Compliant Formulation Development The Key to Successful Pharma Development

Obergeri, May 4th 2012

Dr. R. Rogasch

Regulatory Requirements in Formulation Development

EU Scientifc Guidance Documents EMA (Clinical, CMC, Procedural) EP7 General Chapters, Monographs US FDA Guidance Documents (Clinical, CMS, Procedural) USP General Chapters and Methods (Dissolution Method Development, IVIVC requirements, Statistical Methodology) ICH Q8/Q9/Q10

Regulatory Requirements in Formulation Development

EU Scientifc Guidance Documents Formulation Development IMP Procedure (pre-clinical data, dossier submission requirements, clinical studies) CMC requirements (specifications, stability data, pre-process validation) Bioequivalence or Biowaiver approach

Regulatory Requirements in Formulation Development

EU EP7 requirements Generic Drug Development - Legal status of monographs

Monographs are official standards The Convention on the Elaboration of a European Pharmacopoeia makes the texts of the Ph. Eur. mandatory in all signatory parties The pharmaceutical legislation in the European Union makes monographs obligatory standards (2001/83/EC, 2001/81/EC) Monographs may be accepted as suitable standards even when not obligatory

Regulatory Requirements in Formulation Development

EU EP7 requirements Generic Drug Development - example

Do Ph. Eur. specifications apply throughout shelf-life? A: Yes, specifications apply until time of use for raw materials and throughout period of validity for preparations

B: No, Ph. Eur. requirements are for release only

From ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Breakout D: Pharmacopoeial Requirements, Kuala Lumpur, July 2010

Regulatory Requirements in Formulation Development

EU EP7 requirements Generic Drug Development - example

Do Ph. Eur. specifications apply throughout shelf-life?

A: Yes, specifications apply until time of use for raw materials and throughout period of validity for Preparations (EP7, general notices)

B: No, Ph. Eur. requirements are for release only.

Implications : EP7 mongraph specifications (impurities) are shelf life indicating !

From ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Breakout D: Pharmacopoeial Requirements, Kuala Lumpur, July 2010

ICHQ8/9/10 Paradigm in Formulation Development

Disclaimer
The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG members for the purposes of a training workshop.

QRM as part of development

To assess the critical attributes of
Raw materials Solvents Active Pharmaceutical Ingredient (API) Starting materials Excipients Packaging materials

To establish appropriate specifications, identify critical process parameters and establish manufacturing controls

ICH Q9
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II.3: QRM as part of development

To decrease variability of quality attributes:
reduce product and material defects reduce manufacturing defects

To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer To make use of the design space concept (see ICH Q8)

ICH Q9
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Key Steps for a product under Quality by Design (QbD)

Pharmaceutical Development Prior Knowledge (science, GMP, regulations, ..) Product/Process Development DOE : Design of Experiment QRM principle apply at any stage

Quality Target Product Profile CQA : Critical Quality Attribute CPP : Critical Process Parameter Risk Management

QTPP : Definition of intended use & product

Potential CQA (Critical Quality Attribute) identified & CPP (Critical Process Parameters) determined Design to meet CQA using Risk Management & experimental studies (e.g. DOE) Link raw material attributes and process parameters to CQAs and perform Risk Assessment Methodology

Product/Process Understanding

Opportunities
Control Strategy Quality System PQS

Design Space (DS), RTR testing

Marketing Authorisation

Technology Transfer
PQS & GMP Local Environment

Commercial Manufacturing
Batch Release Strategy Continual improvement
Quality Unit (QP,..) level support by PQS

Manage product lifecycle, including continual improvement

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P2 of CTD as part of a regulatory submission

EXAMPLE

In line with Quality Risk Management ?

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P2 of CTD as Quality Risk Management process ?

