“ich guidelines for the production of...

“ICH guidelines for the production of biologicals”ICH Q8, Q9, Q10, & Q11 QbD ICH Q7A

Lisa Gonzales- Sr. Regulatory Compliance SpecialistGE Healthcare Life Science- FAST TRAKEmail: Lisa.Gonzales@ge.com

2 /Rio UFRJ- ICH Guidelines /

August 6, 2009

Overview

Guidelines- ICH Q8, Q9, Q10 & Q11

Quality by Design (QbD)

August 6, 2009

“Pharmaceutical cGMP for the 21st Century: A Risk-Based Approach” Initiative- Aug. 2002

Integrate quality systems and risk management approaches into existing programsAdopt modern and innovative manufacturing technology Integrate pre-approval review and cGMP programs and achieve more consistent application across agency organization componentsUse existing and emerging science and analysis to ensure that limited resources address important quality issues, especially predicted or identifiable health risksIntended to modernize FDA’s regulation of pharmaceutical quality for veterinary and human drugs and select human biological products such as vaccines

August 6, 2009

Risk-Based Approach to Regulate Pharmaceutical Manufacturing

To keep pace with the many advances in manufacturing quality management

To enable the Agency to more effectively allocate its limited regulatory resources

The approach will be applied to the review, compliance, and inspectional components of FDA regulation

This approach will help the Agency predict where its inspections are likely to achieve the greatest public health impact

August 6, 2009

International Conference on Harmonization (ICH)

• Harmonization process- founded April 1990 • US, EU, & Japan• Six Parties (Expert Working Groups- EWGs)• Technical Topics- Safety, Quality, Efficacy,

Multidisciplinary• 5 step guideline process

August 6, 2009

ICH Guideline Interface

PRODUCT

LIFECYCLE

Pharmaceutical Development

Quality RiskManagement

Pharmaceutical Quality Systems

Technology Transfer

Manufacturing

Enhanced product & process

understanding

Risk management

Robust quality systems

Jeffrey Blumenstein, Pfizer

ConceptPaper

Harmonize submissions

August 6, 2009

ICH Q8- Pharmaceutical Development

Intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors

Indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches

The degree of regulatory flexibility is based on the level of relevant scientific knowledge provided (not the volume of data)

August 6, 2009

ICH Q8- Pharmaceutical Development

Goal: design a quality product and its manufacturing process to consistently deliver the intended performance of the product.

Information and knowledge gained from development studies and manufacturing experience provide:• Scientific understanding to support the

establishment of the design space, specifications, and manufacturing controls.

• Basis for risk management

August 6, 2009

ICH Q8(R1)- Pharmaceutical Development Revisions 1

Pharmaceutical development should include, the following elements:• Defining the target product profile as it relates to Q, S and E• Identifying critical quality attributes (CQAs) of the drug

product, so that those product characteristics having an impact on product quality can be studied and controlled

• Determining the quality attributes of the drug substance, excipients etc. to deliver drug product of the desired quality

• Selecting an appropriate manufacturing process • Identifying a control strategy

August 6, 2009

FDA Challenge to Industry

At the end of the cGMP initiative, the pharmaceutical community has arrived at a crossroad: one path leads towards the desired state* and the other maintains the current state

The path towards the desired state is unfamiliar to many while the current state provides the comfort of predictability

FDA hopes the pharmaceutical industry will choose to move towards the desired state

Marion Weinreb, “Quality by Design” April 2008

desire

dcurrent

*pharmaceutical development using QbD approach

August 6, 2009

Approaches to Pharmaceutical Development

Minimal Approach (current)

Development • Mainly empirical• Developmental research often

conducted one variable at a time

Manufacturing Process• Fixed • Validation primarily based on initial

full-scale batches • Focus on optimization and

reproducibility

Enhanced (QbD) Approach (desired)

Development • Systematic, relating mechanistic

understanding of input material attributes and process parameters to drug product CQAs

• Multivariate experiments to understand product and process

• Establishment of design space • PAT tools utilized

Manufacturing Process• Adjustable within design space • Lifecycle approach to validation and,

ideally, continuous process verification

• Focus on control strategy and robustness

• Use of statistical process control methods

ICH Q8(R1)- Appendix 1

August 6, 2009

Benefits of the “Enhanced Approach”

• Post- approval CMC regulatory submissions

• Recalls and manufacturing failures

• Uncertainty & Risk

• Costs

• Regulatory burden

• Low value regulatory and/or compliance exercises

• Need for Process Validation

• Documentation

• Regulatory flexibility

• Process understanding “DIRFT”

