rnd process.pdf

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Compliant Formulation Development The

Key to Successful Pharma Development

Obergeri, May 4th 2012

Dr. R. Rogasch


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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


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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


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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 thePh. 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 standardseven when not obligatory


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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


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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


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ICHQ8/9/10 Paradigm in Formulation Development

Disclaimer

The information within this presentation is based on the

ICH Q-IWG members expert ise and experience, and

represents the views of the ICH Q-IWG members for thepurposes of a training workshop.


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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 criticalprocess 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 foradditional 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)

Product/Process Development

Pharmaceutical

Development

PQS & GMP

Local Environment

Commercial Manufacturing

Quality Unit (QP,..) level support by PQS

Manage product lifecycle, inclu ding

continual improvement

Design Space (DS), RTR test ing

Link raw material attributes and process parameters

to CQAs and perform Risk Assessment Methodology

Potential CQA (Critical Quality Attribute) identified &

CPP (Critical Process Parameters) determined

QTPP : Definition of intended use & produc tQuali ty Target

Product Profile

CPP : Crit ical

Process Parameter

CQA : Crit ical

Quality Attribute

Risk Management

Opportunities

Design to meet CQA using Risk Management &

experimental stud ies (e.g. DOE)DOE : Design of Experiment

Control Strategy

Technology Transfer

Batch Release

Strategy

Prior Knowledge (science, GMP,regulations, ..)

Continual

improvement

Product/Process Understanding

QRM principle apply at any stage

Marketing Author isation

Quality System PQS


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P2 of CTD as part of a regulatory submission

In line with Quality Risk Management ?

EXAMPLE


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Target Product Profile

Drug substance properties; prior knowledge

Proposed formulation and manufacturing process

Determination of

Cause Effect relationships(Risk Identification with subsequent Risk Analysis)

Risk-based classification(Risk Evaluation)

Parameters to investigate (e.g. by DOE)(Risk Reduction 1. proposal; 2. verified)

FORMULATIONFORMULATION

DESIGN SPACEDESIGN SPACEPROCESSPROCESS

DESIGN SPACEDESIGN SPACE

BY UNIT OPERATIONBY UNIT OPERATIONCONTROLCONTROL

STRATEGYSTRATEGY

Formulationunderst

anding

Formu

lationunderst

anding

Pro

cessunderstanding

Pro

cessundersta

nding

ReRe--evalu

ationandconf

irmation

evalu

ationandconf

irmation

ReRe--eval

uationandcon

firmation

evaluationandcon

firmation

Product and process

characteristics on the

final drug product

Review events

DevelopmentDevel

opm.

Operat

ion

Research

Phase 1

Phase 2

Phase 3

Launch


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Risk Review

Risk Assessment

Risk Evaluation

unacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identifi cation

Review Events

Risk Acceptance

Initiate

Quality Risk Management Process

Output / Result of the

Quality Risk Management Process

RiskManagementto

olsR

iskCommunication

Teamfocused

Int

ernalconsultation

Stakeholderinvolvement

Responsibilities in regulatory operations

Industry

A) Reviewers

EXAMPLE

B) Inspectorates


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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


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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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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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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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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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Solid Orals - Excipients

Unit dose to contain powders or

controlled release pellets

1%-5%Gelatin

HPMC

Polysaccharides

Capsules

Improves powder flow and prevents

static charging

Less than 1%Fumed silica

Talc

Glidants

Tailors drug release rate10%-95%HPMC

Polyethylene oxide

Polyvinylpyrrolidone (PVP)

Controlled

release/matrix

Aids in breakup of tablets or

granules in aqueous media

Less than 5%Sodium starch glycolate

Croscarmellose sodium Crospovidone

Disintegrants

Prevents sticking of formulation to

processing surfaces

Less than 2%Magnesium stearate Stearic acid

Glyceryl behenate

Lubricants

Provides strength in dry and wet

processing of powders

5%-10%Hydroxypropyl cellulose (HPC)

