Narke Pda Orlando Mar2010 Boot Camp Final

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Boot Camp for FDA CMC/GMP Initiatives for Biotech and Specialty Pharma

Design Space InPharmatics LLCEdward A. Narke

PDA Annual ConferenceMarch 1417, 2010 – Orlando

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Company Information

Design Space InPharmatics (DSI) is a consulting firm providing integrated CMC drug development and CMC Regulatory services to emerging pharmaceutical and biotechnology companies

DSI provides support for its customers from the initial phases of development through successful manufacturing and Regulatory approval

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Objectives of the Presentation

Provide a perspective of the Quality‐by‐Design application for the start‐up to midsize sponsor

Provide a perspective on how CTD Module 3 might be constructed in parallel with milestone target planning during Phase development

Improve alignment with Regulatory expectations, place greater emphasis on sharing critical scientific information essential to regulatory decision making, and help enhance the efficiency of the Regulatory process

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Outline of the Presentation

Drivers for QbD

Why it‘s worth the Effort ‐ Providing Business Benefits

Incentives and Barriers

Examples of how it can work

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Drivers for Quality by Design

Prompted by ICH 1, 2> “Assurance of product quality is derived from careful attention to a number of

factors including selection of quality parts and materials, adequate product and process design, control of the process, and in‐process and end‐product testing.”

> “Due to the complexity of today’s medical products, routine end‐product testing alone often is not sufficient to assure product quality for several reasons.”

More efficient change control assessment; fewer amendments, reduced testing, easier problem solving, less production downtime, fewer failed batches etc.

Empirical approach, anecdotal (disconnected) data still acceptable today, however QbD is the future – so be prepared!

1. ICH Q8, Q9 Q10

2. Guidance for Industry PAT —A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

Drivers

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QbDIntroduced into the CMC review process in 2004 as a result of the pharmaceutical current Good Manufacturing Practice (cGMP) for the 21st Century Initiative

Expectations outlined in PAT Guidance and ICHQ8, Q9 and Q10

Proposed implementation comprised of 5 key steps> Identification of Product Attributes of significant importance to

safety/efficacy

> Quality Target Product Profile (TPPP)

> Critical Quality Attributes (CQAs)

> Design of the Process to deliver these attributes

> A Robust Control Strategy to ensure consistent Process Performance

> Validation and Regulatory Filing of the Process

> Demonstrating the effect of the Control Strategy

Drivers

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QbDFamiliar Foundation for these activities include:> Risk Assessment

> Raw material management

> Use of Statistical Approaches

> PAT etc.

Several Case Studies have already been published highlighting benefits> Yu, L.X. et al. (2004) Applications of process analytical technology to crystallization process. Adv. Drug Deliv. Rev.

56, 349–369

> Gnoth, S. et al. (2007) Process analytical technology (PAT): batch‐to‐batch reproducibility of fermentation processes by robust process operational design and control. J. Biotechnol. 132, 180–186

> Nail, S.L. and Searles, J.A. (2008) Elements of quality by design in development and scale‐up of freeze‐dried parenterals. BioPharm Int. 21 (1), 44–53

> Harms, J. et al. (2008) Defining design space for biotech products: case study of Pichia pastoris fermentation. Biotechnol. Prog. 24, 655–662

Drivers

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Why it‘s worth the effortQbD goal: Use resources in the most efficient manner by producing a better quality data package which will provide flexibility throughout the API/product life cycle> Collect the right data, not necessarily more data*

> Data that is information rich, building product knowledge

> Avoid checkbox mentality*

> Get the most mileage from experiments throughout development. E.g.., use early data/knowledge base to guide DoE – requires initial hard data as input

> Easier to respond to questions from the Agency

Why?

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Why it is worth the effort?

QbD provides a chance to develop new ideas and opportunities to explore new options to meet regulatory requirements and operational flexibility> Gain experience for future Agency expectations

> Still collecting data, but in a different manner

Why?

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Incentives and BarriersCaveats:> Extra effort, DoE in development (Increased $ spent initially during development to define design space = potential returns)‐ Gain Savings depends on project, timing – not guaranteed!

‐ Payoff may be delayed until post approval

‐ Why does it make good business sense to start a QbD effort when 90% of the candidates fail to make it to market?

> Internal fear within companies to push the boundaries / fear of failure and resistance to change – especially near filing time.


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Incentives and BarriersCritical Role of Startups and FirstProduct Companies

Business Perspective

> Provide a new pipeline for New Products

> Return a profit to stakeholders

Regulatory Perspective

> Address recent initiatives and expectations moving forward‐ Quality by design (QbD) continues to receive much attention.

