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. Introduction- Develop extensive knowledge and understanding through:
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 Laboratory
Impeller load based granulation model to control dissolution
Granulation 
Milling
Drying
Blending
Lubrication
Compression
Film Coating
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. Performance Qualification
Development
PQ1
PQ2
IVSR
VSR
Periodic
Review
VMP
Continuous Verification Approach
Commercial supply On -
going verification
Start of
commercial
manufacture PQ
Traditional Approach
RTR confirmation
IVSR= Interim Validation Summary Report
PQ=Performance Qualification
VMP=Validation Master Plan
VSR=Validation Summary Report
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.

13. END