
µm.
2. Due to the low drug loadings of ertugliflozin in the formulation (1.6-6.5%), selective
material adherence to processing equipment and the resulting impact on assay was
highlighted as an elevated risk. Assay trends throughout the process were studied through
blend uniformity, content uniformity, and assay data.
3. Due to the low drug loadings of ertugliflozin in the formulation (1.6-6.5%) and the
selected process, the theoretical segregation potential of the blend is an elevated risk for
the formulation. As such, content uniformity data were collected across scales and
extended content uniformity data at the beginning and end of the compression process
were also collected to gain insight into assay trends.
4. Establishment of appropriate in-process compression controls was a targeted area for
development. The goal of the development studies was to establish appropriate hardness
controls to ensure adequate robustness (elegance) through the film coating step.
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5. The potential for over-lubrication during processing (blending or compression) was

highlighted as a risk to meeting the lower tablet hardness in-process control limit. As

such, the extent of lubrication both during the blending step as well as in the compression
feed frame was studied through generating tabletability profiles to determine the impact
of lubrication on the tablet properties.
6. A film coating multivariate study design was conducted at the commercial scale to study
the impact of processing inputs on tablet elegance as well as water activity. An
evaluation of elegance was conducted that characterized the level, number, and nature of
the defects which aided in defining the design space ranges for the unit operation. Water
activity was monitored as a function of film coating conditions throughout process
development at the pilot and commercial scales. Water activity was linked to the
impurities and degradation products CQA since the film coating process defines the tablet
water activity for the product shelf life (bulk and primary packages designed to maintain
water activity). The water activity response throughout the film coating design space
was assessed against the in-process control of 0.45 aw or below.
1.1.2 Process Parameter Criticality Assessment
The applicant defines a critical process parameter consistent with the definition in ICH Q8 as
a “process parameter whose variability has an impact on a critical quality attribute and
therefore should be monitored or controlled to ensure the process produces the desired
quality”. Critical process parameters (CPPs) are identified through assessment of the extent
to which their variation over established ranges can impact the quality of the drug product
(which includes considerations of scientific first principles, quality risk management, prior
knowledge, and appropriate experimentation).
Changes to all filed process parameter ranges and in-process controls, regardless of
designation as critical or non-critical, are assessed for impact and appropriately evaluated,
documented, and monitored per the internal change control quality system. The guidance
and procedures in the applicant’s Change Control Quality System provide the primary
governing requirements for controlling changes that have the potential to impact the quality
of the product (e.g. identity, strength, purity, bioavailability, regulatory compliance), the
reproducibility of the process (e.g. validation), and downstream site processes. As
appropriate, changes with a potential to adversely affect product quality will be notified to
the Agency in accordance with current regulatory requirements.
1.1.3 Manufacturing Process Development History
As summarized in Sec. 3.2.P.2.2, formulation development was conducted up to a 12 kg

scale. Subsequently, pilot scale execution was conducted between a 40.5 kg and 70 kg scale.
The process was then scaled up to the commercial scale to cover the intended commercial
batch size range of 100 to 300 kg for the 50 mg sitagliptin strengths (5/50 mg, 15/50 mg) and
a batch size range of 100 to 633 kg for the 100 mg sitagliptin strengths (5/100 mg, 15/100
mg). An overview of the batches manufactured during process development is presented in
Table 3.
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Table 3 Process Development Manufacturing History for Ertugliflozin/Sitagliptin

Tablets

Number of Batches
Development Scale Batch Type (Total for all Dose Batch Size Manufacturing Site
Strengths)
Merck Sharp and
Early Development Development 7 12 kg Dohme, West Point,
PA
Rottendorf Pharma
Pilot Development 6 40.5 kg – 70 kg GmbH, Ennigerloh,
Germany
Rottendorf Pharma
Pilot Clinical/Stability 8 40.5 kg – 70 kg GmbH, Ennigerloh,
Germany
12 (Blending); Schering Plough Labo
Commercial Development 12 (Compression); 100 – 633 kg NV, Heist-op-den-
13 (Film Coating) berg, Belgium
The process development studies that were conducted based on the risk assessment are
summarized in Table 4. The process development studies conducted for ertugliflozin/
sitagliptin tablets can be divided into the following stages:
• Early Development Studies: The early development studies were conducted at a 12 kg

laboratory scale and were intended to demonstrate formulation robustness with respect to
meeting the product critical quality attributes with the selected formulations. The data
associated with the early development process studies is included in Sec. 3.2.P.2.2.
• Pilot Scale Development Studies: The objective of the pilot scale development studies
was to build process understanding and identify potential linkages between process inputs
(ertugliflozin and sitagliptin material attributes, process parameters) and process outputs
(in-process attributes, critical quality attributes). These studies were conducted at the
40.5 kg scale for the 5/50 mg and 15/50 mg strengths and the 70 kg scale for the 5/100
mg and 15/100 mg strengths, corresponding to the clinical/stability batch sizes. The pilot
scale studies served as an initial probe into the interactions between select process inputs
and outputs and identified optimal processing conditions for which to run the
clinical/stability batches produced at that scale. Pilot scale studies were also conducted
for select experiments when appropriate. An example of such an experiment was the
tumbling trials conducted to set a preliminary target for the lower hardness of each
image.
• Commercial Scale Development Studies: The objective of the commercial scale
development studies conducted at the 100 – 633 kg scale (31-69% fill level) was to
further probe the relationships between the process inputs and outputs, particularly those
that are scale-dependent such as blend segregation. These studies were designed as
multi-factor studies across unit operations. The data generated at the commercial scale
was used to establish the control strategy for each unit operation.
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Table 4 Process Development Summary by Unit Operation for Ertugliflozin/Sitagliptin Tablets
Process Output(s)
Unit
Process Input(s) In-Process Drug Product Study Design Summary
Operation
Attributes CQAs
Blending  Blender design/scale Blend uniformity  Assay  Univariate study in early development to demonstrate blend uniformity with
 % fill for ertugliflozin  Content the proposed formulation
 # revolutions and sitagliptin Uniformity  Multivariate study at the pilot scale that included dose strength, ertugliflozin
 Ertugliflozin particle (NIRS and HPLC) particle size, and # revolutions. Sitagliptin particle size was also varied
size between the development batches and clinical/stability batches.
 Sitagliptin particle size  Multivariate study at the commercial scale that included ertugliflozin particle
size, % fill, and # revolutions for the 5/100 mg strength; center-point
conditions for 5/50 mg and 15/100 mg strengths; center-point plus worst-case
conditions used for 15/50 mg strength. Sitagliptin particle size was also
varied.
Lubrication  Blender design/scale Blend uniformity  Appearance/  Univariate study in early development to demonstrate blend uniformity with
 % fill for ertugliflozin Elegance the proposed formulation.
 # revolutions and sitagliptin  Univariate study at the pilot scale that demonstrated uniformity at the
(NIRS and HPLC) lubrication endpoint.
and lubricants  Blending multivariate design was progressed through to lubrication.
(NIRS) Multivariate study at the commercial scale that varied lubrication endpoints
for the batches produced at center-point or worst-case blending conditions. .
Compression  Blending/lubrication Tablet attributes  Assay  Univariate study during early development to demonstrate assay and content
conditions (weight/ thickness/  Content uniformity with the proposed formulation.
 Press conditions hardness) Uniformity  Multivariate study at the pilot scale. Blending multivariate design was
 Ertugliflozin particle  Appearance/ progressed through to compression to study the impact on content uniformity.
size Elegance  Pilot scale friability and tumbling trials to establish a minimum hardness
 Sitagliptin particle size target.
 Multivariate study at the commercial scale that included ertugliflozin particle
size, blending % fill, and # revolutions. Blending multivariate design was
progressed through to compression to study the impact on content uniformity.
Film Coating  Tablet hardness Water activity,  Assay (broken  Multivariate study at the pilot scale to study elegance and water activity
 Pan fill Elegance tablets) responses.
 Spray flux, Air:Spray  Impurities &  Multivariate study at the commercial scale to evaluate the impact of coating
Ratio, Bed temperature, degradation conditions on tablet elegance and water activity. A range of tablet hardness
Drum velocity products values were used to confirm the lower limit proposed from the pilot scale
 Appearance/ trials. The water activity response was assessed against the in-process control
Elegance of 0.45 aw or below.
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A summary of the stability batch numbers, referred to as the Formal Stability Study (FSS)
batches, and the clinical batch numbers, referred to as the Reference batches, are presented in
Table 5. The process used to manufacture the FSS/Reference batches and the proposed
commercial process is shown in Table 6. The term "reference batch" is defined here as
representative of both commercial manufacture and of batches used in the bioequivalence
study to demonstrate bioequivalence of the product. The proposed commercial process will
utilize: 1) the same materials and compositions as used in the FSS/Reference batches; 2)
equipment of similar design and operating principle; and 3) similar manufacturing and
environmental controls. Differences from FSS/Reference batches to the proposed
commercial process include changes in tooling embossing and an increase in batch size,
which were shown not to impact product quality or performance (as discussed in this section;
FSS/Reference batch analysis is provided in Sec. 3.2.P.5.4).
Table 5 Summary of Reference Batches and Formal Stability Study Batches for
Ertugliflozin/Sitagliptin Tablets
Lot Number Strength (mg/mg) Type
5434101C1 5/100 Reference, FSS
5434102C2 5/100 FSS
5434103C3 5/100 FSS
5434002C2 15/50 FSS
5434003C3 15/50 FSS
Table 6 Comparison of Formal Stability Study Process and the Proposed

Commercial Manufacturing Process for Ertugliflozin/Sitagliptin Tablets
Attribute FSS/Reference Batches Proposed Commercial Process
Ertugliflozin drug substance
Pfizer, Inc., United Kingdom Pfizer, Inc., Ireland
manufacturer
Sitagliptin drug substance
Divi’s Laboratories Limited, India Divi’s Laboratories Limited, India
manufacturer
Drug Product Manufacturing site Rottendorf Pharma GmBH, Germany Schering Plough Labo NV, Belgium
40.5 kg, 70 kg 100 – 633 kg
Blending/lubrication batch size 40.5 kg – 5/50 mg, 15/50 mg 100 kg – 300 kg – 5/50 mg, 15/50 mg
70 kg – 5/100 mg, 15/100 mg 100 kg – 633 kg – 5/100 mg, 15/100 mg
Diffusion mixer Diffusion mixer
Blending/lubrication equipment
100 L, 250 L 600 L, 1700 L
Blending/lubrication controls Fill level, number of revolutions Fill level, number of revolutions
Compression equipment Rotary tablet press Rotary tablet press
Compression controls Tablet weight, hardness Tablet weight, hardness
Perforated coating pan Perforated coating pan
Film coating equipment
50L 170 L
Pan load, bed temperature, air:spray ratio, Pan load, bed temperature, air:spray ratio,
Film coating controls
spray flux, pan speed, amount sprayed spray flux, pan speed, amount sprayed
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In the following sections, the process development studies leading to the commercial scale
process are presented by unit operation: blending, lubrication, compression, and film coating.

Each section contains a review of the risk assessment pertaining to the particular unit
operation, the description of process development studies conducted at both the pilot and
commercial scales, and a discussion of the control strategy for the specific operation along
with designation of any critical process parameters (CPPs). An overview of the
manufacturing control strategy is provided at the end of each section.
1.2 Blending
1.2.1 Blending Summary
Within this unit operation, ertugliflozin L-PGA, sitagliptin phosphate monohydrate,

microcrystalline cellulose, dibasic calcium phosphate, and croscarmellose sodium are
blended until uniformly mixed in a diffusion mixer (bin blender). The purpose of this step is
to achieve a uniform distribution of both sitagliptin and ertugliflozin in the blend. The step
has been characterized at the pilot and commercial scales and uniform distribution of both
sitagliptin and ertugliflozin was demonstrated based on 10 location blender sampling (thief
sampling) and HPLC analysis. NIRS (Near-Infrared Spectroscopy) monitoring has been
used to support this characterization at the pilot scale for process development purposes. The
NIRS monitoring tracks the drug substances in the blend and a spectral relative standard
deviation (RSD) is calculated based on real time NIRS measurements, indicating the
completeness of the blend. NIRS uniformity is deemed to be achieved when the %RSD
signal reaches steady state for ertugliflozin and sitagliptin, respectively.
Table 7 shows a summary of the development studies carried out for the blending step at the
early development, pilot plant, and commercial scales. During early development, blends at
the 40 L scale were completed as described in Sec. 3.2.P.2.2.1.3.1. For the pilot scale
activities, blender scales of 100 and 250 L have been used. Several fill volumes have been
used across scales and all pilot scale batches have been monitored via NIRS. Commercial
scale work to date has used a 600 L tote and a 1700 L tote. Blend uniformity has been
demonstrated across all scales.
Table 7 Blending Process Development Summary for Ertugliflozin/Sitagliptin

Tablets
Scale Tote Size (L) Batch Size (kg) Fill Level (%) # of Revolutions
Early Development 40 12 56 128
100 40.5 75
Pilot 120 – 240
250 70 52
600 100 - 225 31 – 69
Commercial 120 – 480
1700 633 69
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1.2.2 Blending Risk Assessment

The risk assessment identified the following risks specific to the blending process:
µm.
blend uniformity, content uniformity, and assay data.
It was determined through the risk assessment that the impact of ertugliflozin and sitagliptin
particle size on blend uniformity as well as the risk of under-blending (fill level too high
and/or number of revolutions too low) should be evaluated during development. Blend
uniformity results subsequently impact the content uniformity and assay of the finished
product. Therefore, blending study designs were carried through to the downstream unit
operations and the impact of blending conditions on the drug product critical quality
attributes was studied and assessed.
1.2.3 Blending Prior Knowledge
Prior knowledge, early development data, and best practices to ensure blend uniformity from
Ertugliflozin/Sitagliptin Tablets development, sitagliptin monotherapy tablets development,
and other drug development programs were leveraged to set the target number of revolutions
initially between 120 and 240. This target number was used for the majority of the pilot and
commercial scale development runs; HPLC data was collected in conjunction with NIRS data
at the pilot scale to indicate the number of revolutions necessary to achieve blend uniformity.
Prior knowledge on the blending factors that primarily impact blend efficiency was also used
to design the pilot and commercial scale studies. As such, the % fill and the number of
blending revolutions were built into the study designs while other factors such as the blender
speed were fixed.
1.2.4 Blending Pilot Scale Development
The blender used for pilot scale development was a cylindrical blending tote with baffles in
the lid (see Figure 2 for details). The process parameters controlled during the blending step
are fill level, speed, and number of revolutions. Blending speed is well controlled and
remained fixed at the pilot facility. The number of revolutions at the pilot scale was fixed
and sampled at both 120 and 240 revolutions for the development batches and fixed at 240
revolutions for the clinical/stability batches; however, the actual number of revolutions
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required to achieve uniform distribution of ertugliflozin/sitagliptin drug substances was

evaluated through NIRS monitoring.

A total of 14 pilot scale batches were blended according to the parameters provided in Table
8. Development studies at the pilot scale took a bracketing approach with regards to
ertugliflozin drug loading with more batches being produced at the extremes (5/100 mg and
15/50 mg). Material attribute variations in terms of ertugliflozin particle sizes ranging from
10-31 µm for the mean or volumetric mean diameter (VMD, D[4.3], mean) were specifically
built into development to assess the impact on the blending process. The development
batches included incorporation of ertugliflozin particle sizes with the bracket strengths using
one batch each at 10 µm and 31 µm, respectively. The FSS/reference batches also varied
ertugliflozin particle size between 10 and 25 µm. The sitagliptin particle size was also varied
between the development and clinical/stability batches and was ranged from 52 to 69 µm.
Blend uniformity samples were taken for all development batches and FSS/reference batches
to confirm ertugliflozin/sitagliptin uniformity using thief sampling (and HPLC analysis)
according to the locations described in Figure 2. Blend uniformity samples were taken at the
end of both blending and lubrication for each batch sampled. Blend uniformity samples were
taken at endpoints of both 120 and 240 revolutions for the pilot scale development batches.
The FSS/reference batches used an endpoint of 240 revolutions with blend uniformity
samples taken for the clinical batches at the endpoint. The FSS batches also used an
endpoint of 240 revolutions and used NIR to characterize the blend uniformity. Table 8
summarizes the blend uniformity results for the pilot scale batches.
Figure 2 Pilot Scale Blend Uniformity Sampling Locations for