Initiate Quality Risk Management Process

Formulation & Process design

Risk Assessment Risk Identification

Process understanding Manufacturing Concept Process control Concept Product release Concept Regulatory strategy Review the submission

Risk Analysis

Risk Evaluation
unacceptable

Risk Management tools

Risk Communication

Risk Control Risk Reduction

Risk Acceptance

Output / Result of the Quality Risk Management Process Risk Review Review Events

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Development

Target Product Profile Drug substance properties; prior knowledge

Determination of Cause Effect relationships

(Risk Identification with subsequent Risk Analysis)

Phase 1

Risk-based classification
(Risk Evaluation)

Parameters to investigate (e.g. by DOE)

(Risk Reduction 1. proposal; 2. verified)

Product and process FORMULATION characteristics on the DESIGN SPACE final drug product Phase 2

PROCESS DESIGN SPACE BY UNIT OPERATION

Review events

CONTROL STRATEGY

Phase 3

13 Launch

Process understanding Re-evaluation and confirmation

Developm.

Proposed formulation and manufacturing process Research

Formulation understanding Operation Re-evaluation and confirmation

EXAMPLE

Responsibilities in regulatory operations

Industry
Team focused

Initiate Quality Risk Management Process Risk Assessment Risk Identification

Risk Analysis

Risk Evaluation
unacceptable

Risk Management tools

Risk Communication

Internal consultation

Risk Control Risk Reduction

B) Inspectorates

Risk Acceptance

Stakeholder involvement

Output / Result of the Quality Risk Management Process Risk Review Review Events

A) Reviewers

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Formulation Strategies for Phase I/II Clinical Programs General Outline

The overall sequence for DP development for each phase/clinical trial can be summarized as follows: Define the best formulation, with the choice of excipients based on maximizing the physical and chemical stability of the API Ensure the formulation provides the desired in vitro release of drug Conduct pharmacokinetic studies in animals, if models are available that are known to predict clinical responses. Define the best manufacturing process for DP Place the final DP prototype on accelerated stability in intended packaging Conduct GMP manufacture and packaging of clinical DP Generate batch release data and certificate of analysis (CoA) for clinical DP Initiate an accelerated stability program for clinical DP (batch made at full scale) Submit supporting formulation and analytical data as part of the regulatory filing to request approval (i.e., from the FDA, EU, etc.) for using the DP in a clinical study 15

Formulation Strategies for Phase I/II Clinical Programs General Considerations Oral Dosage Forms
Material Property Assessment

API (solubility, Polymorphism XRD etc.) PSD (DLS, LLD) Morphology (SEM) Compound Dissolution Flow/cohesion Powder compaction Hardness, tensile strength, brittel fracture index Excipient/API interactions Degradation Pathways

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Formulation Strategies for Phase I/II Clinical Programs General Considerations Oral Dosage Forms
Bioavailability Enhancement

API (solubility enhancement) PSD (micronization) Solubility Screening, w/o partition Precipitation inhibition (API/surfactant/polymer combinations) Amorphous Dispersions (solid solutions, dispersion in polymer matrix) Coatings (multi-particulates in capsules) Lipid Systems (fat-matrix, SEDDS, SMEDDS, liposomal carrier)

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Formulation Strategies for Phase I/II Clinical Programs IR-Oral Dosage Forms

Capsule, Tablet (IR dosage forms)

Direct compression Dry Granulation Wet Granulation Tabletting/Capsule Filling Film Coating Hot Melt Extrusion

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Formulation Strategies for Phase I/II Clinical Programs CR - Oral Dosage Forms
Capsule, Tablet (CR dosage forms)

Matrix Multiparticulates Soft Gel Capsules Liquid filled Capsules Fuctional Film Coating Hot Melt Extrusion Osmotic Systems
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Formulation Strategies for Phase I/II Clinical Programs Solid Orals - Excipients
Solid Orals Formulation Excipients

Excipient type Brittle fillers

Materials Lactose Calcium phosphate, dibasic Mannitol Microcrystalline cellulose Starch Hydroxypropyl cellulose (HPC) HPMC Povidone Magnesium stearate Stearic acid Glyceryl behenate Sodium starch glycolate Croscarmellose sodium Crospovidone HPMC Polyethylene oxide Polyvinylpyrrolidone (PVP) Fumed silica Talc Gelatin HPMC Polysaccharides

