how to combine the efforts on the new initiatives – qbd ... · dr jan gustafsson, novo nordisk...

Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14

How to Combine the Efforts on the New Initiatives – QbD, PAT, QRM, and

Validation/Continuous Verification

ISPE Nordic PAT COP meetingMalmö

2007-10-25

Dr Jan Gustafsson, Novo Nordisk A/S Slide no 22007-10-14

Background – Regulatory initiatives

ICH Q10Quality

Systems

ICH Q9 Quality Risk Management

ICH Q8Pharmaceutical

Development

The

Critic

al P

ath

CGMP for the 21st Century

Process Analytical Technology

FUTURE DESIRED STATE

” This industry wastes $50 billion each year because of lack of manufacturing efficiency” Source: George Washington and Washington Universities report (presented 2006)

FDA

Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14Cost and Benefit of QbD

Dev

elop

men

t & M

anuf

actu

ring

Cos

ts

QbD Implementation Progress

Initiate QbDEfforts

QbD FullyRealized

Increased Resources(e.g., development costs,organizational planning)

Current State

• Empirical development approach• Quality by testing & inspection

• Frozen process with reactive changes

Desired State

• Quality by design development• Flexible process & continual improvement

Decreased Expenses(e.g. manufacturing costs,compliance costs)


The New Initiatives• The vision

• Continuous product and process improvement• Transparent, science and risk based dossier submission, review, and

approval as well as operations• Empowerment to manufacturers re. continuous improvement

throughout product and process life-cycles and supply chain• More efficient and effective regulatory oversight

• The new initiatives contain issues such as:• Focus on design (ICH Q8; QbD)• Focus on doing the right things (ICH Q9; QRM)• Focus on understanding and control of the manufacturing process

(FDA; PAT)• Focus on more efficient use of resources re. V&Q (ASTM; quality

verification• Regulatory Flexibility (FDA, EMEA)

• The new initiatives lead to:• Better (mechanistic) Process understanding• Better product/process/facility knowledge• Better use of resources• Regulatory flexibility


The new initiatives, Novo Nordisk way

Quality by Design

QRM QbD & Designspace

PAT V&Q


The QbD process

”Start with the end in mind”

Needs of the patient

Productdesign

Processdesign

Equipmentdesign


ICH Q8 – Introduces new Concepts

• Regulatory Flexibility• Quality by Design• Design Space


• Proposed by applicant and approved by regulator, based on demonstrated product knowledge and process understanding

• Degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided

• Opportunities to facilitate• risk-based regulatory decisions (reviews and inspections)• manufacturing process improvements, within the approved

design space described in the dossier, without further regulatory review

• reduction of post-approval submissions• real-time quality control, leading to a reduction of end-product

release testing

ICH Q8 - Regulatory Flexibility

Source: Moheb Nasr, ONDQA CDER, FDA


Source: Mock P2 Submission presentation by the EFPIA PAT Topic Group

3 batch validation will be replaced by a continuous process verification

Changes of scale will be made immediately without

notifying authorities

Operation within developed design space, a transfer (site A to site B)

could be made immediately without authorities being notified in advance

No additional batch wise end product testing is needed

Regulatory Flexibility

• Regulatory flexibility is proposed for:• Process validation• Scale and equipment change• Site changes• Real time release


Quality by Design (QbD)

• Product designed to meet patient needs and performance requirements

• Process designed to consistently meet product critical quality attributes

• Impact of starting raw materials and process parameters on product quality is understood

• Process continually monitored, evaluated and updated to allow for consistent quality over time

• Critical sources of process variability are identified and controlled

• PAT tools is critical to realisation of QbD. PAT enables a high level of process understanding and process control

ICH Q8 provides clarity to facilitate implementation !!!


Design Space

Knowle

dge Spac

e

Desig

n Spac

e

Normal Operating Ranges

Process variable 1

Pro

cess

vari

ab

le 2

changes within DS is not a change and is

not subject to post approval regulatory changes

Traditional

Specifications

Operating range


4. A GeneralQuality Risk ManagementProcess

Team approach

Risk Review

Risk

Com

mun

ica t

ion

Risk Assessment

Risk Evaluationunacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

RiskM

an agemen ttoo ls

ICH Q9


Patient

Product

Process

FacilitiesOther influences

The ”Influence” and “QRM” Chains

The product influences the patientThe processes influence the product

In addition there are other factors influencing each step

The facilities influence the processes

QRM is done top down

QRM


FDA on PAT

• The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design. (from www.fda.gov)

FDA wants to use the quality concept of PAT to improve quality and enhance efficiency.

