Accelerating Vaccine Development and Manufacturing

Priyabrata Pattnaik, PhD Director – Worldwide Vaccine Initiative

Objective

Vaccine process development and manufacturing tend to be diverged and highly customized.

In this presentation we will discuss: How the divergence in vaccine process can be streamlined

How simple available tools can help speed up process development

The benefits of following a vaccine template/ platform

Global Vaccine Pipeline is Strong

Source: Medicines in Development, Biologics, America’s Biopharmaceutical Research Companies, 2013 Report by PhRMA

There are several vaccine in early stage of clinical development

Vaccines is one of the Strong Growth Driver Vaccine revenue forecast for non US & EU markets (2007-2016)

Source: GBI Research. 4

3.5 b$ in 2007 >>>> 7.5b$ in 2013 Vaccine market is growing in emerging countries @ >10% CAGR

The Journey of a Vaccine to Clinic Often Follows a Long, Tortuous Path

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Challenge Reduce timelines with current or fewer resources

Accelerating the Journey of a Vaccine to Clinic

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Accelerating Vaccine Process Development

Demands on Process Development

Pipelines are growing ⇨ demand on PD resources

Speed to the clinic/market ⇨ faster/more efficient PD

Cost pressure on vaccines ⇨ PD for process economics

QbD, PAT initiatives ⇨ PD for process understanding

Value of Process Development (PD) Example: Therapeutic Antibody

Ineffective PD Effective PD Titer = 200 mg/L 1000 mg/L Yield = 50% 70% Capacity Required(CC) = 2,500 m3/yr 360 m3/yr COGS = 345$/g 91 $/g Capital = $280 MM $73 MM Process Development Payback: $2-4 million investment < 1 year payback!

Source: Parrish M. Gallahar, Achieving Competitive Advantage Through Process Development, bioLOGIC 2002

PD Activities Across Development Stages of Vaccine

Phase I Phase II Preclinical Phase III Manufacturing

● Establish basic process scheme ● Sequence of unit ops fixed ● Use of simple process templates

● Finalize process definition & purification schemes ● Process optimization & control ● Tech transfer to clinical manufacturing

● Process characterization ● Reuse testing & cleaning validation ● Pilot scale studies ● Tech transfer to launch site ● Process validation

● PD activities driven by manufacturing changes or regulatory ● Comparability studies

Company Specific Vaccine PD Strategy

Use un-optimized processes to generate clinical supplies (Fast-to-Efficacy) & Develop commercial process, methods, formulations during clinical development

– Pros: Speed – Cons: another PD phase is required

Use more rigorous methods & formulation for all clinical trials (Front-Load) – Pros: Single development phase – Cons: Slower to clinic

Use either method based on product risk profile (Hybrid) – Low risk → “Front Loading”

– High risk → “Fast-to-Efficacy”

Source: Geoffrey Slaff, Bioprocess International Meeting, Boston, 2005

Accelerating Process Development Some Approaches to ‘Efficient’ Process Development

Tailoring the scope of PD to the stage of development of the vaccine

Company specific strategy Size, knowledge-base and experience

Adopting a template based approach to characteristic vaccine molecules

Tapping into vendor expertise

Role of Vendors in Accelerating Vaccine PD… More than 900 vaccine projects executed by Merck Millipore since 1995

Know-how on process and regulatory trends

Advice on optimization

Minimize risk of scaling

Perform trials with skilled staff

Merck Millipore has >95 engineers & scientists WW providing such support 29 based in Asia / 9 based in China

Let’s review a generic vaccine template……

Most of the unit operations need buffer. Do you pay attention to buffer filtration ?

A Generic Buffer Filter Sizer an attempt to accelerate Process Development (PD)

A Generic Buffer Filter Sizer an attempt to accelerate Process Development (PD)

“Estimate sizing” for a buffer filtration operation based on simple inputs such as volume, time, pressure, etc. Output will be unit operation size & conditions (filter type/area, loading, flux, etc.)

Offers a high level overview of process sizing, configuration and, therefore, filter requirements for a given step

Carry out ‘paper-studies’ to estimate facility fit, analyze different production scenarios as well as system size for a given duty

Note: Use as a complementary tool Not a substitute for Process Development

Case Study: Buffer Filter Sizing

Source: Mok et al., Sterilizing-grade filter sizing based on permeability , Bioprocess International, 2012, 10(6): 58 - 63.

6000L of buffer would require 4 units of 10” filter device to filter at 10psi in 1hr time

Guidance on use of permeate controlled TFF for vaccine applications

Guidance on use of permeate controlled TFF for vaccine applications

Detailed approach to process development of TFF-MF using permeate control method that enables….

– Improved process performance

– Better process control

– Better product recovery

– Longer life of TFF device

Case Study: Permeate controlled TFF-MF

Source: Raghunath et al., Best Practices for Optimization and Scale-Up of Microfiltration TFF Processes, Bioprocessing Journal, 2012, 11(1): 30-40.

Process Templates to Expedite Vaccine Process Development and Manufacturing

Current approach to vaccine development is too diverged

What’s wrong with tailored approach ? Knowledge is not accumulative

Longer developmental time

Supply chain security adds risk

Template and Platform Approach for Vaccines

A template is a preset format, used as a starting point for a particular process, so that the format does not have to be recreated each time it is used.

A platform is an accumulation of know how and experience which can be incorporated in the template A common set of systems that can be used for more than one Vaccine molecule

Facility Platform A single facility has the capability to produce multiple Vaccines without modification

Unit Operation Platform A common series of unit operations (e.g. Centrifugation, Benzonase Treatment, Anion IEX, TFF)

Process Parameter Platform For each unit operation the same process parameters (flow rate, pH, conductivity, load) are used

Essential Points – Platform Processes

The platform includes processes from cell line/ strain selection to supply chain practices

The platform is implemented from process development through manufacturing

The platform provides benefits to Vaccine producers in terms of speed to clinic, risk mitigation and resource optimization

The platform provides a streamlined approach to CMC activities in product commercialization

Platform Options

Centrifuge Harvest

UF/DF Secondary Clarification

DNA Removal

Chrom Filtration

Centrifuge Harvest

Pellicon 2 Polysep II Benzonase Treatment

Fractogel TMAE

Durapore

Centrifuge Harvest

Pellicon 2 Polysep II Benzonase Treatment

28oC pH 7.6

4mM MgCl2 4 hrs

Fractogel TMAE

100 cm/hr pH 7.4 7.5mS 20cm

Durapore

A Generic Viral Vaccine Process Template

Value of template approach for vaccine Process Development

Additive effect of experience

Better understanding of product/process interaction

Enables quick process development (Lower development costs)

Harmonizes multi-centric PD activity

Value of template approach for vaccine Manufacturing Easy implementation in multi-product facility (Enables faster

plant changeover)

Lean inventory management (Raw material supply chain simplification)

Enable quick technology transfer

Better adaptation by CMO for clinical/commercial production

Lower capital costs

Speed to clinical trials and market

Facilitates modular validation approach

Minimizes process specific training

Summary

There are ways to increase productivity of PD and manufacturing by following simple measures

Adopting a template and platform approach for vaccine development has significant benefits

Accelerate vaccine process development by best utilizing vendor/ supplier’s product/ process knowledge and technical support capability