1. World Health Organization
8 April, 2017
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

2. World Health Organization
8 April, 2017
Focus of Presentation
ICH Process
ICH Q8, Q9, Q10
Pharmaceutical Development

3. World Health Organization
8 April, 2017
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

4. World Health Organization
8 April, 2017
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

5. World Health Organization
8 April, 2017
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 America (PhRMA)

6. World Health Organization
8 April, 2017
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)

7. World Health Organization
8 April, 2017
The Five Steps in the ICH Process for Harmonization of Technical Issues

8. New Era With New Challenges
World Health Organization
New Era With New Challenges
8 April, 2017
“risk-based”
concepts and principles of ICH Q8 Q9
Q10
Ref: ICH

9. Pharmaceutical Development Paths
Q8 is not yet finalized by ICH
Design Space
For Continuous Improvement

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

11. QbD- a Well Known Concept of the 50’s Ref: Out of Crisis (1986): W
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:

12. 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

13. World Health Organization
8 April, 2017
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”

14. World Health Organization
8 April, 2017
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

15. World Health Organization
8 April, 2017
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

16. World Health Organization
8 April, 2017
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

17. World Health Organization
8 April, 2017
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

18. World Health Organization
8 April, 2017
Design Space

19. World Health Organization
8 April, 2017
Quality by Design

20. World Health Organization
8 April, 2017
Quality by Design
Definition
Design of Experiment (DOE)
“Mechanistic understanding of how formulation and process factors affect product performance and quality”.

21. World Health Organization
8 April, 2017
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”.

22. World Health Organization
8 April, 2017
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”

23. World Health Organization
8 April, 2017
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”

24. World Health Organization
8 April, 2017
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

25. World Health Organization
8 April, 2017
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

26. World Health Organization
8 April, 2017
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

27. World Health Organization
8 April, 2017
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

28. World Health Organization
8 April, 2017
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

29. World Health Organization
8 April, 2017
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 controlled processes and products

30. 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

31. 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.

32. Pharmaceutical Development
World Health Organization
8 April, 2017
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

33. Pharmaceutical Development
World Health Organization
8 April, 2017
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

34. Pharmaceutical Development
World Health Organization
8 April, 2017
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

35. Q8: Pharmaceutical Development Paths Current Understanding at ICH

36. World Health Organization
8 April, 2017
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

37. World Health Organization
8 April, 2017
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

38. Thank you