Pilot Scale
(100 & 250 L)
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Table 8 Blending Conditions and Blend Uniformity Results for Ertugliflozin/Sitagliptin Pilot Scale Batches*
Ertugliflozin Sitagliptin Blend Uniformity – Blend Uniformity –
Strength Mean Mean Blender % # Blend Ertugliflozin Sitagliptin
Batch ID Tote Size (L)
(mg/mg) Particle Size Particle Size Fill Revolutions Average % Average %
RSD RSD
(µm) (µm) claim claim
53796G05 5/100 31 69 250 52 120 96.5% 1.4 96.8% 1.9
53796G05 5/100 31 69 250 52 240 97.6% 1.6 97.8% 1.4
53796G01 5/100 10 69 250 52 120 99.0% 1.7 97.7% 2.2
53796G01 5/100 10 69 250 52 240 96.9% 2.0 95.8% 2.3
5434101C1†‡ 5/100 18 53 250 52 240 99.4% 1.7 99.9% 1.6
5434102C2† 5/100 25 55 250 52 240 NIR only
5434103C3† 5/100 10 52 250 52 240 NIR only
53796G06 15/100 31 69 250 52 120 98.5% 2.9 97.3% 2.8
53796G06 15/100 31 69 250 52 240 99.6% 1.1 98.5% 1.2
5434201C1†‡ 15/100 18 52 250 52 240 97.9% 3.1 97.8% 3.4
53796G02 5/50 31 69 100 75 120 98.6% 2.3 97.4% 2.3
53796G02 5/50 31 69 100 75 240 97.8% 1.3 96.8% 1.5
5385901C1†‡ 5/50 18 55 100 75 240 97.1% 2.5 96.1% 3.4
53796G03 15/50 10 69 100 75 120 97.4% 2.0 97.7% 2.8
53796G03 15/50 10 69 100 75 240 98.5% 3.2 98.7% 2.8
53796G04 15/50 31 69 100 75 120 99.7% 1.9 99.0% 3.0
53796G04 15/50 31 69 100 75 240 97.7% 1.0 98.1% 0.9
5434001C1†‡ 15/50 18 53 100 75 240 99.2% 2.5 99.6% 3.0
5434002C2† 15/50 25 55 100 75 240 NIR only
5434003C3† 15/50 10 52 100 75 240 NIR only
*
Results shown are from HPLC analysis of 10 location thief samples.
†
Formal Stability Study Batch
‡
Reference Batch
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Acceptable blend uniformity was defined as 90-110% label claim with ≤ 4.0% RSD for
analysis purposes. As indicated, blend uniformity of ertugliflozin was achieved with an
average % label claim range of 96.5 to 99.7% and RSD values between 1.0 and 3.2; blend
uniformity for sitagliptin was also achieved with an average % label claim range of 95.8-
99.9% and RSD values between 0.9-3.4. Acceptable blend uniformity of ertugliflozin and
sitagliptin was achieved for varying fill levels (52 - 75%), ertugliflozin particle sizes (10 - 31
μm), sitagliptin particle sizes (52 – 69 μm) and scales (100 – 250 L) within 120-240
revolutions. The blend uniformity results for the batches after the lubrication step are
reported in Table 11. The lubricated blends were subsequently compressed into tablets.
Content uniformity acceptance values for both ertugliflozin and sitagliptin ranged from 2.3 -
5.7 for all pilot scale batches which is within the specification of less than 15 (see Table 15).
In addition to off-line analysis of thief samples, NIRS was used to monitor ertugliflozin and
sitagliptin uniformity for all pilot scale batches produced at the 100 L and 250 L scales to
track blend uniformity as a function of the number of blender revolutions. Figure 3 displays
the blend NIRS outputs for the pilot scale development batches and the FSS/reference
batches for sitagliptin. Figure 4 displays the NIRS outputs for the pilot scale development
batches and the FSS/reference batches for ertugliflozin.
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Figure 3 NIRS Blend Profiles As a Function of Number of Blend Revolutions for Sitagliptin for Development Batches
(Left) and FSS/Reference Batches (Right)
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Figure 4 NIRS Blend Profiles As a Function of Number of Blend Revolutions for Ertugliflozin for Development Batches
(Left) and FSS/Reference Batches (Right)
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Figure 3 and Figure 4 indicate both sitagliptin and ertugliflozin were adequately
distributed well before 240 revolutions. The percent change in RSD reached a steady
state for all blends by approximately 60-70 revolutions for both sitagliptin and
ertugliflozin. Once steady state was reached, the figure also shows that uniformity was
maintained as additional revolutions were added. This was confirmed by thief sampling
and subsequent analysis of those samples by HPLC (see Table 8). Note that there is a
low spike at 120 revolutions for the development batches in Figure 3 and Figure 4. This
was due to the stoppage of the blender at 120 revolutions in order to collect thief samples.
The blend uniformity data were also used to assess the impact of ertugliflozin and
sitagliptin particle size on the blending process. A range of sitagliptin particle sizes (52 -
69 µm) and ertugliflozin particle sizes (10 – 31 µm) were studied in the pilot scale
batches. The ertugliflozin and sitagliptin mean particle sizes are listed in Table 8 along
with the RSD result from thief samples. The HPLC data in combination with associated
NIR profiles (Figure 3 and Figure 4) indicate that the blending process is robust across a
range of particle sizes and processing conditions.
1.2.5 Blending Commercial Scale Development
Commercial scale development for the blending step included batches at the 600 L and
1700 L scales. The 600 L and 1700 L scale totes are of the same type (diffusion) but they
are different in shape from the pilot scale totes. The totes used for the pilot scale studies
were cylindrical (Figure 2) whereas the totes used at the commercial scale are cuboidal
(Figure 5). The 600 L and 1700 L totes utilize the same size discharge cone and
dimensions. However, the 600L and 1700 L totes are not geometrically (proportionally)
similar to each other with the increase in scale accounted for in the height of the cuboidal
portion of the tote rather than proportionally through the cone as well as the cuboidal
portion. In order to accommodate the larger size of the 1700 L tote, the height of the
cube is increased (Figure 6). Blending speed was well controlled and remained fixed at
the commercial facility.
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Figure 5 Commercial Scale Blend Uniformity Sampling Locations for


Figure 6 Commercial Scale Blending Tote Diagrams: 600L (Left) and 1700L
(Right)
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In terms of blend uniformity results, a total of 12 commercial scale batches were

processed at the 600 and 1700 L scales and the blend uniformity results were analyzed as

a function of the processing inputs (dose strength, ertugliflozin particle size, blender fill,
blending endpoint in number of revolutions, and blender scale). A bracketing approach
was taken for the commercial scale blending work in terms of ertugliflozin drug loading
with five of the batches using the 5/100 mg strength and five of the batches using the
15/50 mg strength. One batch each of the 15/100 mg and 5/50 mg strengths was also
included in the study design.
A multivariate experiment was executed for the 5/100 mg strength with ertugliflozin
particle size, blender fill, and blending endpoint being studied at the 600 L scale. As
shown in Table 9, ertugliflozin particle size was ranged from 27 to 52 µm, blender fill
was ranged from 31 to 69%, and blending endpoint was ranged from 120 to 240 revs for
the 5/100 mg strength. A half-factorial design was executed along with one batch at the
center-point condition (39 µm, 49% fill, 180 revs).
The intermediate strengths in terms of ertugliflozin drug loading (15/100 mg, 5/50 mg)
were executed at the center-point conditions for blender fill and endpoint with
ertugliflozin particle sizes at approximately the center-point of the 5/100 mg design.
Commercial scale batches for the 15/50 mg strength included one batch at the center-
point condition and four batches that focused on worst-case blending conditions or a
range of blending endpoints to define the blending control strategy. Due to the higher
ertugliflozin drug loading in the 15/50 mg formulation, it is theoretically the most
cohesive blend, and therefore represents the worst-case strength in terms of achieving
blend uniformity. As such, batches were executed at both the 600 L and 1700 L scales at
the highest fill level and either the lowest number of revolutions for the blending
endpoint or a range of endpoints in order to properly define the minimum number of
revolutions required to achieve blend uniformity. For the 15/50 mg blends, endpoints of
120, 150, 180, 240, 360, and 480 revolutions were used to show the impact of endpoint
on blend uniformity.
In general, batches executed to a single blending endpoint were used to show the impact
of blending conditions and resulting blend uniformity on the downstream unit operations
and CQAs such as content uniformity. The 15/50 mg batches executed with multiple
blending endpoints were used to define the blending control strategy based on the
endpoint at which blend uniformity was achieved.
Figure 7 visually depicts the processing conditions and inputs used for the commercial
scale batches.
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Figure 7 Commercial Scale Blending Study Design for Ertugliflozin/Sitagliptin

Tablets

The blending conditions outlined in Figure 7 and blend uniformity results for the
commercial scale development batches are shown in Table 9.
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Table 9 Blending Conditions and Blend Uniformity Results for Ertugliflozin/Sitagliptin Commercial Scale Batches
Ertugliflozin Sitagliptin Blend Uniformity Blend Uniformity –
Data Strength Mean Mean Tote Size Blender # Blend – Ertugliflozin Sitagliptin
Batch ID
Point (mg/mg) Particle Size Particle Size (L) % Fill Revolutions Average Average
RSD RSD
(µm) (µm) % claim % claim
Single Endpoint Batches
1 5INTE33000 5/100 27 55 600 31 120 94.9% 1.0 96.6% 1.0
2 5INTE34000 5/100 52 46 600 31 240 97.3% 1.3 95.4% 0.9
3 5INTE35000 5/100 39 52 600 49 180 96.7% 1.5 94.5% 1.1
4 5INTE18000 5/100 27 46 600 69 240 95.3% 1.5 96.3% 1.9
5 5INTE19000 5/100 52 55 600 69 120 99.2% 3.4 97.0% 1.3
6 5INTE20000 15/100 32/39* 52 600 49 180 96.0% 1.1 97.2% 1.1
7 5INTE21000 5/50 39 55 600 49 180 97.7% 1.1 97.4% 0.7
8 5INTE36000 15/50 27 55 600 49 180 94.6% 1.2 96.6% 1.3
9 5INTE22000 15/50 32 46 600 69 120 97.9% 18.6† 97.3% 4.7†
Multiple Endpoint Batches
10 6INTE21000 15/50 7 52 600 69 120 98.3% 3.0 98.8% 0.6
11 6INTE21000 15/50 7 52 600 69 150 97.3% 1.4 97.8% 0.7
12 6INTE21000 15/50 7 52 600 69 180 99.1% 4.0 98.0% 0.7
13 6INTE21000 15/50 7 52 600 69 240 98.2% 0.9 98.1% 0.8
14 6INTE21000 15/50 7 52 600 69 480 99.2% 1.2 100.0% 1.0
15 6INTE20000 15/50 31 52 600 69 120 97.6% 10.5† 97.5% 2.3
16 6INTE20000 15/50 31 52 600 69 150 97.9% 3.9 98.6% 1.4
17 6INTE20000 15/50 31 52 600 69 180 96.4% 2.9 97.7% 1.3
18 6INTE20000 15/50 31 52 600 69 240 97.0% 1.1 97.7% 0.8
19 6INTE20000 15/50 31 52 600 69 480 97.8% 2.4 99.6% 2.1
20 6INTE22000 15/50 28-33‡ 52/55§ 1700 69 120 98.2% 1.9 98.0% 2.1
21 6INTE22000 15/50 28-33‡ 52/55§ 1700 69 150 98.2% 1.2 98.1% 1.1
22 6INTE22000 15/50 28-33‡ 52/55§ 1700 69 180 98.9% 0.9 98.6% 0.8
23 6INTE22000 15/50 28-33‡ 52/55§ 1700 69 240 97.9% 0.6 98.2% 0.5
24 6INTE22000 15/50 28-33‡ 52/55§ 1700 69 360 96.5% 1.0 97.8% 0.8
25 6INTE22000 15/50 28-33‡ 52/55§ 1700 69 480 97.0% 3.3 98.4% 2.3
*
Mixture of two lots of ertugliflozin.
†
Blend uniformity RSD target not achieved at endpoint.
‡
Mixture of multiple lots of ertugliflozin.
§
Mixture of two lots of sitagliptin.
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analysis purposes. In general, blend uniformity of ertugliflozin and sitagliptin was achieved
for varying fill levels (31 - 69%), ertugliflozin particle size distributions (27-52 μm), and
within 120-480 revolutions with a few exceptions related to the 15/50 mg dose strength
(5INTE22000, 6INTE20000).
Batches 5INTE22000 and 6INTE20000 (15/50 mg strength) did not meet acceptable blend
uniformity of ertugliflozin nor sitagliptin after 120 revolutions despite other dose strengths
achieving uniformity at similar processing conditions (Table 9). As such, the results from
these batches identified ertugliflozin blend uniformity for the 15/50 mg strength as the
highest risk for the blending step at the commercial scale. The discrepancy in results
between dose strengths highlighted the impact of ertugliflozin drug loading on the blending
behavior at the commercial scale, presumably due to increased blend cohesivity. Blend
cohesivity combined with the high fill level and blender design was concluded to have
impacted the ability for the ertugliflozin to distribute within 120 revolutions for batches
5INTE22000 and 6INTE20000. The blend uniformity data supported this notion since the
corners of the blender along the axis of rotation took the longest to blend compared to the
other locations (Locations 1, 3, 6, and 8 on Figure 5).
The blend uniformity of batch 5INTE22000 was improved after the lubrication step (48
revolutions) with an ertugliflozin RSD of 8.7% and a sitagliptin RSD of 1.8% but still failed
to meet the blend uniformity RSD target for ertugliflozin even with an additional 48
revolutions. Despite not achieving blend uniformity by the end of the lubrication step, batch
5INTE22000 still demonstrated passing content uniformity results, with acceptance values of
7.2 and 7.4 for ertugliflozin and 2.0 and 3.2 for sitagliptin for the double-sided compression
process. Therefore, while a failure point for blend uniformity was identified, it did not
translate into a failure point for content uniformity. Despite the lack of correlation between
blend uniformity and content uniformity, development studies focused on properly defining
the minimum number of revolutions for the blending step since the purpose of the step is to
achieve adequate distribution of ertugliflozin and sitagliptin and the intention was not to rely
on any mixing downstream to achieve a uniform blend.
Due to the noted interaction between dose strength and blend efficiency, greater emphasis
was placed on blending development work with the 15/50 mg strength. Three commercial
scale batches with the 15/50 mg strength were executed with multiple blending endpoints in
order to define an appropriate endpoint based on blend uniformity results. These batches
involved two batches at the 600 L scale and one batch at the 1700 L scale, all at the highest
blender fill of 69%. The two batches at the 600 L scale used a small ertugliflozin particle
size (7 µm) as well as an ertugliflozin lot that was thought representative of a typical particle
size distribution (31 µm). Due to the nature of the milling process for ertugliflozin L-PGA,
there is a practical lower limit to the achievable particle size; the ertugliflozin lot used for the
600 L scale batch was milled twice with very aggressive conditions and deemed to be even
lower than the lowest feasible particle size achievable with the milling process (7 µm). The
1700 L batch also used ertugliflozin material that was representative of a typical particle size
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distribution and a direct comparison could then be made to the 600 L scale results to
determine the impact of blend scale on blend uniformity.

The three batches executed for the 15/50 mg strength involved a number of blending
endpoints, with blend uniformity samples being taken at 120, 150, 180, 240, 360, and 480
revolutions with the blend uniformity results for the majority of these points reported in
Table 9 (the 360 revolution point was not tested for 6INTE20000 and 6INTE21000 due to
good results at both 240 and 480 revolutions). Batches 6INTE21000 and 6INTE22000
demonstrated blend uniformity RSD results less than 4.0% for all blending endpoints used
(120-480 revolutions). As noted, batch 6INTE20000 did not achieve blend uniformity after
120 revolutions with an ertugliflozin RSD value of 10.6%.
Despite not achieving blend uniformity after 120 revolutions, both batches 5INTE22000 and
6INTE20000 showed improved ertugliflozin RSD values after additional revolutions. After
an additional 48 revolutions during lubrication for batch 5INTE22000, the ertugliflozin RSD
improved to 8.7% RSD (Table 12). The sitagliptin RSD also improved from 4.7% to 1.8%
RSD. Similarly, for 6INTE20000, the blend uniformity data from the remainder of the
endpoints used for blending (150, 180, 240, and 480 revolutions) were below the target of
4.0%.
Figure 8 overlays the overall blend uniformity results over the experimental design as
depicted in Figure 7.
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Figure 8 Commercial Scale Blending Study Design and Blend Uniformity Results
for Ertugliflozin/Sitagliptin Tablets

(Numbers correspond to data point numbers in (Table 9)
In order to analyze the blend uniformity data, an empirical model was fit to the 15/50 mg
blend uniformity data specifically. The 15/50 mg blend uniformity data was selected since
there was a range of blend uniformity results from passing to failing and a trend could be
established between blending conditions and the ertugliflozin blend uniformity RSD values.
Since the batches were executed at different scales, fill levels, and endpoints, a scale-
independent grouped factor was used to describe the extent of blending or the blending
efficiency of the process. An alternative to assessing the impact of individual blend
parameters on the blend uniformity results is to group the relevant parameters into one scale-
independent parameter. Recent literature has suggested that a term that groups the blender
volume, the void fraction in the blender, and the number of rotations can be used to
successfully scale a blending process whilst maintaining a constant degree of lubrication1.
This scale-independent factor is a grouping of the following terms:
1
J. Kushner IV, F. Moore. Scale-up model describing the impact of lubrication on tablet tensile strength. International
Journal of Pharmaceutics 399 (2010) 19-30.
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1
3

