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

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

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

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

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)

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)

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

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

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

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

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: http://deming.eng.clemson.edu/pub/den/files/varman.txt http://deming.eng.clemson.edu/pub/den/files/varman.txt

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

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”

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

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

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

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

World Health Organization 8 April, 2017 Design Space

World Health Organization 8 April, 2017 Quality by Design

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”.

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”.

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”

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”

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

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

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

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

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

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

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

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.

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

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

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

Q8: Pharmaceutical Development Paths Current Understanding at ICH

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

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

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