HPMCPovidone

Binders

Imparts compressibility and tensile

strength to tablets

10%-95%Mannitol

Microcrystalline cellulose Starch

Ductile fillers

Imparts hardness and strength to

tablets

10%-95%Lactose

Calcium phosphate, dibasic

Brittle fillers

FunctionApproximate

ranges (%)MaterialsExcipient type

Formulation ExcipientsSolid Orals


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Cosmetic or controlled release coatings1%-30%HPMC

Cellulose acetate , Ethylcellulose,

Polymeric acrylates

Coating ingredients Film

polymers

Cosmetic appearance, marketingLess than 2%Titanium dioxide, Iron oxides, Dyes and

lakes

Colorants

Hide unpleasant drug taste, essential for

chewable formulations

1%-5%Sucrose

Aspartame

Mannitol

Flavors

Taste masking agents

Mitigate chemical degradation,

oxidation

Less than 1%BHT/BHA

Citric acid

Chemical stabilizers

Improve solubility and wettability of

hydrophobic drugs and improve

bioavailability

0.5%-5%Poloxamer 407

SLS

CyclodextrinsHPMC and acid derivatives

HPC

Solubilizers, dispersants,

precipitation inhibitors


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Improve processability, Prevent

sticking

Less than 1% Less

than 0.5%

Glycerol triacetate, Fatty acid salts,

esters, Polyethylene glycol,

Talc

Plasticizers, Anti-tack

agent


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Parenteral Dosage Forms

Parenteral/injectable Solutions (lyophilization)

Colloidal Suspensions (peptides, proteins)

Emulsions

Liposomal Systems

Suspensions


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Liquid Orals/Parenterals Excipients

Maintain osmolarity forparenterals, adjustviscosity, mechanicalstability for lyophilizedcakes

Less than 10%Sodium chlorideHydroxypropylmethylcellulose(HPMC)Mannitol Dextrose

Bulking agents

Maintain pH for optimumsolubility, and comfortfor injectableformulations

Enough foradjusting todesired pH

Sodium chloride Sodiumacetate Sodiumphosphate (andcorrespondingacids) Sodium

hydroxide

Buffering agents

Helps with poorly aqueoussoluble drugs20%-50%EthanolPolyethylene glycolPropylene glycolN-Methylpyrrolidone

Cosolvents

Main solubilizing/suspendingvehicle for allcomponents

50%-90%WaterVegetable oils

Polyethylene glycolPropylene glycol

Diluent

Functionpproximateranges (%)

Materialsxcipient type


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Oral Liquid/Parenteral - Excipients

Sweeteners Masking of

drug tast

Less than

2%

Sucrose, aspartame

Peppermint oil,

flavors

Flavoring/tastemasking

Antioxidants, free radicalscavengers

Less than2%

Butylatedhydroxytoluene/anisole

(BHT/BHA)

Citric acid/citrate

Chemical stabilizers

Prevent microbial growthLess than

2%

Benzyl alcohol Methyl/

propyl parabens

Benzalkonium

chloride Thimerosal

Preservatives

Bind metal impurities to

prevent

complexation and

reactions

Less than

1%

Edetate sodium (EDTA)

Citric acid/citrate

Chelating agents

Improve drug solubility,

emulsification,

suspension of drugparticles, prevent

precipitation

Less than

5%

Hydroxypropyl-beta-

cyclodextrin

Sulfobutylether-beta-cyclodextrin

HPMC

Polaxamer 407

Sodium lauryl sulfate

(SLS)

Phospholipids

Cremophors

Labrasol

Vitamin E TPGS

Solubilizers/surfactants


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Project Case Study

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.