In this term, V is the blender volume in liters, F is the void fraction of the blender (100%
minus the fill volume in %), and r is the number of blender revolutions. In order to account
for the difference in blender geometries across scales, the scale independent factor was
altered slightly to include the percent fill by height as opposed to the percent fill by volume.
The percent fill by height was found to be more significant in terms of representing blend
efficiency since the 600 L tote experiences a much higher % fill by height at a given % fill by
volume and therefore represents a worst-case fill when compared to the 1700 L tote.
Therefore, the following term was used to group the blending parameters:
1
3
In this term, V is the blender volume in liters, H is the void fraction of the blender (100%
minus the fill height in %), and r is the number of blender revolutions for the lubrication
process. For the purposes of evaluation versus the 15/50 mg blend uniformity data, the term
was abbreviated as the blend efficiency factor, “VFR” by volume, or “VHR” by height.
While VFR was used for lubrication in the literature, the premise of the term is blending
efficiency. Therefore, it was successfully applied to the 15/50 mg blend uniformity data and
resulted in a good fit between VHR and the ertugliflozin RSD for the 15/50 mg strength.
Figure 9 shows the correlation between the blending efficiency factor (VHR) and the
ertugliflozin RSD alongside the correlation between the number of blender revolutions and
the ertugliflozin RSD.
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Figure 9 Blending Efficiency Factor (VHR) and Number of Revolutions versus Ertugliflozin RSD Blend Uniformity Results for the
15/50 mg Ertugliflozin/Sitagliptin Dose Strength
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As shown in Figure 9, the ertugliflozin RSD values decrease fairly rapidly initially and then
reach a plateau for all the blends conducted. This behavior is also expected for the other dose
strengths but occurred prior to the lowest endpoint used of 120 revolutions. Figure 9 also
shows that there is a greater amount of variability in terms of blend uniformity results at the
early endpoints; therefore, as the extent of blending is increased, the variability in the data is
reduced in addition to the ertugliflozin RSD value.
The use of VHR allows the data across the various scales and batches to be collapsed to
better demonstrate the impact of extent of blending on the ertugliflozin RSD result. As noted
previously, the blend uniformity ertugliflozin RSD reached the target of less than 4.0% for
blending endpoints of 150 through 480 revolutions. However, Figure 9 shows that despite
passing results, the ertugliflozin RSD at 150 revolutions as well as the batch to batch
variability is higher than other endpoints.
In order to ensure the blending process is robust, blending endpoints along the plateau of the
curve should be targeted. As shown in Figure 9, the ertugliflozin RSD plateau for the
blending process is reached at a VHR value of approximately 450. Translating the VHR
value back to the number of revolutions leads to a minimum number of revolutions of 240
revolutions for the 600 L tote and 120 revs for the 1700 L tote at a worst case fill. Therefore,
the blend uniformity results indicate that the 15/50 mg strength reaches the plateau as well as
the target of less than 4.0% RSD for ertugliflozin by 240 revolutions across both blender
scales and across a range of ertugliflozin particle sizes.
1.2.6 Blending Design Space Definition
The approach to control strategy definition for blend step for Ertugliflozin/Sitagliptin Tablets
was to define one control strategy that would apply to all dose strengths as well as batch
sizes. Due to the design differences highlighted between the pilot and commercial scales as
well as the increased risk at the commercial scale, the control strategy definition process
therefore solely used the commercial scale blend uniformity data.
The intended commercial batch size range will incorporate fill levels between 31 and 69%
across the commercial scale totes of 600 L and 1700 L. The commercial scale experience
has demonstrated successful blend uniformity at fill levels between 31 and 69% and therefore
the blending control strategy will incorporate this range. The minimum number of
revolutions required for the blending process was based on worst-case blending conditions as
highlighted through the multivariate study executed at the commercial scale (15/50 mg
strength, high fill level).
Based on the data presented in Table 9, the minimum number of revolutions at which blend
uniformity was achieved for the 15/50 mg strength at a high fill level was 150 revolutions.
However, Figure 9 shows that at 150 revolutions, the blending process is still variable and is
not at the plateau of ertugliflozin RSD. As such, the relationship between the extent of
blending and ertugliflozin RSD was used to determine the number of revolutions required to
reach the plateau of the process in order to define a control strategy that is robust across all
processing conditions and scales. The outcome of this analysis was a minimum number of
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revolutions of 240 for the 600 L tote and 120 for the 1700 L tote. Consequently, a minimum
number of revolutions of 240 was selected for the Ertugliflozin/Sitagliptin Tablets blending

control strategy. No additional risk was highlighted for increasing blender revolutions and
therefore the upper range for blending endpoint was set at 480 revolutions based on the
commercial scale experience.
The blending control strategy will include both a range for blender fill level as well as
blending endpoint. Due to the multivariate nature in which the blending step was studied as
well as the demonstrated understanding of the process, the blending control strategy is
proposed as a design space.
1.2.7 Blending Conclusions & Control Strategy
Blend uniformity has been demonstrated for Ertugliflozin/Sitagliptin Tablets across all scales
explored during development. For all strengths and conditions studied, blend uniformity was
achieved within 240-480 revolutions. The blending process was also confirmed to be robust
with respect to particle size distribution of ertugliflozin and sitagliptin.
The control strategy for the blending process is summarized in Table 10. The intended
commercial scale blending process will be conducted in either a 600 L or 1700 L diffusion
blender. The proposed controls summarized in Table 10 will ensure the robustness of the
blending process and that it will meet all the critical quality attributes associated with the
blend without any critical process parameters (CPPs).
Table 10 Blending Control Strategy for Ertugliflozin/Sitagliptin Tablets

Operation Parameter / Critical Process
Unit Operation Design Space Range
In-Process Control Parameter?
Fill Level 31 - 69%* No

Blending
# of Revolutions 240 - 480 No
*
Fill level is based on the lubricated blend batch size.
1.3 Lubrication
1.3.1 Lubrication Summary
The lubrication step for Ertugliflozin/Sitagliptin Tablets takes place following the blending
step. For the lubrication step, magnesium stearate and sodium stearyl fumarate are added to
a diffusion blender containing the blend from the previous process step and blended to
endpoint. The purpose of the lubrication step is to distribute the lubricant throughout the
powder blend while minimizing the potential for over-lubrication in order to provide optimal
performance during compression.
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The lubrication step has been characterized at the pilot and commercial scales using thief
sampling and HPLC analysis for both ertugliflozin and sitagliptin. The HPLC results for

ertugliflozin and sitagliptin were used to demonstrate that distribution of both active
ingredients was maintained through the lubrication step and also that the lubricant
distribution was sufficient in that it did not interfere with the active HPLC results. NIRS
(Near-Infrared Spectroscopy) monitoring has been used to support this characterization at the
pilot scale for process development purposes. NIRS monitoring was used at the pilot scale to
monitor the distribution of ertugliflozin, sitagliptin, and the lubricants. The peak being
monitored by NIRS for the lubricants is the aliphatic chain of the fatty acid associated with
both sodium stearyl fumarate and magnesium stearate; therefore, the RSD reported is
associated with both lubricants. The NIRS data obtained at the pilot scale was used to
determine the number of revolutions at which lubricant distribution was achieved. It also
served to demonstrate that the NIRS traces for all three components (ertugliflozin, sitagliptin,
and the lubricants) are very similar for the lubrication step and that all achieve distribution at
approximately the same rate.
1.3.2 Lubrication Risk Assessment
The risk assessment identified the following risks specific to the lubrication process:
µm.
blend uniformity, content uniformity, and assay data. ‘
such, the extent of lubrication both during the blending step as well as in the compression
feed frame was studied through generating tabletability profiles to determine the impact
of lubrication on the tablet properties.
It was established through the risk assessment that the risks associated with the lubrication
step are under-blending of the lubricants due to non-ideal blending conditions as well as
over-lubrication of the blend, which leads to reduced tablet hardness/tensile strength values
upon compression. Therefore, specific experiments outlined in section 1.3.6 were planned
beyond those needed to establish lubricant uniformity in order to probe the lubrication
sensitivity of the blend.
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1.3.3 Lubrication Prior Knowledge

Prior knowledge, early development data, and internal best practices from ertugliflozin/
sitagliptin tablets development, sitagliptin monotherapy tablets development, and other drug
development programs were leveraged to set the target number of revolutions at 96 for
lubrication at pilot scale. This target number was used for all the pilot scale batches and the
commercial scale batches had endpoints that centered on this value (48-192 revolutions).
Prior knowledge concerning the blending factors that primarily impact blend efficiency was
also used to design the pilot and commercial scale studies. As such, the % fill and the
number of blending revolutions were built into the study designs while other factors such as
the blender speed were fixed.
1.3.4 Lubrication Pilot Scale Development Summary
The process parameters controlled during the lubrication step are fill level, speed, and
number of revolutions. Blender speed is well controlled and remained fixed at the pilot
facility. The number of revolutions at the pilot scale was fixed at 96; however, the actual
number of revolutions required to achieve uniform distribution of ertugliflozin, sitagliptin,
magnesium stearate, and sodium stearyl fumarate was also evaluated through NIRS
monitoring.
A total of 14 batches were blended and studied according to the parameters provided in
Table 11. Development studies at the pilot scale took a bracketing approach with regards to
ertugliflozin drug loading with more batches being produced at the extremes (5/100 mg and
15/50 mg). The blending study design in terms of varying ertugliflozin and sitagliptin
particle size was carried through to the lubrication step. Thief samples were taken at ten
blender locations in the 100 L and 250 L diffusion blender as shown in Figure 2. Table 11
summarizes the lubrication conditions and blend uniformity results for the FSS/reference and
development batches at the pilot scale.
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Table 11 Lubrication Conditions and Blend Uniformity Results (Lubrication) for Ertugliflozin/Sitagliptin Pilot Scale
Batches*
Blend Uniformity – Blend Uniformity –
Ertugliflozin Sitagliptin
Strength Tote Size Blender # Lubrication Ertugliflozin Sitagliptin
Batch ID Mean Particle Mean Particle
(mg/mg) (L) % Fill Revolutions Average Average
Size (µm) Size (µm) RSD RSD
% claim % claim
53796G05 5/100 31 69 250 52 96 99.7% 1.3 100.6% 1.0
53796G01 5/100 10 69 250 52 96 100.7% 1.1 100.3% 1.5
5434101C1†‡ 5/100 18 53 250 52 96 99.9% 1.8 101.2% 2.1
5434102C2† 5/100 25 55 250 52 96 NIR only
5434103C3† 5/100 10 52 250 52 96 NIR only
53796G06 15/100 31 69 250 52 96 98.8% 1.3 99.1% 0.9
5434201C1†‡ 15/100 18 52 250 52 96 100.1% 2.1 101.0% 1.4
53796G02 5/50 31 69 100 75 96 99.4% 1.2 101.1% 1.0
5385901C1†‡ 5/50 18 55 100 75 96 98.7% 1.2 99.5% 0.7
53796G03 15/50 10 69 100 75 96 98.8% 0.8 98.1% 1.0
53796G04 15/50 31 69 100 75 96 100.7% 1.3 101.7% 2.6
5434001C1†‡ 15/50 18 53 100 75 96 100.8% 2.1 101.3% 1.9
5434002C2† 15/50 25 55 100 75 96 NIR only
5434003C3† 15/50 10 52 100 75 96 NIR only
*
Results shown are from HPLC analysis of 10 location thief samples.
†
‡
Reference Batch
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analysis purposes. As indicated, blend uniformity of ertugliflozin was achieved with an
average % label claim range of 98.7 to 100.8% and RSD values between 0.8 and 2.1;
blend uniformity for sitagliptin was also achieved with an average % label claim range of
98.1-101.7% and RSD values between 0.7-2.6. Acceptable blend uniformity of
ertugliflozin and sitagliptin was achieved for varying fill levels (52 - 75%), ertugliflozin
particle sizes (10 - 31 μm), sitagliptin particle sizes (52 – 69 μm) and scales (100 – 250
L) within 120-240 revolutions. The lubricated blends were subsequently compressed into
tablets. Content uniformity acceptance values for both ertugliflozin and sitagliptin
ranged from 2.3 - 5.7 for all pilot scale batches which is within the specification of less
than 15 (see Table 15).
In addition to off-line analysis of thief samples, NIRS was used to monitor ertugliflozin,
sitagliptin, and the lubricants for all pilot scale batches produced at the 100 L and 250 L
scales to track blend uniformity as a function of the number of blender revolutions. The
NIRS output for the FSS/reference batches for ertugliflozin, sitagliptin, and the lubricants
is given in Figure 10.
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Figure 10 NIRS Blend Profiles as a Function of Lubrication Revolutions for the Reference Batches for Ertugliflozin
and Sitagliptin (Left) and Lubricants (Right)
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Figure 10 indicates blend uniformity of ertugliflozin, sitagliptin, magnesium stearate, and

sodium stearyl fumarate was achieved prior to the endpoint of 96 blender revolutions. Based
on the NIRS outputs in Figure 10, steady state for the batches was reached at ~ 40 revs for
both ertugliflozin and sitagliptin and ~ 50 revs for the lubricants. Once steady state was
reached, the figure also shows that uniformity was maintained as additional revolutions were
added. This was confirmed by thief sampling and subsequent analysis of those samples by
HPLC (see Table 11).
The blend uniformity data were also used to assess the impact of ertugliflozin and sitagliptin
particle size on the lubrication process. A range of ertugliflozin particle sizes (10 – 31 µm)
and sitagliptin particle sizes (52 – 69 µm) were studied in the pilot scale batches. Table 9
shows blend uniformity results of all available pilot scale data as a function of ertugliflozin
and sitagliptin particle size. The HPLC data in combination with associated NIR profiles
(Figure 10) indicate that the blending process is robust across a range of particle sizes and
processing conditions.
1.3.5 Lubrication Commercial Scale Development Summary
Commercial scale development for the lubrication step included the 600 L and 1700 L scales.
The process parameters controlled during the commercial scale lubrication step are fill level,
speed, and number of revolutions. Blender speed is well controlled and remained fixed at the
commercial scale. The number of revolutions at the commercial scale were ranged between
48 and 192 revolutions to determine if the lubrication endpoint has an impact on blend
uniformity or compression performance.
Commercial scale development batches were conducted at the 600 L scale and the 1700 L
scale per the conditions described in Table 12. A total of 12 commercial scale batches were
conducted and the blend uniformity results after lubrication were analyzed as a function of
the processing inputs (dose strength, ertugliflozin particle size, blender fill, blending
endpoint, and blender scale). A bracketing approach was taken for the commercial scale
lubrication studies in terms of strength with five of the batches using the 5/100 mg strength
and five of the batches using the 15/50 mg strength. One batch each of the 15/100 mg and
5/50 mg strengths was also included in the study design.
A multivariate experiment was executed for the 5/100 mg strength for the blending step as
described in section 1.2.5 which included varying the blending step endpoint. As such, the
lubrication study design included having the number of lubrication revolutions kept constant
at 96 to allow the study of blending endpoint to be carried through to subsequent unit
operations and critical quality attributes (i.e. to study the impact of blending endpoint on
content uniformity). For the remainder of the lubrication batches, variability was introduced
to the lubrication endpoint (48 – 192 revolutions) since these batches were processed at either
a center-point condition or a worst-case condition. Worst-case blending conditions in terms
of a high fill level and low number of revolutions for the blending endpoint were
purposefully selected to also have a low number of revolutions for the lubrication endpoint in
order to demonstrate worst-case conditions across unit operations.
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Similar to the blending unit operation, commercial scale batches for the 15/50 mg strength
included two batches at a single lubrication endpoint (5INTE36000 at 192 revs and

5INTE22000 at 48 revs) and three batches for which multiple endpoints were used
(6INTE20000, 6INTE21000, and 6INTE22000). For the 15/50 mg blends with multiple
endpoints, endpoints of 48 and 192 revolutions were used to show the impact of endpoint on
blend uniformity. In general, batches executed to a single blending endpoint were used to
show the impact of blending conditions and resulting blend uniformity on the downstream
unit operations and CQAs such as content uniformity. The 15/50 mg batches executed with
multiple lubrication endpoints were used to define the lubrication control strategy based on
the endpoint at which blend uniformity was achieved.
Thief sampling and HPLC analysis was conducted for the commercial scale development
lots. Thief samples were taken at ten blender locations in the 600 L and 1700 L diffusion
blender as shown in Figure 5. The lubrication blend uniformity summary results for the
commercial scale development batches are provided in Table 12.
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Table 12 Lubrication Conditions and Blend Uniformity (Lubrication) Results for Ertugliflozin/Sitagliptin
Commercial Scale Batches
Blend Uniformity – Blend Uniformity –
Strength Tote Size Blender % # Lubrication Ertugliflozin Sitagliptin
Batch ID Mean Particle Mean Particle
(mg/mg) (L) Fill Revolutions Average Average
Size (µm) Size (µm) RSD RSD
% claim % claim
Single Endpoint Batches
5INTE33000 5/100 27 55 600 31 96 99.1% 3.9 100.7% 3.7
5INTE34000 5/100 52 46 600 31 96 99.5% 1.2 98.9% 0.9
5INTE35000 5/100 39 52 600 49 96 98.8% 3.6 98.2% 3.8
5INTE18000 5/100 27 46 600 69 96 97.5% 0.7 98.9% 0.6
5INTE19000 5/100 52 55 600 69 96 99.3% 0.6 98.7% 0.5
5INTE20000 15/100 32/39* 52 600 49 48 98.3% 0.6 99.8% 0.7
5INTE21000 5/50 39 55 600 49 192 99.9% 0.9 100.0% 0.8
5INTE36000 15/50 27 55 600 49 192 97.2% 1.0 99.2% 1.1
5INTE22000 15/50 32 46 600 69 48 100.0% 8.7† 100.5% 1.8
Multiple Endpoint Batches
6INTE21000 15/50 7 52 600 69 48 98.8% 1.3 98.7% 1.5
6INTE21000 15/50 7 52 600 69 192 99.8% 0.4 99.5% 0.4
6INTE20000 15/50 31 52 600 69 48 98.5% 0.8 98.5% 0.8
6INTE20000 15/50 31 52 600 69 192 98.8% 0.4 99.0% 0.4
6INTE22000 15/50 28-33‡ 52/55§ 1700 69 48 100.4% 1.2 100.0% 0.9
6INTE22000 15/50 28-33‡ 52/55§ 1700 69 192 99.9% 0.4 99.4% 0.4
*
Mixture of two lots of ertugliflozin.
†
Blend uniformity RSD target not achieved at endpoint.
‡
Mixture of multiple lots of ertugliflozin.
§
Mixture of two lots of sitagliptin.
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Acceptable blend uniformity was defined as 90-110% label claim with ≤ 4.0 RSD for
analysis purposes. Acceptable blend uniformity of ertugliflozin and sitagliptin was
achieved for varying fill levels (31 - 69%), ertugliflozin particle size distributions (27-52
μm), and within 48-192 revolutions, with one exception.
Batch 5INTE22000 did not meet acceptable blend uniformity of ertugliflozin after 120
blending revolutions with an ertugliflozin RSD of 18.6% (section 1.2.5). The blend
uniformity of batch 5INTE22000 was improved after the lubrication step (48 revolutions)
with an ertugliflozin RSD of 8.7% and a sitagliptin RSD of 1.8% but still failed to meet
the blend uniformity RSD target for ertugliflozin. The blend uniformity failure for batch
5INTE22000 was a result of poor blend uniformity after the blending step.
Additional 15/50 mg strength batches included a range of lubrication endpoints to

