dr n dharmadhikari -qbd in product development

This document is the property of SPARCL18th Dec ’12 1

Regulatory Compliance for Global Pharma Market

Dr. Nitin Dharmadhikari

Sun Pharma Advanced Research Company Ltd.,

Mumbai

Quality by Design (QbD) in Product

Development

This document is the property of SPARCL18th Dec ’12

What is QbD?

Systematic, holistic and proactive approach to

pharmaceutical development.

Begins with predefined objectives

Emphasizes product and process understanding and

process control

Based on sound science and quality risk managementRef.: ICH Q8 (R2)

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Why QbD?

Generic industry business model: Regulator’s perspective

File first, learn later

Major amendments during review process

- Exhibit batch stability failure, formulation revision

Longer time for generic product approval

Approved product may not be marketed

Post approval changes – prior approval supplements

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How QbD will help improve?

Ensure higher level of assurance of product quality for patient Improved product and process design &

understandingMonitoring, tracking & trending of product & process.

More efficient regulatory oversight Efficiency and cost saving for industry

Increase efficiency of manufacturing processMinimize / eliminate potential compliance actions

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Overview of QbD

Quality Target Product Profile

Product Design and

Understanding

Process Design and

Understanding

Control Strategy

Continuous Improvement

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Quality Target Product Profile (QTPP)

Define Critical Quality Attributes (CQAs)

Perform risk assessment

Link raw material attributes and process parameters to CQAs

Design and implement a control strategy

Manage product lifecycle, including continuous improvement

Elements of QbD

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Quality Target Product Profile-QTPP

What is QTPP? A set of elements that defines the drug product The target or goal set in advance A guide to Drug Product development

What forms the basis for QTPP? The RLD and its label Applicable regulatory guidelines

When to define QTPP? At the start of development Knowledge gained in development may change some

elements

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Components of QTPP

Components related to safety, efficacy, identity, purity and potency

Critical and non-critical components, e.g. Critical: Assay, content uniformity Non-critical: Appearance

Fixed and variable components Fixed elements must be presente.g. Dosage form, strength Variable elements may have a range of acceptable valuese.g. Tablet weight, assay

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QTPP components for IR tablet -Example

Dosage FormRoute of administrationStrengthWeightPharmacokineticsAppearanceIdentityAssayImpuritiesContent uniformityFriabilityDissolutionResidual solvents

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Specific requirements in QTPP

Scored tabletsWeight variation between two halvesDissolution of half tablet

Orally Disintegrating tabletsHardnessDisintegration timeContainer closure

Extended Release productsAlcohol induced dose dumping

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Critical Quality Attributes – CQAs

CQAs are a subset of the QTPP

Include critical parameters that are likely to change

based upon variations in raw materials and processes-Identity test for dosage form – Not a CQA-Assay, Content uniformity – CQAs

CQAs are monitored throughout the DP development.

CQAs ensure that DP remains within safe and

effective levels.

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QTPP and CQAs

QTPP componentsDosage Form

Route of administrationStrengthWeight

PharmacokineticsAppearance

IdentityAssay

ImpuritiesContent uniformity

FriabilityDissolution

Residual solvents

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CQAsAssay (efficacy)

Impurities (safety)C.U. (efficacy)

Dissolution (efficacy)


QTPP and Specifications

QTPP Desired target for developmental work

Components of QTPP may or may not

be in specification- Not in spec – Dosage form, strength- In spec – Assay, impurities Does not include acceptance criteria

Specifications Includes all of the CQAs

Specification is a list of - tests, - references to analytical

procedures - acceptance criteria

Establishes the set of criteria to

which DP should conform to be

considered acceptable for its

intended use

Defining a QTPP does not mean setting all acceptance criteria or the product specifications before development work begins.

