biomanufacturing jim dekloe

Biotechnology 101Business and Regulatory Practices

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Biomanufacturing

Jim DeKloe


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Biotechnology is the intersection of

Science

Business

Government


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Drugs versus “biotech”

Traditional Pharmaceutical

“Big Pharma”

Drugs

Small molecules

Produced by Chemistry

Example: Aspirin

Biotechnology companies

“Biotech”

Proteins

Large Molecules

Produced by Living Organisms

Example: EPO


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History

Drugs

Small molecules

Produced by Chemistry

Simple Pure Molecules

Easy to Test Quality

Example: Aspirin

Biologics

Complicated Mixture of Large Molecules

Difficult to Test Purity

Emphasis on Consistent Process

Examples:

Vaccines, Plasma and Serum


Technician Training

Biotech clusters thrive when all elements of the industry are represented

Until recently, the emphasis on R & D meant that formal training targeting technicians was rare

Community Colleges have moved into this niche

Technician training will be even more important as more companies move from R & D into biomanufacturing


A Model Academic - Industry Collaboration

Building biomanufacturing curriculum

Tailoring curriculum to develop specific required skills

Incorporating regulatory requirements into curriculum


Genentech suppliedSabbatical Experience

Expertise

Donated Equipment

Presence on Advisory Committee

Guest Speakers


Traditional versus IndustrialTraditional Industrial

Education Training

Lab Atmosphere Pilot Plant Atmosphere

Set Times Shifts

Lab Protocols SOP

Lab Notebook Batch Records

Individual Team


Question Authority!Change Academic Paradigm

Borrow vocational tech and business ideas

Teach skills as well as educate

Emulate the industrial experience

Share the ideas that work


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Back to Basics - Cells


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Eukaryotic Cells can be Engineered Also


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Protein!

The Protein is the Product!


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Protein Structure

Proteins can be modified after they are synthesized

The addition of sugars – glycosylation – may be important – it affects solubility and pharmacokinetics (blood half live)

Glycosylation patterns may vary

Repeat because it is so important: If a protein loses this shape, it loses its function


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Protein!

The protein must not be unfolded (denatured) or it loses its function. Proteins can be denatured by:

•pH extremes

•temperature extremes

•organic chemicals

•agitation


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Protein!

DNA is the Flash

Protein is the Cash


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Protein!

DNA is the Show

Protein is the Dough


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Protein!

DNA is the Bling

Protein is the Thing


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Bacterial Cells – Prokaryotic Cells


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Cells are grown in a large scale


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Upstream

Cells Divide and are transferred to larger and larger volumes

Cells are induced to produce protein

Many in-process samples are taken; some are sent to QC for a variety of tests. For mammalian cells, they will check for contamination by viruses and mycoplasma


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Recovery - Downstream

Cells are separated from the medium surrounding them by filtration or centrifugation.

Typically:

In E. coli culture (slang is fermentation), the cells are retained and the medium is discarded

In cell culture (CHO cells), the cells have been engineered to secrete the protein, so the cells are discarded and the protein-containing medium is retained


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Protein Purification

The protein of interest must be separated from the other proteins in the cells or medium until it is 99.99% pure.

This is accomplished by ultrafiltration and chromatography


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Ultrafiltration

In ultrafiltration the protein containing solution is passed through a filter with pores of a defined size. This can separate proteins of different sizes from one another, or can separate protein from medium components.


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Chromatography

Chromatography methods use resins of different types to exploit the characteristics of the protein to interest to separate it from other contaminating protein


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Types of Chromatography

Type of Chromatography Protein Property

•Gel Filtration (Size Exclusion) - Size

•Ion Exchange (Cation or Anion) – Charge

•Hydrophobic Interaction Chrom. – Hydrophobicity

•Affinity Chromatography - Function or Special Characteristic


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Formulation

Once the protein has been purified, the bulk purified protein will be placed in the formulation buffer and sterile filtered. During formulation, adjuncts are added to:

•Stablize pH

•Adjust osmolarity

•Prevent aggregation

•Cryoprotect (for lyophilized products)


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Fill

Fill is completed in a special facility that has highly filtered air, gowned personnel with special training, This process is highly automated.

A measured amount of the formulated protein is aliquoted into sterile ampules


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Finish

The protein may be lyophilized (freeze dried). This makes it more stable, but physicians may find this form of the drug less convenient to use.

Closures are added

Labels are applied.


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Quality Assurance

The law requires a QA/QC department that is separate from manufacturing

They will test:

Raw Materials

In-Process Samples

Utilities

Environmental Monitoring

The final protein product


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Regulation

In the United States, the Food and Drug Administration regulates pharmaceutical production

•Part of the executive branch

•Regulates $ 1 trillion of commerce a year

•Center for Drug Evaluation and Research

•Center for Biologics Evaluation and Research


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What Are GMPs?

Subpart DescriptionA General Provisions

B Organization and Personnel

C Buildings and Facilities

D Equipment

E Control of Components and Drug Product Containers and Closures

F Production and Process Controls

G Packaging and Labeling Controls

H Holding and Distribution

I Laboratory Controls

J Records and Reports

K Returned and Salvaged Drug Products

biomanufacturing jim dekloe

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