demonstrate that when blend uniformity for ertugliflozin and sitagliptin is achieved
during the blending step, uniformity is achieved in the lubrication step regardless of
endpoint within the range of 48-192 revolutions. The blend uniformity results from these
batches, ertugliflozin average values of 98.5 – 100.4% with RSD values of 0.4 – 1.3, and
sitagliptin average values of 98.5 – 100.0% with RSD values of 0.4 – 1.5 confirm that
when the actives are properly distributed in the blending step, blend uniformity is also
achieved for the lubrication step.
Blends at the commercial scale were subsequently compressed into tablets which met all
critical quality attributes (CQAs). Mean content uniformity of tablets produced is listed
in Table 17. Furthermore, a range of ertugliflozin particle sizes (27– 52 µm) and
sitagliptin particle sizes (46 – 57 µm) were used for the commercial scale batches. A
direct comparison between the low (27 µm) and high (52 µm) ertugliflozin particle sizes
at the same fill level (69 %) was demonstrated by batches 5INTE18000 and 5INTE19000
with both yielding acceptable blend uniformity. For all commercial scale batches,
acceptable blend uniformity was achieved (except 5INTE22000 as discussed above),
indicating that ertugliflozin and sitagliptin particle sizes have no impact on the lubrication
step.
1.3.6 Impact of Lubrication Endpoint on Final Blend Tabletability
Lubrication sensitivity of the final blend was studied at the commercial scale with a range
of lubrication endpoints (48, 96, and 192 revolutions). All final blends were carried
forward into compression and hardness-compression profiles were generated. In order to
compare results across images, these profiles were made image independent and
converted to tabletability profiles (tensile strength vs. compaction pressure). Section
1.4.4 explains the image independent development approach taken and the use of tensile
strength to normalize the compression results across images.
For comparison purposes, similar press conditions were used to compare the tableting
performance as a function of only the lubrication endpoint. Figure 11 shows the
tabletability profiles for the various formulations arranged to show the impact of
lubrication endpoint on the compaction pressure/tensile strength relationship. Minimal
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impact of lubrication endpoints was observed on the tabletability profile across all the
ertugliflozin/sitagliptin formulations. As such, it was determined that the full range of

lubrication endpoints can be used with no impact to downstream tablet properties.
Figure 11 Tabletability Profiles as a Function of Lubrication Endpoint for

1.3.7 Lubrication Design Space Definition
Similar to the blending control strategy, the approach to control strategy definition for
lubrication step for Ertugliflozin/Sitagliptin Tablets was to define one control strategy
that would apply to all dose strengths as well as batch sizes. Due to the design
differences highlighted between the pilot and commercial scales as well as the increased
risk at the commercial scale, the control strategy definition process therefore solely used
the commercial scale blend uniformity data.
The intended commercial batch size range will incorporate fill levels between 31 and
69% across the commercial scale totes of 600 and 1700 L. The commercial scale
experience has demonstrated successful blend uniformity at fill levels between 31 and
69% and therefore the blending control strategy will incorporate this range. The
commercial scale development data for lubrication has shown that when blend uniformity
is achieved during blending, it is achieved within the full range of fill levels and
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lubrication endpoints studied. Based on the data presented in Table 12, blend uniformity
was achieved after the lubrication step for varying fill levels (31 - 69%) within 48-192

revolutions.
The lubrication control strategy will include both a range for blender fill level as well as
blending endpoint. Due to the multivariate nature in which the blending and lubrication
steps were studied as well as the demonstrated understanding of the process, the
lubrication control strategy is proposed as a design space.
1.3.8 Lubrication Conclusion and Control Strategy
Lubrication development focused on demonstrating blend uniformity, mitigating over-

lubrication of the blend, and understanding the downstream impact of uniformity and
extent of lubrication. Thief sampling blend uniformity data, NIRS data at pilot scale, and
tablet content uniformity data confirm that blend uniformity for the lubrication step has
been achieved at all scales when incoming material from the blending step has achieved
blend uniformity. The risk of over-lubricating the blend during the lubrication step is low
based on the tabletability data as a function of lubrication endpoint.
The development studies at the commercial scale focused on optimizing the process with
respect to blend uniformity, process robustness, and to optimize the number of
revolutions required for lubrication. The fill range of 31 to 69% was explored during
commercial development and found to achieve blend uniformity regardless of the
lubrication revolutions (48 – 192). The process was also determined to be robust with
respect to ertugliflozin and sitagliptin particle sizes and fill level.
The proposed controls summarized in Table 13 will ensure the robustness of the
lubrication process and that it will meet all the critical quality attributes associated with
the ertugliflozin/sitagliptin blend without any critical process parameters (CPPs).
Table 13 Lubrication Control Strategy for Ertugliflozin/Sitagliptin Tablets

Operation Parameter / Design Space Critical Process
Unit Operation
In-Process Control Range Parameter?
Fill Level 31-69%* No

Lubrication
# of Revolutions 48 - 192 No
*
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1.4 Compression

1.4.1 Compression Overview
The ertugliflozin/sitagliptin lubricated blend is compressed into four images

corresponding to strengths of 5/100 mg, 15/100 mg, 5/50 mg, and 15/50 mg. The 100 mg
sitagliptin strengths have a core tablet weight of 400 mg and the 50 mg sitagliptin
strengths have a core tablet weight of 300 mg. The commercial images will be almond-
shaped tablets for all doses. During development, all images were evaluated for
weight/thickness/hardness, content uniformity, assay, friability, elegance, and
disintegration/dissolution. Correlations between core tablet attributes were investigated
in order to identify the appropriate in-process controls. Image independent properties
such as tensile strength were used to streamline development and analysis but were
translated back into the image dependent in-process controls such as hardness for the
control strategy.
1.4.2 Compression Risk Assessment
The risk assessment identified the following risks specific to the compression process:
1. The impact of ertugliflozin particle size and sitagliptin particle size on blend
uniformity, content uniformity, and assay was studied across scales. Blend
uniformity was measured both by traditional thief sampling and HPLC analysis and
also through NIR monitoring at the pilot scale for development purposes. The
intention behind studying the blend uniformity, content uniformity, and assay data as
a function of the ertugliflozin particle size was to aid in establishment of the
ertugliflozin particle size specification of NMT 52 µm.
highlighted as an elevated risk. Assay trends throughout the process were studied
through blend uniformity, content uniformity, and assay data.
3. Due to the low drug loadings of ertugliflozin in the formulation (1.6-6.5%) and the
selected process, the theoretical segregation potential of the blend is an elevated risk
for the formulation. As such, content uniformity data were collected across scales
and extended content uniformity data at the beginning and end of the compression
process were also collected to gain insight into assay trends.
4. Establishment of appropriate in-process compression controls was a targeted area for
development. The goal of the development studies was to establish appropriate
hardness controls to ensure adequate robustness (elegance) through the film coating
step as well as dissolution performance.
such, the extent of lubrication both during the blending step as well as in the
compression feed frame was studied through generating tabletability profiles to
determine the impact of lubrication on the tablet properties.
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The risk assessment for Ertugliflozin/Sitagliptin Tablets established that the main risks
associated with the compression step are assay and content uniformity risks due to

material segregation during compression. Due to the low drug loadings of ertugliflozin in
the blends (1.6-6.5%), segregation was highlighted as a theoretical risk. Selective
material loss was also highlighted as a risk to assay. Traditional content uniformity
samples were taken and analyzed (10 locations equally spaced throughout the run) and
extended content uniformity samples were taken at the beginning and end of the process
to assess any trends.
The risk assessment also highlighted the need for proper establishment of in-process
compression specifications in order to ensure adequate tablet robustness. Therefore,
specific experiments were planned at the pilot and commercial scales to investigate the
impact of incoming materials and press conditions on the resulting tablet hardness/tensile
strength. Friability as a function of tablet properties, tumbling trials, and film coating
runs were all conducted to assess the impact of tablet tensile strength on the erosion
response during film coating as well as to confirm that the lower hardness/tensile strength
limit resulted in adequate elegance at the commercial scale. Lastly, the impact of extent
of lubrication both during the blend lubrication step and in the press feed frame was
evaluated with regards to ability to achieve the minimum tensile strength/hardness to
ensure tablet robustness. Tablets across processing conditions were tested for both
dissolution and disintegration in order to confirm the low risk highlighted between
processing and the dissolution/disintegration CQA. The disintegration data was also used
to establish a correlation between the tablet hardness/tensile strength values and the
disintegration time of the Ertugliflozin/Sitagliptin Tablets.
1.4.3 Compression Prior Knowledge
Prior knowledge aided in identifying the key risks for compression of a fixed dose
combination with low drug loading blends as well as with a sitagliptin-based formulation.
These key risks included segregation potential and the resulting impact on assay and
content uniformity as well as preferential material adherence during processing and the
resulting impact on assay.
1.4.4 Compression - Image Independent Development Approach
In order to bridge between all images, input terms and responses from the compression
process were made image independent for the data analysis performed. For example, an
input factor such as punch force (kN) was converted to compaction pressure (MPa) to
take into account the image size and shape; likewise, the response of tablet hardness (kP
or N) was converted to tensile strength (MPa). Tensile strength calculations for curved
and shaped tablets are complex and have not been established for some shapes; therefore,
a simplified version of the calculation typically used for flat-faced round tablets and
based on tablet hardness and thickness was used to estimate tensile strength. The tensile
strength calculation was applied to the ertugliflozin/sitagliptin images and the axis of
breakage during hardness testing was used to normalize the resulting values. Figure 12
shows that once the conversion to tensile strength for all images is performed, the
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tabletability profiles (tensile strength versus compaction pressure) for all the images at
similar compression conditions overlay. As such, by using the tensile strength, the

compression data collected for all images was compiled and analyzed to draw
conclusions across all images.
Figure 12 Tabletability Profiles for Ertugliflozin/Sitagliptin 5/100 mg, 15/100

mg, 5/50 mg, and 15/50 mg Images Under Similar Compression
Conditions
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1.4.5 Compression Pilot Scale Development

All pilot scale development studies for Ertugliflozin/Sitagliptin Tablets were conducted
on a Kilian T200 rotary press with 28 stations and a force feeder. Kilian-design standard
paddles and wire paddles were both used during development to study the impact of the
feeder design on tablet weight uniformity. Since the press design at the pilot scale was
different than that at the commercial scale (Fette 3090), the development conducted at the
pilot scale mainly served to identify tablet properties that would scale to the commercial
process as well as optimal conditions at which to process the clinical/stability batches.
Material attribute variations in terms of ertugliflozin particle sizes ranging from 10-31
µm were built into development at the pilot scale but the majority of process
development work was conducted at the commercial scale. The tooling used at the pilot
scale was of the same shape (almond) and dimensions as the final market image (FMI)
tooling with the exception that it was plain tooling and did not include the FMI markings.
Development studies at the pilot scale took a bracketing approach with regards to
ertugliflozin drug loading with more batches being produced at the extremes (5/100 mg
and 15/50 mg). A total of 6 development batches (2 x 5/100 mg, 1 x 15/100 mg, 1 x 5/50
mg, 2 x 15/50 mg) and 8 clinical/stability batches (3 x 5/100 mg, 1 x 15/100 mg, 1 x 5/50
mg, 3 x 15/50 mg) were run at the pilot scale. Table 14 summarizes the compression in
process data for the development and clinical/stability batches carried out at the pilot
scale.
Table 14 Summary of Pilot Scale Compression Batches for

Sitagliptin Average
Ertugliflozin Target Average Average Average
Compression Mean Tensile
Mean Particle Hardness Weight Thickness Hardness
Batch ID Particle Size Strength
Size (µm) (kP) (mg) (mm) (kP)
(µm) (MPa)
5/100 mg Batches, 400 mg Image
53796G01* 10 69 12.0 399 4.82 11.5 1.49
53796G05 31 69 15.0 401 4.30 14.6 1.76
5434103C3† 10 52 14.8 398 4.29 14.2 1.72
5434101C1†‡ 18 53 14.8 401 4.30 14.5 1.76
5434102C2* 25 55 14.8 399 4.31 14.4 1.74
53796G06 31 69 15.0 401 4.28 16.4 1.99
5434201C1†‡ 18 52 14.8 397 4.31 14.4 1.74
53796G02 31 69 9.0 301 3.99 10.9 1.56
5385901C1†‡ 18 55 12.2 302 3.98 12.4 1.78
53796G03 10 69 9.0 298 3.89 11.8 1.74
53796G04 31 69 9.0 299 4.00 11.0 1.57
5434003C3† 10 52 12.2 303 4.00 12.8 1.84
5434001C1†‡ 18 53 12.2 302 3.98 12.0 1.73
5434002C2* 25 55 12.2 301 3.99 11.8 1.70
*
Batch compressed with standard round concave (SRC) tooling as opposed to almond-shaped tooling.
†
‡
Reference Batch
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The results from the development and clinical/stability compression runs indicate that the
compression step is reproducible in terms of achieving target weights and hardness

values. At the pilot scale, tablets ranging in tensile strength from 1.49 to 1.99 MPa were
produced and taken forward into the film coating step. The intention of compression
work at the pilot scale was to produce tablets at a target hardness/tensile strength; the
impact of tensile strength on elegance during film coating was formally studied at the
commercial scale.
In addition to in-process testing, content uniformity data were collected at 10 locations

for each of the development and clinical/stability batches. Table 15 gives the pilot scale
content uniformity results as well as weight uniformity and incoming ertugliflozin and
sitagliptin material properties.
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Table 15 Content Uniformity Results for Ertugliflozin/Sitagliptin Pilot Scale Batches

Content Content
Ertugliflozin Sitagliptin Content Content
Strength Core Tablet Uniformity Uniformity
Batch ID Mean Particle Mean Particle Uniformity AV - Uniformity AV -
(mg/mg) Weight RSD Avg/RSD - Avg/RSD -
Size (µm) Size (µm) Ertugliflozin Sitagliptin
53796G05 5/100 31 69 2.2 100.5% / 2.1 4.2 101.0% / 2.2 4.4
53796G01 5/100 10 69 2.0 101.4% / 2.3 4.8 100.4% / 2.4 4.7
†
5434103C3 5/100 10 52 1.8 100.0% / 2.3 5.4 99.7% / 2.2 5.4
5434101C1†‡ 5/100 18 53 1.3 99.5% / 1.3 2.6 99.7% / 1.3 2.5
†
5434102C2 5/100 25 55 1.3 100.2% / 1.9 4.5 99.5% / 1.7 4.1
53796G06 15/100 31 69 1.9 100.4% / 2.1 4.2 100.4% / 2.1 4.3
†‡
5434201C1 15/100 18 52 2.6 99.8% / 2.9 5.7 99.4% / 2.9 5.7
53796G02 5/50 31 69 3.1 101.7% / 2.5 5.4 100.7% / 2.6 5.2
5385901C1†‡ 5/50 18 55 0.9 100.3% / 1.6 3.1 100.9% / 1.6 3.2
53796G03 15/50 10 69 1.6 99.8% / 1.2 2.3 99.4% / 1.2 2.4
53796G04 15/50 31 69 1.9 100.3% / 1.7 3.5 99.7% / 1.7 3.3
†
5434003C3 15/50 10 52 1.9 100.5% / 2.2 5.3 100.6% / 2.1 5.0
†‡
5434001C1 15/50 18 53 1.2 100.0% / 2.0 3.9 100.5% / 2.0 4.0
†
5434002C2 15/50 25 55 1.5 101.1% / 1.3 3.1 100.6% / 1.2 2.9
†
‡
Reference Batch
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All batches processed at the pilot scale had passing content uniformity results. Content
uniformity acceptance values for both ertugliflozin and sitagliptin ranged from 2.3 - 5.7 for
all pilot scale batches which is well within the specification of less than 15. Average assay
values across the batches also range from 99-101% indicating no assay losses for either
ertugliflozin or sitagliptin at the pilot scale. Furthermore, there is no assay trend across any
of the pilot scale batches indicating that limited segregation or assay loss occurred on the
pilot scale compression module.
The content uniformity data was also analyzed in order to determine if there were any trends
between the incoming ertugliflozin and sitagliptin particle size or processing conditions on
the content uniformity data. The development and clinical/stability batches conducted at the
pilot scale mainly focused on studying the impact of ertugliflozin particle size on content
uniformity, with the majority of the other materials being kept consistent. Ertugliflozin mean
particle sizes from 10 to 31 µm were studied at the pilot scale with no impact observed on the
content uniformity results. Sitagliptin particle size was also varied between the pilot scale
development batches and the clinical/stability batches (69 and 52 µm, respectively) with both
sets of batches giving passing content uniformity results and no trends observed.
The main focus at the pilot scale was to optimize the weight uniformity to the greatest extent
possible within the equipment design limitations in order to ensure passing content
uniformity acceptance values. The clinical/stability batches had weight uniformity RSD
values between 0.9 and 2.6% (compared to 1.6 – 3.1% for the development batches) which
resulted in passing acceptance values between 2.3 and 5.7 for ertugliflozin and 2.4 and 5.7
for sitagliptin.
Overall, the pilot scale batches demonstrated a robust process across strengths with regards to
meeting target hardness values as well as assay and content uniformity using the pilot scale
module. The pilot scale compression module has minimal transfers or drops associated with
the setup though and so these risks were still highlighted for the commercial scale process
since the module design is different. The learnings obtained from the pilot scale with regards
to weight uniformity optimization as well as tabletability performance of the formulations
were carried forward to commercial scale development for further process development.
1.4.6 Compression Commercial Scale Development
Compression at the commercial scale takes place on a Fette 3090 double-sided tablet press
with 49 stations; development work at the commercial scale focused on evaluating the impact
of ertugliflozin and sitagliptin particle size on content uniformity. All 12 batches presented
in commercial scale blending section (1.2.5) were carried forward to the compression step
and analyzed for assay in addition to the blend uniformity data presented; 9 of the 12 batches
were used for the analysis of tablet properties and content uniformity data.
All dose strengths were studied at the commercial scale with at least one batch. Similar to
the pilot scale, commercial scale development took a bracketing approach with the majority
of the batches focusing on the 5/100 mg and 15/50 mg ertugliflozin/sitagliptin strengths.
Image independent properties such as tensile strength were used to bridge all tablet images
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rather than image dependent properties such as tablet hardness (refer to 1.4.4 for additional
information). The commercial scale blending/lubrication study design was carried forward

into compression and so the impact of those processing conditions on content uniformity and
compression performance was evaluated. Table 16 summarizes the compression in-process
data for the development batches carried out at the commercial scale.
Target tablet hardness was varied for different batches and portions of batches in order to
study the impact of tablet hardness on elegance in the film coating step. The low hardness
for both images was set based on the 1.25 MPa tensile strength criteria identified through
friability and erosion testing (section 1.4.7). The lower tensile strength of 1.25 MPa is
equivalent to a hardness of 9.0 kP for the 300 mg image and 10.7 kP for the 400 mg image.
Table 16 Summary of Commercial Scale Compression Batches for

