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Manufacturing ofCell-Based Products

Herbert S. Bresler, Ph.D.

Chief Scientist, Health & Life Sciences

BattelleColumbus, Ohio

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Manufacturing Scale-up Issues Companies developing cell-based

products all begin, by the nature of theiracademic origins, as research companies.They are inclined toward processdevelopment and exploration.

A consistent problem is that companiescling inappropriately to their old

manufacturing practices. Most companiessimply move their academically-derived,manual processes into clean rooms andperform the same manual operations.

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Manufacturing Scale-up Issues (2)

The flexibility of labor-intensive, manual

processing eventually becomes anobstacle to satisfying the necessaryregulatory requirements and businessneeds.

More so than for other products, cell-based product success is critically

dependent upon manufacturing success.

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Manufacturing Scale-up

Challenges Manufacturing must be improved over the

course of product development to allow for thesuccess of early clinical trials to be translatedinto commercial products.

New devices for manufacture of cell-based

products need to be developed that will controlthe process, allow for easier validation andprovide a basis for better documentation. Thesedevices will have to be customized for eachproduct because each manufacturing process isunique.

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Manufacturing Scale-up

Challenges (2) The industry needs to be equipped to make the

transition to well-engineered manufacturingtechnologies that maintain the biologic integrityof their products.

A rigorous but flexible method to approach

manufacturing improvement for products wouldbe a great help.

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Control of Variables The creation of custom tools for manufacturing

that can be verified and validated to perform

specific jobs within specified limits reduces theinfluence of technical skill and reduces errors.

Benefits to the manufacturer include:

Standardization of manufacturing processes Greater consistency and control over manufacturing

parameters for reproducible process results

Higher quality, greater reliability Less dependence upon operator technical skill

Reduced risk of product contamination

Simplified documentation of processes and batchrecords

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Challenges and Questions The industry needs to be equipped to make the transition

to well-engineered manufacturing technologies that

maintain the biologic integrity of their products. What tools might be provided to companies to help

them anticipate the necessary changes in theirmanufacturing, plan for these changes and make a

smooth transition to commercial-scale production? A rigorous but flexible method to approach

manufacturing improvement for products is lacking.

What are the critical elements of good

manufacturing, and those required for evolution ofgood manufacturing practices to scale-up theseunusual products?

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Challenges and Questions (2) Manufacturing preparedness and adequate product

characterization are the two most critical regulatory

hurdles for cell-based therapy companies. What in-process quality controls could serve as

indicators that companies could use to monitormanufacturing, and assess the transition from

legacy processes to scalable manufacturingtechniques? Are these the same, or modifiedversions, of the assays used for product release?

Acceptance criteria of source materials, especially those

derived from patients or donors, is another area ofconcern.

Can in-process quality controls be flexible enough toallow for a broad acceptance of starting materials

into the manufacturing process while maintaininghigh product quality?

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Challenges and Questions (3) Creation of economical, validated manufacturing

systems for cell-based products requires application of

systems and manufacturing engineering alongsidebiology and medicine.

What standards and best-practices are beingconsidered to help companies integrate the

engineering and biological sciences? One possibility is to apply the standards and practices

used for medical devices to cell-based productmanufacturing devices.

Would it help the manufacturing transition to viewcell-based product manufacturing equipment from aDevice perspective; using those tools to develop andvalidate new manufacturing devices?

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Integration of Diverse Technical

CapabilitiesTechnicalDisciplines

Cell Biology

Engineering

Microbiology

Biochemistry

Materials Science Statistics

Regulatory Affairs

Derived Capabilities

Process Systems Modeling

Device Design &

Optimization

BiocompatibleEngineered Processes

Process Enhancement

Intelligent Process Control

Enables Efficient Manufacturingof Cell-Based Products

Customized System Economical

Closed

Optimized

Controlled

Easily Documented

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Important Steps The steps involved in translating laboratory-basedprocesses to commercially viable manufacturing include:

Engineering process flow mapping and analysis of the existingprocess

Creation of a segmentation map, that supports translation of thetypical lab-based process into manufacturing engineering terms

Derivation of manufacturing system requirements (one of which isto close the system, and eliminate the need for biosafety hoods)

Ideation of alternate manufacturing processes

Manufacturing sub-system concept development

Establishment of new system and sub-system specifications Development of process requirements, specifications, traceability

and verification test plans

Development and testing of new device prototypes

Production, packaging and sterilization of new device disposables