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Essential aspects in the ACE and

ANDA IR QbD case studies

June 6, 2012

Michal Arnon, Formulation R&D Manager,

Perrigo Pharmaceuticals Israel

Agenda

• QbD Definition

• QbD Example for NDA “ACE Tablets” Case study

• Specific emphasis for Generic Products

(GPhA/FDA CMC Workshop – May 2012)

• QbD Example for ANDA – IR Tablets

• Summary

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QbD - Definition

• Systemic Approach

• Predefined Objectives

• Product and Process Understanding

• Control

• Based on Quality Risk Management

Six Steps to QbD1. Define QTPP

2. Define CQA

3. Risk Assessment

4. Lab work, DOE to

identify Critical

Parameters

5. Determine Control

Strategy

6. Update Risk

Assessment

Define Your Quality Target

Product Profile

Critical Quality Attributes

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Pharmaceutical Development

Case Study:

“ACE Tablets”

Prepared by CMC-IM Working Group

March 13, 2008

CriticalityTargetQuality Attribute

Not ApplicableTablet, Maximum weight 200mgDosage form

CriticalTablet confirm with the description of

shape and sizeAppearance

Critical95-105%Assay

CriticalACE 12345 NMT 0.5%

Other imp. NMT 0.2%

Total NMT 1%

Impurities

Not critical – API not

sensitive to hydrolysisNMT 1%Water content

CriticalMeets USPContent Uniformity

Not critical since related to

dissolution5-12 kPHardness

Not CriticalNMT 1%Friability

CriticalConsistent with immediate releaseDissolution

Not critical, a precursor to

dissolutionNMT 15 min.Disintegration

Critical only if drug product

support microbial growthMeets USP criteriaMicrobiology

QTPP – Quality Target Product Profile

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Ingredient % w/w Total tablet weight Function

Intra-Granular

Acetriptan 10 Active

Lactose monohydrate 40.25 Diluent

Microcrystalline Cellulose 40 Diluent

Croscarmellose Sodium 3.0 Disintergrant

Magnesium Stearate 1.5 Lubricant

Extra-granular

Talc 5.0 Glidant

Magnesium Stearate 0.25 Lubricant

Total 100

Initial Prototype Formulation

(Was used in the pivotal clinical trial)

Formulation Attributes

DP CQAs API

Level

API

Particle

size

Lactose

level

Disintergrant

level

MCC

particle

size

Glidant

level

Mg. St.

level

Appearance Low Low Low Low Low Low High

Identity Low Low Low Low Low Low Low

Assay Low Low Low Low Low Low Low

Imp. Low Low Low Low Low Low Low

Content

UniformityHigh High Low Low High Low Low

DissolutionHigh

High Low High Low Low High

Formulation Composition Risk Assessment

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Ingredient % w/w Total tablet weight Function

Intra-Granular

Acetriptan 10 Active

Lactose monohydrate 40.25 Diluent

Microcrystalline Cellulose 40 Diluent

Croscarmellose Sodium 3.0 Disintergrant

Magnesium Stearate 1.5 Lubricant

Extra-granular

Talc 5.0 Glidant

Magnesium Stearate 0.25 Lubricant

Total 100

Initial Prototype Formulation

(Was used in the pivotal clinical trial)

Factors:

• Acetriptan particle size D90: 10, 25 & 40 µm

• Lubricant (Magnesium Stearate) level: 1, 1.5 & 2%

Responses:

• Tablet Hardness

• Dissolution average at 30 min.

• Tablet weight uniformity

DOE Study – API PSD and Magnesium stearate

(Lubricant) Interaction Study

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Interaction Profile for Hardness Response at fixed

compression pressure

Contour Plot of Dissolution at a Set Target Tablet

Hardness of 12kP

(Dissolution Acceptance Criteria > 80%)

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Summary – Formulation Components Studies

FDA QbD Example for an ANDA

Acetriptan IR Tablets

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FDA OGD-QbD Expectations Lawrence Yu Deputy Director of Science and Chemistry

Encouraged• Quality target product profile (QTPP), including CQA identification

• Product design and understanding

• Process design and understanding

• Control strategy, including justification

Optional • PAT: Process Analytical Technology

• Real time release

Others • Design space

• Risk assessment

• DOE - Design of experiments and data analysis

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RLD Characterization

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QTPP

Suzan Zuk - OGD

QTPP – Continue

Suzan Zuk - OGD

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CQA – Critical Quality Attributes

Suzan Zuk - OGD

• Identification of a CQA is based on the severity of harm

to a patient (safety and efficacy) resulting from failure to

meet that quality attributes.

• Only the subset of CQA’s that have a high potential to be

impacted by the formulation or process variables will be

investigated and discussed in details.

Identification of CQA – Critical Quality Attributes

IdentificationPositive for

AcetriptanYes*

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Formulation Risk Assessment

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Risk Assessment Justification

• Drug Substance particle size: Data demonstrate that particle size of drug substance significantly impacts dissolution profile.

• MCC/Lactose Ratio can effect dissolution via the hardness of the tablets. Hardness can be controlled during compression.

• Disintegrant Level: Due to the need for rapid dissolution and the need for product disintegration not to be a limiting step.

Study Design

Testing Parameters:

• Acetriptan PS D90: 15, 30 & 45mn

• MCC/ Lactose Ratio: 0.5, 1 & 2

• Disintegrant level: 1-4%

Response Variables:

• Tablet hardness at fixed compression force

• Dissolution average at fixed hardness of 12kP (11-13)

• Tablet content uniformity

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Results - Dissolution

15 30 45 1 2.5 4

Disintegrant %PS D90

Dissolution

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Updated Risk Assessment

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Dissolution

Compression

Force: 7-13 kN

Hardness

Ranges: 5-10 kP

Pre-compression Force: 0-1kN

One Parameter Test: Press Speed

Pre-compression force: 0.5kN

Compression force: 9.0 kN

Press Speed (rpm) Tablet weight Range

(mg)

RSD %

15 198-202 1.8

25 197-203 2.3

30 198-203 1.5

35 197-204 3.0

50 197-205 2.9

RSD > 5

Conclusion: Press Speeds was not critical at small scales.

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In-Process Controls

Test Limits Comments

Individual Weight Variation 200mg + 3.0% Discussed above

Weight of 20 tablets 4.00g + 3.0% Discussed above

Hardness 5-10kP Discussed above

Friability NMT 1.0%

Based upon actual data.

Controlled by compression force,

which is correlated with

hardness.

Table 43: Proposed in Process Limits for tablets compression

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Summary: Compression Process Parameters

Summary

• Use the FDA examples to create a template for development planning, results summary and conclusions.

• Make sure you have all the necessary stages: Start from Defining your target product (QTPP), and direct your development to achieve this target.

• QBD summery reflects the product development process:

� A systematic approach

� Using predefined objectives

� Product and process understanding

� process control

� based on sound science and quality risk management.

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• Pharmaceutical Development Case Study:

“ACE Tablets” Prepared by CMC-IM Working Group March 13, 2008

• Quality by Design for ANDA’s – An Example for Immediate release

dosage forms.

• FDA presentations GPhA/FDA CMC workshop, May 2012

References

Questions?

Thank you for your attention