1. Workshop Session 3 Questions 1 How would a control strategy look different in a traditional submission vs a QbD submission? How would parameters that are not specified in the license be handled and what will be the agency involvement? Are there additional considerations beyond criticality of a given attribute that factor into the control strategy development? Are Expanded Change Protocols (eCP) and EU Post Approval Change Management Protocols (PAMP) the same? If not, what are the key differences?

2. 2 Illustrate Relationship of Process to Product Critical Material Inputs Critical Process Parameters Key Process Parameters Target Product Profile Control of Critical Inputs and Process Parameters Design Space Ensure Control of Critical Outputs Vaccine Slide from Lynne Krummen (Genentech)

3. 3 Example: Vaccine Protein Fragmentation Fragment 1 Fragment 3 Fragment 2 Intact Protein (Immunogenic) Immunogenic Non-immunogenic

4. 4 Is Fragmentation a CQA? Impact: 8 (medium) Literature identifies potential impact of fragments (decreased immunogenicity) Green: low impact Yellow: medium impact Category Risk Assessment Impact on Efficacy Impact on Safety ImmunogenicityToxicity Literature or similar products Available literature on potential impact Info on potential impact based on similar products Laboratory experience Test fragments and fragment enriched samples to assess impact Non-clinical experience Assess impact in animal models Clinical experience Efficacy and safety results from clinical study84

5. 5 Process Capability Immunogenicity operating space Both processes result in a product with a highly consistent fragmentation profile Fragment 1 Fragment 3 Fragment 2

6. 6 Control Strategy Fragmentation Impacted by Production scale upX Manufacturing site Cell LineX Raw materials Production bioreactorX Harvest Cation exchange chromatographyX Anion exchange chromatographyX Nanofiltration Low pH inactivationX Hydroxyapatite chromatography Formulation Criticality of attributes Controls Raw material control Process clearance capability Critical operational parametersX Procedural controls Process validation In-process controlX Lot release testingX Stability testingX Characterization testingX

7. 7 Risk Analysis (Likelihood) Manufacturing process consistently produces material that is well within the range of the prior product knowledge Vaccine processes result in products with different proportions of the same fragments having similar safety and efficacy In this case, fragments have low impact if they are controlled within a range Therefore, the likelihood of adverse effect occurrence due to variation in fragmentation proportions is very low

8. 8 Overall Process Risk Minimized Risk index

9. 9 July 2010 Where Innovation Operates Management Consultants Quality by Design VACCINE-BASED CASE STUDY Sam Venugopal Principal T+1 650.864.3522 F +1 650.967.6367 M+1 408.396.9649 svenugopal@prtm.com 444 Castro Street Suite 400 Mountain View, CA 94041 U.S.A. www.prtm.com John Berridge Pharmaceutical Ccnsultant T+ 011447971324939 johnberridge@btopenworld.com Bracklyn, St. Clare Road Walmer Deal CT14 7QB

10. 10 Questions for discussion What challenges would there be to justifying the described immunogenicity design space? What studies would be needed for a therapeutic protein to justify an immunogenicity “design space”, where immunogenicity is undesirable?

11. 11 Questions for discussion QbD has several elements that can be applied across multiple product types and associated systems. What are the essential components of QbD that can be applied most generally? What elements of QbD appear to be the most difficult/costly/time consuming? How are companies making decisions over how much, if at all, QbD will be applied to a particular product, especially considering early phase, late phase and licensed products? Global acceptance of QbD by regulators is one barrier to the implementation of QbD on a holistic basis. How are companies managing with global filings? What other concerns do companies have in implementing QbD? Apart from process and product, on what other applications can QbD have an impact?