Best Practice in Biomanufacturing Round Table

AAPS National Biotechnology Conference June 2015 San Francisco

Jason Starkey, Satish Singh, Michael Adler, Karoline Bechtold-Peters, Katie Maass, Pankaj Paranjpe [Pfizer, Roche, MIT, Celgene]

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Best Practice in Biomanufacturing: People

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• Organizer/Moderator: Satish Singh, Pfizer

• Moderator/Presenter: Jason Starkey, Pfizer

• Presenter: Michael Adler, Roche

• Presenter: Karoline Bechtold-Peters, Roche

• Student moderator: Katie Maass, MIT

Best Practice in Biomanufacturing

Agenda

• Introduction (10 min)

• Topics (10 min each x 3)

• Process risk assessment and control strategies-Michael Adler

• PAT solutions-in line/at line and latest developments-Jason Starkey

• Single-use technologies in biologics DP mfg. processes- Karoline Bechtold-Peters

• Q&A (50 min)

Format

• Round Table

• Q&A:

• Please use microphone to ask Questions OR

• Submit Questions using index cards to Katie

• Participate, debate, present alternative point of view!

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BioPharma- New Paradigm

Capacity

Smaller Batch sizes

Smaller Budgets

Increased flexibility

Improved turn around

Multi-product facilities

Product Robustness

Process control

Fast, Flexible, Inexpensive

Adapted from Xcellerex Presentation , 2007. Parrish Galliher

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AAPS NBC Roundtable Discussion

Process Risk Assessment and Control

Strategy

Michael Adler

Process Risk Assessments during Product

Life Cycle

Taken from A-Mab Case Study

Approaches to Control Strategy

Traditional Approach:

Identify potential CQAs

Process development research often conducted one variable at a time

Define an appropriate manufacturing process

Define a control strategy to ensure process performance and product quality

Enhanced Approach:

Identify potential CQAs

Determining the functional relationships that link material attributes and process parameters to CQAs

Multivariate experiments to understand product and process

Use enhanced knowledge to establish a risk based control strategy which can include a proposal for a design space(s) or real-time release testing

Control Strategy not

systematically linked

to understanding of

CQA criticality or

process control

Control Strategy

systematically linked

to understanding of

CQA criticality and

process control

QbD Approach to Control Strategy Design

CQAIdentification

Using RA Tool

Assess Process

Impact/Stability

Impact

Design Attribute Testing

Strategy based on CQA

and Process Impact

Knowledge

Determine CQA

Acceptance

Criterion (CQA-AC)

Overall Control

Strategy

What attributes are

important? What levels?

Does the process control the

CQAs within those levels?

Are they stable?

What needs to be tested?

QbD provides a systematic approach to answer these questions

Critical Quality Attributes Process Control

Control Strategy

Do we have a robust process

& testing strategy?

Doing now what patients need next

Application of PAT in Biologics Manufacturing Jason Starkey Ph.D.

Pfizer, Inc

Focus: PAT in Manufacturing

Expected Outcome

State of the Art

Questions Next Steps

Focus of PAT How can process analytical technologies facilitate the manufacture and development of biological drug substance and drug products?

Move the analytics to the process

Expected Outcome: Where is the value of PAT

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Process

Understanding

Process

Control

State-of-the-Art Technologies • Evolving Technologies

– Optical Sensors and Visual Detection

– Spectroscopy

• Moisture quantitation

• Excipients quantitation

• TDLAS

– Chemometric Models

– On-line UPLC

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Next Steps: What are the most daunting challenges?

• Flexible and Adaptive Manufacturing Capabilities – Analytics and technologies to allow scale and site

transfers – Single use sensors

• Rapid Microbial Methods – Real time endotoxin and bioburden testing

• Real Time Release Capabilities

– Remote and real-time monitoring, at-line and on-line data

– Future capability to replace DS release testing

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Application of single use technologies in

biologics drug product manufacturing

processes

Karoline Bechtold-Peters1,

Christian Matz1, Satish Singh2

1 F. Hoffmann-La Roche

2 Pfizer

What SUTs can be used in DP manufacture?

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Isolators

Storage, mixing and holding bags (2D/2D)

Tubing, needles, surge tanks, assembled whole filling sets

Filters

Liquid Transfer Ports and other ports

Transfer bags

Powder bags

Aseptic connectors

Sampling bags

Covers

Pros and cons (here specifically for material in contact with product)

Advantages

• Less discussion on cross-contamination when dealing with high potent drugs manufacture

• Avoidance of cleaning validation or verification

• No discussion on dedication of equipment or not

• Increased sterility assurance (closed system)

• Reduced burden to qualify/calibrate/store/purchase and use of stainless-steel equipment,

– Saving of maintenance costs

– Saving of CIP/SIP-(re-)validation costs

– Energy savings of WFI and clean steam for CIP/SIP

– Reduction of capital bound as CAPEX

• Higher production flexibility e.g. because various sizes available

• Provision lead times may be no issue (if inventory well managed)

• No metal ion leaching (discolor., oxidation, aggr.)

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Disadvantages

• Discussion on leachables and when to generate/use product-specific data during development (phase-appropriate)

• Difficulty to align within global companies since plethora of disposible items on the market

• Absence of standardization

• Dependency on supplier and his quality systems (changes, consistency of manufacturing process, sterilization)

• Costs on long run ?

• Waste management (volume!)

• Interchangeability discussion

• «Compatibility» (interconnection) of various systems?

• Adsorption/permeation of active or of excipients

• Potential of damage during transportation and handling

Considerations when switching to SUT in DP manufacturing

• DP and DS may be handled here differently, since there is no further purification step after SUT exposure in DP manufacture

• Differentiation between SUT in direct product contact and non-contact material, long-term or short-term contact

• Critical features are e.g.:

– Leachables/extractables

– Endotoxins

– Particulates

– Compatibility with product

– Sterility

• A reasonable and risk-based approach during clinical development may depend on prior knowledge/experience, i.e. a generic rationale (non product –specific) may be adequate during clinical development based on supplier data, surrogate data (e.g. with WFI, WFI plus surfactant) and previous product data

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Doing now what patients need next