1. An Update on ICH Guideline – Pharmaceutical Development
ISPE Vienna Congress 2006

2. Presentation Outline Background to Q8 Experience of Q8 to date
Implications of Q8
Future strategy for Q8

3. July 2003: An ICH vision

4. Q8– an opportunity for change
Traditional Future
Empirical
Data Driven
Retrospective
“Test to document quality”
Acceptance criteria based on limited batch data
Variability not understood and avoided
Systematic
Knowledge driven
Prospective
Science and Risk based
Acceptance criteria based on patient needs
Variability explored and understood (Design Space) Q8

5. On July 20th 2004 you were told Q8 could deliver:-
Product quality and performance achieved and assured by design of effective and efficient manufacturing processes
Product specifications based on mechanistic understanding of how formulation and process factors impact product performance
An ability to effect Continuous Improvement and Continuous "real time" assurance of quality

6. The EWG has delivered the core guideline
Q8 is a 2 part guideline
Part 1
Core document
Baseline expectations
Optional information
Regulatory Flexibility
Revision
Annexes relating to specific dosage forms (as Q6a)
References to use of risk management
Focus on guiding towards Desired State
Drafting underway
Step 4: Nov 2005

7. Presentation Outline Background to Q8 Experience of Q8 to date
Implications of Q8
Future strategy for Q8

8. We have recognised Q8 encourages a new development paradigm – Quality by Design
Target
Product
Profile
Product/
Process
Dev.
Product/
Process
Design
Space
Control
Strategy
Define product intended use & quality targets (wrt efficacy & safety)
Incorporate prior knowledge, Risk Assessment, DoE and PAT to create New Scientific Knowledge,
Through hypothesis testing, create scientific understanding of product and process. Identify ’critical to quality attributes’ and establish multi-variate ”Design Space” that assures Quality
Define control strategy based on Quality Risk Mgmt & Design Space leading to control of quality relevant to safety and efficacy.

9. … to the variability of input materials
Quality by Design starts with the Patient, delivers consistently to the patient, but welcomes variability!
..we need to manufacture by a process that is well understood, robust, but adaptable…
To provide a product that consistently meets their needs….
… to the variability of input materials
API, Excipients etc
= DESIGN SPACE

10. Design Space: 3 key concepts
Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.
Design space is proposed by the applicant and is subject to regulatory assessment and approval.

11. Q8 applies throughout product life-cycle
Development
Technology
Transfer
Commercial
Manufacture
Design quality product & process to consistently deliver intended performance.
Knowledge gained from development studies & manufacturing experience provide scientific understanding to support the establishment of the design space, specs, & manufacturing controls.
Demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.
Risk-based regulatory decisions (reviews and inspections);
Manufacturing process improvements, within the approved design space, without further regulatory review.
Reduction of post-approval submissions
Real-time quality control, leading to a reduction of end-product release testing

12. Industry is capitalising on Q8
NDA/CTD submissions are changing
‘Here is my science, here is my manufacturing scheme which was developed through my science, here is how they link together’
M Kovalycsik - Wyeth
FDA pilot program
Design Space submissions
Continuous process verification
Compliance policy 7132c.08
Already Q8 is delivering value to the Industry, the Regulators and, ultimately, the patient

13. Presentation Outline Background to Q8 Experience of Q8 to date
Implications of Q8
Future strategy for Q8

14. Understanding the full implications of Q8 is not easy
The Q8 EWG believes the core guideline needs exemplifying
What is Quality by Design?
What’s the difference from the way pharmaceutical development has been approached and described until now?
Can we help in distinguishing baseline or ‘minimum’ from enhanced?
How exactly does the applicant describe the Design Space?

15. Q8 challenge example – What is Design Space?
Carry out the crystallisation to create particles at size/shape <criterion> varying the temperature, stirring rate and super saturation according to the relationship:
Size = f(temperature) + f(stirring) + f(super saturation)
60C
2.0
5.0 pH
30C
Traditional Method:
Carry out the reaction at pH 2-5 and between 30 and 60C
= ‘Proven Acceptable Ranges’
How do we describe the <criterion>, relationship and associated control strategy?

16. Wider implications of Q8 development
Can we clearly articulate what we mean by Quality by Design and understand its implications for both the Industry and Regulators?
As we complete revision of Q8 should we add a glossary of key terms, perhaps illustrated through examples?
How should we address API development & manufacture for both chemical and biotech?
Draft concept paper for NCE API available
Biotech paper not endorsed by ICH
Critical we assess implications of “Quality by Design”
Q8 is impacting the way we define specifications (Q6A & Q6B)
There may be other things needing consideration
E.g. analytical methods
These issues likely to be raised at ICH quality strategy discussion

17. Presentation Outline Background to Q8 Experience of Q8 to date
Implications of Q8
Future strategy for Q8

18. Progression of Q8
EWG has changed its focus for the revision from parenterals to solid oral dosage forms
Because it provides the greatest opportunity (lots of background and expertise) and is most common dosage form
When oral solids agreed, we will address the other types of dosage form
Illustrate QbD principles
Examples drawn from EFPIA mock P2 document
Ensure that we are clear on Design Space
Step 2 date hard to predict

19. Regulators are responding supportively
Progression should continue since Q8 is positively impacting Industry and Regulatory Practices
Science-based (Quality by Design) approaches will bring needed medicines to patients in more robust and effective way and unlock the innovative potential of the industry
Regulators are responding supportively
FDA:
Development of elite teams comprising investigators, analysts and compliance officers from field and CDER organisations : capable of making judgements about a firm’s risk management programmes, product and process knowledge, process capability and robustness of quality systems.
Considering making revisions to its post-approval change reporting regulations (21 CFR ) to accommodate more "regulatory flexibility" for drug makers operating within their pre-disclosed design space
J Clark
EMEA: Revision of Variations Regulations
“We have come to the conclusion that the concepts laid down in these guidelines – also taking into account the ongoing work of Q10 – could not be properly implemented in the EU without amendments to the Variations Regulations”
G Lalis, EC;

20. Ultimately, it’s all about structured KNOWLEDGE: this links with Q10
Comm
Production
Tech
Transfer
Clin Dev
TPP Prod/Proc Design Control
Development Space Strategy

21. Q8, Q9, Q10 – the opportunity
To deliver the ICH Vision and modernize Pharmaceutical Manufacturing and associated regulatory processes……….
BOTH Industry and Regulators need to work together to change the current paradigm and mindsets……..
Q8 / Q9 / Q10 providing a ‘once in a lifetime’ opportunity
Let us progress the concepts and guidelines with enthusiasm and optimism!