QbD Concepts Applied to Qualification and

Transfer of Analytical Methods

CMC Strategy Forum

Latin America - 2014

Patrick Swann

Senior Director

Technical Development

QbD = Quality by Design

►QbD - A systematic approach to development that begins with

predefined objectives and emphasizes product and process

understanding and process control, based on sound science and

quality risk management - ICH Q8(R2)

►Part of a new Quality paradigm proposed at ICH meeting in Brussels

in 2003: “Develop a harmonised pharmaceutical quality system

applicable across the lifecycle of the product emphasizing an

integrated approach to quality risk management and science”.

► Includes guidance on Pharmaceutical Development (Q8(R2)), Quality

Risk Management (Q9), Pharmaceutical Quality Systems (Q10) and

Development and Manufacture of Drug Substance (Q11).

►Can we apply some of the general systematic approaches described

in ICH Q8-11 to the Qualification and Transfer of Analytical Methods?

2

Outline of Today’s Presentation

1. QbD concepts applied to qualification of method under

consideration for use in possible application of Process Analytical

Technology (PAT) to a commercial product

► Emphasizes interrelationship between development of method and

process.

► Applies QRM and scientific approaches across lifecycle of the product

► Facilitates ongoing improvements while maintaining assurance of quality

2. QbD concepts applied to method transfer to facilitate efficient

continued process verification

► Based on risk management concepts found in current guidance and

standards for method transfer as applied to Analytical Development at

Biogen Idec

► Maintains appropriate controls to assure accuracy and reliability of results

after transfer3

TOPIC #1: USE OF A QUALIFIED

METHOD TO EXPLORE

POSSIBLE PAT APPLICATIONS

FOR A COMMERCIAL PRODUCT

Method “Qualification” versus “Validation”?

BioProcess International, September 2004

Method “Qualification” versus “Validation”?

► No predetermined method performance

specifications

► Qualification studies are used to

determine method performance

capabilities

► A method cannot fail qualification; it

should be reoptimized until it can

achieve required performance

► If it cannot achieve required

performance, it should be rejected.

► Method performance specifications

should be established before validation

begins

► Method performance specifications must

be met by every trial run for the study to

pass

► A method can fail validation. If it does,

assignable cause for the failure should

be investigated and resolved before the

method can be considered fully

validated.

Ritter et al, BioProcess International, September 2004

6

ValidationQualification

Process Validation Guidance

► Stage 1 – Process Design

► Process defined during development

and scale up

► Stage 2 – Process Qualification

► Process evaluated to determine if

capable of reproducible commercial

manufacturing

► Stage 3 – Continued Process

Verification

► Ongoing assurance is gained during

routine production

► Validated analytical methods are not

necessarily required during product- and

process-development activities or when

used in characterization studies.

► New analytical technology and

modifications to existing technology are

continually being developed and can be

used to characterize the process or the

product.

► Use of these methods is particularly

appropriate when they reduce risk by

providing greater understanding or

control of product quality.

FDA, 2011

7

Analytical MethodsLifecycle Approach

Monitoring Quality Attributes In-Process

►Additional insight of sources of variability affecting PQAs

► Model building to extend beyond process parameters to include

quality attribute linkages to raw materials, process parameters

► Possible input for adaptive controls downstream

► Real-time control and feedback

►Real-time release testing in lieu of drug substance or drug product

release testing

►Parametric release

8

Standard Guide for Risk-Based Validation of Analytical Methods for PAT Applications (ASTM E2898-13)

• Input to Validation – Intended purpose drives documentation requirements

– Low Impact Applications are used to support product and process development

– Medium Impact Applications are intended to assure quality but are not measures of quality (e.g. design space for CQAs that may have a release test or measurements used for control but not specifically for release)

– High Impact Applications fall into the RTRT category and can substitute for a specification test

© ICH, November 2010

ICH Q10 Pharmaceutical Quality System

GMP

Pharmaceutical

Development

Commercial

ManufacturingDiscontinuation

Technology

Transfer

Investigational products

Management Responsibilities

Process Performance & Product Quality Monitoring System

Corrective Action / Preventive Action (CAPA) System

Change Management System

Management Review

PQS

elements

Knowledge Management

Quality Risk ManagementEnablers

How Analytical Development fits in – Proposed model based on Q10

TOPIC #2: QUALITY RISK

MANAGEMENT CONCEPTS

APPLIED TO METHOD

TRANSFER

Quality Risk Management and Method Transfer

►Risk Management Concepts from USP <1224>

► Comparative Testing using pre-determined criteria

► Testing by both sending unit (SU) and receiving unit (RU)

