training workshop on pharmaceutical development with a focus on paediatric medicines / 15-19 october...

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20071 |

Regulatory Aspects of Product Development

ICH Process Q8, Q9, Q10

WHO Workshop, October 2007

Regulatory Aspects of Product Development

ICH Process Q8, Q9, Q10

WHO Workshop, October 2007

Sultan Ghani, DirectorBureau of Pharmaceutical Sciences

Therapeutic Products Directorate, Health Canada


Focus of PresentationFocus of Presentation

ICH Process

ICH Q8, Q9, Q10

Pharmaceutical Development


ICHICH

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


ICHICH

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


ICHICH

ICH STRUCTUREFounding 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)


ICHICH

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)


The Five Steps in the ICH Process forHarmonization of Technical Issues

The Five Steps in the ICH Process forHarmonization 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


“risk-based”

concepts and principles of ICH

New Era With New Challenges

Q8Q9 Q10Ref: ICH


Pharmaceutical Development PathsPharmaceutical Development Paths

Q8

Traditional pharmaceutical

developmentQbD

DOEFactorial design

DOEMultivariate analysis

FME(C)AEssential DOE

Process Validation

Design SpaceFor Continuous Improvement

Q8 is not yet finalized by ICH


ICH’s Vision of the FutureICH’s Vision of the Future

Adapted from EFPIA, PAT Topic Group, 2005

Traditional ApproachQbD 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.

QualityPost-manufacture sampling and quality testing.Process Validation.

Management of variabilityProcess control focused on critical attributes.Continuous Quality Verification.

SystemsSystems 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.

RegulatoryCompliance focus.Changes require prior approval.

Regulatory scrutiny adjusted to level of Process Understanding. Continuous improvement allowed within Design Space.


QbD- a Well Known Concept of the 50’sRef: Out of Crisis (1986): W. Edwards Deming

QbD- a Well Known Concept of the 50’sRef: 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.txthttp://deming.eng.clemson.edu/pub/den/files/varman.txt


Traditional PD vTraditional PD versusersus QbD QbDTraditional PD vTraditional PD versusersus QbD 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


Quality by DesignQuality 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”



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



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



TraditionalProduct 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



TraditionalEstablishment of Product

SpecificationCompendial (mostly)Critical process parameterCan be related to product safety and efficacy as per clinical

trialsBased on process capabilityLiteratureExperience


Design SpaceDesign Space

Design SpaceControlSpace

Internal TargetSpecification

Continuous improvementwithout regulatory

approval Design Space

Knowledge Space



Future

Science

Statistic

Correlation

DOE PAT Real Time

CQA

C & ECPP

Investigation

ICH - Q8Process

Development

Drug ProductDevelopment

Process Mapping

ICH - Q9Risk

Assessment

ICH - Q6Specification



Definition

Design of Experiment (DOE)

“Mechanistic understanding of how formulation and process factors affect product performance and quality”.



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”.



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”



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”



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



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



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



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



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



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 Q9Future 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 ManagementQuality 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 DevelopmentPharmaceutical 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



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



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 PathsCurrent Understanding at ICH

Q8: Pharmaceutical Development PathsCurrent Understanding at ICH

API & Dosage FormsFor small & large molecules

Traditional (basic)pharmaceutical

development

Enhanced (QbD)In-depth understanding of process

Design SpaceProcess Validation



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



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


Thank youThank you

training workshop on pharmaceutical development with a focus on paediatric medicines / 15-19 october...

Documents

ich future of ich

ich background ich

harmonization ich

training workshop

paediatric medicines

ich ich structure contd

future activities of

current ich guidelines