Approximate ranges (%) 10%-95%

Function Imparts hardness and strength to tablets Imparts compressibility and tensile strength to tablets Provides strength in dry and wet processing of powders

Ductile fillers

10%-95%

Binders

5%-10%

Lubricants

Less than 2%

Prevents sticking of formulation to processing surfaces Aids in breakup of tablets or granules in aqueous media Tailors drug release rate

Disintegrants

Less than 5%

Controlled release/matrix

10%-95%

Glidants

Less than 1%

Improves powder flow and prevents static charging Unit dose to contain powders or controlled release pellets

Capsules

1%-5%

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Formulation Strategies for Phase I/II Clinical Programs Solid Orals - Excipients
Solubilizers, dispersants, precipitation inhibitors Poloxamer 407 SLS Cyclodextrins HPMC and acid derivatives HPC 0.5%-5% Improve solubility and wettability of hydrophobic drugs and improve bioavailability

Chemical stabilizers

BHT/BHA Citric acid

Less than 1%

Mitigate chemical degradation, oxidation

Taste masking agents

Sucrose Aspartame Mannitol Flavors

1%-5%

Hide unpleasant drug taste, essential for chewable formulations

Colorants

Titanium dioxide, Iron oxides, Dyes and lakes

Less than 2%

Cosmetic appearance, marketing

Coating ingredients Film polymers

HPMC Cellulose acetate , Ethylcellulose, Polymeric acrylates

1%-30%

Cosmetic or controlled release coatings

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Formulation Strategies for Phase I/II Clinical Programs Solid Orals - Excipients

Plasticizers, Anti-tack agent

Glycerol triacetate, Fatty acid salts, esters, Polyethylene glycol, Talc

Less than 1% Less than 0.5%

Improve processability, Prevent sticking

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Formulation Strategies for Phase I/II Clinical Programs Parenteral Dosage Forms

Parenteral/injectable Solutions (lyophilization) Colloidal Suspensions (peptides, proteins) Emulsions Liposomal Systems Suspensions

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Formulation Strategies for Phase I/II Clinical Programs Liquid Orals/Parenterals Excipients
Excipient type Materials Approximate ranges (%) Function

Diluent

Water Vegetable oils Polyethylene glycol Propylene glycol Ethanol Polyethylene glycol Propylene glycol NMethylpyrrolidone Sodium chloride Sodium acetate Sodium phosphate (and corresponding acids) Sodium hydroxide Sodium chloride Hydroxypropyl methylcellulose (HPMC) Mannitol Dextrose

50%-90%

Main solubilizing/suspending vehicle for all components

Cosolvents

20%-50%

Helps with poorly aqueous soluble drugs

Buffering agents

Enough for adjusting to desired pH

Maintain pH for optimum solubility, and comfort for injectable formulations

Bulking agents

Less than 10%

Maintain osmolarity for parenterals, adjust viscosity, mechanical stability for lyophilized cakes

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Formulation Strategies for Phase I/II Clinical Programs Oral Liquid/Parenteral - Excipients
Solubilizers/surfactants Hydroxypropyl-betacyclodextrin Sulfobutyletherbeta-cyclodextrin HPMC Polaxamer 407 Sodium lauryl sulfate (SLS) Phospholipids Cremophors Labrasol Vitamin E TPGS Edetate sodium (EDTA) Citric acid/citrate Less than 5% Improve drug solubility, emulsification, suspension of drug particles, prevent precipitation

Chelating agents

Less than 1%

Bind metal impurities to prevent complexation and reactions Prevent microbial growth

Preservatives

Benzyl alcohol Methyl/ propyl parabens Benzalkonium chloride Thimerosal Butylated hydroxytoluene/anisole (BHT/BHA) Citric acid/citrate

Less than 2%

Chemical stabilizers

Less than 2%

Antioxidants, free radical scavengers

Flavoring/tastemasking

Sucrose, aspartame Peppermint oil, flavors

Less than 2%

Sweeteners Masking of drug tast

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Project Case Study Disclaimer

The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG members for the purposes of a training workshop.

