Process Development

Dr Karen O’Connor
11th March 2024
Introduction
to Zoetis
 Zoetis at a Glance
We provide:
70+ $8.1B 7 1,430 Medicines
Years Annual Major product Approximate
of experience revenue categories R&D colleagues Vaccines

Diagnostics

1 1 Genetic tests
64% 35% 13,800
8 Revenue from Revenue from Approximate
Biodevices
Core animal species companion animal livestock colleagues Precision
products products worldwide animal health

100+ 29 4,200
Approximate
Countries with market Manufacturing
field force
presence sites
members

Note: Facts and figures shown are as of Dec. 31, 2022

3 1Excludesrevenue associated with Client Supply Services and Human Health, which represented 1% of total 2022 revenue.
Our History and Heritage

Researchers at
Pfizer, the former
parent company of
Zoetis, discovered
Terramycin, marking Pfizer sold minority stake in
our entry into animal Launched Liquamycin Acquired SmithKline Established vaccine Zoetis. Zoetis became a
health LA 200 Beecham’s animal health Launched Draxxin,Convenia, manufacturing capabilities standalone company
division Cerenia, Palladia & Improvest in China
1950 1980 2013
1952 1990s 2000s 2012
Animal Agriculture Launched Dectomax, Acquired Pharmacia Acquired Embrex Inc., Catapult Genetics, Pfizer announced that its
division formed; Rimadyl, Clavamox and Corporation and CSL Bovigen LLC, Wyeth and Fort Dodge Animal Animal Health business w ill
renamed Pfizer Revolution Animal Health Health, Microtek International Inc., Synbiotics become a standalone
Animal Health Corporation, King Pharmaceuticals Inc. and company called Zoetis
in 1988 Alpharma

Established dedicated
R&D headquarters
in Kalamazoo, Mich.

4 Zoetis Corporate Overview

OUR PURPOSE

To nurture
our world and
humankind by
advancing care
for animals
CONTINUUM OF CARE

Innovating Across
the Continuum of Care
PREDICT
Genetics

Vaccines, robotics
and automation
PREVENT

Data analytics
and sensors

DETECT Diagnostics

TREAT Medicines

6 Zoetis Corporate Overview

Diverse, 7
Durable and therapeutic
8
core species
areas
Innovative
Portfolio
Diversity across 15 1
~30 2

geographies, species year average market life

blockbusters
and therapeutic areas of key brands in portfolio
drives steady
performance
~300 >2,000
product lines new products and lifecycle
innovations introduced
in last 10 years

1 Number of blockbuster products w ith revenues of $100M or more as of year-end 2022

7 Zoetis Corporate Overview 2 Market life refers to the number of years a product has been commercially available.
High-Quality Products, Delivered by Our
World-Class Manufacturing Operations
Excellence in quality
Tallaght, Tullamore
and Rathdrum, Ireland
Chicago Heights, IL
Overhalla, Norway
Breadth of expertise
Charles City, IA Klofta, Norway
Farum, Denmark
Eagle Grove, IA
LLN, Belgium
Kalamazoo, MI Weibern, Austria
Reliable supply Lincoln, NE Willow Island, WV Medolla, Italy
Union City, CA Salisbury, MD Catania, Italy
Buellton, CA Olot, Spain Suzhou, China
Durham, NC
San Diego, CA
Speed to market White Hall, IL Atlanta, GA

Cost/efficiency
improvements Campinas, Brazil
Rutherford, Australia
Melbourne, Australia
Carbon neutrality and
renewable energy by 2030 NOTE: Sites shown are as of May 10, 2023
Wellington, NZ

8 Zoetis Corporate Overview

Process
Development

9
Learning 01 Explain the concept of Quality by Design (QbD)

Objectives Explain the relationship between Quality Target Product

02 Profile, Critical Quality Attributes, material attributes and
process parameters

Describe the various phases of process development,

03 from Research to Process Control

04 Explain the objectives and activities of each phase

Quality by Design (QbD)
Quality by Design

ICH Q8 Pharmaceutical Development

ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System
Quality by Design
Quality by Design
Quality Target Critical
Product Quality
Profile Attributes
(QTPP) (CQA’s)

