QbD In Drug Development Mathew Cherian Ph.D. Director & Senior Fellow Pfizer, USA

The Origin of QbD

The concept of Quality by Design (QbD) was introduced by Romanian born US engineer Joseph Juran QbD was first used in the automobile industry

Recent Changes in Regulatory Environment

Quality cannot be tested into products; rather it must be built in . ICH Guidelines provide the underpinnings for QbD

ICH Q8(R2): Pharmaceutical Development (2005 R1, 2009 R2) ICH Q9: Quality Risk Management (2005) ICH Q10: Pharmaceutical Quality Systems (2008) ICH Q11: Drug Substance Development (2011)

Quality by Design ICH Q 8, 9, 10

Pharma Industry vs Others

Basic Principles of QbD QbD Processes Objectives

Quality Target Product Profile

(QTPP)

The first objective is to define target and minimum objectives for the product that meet patient

needs.

A second objective is to define target and minimum development objectives that meet business

needs.

Pharmaceutical Development (ICH

Q8 & Q11)

Determine the nexus of clinical safety/efficacy (and business) requirements to quality of drug

product and drug substance

Carry out development studies that lead to an deeper knowledge of product performance over a

wider range of material attributes, processing options and process parameters.

Communicate the knowledge that establishes that the formulation and type of dosage form

selected are appropriate for the intended use.

Ensure that a product of the required quality will be produced consistently by identifying,

understanding and controlling sources of variability.

Risk Management Process (ICH

Q9)

Define quality risk management process that encompass development, manufacturing,

inspection, distribution and submission/review processes during the lifecycle of drug

substances, drug products

Regulatory Application Successfully file “QbD” regulatory applications in each global region

Pharmaceutical Quality Systems

(ICH Q10)

Develop quality systems that support development and manufacture of pharmaceutical drug

substances, and drug products, throughout the product lifecycle.

Ensure that product quality is consistently achieved throughout a product’s lifecycle.

Motivation for QbD

Financial

Less spending for development/

lifecycle management of products

Lower cost to maintain marketed

products

Reduced rework or product rejection

Prioritized spending for development

and commercialized product

Regulatory

Because we have to. Most regulatory

agencies require QbD submissions

Potential for regulatory relief when

filing post-approval changes

Potential for reduced submission

review time or less onerous reporting

Enhanced submission quality

Consistent with FDA, JP & EU

regulatory requirements

Quality

Robust products and processes leading to reduced

rework or product reduction

Predictive processes

Risk-based, prioritized continuous improvement

Rapid troubleshooting

Reduced compliance risk

Product Development & Commercial Support

Clear development focus

Resources focused on key development &

commercial development objectives

Efficient development processes

Better definition of development & commercial

risks

Traditional Approach to Quality

Traditionally quality is ensured by testing the product This approach has the obvious weakness that the testing happens after the product is made- any flaw discovered in testing can help in making future products only The oft- repeated cliché is: You cannot test quality into a product

ICH and FDA Guidelines ICH Q8 was the first guideline ever on QbD in the pharmaceutical industry FDA followed Q8 with its own guideline, closely aligning with ICH. FDA’s guideline states “The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

Challenges in Implementing QbD

To successfully implement QbD, we must have thorough knowledge of the product detailed and complete knowledge of the process understanding of the variability in raw materials, and all manufacturing components understanding relationship between the process and CQAs Understanding the relation between CQA and clinical safety and efficacy

The goal is to make safe and effective products

Design Space & Its Significance

Definition of Design Space. Design Space is: – the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. ICH Q8(R2) (Step 4, August 2009), “Pharmaceutical Development” Design space is proposed by the applicant , and is subject to regulatory assessment and approval Typically there is less regulatory burden when using QbD

Traditional Approach to Drug Development

Select purest active drug and excipients Develop a process, and use knowledge derived from process characterization to define critical, key and non- key process parameters The critical process parameters are then controlled within a narrow range, and the process is validated The narrowest practical range is selected for process parameters, and the ingredients are specified at the narrowest possible ranges

Rewards of Design Space

Design Space in QbD provides regulatory flexibility

Working within the design space is not considered a change by regulatory authorities. Movement out of the design space is considered a change and would normally initiate a regulatory post-approval change process. (FDA Guidance)

Movement within design space does not require prior approval

At present there are several thousand supplemental applications every year at the FDA Changes made within design space may require reporting- usually less onerous than regular post approval change

Steps to Define Design Space

It is necessary to define Target Product Profile (TPP) at the beginning of drug development TPP spells out

Products desired characteristics and features Studies and activities that must be completed to demonstrate the products efficacy, safety and performance When possible also defines what competitive advantages the product will have over a similar product

TPP (continued)

TPP is not an unchanging credo TPP is dynamic, and during the course of development can be revised and updated TPP is

