This document discusses moving from a quality by testing approach to a quality by design approach for method validation and transfer. It proposes a three stage lifecycle process for method validation that begins with method design to define objectives and critical controls. Stage two involves method qualification to confirm the method meets its design. Stage three provides for continued method verification to ensure the method remains fit for use. This lifecycle approach focuses on collecting data and knowledge throughout the method's use to consistently deliver quality results. The document advocates applying quality by design principles to stability studies to reduce testing and costs by focusing on attributes likely to change over time.

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

2. Current Approach – Quality By
Testing
Excipient
Pass / Fail
Specification
API
Pass / Fail
Specification In Process
Testing
Pass / Fail
Specification
QC 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
Feedback loop
Manufacture
In process
testing
QC testing Finished
Specs
API meets
spec
Excipients meet
spec
If fails,
understanding /
root cause and fix
Acceptance criteria
based on
performance.
Testing no
necessarily
required
Only confirms
quality – not the
place to root cause
analysis and fix

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:
1.The importance of having PREDEFINED objectives
2.The need to UNDERSTAND the method
3.Ensure that the method delivers quality data CONSISTENTLY
in all intended environments.
4.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
STAGE 1: Method Design
Define method requirements and conditions and identify critical controls
STAGE 2: 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
STAGE 1: 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
STAGE 2: 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
STAGE 3: 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