‐ Although several QbD concepts are being practiced, continued dialogue and partnership between the industry and its regulators will be the key to successful QbD realization


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Incentives and BarriersThe Facts

“The degree of sponsor experience with FDA regulations and procedures is generally of importance. Large USbased companies have the highest firstcycle approval rate, at approximately twice the rate of small biotechnology companies with no prior FDA approvals.

The underlying drivers seem to be lack of personnel with US regulatory experience and suboptimalinternal regulatory processes’”(1)

1. Independent Evaluation of FDA's First Cycle Review Performance Retrospective Analysis Final Report, Booz, Allen, Hamilton. FDA (January 2006).


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Incentives and BarriersShortfall of Startups and FirstProduct Companies

Management in these companies encounter the constant pressure of

> Raising funds

> Building a creative and effective team

> Keeping ahead of the competition

Focus is on ensuring a viable and effective clinical development strategy to keep the product moving forward

CMC Clin/Nonclinical

Medical Affairs

Pharm/Tox

Clinical Research

CMC Operations

Quality Assurance

CMC Regulatory


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Incentives and BarriersConsequences of Shortfalls

In many instances

> Few resources are available to devote to the challenge of developing a viable and effective longterm CMC regulatory strategy

Lack of focus in this area, coupled with frequent lack of CMC regulatory compliance experience can be a formula for disaster

CMC Clin/Nonclinical


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Barriers

Challenges (in the new economy)> Little control on knowledge base for late stage in‐licensed, acquired compounds‐ Gaps exist between FIH and POC

> Late changes in process, methods etc. that limit the utility of previous data

> When using Contract Manufacturing ‐ Gaps occur between vendors

‐ Lack of sharing the knowledge between sponsor and CMO

‐ Limited resources do not allow for scientific understanding


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Incentives

Motivation for Business Benefit> Better scientific understanding, easier decisions, (less data and samples to manage?)

> Need commitment and better understanding of the benefits to build momentum (QbD is extra work during development, streamlining will be a challenge)

> When using Contract Manufacturing ‐ Create an environment of knowledge sharing


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Milestone planning

QbD Blueprint

Development Phases

Example of how it might workHow it might Work

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Milestone planning – Everyone has a Target

QbD Blueprint

Development Phases

Example of how it might workHow it might Work

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Discovery Pre‐INDEarly Dev (Phase 1/2)

POC(Phase 2/3)

Registration Post‐Approval

Planning andDefinition Phase

CMC‘s Role in the Development ProcessMilestone Planning

DISCOVERY NEW CHEMICAL ENTITY PRODUCT DEVELOPMENT

PRECLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW

Synthesis & Purification

Formulation/Process Optimization

Phase 1

Phase 2

Phase 3

Accelerated Development/Review

Manufacturing

Treatment IND

Parallel TrackAnimal Testing

ShortTerm

LongTerm

2 5 years 1 3 years 8 15 years

IND submitted

Lead Identification

Lead OptimizationIdentify Candidate

Synthesis & Characterization

ScreeningPreFormulation

Assays for Therapeutic Efficacy

Institutional Review Boards

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Design Phase = Building the Basics•API Route scouting•API Impurity Identification•API Solid Form Selection•Initial Risk Assessment•Tox Formulation•FIH Formulation

Optimize Phase = Building Robustness•API Alternate Route Scouting•To‐Be Marketed, Formulation Design•Site Transfer•QbD/PAT•IVIVC

Continuous Improvement

Confirmation Phase = Product Knowledge•Process Optimization•Design‐space defined•Validation via QbD•Optimization within filied ranges•Post‐launch support•Life Cycle Strategy

You Must Have a Target!Milestone Planning

IND submitted

What?

What causesWhat?

And How?

NDA submitted


POC(Phase 2/3)


What is correlatedto What?

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Management of Targets in the CTD

Management of Knowledge in Module 3

> Provide interwoven experimental evidence that supports a more systematic approach to product development.

> Emphasize critical knowledge, analysis and assessment

Start with standardized templates> Provides framework for most CMC dossier projects

> Ensures proper implementation of regulatory strategy in dossier filings

‐ Enhances quality and reduces risks in CMC dossier projects

> Helps achieve on‐time delivery of NDA/MAA CMC investigational and marketing application filings

Milestone Planning

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Manage Knowledge in Module 3

Compliance DataAPI and Product general properties

Control of starting materials and Excipients

Control of reagents, solvents, auxiliary materials

Control of intermediates

Elucidation of API structure

List of impurities

Specifications

Milestone Planning

Justification of Specification

Methods

Validation of methods

Analytical development history

Typical batch data

Reference standards

Stability

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Manage Knowledge in Module 3

Continuous Conformance DataUse CTD Module 3: P2, S26 and S45, P55 as the primary review documents

Present to regulators all they need to know to make an approval decision

Present a compelling description and critique of the Quality component in the CTD to make it information and knowledge rich

Milestone Planning

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Manage Knowledge in Module 3P.2.1 Components of the Drug Product

> Which physical chemical characteristics of the drug substance affect drug product development, manufacture, or performance?

