change managament enabling quality

8/9/2019 Change Managament Enabling Quality

1/14


2/14

WHY CHANGE ?

WHY CHANGE ?

It is not the strongest of the species that survive, nor the

most intelligent, but the one most responsive tochange.

~Author unknown, commonly misattributed to Charles Darwin

P10: Change Management By Bernadette Doyle, PhD


3/14

….

“Double S” curve of Improvement ”

Improvement

Time

Transformational

(disruptiveintervention)

Incremental

(continuousimprovement)



4/14

ICH Q10 and Change Management

Change Management A systematic approach to proposing, evaluating, approving,implementing and reviewing changes (ICH Q10)

The scope of change management is much broader thanchange control, which was typically applied to one changeat a time

Change management includes the oversight andmanagement of the entire portfolio of changes and thechange process, including all the components of changecontrol

In a Pharmaceutical Quality System (PQS) developedaccording to Q10, change management applies across theentire product lifecycle

Change Management System

A company should have an effective change management system inorder to evaluate, approve and implement changes

The change management system should include the following :

Quality risk management should be utilised to evaluate proposed changes;The level of effort and formality of the evaluation should be commensuratewith the level of risk;Proposed changes should be evaluated relative to the marketingauthorisation, including current product and process understanding and/ordesign space, where established;

Expert teams, with appropriate expertise and knowledge, shouldevaluate proposed changes; An evaluation of the change should be undertaken after implementation toconfirm the change objectives were achieved.



5/14

ICH Q10 and Continual Improvement

Implementation of ICH Q10 throughout the product lifecycle shouldfacilitate innovation and continual improvement and strengthen thelink between pharmaceutical development and manufacturingactivities (ICH Q10 )Facilitate Continual Improvement

To identify and implement appropriate product quality improvements,process improvements, variability reduction, innovations andpharmaceutical quality system enhancements, thereby increasing theability to fulfil quality needs consistently (ICH Q10)

Key enablers

Quality risk management

Knowledge management

Opportunit ies from implementing Q8, Q9 and Q10?

Product and process understanding, the use of quality riskmanagement principles, supported by the implementationof an effective PQS ( i.e. applying ICH Q8, ICH Q9 and ICHQ10 principles) provides the opportunity to:

optimise science and ri sk based post-approval changeprocesses to maximise benefits from innovation andcontinual improvement (ICH Q10)



6/14

Applying Q8 and Q9 to Change Management in Q10

Collect datafor critical

parameters

Assessvariation

Change

process,materials,specifications

as required

Monitor/ ContinuousProcess Verification and

update knowledge

Perform Risk Assessment

Business triggerfor change

“ Straightforward” Excipient Supplier Changes ?

12

Impact on Drug Product Control Strategy

Surface of API fluorescesdue to surface peroxidation

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 5 10 15 20 25 30 35 40Timepoint (Months)

N - O x

i d e

( a / a )

Tighter control of additionsof mineral oil andmanufacturing process

Enhanced GC testperformed by supplier andreviewed by Site prior toshipment

New Excipient supplier deliveredmaterial to agreed specification

Excipient manufacturing processallowed addition of mineral oil tobring batches into specification

Criticality of replacing catalystto control hydrogenation notrecognised

C a s e S t u d y

1



7/14

Fermentation Product Impurity contr ol 2010

SolutionIdentification of interactionbetween rape seed oil quality(fermentation), Crystal Form(Extraction Process) andExtraction equipmentmechanical force (Equipment)Controls put in place to tackleall three causes

C a s e S t u d y

2

Which Tools used?Complex Root Cause Analysis using modified Britest tools Process via Metabolic Pathway andMechanism Map,True root causes verified in controlled conditions using classical experimentation

Benefi t – Failure rate reduced from 15% to zero,No impuri ty levels > 0.6% for five years,Reduction in hidden factory investigations, confidence in process.

Equipmentfailureunderstood

UnivariateControl

Multi variate Control

Problem :Fermentation product producing high levels of impurity restricting supply of critical medicine

Multiple potential root causes.Initial univariate root cause solution only partially solved problem.

• High Cost of Waste and risk of stock out for life ‐saving medication

• Complex system that is inherently close to the edge of failure with respect to its propensity for API aggregation

• Very subtle changes in raw material properties and processing parameters can result in aggregation

• Internal & external experts advised the root cause of the aggregation failure is inherent and linked to the formulation

C

a s e S t u d y

3



8/14


9/14

Trend Plot of 2010 batches (mech)

Spreadsheet2 in NewBatches2009.stw

BatchNo

343112348117

358316361789

367138377305

380834386983

390276397687

402227406400

2.8

3.0

3.2

3.4

3.6

3.8

4.0

4.2

2 0 1 0 b a t c h e s

( m e c

h )

Mean

USL

Mean = 2.97 umPpK > 2

Results following Improvements to Functional Specifications

R e

s u

l t s o

f C o r r e c

t i v e

A c t

i o n s

ICHQ10 and Management Responsibili ty

Management should -:

Participate in the design, implementation and monitoring of thepharmaceutical quality system

Ensure a timely and effective communication and escalation processexists to raise Quality issues to the appropriate levels of management….



10/14

How to translate QbD“Effective Control Strategy on the shop floor” A major part of execution is the Batch Document

– It should be articulated into an effective set of instructions, SOPs , guides … leading to:

A clearly understood Control Strategy at a level where the product is made

Effective Control Strategy

Continuous Improvement-:

GEMBA (Go See)

Product Data Trending Review

IPNs/AARs/operator feedback,

Product Quality Control Strategy

Master Batch Document

Validation Continuous Verification

ProductTechnical

RiskAssessment

SB480848 Manufacturing Performance 32Enteric Film Coated Inspected Tablet (160mg) - Individual & Mean Assay (%LC)

Performance Management Systems



11/14

Performance Management Systems

Perfo rmance Management Systems



12/14

Other Considerations …

Regulatory Challenges to Implement Changes

Lack of a harmonised regulatory system for managing post-approvalchanges

EU vs US vs Japan vs ROW

‘Registered detail’

not a common agreement of what constitutes ‘registered detail’ and whatwe need to change via a variation

Leads to different requirements and timelines for approval, and differenttypes of variations

Particularly challenging when trying to manage manufacturing changesglobally



13/14

Opportunities

Implementing Q8, Q9 and Q1O provide opportunities to optimisescience and risk based pos t-approval change pro cesses tomaximise benefits from innovation and continual improvement

Legacy products are also improved under the ICH Q10 changemanagement system over the lifecycle

Q8, Q9 and Q10 are moving Industry and Regulators in the rightdirection

Are we realising opportunities or obtaining benefits as quickly as weshould ?

How can we facilitate this?

Summary

Drivers for Change

ICH Q10 and how change can be supported

Implementation of ICH Q8, Q9 and Q10

Case Studies

ICH Q10 and Management Responsibility

Considerations and Opportunities



14/14

change managament enabling quality

Documents