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Outline of Presentation
Key Steps for Quality by Design Case Study Organization Introducing API and Drug Product
Discussion of concepts of Quality Target Product Profile, processes, composition

Description of API & Drug Product process development

Discussion of illustrative examples of detailed approaches from the case study

Batch release

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Purpose of Case Study

Illustrative example
Covers the concepts and integrated implementation of ICH Q8, 9 and 10 Not the complete content for a regulatory filing

Note: this example is not intended to represent the preferred or required approach.

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Case Study Organization

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Basis for Development Information

Fictional active pharmaceutical ingredient (API) Drug product information is based on the Sakura Tablet case study
Full Sakura case study can be found at http://www.nihs.go.jp/drug/DrugDiv-E.html

Alignment between API and drug product

API Particle size and drug product dissolution Hydrolytic degradation and dry granulation /direct compression

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Organization of Content

Quality Target Product Profile (QTPP) API properties and assumptions Process and Drug product composition overview Initial risk assessment of unit operations Quality by Design assessment of selected unit operations

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Technical Examples

Process focus
API - Final crystallization step Drug Product - Blending - Direct compression

Quality attribute focus

- Particle size control - Assay and content uniformity - Dissolution

API Crystallization

Blending

Compression

Real Time Release testing

(Assay, CU, Dissolution)

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Process Step Analysis

For each example
Risk assessment Design of experiments
Experimental planning, execution & data analysis

Design space definition Control strategy Batch release

QRM

Design of Experiments

Design Space

Control Strategy

Batch Release

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QbD Story per Unit Operation

QTPP & CQAs

Process Variables

Quality Risk Management

Design of Experiments

Design Space

Control Strategy

Batch Release

Illustrative Examples of Unit Operations:

API Crystallization Blending Compression Real Time Release testing
(Assay, CU, Dissolution)

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Introducing API and Drug Product

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Assumptions & Prior Knowledge

API is designated as Amokinol

Single, neutral polymorph Biopharmaceutical Classification System (BCS) class II low solubility & high permeability API solubility (dissolution) affected by particle size
Crystallization step impacts particle size Higher water levels and elevated temperatures will increase degradation Degradates are water soluble, so last processing removal point is the aqueous extraction step Degradates are not rejected in the crystallization step

Degrades by hydrolytic mechanism

In vitro-in vivo correlation (IVIVC) established allows dissolution to be used as surrogate for clinical performance Drug product is oral immediate release tablet

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Quality Target Product Profile (QTPP)

Safety and Efficacy Requirements
Translation into Quality Target Product Profile (QTPP)
Identity, Assay and Uniformity

Tablet

Characteristics / Requirements

Dose

30 mg

Subjective Properties

No off-taste, uniform color, and suitable for global market

Appearance, elegance, size, unit integrity and other characteristics

Patient Safety chemical purity

Impurities and/or degradates below ICH or to be qualified

Acceptable hydrolysis degradate levels at release, appropriate manufacturing environment controls

Patient efficacy Size Distribution (PSD)

Particle

PSD that does not impact bioperformance or pharm processing

Acceptable API PSD Dissolution

Chemical and Drug Product Stability: year shelf life (worldwide = 30C)

Degradates below ICH or to be qualified and no changes in bioperformance over expiry period

Hydrolysis degradation & dissolution changes controlled by packaging

QTPP may evolve during lifecycle during development and commercial manufacture - as new knowledge is gained e.g. new patient needs are identified, new technical information is obtained about the product etc.