Disclaimer


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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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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
http://www.nihs.go.jp/drug/DrugDiv-E.htmlhttp://www.nihs.go.jp/drug/DrugDiv-E.html


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Quality attr ibute focus

Technical Examples

API

Drug Product

CompressionReal Time

Release testing(Assay, CU, Dissolution)

BlendingAPI

Crystallization

- Final crystallization step

- Blending

- Direct compression

- Particle size control

- Assay and content uniformity

- Dissolution

Process focus


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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

Design of

ExperimentsDesign

Space

Control

StrategyBatch

ReleaseQRM


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QbD Story per Unit Operation

Process

Variables

Design of

Experiments

Quality

Risk Management

Illustrative Examples of Unit Operations:

QTPP

& CQAs

Design

Space

Control

StrategyBatch

Release

CompressionReal Time

Release testing(Assay, CU, Dissolution)

BlendingAPI

Crystallization


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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

Degrades by hydrolytic mechanism 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

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

Appearance, elegance, size,

unit integrity and other characteristics

No off-taste, uniform color,

and suitable for global marketSubjective Properties

Hydrolysis degradation & dissolution changescontroll ed by packaging

Degradates below ICH or to be qualified and nochanges in bioperformance over expiry period

Chemical and Drug Product Stability: 2year shelf life (worldwide = 30C)

Acceptable API PSD

Dissolution

PSD that does not impact bioperformance or pharm

processing

Patient efficacy Particle

Size Distribution (PSD)

Accept able hydrolysis degradate levels at release,

appropriate manufacturing environment controls

Impurities and/or degradates

below ICH or to be qualifiedPatient Safety chemical purity

Identity, Assay and Uniformity30 mgDose

Translation into

Quality Target Product Profile (QTPP)Characteristics / RequirementsTablet

QTPP may evolve during li fecycle during development and commercial manufacture - as new knowledge is

gained e.g. new patient needs are identified, new technical information is obt ained about the product etc.


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Tablet Formulation

Pharmacopoeial

or othercompendial

specification


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Drug Product Process

Blending

Lubrication

Compression

Film coating

API and ExcipientsAmokinol

D-mannitol

Calcium hydrogen phosphate hydrate

Sodium starch glycolateLubricantMagnesium Stearate

CoatingHPMCMacrogol 6000

titanium oxide

iron sesquioxide


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Overall Risk Assessment for Process

Cou

pling

Rea

ction

Aqu

eous

Ex

tra

ctions

Distillative

So

lven

tSw

itc

h

e

m

-

Cont

inuous

Crsta

lliza

tion

Cen

trifuga

l

Filtra

tion

Ro

tary

Dry

ing

Manu

fac

ture

Mo

istur

eCon

tro

l

Blen

ding

Lu

brica

tion

Comp

ress

ion

Coa

ting

Pack

ag

ing

in vivo performance*

Dissolution

Assay

Degradation

Content Uniformity

Appearance

Friability

Stability-chemical

Stability-physical

Drug Substance Drug Product

* includes bioperformace of API, and

safety(API purity)

additional study required

known or potential impact to CQA


current controls mitigate risk

no impact to CQA

Process Steps

CQA

Example from Case Study


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Overall Risk Assessment for Process

Cou

pling

Rea

ction

Aqu

eous

Ex

tra

ctions

Distillative

So

lven

tSw

itc

h

e

m

-

Cont

inuous

Crsta

lliza

tion

Cen

trifuga

l

Filtra

tion

Ro

tary

Dry

ing

Manu

fac

ture

Mo

istur

eCon

tro

l

Blen

ding

Lu

brica

tion

Comp

ress

ion

Coa

ting

Pack

ag

ing

in vivo performance*

Dissolution

Assay

Degradation

Content Uniformity

Appearance

Friability

Stability-chemical

Stability-physical

Drug Substance Drug Product

* includes bioperformace of API, and

safety(API purity)

additional study required



current controls mitigate risk

no impact to CQA

Process Steps

CQA


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API Semi-Continuous Crystallization

Designed to minimize hydrolytic degradation (degradate belowqualified 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 inwater 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 crystallizationand crystallization itself are conducted at lower temperatures and no degradationoccurs 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 ofDOE data

Particle size distribution (PSD) qualified in formulation DOE anddissolution studies


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Risk Assessment:Particle Size Distribution (PSD) Control

What is the Impact that ------------- will have on PSD? 1) minimal5) moderate9) significantWhat is the Probability that variations in ------------ will occur? 1) unlikely5) moderately likely 9) highly likely

What is ourAbil ity to Detect a meaningful variation in --------------- at a meaningful control point? 1) certain5) moderate 9) unlikely

Unit Operation Parameter IM

PACT

PROB

.