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QbD Tools – Risk Assessment

Why risk assessment in product development? To identify relative risk levels at the beginning of product

development

To prioritize limited development resources

To document the decision making process throughout development

To assess the needs of additional studies for scale up and technology transfer

To identify appropriate specifications, critical process parameters and manufacturing controls

To decrease variability of critical quality attributes

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Risk Assessment

Risk assessment for Formulation – starting material properties, levels of

components Manufacturing process

Steps for risk assessment List out all components / processes Prepare the process flow chart Identify all potential failure modes for each item with

risk query (what might go wrong?) Risk analysis Risk evaluation

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Risk Assessment

Various formal methodologies available for risk assessment

Failure Mode Effects Analysis & Failure Mode Effects & Criticality Analysis

Hazard & Operability Analysis

Supporting statistical tools

It is neither always appropriate nor always necessary to use a formal risk

management process….. The use of informal risk assessment processes can

also be considered acceptable. – ICH Q9

A risk-based justification based on experience and data is always

necessary!

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Risk Assessment

Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms

Generic product development for Acetriptan Tablets, 20 mg.Acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range.It exists in three different polymorphic forms which may affect dissolution.Polymorph III is the most stable polymorph. Drug product is prepared with roller compaction process.

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Risk assessment Risk assessment for formulation components

Drug Product CQAFormulation Variables

Drug Substance PSD

MCC/Lactose Ratio

CCS Level Talc Level Magnesium

Stearate Level

Assay MEDIUM MEDIUM LOW LOW LOW

Content Uniformity HIGH HIGH LOW LOW LOW

Dissolution HIGH MEDIUM HIGH LOW HIGH

Degradation Products

LOW LOW LOW LOW MEDIUM

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Risk assessment

Risk assessment of DP manufacturing process

Drug Product CQAs

Process Steps

Pre-RC* Blending and Lubrication

Roller Compaction Milling

Final Blending and

LubricationCompression

Assay MEDIUM LOW MEDIUM LOW MEDIUM

Content Uniformity

HIGH HIGH HIGH LOW HIGH

Dissolution MEDIUM HIGH MEDIUM HIGH HIGH

Degradation Products

LOW LOW LOW LOW LOW

* RC: Roller compaction

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Justification for assigned risks

Process Steps

Drug Product CQAs

Assigned Risk Justification

Pre-Roller

Compaction

Blending

and

Lubrication

Assay MEDIUMSuboptimal pre-roller compaction blending and lubrication

may cause variable flowability of the blend affecting

Assay.

Content Uniformity HIGH

The PSD and cohesiveness of the drug substance

adversely impact its flowability. If not blended properly

with excipients, it may affect CU.

Dissolution MEDIUMBlending process variables may impact the distribution of

CCS in the blend which could impact disintegration of the

granules and ultimately, dissolution of the tablets.

Degradation Products LOW

Blending process variables are unrelated to the

degradation products of Generic Acetriptan Tablets, 20

mg. 20


CMAs, CPPs and CQAs

What factors affect drug product CQAs? Properties of Input Materials- Identify Critical Material Attributes

(CMAs) Properties of in-process materials- CQAs of one step become

CMAs for a downstream unit operation Manufacturing process parameters- Identify Critical Process

Parameters (CPPs)

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Input Materials

CMAs1

Output Materials

ProductCQAs

CPPs1

Unit Operation 1

Unit Operation 2

CMAs2

CPPs2


Critical Material Attributes (CMAs)

Drug Product CQAs

Drug Substance AttributesSolid State Form

Hygroscopicity Particle Size

Residual Solvents

Process Impurities

Chemical Stability

Physical Attributes (size and splitability)

LOW LOW LOW LOW LOW LOW

Assay LOW LOW LOW LOW LOW LOW

Content Uniformity

LOW LOW LOW LOW LOW LOW

Drug Release HIGH LOW HIGH LOW LOW LOW

Risk Assessment of the drug substance attributes

Solid state form and particle size of DS are CMAs

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CPPs Risk assessment of manufacturing process

Identify high risk steps (unit operation) that affect the CQAs of DP.