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API Unit Operations

Example from Case Study

Coupling Reaction

Coupling of API Starting Materials

Removes unreacted materials. Done Aqueous Extractions cold to minimize risk of degradation Understand formation & removal of impurities Distillative Solvent Switch Semi Continuous Crystallization Removes water, prepares API for crystallization step Addition of API in solution and anti-solvent to a seed slurry

Centrifugal Filtration Filtration and washing of API Rotary Drying Drying off crystallization solvents

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Tablet Formulation

Pharmacopoeial or other compendial specification

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Drug Product Process

API and Excipients

Amokinol D-mannitol Calcium hydrogen phosphate hydrate Sodium starch glycolate

Blending

Lubricant
Magnesium Stearate

Lubrication Compression

HPMCMacrogol 6000 titanium oxide iron sesquioxide

Coating

Film coating
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Overview of API and Drug Product Case Study Elements

Representative Examples from the full Case Study

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Overall Risk Assessment for Process

Example from Case Study

Process Steps
no impact to CQA known or potential impact to CQA current controls mitigate risk

Drug Substance
Manufacture Moisture Control Distillative Solvent Switch SemiContinuous Crystallization Centrifugal Filtration Rotary Drying Aqueous Extractions Coupling Reaction Blending

Drug Product
Compression Lubrication Packaging Coating

known or potential impact to CQA additional study required * includes bioperformace of API, and safety(API purity)

CQA
in vivo performance* Dissolution Assay Degradation Content Uniformity Appearance Friability Stability-chemical Stability-physical

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Overall Risk Assessment for Process

Process Steps
no impact to CQA known or potential impact to CQA current controls mitigate risk

Drug Substance
Manufacture Moisture Control Distillative Solvent Switch SemiContinuous Crystallization Centrifugal Filtration Rotary Drying Aqueous Extractions Coupling Reaction Blending

Drug Product
Compression Lubrication Packaging Coating

known or potential impact to CQA additional study required * includes bioperformace of API, and safety(API purity)

CQA
in vivo performance* Dissolution Assay Degradation Content Uniformity Appearance Friability Stability-chemical Stability-physical

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API Semi-Continuous Crystallization

Designed to minimize hydrolytic degradation (degradate below qualified levels)
Univariate experimentation example
FMEA of crystallization process parameters

High risk for temperature, feed time, water level

Test upper end of parameter ranges (represents worst case) with variation in water content only and monitor degradation Proven acceptable upper limits defined for above parameters

Note that in this case study, the distillative solvent switch prior to crystallization and crystallization itself are conducted at lower temperatures and no degradation occurs in these steps

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API Semi-Continuous Crystallization

Designed to control particle size
Multivariate DOE example leading to predictive model
FMEA of parameters using prior knowledge

High risk for addition time, % seed, temperature, agitation

DOE: half fraction factorial using experimental ranges based on QTPP, operational flexibility & prior knowledge Design space based on predictive model obtained by statistical analysis of DOE data

Particle size distribution (PSD) qualified in formulation DOE and dissolution studies

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Risk Assessment:
Particle Size Distribution (PSD) Control
What is the Impact that ------------- will have on PSD? 1) minimal 5) moderate 9) significant What is the Probability that variations in ------------ will occur? 1) unlikely 5) moderately likely 9) highly likely What is our Ability to Detect a meaningful variation in --------------- at a meaningful control point? 1) certain 5) moderate 9) unlikely

Unit Operation

Parameter

PA C PR T OB De . tec t

Comments

IM

RPN

Crystallization

Feed Temperature

1 5 1

Crystallization Crystallization

Water content of Feed Addition Time (Feed Rate)

1 5 5 9 5 9

Prior knowledge (slowness of crystallization kinetics) ensures that the hot crystallizer feed will be well dispersed and thermally equilibrated 5 before crystallizing. Hence no impact of feed temp variation on crystal size. Prior knowledge (solubility data) shows that small variations in water 25 do not affect crystalliation kinetics. Fast addition could result in uncontrolled crystallization. Detection of 405 short addition time could occur too late to prevent this uncontrolled crystallization, and thus impact final PSD. 225 Prior knowledge (Chemical Engineering theory) highlights seed wt percentage variations as a potential source of final PSD variation

To be investigated in DOE

Crystallization

Seed wt percentage

9 5 5

Crystallization

Antisolvent percentage

1 1 1

Crystallization Crystallization Crystallization Crystallization

Temperature Agitation (tip speed) Seed particle size distribution Feed Concentration

