Linking ICH Quality Guidelines to GMP

Prof A J (Tony) WebberPresident, Queensland Clinical Trials Network, Inc (QCTN)

Agenda

• Queensland Clinical Trials Network Inc.• Introduction to ICH Quality Risk Management• Risks in Practice• Examples• FDA• Q-Gen

Brisbane

Queensland Clinical Trials Network Inc.

Queensland government established QCTN in 2005

QCTN is an independent association of clinical R&D service providers and hospitals

Industry or “umbrella” organisation

Not a government entity

Aim: To help organisations undertake clinical trial activities in Queensland

Perkins Resources (HR), LFS, WorldCourier, Marsh, SWIFT, RJNeville & Associates, Farmout, IMBcom, biostate, etc.

TetraQ,

Q-Gen, BPAAGEN, SNP, NeuromathixCentres for Health Research (PA)Q-PID, etc.

Q-Pharm, Core Research,CNS, Wesley Research Institute, Emphron,ACCMER, Centres for Health Research (PA),GRC, Queensland Clinical Trials Centre, AKTNHOCA, Hospitals (Cairns, Redland, etc.)

QIMRGenomics Research CentreBioAssayLinkAGRF, etc.

Target & Drug Discovery

TargetValidation

LeadOptimization

Safety & Clinical TestSubstance

ProductionClinical TestSubstance

Clinical TrialsPhases I, IIA

Clinical TrialsPhases IIB, IIIand IV

Gene expression profiles

High-thoughputscreening

Molecular Analysis

Array Technologies

Proof of Concept

Human Cell Models

In vitro stem cell screening

In vitro embryotoxscreening

Animal Models

Molecular & functional testing

Physiochemical characterisation

Recombinant proteins

Cell therapies

Process development

First in Man

Safety

Pharmco-kinetics & dynamics

Dose-finding

Efficacy

Superiority

Sub-groups

PMS

QCTN Members offer the Best-of-Breed Services for Drug Development

ICH Quality Risk Management ICH Documents

• Q1 Stability• Q2 Analytical Validation• Q3 Impurities• Q4 Pharmacopeias• Q5 Quality of

Biotechnological Products• Q6 Specifications• Q7 Good Manufacturing

Practice

• Q8 Pharmaceutical Development

• Q9 Quality Risk Management

• Q10 Pharmaceutical Quality Systems

ICH1 Expert Working Groups

• ICH Q8, on Pharmaceutical Development, doc. approved 2005ICH Q9, on Quality Risk Management, doc. approved 2005

• ICH Q10, on Quality Systems, topic accepted 2005

1 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

ICH Quality Risk Management (QRM)

• Q9 together with Q8 and Q10 encourage developments that combines science with risk based approaches to quality and aims to focus the behaviourof industry and regulatory authorities on two primary QRM principals:• The evaluation of the risk to quality should be based on

scientific knowledge and ultimately link to the protection of the patient; &

• The level of effort, formality and documentation of the Quality Risk Management process should be commensurate with the level of risk

Hazards in QualityAnything that has the

potential to harm patients, product quality

or the business (loss, interruption, image)

Potential Threat- Chemical reaction- Manufacturing issues- Facilities and equipment

System Defect- Not detected

- Insufficiently prevented- Emerges by degree

Failure-Technical breakdown- Human breakdown- Extrinsic effect

Hazard

S. Ronninger, Roche, 2004

Risks in Practice

• The following slides are based on the experiences of a QCTN member, Q-Gen Pty Ltd, a company established in 2002 as a cGMP manufacturing unit of the Queensland Institute of Medical Research

• Q-Gen was licensed by the Australian Therapeutic Goods Administration in May 2003 for the Production of Sterile Human Therapeutics

Biologics from Bench to Bedside

fail fast and fail cheaply“easy to say harder to do”

the difference between what we know and what we know we don’t know and can’t afford to find out

…. yet

Product Knowledge

What the regulators would like to believe

Product development to enable clinical studies

Product development to enable Registration and

commercialization

Development Time

Registration

Reproduced from Jeffery Blumenstein Pfizer Global research & Development Slides– A New CMC Paradigm for Product Quality

Product Knowledge

The reality

Product development to enable clinical studies

Development Time

Registration

Reproduced from Jeffery Blumenstein Pfizer Global research & Development Slides– A New CMC Paradigm for Product Quality