A strategic tool Useful for communicating with management, peers, investors, partners, and regulatory authorities Useful for tracking progress The first step in development using QbD is to define TPP

QTPP- Example Sterile Emulsion

QTTP Element Target Justification

Dosage form Emulsion Drug poorly water soluble

Dosage design Sub- micron particle size Current emulsion products found safe within this range

Dosage strength

5 mg/mL 100- 200 mg of drug to be delivered

Pharmacokinetics

Immediate release, T1/2 less than 15 minutes

Onset and maintenance of anesthesia

Stability 24 months at room temperature

Ideal for worldwide distribution

Primary Packaging

Glass vials and syringes Vials for multiple doses, and syringes for quick dose titration in OR

Compatibility with plastics

Compatible with PVC and polypropylene

Widely used in bags and tubes

QTTP (continued)

QTPP Element Target Justification

Processing Non- aseptic emulsification

Terminally heat sterilizable

Route of administration

IV at Y- site and / or from bags

Typical usage in OR

Particle size 100 – 150 nm Safety established with other similar products

Sterility Sterile Compendial

Endotoxin NMT 1 EU / mL Based on total volume expected

Anti- microbial preservative

Yes Multi-dose presentation

Safety & Efficacy-Basis for CQAs

Critical Quality Attributes (CQA)

Define your Critical Quality Attributes A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials), and drug product. (FDA definition) Process considerations should be kept separate from CQAs and should be listed under Critical Process Parameters (CPP)

CQA impact on safety and efficacy is generally independent of CPPs

CQAs (continued)

For structured products like emulsions and liposomes, CPPs have very strong bearing on CQAs

Changes in CPPs likely influence CQAs. In such cases they need to be considered together

Critical Process Parameters(CPP)

What part of the process inputs (materials and process parameters) most influences the final product quality

ICH Q8(R2) A critical process parameter is a process parameter whose variability has an impact on the critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Risk Assessment

Risk assessment is based on scientific principles Used to determine functional relationship, if any, between material attributes and process parameters on product CQAs Performed early in development and often repeated during development as more refined data are obtained Initially an exhaustive list of all material attributes ad process parameters is prepared. The list is whittled down based on prior knowledge and scientific assessment Additional experimental work is done, based on which the list can be shortened still further, and attributes and parameters prioritized still further

Risk assessment (contd)

Once significant parameters and attributes have been identified, they can be further investigated by a factorial design of experiments

Risk Assessment

Some challenging questions How much risk is too much? Are some risks cumulative? What are unforeseen consequences of risks?

Risk Assessment of a Drug substance

Justification for Initial Risk Assessment

Assessing Risk: Ranking CPPs and CQAs

Design Space

Definition of Design Space. Design Space is: – the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. ICH Q8(R2) (Step 4, August 2009), “Pharmaceutical Development” Design space is proposed by the applicant , and is subject to regulatory assessment and approval Typically there is less regulatory burden when using QbD

Design Space

ICH Q8 tells us what is meant by design space But it does not spell out how to define the design space

QbD Regulatory Applications

US FDA requires that all new drug applications follow QbD All ANDAs are submitted with some level of adherence to QbD Although QbD was conceived to give complete freedom to the applicant, at present it has given only a lower level of reporting (e.g. CBE 30) to the regulatory authorities

QbD by Phase of Development

Use of QbD depends to a great degree on the development phase of the drug At preclinical and Phase I an overt attempt at full adherence to QbD is seldom seen in the industry TPP is drafted early on Select CQAs and CPPs are given attention, and select QbD activities are often embedded in other traditional activities No systematic QbD is typically executed in preclinical / Phase I

Implementing QbD

Example: Weighting of Quality Attribute on safety and efficacy

Impact of QbD Implementation

Over the life of the product, QbD is expected to be cost effective in view of more robust and well characterized processes However, during initial development QbD can entail more expenses ‘Edge of failure’ experiments’ are not often conducted When properly executed QbD will make life cycle management easier to carry out

Where are with QbD

US FDA has required sponsors to use QbD in drug development and submissions since January 1, 2013 Typically full-blown QbD is not used in pre- clinical or Phase I stage

Often platform technologies available in- house are used, with little or no change in parameters

Key aspects of QbD like TPP, CQA and CPP are embedded in traditional development practices, and followed in the early phases QbD programs may kick in Phase II

Where are we ? (cont’d)

Products by full- blown QbD is significantly more expensive to develop Much product knowledge is gained The regulatory relief expected by traversing the entire design space in development has not materialized- not yet If anything, the level of reporting required has been mitigated somewhat ‘Edge-of-failure’ conditions are often not studied, especially in CQAs

Thank You

Acknowledgements: Carol Kirchoff, Pfizer, USA Parag Kohle, Pfizer, USA