9 5 9 9 5 5 9 1 1 1 1 1

Yield loss to crystallization already low (< 5%), so reasonable variations in antisolvent percentage (+/- 10%) will not affect the percent of batch crystallized, and will not affect PSD Change in crystallization temperature is easily detected, but rated 405 high since no possible corrective action (such as, if seed has been dissolved) Prior knowledge indicates that final PSD highly sensitive to Agitation, 225 thus requiring further study. Seed PSD controlled by release assay performed after air attrition 9 milling. 1 Same logic as for antisolvent percentage 1

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Options for Depicting a Design Space

Seed wt%

Oval = full design space represented by equation Rectangle represent ranges

Simple, but a portion of the design space is not utilized Could use other rectangles within oval

Pressure

Exact choice of above options can be driven by business factors

Temperature

Large square represents the ranges tested in the DOE. Red area represents points of failure Green area represents points of success.
For purposes of this case study, an acceptable design space based on ranges was chosen

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API Crystallization: Design Space & Control Strategy

Control Strategy should address: Parameter controls

Distillative solvent switch achieves target water content Crystallization parameters are within the design space

Testing
API feed solution tested for water content Final API will be tested for hydrolysis degradate Using the predictive model, PSD does not need to be routinely tested since it is consistently controlled by the process parameters

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Design Space / Control Strategy Parameter controls & Testing

Example from Case Study

Particle Size Particle Size

Crystallization Crystallization

Temperature Feed Time

20 to 30C

Control between 23 and 27C

5 to 15 hours Control via flow rate settings Quality system should ensure 1.1 to 2.5 m/s changes in agitator size result in change to speed setting 1 to 2 wt% < 1 vol% Controlled through weigh scales and overcheck Control via in-process assay

Particle Size

Crystallization

Agitation

Particle Size Hydrolysis Degradate

Crystallization Distillation / Crystallization

Seed Wt% Water Content

Particle size will be tested in this example, since the result is included in the mathematical model used for dissolution.
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Drug Product
Immediate release tablet containing 30 mg Amokinol Rationale for formulation composition and process selection provided In vitro-in vivo correlation (IVIVC) determination
Correlation shown between pharmacokinetic data and dissolution results Robust dissolution measurement needed
For a low solubility drug, close monitoring is important

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Drug Product Direct Compression Manufacturing Process Example from Case Study

Focus of Story
Lubrication

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Example from Case Study

Initial Quality Risk Assessment

Impact of Formulation and Process unit operations on Tablet CQAs assessed using prior knowledge
Also consider the impact of excipient characteristics on the CQAs
Drug substance particle size Moisture content in manufacture

Blending

Lubrication

Compression

Coating

Packaging

in vivo performance
Dissolution Assay Degradation Content uniformity Appearance Friability Stability-chemical Stability-physical - Low risk - Medium risk - High risk

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Drug Product CQA Dissolution Summary

Quality risk assessment

High impact risk for API particle size, filler, lubrication and compression
Fillers selected based on experimental work to confirm compatibility with Amokinol and acceptable compression and product dissolution characteristics

API particle size affects both bioavailability & dissolution

Multivariate DOE to determine factors that affect dissolution and extent of their impact Predictive mathematical model generated
Confirmed by comparison of results from model vs. actual dissolution testing

Possible graphical representations of this design space

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Predictive Model for Dissolution

A mathematical representation of the design space

Example from Case Study

Prediction algorithm: Diss = 108.9 11.96 API 7.55610-5 MgSt 0.1849 LubT 3.78310-2 Hard 2.55710-5 MgSt LubT

Factors include: API PSD, lubricant (magnesium stearate) specific surface area, lubrication time, tablet hardness (via compression force)

Confirmation of model
Batch 1
Model prediction 89.8

Batch 2
87.3

Batch 3
88.5

Dissolution testing result

92.8 (88.494.2)

90.3 (89.0-102.5)

91.5 (90.5-93.5)

Continue model verification with dissolution testing of production material, as needed

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Dissolution: Control Strategy

Controls of input material CQAs
API particle size
Control of crystallisation step