Hardness
Ertugliflozin Sitagliptin Average
Target Average Average Average
Compression Mean Mean Tensile
(Low, Weight Thickness Hardness
Batch ID Particle Size Particle Size Strength
Target, (mg) (mm) (kP)
(µm) (µm) (MPa)
High)
5INTE33000 27 55 Target 400 4.33 16.1 1.93
5INTE34000 52 46 High 404 4.29 17.6 2.13
5INTE35000 39 52 Target 401 4.39 15.1 1.79
Low 403 4.62 10.1 1.14
5INTE18000 27 46
High 399 4.30 18.0 2.18
Target 402 4.40 15.5 1.84
5INTE19000 52 55
Low 400 4.60 9.5 1.07
5INTE20000 32/39 52 Target 401 4.41 14.1 1.66
5INTE21000 39 55 Low 301 4.11 9.4 1.30
5INTE36000 27 55 High 300 3.94 14.1 2.05
Low 301 4.16 9.2 1.26
5INTE22000 32 46
High 298 3.95 13.4 1.94
Low 300 4.16 8.9 1.23
5INTE37000* N/A 46
Low 299 4.08 10.2 1.43
*
Batch only contained sitagliptin. Intention of the batch was to produce tablet cores for the film coating study.
The results from the development runs indicate that the compression step is reproducible in
terms of achieving target weights and hardness values regardless of the target. Tablet cores
were successfully produced at varying tablet hardnesses in order to confirm the lower tensile
strength of 1.25 MPa is appropriate to deliver robust tablets through the film coating process.
Tablet cores with a tensile strength as low as 1.07 MPa for the 400 mg image and 1.23 MPa
for the 300 mg were taken forward into film coating.
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1.4.6.1 Compression Commercial Scale Development – Content Uniformity Results

Content uniformity data were collected at 10 locations for each of the batches. Table 17
gives the commercial scale content uniformity results as well as blend uniformity, core tablet
weight uniformity, and incoming ertugliflozin and sitagliptin material properties. All batches
were processed on a double-sided press and so content uniformity results are reported for
each side of the press.
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Table 17 Content Uniformity Results for Ertugliflozin/Sitagliptin Commercial Scale Batches
Blend Blend Content Content Content Content

Sitagliptin Core
Ertugliflozin Uniformity Uniformity Uniformity Uniformity Uniformity Uniformity
Strength Mean Tablet
Batch ID Mean Particle Avg/RSD – Avg/RSD - Avg/RSD/AV Avg/RSD/AV Avg/RSD/AV Avg/RSD/AV
(mg/mg) Particle Weight
Size (µm) Lubrication Lubrication - Side 1 - - Side 2 - - Side 1 - - Side 2 -
Size (µm) RSD
Ertugliflozin Sitagliptin Ertugliflozin Ertugliflozin Sitagliptin Sitagliptin
97.4% / 1.6 / 98.0% / 1.3 / 99.6% / 1.3 / 99.6% / 1.2 /
5INTE33000 5/100 27 55 2.2 99.1% / 3.9 100.7% / 3.7
4.1 3.1 2.6 2.4
100.3% / 1.2 / 100.8% / 1.0 / 100.0% / 1.0 / 99.8% / 1.0 /
5INTE34000 5/100 52 46 1.2 99.5% / 1.2 98.9% / 0.9
2.4 1.9 2.1 2.0
99.4% / 1.9 / 100.6% / 1.1 / 98.9% / 1.8 / 100.0% / 1.1 /
5INTE35000 5/100 39 52 1.1 98.8% / 3.6 98.2% / 3.8
3.7 2.3 3.6 2.2
100.0% / 2.1 / 97.0% / 4.1 / 101.9% / 2.1 / 98.8% / 4.0 /
5INTE18000 5/100 27 46 3.2 97.5% / 0.7 98.9% / 0.6
4.2 9.5 4.7 7.8
99.7% / 1.2 / 99.5% / 1.5 / 99.5% / 1.2 / 99.8% / 1.4 /
5INTE19000 5/100 52 55 1.2 99.3% / 0.6 98.7% / 0.5
2.4 2.9 2.3 2.8
97.5% / 2.9 / 97.2% / 1.3 / 99.9% / 1.9 / 99.1% / 1.0 /
5INTE20000 15/100 32/39 52 1.2 98.3% / 0.6 99.8% / 0.7
6.8 4.0 3.8 2.0
100.6% / 1.3 / 100.6% / 1.4 / 100.6% / 1.4 / 100.3% / 1.2 /
5INTE21000 5/50 39 55 1.2 99.9% / 0.9 100.0% / 0.8
2.7 2.8 2.7 2.4
97.3% / 1.0 / 97.7% / 1.8 / 99.7% / 0.9 / 99.6% / 1.2 /
5INTE36000 15/50 27 55 1.5 97.2% / 1.0 99.2% / 1.1
3.2 4.4 1.8 2.4
97.8% / 3.4 / 97.6% / 3.2 / 99.8% / 1.6 / 99.0% / 1.0 /
5INTE22000 15/50 32 46 1.3 100.0% / 8.7 100.5% / 1.8
7.4 7.2 3.2 2.0
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All batches processed at the commercial scale had passing content uniformity results with
acceptance values for both ertugliflozin and sitagliptin ranging from 1.8-9.5 regardless of

incoming process or ertugliflozin/sitagliptin particle size variations (27-52 µm for
ertugliflozin and 46-55 µm for sitagliptin). The variations in blending or lubrication
endpoints during upstream processing did not impact the content uniformity results with all
conditions resulting in passing acceptance values.
The content uniformity data were also analyzed in order to determine if there were any trends
between the incoming ertugliflozin/sitagliptin properties or processing conditions on the
content uniformity data. As shown in Table 17, there are no obvious trends between the
incoming ertugliflozin/sitagliptin particle sizes, blend uniformity results, or weight
uniformity results, and the content uniformity response of the commercial scale batches.
Content uniformity is a function of all these inputs and for the Ertugliflozin/Sitagliptin
Tablets process, one input is not dominating the response over the others.
In analyzing the location-based data, Location 1 results for most batches were slightly lower
than the steady state values for both ertugliflozin and sitagliptin. The low results were more
pronounced for ertugliflozin than sitagliptin with Location 1 values generally ranging from
96-99% for sitagliptin. Extended content uniformity samples were taken between Locations
1 and 2 to assess the processing point at which steady state values were achieved for the
process. Figure 13 shows the weight-adjusted content uniformity data by location for
ertugliflozin and sitagliptin, respectively. Location 1 for all batches consisted of the first
tablets off the press immediately following setup with setup waste ranging between 0.6 and
2.6 kg which is very low for a double-sided press; therefore, the Location 1 data generated
for the development batches represented a worst-case scenario.
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Figure 13 Content Uniformity Results by Location Adjusted for Tablet Weight for Ertugliflozin (Left) and Sitagliptin
(Right) for Ertugliflozin/Sitagliptin Commercial Scale Batches
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The Location 1 values for ertugliflozin were noted to be dependent on the setup of the
compression module. A polyethylene (PE) liner transfers the blend from the blender tote to
the press. Representative setups for the liner include (1) use of a new liner for the first batch
of a campaign or dose strength or (2) use of the same liner for batches run sequentially of the
same dose strength. All batches processed with a new liner had Location 1 assay values
between 92% and 97%; batches processed with a used liner and the same dose strength had
Location 1 values between 98% and 100%. Therefore, overall, batches processed with
representative compression module setups had Location 1 assay values between 92% and
100% for ertugliflozin.
Analysis of the extended samples between Locations 1 and 2 indicate that steady state is
achieved quickly for the process. Figure 14 shows the early location data for ertugliflozin in
terms of kilograms of material processed rather than location number.
Figure 14 Ertugliflozin Content Uniformity Results by Kilograms of Material

Processed (1-20 kg) Adjusted for Tablet Weight for
Ertugliflozin/Sitagliptin Commercial Scale Batches
Figure 14 shows that the ertugliflozin assay values reach steady state within 1-2 kg of
material of Location 1 which is a low percentage of the batch. Based on the setup
dependence of Location 1 values and the fact that no assay trend is present at the end of the
compression batch, the front end trend was concluded to be due to selective material
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adherence rather than segregation of the blend. For all batches processed at the commercial
scale, the Location 1 results had no negative impact on the ability to pass content uniformity

criteria. As noted, all batches had acceptance values between 1.8 and 9.5 for sitagliptin and
ertugliflozin which is within the specification of less than 15. Location 1 results were also
noted to have minimal impact on the assay results.
1.4.6.2 Compression Commercial Scale Development – Assay Results
Due to the nature of the development campaign, compression batches were split or combined
in order to complete the film coating study design which included multiple batches sizes and
incoming tablet tensile strengths. Assay samples for the commercial scale batches were
taken from the final processing step, film coating, for most of the batches. The tablet cores
from 6INTE20000, 6INTE21000, and 6INTE22000 were not taken forward into film coating
and so a composite sample was taken from the compression step for assay testing. An n=2
assay result was generated for all batches along with an n=10 result for select batches in
order to gauge the impact of variability on the assay result. Table 18 summarizes the assay
results for the commercial scale tablets. For reference, the blend uniformity results for the
last sampling point prior to compression and the content uniformity results are also included
as inputs to assay.
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Table 18 Assay Results for Ertugliflozin/Sitagliptin Commercial Scale Batches

Content Uniformity Content Uniformity
Blending/ Blend Uniformity Assay - Ertugliflozin Blend Uniformity Assay - Sitagliptin –
Film Coating Strength Avg/RSD/AV - Avg/RSD/AV -
Compression Avg/RSD - - n=2; Avg/RSD – n=2;
Batch ID (mg/mg) Ertugliflozin Sitagliptin
Batch ID Ertugliflozin (n=10 avg, sd)* Sitagliptin (n=10 avg, sd) *
(Side 1, Side 2) (Side 1, Side 2)
5INTE40000 97.4% / 1.6 / 4.1 99.8% 99.6% / 1.3 / 2.6 100.7%
5INTE33000 5/100 99.1% / 3.9 100.7% / 3.7
5INTE41000 98.0% / 1.3 / 3.1 98.4% 99.6% / 1.2 / 2.4 99.6%
5INTE40000 100.3% / 1.2 / 2.4 99.8% 100.0% / 1.0 / 2.1 100.7%
5INTE34000 5/100 99.5% / 1.2 98.9% / 0.9
5INTE41000 100.8% / 1.0 / 1.9 98.4% 99.8% / 1.0 / 2.0 99.6%
5INTE38000 99.4% / 1.9 / 3.7 99.4% 98.9% / 1.8 / 3.6 99.2%
5INTE35000 5/100 98.8% / 3.6 98.2% / 3.8
5INTE41000 100.6% / 1.1 / 2.3 98.4% 100.0% / 1.1 / 2.2 99.6%
5INTE90000 97.4% 98.9%
5INTE25000 100.0% / 2.1 / 4.2 99.3% 101.9% / 2.1 / 4.7 99.1%
5INTE18000 5/100 97.5% / 0.7 98.9% / 0.6
5INTE26000 97.0% / 4.1 / 9.5 99.7% 98.8% / 4.0 / 7.8 99.5%
5INTE31000 98.3% 100.4%
5INTE90000 97.4% 98.9%
5INTE25000 99.7% / 1.2 / 2.4 99.3% 99.5% / 1.2 / 2.3 99.1%
5INTE19000 5/100 99.3% / 0.6 98.7% / 0.5
5INTE26000 99.5% / 1.5 / 2.9 99.7% 99.8% / 1.4 / 2.8 99.5%
5INTE31000 98.3% 100.4%
97.5% / 2.9 / 6.8 99.9% / 1.9 / 3.8
5INTE30000 5INTE20000 15/100 98.3% / 0.6 97.4%; (97.5%/0.5) 99.8% / 0.7 99.4%; (100.4%/0.8)
97.2% / 1.3 / 4.0 99.1% / 1.0 / 2.0
100.6% / 1.3 / 2.7 100.6% / 1.4 / 2.7
5INTE91000 5INTE21000 5/50 99.9% / 0.9 100.3% 100.0% / 0.8 100.1%
100.6% / 1.4 / 2.8 100.3% / 1.2 / 2.4
97.3% / 1.0 / 3.2 99.7% / 0.9 / 1.8
5INTE39000 5INTE36000 15/50 97.2% / 1.0 96.0%; (97.6%/1.1) 99.2% / 1.1 99.5%; (100.3%/0.8)
97.7% / 1.8 / 4.4 99.6% / 1.2 / 2.4
5INTE29000 97.8% / 3.4 / 7.4 97.1%; (97.0%/1.1) 99.8% / 1.6 / 3.2 98.7%; (98.9%/0.5)
5INTE22000 15/50 100.0% / 8.7 100.5% / 1.8
5INTE92000 97.6% / 3.2 / 7.2 96.0%; (97.0%/0.9) 99.0% / 1.0 / 2.0 99.0%; (99.2%/0.8)
N/A 6INTE21000 15/50 99.8% / 0.4 N/A 100.4%; (100.1%/0.4) 99.5% / 0.4 N/A 99.7%; (99.8%/0.5)
N/A 6INTE20000 15/50 98.8% / 0.4 N/A 100.1% (99.5%/0.5) 99.0% / 0.4 N/A 100.1%; (99.6%/0.8)
N/A 6INTE22000 15/50 99.9% / 0.4 N/A 99.0%; (99.6%/0.5) 99.4% / 0.4 N/A 98.6%; (99.3%/0.7)
*
n=10 assay data included in parentheses for select batches along with the standard deviation.
.
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The assay results for both ertugliflozin and sitagliptin are within 95 to 105% with
ertugliflozin results ranging from 96.0 to 100.3% and sitagliptin results ranging from 98.7 to
100.7%. In analyzing the assay trends across the processing train, the sitagliptin results are
all very consistent and are between 99 and 101% throughout blending and compression.
Ertugliflozin, however, does appear to have some lower assay values for some batches,
5INTE18000, 5INTE20000, 5INTE36000, and 5INTE22000 in particular. Based on the
assay data presented in Table 18, it appears that ertugliflozin contact with polyethylene (PE)
is playing a role in the ertugliflozin assay losses; in particular, the lower assay values were
specifically notes for those batches processed with a new liner in the compression module.
The last three batches presented in Table 18 (the 6INTE series) were used to further study the
impact of site procedures and setup on ertugliflozin assay trends during processing. The
number of contact points with PE was minimized and a new set of PE liners were used for
the compression module with an anti-static coating on the liner. A new PE liner was also
used for each batch in order to study the worst-case scenario of a new, clean liner. As shown
in Table 18, all assay values for the 6INTE series batches range from 99.0 to 100.4% for
ertugliflozin and 98.6 to 100.1% for sitagliptin indicating no significant losses of either
ertugliflozin or sitagliptin. Therefore, it was concluded that although ertugliflozin has
demonstrated a preferential adherence to PE, adherence can be mitigated with material
handling and module setup.
1.4.6.3 Compression Commercial Scale Development – Impact of Ertugliflozin and

Sitagliptin Particle Size and Process Conditions on Compression
Performance
In addition to studying assay and content uniformity at the commercial scale, compression
performance was also studied as a function of ertugliflozin/sitagliptin particle size variations
as well as processing conditions. The commercial scale blending/lubrication study outlined
in Section 1.2.5 was carried forward to compression. Tabletability profiles (tablet tensile
strength as a function of compaction pressure) were generated and analyzed as a function of
ertugliflozin and sitagliptin particle size, blend lubrication conditions (48, 96, 192
revolutions), and press conditions.
Ertugliflozin/Sitaglitpin Particle Size:
As part of commercial scale development, ertugliflozin and sitagliptin particle sizes were
varied in order to study the impact on blend and content uniformity (covered in 1.2.5 and 0)
as well as compression performance.
Ertugliflozin particle sizes between 27 and 52 µm were used for the majority of the
commercial scale development batches as shown in Table 16 and Table 17. A structured
multivariate study was used for the 5/100 mg strength with two batches each being produced
at the extremes of the ertugliflozin particle size range (2 batches at 27 µm and 2 batches at 52
µm) and one batch produced at the ertugliflozin mid-point of 39 µm. The intermediate
ertugliflozin drug loading strengths (15/100 mg and 5/50 mg) used ertugliflozin particle sizes
around the mid-point (32-39 µm). The 15/50 mg strength has 2 batches used to analyze
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compression performance, both at a low ertugliflozin particle size (27 and 32 µm).
Sitagliptin particle sizes ranging from 46 to 55 µm were also used for commercial scale

development.
Figure 15 shows the tabletability profiles (tensile strength versus compaction pressure) for
the dose strengths arranged to show the impact of ertugliflozin and sitagliptin particle size
variations on the tabletability response. For comparison purposes, similar press conditions
were used to compare the profiles shown in the figure.
Figure 15 Tabletability Profiles as a Function of Ertugliflozin and Sitagliptin