PAT is considered a win-win strategy for industry and customers.


Current state

ProcessVariable

input

Fixedprocess

Variable output

OOS or Reject unacceptable

products

Quality by Inspection

End product testing


Desired future state

ProcessVariable

input

Robust and Adjustable

Process

Constantoutput

Quality by Design

Real time moni-toring and control

Facilitated e.g.

by PAT / DS


The feedback mechanisms of PAT


Current situation

• 3 batches • Science?• Generally accepted


Continuous Verification

• ICH Q8• Glossary: “Continuous Quality Verification”: “An alternative approach

to process validation in which manufacturing process performance is continuously monitored and evaluated”

• EMEA, Mock P2 submission• Assurance is given that each step is routinely and reproducibly

producing material for the next step through consequent manufacturing within established Design Spaces

• Process verification in compliance with the design space• Application by the control strategy

• Conclusion: “Therefore the 3 batch validation will be replaced by a continuous process verification


Continuous Verification

• ASTM E55, WK9935

• Describes Continuous Quality Verification• Continuous Quality Verification (CQV) is an approach to verify that a

process will consistently produce product meeting its pre-determined critical quality attributes in which manufacturing process performance is continuously monitored and evaluated.

• The use of various Process Analytical Technology Principles and Tools will provide the means for Continuous Quality Verification

• A review of the process control strategy, acceptance criteria and process monitoring requirements, manufacturing documentation, and an evaluation and documentation of the Continuous Quality Verification data should be conducted at a predefined stage of aprocess or batch to make an assessment and conclusion of the process validity.


EA Board

Focus GroupQuality by Design

Organisation of QbD – Novo Nordisk

Quality RM Work Group

QRM Coordination Group

Val. & Qual. Work Group

Val. & Qual. Coordination Group

QbD & DS Work Group

QbD & DS Coordination Group

EA PAT Work Group

PAT Coordination Group

=Not yet set up – on hold

=Forming

Steering Group

Implementation Project

Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14

Engineering

Project Change Management

Configuration Management

Technology Transfer

Manufacturing & Quality Verification

Facility Design & Verification

Corporate Change Control

Quality by Design – Future Desired State

Transfer to Production Scale

Product Development &

Design

TransferFrom Discovery

Manufacturing Core Process

Quality by Design

QRM1

Commissioning plans and reports

Qualification Plans andReports

QRM3

QRM4

Quality by Design – Future Desired State

Development core Process Manufacturing Development & Verification Core Process

Technology Transfer to Production Scale

ProcessDevelopment

Transfer from Discovery

QRM2

Define Facility Design

Project Quality Planning

Testing

Design ReviewsQRM

= QualityRiskManagementActivities

Development Core Process, Product

Development Core Process, Process


QbD – Proposed Document Structure

FG QbD

QbD/DS WGPAT WGC&Q WGQRM WG

General

+ Flow

Applic´s

Product Development &

Design

Process Development &

Design

Facility Design & Verification

Manufacturing & Quality Verification

Flow

Procedures

(When to

apply what)

Application

Procedures

(How to apply)

Applic´sApplic´sApplic´s


PQLI

PQLI = Product Quality Lifecycle Implementation

• Builds on:• ICH Q8, Q9, and potentially on Q10

• QbD• Design Space

• Regulatory flexibility within Design Space• 21st cGMPs• PAT guidance

• Supported by EMEA• It is a five year programme• Outputs – White Papers, Articles, Documents• Embraces Regions that use ICH Guidelines


ISPE´s Industry Driven Transparent Forum

• Common understanding of QbD• Pragmatic approach to QbD implementation• Enhance quality of QbD submissions• Reduce need for post approval submissions• Enable focused GMP inspections by regulators• Pragmatic solutions to manage product development

and quality throughout product life cycle• Process and product understanding• Science and risk based


Task Teams

• TT Design Space DP/API• TT Critical vs. Non-Critical DP/API• TT Control Strategies DP/API• TT Legacy Products DP/API (new)


Meetings in Europe

• Latest:• Berlin, September 2007

• Next• Copenhagen, April 2008