> What evidence supports compatibility between excipients and the excipients and the drug substance?

P.2.2 Drug Product

> What attributes should the drug product possess?

> How was the drug product designed to have these attributes?

> What (if any) were alternative formulations or mechanisms that have been investigated?

> How were the excipients and their grades selected?

> How was the final formulation optimized?

> What are the design space for critical parameters and attributes, and how justified?

P.2.3 Manufacturing Process Development

> Why was the manufacturing process described in P.3 selected for this drug product?

> How are the manufacturing steps (unit operations) related to the drug product quality?

> How were the critical process parameters identified, monitored, and/or controlled?

> What is the scaleup experiencewith the unit operations in this process?

> What are the design space for critical parameters and attributes, and how can they be justified?

Milestone Planning

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Manage Knowledge in Module 3Milestone Planning

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Milestone planning

QbD Blueprint – Creating the Data> Build Quality Target Product Profile

> Identify CQAs

> Characterize Design Space

> Identify Control Strategy

> Validation the Process

> File the Data

Development Phases

Blueprint for how it can workBlueprint

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Blueprint for QbD – An Overview

QbD Blueprint

Build Quality Target Product Profile (QTPP)

Identify Critical Quality Attributes (CQAs)

Characterize Design Space

Identify Control Strategy

Validate the Process

File the Data!

Blueprint

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QbD Blueprint

Build Quality Target Product Profile (QTPP)

QTPP

CQAs

Design Space

Control Strategy

Validation

File the Data

Key Questions

Conditions/Features

Basis/Considerations

Milestone/Result ‐Further Actions

What would need to be achieved to ensure that quality affecting safety and efficacy is realized?Start at the End and work backwards!

Build a ‘‘prospective” summary of the quality characteristicsDosage form and route of administration strength(s) Therapeutic moiety release or delivery

Pharmacokinetic characteristics (e.g. dissolution and bioavailability) appropriate to the dosage formQuality criteria (e.g. sterility and purity)

QTPP should be established as soon as product has been identified as a viable candidate for commercialization and should be revisited at key stages of developmentForms the basis of design for the product

QTPP

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QbD Blueprint

Identify Critical Quality Attributes (CQAs)

QTPP

CQAs

Design Space

Control Strategy

Validation

File the Data

Key Questions

Conditions/Features

Basis/ Considerations


Desired attributes of a successful Product include?What are the relevant CQAs?

Attributes known to impact safety and efficacy (such as dissolution, sterility, solubility or aggregate species) rank high in criticality To have no impact on safety and efficacy (such as qualified impurities) rank low in criticality

The Critical Attributes used to guide the product and process development!Along with QTPP, forms the basis of Design for the product!

CQA identification can be performed using risk‐based analysis, in accordance with the ICH Q9 guidance Risk assessment should account for design of the molecule (hot spots); engineering studies, non‐clinical studies, clinical studies with the product and/or other platform products; and published literature

CQAs

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QbD Blueprint

Design and Characterize

QTPP

CQAs

Design Space

Control Strategy

Validation

File the Data

Considerations

Characterizing the Product Design SpaceOnce CQAs have been identified, the concept of design space can be extended to product qualityThis product design space should be documented in the regulatory filing in the form of in‐process and release specifications that define the acceptable variability in CQAs

Characterizing the Process Design SpaceProcess characterization studies can be used to define the acceptable variability in process parametersThe approach for defining a process design space has been discussed often in the literature e.g. risk analysis, design of experiments (DOE), linkage of the inputs versus the critical attributesThe acceptable ranges for a process should be documented in the regulatory filing.

Design Space

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QbD Blueprint

Identify Control Strategy

QTPP

CQAs

Design Space

Control Strategy

Validation

File the Data

Key Questions

What assures process performance and product quality?What are the controls, derived product and process understanding that assures process and product quality?

Will depend of the criticality of the quality attribute and capability of the process and analytical methods

Using an active control strategy allows manufacturing controls to be altered (within the design) to remove or reduce the variability caused by process inputsQC moved Upstream!

