Regulatory Aspects of Product

Development
ICH Process Q8, Q9, Q10
WHO Workshop, October 2007

Sultan Ghani, Director

Bureau of Pharmaceutical Sciences
Therapeutic Products Directorate, Health Canada

Training Workshop on Pharmaceutical

1 | Development
 Focus of Presentation

ICH Process
ICH Q8, Q9, Q10
Pharmaceutical Development

Training Workshop on Pharmaceutical

2 | Development
 ICH
BACKGROUND
 ICH established in 1990 as joint industry/ regulatory
project to improve through harmonization the efficiency
of the process for developing and registering new
medicinal products
 The Fourth International Conference on Harmonization
(ICH 4), Brussels, 1997 marks the completion of the
first phase
 It was agreed that the second phase of harmonization
continue to ensure the future activities of ICH

Training Workshop on Pharmaceutical

3 | Development
 ICH

FUTURE OF ICH
 A Continuation of Harmonization
– Activity/Mechanism to harmonize new technical requirements
– Process for updating and supplementing the current ICH
Guidelines
– Prevent future disharmony through early collaboration and
exchange of information

Training Workshop on Pharmaceutical

4 | Development
 ICH
ICH STRUCTURE
 Founding Members:
– Europe
• European Commission (EC)
• European Federation of Pharmaceutical Industries
Associations (EFPIA)
– Japan
• Ministry of Health and Welfare (MHW)
• Japan Pharmaceutical Manufacturers Association
(JPMA)
– U.S.A.
• U.S. Food and Drug Administration (FDA)
• Pharmaceutical Research and Manufacturers of
Training Workshop on Pharmaceutical
5| America (PhRMA)
Development
 ICH
ICH STRUCTURE (cont’d)
 Other Members:
– Observers
• World Health Organization (WHO)
• Therapeutic Products Programme (TPP)
• European Free Trade Association (EFTA)
– Extended Working Group Members
• Pharmacopoeial Authorities
• Generic Industry Association
• Non-Prescription Pharmaceutical Industry
– Secretariat
• The International Federal of Pharmaceutical
Manufacturers Association (IFPMA)

Training Workshop on Pharmaceutical

6 | Development
 The Five Steps in the ICH Process for
Harmonization of Technical Issues
Step 5: Implementation in the Three
ICH Regions
Step 4: Agreement on Harmonized ICH
Guideline, Adopted by Regulators
Step 3: Regulatory Consultation in the Three Regions
Consolidation of the Comments
Step 2: Agreement by the Steering Committee to Release the
Draft Consensus Text for Wider Consultation
Step 1: Building Scientific Consensus in Joint Regulatory/Industry
Expert Working Groups

Training Workshop on Pharmaceutical

7 | Development
 New Era With New Challenges

“risk-based”
concepts and
principles of ICH

Q8
Ref: ICH
Q9 Q10
Training Workshop on Pharmaceutical
8 | Development
 Pharmaceutical Development Paths
Q8 is not yet finalized by ICH
Q8
Traditional
pharmaceutical
development
QbD
Essential DOE DOE FME(C)A
DOE Factorial design Multivariate analysis

Process Design Space

Validation For Continuous Improvement

Training Workshop on Pharmaceutical

9 | Development
 ICH’s Vision of the Future
Traditional Approach
Broad Quality decisions divorced from
Concept science and risk evaluation.
Adherence to filing commitments.
Quality Post-manufacture sampling and
quality testing.
Process Validation.
Systems Systems designed to inhibit
changes & minimize business
risks. Discourages improvement &
innovation.
Regulatory Compliance focus.
Changes require prior approval.
Training Workshop on Pharmaceutical
10 Development
QbD Approach
Quality decisions and filing commitments
based on Process Understanding and Risk
Management. Design Space concept.
Management of variability
Process control focused on critical attributes.
Continuous Quality Verification.
Changes managed within company's quality
system. Real time batch release feasible.
Higher reliance / trust / understanding on
systems.
Regulatory scrutiny adjusted to level of
Process Understanding. Continuous
improvement allowed within Design
Space.
Adapted from EFPIA, PAT Topic Group, 2005
QbD- a Well Known Concept of the 50’s
Ref: Out of Crisis (1986): W. Edwards Deming

