Ancillary Materials in Cell Therapy Product Development

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Ancillary Materials in Cell Therapy Product Development Nicole M. Provost, PhD Independent Consultant Member of USP BB2 Expert Committee

Transcript of Ancillary Materials in Cell Therapy Product Development

Ancillary Materials in

Cell Therapy

Product Development

Nicole M. Provost, PhD Independent Consultant

Member of USP BB2 Expert Committee

Ancillary Material

Topics to be Covered

Common Sense Approaches

Definitions and Abbreviations

CMO Advantages and Disadvantages

Risk-based Approaches

“Big 3” Questions to Address

Relevant Examples

Take-home Messages

(Intuitively Obvious )

Common Sense Approaches

Figure out what you know, don’t know

Don’t ignore problems

Make plans

Be ready to change your plans

Definitions and Abbreviations

Ancillary Material (“AM”)

◦ Material used and removed during manufacture of a cell or tissue product

Supplier

◦ “Off-the-shelf” manufacturer of AM

Contract Manufacturing Organization (“CMO”)

◦ Custom manufacturer of AM

Product Development (“PD”)

Research and Development (“R&D”)

CMO Advantages

AM Manufactured by CMO

◦ No Manufacturing and Quality personnel to

hire and oversee

◦ Reduced need for additional facilities

◦ Reduced need for additional headcount

Supply Chain Managed by CMO

◦ Fewer suppliers to oversee

◦ Shipping and storage managed by CMO

◦ Multiple suppliers = more flexibility

CMO Disadvantages

AM Manufactured by CMO

◦ Ultimately, CMO issues become yours

◦ Be prepared to troubleshoot

◦ Designate a contact person on your side

Supply Chain Managed by CMO

◦ Sourcing is out of your control

◦ Shipping and storage issues can disrupt your

own manufacturing and R&D

◦ Multiple suppliers may = more variability

Risk-based Approaches to AMs

in a Nutshell

Perform Criticality Assessments

Identify the major risks to cell product: purity, consistency, supply, stability, etc.

Determine AM & product failure mode(s)

Define product/patient impacts

Mitigate or eliminate the major risks

Decide which headaches you own, and which you share with the CMO

Build trust with your CMO

The “Big 3” Questions for PD

What’s in the Ancillary Material?

How does the Ancillary Material affect

the cell product?

• Can the CMO make enough Ancillary

Material?

What’s in the Ancillary Material?

Is it a complex mixture?

◦ Classic examples: culture media and serum

Identify & characterize active component(s)

◦ Sometimes the impurities are active!

◦ Conduct fractionation and add-back experiments

◦ Relative component ratios may be important

Identify major impurities

◦ Common examples: fragments, endotoxin, DNA

How variable are the batches?

◦ Quantitation and characterization assays critical

How Does the AM Affect

the Cell Product?

Is the AM essential to cell product quality?

◦ Damage or omit the AM to assess its criticality

◦ Determine concentration effects, stability in use

◦ Assess many batches or sources

Do impurities affect cell product quality?

◦ Add-back experiments with known impurities

◦ Determine safety limits

Are both AM and impurities removed during cell product manufacturing?

◦ Both can be washed out, taken up by cells, or adsorbed onto production equipment

Can the CMO Make Enough AM?

How much AM do you really need?

◦ Perform titration studies early on

◦ Aim for a broad concentration “sweet spot”

How stable is the AM?

◦ Determine stability under storage, stress, and manufacturing conditions

Can the CMO scale up production?

◦ Look for a back-up supplier

Are you a major customer?

◦ This can be a mixed blessing for everyone

Relevant Examples

DMSO cryoprotectant, and plasticizers

Culture media formulations

Endotoxin impurities

Ancillary Material breakdown byproducts

Scale-up headaches

Plasticizers Leach

from Plastic into Cells

Inoue et al. (2005) Clinica Chimica Acta 358, pp. 159-166

DMSO Cryoprotectant,

and Plasticizers

DMSO increases plasticizer leaching

Check your DMSO source

DMSO can affect the integrity of

equipment, seals and filters

Plasticizers can affect cells, even if DMSO

is washed out

Conduct plasticizer add-back experiments

to estimate risks

Culture Medium – it’s Complex!

Yvonne Genzel, Max-Planck-Institut BPE

Culture Media: Points to Consider

Natural, synthetic, recombinant

◦ Albumin, ferritin, lipids, “secret sauce”

◦ Scale-up, cost, GMP availability issues

Powder vs. liquid formulations

◦ Impacts on stability, cost, logistics, and risk

◦ Switching between liquid & powder is difficult

Lipids can be critical

◦ Solubility issues (especially in powders)

◦ Multiple lipid species, variable amounts

pH indicator – do you really need it?

◦ May be taken up by cell membranes

◦ Useful marker for tracking wash efficiency

Bacterial Endotoxins

Endotoxins in Ancillary Materials

Present in multiple components

◦ Additive effects during manufacturing

◦ Cleanliness indicator for AM manufacturing

“Sticky”, not easily washed away

◦ Added risk for multi-use equipment

Pleiotropic effects on cell products

◦ Inflammatory and cytotoxic effects

◦ Can initiate cytokine cascades

Establish limits for patient safety

◦ Regulatory and safety requirements

◦ Conduct spiking experiments

Ancillary Materials Breakdown

AM Breakdown Byproducts

Cell product manufacturing conditions can

degrade AMs

◦ Temperature, agitation, pH, oxidation

◦ Proteolytic enzymes from damaged cells

◦ Incubate with conditioned medium

AM Fragments may be more active

◦ Chemical adducts, fusion proteins, etc.

De-glycosylation may affect bioactivity

Characterization assays are critical

How Much Will You Need?

AM Scale-up Headaches

Check with your AM supplier

◦ Batch sizes, manufacturing frequency, shelf life, storage conditions, constraints

◦ Impurity profiles can change with scale

Scale-up potential may be limited

◦ Expensive or unstable ingredients

◦ Equipment and facility constraints

◦ Not enough demand

◦ Environmental restrictions

Scale up early in cell product life cycle

◦ Phase 3 surprises are always unwelcome

Take-home Messages

Characterize the AM and cell product early and often in development

◦ Invest in characterization, quantitation, and activity assays early on

◦ Analyze failure modes and stability profiles

◦ Assess and mitigate risks

◦ Measure residuals in final cell product

Work with the AM supplier

◦ Minimize risks

◦ Maximize yields

Thank You