• Application of technology: e.g., PAT & NIR

• Quality

• Regulatory review criteria

• Scientific/technical literacy among regulators

• Development efficiency

• Global harmonization

Marion Weinreb, “Quality by Design” April 2008

August 6, 2009

ICH Q9- Quality Risk Management

Outlines approaches for producing quality pharmaceutical products using science and risk management Intended to provide a practical risk management toolbox implementation of the pharmaceutical development (Q8) and quality systems (Q10)• to evolve a more harmonized and flexible quality oversight processApplies to drug substances, drug products, biological and biotechnological products Supports science-based decision making throughout the product lifecycle• Effective and consistent risk-based decisions

− “Can improve decision making if a quality problem arises”• Regulatory authorities and industry

− Provides regulators with greater assurance of a company’s ability to mitigate potential risks

− Impacts direct regulatory oversight- extent and level

August 6, 2009

ICH Q9- Principles Of Quality Risk ManagementRisk- combination of the probability of occurrence of harmand the severity of that harm

Principles:

• The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient

• The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk

− Aseptic processing- usually high risk− Stable API with minimal degradation in product formula-

probable low risk for stability

August 6, 2009

ICH Q9- Risk Management Process

August 6, 2009

ICH Q10 Pharmaceutical Quality SystemQ10 incorporates the concepts behind ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management” by providing a model for a pharmaceutical quality system that can be implemented throughout a product life cycle

Q10 is meant to complement and add to current good manufacturing practices

The overall goal is to: • facilitate innovation and continual improvement• strengthen the link between pharmaceutical development

and manufacturing activities

Angie Drakulich ePT--the Electronic Newsletter of Pharmaceutical Technology, June 2008

August 6, 2009

ICH Q10 Pharmaceutical Quality System: Objectives

Outlines expectations for the Pharmaceutical Quality Systems and how they can be applied in the management of the:• Design space• Risk assessment Ensure that quality standards are met over the lifecycle of the

product • Quality attributes to meet patient needs• Establish and maintain a state of control

− Process performance and product quality • Facilitate continual improvement

− Product quality, process improvements, reduce variability, innovations, enhance quality system

“PQLI Design Space” ISPE May 2008-John Lepore & James Spavins

August 6, 2009

ICH Q11- Development and Manufacture of Drug Substances

Concept Paper- Key items

Requirements harmonization

High level technical guidance relevant to the design, development, and manufacture of drug substances as part of a total control strategy

Provide guidance for drug substances (Q6A & Q6B)

Identify similarities and differences between biologics and chemical entities

August 6, 2009

ICH Q11- Development and Manufacture of Drug Substances: Guideline Goals

Harmonize submissions• What goes into the CTD• Facilitate regulatory evaluation process

Outline science-based concepts

Offer and recommend approaches for demonstrating process and product understanding

Address the complexity of different manufacturing process & products

Address systematic and enhanced approaches (including design space, control strategies, & real-time release)

August 6, 2009

ICH Q11- Development and Manufacture of Drug Substances: Challenges

Biologics vs. Chemical EntitiesDevelopment Approach• Systematic• EnhancedManufacturing• Validation Level of Detail• Enough to be useful• Not so much to be prescriptive

Quality by Design

August 6, 2009

Definitions

Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property orcharacteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality

Critical Process Parameter: A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality

Proven Acceptable Range: A characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria

Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management

Real-time release: The ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data, which typically include a valid combination of assessed material attributes and process controls.

August 6, 2009

Quality by Design is

• Designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process

• Quality by design, in conjunction with a quality system, provides a sound framework for the transfer of product knowledge and process understanding from drug development to the commercial manufacturing processes and for post-development changes and optimization

Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations Sept 2006

QbD is a systematic approach to development

August 6, 2009

Quality by Design is

“…products and processes that make them are designed in advance to meet their product quality specifications and process control requirements.”“…is based on solid science, valid statistical tools, and sound management techniques that have proven their industrial value for many decades.”This includes:Product profilingExperimental designProcess mappingRisk assessment Automated process controls

Torbeck and Branning BioPharm Int’l May 2009

Goal: to apply these tools in a structured manner

August 6, 2009

Quality by Design Approach

A systematic evaluation, understanding and refining of the formulation and manufacturing process, including: • Identifying, through e.g., prior knowledge, experimentation, and risk

assessment, the material attributes and process parameters that can have an effect on product CQAs

• Determining the functional relationships that link material attributes and process parameters to product CQAs

Using the enhanced process understanding in combination with quality risk management to establish an appropriate control strategy which can, for example, include a proposal for design space(s) and/or real-time release

As a result, this more systematic approach could facilitate continual improvement and innovation throughout the product lifecycle (See ICH Q10 Pharmaceutical Quality System).

