Application of Quality by Design (QbD) in product development

James E. Polli jpolli@rx.umaryland.edu

September 16, 2015

Pharmaceutical Equivalence

• Same active ingredient(s) • Same dosage form • Same route of administration • Identical in strength or concentration • Meet compendial or other applicable

standards of strength, quality, purity, and identity

• May differ in shape, excipients, packaging...

What is Pharmaceutical Quality? • Free of contamination and reproducibly

delivers the therapeutic benefit promised in the label

• ICH Q8 R(2) – The suitability of either a drug substance

or a drug product for its intended use • Quality cannot be tested into products;

quality can only be built into products

Pharmaceutical Quality = ƒ (Drug substance, excipients, manufacturing, and packaging)

Quality by Design • ICH Q8(R2)

– The pharmaceutical Quality by Design (QbD) is 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

• Quality by Design Tools – Design of Experiments (DoE) – Risk assessment

5

Quality by Design (QbD) and Question-based Review (QbR)

Applicant: Implementing QbD in development, manufacturing, and control

FDA: Developed a system that assesses applicant’s QbD NDAs and ANDAs

FDA’s Pharmaceutical Quality for the 21st Century QbD Initiative, ICH Q8, Q9, Q10, and Q11. Q12 in-process.

QbD: Required or Optional ? • Required

– Quality target product profile (QTPP) • Including critical quality attributes (CQAs) of the drug product

– Product design and understanding • Critical material attributes (CMAs) of the drug substance and

excipients – Process design and understanding

• Critical process parameters (CPPs) – Control strategy, including justification

• Optional – Design Space – Process Analytical Technology

Overview of QbD Labeled Use Safety and Efficacy

DEFINE Quality Target Product Profile

IDENTIFY Critical Material Attributes and Critical Process Parameters

DESIGN Formulation and Process

CONTROL Materials and Process

TARGET DESIGN and UNDERSTANDING IMPLEMENTATION

Yu. Pharm. Res. 25:781-791 (2008)

• Guidance for Industry and Review Staff

• Target Product Profile — A Strategic Development Process Tool

• U.S. Department of Health and Human Services • Food and Drug Administration • Center for Drug Evaluation and Research (CDER)

• March 2007

Target Product Profile (TPP) • Organized according to key sections in the product’s

labeling – Description – Clinical Pharmacology – Indications and Usage – Contraindications – Warnings – Precautions – Adverse Reactions – Drug Abuse and Dependence – Overdosage – Dosage and Administration – How Supplied – Animal Pharmacology and/or Animal Toxicology – Clinical Studies

Quality Target Product Profile (QTPP) • A natural extension of Target Product

Profile for product quality – A prospective summary of the quality

characteristics of a drug product that will ideally be achieved to ensure the desired quality (performance)

• Guide to establish formulation strategy and keep the formulation effort focused and efficient

What Does Quality Target Product Profile Include?

• Intended use in clinical setting – Route of administration, dosage form (delivery

systems), and container closure system

• Quality attributes of drug product – Appearance, Identity, Strength, Assay, Uniformity,

Purity/Impurity, Stability, and others

• Active pharmaceutical ingredient release or delivery and attributes affecting pharmacokinetic characteristics (Safety and efficacy) – Dissolution, aerodynamic performance

Basis for Establishing QTPP

• Pharmaceutical equivalence and bioequivalence

• Analysis of the reference listed drug product – Clinical use – Pharmacokinetics – Drug release – Physicochemical characterization

• Product labeling/administration

Critical Quality Attributes of Drug Product

• Quality attributes of drug product can be critical or non-critical

• ICH Q8 R(2) – 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

– Critical Quality Attributes (CQAs) of drug product are those that can be impacted by formulation and manufacturing processes

• For example: Identity and dosage form are not CQAs, but assay and content uniformity are

