This document discusses Quality by Design (QbD) and its application to regulatory filings. QbD takes a systematic, science-based approach to building quality into a medicine's production process and relies less on final product testing. Fully implementing QbD can provide regulatory flexibility, faster approvals, a more efficient production process, and better quality. It involves a risk-based approach to determine critical method parameters and criteria. Methods are developed more consistently using toolkits and investigated more rigorously. A fully QbD approach scientifically supports small or large method modifications and allows methods to evolve with technology. It shifts method review from registration to inspection and uses continuous improvement. Taking a holistic QbD approach across the entire

1. QbD – Quality by Design Exploitation of all that data – How best to apply to our regulatory filings? Steven T Mount – 4th April 2011 – Analytical QbD Discussion Group

2. QbD – Quality by Design Building in Quality at key points in the production of a medicine Systematic approach with predefined objectives Based upon science and management of risk (associated with Quality) Shift in emphasis in assurance of Quality of the medicine by testing or controlling key attributes of the production process, and having less reliance on testing of the final product Pharma Industry Direction in Response to QbD

3. A lot of extra work put in up front leads to.... ....more regulatory flexibility ....fast-tracked approvals of regulatory files ....a more efficient production process? ....better use of improved technology? ....a better Quality of medicine .... Through focus on the following: A risk based approach is being used to assess the need for results (e.g. Do we need to measure water content if it’s always zero?) Focus on the Critical Method Performance Criteria and Critical Method Parameters determined by Risk Assessment Pharma Industry Direction in Response to QbD

4. Methods are being developed in a more consistent manner Using “toolkit” approaches to harmonise how methods are determined through column/mobile phase screens Often generating an excess of data to fully support a scientific justification Development is possibly using more resource to generate the same method (hence the enthusiasm to streamline it through use of toolkits) Methods are then more vigorously investigated for ruggedness and robustness, generating further data to map out the robust regions of the parameters employed Method Development

5. We’ve seen the traditional approach: Filing of these Methods

6. We’ve seen a modified QbD approach Filing of these Methods

7. The next step….? Filing of these Methods

8. Advantages of the Fully QbD approach It is risk based and scientifically supported Greater flexibility with the regulators to make changes to the method (whilst still fitting the ATP) It allows for small modifications (e.g. column change) and larger modifications, e.g. HPLC to UHPLC It allows for a complete change, if for example the separation no longer needs to be chromatographic, and technology allows for it to be done by IR Review of the formal method would become part of an inspection by the Authorities, rather than a registration (or re-registration) Filing of these Methods

9. QbD Lifecycle Design Intent Using a risk based approach what does the method need to do – the ATP Design Selection Method Development, invention of the control method Start Evolution of the Control Strategy Control Definition Validation and Use of the Method for Control of the Process Continuous Improvement revision of the risk assessment, has the process improved, does it need more or less monitoring

10. This type of Fully QbD approach, taking full advantage is bold, but fully aligned with the ethos of the ICH guidelines and what the FDA have said they want It is probably not something which can be done in isolation of the rest of a Regulatory Filing The holistic approach means we should be considering the rest of the chemistry and formulation Implementing controls elsewhere in the manufacture and production Can we apply the same flexibility across the entire control strategy of the manufacture, and gain advantage in the flexibility of our registration of methods? It uses the scientific data from all the laboratory and pilot plant manufacture of active ingredient and formulated medicines, where everyone applies a risk based approach Holistic Approach

11. QbD Lifecycle Design Intent Using a risk based approach what does the method need to do – the ATP Design Selection Method Development, invention of the control method Start Evolution of the Control Strategy Control Definition Validation and Use of the Method for Control of the Process Continuous Improvement revision of the risk assessment, has the process improved, does it need more or less monitoring