Particle Size for Ertugliflozin/Sitagliptin Tablets
As shown, the tabletability profiles for all strengths and ertugliflozin/sitagliptin particle sizes
are similar with no significant trends observed. As such, the compression performance for
Ertugliflozin/Sitagliptin Tablets has been shown to have little sensitivity to incoming
ertugliflozin and sitagliptin particle size.
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Blend Lubrication Conditions:

The commercial scale blending/lubrication study design was carried forward into
compression and so the impact of those processing conditions on compression performance
was able to be evaluated. The blend lubrication step was varied for the commercial scale
batches with endpoints of 48, 96, and 192 revolutions being used.
Figure 13 in section 1.3.6 shows the tabletability profiles for the various formulations
arranged to show the impact of lubrication endpoint on the compaction pressure/tensile
strength relationship. Figure 13 shows that the lubrication endpoint has little to no impact on
the tabletability profile achieved across all the ertugliflozin/sitagliptin formulations.
Press Conditions:
Tabletability was studied as a function of press conditions in order to gauge if the

ertugliflozin/sitagliptin formulation is prone to lubrication sensitivity in the press feed frame
or if there is any strain rate sensitivity of the formulation across a range of production speeds.
The tabletability profiles at a variety of press conditions is shown in Figure 16 for all dose
strengths. In the legend of the figure, the first number refers to the turret speed used on the
press in RPM and the second number refers to the feeder speed used in RPM.
Figure 16 Tabletability Profiles as a Function of Press Conditions for

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As shown, the tabletability profiles for all strengths and press conditions are similar with no
significant trends across various press speeds or feeder speeds. As such, the compression

performance for Ertugliflozin/Sitagliptin Tablets has little strain rate or lubrication sensitivity
at the commercial scale and can be processed using a wide range of conditions.
1.4.7 Compression – Establishment of Hardness In-Process Controls Based on

Tablet Friability/ Erosion and Disintegration/Dissolution Responses
The compression in-process controls for Ertugliflozin/Sitagliptin Tablets were established

based on tablet friability/erosion data for the lower hardness control and dissolution as well
as disintegration data was used to justify the lack of an upper hardness control.
1.4.7.1 Compression – Establishment of the Lower Hardness In-Process Control

Based on Tablet Friability/Erosion Response
Development studies were conducted at the pilot scale to set a lower limit for tensile strength
and the corresponding image hardnesses. The pilot scale work included extended friability as
a function of tablet tensile strength as well as film coating tumbling trials designed to study
the tablet erosion response as a function of tensile strength. Setting a lower limit for tensile
strength based on friability and erosion was desired in order to mitigate elegance risks during
the film coating step. This proposed limit was then taken forward and confirmed with
commercial scale film coating runs to demonstrate that the lower hardness limit resulted in
passing elegance after film coating.
Tablet cores of all dose strengths and ertugliflozin/sitagliptin images were produced at
various tensile strengths and extended friability testing was conducted. A good correlation
between the tablet friability at 100, 200, and 500 revolutions/drops and the tablet core tensile
strength was established. Figure 17 shows the relationship between friability and tensile
strength for all sitagliptin/ertugliflozin images.
The friability data show that as the number of revolutions is increased, the % friability of the
tablets increases, with the most significant increase being noted for the lower tensile strength
tablet cores. The results also show that the relationship between tablet friability and tensile
strength is image independent, with all images resulting in overlaying curves. Therefore,
setting a lower tensile strength limit for all images is appropriate to ensure tablet robustness.
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Figure 17 Tablet Friability as a Function of Core Tablet Tensile Strength for Ertugliflozin/Sitagliptin Tablets
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In addition to friability testing, a tumbling study was conducted which involved using both
the 300 mg and 400 mg image sizes to study the erosion response of the tablet cores. The

tablet cores were tumbled in a 35 L film coating pan for a total of 35 minutes at a speed of 14
rpm (linear speed of 50 cm/s) which is equivalent to 490 rotations inside the coating pan. At
the commercial scale, 490 rotations inside the film coating pan is equivalent to 62 to 98
minutes of coating time at pan speeds of 5-8 rpm which is approximately 20 to 100% of the
film coating process duration depending on the conditions (spray times of 86 to 280 minutes
reported in Table 26). During the tumbling trials, no suspension was applied and therefore
the test represented a worst-case condition in the coater for tablet erosion. Samples were
taken at 0, 15, 25, and 35 minutes and an average weight of the tablets was recorded along
with observations of any defects observed.
A tensile strength range of 0.35-2.04 MPa was studied for the 400 mg image (0.35, 1.05,
1.40, and 2.04 MPa) and the 300 mg tablets used for the study were at a tensile strength of
1.50 MPa. It was noted that tablets with a tensile strength of 0.35 MPa started to show edge
chipping defects by the first sampling point (15 minutes) and had significant weight loss
throughout the tumbling trial. The remainder of the tablets, however, had minimum weight
loss throughout the entire tumbling trial (less than 0.75%) and also had minimal defects
observed. The results indicate that tablet tensile strengths of 1.05 MPa and above are robust
to tumbling in the film coating pan through 35 minutes of tumbling.
The fact that 400 mg tablet cores from the same batch were used for both the extended
friability testing and the tumbling trial allowed the % weight loss between the two
mechanisms of testing to be compared. The comparison between the extended friability data
and the tumbling trial data are shown in Figure 18. At 200 revolutions/drops, the results
from the tumbling trial were very much in line with the extended friability data for the 200
revolution point for % weight loss. At ~500 revolutions/drops, the tumbling trial resulted in
slightly higher amounts of weight loss, indicating that is a slightly more aggressive test at the
later time points. Overall, the two tests lined up very well though and both were used to help
set the minimum hardness limit for each image.
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Figure 18 Tumbling Trial and Standard Friability Results for % Weight Loss as a
Function of Tablet Tensile Strength for Ertugliflozin/Sitagliptin Tablets
To conservatively cover tablet robustness of Ertugliflozin/Sitagliptin Tablets, a weight loss

target of less than 1% through 500 friability drops was used. As a result, the minimum tablet
tensile strength was estimated to be ~1.25 MPa to ensure adequate robustness during film
coating. The proposed minimum tensile strength of 1.25 MPa is shown on Figure 18 which
is approximately the inflection point for the tensile strength/weight loss correlation.
Therefore, tablets made at 1.25 MPa and above all have similar tablet robustness as measured
by extended friability as well as tumbling. As such, the minimum tensile strength value of
1.25 MPa was selected for the sitagliptin/ertugliflozin tablets.
The minimum tablet tensile strength was further confirmed through commercial scale film
coating runs at the lower tablet tensile strength values (1.5.6). Commercial scale
development work involved compressing tablets at various target hardness/tensile strength
values and taking those tablet cores through film coating. A range of tablet core tensile
strength values from 1.07 – 2.18 MPa were film coated at the commercial scale and gave
passing elegance results. Therefore, the lower tensile strength limit of 1.25 MPa was
confirmed to ensure tablet core robustness during film coating.
As a result of the minimum tensile strength value being established, the in-process control for
tablet hardness could then be calculated for each image. Figure 19 shows the correlation
between tensile strength and hardness for the 300 mg and 400 mg images which takes into
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account the tablet dimensions (length and thickness). The data shown in Figure 19
incorporates all the commercial scale hardness and tensile strength data at a number of press

conditions. Table 19 then shows the lower hardness limit for each image as calculated from
the correlations shown in Figure 19
Figure 19 Tablet Tensile Strength versus Tablet Hardness for the 300 mg and 400
mg Ertugliflozin/Sitagliptin Images
Table 19 Lower Tablet Tensile Strength/Hardness Limits for

Ertugliflozin/Sitagliptin Tablets as Established by Tablet
Friability/Erosion
Strength (mg/mg) Lower Tensile Strength Limit (Mpa) Lower Hardness Limit (kP)
5/100 1.25 10.7
15/100 1.25 10.7
5/50 1.25 9.0
15/50 1.25 9.0
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1.4.7.2 Compression – Justification for No Upper Hardness Limit Based on Tablet

Disintegration/Dissolution Response

An upper hardness limit was also considered for Ertugliflozin/Sitagliptin Tablets to ensure
adequate dissolution performance of the final dosage form. Sitagliptin-based formulations
are known to have very fast disintegration times and dissolution profiles but that trend with
the Ertugliflozin/Sitagliptin Tablets was desired to be confirmed. The tablets produced for
the tabletability profiles at the commercial scale were tested for disintegration and dissolution
profiles were also generated for selected samples. Disintegration and dissolution data was
generated across a wide range of press conditions (turret speeds of 15 - 60 rpm and feeder
speeds of 20 - 100 rpm). A wide range of compression forces and resulting tablet hardnesses
and tensile strengths were studied which spanned the entire hardness-compression profile or
tabletability profile within the tooling force limits for each image. Therefore, the tablets
produced for disintegration and dissolution testing represented the highest hardness/tensile
strength values that would be expected for Ertugliflozin/Sitagliptin Tablets.
A dissolution profile for both sitagliptin and ertugliflozin was generated with time points of
5, 10, 15, 20, 30, and 60 minutes. Sitagliptin release averaged 100% for all the samples
tested at the 5 minute time point. Ertugliflozin release in general trended slower than
sitagliptin, with greater than 80% released by 5 minutes across all the samples tested. Due
to the fact that the dissolution profiles for both ertugliflozin and sitagliptin were so fast, the
test did not pick up the differences in compression; for example, tablets produced at various
hardness values or tensile strength values all had similar profiles with no clear trend between
the tablet properties and the dissolution response.
The disintegration times for Ertugliflozin/Sitagliptin Tablets were measured to range between
0.1 and 1.33 minutes across the entire hardness/tensile strength range for both images. A
good correlation between the tablet hardness for each image and disintegration was
established as shown in Figure 20. Figure 20 also shows that by using the image-
independent attribute of tablet tensile strength, the disintegration response can be normalized
for both images across the full range of processing conditions.
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Figure 20 Disintegration Time as a Function of Tablet Hardness (Left) and Tablet Tensile Strength (Right) for
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The conclusion drawn from the disintegration and dissolution data generated was that an
upper hardness limit is not necessary for Ertugliflozin/Sitagliptin Tablets. The disintegration
and dissolution data were reported across the entire range of tablet hardness values feasible
for Ertugliflozin/Sitagliptin Tablets. Although a correlation was found between
disintegration time and tablet hardness, the longest disintegration time reported was 1.33
minutes which was generated at the highest tablet hardness feasible within the tooling force
limitations. Additionally, all tablets tested for dissolution had greater than 85% released at
15 minutes. As such, no upper hardness limit is proposed for Ertugliflozin/Sitagliptin
Tablets and the in-process specification will be represented as greater than or equal to the
lower hardness limit established through friability and erosion testing in section 1.4.7.1.
1.4.8 Compression Conclusion and Control Strategy
Pilot scale and commercial scale data on Ertugliflozin/Sitagliptin Tablets have demonstrated
robustness of the compression process in terms of meeting content uniformity and assay
criteria regardless of upstream processing conditions, ertugliflozin and sitagliptin particle
size variations, and dose strength. Hardness specifications were set for
Ertugliflozin/Sitagliptin Tablets based on pilot scale friability and erosion data and taken
forward to film coating runs at the commercial scale to demonstrate that the proposed lower
limit is appropriate and ensures adequate tablet elegance. A one-sided hardness specification
is proposed based on the fast disintegration time of the core tablet as well as the
demonstrated understanding of the relationship between tablet hardness and disintegration.
Over-lubrication from either the blend lubrication step or the press feed frame was shown to
have minimal impact on the ertugliflozin/sitagliptin tabletability.
In-process controls have been established to meet all the critical quality attributes associated
with the drug product without identifying any critical process parameters (CPPs). The
control strategy for compression includes in-process controls for both average tablet weight
and average tablet hardness. Table 20 summarizes the control strategy for the compression
step.
Table 20 Compression Control Strategy for Ertugliflozin/Sitagliptin Tablets

Operation Parameter / In-Process Control Range Critical Process
Unit Operation
In-Process Control Parameter?
Average Tablet Weight (mg) 95 – 105% target N/A
Compression 5/100 mg: ≥ 10.7 kP

15/100 mg: ≥ 10.7 kP
Average Tablet Hardness (kP) N/A
5/50 mg: ≥ 9.0 kP
15/50 mg: ≥ 9.0 kP
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1.5 Film Coating

1.5.1 Film Coating Summary
Following the compression step, each image is subsequently film coated with a color coating.
The purpose of the film coating step is to provide enhanced product differentiation based on
the color of the film coating for each image. For the pilot scale activities, a coater scale of
28” diameter pan has been used. Commercial scale studies have all taken place on a 48”
diameter film coating pan. Table 21 summarizes the development work at each scale.
Multivariate experiments were used to establish understanding between the process inputs
and outputs. The resulting control strategy uses a design space including ranges for bed
temperature, spray flux, and air:spray ratio to ensure acceptable elegance, appearance, and
water activity.
Table 21 Film Coating Process Development Summary for Ertugliflozin/Sitagliptin

Tablets
Equipment Pan Diameter Pan Volume Batch Size Pan Charge h/D
Scale
Brand/Model (in) (L) Range (kg) Range (kg) Range2
Pilot Bohle BFC-50 28 75 40.5-70 33-60 0.16-0.29
Manesty Accelacota
Commercial 48 170 100-150 88-140 0.19-0.26
150
Prior to film coating, a film coating suspension is prepared. The film coating agent used for
Ertugliflozin/Sitagliptin Tablets is an Opadry® film coat solids blend. The suspension
preparation has been found to be robust and produces suspension of uniform solids content
within standard mixing times, suspension vessel, and agitator location in the vessel. The
same film coating agent and suspension preparation process will be used for all tablet
strengths; each strength will be coated with a different color for differentiation purposes as
listed in Table 22.
The film coating process for Ertugliflozin/Sitagliptin Tablets applies the suspension to the
tablets until a coating end point of 0.05 mg/mm2 solids gain is achieved. The color of film
coat solids blend applied along with the percent solids applied is image dependent, with the
amount applied in milligrams per tablet being dependent on the theoretical surface area of the
tablet as noted in Table 22. Subsequent to film coating, a waxing step is performed to
uniformly distribute wax onto the tablets. The purpose of wax addition to the tablets is to aid
in processability of packaging operations.
2
h/D is the dimensionless parameter to characterize the fill level of a batch as discussed in Sec. 1.5.4.
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Table 22 Film Coat Color and Addition Amount per Ertugliflozin/Sitagliptin

Strength

Strength (mg/mg) Film Coat Color Film Coat Weight Gain (mg)
5/100 Beige 11.77
15/100 Brown 11.77
5/50 Pink 9.794
15/50 Purple 9.794
1.5.2 Film Coating Risk Assessment
The risk assessment identified the following risks specific to the film coating process:
6 A film coating multivariate study design was conducted at the commercial scale to
study the impact of processing inputs on tablet elegance as well as water activity. An
evaluation of elegance was conducted that characterized the level, number, and nature
of the defects which aided in defining the design space ranges for the unit operation.
Water activity was monitored as a function of film coating conditions throughout
process development at the pilot and commercial scales. Water activity was linked to
the impurities and degradation products CQA since the film coating process defines
the tablet water activity for the product shelf life (bulk and primary packages
designed to maintain water activity). The water activity response throughout the film
coating design space was assessed against the in-process control of 0.45 aw or below.
The primary risks for the film coating process are the resulting final film coated tablet
elegance and water activity. Elegance was monitored throughout development as a function
of tablet tensile strength as well as the film coating processing conditions. The friability of
the tablet cores as a function of tensile strength and its relationship to core elegance was
established through tumbling trials as described in section 1.4.7.1 and was confirmed through
commercial scale development work as described in section 1.5.6.
Water activity was also monitored throughout film coating process development. Due to
chemical stability being a function of water activity, the product characterization study
results were used to set an in-process control on the final tablet water activity. This in-
process control was set at aw ≤ 0.45 as measured by equilibrium headspace moisture based on
chemical stability data (refer to Sec. 3.2.P.2.2.2.2.3). Experiments were designed to explore
the response of tablet water activity at each scale of film coating as a function of the
processing conditions as well as processing time. Since the intention of the bulk package as
well as the primary package is to maintain water activity to the end of shelf life, the film
coating step defines the water activity of the product. The water activity data were assessed
against the in-process control of less than 0.45 aw at both the pilot and commercial scales.
At the pilot scale, elegance as well as water activity data were used to determine the optimal
operating conditions for the clinical/stability batches. At the commercial scale, elegance and
water activity data were both taken into account in order to establish the design space ranges
for the process.
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1.5.3 Film Coating Prior Knowledge