Overview of QbD Labeled Use Safety and Efficacy

DEFINE Quality Target Product Profile

IDENTIFY Critical Material Attributes and Critical Process Parameters

DESIGN Formulation and Process

CONTROL Materials and Process

TARGET DESIGN and UNDERSTANDING IMPLEMENTATION

Yu. Pharm. Res. 25:781-791 (2008)

Drug Substance Property

• Physical properties – Physical description

• Appearance, shape, particle size, and distribution – Salt form, polymorphism – Melting point – Aqueous solubility as function of pH – Hygroscopicity – Density (Bulk,

Tapped, True) – Flow property – Others

Aqueous Solubility Profile

120

121

122

123

124

125

0 2 4 6 8

pH

Solu

bilit

y (m

g/m

l)

Solubility of Z

Drug Substance Property

• Chemical properties – pKa – Chemical stability in solid states (crystalline &

amorphous), and in solution • Degradation pathways

– Photolytic Stability – Oxidative Stability – Others

Drug Substance Property

• Biological properties – Partition coefficient, membrane permeability, and/or

pharmacokinetic information – Biopharmaceutics Classification System

BiopharmaceuticsClass

Solubility Permeability

I High High

II Low High

III High Low

IV Low Low

Excipient

• Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form

– Aid in the processing of the dosage form during its manufacture

– Protect, support, or enhance stability, bioavailability, or patient acceptability

– Assist in product identification – Enhance any other attribute of the overall safety,

effectiveness, or delivery of the drug during storage or use

Excipient

• Physical property – Particle size, shape, density, hygroscopicity, aqueous

solubility, pKa, and viscosity of polymer dispersion.

• Chemical property – Chemical identity, purity, incompatibility with drug

substance

• Biological property • Mechanical property • Excipient quality

Steps for Product Understanding

1. Identify all possible drug substance and excipient attributes that could impact the performance of the product

2. Use risk assessment to identify high risk drug substance and excipient attributes

3. Determine levels or ranges of these attributes to be investigated

4. Use Design of Experiments (DoE) to design experiments

5. Conduct actual experiments 6. Analyze experimental data to determine

appropriate ranges of these attributes (design space)

Overview of QbD Labeled Use Safety and Efficacy

DEFINE Quality Target Product Profile

IDENTIFY Critical Material Attributes and Critical Process Parameters

DESIGN Formulation and Process

CONTROL Materials and Process

TARGET DESIGN and UNDERSTANDING IMPLEMENTATION

Yu. Pharm. Res. 25:781-791 (2008)

Critical Material Attribute and Critical Process Parameter

• Critical Material Attribute (CMA) – A physical, chemical, biological or microbiological

property or characteristic of an (input) material that should be within an appropriate limit, range, or distribution to ensure the desired quality of drug substance, excipient, and in process materials

• Critical Process Parameter (CPP) – A process parameter whose variability has an impact

on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality

Relationship of CMA, CPP, and CQA

Pharmaceutical Unit Operation Input

Materials

Output Materials or Product

CPPs

CMAs CQAs

A CQA of an output material may become a CMA if it becomes an input material of another unit operation

Process Understanding: Linking CMAs and CPPs to CQAs

Y = ƒ(X)

OUTPUT

Y

Inputs to the process control variability of the Output

Priori knowledge Risk Assessment Mechanistic models DoE

Process

I N P U T S (X)

Material

Steps for Process Understanding 1. Identify all possible process parameters and material attributes

that could impact the performance of the process 2. Use risk assessment to identify high risk parameters and/or

attributes 3. Determine levels or ranges of these high risk parameters and

attributes 4. Use appropriate DOE to design experiments 5. Conduct actual experiments 6. Analyze the experimental data to determine if a process parameter

or material attribute is critical – A process parameter/material attribute is critical when a

realistic change in that process parameter/material attribute can cause the product to fail to meet CQAs

– For critical parameters or attributes, define acceptable ranges (Design Space). While for non critical parameters or attributes, the acceptable range is the range investigated

Design Space • Design Space

– The multidimensional combination and interaction of input variables (e.g. Material Attributes) and process parameters that have been demonstrated to provide assurance of quality

– Use sound science, design space developed at lab or pilot scale can be proposed for commercial scale, but it needs to be verified at production scale,

• Regulatory Implication – Movement out of the design space is considered to be

a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

Scale Effect on Design Space

10 Fold

= ? Commercial Scale Design Space

Generation

Lab Scale Design Space

Confirmation

Design Space of What?

