Quality by Design Approach for Determining Excipient...

Quality by Design Approach for Determining Excipient Specifications for a Formulation

M. Kallam, J. Farina, N. Deorkar Avantor Performance Materials, Inc.

Not All Materials are Created Equal and One Size Doesn’t Fit All

• Functionality and specifications depends on formulation • Different materials – different designs • Synergistic excipients – simplified designs • Customize QbD to your needs

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Outline • Typical Formulation Development Practices • Concept of Quality by Design • Design of Experiments for QbD • Role of High-Functionality Excipients in QbD • Example of QbD application • Validations under QbD • Conclusions

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What works well for Pharma Industry? Which is better ??

Typical Formulation Practices

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Define Target Quality Attributes

Ex: Round Tablet, Tablet Weight: NMT 350 mg Clear Embossing Dissolution: NLT 80% in 30 min Potency: 200 mg Hardness: NLT 80N and NMT 150N Assay: Within 95–110% of label claim Content Uniformity: NMT 5% RSD Stability: 6 month accelerated stability within ± 5% of initial results


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Alter composition or process

Scale up to pilot scale

Meets criteria

Yes

No

Test product

Literature search

Trial runs Components and process


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Alter composition or process

Scale up to production

Meets criteria

Yes

No

Test product Trial runs-Statistics

Pilot scale

Validate process

Write Master Batch Manufacturing Record

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Validated process

Formulation fixed at a specified composition

Process fixed at specified parameters

Any deviation from fixed values calls for investigation and holding batch until resolved or rejecting batch

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Advantages Disadvantages Fast to market Poor understanding of input and

response Lower developmental costs Many non-conforming incidents

(NCI) Lost time due to investigations of NCI’s Rejected batches Higher manufacturing costs in the long run Changing process requires regulatory approval

Typical Formulation Process

Quality by Design

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Define target quality attributes - same as before

Ex: Round Tablet, Tablet Weight: NMT 350 mg Clear Embossing Dissolution: NLT 80% in 30 min Potency: 200 mg Hardness: NLT 80N and NMT 150N Assay: Within 95–110% of label claim Content Uniformity: NMT 5% RSD Stability: 6 month accelerated stability within ± 5% of initial results

Quality by Design

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Design experiments to study cause and effect relation

Literature search

Map the inputs that affect on CQA’s

Components and process

Propose design space from the results

Verify design space at pilot

scale

Scale up to production

Validate at extreme design space points

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Parameter Blend Time

Lubrica’n Time

Blender Fill %

Compr’n Force

Tablet Press Speed CQA

Assay Low Low Low Low Low

Stability Low Low Low Low Low

Content Uniformity

High Low High Low High

Hardness /Friability

Low Low Low High High

Embossing Low High Low High High

Dissolution Low High Low High High

QbD: Cause and Effect Mapping for Blending & Tableting Process

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Component API PSD Major Excipient PSD

Lubricant Major Excipient LOD

Other Functional Excipient CQA

Assay Low Low Low Low Low

Stability Moderate Low Moderate Moderate Moderate

Content Uniformity

High High Low Low Low

Hardness /friability

Low Low High Moderate Low

Embossing Low Low High High Low

Dissolution High Low High Low High

Use DOE to Determine Effects

DOE: • Full or factorial designs

or • Available standard

designs or • Custom defined

designs

After experiments: • Replicate each experiment

at least twice. • Analyze the data • Determine effects of each

factor • Develop contour plots • Overlay contour plots • Determine design space

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Role of Co-Processed Excipients in QbD

• Simplifies the Design • One Input – Multiple Responses • Better Control Strategies – PAT • Low Process Variance • Risk Mitigation • Fast to Market

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Example:

• Objective: • Use QbD principles to determine API and excipient

specifications for formulating 200 mg ibuprofen tablets by direct compression.

• Target Quality attributes: • Tablet weight variation (Content Uniformity) less than

1% RSD at high press speeds • Hardness of 80–120 N • Dissolution of NLT 90% in 5 minutes • Defect free round bi-convex tablets

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Materials

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Material Manufacturer

J.T.Baker® PanExcea™MHC300G, an MCC based co-processed excipient

Avantor Performance Materials, Inc

Ibuprofen 40 and 70 grades Albemarle Corporation Silica (Rxcipients® GL-100) J.M. Huber Corporation Stearic acid (Hystrene®) PMC Biogenix, Inc Croscarmellose sodium (Vivasol®)

JRS Pharma GmbH

PanExcea™ is a trademark of Avantor Performance Materials, Inc Vivasol ® is a trademark of JRS PharmaGmbH Hystrene® is a trademark of PMC group RxCipients® is trademark of J.M. Huber Corporation

Factors • Evaluate Effect of the Following on CQA’s:

• API Particle Size • Excipient Particle Size • Excipient LOD

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Levels • API Particle Size

• Two Levels – (D50 of 40 microns and 70 microns) • Excipient Particle Size

• Two Levels- (D50 of 95 microns and 145 microns) • Excipient LOD

• Two Levels- (LOD of 4.4 and 2.0)

Different Grades of Raw Materials

• May not always be available

• If available • Different Manufacturers • Different Processes • Different Methods

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Different Grades of Excipient

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PanExcea™ MHC300G 1400 grams



LOD 4.4, D50= 95 microns


LOD 2.0, D50= 95 microns

Dried for 30 minutes

Different Grades of Excipients

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LOD 4.4, D50=145 microns


LOD 2.0, D50=145 microns

Dried for 30 minutes

Sieved using #140 mesh

Discarded Pass through Blended for 10

minutes

Retained

Process

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Preblend

Mill using Comil

Main Blending Lubricating Tableting

Full Factorial Design (3 factors, 2 levels)

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StdOrder RunOrder CenterPt Blocks PSD Excipient PSD API LOD Excipient

7 1 1 1 95 70 4.4

5 2 1 1 95 40 4.4

6 3 1 1 145 40 4.4

8 4 1 1 145 70 4.4

1 5 1 1 95 40 2

4 6 1 1 145 70 2

3 7 1 1 95 70 2

2 8 1 1 145 40 2

Results

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COD AOR Hardness Dis. time Dissoln at

5 min CU % RSD

2 36.9 92 33 98 0.9

6 39.3 82 25 90 1.3

4 39 118 38 97 1.1

2 36.4 94 36 100 0.4

3 39.8 100 37 85 1.1

2 35.6 88 28 84 1.1

3 37.7 89 32 94 1

3 38.1 95 35 84 1.8

COD: Critical Orifice Diameter AOR: Angle of Repose

Analysis- Main Effects

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Analysis- Contour Plots

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Analysis- Design Space

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Preferred working Space

Design Space

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Design space for API D5040-70 microns

Preferred working space

Analysis- Design Space

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Preffered working Space

Impact of Different Excipient Type • Design space comparison -

PanExcea™MHC300G and MCC – Poor responses with MCC at similar drug

loading – Unable to evaluate main and interaction

Effects – Unable to propose a design space

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Process Validation under QbD • Design space must be validated at extremes • Validations at pilot scale or production scale • Process validations are extensive and costly • Advantages:

• Flexibility within design space • Allows in process control instruments (PAT’s) • Robust process • Deviation from batch record within design space • Less downtime for investigations • Less rejects and other wastes

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Conclusions • QbD can be used to:

• Determine specifications for raw materials • Establish design space for

- Process parameters - Composition

• Develop control strategies to mitigate risks • Reduced quality control testing

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