August 6, 2009

QbD Structure

Establishing the relationship between quality attributes and clinical performance

Allows more effective dialogue between industry and regulator during review process*• Shows the connection between Design Space,

Criticality and Control Strategy• Reducing change filings snags

*“PQLI Design Space” ISPE May 2008-John Lepore & James Spavins

August 6, 2009

Regulatory Flexibility: Why?

Facilitate continuous improvement and innovation to improve quality, efficiency, knowledge, and availability

High level of process understanding and control capability can further improve our ability to ensure quality on every batch • compared to a validated process with insufficient

understanding and for which “state of control" is based primarily on compendial testing

The PAT Guidance

CPG 7132c.08

August 6, 2009

Regulatory Flexibility: How?

Quality by design• Structured product and process development• Process understanding and control capability• Design space

Integration of prior knowledge and pharmaceutical development into C, M, C submission and review• Present the knowledge gained to provide a more comprehensive

understanding of the product and manufacturing process for reviewers and inspectors

• Risk based assessment and investigations and knowledge sharing (over a product’s life cycle)

The PAT Guidance ICH Q8 (9 &10)CPG 7132c.08

August 6, 2009

Risk Management

• Risk Assessment

• Risk Control

• Risk Communication

• Risk Review

1. What might go wrong?

2. What is the likelihood (probability) it will go wrong?

3. What are the consequences (severity)?

Risk assessmentSteps

ICH Q9, Quality Risk Management

Types of risk: patient safety, regulatory, business

August 6, 2009

Quality by Design Concept

• Quality cannot be tested into products.

• It has to be built in by design

ICH Q8, Pharmaceutical Development, May 2006

This design incorporates knowledge of the product and the process to ensure all critical quality parameters are adequately controlled.

Barry Cherney, Deputy Director, DTP/OBP/CDER, Oral Presentation, Quality by Design: A Perspective From the Office of Biotechnology Products, PDA Annual Meeting, April 2006

August 6, 2009

“Design Space”

The established range of process parameters that has been demonstrated to provide assurance of quality

Working within the design space is not generally considered as a change of the approved ranges for process parameters…

Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process

ICH Q8, Pharmaceutical Development, May 2006

August 6, 2009

Design Space…

“Is linked to criticality through the results of risk assessment, which differentiates between those product attributes and process parameters that are critical to product quality”

Once Critical Quality Attributes and Critical Process Parameters are identified and understood, they will need to be controlled

“PQLI Design Space” ISPE May 2008-John Lepore & James Spavins

August 6, 2009

A Process is well understood when…

All critical sources of variability are identified and explained

Variability is managed by the process

Product quality attributes can be accurately and reliably predicted over the design space …

The PAT Guidance

August 6, 2009

Process Robustness

• The ability of a process to demonstrate acceptable quality and performance while tolerating variability in inputs

• Requires − Robustness/characterization studies utilizing DoE− Understanding manufacturing capabilities in

development• Enables definition of “design space”

August 6, 2009

Process Robustness/Characterization Studies

These studies provide a further understanding of the relationship between process and product • identify critical parameters• identify limits of each parameter• test to limits• test to failure, where appropriate• results not predefined

Adapted from A. Mire-Sluis, Principal Advisor to Director-Product Quality OTTR, CBER, FDAIBC Process Validation for Biologicals, March 2003

August 6, 2009

Design Space for Biotech ProductsAcceptable Range

Operating Range

Characterization Range

Process characterization

studies

Acceptable variability in Key & Critical

Quality Attributes

(CQAs)

Rathore, Branning, Cecchini (April 2007)

August 6, 2009

Knowledge BaseProduct-specificProcess-specific

Quality Risks

Quality Life Cycle

Confirm(Control/Predict)

Conformance Lots“Validation Studies”

MonitorPost-Approval

Optimize(Continuous

Improvement Innovation)

Change Control

ProposeDesign- Evaluation (Quality by Design)

Identify(Critical/Key Parameters & Ranges)

DevelopmentStudies Process Characterization(DOE, EOF, robustness)

Patrick Swann, Ph.D. FDA-CDER, Quality by Design for Biopharmaceuticals: Concepts and Implementation.

PDA Workshop May 2007

Risk assessment(FMEA)

August 6, 2009

RobustnessCharacterization

Process validation

Manufacturing of licensed productProcess U

nderstanding

Design Space

Quality by Design

Risk Assessment

Design Space

August 6, 2009

Where are we today?