• Lab scale design space • Pilot scale design space • Commercial scale design space • Only commercial scale design space can have

meaningful regulatory flexibility as defined in ICH Q8(R2)

Overview of QbD Labeled Use Safety and Efficacy

DEFINE Quality Target Product Profile

IDENTIFY Critical Material Attributes and Critical Process Parameters

DESIGN Formulation and Process

CONTROL Materials and Process

TARGET DESIGN and UNDERSTANDING IMPLEMENTATION

Yu. Pharm. Res. 25:781-791 (2008)

ICH Q8 Control Strategy

• Input material control (specification) • Product control (specification) • Manufacturing process (unit operation)

control • In-process control or real-time release testing

(RTRT) in lieu of end-product testing • A monitoring program (e.g., full product

testing at regular intervals) for verifying multivariate prediction models

Control Strategies Level of Control

Level of Freedom

Level 1: Extensive end product testing + Fixed Critical Process Parameters (CPPs)

Level 2: Reduced end product testing + Flexible manufacturing process within fixed design space

Level 3: PAT, Real-time automatic “engineering control”+ Flexible manufacturing process

Increase

QbD Tools

Risk Assessment Variables and Unit Operations

DP CQA Pharmacy weighing

IR granulation ER beads-drug

layering

Sieving I ER coating Sieving II Final blending

Compression

Appearance Low Low Low Low Low Low High Medium

Assay Medium Low High Low Low Low Medium Medium

Content Uniformity

Low Low Medium Low Low Low High High

Drug Release (IR portion)

Low High Low Low Low Low Medium High

Drug Release (ER portion)

Low Low Medium Low High Medium Medium High

Drug Release (whole tablets)

Low High Medium Low High Medium Medium High

Drug Release (whole tablets vs. half tablets)

Low Low Low Low Low Low Low High

Alcohol Induced Dose Dumping

Low Low Low Low High Low Low High

Relative risk ranking: Low risk: no further investigation is needed. Medium risk: further investigation may be needed. High risk: further investigation is needed.

Design of Experiment (DoE)

• A structured, organized method for determining the relationship between factors affecting a process and the output of that process

• For example – Plackett and Burman design – Factorial design – Central composite design – Box-Behnken design – D-optimal DOE – etc.

Predictive In Vitro Dissolution for IR Products

• For BCS Class I and III drugs formulated in IR dosage forms, in vitro dissolution can be a good surrogate for in vivo performance

• For BCS Class II and IV drugs formulated in IR dosage forms, in vitro dissolution is expected to be predictive of in vivo performance. Therefore, ANDA applicants should make effort to develop predictive in vitro dissolution – Effect of different particle size

Predictive In Vitro Dissolution for MR Products

• For MR products, in vitro dissolution is expected to be predictive of in vivo performance. Therefore, ANDA applicants should make effort to develop predictive dissolution – Effect of slow, medium, and fast dissolution

Conclusion • Quality by Design

– Define quality target product profile – Identify drug product critical quality attributes – Design and develop formulation and process to meet target product

quality profile – Identify critical raw material attributes, process parameters, and

sources of variability – Control raw materials and process to produce consistent quality over

time • DOE and risk assessment are tools to facilitate the

implementation of QbD • AND and ANDA applicants should make every effort to

develop predictive dissolution for IR products of poorly soluble drugs and MR products