Quality by Design for Better Method Validation and Transfer

1. Quality by Design for Better Method Validation and Transfer Joanne Parkin, Director and Co Founder

2. Excipient Pass / Fail Specification Current Approach – Quality By Testing API Pass / Fail Specification QC Testing Pass / Fail Specification In Process Testing Pass / Fail Specification • Acceptance criteria set on limited data eg 1 batch. • Testing must be performed for batch to be released. • Failing batch only investigated at end of process

3. Current Practise for Method Validation and Transfer • Current Focus of Method Validation • One off exercise, very little consideration on how the method will work in the “real world”, operational conditions. • Does it look good on paper – works for three batches so all ok? • Robustness of documentation, not method • No consideration of who will use method, what equipment, technology advances. • Current Focus of Method Transfer • One off exercise, usually seen as an exercise that gets in the way of the real work. • No transfer of method knowledge. • Usually performed by most competent analyst – no consideration of day to day use.

4. Method validation / transfer hasn’t worked and everyone is surprised!! • Root cause is usually found to be insufficient consideration of the routine operating environment of the method during the method validation exercise and the lack of a process to capture and transfer method knowledge.

5. Quality By Design – The Lifecycle Approach • QbD is defined as “a systematic approach to development that begins with predefined objectives and emphasises product and process understanding based on sound science and quality risk management” • Background • A concept founded by Joseph M Juran • He said quality can be planned and that most problems related to the way that quality was planned (or not!) in the first place. • Quality cannot be tested into products – it has to be built by design.

6. Quality By Design – The Lifecycle Approach Introduced by FDA in 2002 ICH Q8 + ICH Q9 + ICH Q10 Pharmaceutical Quality Risk Pharmaceutical Development Management Quality Systems = Quality By Design Quality by Design – GMP for the 21st Century

7. Quality By Design – The Pharmaceutical Industry

8. Quality By Design – The Pharmaceutical Industry API meets spec Feedback loop Finished Specs In process testing QC testing Manufacture Only confirms quality – not the place to root cause analysis and fix If fails, understanding / root cause and fix Acceptance criteria based on performance. Testing no necessarily required Excipients meet spec

9. A QbD Framework for Method Validation and Transfer Lifecycle Process • When considering a lifecycle approach to method validation, a similar definition could be adopted • “The collection and evaluation of data and knowledge from the method design stage throughout its lifecycle of use which establishes scientific evidence that a method is capable of consistently delivering quality data.”

10. A QbD Framework for Method Validation and Transfer Lifecycle Process • Key Factors: • The importance of having PREDEFINED objectives • The need to UNDERSTAND the method • Ensure that the method delivers quality data CONSISTENTLY in all intended environments. • The need to CONTINUOUSLY assess method performance from method design all the way through its lifecycle.

11. Quality by Testing and Inspection Quality By Design

12. A QbD Framework for Method Validation and Transfer Lifecycle Process 3 STAGE PROCESS STAGE1: Method Design Define method requirements and conditions and identify critical controls STAGE2: Method Qualification Confirm method is capable of meeting design intent STAGE 3: Continued Method Verification Ongoing assurance that method is fit for use URS/DQ (IQ) OQ PQ

13. A QbD Framework for Method Validation and Transfer Lifecycle Process • STAGE1: Method Design (Design Space) • Its essential at this stage that thought is given to intended use and performance requirements. • Capture objectives (critical quality attributes) in a analytical target protocol, ATP • Do not use ICH2 as a tick box exercise – consider the method, equipment, drug etc. in conjunction with ICH 2 • Once objectives are set, next step is to define the criteria. Needs to be meaningful, not an arbitrary number. Need to have knowledge of proposed specifications and process variability's.

14. A QbD Framework for Method Validation and Transfer Lifecycle Process • Method Development • Proceed once ATP defined • Choose appropriate conditions, technique etc. to meet the ATP criteria. • Method Understanding • Understanding of key variables that will impact on the method. • From this a set of controls can be applied • Robustness/ruggedness experiments • Consider: different equipment makes, analysts, chemicals etc. • Method Design Output • At the end of stage one a set of method conditions will have been defined that are expected to meet the ATP requirements.

15. A QbD Framework for Method Validation and Transfer Lifecycle Process • STAGE2: Method Qualification • Similar to equipment qualification it can be broken down into: • Method Installation Qualification • Method Operational Qualification • Method Performance Qualification • Method Installation Qualification • Check on equipment status, analyst training etc • Method walkthrough if qualification to be a different analyst from the one who developed it

16. A QbD Framework for Method Validation and Transfer Lifecycle Process • Method Operational Qualification • Traditional method validation stage but not a tick box exercise. • Proving that method meets its design criteria. • Method Performance Qualification • Actual samples tested in the laboratory, equipment and by personnel who will use the method routinely. • The method should perform exactly as defined in the original ATP including system suitability.

17. A QbD Framework for Method Validation and Transfer Lifecycle Process • STAGE3: Continued Method Verification • Continuous assurance that method is fit for use • Trending system suitability data • Record out of spec or out of trend system suitability • Action failures • USP requirement, soon to be of Ph Eur / BP

18. A QbD Framework for Method Validation and Transfer Lifecycle Process Change Control

19. A QbD Framework for Stability Studies • Quality By Design – need to collect the right data – not necessarily MORE data • ICH Q1A - “Alternative approaches can be used when there are scientifically justifiable reasons.” • Data that is informative – builds scientific knowledge of product – better informed decisions in future. • Avoid “check box‟ testing –e.g. test that is mentioned in a guidance, but tells nothing new or important about stability of the product. • QbD provides opportunity to develop new ideas and explore new options to meet stability regulatory requirements and operating flexibility

20. A QbD Framework for Stability Studies • Doing things right first time – The Design Space • Test only what is likely to change over time –perform other tests only as needed • Shelf-life often determined by impurity level -not potency, or water content. If shown through development or registrational studies that potency or other attribute does not change with time –don’t restudy. • No reconfirming photo-instability or stability • No reconfirming the light protection properties of outer paperboard boxes • No continued testing the stability of pH of buffered systems • …no need for “checkbox tests” REDUCE NUMBER OF SAMPLES, REDUCE TESTING, REDUCE COST!!

21. A QbD Framework for Stability Studies • Doing things right first time – The Design Space • Product Design • understanding material interactions that affect chemical and physical stability • Understand packaging needs for the product • Process Design • understanding processing parameters that affect product purity and stability • understanding interactions between process parameters and material attributes • designing effective control strategies to consistently deliver product quality over entire shelf-life REDUCE NUMBER OF SAMPLES, REDUCE TESTING, REDUCE COST!!

22. Pros and Cons • Scientific understanding • Holistic approach • Less data to manage • Meaningful data • Fewer non conformances • Lean processes – more cost efficient • Better control of process • Continuous improvement • Managed based on risk • Patient first approach • Up to 30% savings* • New concept – hard to get buy in • Just starting to be recognised by authorities • Culture change • Investment up front • Time to get to know process and product • Difficult to apply retrospectively * Pharma 2020 survey

23. “Quality can not be tested into products; it has to be built in by design” Jospeh M Juran