17 May 2011, Beijing, China

1. Learnings from Pre-approval Joint Inspection of a GSK QbD Product with US-FDA & EMA and the application of Continuous Verification 17 May 2011, Beijing, China Chi Li, GSK-Tianjin

2. Quality by Design Introduction- Develop extensive knowledge and understanding through: • Risk assessment and DOE based selection of CQA/QA/QCPP/QPPs • Evaluation of input material functional characteristics • Implementation of PAT based process controls, example time independent granulation endpoint • Establishment of design space, knowledge space and control space across critical unit operations and determination of multivariate relationships and interactions • Effective control strategy established for all DP CQAs which will lead to reproducible drug product manufacture. • This enhanced assessment and control of quality during manufacture in real time • Removes the need to take an end-of-batch sample for subsequent laboratory analysis and verification of manufacturing processes on a continuous, rather than a discrete basis.

3. Traditional Release Approach RTR Testing Approach Impeller load based granulation model to control dissolution NIR granule drying endpoint model LOD endpoint NIR blend uniformity Weight, thickness, hardness, disintegration, friability -NIR composite assay -On-line dosage uniformity by tablet press weight control -Main compression height to control dissolution -10X Tandem correlation to hardness AQL DP release tests Description ID Content (HPLC) Impurity (HPLC) Uniformity (Mass) Dissolution Description by AQL NIR for ID Laboratory

4. GSK Parallel Testing • Parallel testing is needed and is conventional, laboratory based, end point testing, compared with Real Time Assurance at line/on line tests. • Parallel Testing was performed on 30 commercial scale batches • Real time release may be implemented for tablets upon meeting pre-defined acceptance criteria for these 30 batches. A risk assessment was conducted after the 30 batch parallel testing exercise and prior to implementation of real time release. • 30 batches chosen to evaluate process control and variability in input materials to provide adequate statistical power for control charts and setting meaningful control limits

5. What is Continuous Verification Good scientific knowledge and understanding of the product and process is accumulated during development. Critical sources of variation are understood and controlled and that the relationships between input material attributes, process parameters and product CQAs are well-understood. GSK plans to use a continuous verification approach to validate the manufacturing process rather than validate following the conventional three batch approach. The accumulated product and process knowledge gained during development has been used to identify the CQAs and the Control Strategy, based on risk assessment. Together with data demonstrating that the Control Strategy consistently produces product which meets its CQAs, this will provide the confidence needed to initiate commercial production and enable GSK to verify the acceptability of each batch.

6. Start of Start of commercial commercial manufacture Traditional Approach Traditional Approach Development Development Commercial supply Commercial supply PQ PQ Periodic Periodic Periodic Periodic VMP VMP VSR VSR Review Review Review Review Continuous Verification Approach Continuous Verification Approach Development Development Commercial supply Commercial supply PQ1 PQ1 PQ2 PQ2 On On - - going verification going verification Periodic Periodic VMP VMP IVSR IVSR VSR VSR Review Review RTR confirmation Performance Qualification • The Continuous Verification approach consists of two stages: • Provision of confidence that material produced is suitable for commercial use (Performance Qualification1), • Continuous Verification of process performance over the commercial life of the product (Performance Qualification 2 and on-going batch verification).

7. Traditional Vs CV

8. General Focus of Audit Information • Risk Assessment (FMEA) • Rationale of Design of Experiment • Detailed result interpretation (explain multi-variate interaction) • Model cross validation • Scale up approach • Verification of Design Space in commercial scale • Control Strategy • Continual Improvement

9. FDA\MHRA Audit Some General Learnings • Was first joint inspection hosted by GSK and was resource intensive, 9 Auditors in Total with varying background • Many more documents to prepare and provide fronters • Keep things simple – Granulation endpoint • MVA interactions should be identified • RTR should start as early as possible • Keeping teams small to get the work done • Mindset a challenge across the industry • Confusion between CV and RTR

10. Learnings From Continuous Verification • Personnel should be involved with process development early on • Requires team to work closer as an integrated team. • Requires systems for monitoring and trending of input material, process parameters and attributes • QbD allows for : • assurance of quality, safety and efficacy • real time release • reduced waste ???......samples! • may lead to Regulatory flexibility (Not simple batch failure) • improved change management

11. Learnings from Parallel Testing • The requirement of 30 batch parallel testing is new and agreement of factors to include has driven significant resource • 30 batches based on statistical analysis and is dependent on test type. • Differences in clinical and commercial test methods means logistics of test site is complicated • Batch docs for RTR are expected to be different from traditional , have available as early as possible • Decision trees are being generated to ensure solution to potential issues encountered during the 30 batches are agreed up front • Batch Release requirements of QP have been finalised for both traditional and RTR approach • Perform a test run using full proposed commercial control to ensure confidence in commercial process as early as possible and equipment robustness.

12. Learnings From Conformance • Marketing applications take longer to write and review due to the complexity of RTR and CV aspects • Has lead to numerous face to face meetings with regulatory agencies such as FDA an various EU countries on RTR and CV • Additional agency discussion covering statistics may be beneficial • Good feedback from FDA identifying areas which we need to work on • Direct measurement Assay and ID • Need convincing of inferential methods • Sampling numbers • Potential of two approaches for different markets / regulatory bodies resulting in logistical issues if difference is accepted • Less time to produce annual report as data already trended as part of monthly CV review.

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