Due to the fact that film coating development occurred across various scales, prior
knowledge was used to design experiments in terms of scale independent process parameters.
The use of scale independent terms allowed conditions across scales to be compared and for
the pilot scale experience to be incorporated into the commercial scale study design.
1.5.4 Film Coating Development Approach
To address potential risks identified in the initial risk assessment, the development of the film
coating process focused on specifying the relevant process parameters necessary to produce
tablets with acceptable elegance and water activity while providing an understanding of how
process inputs might impact the drug product critical quality attributes. Film coated tablets
manufactured at the pilot and commercial scales were evaluated for elegance using
acceptable quality limits (AQL) for a number of defect classes: Critical, Major, Minor and
Observable. Each of these defect classes has a decreasing quality impact and a
correspondingly increasing AQL. The number of tablets evaluated and the AQL per defect
class is determined statistically based on total number of tablets per batch3.
Historically, the film coating process has been defined by the scale-dependent parameters
such as spray rate, inlet-air flow rate, and inlet or outlet temperatures. While this approach is
acceptable for a given film coating pan or processing scale, the level of understanding
achieved using scale-dependent parameters is only correlative and is not sufficient to predict
the process ranges when a change of scale or change in equipment design is undertaken.
Through use of a scale-independent basis for development, the result of process development
moves from a correlative understanding to a mechanistic understanding. This increased
understanding allows learnings to be applied across scales and streamlines the development
approach.
As a result, the approach taken for the Ertugliflozin/Sitagliptin Tablet film coating process
development was to define the design space ranges using relevant scale-independent process
parameters. The development studies established parameter ranges for spray flux, bed
temperature, and air-to-spray ratio (air:water spray ratio). The design space ranges for each
of these parameters were established based on the elegance and water activity responses at
the commercial scale. Within the established scale-independent parameter ranges, the film
coating process development results demonstrated that the parameters do not influence the
product’s critical quality attributes.
The scale-independent parameters characterizing the film coating process are defined as
follows:
3
Using ANSI/ASW z-1.4-2013 standard.
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 Spray Flux, g-water/min/cm2, is the mass of water sprayed per minute per the

measured surface area of the spray zone. The spray flux is calculated as the mass
flow rate of water in the suspension spray (g-water/minute) divided by the area of the
spray zone (cm2). The spray zone, as shown in Figure 21, is the area covered by the
spray at the surface of the tablet bed. The spray flux influences the local wetting
conditions of the tablets and the rate at which coating solids are applied.
 Bed Temperature, °C, is the surface temperature of the bed in the area outside of the
spray zone. In many instances, bed temperature can be directly measured during the
film coating process; however, most coating equipment does not provide for process
control directly to bed temperature. Coating on commercial scale equipment is
typically designed to control exhaust temperature of the coating pan. The exhaust
temperature set point is selected to achieve the target bed temperature during coating.
The correlation between exhaust temperature and bed temperature is established
during development for each unique coating pan.
 Air:Spray Ratio, (ft3/g), is calculated as the flow rate of inlet air divided by the total
spray rate of water. Drier conditions are expected at higher air:spray ratios.
 Drum Velocity, (cm/s), is the linear speed at which the drum rotates during the film
coating process.
 h/D, a fill parameter, is the ratio of the height of the tablet bed and the diameter of the
film coating pan.
Through control of these scale-independent parameters during the process within the ranges
determined during product development ensures acceptable tablet elegance and water activity
with no impact on other product CQAs.
Figure 21 Film Coating Process Diagram
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1.5.5 Film Coating Pilot Scale Development

All pilot scale development studies were conducted on a 28” perforated pan. The film coater
design at the pilot scale is different than that at the commercial scale (Manesty Accelacota
150) which impacts the air flow through the pan. In the Bohle coater (pilot scale), the
position of the inlet and exhaust air differs from the position of the inlet and exhaust air in
most common film coating pans. This design difference impacts the overall drying
efficiency and causes the Bohle pan to operate at a higher local wetness, particularly at
higher pan fills. This difference can be attributed to the tablet bed impeding the pathway of
air to the spray zone especially at higher fill levels. Due to the difference in pans, pilot scale
batches were not used to develop the final control strategy.
Initial pilot scale development batches probed the operating space in the pan at which
acceptable elegance could be achieved and subsequent batches focused on optimizing the
conditions which generally involved using drier conditions at the higher pan fills. Therefore,
the development conducted at the pilot scale mainly served to identify optimal conditions at
which to process the FSS/Reference batches. The pilot scale batches did however provide
useful information regarding the type of defects most common for the
Ertugliflozin/Sitagliptin Tablets and film coating system (film coat chipping at dry conditions
or film coat picking/sticking at wet conditions). The water activity data generated as a
function of conditions as well as process time also provided an initial guide as to the rate and
extent to which the Ertugliflozin/Sitagliptin Tablets increase in moisture throughout the
process.
Table 23 summarizes the actual film coating conditions of the development batches
conducted at the pilot scale as well as the elegance result and final tablet water activity
values. The pilot scale film coating development was designed in a multivariate format to
explore the effects of spray flux, bed temperature, and pan load on the responses of elegance
and water activity. While the exhaust temperature was used as the process control on the
film coating unit, the bed temperature was also measured for each run and recorded as a scale
independent input. The development batches explored the space from dry to wet conditions
at two target pan loads (40.5 kg and 70 kg) by operating at the extremes of the process as
well as at center point conditions as shown in Table 23.
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Table 23 Film Coating Conditions for Ertugliflozin/Sitagliptin Pilot Scale Batches
Final
Pan Tensile Bed Drum
Run Strength Batch Size Spray Flux Air:Spray Water
Batch ID Charge h/D Strength Temperature Velocity
# (mg/mg) (kg) (g/min/cm2) Ratio (ft3/g) Activity
(kg) (MPa) (°C) (cm/s)
(aw)
1 53796G05* 5/100 70 60 0.29 1.76 0.49 45 6.7 29 0.19
2 53796G01† 5/100 70 59 0.29 1.49 0.58 40 3.4 26 0.30
7 5434103C3‡† 5/100 70 60 0.26 1.72 0.38 42 4.8 33 0.21

*‡§
8 5434101C1 5/100 70 61 0.26 1.76 0.26 45 6.4 33 0.25
9 5434102C2*‡ 5/100 70 60 0.26 1.74 0.24 45 6.6 33 0.15
3 53796G06† 15/100 70 59 0.29 1.99 0.66 42 4.6 29 0.22
10 5434201C1*‡§ 15/100 70 51 0.26 1.74 0.26 46 6.5 33 0.24
4 53796G02* 5/50 40.5 35 0.19 1.56 0.45 42 5.0 26 0.16

*‡§
14 5385901C1 5/50 40.5 33 0.17 1.78 0.26 45 6.6 33 0.20
*
5 53796G03 15/50 40.5 33 0.19 1.74 0.52 45 5.9 33 0.15
*
6 53796G04 15/50 40.5 34 0.19 1.57 0.40 40 4.6 26 0.19
11 5434003C3*‡ 15/50 40.5 27 0.16 1.84 0.23 45 6.6 33 0.13
12 5434001C1*‡§ 15/50 40.5 32 0.17 1.73 0.24 45 6.5 33 0.30
13 5434002C2*‡ 15/50 40.5 34 0.17 1.70 0.25 45 6.5 33 0.14

*
Passed elegance evaluation.
†
Failed elegance evaluation for picking & sticking defects caused by local over-wetting conditions.
‡
§
Reference Batch
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Table 23 shows that the final tablet water activity at the pilot scale was below 0.45 for all the
conditions with results ranging from 0.13 to 0.30 aw. The majority of the batches also passed
elegance testing with a few exceptions.
The film coated tablets failed the elegance evaluation for three batches (Batches #2, #3 & #7)
as noted in Table 23. These batches were all run at the higher target pan fill of 70 kg which
caused a higher local wetness at the bed surface at a given spray flux due to the nature of the
pan design. The failed batches were also operated at a combination of higher spray flux,
lower bed temperature, and/or lower air to spray ratios. The type of elegance defects
observed at the wet conditions were picking and sticking of the film coat which was
attributed to local over-wetting.
Batches performed at the combination of lower spray flux, higher temperature, and/or higher
air to spray ratios passed elegance as shown in Table 24. In addition, batches processed at
the lower batch size of 40.5 kg passed elegance at all conditions studied. Conditions for the
clinical/stability batches were selected based on attempts to optimize elegance. There were
no core elegance defects (i.e. core chipping) observed due to variation of tablet tensile
strength within the range of 1.49 - 1.99 MPa.
Table 24 Pilot Scale Film Coating Factor Ranges Studied and Factor Ranges with
Passing Elegance for Ertugliflozin/Sitagliptin Tablets
40.5 kg Batch Size 70 kg Batch Size

Factor
Range Range with Range Range with
Studied Passing Elegance Studied Passing Elegance
Tensile Strength (MPa) 1.49-1.99*
Pan Charge (kg) 27-61
h/D 0.16-0.29
Spray Flux (g/min/cm2) 0.23-0.52 0.24-0.66 0.24-0.49†
Bed Temperature (°C) 40-45 40-46 45-46
Air:Spray Ratio (ft3/g) 4.6-6.6 3.4-6.7 6.4-6.7
Drum Velocity (cm/s) 26-33
Final Water Activity (aw) 0.13-0.30
*
No core elegance defects (i.e. core chipping) observed due to variation of tablet tensile strength.
†
Batch 5434103C3 (Run # 7) had failing elegance results at a spray flux of 0.39 g/min/cm2 which is within the range of
passing elegance results for spray flux; however, this batch was also run with a low air:spray ratio of 4.8 ft3/g.
Water activity was profiled throughout the film coating process and was found to vary with
bed temperature and air to spray ratio since they directly impact the overall moisture of the
pan. The water activity profiles as a function of spray time for the pilot scale film coating
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runs are shown in Figure 22. Bed temperature was found to trend nicely with the tablet water
activity as shown by the color-coding of the profiles in Figure 22. As shown, batches

conducted at wetter conditions resulted in the highest observed water activity. Even at these
conditions, the water activity was maintained at or below 0.37 aw at all processing times
sampled. Across all conditions and spray times, the final tablet water activity ranged
between 0.13 aw and 0.30 aw, well below the in-process control of 0.45 aw. Therefore, the
film coating process at the pilot scale was limited by elegance rather than water activity and
conditions were selected for the clinical batches to optimize elegance.
Figure 22 Water Activity Response as a Function of Time for the

Ertugliflozin/Sitagliptin Pilot Scale Batches
1.5.6 Film Coating Commercial Scale Development
Design space ranges for film coating process parameters were defined at the commercial
scale using all dose strengths (5/100 mg, 15/100 mg, 5/50 mg, 15/50 mg), corresponding
images (300 mg, 400 mg), and across the intended range of film coating batch sizes (100 -
150 kg). A multivariate study design, as illustrated in Table 25 and Figure 23 was performed
to gain a thorough understanding of the relationship between the scale-independent process
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parameters and the process responses of elegance and water activity. The study explored the
effects of factors, listed in Table 25, by executing 13 runs with multiple runs performed at the

worst-case conditions for each defect type as well as center point conditions. The results
from the multivariate study design were used to establish the design space ranges for the film
coating control strategy which ensures a robust commercial manufacturing process able to
reliably produce tablets meeting all acceptance criteria.
Table 25 Commercial Scale Film Coating Study Design Factors and Ranges for
Factors Studied Low Set Point High Set Point
2
Spray Flux (g/min/cm ) 0.40 0.80
3
Air:Spray Ratio (ft /g) 6.0 8.0
Bed Temperature (°C) 43 48
Drum Velocity (cm/s) 32 51
Batch Size (kg) 100 150
h/D 0.19 0.26
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Figure 23 Commercial Scale Film Coating Study Design for Ertugliflozin/Sitagliptin

Tablets

(Red Dotted Outline = 300 mg tablet; Black Solid Outline = 400 mg tablet; Blue Fill = 150 kg; Green Fill = 100 kg)
The film coating study was performed using all four film coat colors on all dose strengths on
a 48” perforated coating pan. The study included spray flux, bed temperature, drum velocity,
air:spray ratio and batch size as factors and elegance/appearance and water activity as
responses. Spray flux and air:spray ratio are inter-dependent factors in the study design as
shown in Figure 23. The lower tablet tensile strength identified through friability and
tumbling trials in Section 1.4.7.1 was also taken forward into the film coating design and
varied in order to confirm tablet robustness across a tensile strength range. The lower tensile
strength tablet cores were used for the theoretical worst-case conditions for tablet erosion
(low spray flux, high bed temperature, high pan speed). Elegance observations were noted in
terms of defect type in order to confirm the lack of response of tablet core tensile strength on
tablet erosion in particular. Table 26 summarizes the actual film coating conditions of the
development batches conducted at the commercial scale as well as the responses of elegance
and water activity.
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Table 26 Film Coating Conditions and Responses for Ertugliflozin/Sitagliptin Commercial Scale Batches
Tablet Core Final

Pan Bed Air:Spray Drum
Strength Batch * Tensile Spray Flux† Water
Run # Batch ID Charge h/D Temperature Ratio† Velocity
(mg/mg) Size (kg) Strength (g/min/cm2) Activity
(kg) (°C) (ft3/g) (cm/s)
(MPa) (aw)
3 5INTE25000‡ 5/100 150 120 0.24 1.07 0.80 (0.83) 48 6.0 (6.0) 51 0.22
4 5INTE26000‡ 5/100 100 95 0.20 1.74 0.80 (0.84) 48 6.0 (6.0) 32 0.23
‡
7 5INTE31000 5/100 100 88 0.19 2.16 0.80 (0.81) 43 6.0 (6.1) 51 0.30
‡
8 5INTE40000 5/100 100 93 0.19 2.05 0.80 (0.69) 43 6.0 (6.0) 32 0.32
‡
10 5INTE38000 5/100 150 140 0.26 1.79 0.60 (0.72) 45 7.0 (7.0) 41 0.26
‡
11 5INTE41000 5/100 100 90 0.21 2.00 0.60 (0.57) 45 7.0 (6.9) 41 0.26
‡
6 5INTE30000 15/100 150 123 0.24 1.69 0.40 (0.42) 43 8.0 (8.0) 51 0.22
‡
1 5TEST91000 5/50 150 137 0.26 1.30 0.40 (0.38) 48 8.0 (8.1) 32 0.16
§
2 5TEST92000 15/50 100 93 0.21 1.26 0.40 (0.43) 48 8.0 (8.1) 51 0.19
‡
5 5INTE29000 15/50 100 95 0.20 1.94 0.40 (0.41) 43 8.0 (8.1) 32 0.27
‡
9 5INTE39000 15/50 150 140 0.25 2.05 0.80 (0.73) 43 6.0 (6.0) 32 0.32
§
12 5INTE43000 0/50 100 93 0.21 1.23 0.40 (0.45) 48 8.0 (8.0) 51 0.19
‡
13 5INTE42000 0/50 100 94 0.21 1.43 0.40 (0.50) 48 8.0 (8.0) 51 0.19
*
Calculated based on measured dimensions of pan charge.
†
Set point values listed. Actual values, listed in parenthesis, vary from set points due to equipment variability.
‡
Passed elegance evaluation.
§
Failed elegance evaluation due to film coat edge chipping defects caused by dry conditions.
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Table 26 shows that the final tablet water activity at the commercial scale was below 0.45 aw
for all the conditions with results ranging from 0.16 to 0.32 aw. The majority of the batches
also passed elegance testing with a few exceptions.
The film coated tablets for the worst-case dry conditions of high drum velocity, high
temperature and low spray flux did not pass the elegance evaluation for two of the three
batches run at that condition. These conditions lead to defects resulting from film coat edge
chipping for batch #2 and batch #12. To mitigate these defects, setup adjustments were made
for the third batch processed at these conditions (batch #13). Specifically, batch #13 was run
at a lower atomization pressure to theoretically increase suspension droplet size in order to
improve upon the film coat chipping observed. The tablets from this run passed the elegance
evaluation due to this adjustment.
The elegance results for the worst-case wet conditions (batches #8 and #9) of low drum
velocity, low temperature and high spray flux passed the elegance evaluation with minimal
defects due to film coat picking and sticking typically observed at wet conditions. Therefore,
the multivariate study yielded acceptable elegance at all conditions for at least one batch.
The one exception was the worst-case dry condition but passing conditions were achieved
with modification to setup.
As part of the commercial scale batch work, the impact of tablet tensile strength on elegance
was conducted to assess any potential impact on elegance due to erosion, core chipping or
broken tablets. The input tablet core tensile strength was varied between 1.07 MPa and 2.16
MPa. Multiple batches with low tensile strength cores were used for the dry conditions with
high drum velocity. This elegance evaluation showed that the tensile strength had no
meaningful effect on elegance within the studied ranges and confirmed that the tumbling
trials properly established the minimum hardness specification in section 1.4.7.
Similar to the pilot scale results, water activity was profiled throughout the film coating
process and was found to trend reasonably well with bed temperature. The water activity
profile of each film coating run is shown in Figure 24.
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Figure 24 Water Activity Response as a Function of Time for

Ertugliflozin/Sitagliptin Commercial Scale Batches

As expected, batches conducted at the wetter conditions and low bed temperatures (43 °C)
resulted in the highest observed water activity. Even at these conditions, the water activity
was maintained below 0.33 aw. It was also noted that there is minimal uptake of moisture as
spray time increases since the tablets are equilibrating early in the process. Across all
conditions and spray times, the final tablet water activity ranged between 0.16 and 0.32 aw.
Water activity was well below the in-process control of 0.45 aw at all processing conditions
studied.
A statistical analysis of water activity profile data was conducted to further understand the
implications of the input parameters on tablet moisture. The results from the runs in terms of
image and scale independent input factors, listed in Table 26, were analyzed with statistical
software. The statistical model evaluated the impact of tablet h/D, spray time, spray flux,
air:spray ratio, and bed temperature on the response of tablet water activity. The selected
model consists of h/D, spray flux, air:spray ratio, bed temperature as linear terms; spray time
as a quadratic term; and a two-way interaction term between spray time and air:spray ratio.
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Table 27 ANOVA Regression Analysis for the Water Activity Response for the
Ertugliflozin/Sitagliptin Commercial Scale Film Coating Process