Magnesium stearate specific surface area

Specification for incoming material

Controls of process parameter CPPs

Lubrication step blending time within design space Compression force (set for tablet hardness) within design space
Tablet press force-feedback control system

Prediction mathematical model

Use in place of dissolution testing of finished drug product Potentially allows process to be adjusted for variation (e.g. in API particle size) and still assure dissolution performance

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Drug Product CQA Assay & Content Uniformity Summary

Quality risk assessment
Potential impact for API particle size, moisture control, blending, and lubrication Moisture will be controlled in manufacturing environment Experimental plan to develop design space using input material and process factors In-process monitoring

Consider possible control strategy approaches Assay assured by weight control of tablets made from uniform powder blend with acceptable API content by HPLC
Blend homogeneity by on-line NIR to determine blending endpoint, includes feedback loop API assay in blend tested by HPLC Tablet weight by automatic weight control with feedback loop

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Blending Process Control Options

Example from Case Study

Decision on conventional vs. RTR testing

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Process Control Option 2

Blend uniformity monitored using a process analyser
On-line NIR spectrometer used to confirm scale up of blending Blending operation complete when mean spectral std. dev. reaches plateau region
Plateau may be detected using statistical test or rules

Example from Case Study

0.045 mean spectral standard deviation 0.04

0.035 0.03

Feedback control to turn off blender Company verifies blend does not segregate downstream
Assays tablets to confirm uniformity Conducts studies to try to segregate API

Pilot Scale Full Scale

0.025 0.02

0.015 0.01

Plateau region

0.005 0 0 32 64 96 Number of (block Revolutions of Blender Revolution number) 128

Data analysis model will be provided Plan for updating of model available
Acknowledgement: adapted from ISPE PQLI Team 58

Batch Release Strategy

Finished product not tested for assay, CU and dissolution Input materials meet specifications and are tested

API particle size distribution Magnesium stearate specific surface area

Verify (API assay of blend by HPLC) X (tablet weight) Tablet weight by automatic weight control (feedback loop), %RSD of 10 tablets On-line NIR criteria met for end of blending (blend homogeneity) Tablet weight control results checked Predictive model using input and process parameters calculates for each batch that dissolution meets acceptance criteria Input and process parameters used are within the filed design space
Compression force is monitored for tablet hardness

Assay calculation Content Uniformity Dissolution

Water content
NMT 3% in finished product (not covered in this case study)

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Drug Product Specifications

Use for stability, regulatory testing, site change, whenever RTR testing is not possible Input materials meet specifications and are tested

API PSD Magnesium stearate specific surface area

Verify (API assay of blend by HPLC) X (tablet weight) Tablet weight by automatic weight control (feedback loop)
For 10 tablets per sampling point, <2% RSD for weights

Assay calculation (drug product acceptance criteria 95-105% by HPLC)

Content Uniformity (drug product acceptance criteria meets compendia)

On-line NIR criteria met for end of blending (blend homogeneity) Tablet weight control results checked Predictive model using input and process parameters for each batch calculates whether dissolution meets acceptance criteria Input and process parameters are all within the filed design space
Compression force is controlled for tablet hardness

Dissolution (drug product acceptance criteria min 85% in 30 minutes)

Water content (drug product acceptance criteria NMT 3 wt% by KF)

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Iterative risk assessments

High Risk Initial QRA PHA API Crystallization Blending
Beginning

Medium Risk Control strategy

Low Risk

FMEA
API PSD Blend homogeneity Lubricant

Design Space

FMEA
API PSD Blending time Lubricant amount Lubrication time Pressure Tablet weight

FMEA
API PSD model Blending time Feedback control Mg stearate SSA Lubrication time Pressure Automated Weight control

Lubrication Lubrication time

Hardness Compression Content uniformity

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Conclusions
Better process knowledge is the outcome of QbD development Provides the opportunity for flexible change management Use Quality Risk Management proactively Multiple approaches for experimental design are possible Multiple ways of presenting Design Space are acceptable
Predictive models need to be confirmed and maintained

Real Time Release Testing (RTRT) is an option

Opportunity for efficiency and flexibility

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