Quality by Design for Better Method Validation and Transfer

Joanne Parkin, Director and Co Founder

Current Approach – Quality By Testing

ExcipientPass / Fail

Specification

APIPass / Fail

Specification In Process Testing

Pass / Fail Specification

QC TestingPass / 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

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.

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.

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.

Quality By Design – The Lifecycle Approach

Introduced by FDA in 2002

ICH Q8 + ICH Q9 + ICH Q10Pharmaceutical Quality Risk Pharmaceutical Development Management Quality Systems

=Quality By Design

Quality by Design – GMP for the 21st Century

Quality By Design – The Pharmaceutical Industry

Quality By Design – The Pharmaceutical Industry

Manufacture In process testing

QC testing Finished Specs

API meets spec

Excipients meet spec

If fails, understanding /

root cause and fix

Feedback loop

Acceptance criteria based on

performance. Testing no necessarily

required

Only confirms quality – not the

place to root cause analysis and fix

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.”

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.

Quality by Testing and Inspection Quality By Design

A QbD Framework for Method Validation and Transfer Lifecycle

Process

3 STAGE PROCESS

STAGE 1: Method DesignDefine method requirements and conditions and identify critical controls

STAGE 2: Method QualificationConfirm method is capable of meeting design intent

STAGE 3: Continued Method VerificationOngoing assurance that method is fit for use

URS/DQ (IQ) OQ PQ

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.

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.

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 QualificationMethod Operational QualificationMethod 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

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.

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

A QbD Framework for Method Validation and Transfer Lifecycle

Process

Change Control

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

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!!

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!!

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

“Quality can not be tested into products; it has to be built in

by design”

Jospeh M Juran