advanced therapy medicinal products and gmp · 2018-02-14 · advanced therapy medicinal products...

© PharmOut 2016

Advanced Therapy Medicinal

Products and GMP

Ashley Isbel

© PharmOut 2016

Session Overview

What are ATMPs?

The State of Regulations

GMP and Other Challenges for ATMP production

Some Solutions

The Future

© PharmOut 2016

What are ATMPs?

© PharmOut 2016

• Cell therapy products – introduction or re-introduction of whole human cells (normal or modified) to generate an immune response in patients with deficient immunity

• Gene therapy products - introduction of normal or modified genetic material (usually DNA) into a patient to alleviate a genetic deficiency

• Engineered tissue products – the manipulation/growth of biological tissue for implantation/use on tissue deficient patients.

Advanced Therapy Medicinal Products are:

© PharmOut 2016

Cell Therapies

Cell Therapies

• Melanoma, Leukaemia, Lymphoma

• Mostly B-Cell

• More treatments in develpment

Gene Therapies

• Haemophilia, Cystic Fibrosis, Muscular Dystrophy, some imminodeficiences

• More treatments in development

Engineered Tissue

• Cartilage

• Corneas

• Bone

• More treatments in development

© PharmOut 2016

Why are they important?

ATMPs are showing outstanding results in difficult to treat conditions

• Personal, customised medicines, providing next level breakthroughs

• Gene therapies showing promise in repairing/curing genetic disorders

• Cell therapies able to target and destroy disease cells while minimising damage to healthy cells

• Engineered tissue repairing tissue that the body is unable to repair naturally – cartilage, corneas, etc.

© PharmOut 2016


“It’s an extraordinary development that has turned cancer treatment upside down. At the back of our minds everyone is thinking the “c” word (cure),” Dr. Dominic Wall, Chief Scientific Officer, Cell Therapies, Sept 2015

© PharmOut 2016

How do you make them?

Making ATMPs is difficult and expensive

• Typical cell therapy process

© PharmOut 2016


Typical CAR-T/TCR-T cell therapy process

© PharmOut 2016


Typical gene therapy process – DNA production

© PharmOut 2016


Typical manual engineered tissue process

Near future automated engineered tissue process

© PharmOut 2016

The State of Regulations

© PharmOut 2016

The ATMP field has been active for 25-45 years depending on the specific area, but only recently gaining traction as

effective treatments are becoming a reality

Europe – 6 ATMPs received Marketing Authorization (1 withdrawn)

• 1 gene therapy, 3 engineered tissues, 2 cell therapies

• 165 applications for ATMP categorisation

• 14 MA submissions

USA – 12 ATMPs received Marketing Authorization

• 11 cell therapies, 1 gene therapy

• 6 are simple cord blood products

• 2 overlap with Europe (Imylgic and Provenge)

Registered ATMPs

© PharmOut 2016

GMP Production or Clinical Trials?

Currently, the vast majority of ATMPs developed are in clinical trials. Many are in extended (seemingly perpetual)

clinical trials. Why?

• Applying GMP is difficult

• Getting MA is very difficult

• Establishing a reimbursement model that works commercially remains a major concern

© PharmOut 2016

The Current GMPs for ATMPs

• Mostly academic organisations with resistance to GMP bureaucracy

EMA / PICS Part 1

• Challenges around the specific requirement for sterile manufacturing

Annex 1

• Helps define the GMP line

Annex 2

• Creates a big headache!

Annex 15

© PharmOut 2016

The Future GMPs?

© PharmOut 2016

The Future GMPs?

ATMP specific GMP

•Has undergone public consultation

•Specific for ATMPs, trying to be flexible

•Standalone – replaces GMP guide and annexes (but based on existing guide)

•Applicable to IMPs and MA

But

•ATMP manufacturers generally unhappy. Don’t want two sets of rules

•Prefer interpretation of existing GMPs or

• Implementation of new Annex

And

•Very interesting comment from Dutch regulator on ATMP GMP Panel:

• “I am very sure that the ATMP GMP will be adopted. I am equally sure that manufacturers and regulators will not use it”

© PharmOut 2016

GMP and Other Challenges for ATMPs

© PharmOut 2016

GMP Challenges – Starting Materials

• Variability of growth media and ‘active’ biological materials

• Poor supply chain (falsified/adulterated material)

• Pooling – improves consistency and feasibility, but increases viral/contamination risks

Variability

• FBS is typically irradiated but HS/HPL is not

• Other VI methods – UV, nanofiltration, HTST, chemical treatment can be problematic for growth media

• In most cases, not possible to inactivate viruses in ‘active’

Viral control

• Segregation of processing

• Ethics

Management of infected donors

© PharmOut 2016

GMP Challenges - Asepsis

Inherently biological process

Usually no sterilisation step – filtration often not an option

Parenteral or implantable products

Immuno-compromised patients

© PharmOut 2016

GMP challenges - Characterisation

Characterisation has different meaning for ATMPs than for conventional medicines

• Identity, purity, potency …

• bioactivity …

• tumourigenicity, genetic stability …

• Assays/bioassays may not be as precise

© PharmOut 2016

GMP challenges - Processing

Scale

• Typically very small scale production

• Often one patient per batch

Reliability

• Processes are not fail safe and have relatively high incidence of failure

Optimisation

• Focus is on successful process, not optimised process

© PharmOut 2016

GMP challenges – Process Validation

High variability in processes –materials, manual processing, process

length, bioassays, administration

Applying QbD as defined within Q8,-Q10 difficult. Q11 (drug substances) and yet to be published Q12 (product

lifecycle management) helping

Due to high variability, can 3 batches be justified?

© PharmOut 2016

GMP challenges – regulator findings

Poor application of SOPs, deviations, validation, change control, records, etc.

Poor compliance with EM, qualification, media fill design and frequency

Poor segregation of responsibilities, esp. relating to release for supply

Responsibility/ownership around material supply/storage

Computer systems capability and CSV – hospital systems

Non-compliant QC analysis for release

Lack of supplier qualification

© PharmOut 2016

Other challenges

Ethics

• Harvesting of human materials for use in other humans has ethical implications. EU particularly sensitive

• Embryonic stem cells

Skilled resources

• There are not enough highly skilled biologists in this field already

Cost

• Currently, the cost of most ATMPs is prohibitive.

• Commercialisation is uncommon as a result

Logistics

• centralised, decentralised, local?

© PharmOut 2016

What are the some of the solutions?

Plant based/synthetic growth media

• Some promise in alleviating cost/quality issues associated with biological media

NK cell lines

• Master cell banks can be established – perpetual, consistent source of material

Leveraging ‘big pharma’ experience

• Involve suppliers and vendors in quality issues

• Standardisation of analysis and process

• Engage with interested parties on reimbursement options

• Embrace QbD

© PharmOut 2016

The future

Centralised and decentralised centres for production, rather than local

Patient customised solutions to become prevalent

Fully automated production facilities by 2030

Increasing focus on consistent starting materials

Increasing isolation of personnel from process

Move away from autologous/allogenic stem cell transplantation – cell and gene therapy to completely replace by 2030

advanced therapy medicinal products and gmp · 2018-02-14 · advanced therapy medicinal products...

Documents