Drug Product CQAs

Process Steps

Pre-RC* Blending and Lubrication

Roller Compaction Milling

Final Blending and Lubrication

Compression

Assay MEDIUM LOW MEDIUM LOW MEDIUM

Content Uniformity HIGH HIGH HIGH LOW HIGH

Dissolution MEDIUM HIGH MEDIUM HIGH HIGH

Degradation Products LOW LOW LOW LOW LOW

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CPPs

CPPs DP CQAs Risk Assessment Justification and Strategy

Main compression force

Content Uniformity LOW CU is dominated by BU and flowability and is

unrelated to main compression force.

Dissolution HIGH Suboptimal compression force may affect tablet

hardness and friability and, ultimately, dissolution.

Press speed (dwell time)

Content Uniformity HIGH

A faster than optimal press speed may cause

inconsistent die filling and weight variability which

may then impact CU and dissolution. For efficiency,

the press speed will be set as fast as practically

possible without adversely impacting tablet quality. Dissolution HIGH

Process Step: Compression

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Control Strategy

“A planned set of controls, derived from current product and process understanding that ensures process performance and product quality…..”

ICH Q8 (R2) & Q10

Control Strategy includes following elements (but not limited to):

Input material attributes (e.g. drug substance, excipients, container closure)

Equipment operating conditions (process parameters) In-process controls Finished product specifications Controls for each unit operations Methods and frequency of monitoring and control.

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Control Strategy

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Control StrategyControl Strategy Implementation Options

Enhanced Approach

Traditional Approach

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Level 1 Real-time automatic

control + Flexible process parameters

Level 2 Reduced end product testing +

Flexibility for critical material attributes and critical process

parameters within design space

Level 3 End product testing + tightly

constrained material attributes and process parameters


QbD Tools – DoEDesign of experiments (DoE)

Useful for screening of variables with significant impact on DP CQAs

Classical approach uses OFAT (One Factor At A Time)

Limited number of experiments gives limited information.

DoE helps study effects of interaction of multiple factors at a time

Used in optimization studies, enables creation of “design space”

“Design space” is proposed by the applicant and subject to regulatory

assessment and approval.

“Design space” developed at lab or pilot scale can be proposed for

commercial scale, but needs to be verified at production scale for

scale dependant parameters.

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Process Analytical Technology (PAT)

Timely measurements during processing Critical quality and performance attributes Raw and in-process materials

At-line, on-line or in-line measurements Founded on “Process Understanding”

Opportunities for improvement More reliable and consistent processes (& product)

Less failures, less reworks, less recalls Flexibility w.r.t. scale and equipment Better / faster Quality Systems Process Enhancement Opportunities

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PAT in Tablet manufacturing

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Stage Technique Measurement

Dispensing NIR / Raman Identification of raw materials

Wet Granulation NIR Moisture distribution

Drying NIR Moisture content

Blending NIR Blend Uniformity

CompressionStrain gauges Compression force

NIR Content Uniformity


PAT Examples

Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD without any dryer modification.

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PAT Examples

Real-time Blend Uniformity by using TruProcess™ Analyzer

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QbD: Required or Optional?

Required Quality target product profile (QTPP) including critical quality

attributes (CQAs) of the drug product and including Product design and understanding

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

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QbD

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QbD

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References for QbD

1. Guidance for Industry: Q8(R2) Pharmaceutical Development

2. Guidance for Industry: Q9 Quality Risk Management

3. Guidance for Industry: Q10 Pharmaceutical Quality System

4. Guidance for Industry PAT: A Framework for Innovative Pharmaceutical

Development, Manufacturing, and Quality Assurance

5. Quality by Design for ANDAs: An Example for Modified Release Dosage

Forms

6. Quality by Design for ANDAs: An Example for Immediate Release Dosage

Forms

7. GPhA presentations

8. Draft QbR updated

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dr n dharmadhikari -qbd in product development

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