IPC testing Raw material controlsSpecificationsProduct characterizationContainer closure systemStability studiesValidationComparability studies

Control Strategy



Conditions/Features

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QbD Blueprint

Validation of Process and Control Strategy

QTPP

CQAs

Design Space

Control Strategy

Process Validation

File the Data

Conditions/Features


Regulatory filing is then compiled, to include Knowledge Linkages

Acceptable ranges for all key and critical operating parameters that define the designed process space, in addition to the more restricted operating space (NOR, PAR) typically described today

Control strategy defined and the product and process design spaces are establishedValidation to demonstrate that the process will deliver a product of acceptable quality if operated within the design space

Validation

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Regulatory SubmissionQbD Blueprint

QTPP

CQAs

Design Space

Control Strategy

Process Validation and Filing

Regulatory Filing

Key Questions


Conditions/Features


Internal quality system of the manufacturer needs to provide adequate oversight during QbD implementation to any changes occurring that do not have to pass through regulatory review and approval

Does your Knowledge have linkages?What does the Agency say?

Can process improvement during the product life cycle in terms of process consistency and throughput be approved with reduced submissions?

With a design space developed and approved under the QbD paradigm, process changes within this design space will not require further review or approval?Any changes to the design space itself need to be characterized, validated and approved by the regulatory authorities prior to implementation

Reg Filing

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Cross reference between CTD section P2 (Pharm. Development) and relevant sections in S (Drug Substance) and in P (Drug Product)

‐ S 1.3 Properties of the active substance

‐ S.2 Manufacture

‐ S 3.1 Studies on Polymorphism (experimental data)

‐ S 4.1 Specifications relating to control of physical forms

‐ S.4.3 Analytical methods used

‐ S 4.5 Justification of Specifications

‐ P 2: Influence of the polymorphic forms on product characteristics – dissolution, stability

‐ P 5.1 Product Specifications

‐ P 5.6 Justification of Specifications

Examples of a LinkagesReg Filing

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QbD – Collecting the Data

Key question: How and when to invest in process science and process characterization to really get to know the manufacturing process and its outcome

Basics: This investment should be made wiselyunderstanding the science does not come cheap

Marginal conditions: ‐ Seek out regulatory authority advice ‐ It’s not about a company believing that it

knows more about its process and product than the regulatory authority

‐ It’s about involving the regulatory authority as a team player

Milestones: ‐ A reality check for your CMC regulatory compliance strategy at any transition

Blueprint

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Milestone planning

QbD Blueprint

Development Phase> Pre‐IND

> Initiating Phase 1

> Early Clin Dev

> Clinical Transition from Phase 2 to Phase 3

> POC to Registration

> Continuous Improvement

A Target for each MilestoneDevelopment Phases ‐ Overview

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Development Phases ‐ Overview

Development Phases

Pre‐IND

Initiating Phase 1

Early Clin Dev

Transition from Ph 2 to Ph 3

POC to Registration



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Critical Role of Integrated Planning

Not in the Guidances

Applies to Small Molecules, Biotech and Vaccines

Most Traditional approach:

> Design Phase ‐ Initiating Phase 1 clinical trials

> Optimize Phase ‐ Clinical transition from Phase 2 to Phase 3

> Confirm Phase ‐ Submission of the marketing application

Everyone has a Target!

Milestone Planning

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Trials, Scale-upnon-GMP/GMP

Planning andDefinition Phase

The Development Process

•CMC•API Characterization•API Route and Scale‐up•Toxicology/FIH Formulation•Definition of QTPP•ID CQAs•Methods Development•Stability Program

•Clin•TPP

•Preclin•Proof of Concept•Tox •DDI

Design Phase

•QbD Implementation•Risk Assessment•To‐Be marketed Formulation Design

•Process Design•Control Strategy•IVIVC•ID CQAs•Transfer to Operations

Optimize Phase •Process Optimization

•Design Space Validation•TechTransfer/•Additional Supply Chain etc.

Confirmation Phase

• Life‐Cycle management.



POC(Phase 2/3)



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Development Phases

Pre‐IND Phase

PreIND

Initiating Phase 1

Early Clin Dev

Transition Ph2 to Ph3

POC to Registration

Continuous Improve

Key Questions

Conditions/Features



•Are you ready to File the IND?

•Have you defined the Quality Target Product Profile?

•API Characterization

•API Route and Scale up

•Toxicology/FIH Formulation Design

•Methods Development

•Initial Stability Program

Items that affect safety and that can trigger a clinical hold can be determined/ruled out via the QTPP and identifiaction of the critical attributes!

Pre‐IND

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Development Phases

Initiating Phase 1

Pre‐IND

Initiating Phase 1

Early Clin Dev


POC to Registration

Cont‘ Improvement


How Much? How Controlled? How Tight?