*Early development: Knowledge for QbD is very limited or nonexistent

Licensed products: Knowledge is often limited for many biotech products

Quality by design is NOT quality by control

Quality by design enables rational design• e.g., protein engineering

**The QbD approach is still eyed with caution. Many voiced concerns that they would invest time and resources in a QbD approach and regulators would still rigidly link specifications to clinical experience.

“We have very little experience with QbD, but we are interested in getting some.” Steve Kozlowski, MD, CDER, FDA

*Adapted from Barry Cherney, Deputy Director, DTP/OBP/CDEROral Presentation, Quality by Design: A Perspective From the

Office of Biotechnology Products, PDA Annual Meeting, April 2006

**BioQuality Feb. 2008: California Separation Science Society- Wash. DC Jan 2008 meeting

August 6, 2009

QbD Case Study- Regulatory Emphasis & Lifecycle Validation Thinking

A firm recently received an FDA injunction.

Judge’s order: “defendant shall establish and follow scientific product development and manufacturing process design procedures…to control all significant variables, including material attributes and processing parameters, affecting the process materials and final drug product specifications and quality attributes. ”

Demonstration of a firm manufacturing multiple products not in a state of control.

Key is lack of process validation and related issues-• Development, science, technology, use of investigations,

handling deviations, etc.FDA CDER Official ISPE Conference June 2009International Pharmaceutical Quality May/June 2009

August 6, 2009

Successful Implementation of QbD

Product meets patient needsProcess consistently meets its CQAsUnderstood impact of formulation components and process parameters on quality Identification and control of critical sources of process variability (using PAT)Process continually monitored and updated to assure consistent quality over timeWill require multi-disciplinary and multi-functional teams working togetherMeet FDA expectationsReduce Cost

ICH Q7A

GMP Guidance for Active Pharmaceutical Ingredients

August 6, 2009

ICH Q7A Objective

Provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality.

Define manufacturing operations to include:• Receipt of materials• Production• Packaging • Repackaging• Labeling and relabeling• Quality control • Release• Storage• Distribution of APIs and the related controls

August 6, 2009

ICH Q7A- Section 18

SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION

Covers cell culture, fermentation (CCF), tissue or animal sources including transgenic animals

Early process steps may be subject to GMP but are not covered by Q7A (e.g., cell banking)

Vaccines are not included

Should not use as a stand-alone section

August 6, 2009

ICH Q7A- Section 18: Cell Culture and Fermentation

All previous sections apply to CCF but some issues not in adequate detail

Complexity:• Inherent heterogeneity• Full characterization is difficult• Contamination potential with infectious agents• Sensitivity to subtle or minor process changes

− Changes in the process, facilities or equipment may lead to unexpected product quality

• Manufacturing process contributes to product definition• Process includes facility, equipment, quality of materials

August 6, 2009

Doesn’t cover:• Cell bank creation (ICH Q5D)• Nature of the organism used in manufacturing or

herd maintenance differences• Descriptions of different systems (roller bottles,

fermentors, bioreactors, etc.) transfer methods or monitoring information

• Custom features- inducible or selection systems

August 6, 2009

Greater controls• To prevent (and detect) contamination

− Monitor endotoxin & bioburden for materials and/or process o Manufacturer defines acceptable limits at each stage

− Design adequate ventilation and exhaust systems• For biotechnology products than classical fermentation • For classified environments and EM programs• Validated reprocessing steps• Equipment sterilization between batches (cleaning validation section 12.7)• Water quality (Purified Water or WFI)• Viral removal/inactivation

− Critical steps should be under validated parameters − Pre and post inactivation activities clearly defined (SOPs, equipment,

segregation) − Go to Q5A

August 6, 2009

ICH Q7A- Section 19

APIs FOR USE IN CLINICAL TRIALS

Why is there a special section?• Processes and controls change during

development • Few batches may be identically produced• Batches frequently produced in small non-

commercial scale equipment

August 6, 2009

Final notes-1

Know thy process, know thy productRegulatory Emphasis & Lifecycle Validation Thinking• Cost of Quality System failure and not implementing

ICH guidelines through product lifecycleQ7A- default international standard for GMP in the API industry• FDA can’t enforce but is a position of high influenceIPQ predicts Q8, annex, Q9, & Q10 will become an FDA expectation

August 6, 2009

Final notes-2If your company has:• Good design and control

strategies• Good Risk Management

Practices• Good Quality Systems

Regulatory Quality System

Quality Risk Management

Quality by DesignQ8

Pharmaceutical Quality System

Decreased:

Regulatory oversight

Submissions for changes/variations

Inspection of Quality Systems

August 6, 2009

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