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

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

July 2003: An ICH vision

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

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

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

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

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.

… 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

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.

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

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

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

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?

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?

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

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

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

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 314.70) to accommodate more "regulatory flexibility" for drug makers operating within their pre-disclosed design space J Clark 28-8-06 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; 16-3-06

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

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!