Products do not lend themselves readily to questions of "how much?", "how controlled?" and "how tight?" at Phase 1An effective quality risk management assessment does not simply list all of the CMC challenges for a product at Phase 1, but prioritizes what the sponsor absolutely needs to do or identify at this early stage of drug development to address these challenges ...(CQAs?)

At Phase I, it is too early to think "test method validation" (instead, think "suitable for use and scientifically sound") or "manufacturing consistency" (instead, think "manufacturing control") or "product maximum shelf life" (instead, think "stable for the duration of the planned study")

Modifications to the method of preparation of the new drug substance and dosage form, and even changes in the dosage form itself, are likely as the investigation progresses.Emphasis in an initial Phase 1 CMC submission should, therefore, be placed on providing information that will allow evaluation of the safety of subjects in the proposed studyThe identification of a safety concern or insufficient data to make an evaluation of safety is the only basis for a clinical hold

Phase 1

Key Questions

Conditions/Features

Basis/ Considerations

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Development Phases

Early Clinical Development

Pre‐IND

Initiating Phase 1

Early Clin Dev


POC to Registration

Cont‘ Improvement

Considerations

The manufacturing process is critical to ensure the correct composition, Quality, and Safety of the product

It becomes more critical to carefully control and record process development in conjunction with the appropriate testing to reproduce a comparable Phase 2 investigational drug

Appropriate equipment and controls should be in place in manufacturing to ensure that unit operations with safety‐related functions (e.g., viral clearance, virus/toxin attenuation. sterilization) perform their function with a high degree of assurance. Specific IPC testing may also serve to complement these functions and can eliminate testing down the chain

When evaluating the manufacturing process for early Phase 1&2 investigational drugs, it is of particular importance to begin to evaluate the process and scale you will need to be at the confirmation stage

Best time to define Design Space is before you are locked into a ‘process’ for pivotal studies.

Phase 1/2

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Development Phases

Transition from Phase 2 to Phase 3

Pre‐IND

Iniatiating Phase 1

Early Clin Dev

Transition Ph 2 to Ph 3

POC to Registration

Continuous Improve

Key Questions

Are manufacturing decisions scientifically based on enhanced knowledge of product performance over a wider range of material attributes, processing options and process?

Want to avoid CMC regulatory compliance delays? Seek out Agency advice. Regulatory authorities do not expect a company to agree with them in every instance, but they do expect thoughtful consideration and a scientifically justified response.

An effective regulatory compliance strategy is critical at this stage to ensure All chemistry, manufacturing and controls (CMC) activities necessary for eventual market approval are being plannedAny identified CMC impediment should be discussed with the regulatory agency

Quality by Chance (QbC), is a very risky optionThis investment in QbD should be made wisely

Understanding the science does not come cheapBe selective in how limited time, resources and money are investedGoal is to increase the level of manufacturing process knowledge and understanding, not just to generate volumes of scientific data

Phase 2 to 3



Conditions/Features

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Development Phases

POC to Registration

Pre‐IND

Initiating Phase 1

Early Clin Dev


POC to Registration


Conditions/Features


Utilize the knowledge

Provide enough information to permit the regulatory authority to determine

Whether the process used in manufacturing the drug and the controls used to maintain its quality are appropriate and adequate

Phase 3 to Registration

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Continuous ImprovementDevelopment Phases

Pre‐IND

Initiating Phase 1

Early Clinical Dev


POC to Registration

Cont‘ Improvement

Key Questions


Conditions/Features


As the expanded body of manufacturing knowledge occurs with the contract partner, management should ensure that continual process improvement is evaluated and given an appropriate responseFacilitate continual improvement: the ICH Q10 mandate for managementAvoid slippage of current Good Manufacturing Practice (cGMP) compliance

Are you capable to building adequate commercial inventories?How does market expansion opportunities affect Supply Chain?

The people involved, their competency, training, and cooperation, are the key element to the success or failure of managing a process and product

Lifecycle Management

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SummaryDevelop strategies for a QbD approach> These quality initiatives should not be a “one size fits all“ approach to

development

Put together alignment, guide transition and build a value chain> Strive for seamless Transition and Knowledge Transfer from early

Development to launch and beyond

> There will always be questions but they should be managed based on the level of risk to quality

Enablers – ICH guidance’s Q8, Q9 and Q10 (and soon Q11)> Implementation will take time and experience as well as Open

Communication

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Acknowledgements

Anthony Durning

David Urquhart

Daniel Torok

Suzan Aschmies

Hedley Rees

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Thank you …

Narke Pda Orlando Mar2010 Boot Camp Final

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