 Depending on inspection is like treating a symptom while

the disease is killing you. The need for inspection results
from excessive variability in the process. The disease is
the variability. Ceasing dependence on inspection means
you must understand your processes so well that you
can predict the quality of their output from upstream
activities and measurements. To accomplish this you
must have a thorough understanding of the sources of
variation in your processes and then work toward
reducing the variation. Ceasing dependence on
inspection forces you to reduce variability.
Ref: http://deming.eng.clemson.edu/pub/den/files/varman.txt
http://deming.eng.clemson.edu/pub/den/files/varman.txt

Training Workshop on Pharmaceutical

11 Development
 Traditional PD versus QbD
 Traditional Product Development:
– Limited development and scale-up work
– Final confirmation by validation of 3 batches
– ‘Worst-case' scenarios supposed to be included
• Market recalls and underutilization of capacity indicate
this approach has had limited success.
 QbD:
– Complete understanding of process and monitoring of all critical steps.
Corrective actions are taken to prevent product failure.
– Acceptable quality of the product is ensured:
• No recalls
• Innovation encouraged
• Maximize utilization of capacity
Training Workshop on Pharmaceutical
12 Development
 Quality by Design

Traditional
Process Validation
Establish documented evidence which will provide a high
degree of assurance that a specific process will
consistently produce a product meeting its predetermined
specification”

Training Workshop on Pharmaceutical

13 Development
 Quality by Design

Traditional
Process Validation (cont’d)
Process Validation Protocol
Three lots
Extensive and frequent sampling
More than routine testing
Proven homogeneity within a lot
Consistent product quality between three lots

Training Workshop on Pharmaceutical

14 Development
 Quality by Design
Traditional
Process Validation (cont’d)
Well documented Protocol and Report
Well prepared demo that product can be produced three
times
Resolution of all deviation
Investigation report with justification
Review and approval

Training Workshop on Pharmaceutical

15 Development
 Quality by Design
Traditional
Product Development . .
Complex multivariate physiochemical system
Treated as uni-variate system (one factor at a time)
Materials not well characterized
Process factors not well understood
Time crunch
Reluctant for post approval changes

Training Workshop on Pharmaceutical

16 Development
 Quality by Design
Traditional
Establishment of Product
Specification
Compendial (mostly)
Critical process parameter
Can be related to product safety and efficacy as per clinical
trials
Based on process capability
Literature
Experience
Training Workshop on Pharmaceutical
17 Development
 Design Space

Specification Internal Target

Control
Design Space

Space

Continuous improvement
without regulatory
Design Space
approval

Knowledge Space

Training Workshop on Pharmaceutical

18 Development
 Quality by Design
Future
ICH - Q8
Science Process Correlation
Development
Drug Product Real Time
DOE Development PAT
Statistic
CQA

ICH - Q9
Risk C&E ICH - Q6
Assessment CPP Specification

Investigation
Process Mapping

Training Workshop on Pharmaceutical

19 Development
 Quality by Design
Definition
Design of Experiment (DOE)
“Mechanistic understanding of how formulation and
process factors affect product performance and quality”.

Training Workshop on Pharmaceutical

20 Development
 Quality by Design
Definition
Process Analytical Technology (PAT)
“A system of designing, analyzing and controlling
manufacturing through timely measurements (during
processing) of critical quality attributes of in-process
materials and processes with the objective of ensuring
end product quality in each lot”.

Training Workshop on Pharmaceutical

21 Development
 Quality by Design
Definition
Risk Management
“Systematic process for the identification, assessment
and control of risk to the quality of pharmaceutical across
the product lifecycle”
FMEA “A structured process for identifying the way a
product or process can fail”

Training Workshop on Pharmaceutical

22 Development
 Quality by Design
Definition
Critical Quality Attributes (CQA)
“Property of a material, product or output of a process
that is key to the process performance”
Critical Process Parameters (CPP)
“A process parameter, e.g. temp, time, speed, when
variable it can affect the CQA of a product or process”
Cause and Effect Analysis (C&E)
“An investigational tool to find and quantify the cause
and effect relationship for a process or product failure”
Training Workshop on Pharmaceutical
23 Development
 Quality by Design
Good DOE requires
Scientific understanding of how formulation and process
factors effect product performance
Understanding and identification of CPP and their effects
on CQA
Experiment based on the principles of statistics
Identifying and studying the effect and interaction of
product and process variables
Use of the multivariate data analysis