Decisions on
form ulation
and process

Product Link CMA’s

Lifecycle and CPP’s to
Management CQA’s

Establish
Establish
control
Design Space
strategy
Definitions
 Definitions
Critical Material Attribute (CMA): A material attribute 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 Parameter (CPP): 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.
 Quality by Design

Aspects
 Quality by Design
Conventional Approach
Variable Inputs Fixed Process Variable Quality

Materials

Equipment

Specification
XX
X
Environment

People
 Quality by Design
Enhanced Approach
Variable Inputs Variable Process within the Design Pre-defined Quality
Space

Materials

Equipment

Specification
X
X
X
Environment

Continuous real-time monitoring &

control of quality

People
Process Development
Process Development
Process Development is that stage of
development pharmaceutics that starts
after the product formulation has been
designed and optimised and ends when its
manufacturing process has been designed
and optimised sufficiently.

Granulation suite for full-scale manufacture of tablets

Development of a New Product
Product Development /
Formulation

Process Development

Process Scale-up

Production-scale manufacturing

Process Control
(Continuous Process Verification)
Process Development

Process Process
Research Design & Performance Process
Optimisation Qualification Control
Process Development Formulation
Development

Cross-functional team required Quality Procurement

Quality
Control Production
Laboratories
Process
Development
Department

Validation Engineering

Environment,
Planning Health &
Safety
Research

• Investigate Product Development to date.

• Research the current process and latest

technical and scientific developments in
this field.
Research
Product Research
• Product formulation
• Pharmaceutical and pharmacological information
• Raw materials – specifications, safety, stability, suppliers
• Finished product – specification, stability

Process Research
• Investigate the current process
• Examine existing equipment capabilities
• Review equipment qualification status
• Examine existing utilities
• Benchmark companies using similar technologies
Research
Should result in a good understanding of:

• The Quality Target Product Profile (QTPP)

• The Critical Quality Attributes (CQA’s) for the product

• Any available information on the Critical Process Parameters

(CPP’s) and Critical Material Attributes (CMA’s) and their
interdependence Report
• The specifications for the raw materials and finished product

• Material safety handling requirements

• Equipment requirements

• Extent of qualification work required

Process Development

Process Process
Performance Process
Research Design &
Qualification Control
Optimisation
Process Design & Optimisation
Processing End-points
Finished Product Specification (Release & Stability) - Example for tablet product (US market):
Attribute Release Specification

Appearance (Tablet colour, shape, embossing)

Identification Retention time of API peaks in the chromatograms correspond to those in the
reference standard chromatograms when run under the same conditions.
Water Content NMT 5%

Uniformity of Content USP <905>

Antioxidant Content 80 – 110%

API Assay 90.0 – 110.0% of Label Claim

Degradation Products Individuals (named) NMT 1.0%; Total NMT 3.0%

Dissolution USP <711>

Microbial Levels USP <61> / USP <62>

Process Design & Optimisation
• Process Flow Diagram
Select processing parameters
• Draft Master Batch Record

Risk Assessment

Trials – lab / pilot / full scale

Process Capability Analysis

NO
Is process consistent / reproducible?
YES
Process Development Report(s)
Process Design & Optimisation
Example: High-level Process Flow Diagram for a tablet product:

Screening & Wet Fluidized Bed Milling, Blending & Compression

Blending Granulation Drying Lubrication

Materials from
blending step

Material Lift

Materials for
spray solution
FBD Bowl
Spray
solution tank Wet Mill
High Shear
Granulator TO FLUID BED DRYER
Process Design & Optimisation
Examples:

CQA CPP’s

Content Uniformity Blending Step (final blend):

• Blender speed (RPM)
• Blending time

Process Step:
Transfer Granulate A (API granulate) to the V-cone blender over 10 minutes,
add Blend A (excipients added during final blend) over 5 mins and run the
blender at 150RPM for 30mins.