► Testing by RU only

► Transfer Waiver

► New product composition is comparable to existing product at RU

using methods for which RU has experience

► Method is similar to one in use at RU

► Personnel from sending unit involved with development, validation or

routine use of method move to RU

► Compendial method (requires verification*)

► Co-Validation or Re-Validation

13

Guidance on Transfer of Methods

►Procedures for transfer of Validated Methods described by

WHO TRS 961, Annex 7

►Principles for transfer of any method described by ISPE

Good Practice Guide on Technology Transfer (ISPE 2014)

► Scope includes method transfer from development to manufacturer,

manufacturer to manufacturer and between development groups

► Describes need for effective communication between SU and RU;

knowledge to be transferred (list similar to WHO; see next slide)

► References a risk management plan including assessment of

technical and operational risks

► Technical risks include concepts as found in USP <1224>

14

Method Transfer Guidance: WHO and ISPE

► SU responsibilities: Provide approved

procedures and training; define

experimental design, sampling methods

and acceptance criteria; provide

validation reports including details of the

equipment used, reference samples;

review and approve transfer reports.

► RU responsibilities: Review methods

provided by SU; agree to transfer

protocol; ensure equipment is qualified;

provide capable documentation system

► Knowledge transfer to include:

► Analytical Target Profile,

► procedures including any critical

controls and equipment requirements;

► development hx of procedure including

trends and deviations; change control

► reference stds;

► regulatory status, EHS requirements;

and role of the method in the overall

control strategy

Activities to consider

15

ISPE Technology TransferWHO TRS961

Guidance on Transfer of Methods

►Parenteral Drug Association Technical Report No. 57;

Analytical Method Validation and Transfer of Biotechnology

Products

► Technical risks include concepts as found in USP <1224>

► SU and RU responsibilities as found in WHO

► Design of Comparative Studies

► Acceptance criteria, number of samples needed, statistical tests;

documentation and example

16

Method Transfer Approach to Measurement of DNA as used in Confirmatory Column Lifetime Studies

►Confirmation of manufacturing process chromatographic

column lifetime performed at scale as part of Continued

Process Verification

►DNA tests performed for small-scale column lifetime studies

appropriately qualified

►Propose to transfer DNA tests to contract research

organization

►What are appropriate procedures and comparative test

transfer criteria?

17

PDA TR 57: Analytical Method Transfer Example

Method Type AMT Execution Matrix Acceptance Criteria

Impurities (quantitative) –

process- and/or product-

related

Two operators and/or

instruments on different

days, three batches in

duplicate, consider

spiking at different levels

for confirming precision,

accuracy and

quantitation limits

System suitability met,

quantitation limits

confirmed, TOST

difference of less than or

equal to 10% with 95%

confidence for

moderately high level

impurities, or absolute

difference of the means

between laboratories

between ± 25% for low

levels of impurities.

18

References

1. ICH guidance including Q8, Q9, and Q10 training materials can

be found at www.ich.org

2. Proceedings from the WCBP CMC Strategy Forum on Test

Method Qualification can be found at

http://c.ymcdn.com/sites/www.casss.org/resource/resmgr/importe

d/Test%20Method%20Qualifications%20Article.pdf

3. FDA Process Validation guidance can be found at

http://www.fda.gov/downloads/Drugs/Guidances/UCM070336.pdf

4. ASTM guide on validation analytical methods used for PAT can

be found at

http://enterprise.astm.org/filtrexx40.cgi?+REDLINE_PAGES/E28

98.htm ($)

19

References

5. On demand training on USP <1224> can be found at

http://www.usp.org/meetings-courses/courses/transfer-analytical-

procedures ($)

6. WHO guidelines on transfer of technology can be found at

http://apps.who.int/prequal/info_general/documents/TRS961/TRS

961_Annex7.pdf

7. ISPE good practice guide on technology transfer can be found at

http://www.ispe.org/ispe-good-practice-guides/technology-

transfer ($)

8. PDA Technical Reports can be found at www.pda.org ($)

20