Training Workshop on Pharmaceutical

24 Development
 Quality by Design
Risk Assessment
Process of risk assessment to mitigate risks
Identify the root causes of process failure
Help prevent problems from happening
Quantitative prioritization of potential failure
Improve quality and reliability of product
Documented proof of action taken to reduce and
eliminate risks
Key inputs of risk assessment
Training Workshop on Pharmaceutical
25 Development
 Quality by Design
Traditional
Online Control (QA Inspection)
– Statistical and process controls applied at manufacturing stage
(hard work after the examination)

Future
Offline Control (quality by design)
– Statistics and process engineering application at design phase
of the product

Training Workshop on Pharmaceutical

26 Development
 Quality by Design
Establishment of Product
Specification
Provide assurance to maintain product quality
Specification to confirm the quality vs characterization
Linked to manufacturing process
Account for the stability
Linked to preclinical and clinical studies
Linked to analytical procedures

Training Workshop on Pharmaceutical

27 Development
 Quality by Design
The outcome
Provision of greater understanding of pharmaceutical
and manufacturing sciences creates a basis for flexible
regulatory approach
Establishing a meaningful product specification (Q6) and
the risk-based approach (Q9) can create flexibility for the
continuous improvement (e.g. post-approval changes)
without the need for prior approval supplement
Industry can assist the CMC reviewer and GMP
inspectors by providing the optional information in CTD

Training Workshop on Pharmaceutical

28 Development
 Quality by Design
The outcome (cont’d)
Gives Industry the opportunity via a harmonized
standard to realize the full potential of Q8 and to utilize
Q9
Encourages and motivates Industry to improve and
optimize processes, equipment, facilities, systems and
procedures
Gives Regulators the confidence that Industry can be
responsible for greater self-management of
improvements and changes
– Companies with good quality management systems
– Well
Training controlled
Workshop processes and
on Pharmaceutical products
29 Development
 Future Vision Is Driven by ICH Q9

Manage risk to patient, based on science:

– Product, process and facility
– Robustness of Quality System
– Relevant controls to assess & mitigate risk
Level of oversight required commensurate with the
level of risk to patient for:
– Marketing authorization applications
– Post-approval change review
– GMP inspections

Ref: ICH
Training Workshop on Pharmaceutical
30 Development
 Quality Risk Management

 Quality: Degree to which a set of inherent properties of

a product, system or process fulfills requirements.
 Risk: defined as the combination of the probability of
occurrence of harm and the severity of that harm.
 Management: Systematic process for the
assessment, control, communication and review of
risks to the quality of the drug (medicinal) product
across the product lifecycle.

Training Workshop on Pharmaceutical

31 Development
 Pharmaceutical Development
 To design a quality product and its manufacturing
process to deliver the intended performance of the
product
 To provide scientific understanding to support the
establishment of design, specifications and
manufacturing
 Product development studies form a basis of quality
risk management

Training Workshop on Pharmaceutical

32 Development
 Pharmaceutical Development
 Quality cannot be tested in the product; it should be
built in by design
 Design space proposed by applicant is subject to
regulatory assessment and working within the space
is not a change
 Movement out of design space is considered to be a
change and requires post-approval change process

Training Workshop on Pharmaceutical

33 Development
 Pharmaceutical Development
 Critical aspect of drug substances, excipients,
container closure system and manufacturing process
should be determined
 Opportunities exist to develop more flexible regulatory
approach, e.g.
– Risk-based regulatory decisions
– Process improvement within the approved design space
without further regulatory review
– Reduction in post-approval submissions
– Real time quality control, leading to a reduction of end
product testing
Training Workshop on Pharmaceutical
34 Development
Q8: Pharmaceutical Development Paths
Current Understanding at ICH
API & Dosage Forms
For small & large molecules

Traditional (basic)
pharmaceutical Enhanced (QbD)
In-depth understanding of process
development

Process Design Space

Validation

Training Workshop on Pharmaceutical

35 Development
 Quality by Design
Summary
The quality of drug substances and drug products is
defined by their design, development, in-process
controls, process validation, and by specifications
applied to them throughout the development and
manufacture
With the use of mathematics and statistical approaches,
the DOE will prove theoretical critical control points in a
process
Optimum yield, reduce variation, build robustness in the
product and process requires Design of Experiment
Training Workshop on Pharmaceutical
36 Development
 Quality by Design
Summary (cont’d)
Optimization of product and process performance
Cost and Quality built in the product and process
Fast to market – substantial reduction of R&D cost and
time
Reduce complaints, recalls and on-conformances
Scientific approach toward setting the specifications

Training Workshop on Pharmaceutical

37 Development
 Thank you

Training Workshop on Pharmaceutical

38 Development