Product development to enableregistration& commercialisation

Biologics from Bench to Bedside

fail fast and fail cheaply“easy to say harder to do”

The Application of Risk Management

Cautious & Calculated Risks

• How the ICH Q9, fits in

Design

Process

Materials

FacilitiesPatient

Distribution

Manufacturing

Q8 Q10

Q9 risk consideration throughoutdesign and quality management

Reproduced from Jeffery Blumenstein Pfizer Global research & Development Slides– A New CMC Paradigm for Product Quality

Risk in Practice

Contract Scoping

Considerationof the

ProductAssay Qualification Analytical Assays

Considerationof the

ProcessCCP data mining

& comparability

Considerationfor ReleaseOOS

Non ConformingProducts

Contract Scoping

• Assessment of technology• Assessment of processes and changes required• Assessment of the character of the product and what

changes may occur during development• Alignment of Clients Budget with expectations• Consideration of the risks to our business

• Ability to deliver• Product liability• Regulatory compliance• Errors and omissions• Reputation and track record

Consideration of the Product

• Safety, Potency, Purity, Identity• Identification of assays – risk tolerance• Assay qualification

• Minimum usually more then clients expectations and clients budget

• Standards• Stability• Risk tolerance

Consideration of the Process

• Scale up- start where you mean to end up!• Process optimisation• Lack of data and cost of collection

Consideration for release

• Pre-emptive acceptance criteria• Out of Specification Results and Quality Review• Failed batch vs Clinical need

Acceptable Risk

• Essential to predetermine the companies tolerance for risk

• Risk provides framework for building quality systems Q10, developing processes and compliance with regulatory guidelines Q9.

Documenting Risk Strategy

• It is as important if not more important to document what you decide to do as what you decide not to do.

• A thoroughly documented choice is a defendable position an undocumented one is just something you forgot to do!!

Example 1

Decision to release contaminated material into a dendritic cell vaccine

• Patient derived raw material contamination rate 50%• Rejection of material doubling the cost of the trial, halving

the recruitment rate• Concern over improper handling of material vs intrinsic

contamination (dissection of lymph node).• Risk acceptable• Documentation – investigation report, hypothesis, risk

assessment, risk minimisation of improper handling concerns, change control, bioburden testing, changes to procedures and specifications, notification to regulator.

Example 2

Decision not to do viral evaluation on cellular product for patient group with clinical life expectancy of < 6 months

• Consideration of clinical need vs risk• Risk assessment• Risk tolerance decision• Risk minimisation strategies• Full risk strategy documented as part of technical

masterfile.

Benefits to a Quality Risk Management System

• Supports a science based decision making process• Focuses resources based on risks to patients• Avoids restrictive and unnecessary requirements and

costs associated with unrealistic expectations on early phase development.

• Recognisable process and documentation format for both industry and regulators

Acknowledgment

• The assistance of Ms Allison McLean, CEO of Q-Gen Pty Ltd, in the preparation of this presentation and provision of the two “Case Studies”, drawn from company records, is gratefully acknowledged.

Thank You for Your Attention

SERVICES

Bioreactor Process Design Q-Gen has in total ten (10) fermenters ranging from 3 to 70 litre capacity. These can be configured for batch, fed batch or continuous processing.

Cellular Therapies Q-Gen has expertise in a range of Cellular therapy products, Dendritic, T Cell and Stem Cell.

Viral Vaccines Q-Gen uses conventional bioreactors in the development and manufacture of vaccines.

Recombinant Proteins Q-Gen has expertise in recombinant expressions systems both eukaryotic and prokaryotic for the production of antigens and antibodies.

Cell Banking Q-Gen offers both Master and Working cell banks.

Aseptic Filling Q-Gen can provide sterile filling of vials up to 100.0 ml

Ancillary Testing Q-Gen provides all associated analytical, stability testing on components, and final product.

Regulatory Services Q-Gen can prepare all associated and required regulatory documents to support your regulatory applications.

Consultancy ServicesQ-Gen can offer fee for service in working with clients to provide Gap Analysis, Product Characterisation

and Technology Assessment. In our experience these services can lead to a reduction in the time line for the manufacture and supply of a product that will meet the necessary quality and regulatory requirements.

Q-Gen: Services