CPP’s for this step:

• 150RPM
• 30mins
Process Design & Optimisation
Select processing parameters

• Risk Assessment Report

Risk Assessment
• Draft CPP & CMA document

Trials – lab / pilot / full scale

Process Capability Analysis

NO
Is process consistent / reproducible?
YES
Process Development Report(s)
Process Design & Optimisation
Failure Mode & Effect Analysis (FMEA)

• A formalised technique that enables assessment of the manufacturing

process, to ensure that potential failures have been identified and
addressed.

• Results in a list of corrective actions to:

> eliminate the causes of failure
> reduce the probability of failure
> increase the likelihood of detection.
Process Design & Optimisation
Process Design & Optimisation
Failure Mode & Effect Analysis (FMEA)

Example:
Risk of low blending speed during the blending step (final
blend).

S = 4 (inadequate mixing and content uniformity issues)

P = 3 (blender controlled by PLC)
D = 1 (feedback from PLC; alarm in place)

Risk Priority Number (RPN) = 12 [LOW RISK]

Process Design & Optimisation
Select processing parameters

Risk Assessment

Trials – lab / pilot / full scale

Process Capability Analysis

NO
Is process consistent / reproducible?
YES
Process Development Report(s)
Process Design & Optimisation
Pilot-scale studies
Process Design & Optimisation
Execution of Trials:
• Include worst-case conditions Setting

• Establish:
✓ Normal Limits of Operation for process
parameters Normal Limits of
Operation
✓ Proven Acceptable Ranges (Design Space?)
• Consider use of multivariate analysis for
establishing Design Space Proven
Acceptable
Range
Process Performance Qualification
Example:
Transfer Granulate A (API granulate) to the V-cone blender over 10 minutes, add Blend
A (excipients added during final blend) over 5 mins and run the blender at 150RPM for
30mins.

Established limits for the blender speed CPP

PAR: 140 - 160 RPM
NLO: 148 - 152 RPM
Process Design & Optimisation
Select processing parameters

Risk Assessment

Trials – lab / pilot / full scale

Process Capability Analysis

NO
Is process consistent / reproducible?
YES
Process Development Report(s)
Process Design & Optimisation
Process Capability Analysis Assay
(Limit 96.0 – 102.0%)
Statistical measure of the degree to
which the process meets
requirements

Is the process in control?

Is the process centred?

Process Design & Optimisation
Select processing parameters

Risk Assessment

Trials – lab / pilot / full scale

Process Capability Analysis

NO
Is process consistent / reproducible?
YES
• Master Batch Record
Process Development Report(s)
• Draft Control Strategy
Process Development

Process Process
Research Design & Process
Performance
Optimisation Control
Qualification
Process Performance Qualification
Process Performance Qualification is the action of proving and documenting that a process
will result in a product meeting its predetermined specification and quality attributes.

Prepare Process Performance Qualification (PPQ) Protocol

Manufacture & test PPQ batches

Statistically analyse the data

Prepare Process Performance Qualification (PPQ) Report

Update:
Development Report
CPP & CMA Document
Master Batch Record
Control Strategy
Process Development

Process Process
Research Design & Process
Performance
Optimisation Qualification Control
Process Control
Relates to Commercial Manufacture

• Control Strategy implemented

• Continuous Process Verification: Ongoing assurance that the routine process remains in a state of
control.

• Product Life Cycle Management (LCM)

Commercial
Considerations
 Commercial Considerations
Meeting Patients’ and Payers’ Needs

• Striving to meet all patients’ needs can result in the development of new formulations
and new processes, e.g. different formats / delivery devices

• In the case of some markets, alternative pack formats are required, e.g. smaller unit
sizes for some markets in Asia, 10-packs for Japan

• Some markets have unique requirements, e.g. importance of ensuring absence of

aesthetic defects for Japan – additional acceptance criteria during process qualification

• Growing importance of pharmacoeconomics (comparing the value of one pharmaceutical

p.
drug or drug therapy to another) – requirement to meet Payers’ expectations for cost-
04 effectiveness
9
Learning 01 Explain the concept of Quality by Design (QbD)

Objectives Explain the relationship between Quality Target Product

02 Profile, Critical Quality Attributes, material attributes and
process parameters

Describe the various phases of process development,

03 from Research to Process Control

04 Explain the objectives and activities of each phase

Thank You