Source Mean Square F-Value p-value (Prob > F)
Model 0.025 129.53 < 0.0001
A-h/d 3.08E-03 16.19 0.0001
B-Spray Time 1.94E-03 10.2 0.002
C-Spray Flux 7.32E-04 3.84 0.0534
D-Air:Spray Ratio 0.009274 48.7 < 0.0001
E-Bed Temperature 0.07 368.67 < 0.0001
BD 4.79E-03 25.15 < 0.0001
B2 1.13E-03 5.93 0.0171
R-Squared 0.92
Adj R-Squared 0.91
Pred R-Squared 0.90
The analysis of the scale independent input factors resulted in almost all being statistically
significant to some extent based on the model’s and parameters’ p-values shown in Table 27.
The goodness of fit and prediction are also listed in Table 27. Since the predicted R2 is 0.90,
the model can be used for predicting water activity within the design space. Based on the
perturbation plot shown in Figure 25 and the F-Values shown in Table 27, the factors with
the highest impact on the final moisture content were the bed temperature and air:spray ratio
term of the coating process. The interaction between air:spray ratio and spray time was also
found to have a high impact on the final moisture content. Lower impact factors included the
spray time, h/D, and spray flux of the process. The tablet SA/V (surface area to volume
ratio) and drum velocity had no impact on the moisture uptake of tablets and were therefore
removed from the model.
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Figure 25 Perturbation Responses of Ertugliflozin/Sitagliptin Tablet Water Activity

to Commercial Scale Film Coating Inputs

Design-Expert® Software
Factor Coding: Actual Perturbation
FCT Tablet Water Activity (aw)
0.35
Actual Factors
A: h/d = 0.22
B: Spray Time = 140
C: Spray Flux = 0.6
FCT Tablet Water Activity (aw)

D: Air:Spray Ratio = 7
E: Bed Temperature = 46 0.3 D
E B
C
A
0.25
B C A
E
0.2 D
0.15
-1.200 -0.600 0.000 0.600 1.200
Deviation from Reference Point (Coded Units)
The perturbation responses show the relative ranking of the factors in terms of their impact
on the response of water activity as well as the directionality of the impact. Bed temperature
and air:spray ratio were noted to have the largest impact on the water activity with increases
in both factors resulting in a decreased water activity. The coating time is directly related to
the spray flux as the end point of coating is prolonged by a slower spray rate at a given target
weight gain. As shown in Table 27, spray time has more of an impact on the water activity
than spray flux; therefore, as the spray time of the process is increased, the tablet water
activity also increases.
As a result, in terms of spray time, a worst-case process for achieving high water activity is
to execute a batch with low spray flux (0.4 g/min/cm2) for a 150 kg batch size and high pan
fill (h/D = 0.26) which would lead to a long spray time (269 min) to achieve the target weight
gain. The contour plot for water activity in Figure 26 shows the possible ranges for bed
temperature and air:spray ratio that can be used in combination with the worst-case process
in terms of spray time to deliver a a final tablet water activity of less than 0.45 aw. This
process would only result in water activity greater than 0.45 aw if the combination of
air:spray ratio (< 6 ft3/g) and bed temperature (<43 °C) is outside of the studied design space
as shown in Figure 27. Therefore, within the design space ranges established for the film
coating process (as shown in the highlighted area in Figure 27), water activity is expected to
be well controlled to less than 0.45 aw.
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Figure 26 Contour Plot Response of Ertugliflozin/Sitagliptin Tablet Moisture to

Air:Spray Ratio and Bed Temperature at the Commercial Scale

Design-Expert® Software
Factor Coding: Actual FCT Tablet Water Activity (aw)
FCT Tablet Water Activity (aw) 8
0.45
0.2
0.22
0
0.24
X1 = E: Bed Temperature
X2 = D: Air:Spray Ratio 0.26
7.5
D: Air:Spray Ratio (ft3/g)

Actual Factors
A: h/d = 0.26
B: Spray Time = 269 0.28
C: Spray Flux = 0.4
7 0.3
0.32
6.5 0.34
0.36
0.38
0.4
6
43 44 45 46 47 48
E: Bed Temperature (deg C)
Figure 27 Overlay Plot Response of Bed Temperature and Air:Spray Ratio

Resulting in Tablet Water Activity Below 0.45 for
Ertugliflozin/Sitagliptin Tablets at the Commercial Scale
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1.5.7 Film Coating Design Space Definition

The approach to control strategy definition for film coating step for Ertugliflozin/Sitagliptin
Tablets was to define one control strategy that would apply to all tablet strengths as well as
batch sizes. Due to the design differences highlighted between the pilot and commercial
scale equipment, the control strategy definition therefore solely used the commercial scale
film coating data.
The commercial scale film coating studies were designed with scale-independent parameters
and the process responses of elegance and water activity were evaluated as a function of
those inputs. The water activity response was shown to be primarily a function of the bed
temperature as well as the air:spray ratio of the film coating process. These parameters
dictate the overall thermodynamic conditions inside the film coating pan. In addition to these
parameters, the local conditions were found to have an impact on the elegance response, such
as the spray flux of the process. Therefore, the film coating design space will incorporate a
range for spray flux, bed temperature, and the air:spray ratio.
Across all conditions studied at the commercial scale, the final tablet water activity ranged
between 0.16 and 0.32 aw. Therefore, water activity was well below the in-process control of
0.45 aw at all processing conditions studied. Additionally, the multivariate study yielded
acceptable elegance at all conditions.
The film coating control strategy will therefore include a range of 0.4 to 0.8 g/min/cm2 for
the spray flux, 43 - 48 °C for the bed temperature, and 6.0 - 8.0 ft3/g for the air:spray ratio.
Due to the multivariate nature in which the film coating step was studied as well as the
demonstrated mechanistic understanding of the process, the control strategy is proposed as a
design space.
1.5.8 Film Coating Conclusion and Control Strategy
A wide range of film coating conditions has been explored at the commercial scale, all of
which have produced elegant tablets at a final water activity less than 0.45 aw. In order to
understand the impact of the coating conditions and the interaction between the inputs, the
design space was defined in terms of scale-independent terms such as spray flux, bed
temperature and air:spray ratio. In general, the in-process control of water activity can be
met within the entire range defined for each of the film coating process parameters.
The primary risks of tablet elegance and tablet water activity are effectively mitigated within
the established design space ranges. The process knowledge and controls that have been
developed ensure the robustness of the film coating process and that it will meet all the
critical quality attributes associated with the drug product without any identifying critical
process parameters (CPPs). Table 28 summarizes the film coating process control strategy.
The target weight gain for each image is described for each image in Sec. 3.2.P.1.
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Table 28 Film Coating Control Strategy for Ertugliflozin/Sitagliptin Tablets

Unit Operation Parameter / Design Space In-Process Control Critical Process
Operation In-Process Control Range Range Parameter?
Spray Flux (g/min/cm2) 0.4 – 0.8 N/A No
Bed Temperature (°C) 43 - 48 N/A No

Film Coating
Air:Spray Ratio (ft3/g) 6.0 – 8.0 N/A No
Water Activity N/A NMT 0.45 N/A
1.6 Batch Size Flexibility
The proposed commercial batch formulas and batch size ranges for Ertugliflozin/Sitagliptin
Tablets, 5/50 mg, 5/100 mg, 15/50 mg, and 15/100 mg dose strengths are provided in Section
3.2.P.3.2. The proposed batch sizes for the 5/50 mg and 15/50 mg strengths will vary
between a minimum batch size of 100 kg and a maximum batch size of 300 kg. The
proposed batch sizes for the 5/100 mg and 15/100 mg strengths will vary between a
minimum batch size of 100 kg and a maximum batch size of 633 kg. The batch size for the
formal stability study batches (40 kg for the 5/50 mg and 15/50 mg dose strengths; 70 kg for
the 5/100 mg and 15/100 mg dose strengths) was greater than 1/10th of the maximum batch
size proposed for each dose strength.
The fill level in the blending and lubrication steps is the sole parameter impacted by the
proposed batch size range across the process train. The continuous nature of compression
allows the unit operation and its CQA responses to remain flexible to batch size; similarly,
the ability to split batches into multiple film coating runs based on the pan size allows film
coating to also remain flexible to batch size. Based on the commercial scale blending
equipment, a batch size of 100 kg for all dose strengths corresponds to a blender % fill of
31% based on the average bulk density for a 600 L tote. Similarly, a batch size 633 kg
corresponds to a blender % fill of 69% using a 1700 L tote. The fill level range associated
with the proposed full batch size ranges in Sec. 3.2.P.3.2 was tested at the commercial scale
and the blending control strategy was developed to cover the entire fill range for all dose
strengths.
At the commercial scale, extensive blend uniformity data were generated across the fill level
range proposed in order to ensure the control strategy was robust across the entire proposed
batch size range. A total of 12 commercial scale batches were executed to support the
development of the Ertugliflozin/Sitagliptin Tablet blending process. The 12 commercial
scale batches ranged from 100 kg to 633 kg and covered all dose strengths. The blend
uniformity data used to develop the blending and lubrication control strategies are presented
in Table 9 and Table 12 for blending and lubrication, respectively. As shown in Table 9,
within the blending control strategy of 240-480 revolutions, all batch sizes and corresponding
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fill levels gave acceptable blend uniformity results with ertugliflozin RSD values ranging
from 0.9 to 3.3% and sitagliptin RSD values ranging from 0.8 to 2.3%. Additionally, as

shown in Table 17, all batches at the commercial scale had passing content uniformity
results, regardless of batch size or blending conditions.
Through analysis of the blend uniformity data across dose strengths and blender fill levels,
the combination of the highest ertugliflozin drug loading (15/50 mg dose strength) and a high
blender fill level was found to be the highest risk condition for blend uniformity. The
commercial scale development studies therefore focused on the 15/50 mg dose strength and
the highest blender fill level at both the 600 L and 1700 L scales to define the minimum
number of revolutions required for the blending step.
A scale-independent model was used to empirically fit the blend uniformity results obtained
at the commercial scale and aiding in defining the blending design space. The resulting
blending control strategy therefore supports the batch size flexibility since it was defined
using all commercial scale data across the full batch size range.
1.7 Environmental and Packaging Controls
As described, tablet water activity can impact the critical quality attribute of impurities and
degradation products. To ensure the tablet water activity is maintained after the film coating
step, environmental conditions in the key processing and packaging areas are controlled.
Additionally, Ertugliflozin/Sitagliptin Tablets are stored in HDPE drums with desiccant as a
bulk package.
1.8 Ertugliflozin/Sitagliptin Tablet Control Strategy Summary
The material and process control strategy for the manufacturing process of
Ertugliflozin/Sitagliptin Tablets is designed to ensure consistent production of the finished
drug product to meet established criteria for all critical quality attributes. The control
strategy is based on process understanding derived from the process development studies.
In-process controls have been established to ensure the finished drug product meets all
critical quality attributes. Table 29 shows a summary of the material control strategy as
established by the process development studies presented in this section and Table 30 shows
a summary of the process control strategy for each of the unit operations used for
manufacture of Ertugliflozin/Sitagliptin Tablets.
During manufacture, process parameters are maintained within established ranges determined
by the applicable design space ranges shown in Table 30. The manufacturing process has
been demonstrated to be robust and reproducible during production when process parameters
are controlled within these ranges.
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Table 29 Material Control Strategy Summary for Ertugliflozin/Sitagliptin Tablets

Established Through Process Development

Material Material Attribute Specification
Ertugliflozin Particle Size NMT 52 µm
Table 30 Process Control Strategy Summary for Ertugliflozin/Sitagliptin Tablets

In-Process Control
Unit Operation Process Parameter Design Space Range In-Process Control
Range
Fill Level 31– 69 %*
Blending N/A N/A
# of revolutions 240 - 480
Fill Level 31 – 69 %*
Lubrication N/A N/A
# of revolutions 48 - 192
Average Tablet Weight
95 – 105% of target
(mg)
5/100 mg: ≥ 10.7 kP
Compression N/A N/A
15/100 mg: ≥ 10.7 kP
Average Hardness (kP)
5/50 mg: ≥ 9.0 kP
15/50 mg: ≥ 9.0 kP
Spray Flux (g/min/cm2) 0.4 – 0.8
Film Coating Bed Temperature (°C) 43 – 48 Water Activity NMT 0.45

Air:Spray Ratio (ft3/g) 6.0 – 8.0
*
A final risk assessment was conducted for Ertugliflozin/Sitagliptin Tablets taking into
account the knowledge gained during process development as well as the implemented
control strategy. Upon evaluation, it was determined that there were no remaining confirmed
risks to the process based on the control strategy implementation for each unit operation.
The final risk assessment was presented in section 1.1.1 and is repeated in Table 31 for
completeness.
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Table 31 Final Risk Assessment for Ertugliflozin/Sitagliptin Tablets
Handling/Environm
ental Exposure
Film Coating
Compression
Ertugliflozin
Lubrication
CQA
Sitaglptin
Blending
Material
Assay ○ ○ ○ ○ ○ ○
Content Uniformity ○ ○ ○ ○
Impurities and Degradation Products ○ ○ ○ ○
Appearance/Elegance ○ ○ ○ ○ ○ ○
Dissolution/Disintegration ○ ○ ○
Legend
No impact to CQA
○ Confirmed impact to CQA.
● Confirmed impact to CQA.
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MK-8835A PAGE 1 ERTUGLIFLOZIN/SITAGLIPTIN TABLET

3.2.P.2.3 MANUFACTURING PROCESS DEVELOPMENT

1 MANUFACTURING PROCESS DEVELOPMENT ...................................................6

1.4.6.3 Compression Commercial Scale Development – Impact of

Table 9 Blending Conditions and Blend Uniformity Results for

1 MANUFACTURING PROCESS DEVELOPMENT

1.1 Overview of Process Development

The objective of manufacturing process development was to develop a process to produce

The development objectives were accomplished through experimentation to identify linkages

As described in Sec. 3.2.P.2.1, ertugliflozin is a cocrystal with L-PGA (L-pyroglutamic acid).

1.1.1 Drug Product Risk Assessment Review

Table 1 Initial Risk Assessment for Ertugliflozin/Sitagliptin Tablets

Table 2 Final Risk Assessment for Ertugliflozin/Sitagliptin Tablets

5. The potential for over-lubrication during processing (blending or compression) was

1.1.2 Process Parameter Criticality Assessment

1.1.3 Manufacturing Process Development History

As summarized in Sec. 3.2.P.2.2, formulation development was conducted up to a 12 kg

Table 3 Process Development Manufacturing History for Ertugliflozin/Sitagliptin

• Early Development Studies: The early development studies were conducted at a 12 kg

Table 6 Comparison of Formal Stability Study Process and the Proposed

1.2.1 Blending Summary

Within this unit operation, ertugliflozin L-PGA, sitagliptin phosphate monohydrate,

Table 7 Blending Process Development Summary for Ertugliflozin/Sitagliptin

1.2.2 Blending Risk Assessment

1.2.3 Blending Prior Knowledge

1.2.4 Blending Pilot Scale Development

required to achieve uniform distribution of ertugliflozin/sitagliptin drug substances was

Figure 2 Pilot Scale Blend Uniformity Sampling Locations for

(100 & 250 L)

1.2.5 Blending Commercial Scale Development

Figure 5 Commercial Scale Blend Uniformity Sampling Locations for

In terms of blend uniformity results, a total of 12 commercial scale batches were

Figure 7 Commercial Scale Blending Study Design for Ertugliflozin/Sitagliptin

(Numbers correspond to data point numbers in (Table 9)

1.2.6 Blending Design Space Definition

1.2.7 Blending Conclusions & Control Strategy

Table 10 Blending Control Strategy for Ertugliflozin/Sitagliptin Tablets

Fill Level 31 - 69%* No

1.3.1 Lubrication Summary

1.3.2 Lubrication Risk Assessment

1.3.3 Lubrication Prior Knowledge

1.3.4 Lubrication Pilot Scale Development Summary

Figure 10 indicates blend uniformity of ertugliflozin, sitagliptin, magnesium stearate, and

1.3.5 Lubrication Commercial Scale Development Summary

Additional 15/50 mg strength batches included a range of lubrication endpoints to

1.3.6 Impact of Lubrication Endpoint on Final Blend Tabletability

Figure 11 Tabletability Profiles as a Function of Lubrication Endpoint for

1.3.7 Lubrication Design Space Definition

1.3.8 Lubrication Conclusion and Control Strategy

Lubrication development focused on demonstrating blend uniformity, mitigating over-

Table 13 Lubrication Control Strategy for Ertugliflozin/Sitagliptin Tablets

Fill Level 31-69%* No

The ertugliflozin/sitagliptin lubricated blend is compressed into four images

1.4.2 Compression Risk Assessment

1.4.3 Compression Prior Knowledge

1.4.4 Compression - Image Independent Development Approach

Figure 12 Tabletability Profiles for Ertugliflozin/Sitagliptin 5/100 mg, 15/100

1.4.5 Compression Pilot Scale Development

Table 14 Summary of Pilot Scale Compression Batches for

In addition to in-process testing, content uniformity data were collected at 10 locations

Table 15 Content Uniformity Results for Ertugliflozin/Sitagliptin Pilot Scale Batches

1.4.6 Compression Commercial Scale Development

Table 16 Summary of Commercial Scale Compression Batches for