Dete

ct

RPN

Comments

Crystallization Feed Temperature 1 5 1 5

Prior knowledge (slowness of crystallization kinetics) ensures that thehot crystallizer feed will be well dispersed and thermally equilibrated

before crystallizing. Hence no impact of feed temp variation oncrystal size.

Crystallization Water content of Feed 1 5 5 25Prior knowledge (solubility data) shows that small variations in waterdo not affect crystalliation kinetics.

Crystallization Addition Time (Feed Rate) 9 5 9 405

Fast addition could result in uncontrolled crystallization. Detection of

short addition time could occur too late to prevent this uncontrolledcrystallization, and thus impact final PSD.

Crystallization Seed wt percentage 9 5 5 225Prior knowledge (Chemical Engineering theory) highlights seed wtpercentage variations as a potential source of final PSD variation

Crystallization Antisolvent percentage 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

Crystallization Temperature 9 5 9 405Change in crystallization temperature is easily detected, but ratedhigh since no possible corrective action (such as, if seed has been

dissolved)

Crystallization Agitation (tip speed) 9 5 5 225Prior knowledge indicates that final PSD highly sensitive to Agitation,

thus requiring further study.

Crystallization Seed particle size distribution 9 1 1 9Seed PSD controlled by release assay performed after air attrition

milling.

Crystallization Feed Concentration 1 1 1 1 Same logic as for antisolvent percentage

To be investigated

in DOE


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Options for Depicting a Design Space

Large square represents the ranges tested in the DOE.

Red area represents points of failure

Green area represents points of success.

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

Exact choice of above options can bedriven by business factors

Temperature

Pressure

For purposes of this case study, an acceptable design space based on ranges was chosen

Seedwt%

API C t lli ti


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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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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

D P d t Di t C i M f t i


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Drug Product Direct Compression Manufacturing

Process

Focus of

Story


Lubrication


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Initial Quality Risk Assessment

Impact of Formulation and Process unit operations on Tablet CQAsassessed 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

- Low risk

- Medium risk

- High risk

Degradation

Content uniformity

Appearance

Friability

Stability-chemical

Stability-physical

in vivoperformance

Dissolution

Assay



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Predictive Model for DissolutionA mathematical representation of the design space

Batch 1 Batch 2 Batch 3

Model prediction 89.8 87.3 88.5

Dissolution testing result92.8

(88.494.2)

90.3

(89.0-102.5)

91.5

(90.5-93.5)

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


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


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Drug Product CQA -

Assay & Content Uniformity Summary

Quality r isk assessment Potential impact for API particle size, moisture control, blending, and lubrication

Moisture will be controlled in manufacturing environment

Consider possible control strategy approaches Experimental plan to develop design space using input material and process factors

In-process monitoring

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

Decision on conventional vs. RTR testing


P C t l O ti 2


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Process Control Option 2Blend 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

Feedback control to turn off blenderCompany verifies blend does not

segregate downstream Assays tablets to confirm uniformity

Conducts studies to try to segregate API

0

0.005

0.01

0.015

0.02

0.025

0.03

0.035

0.04

0.045

0 32 64 96 128

Revolution (block number)

meanspectralstan

darddeviation

Pilot Scale

Full Scale

Plateau region

Number of Revolutions of Bl ender

Data analysis model will be provided

Plan for updating of model availableAcknowledgement: adapted from ISPE PQLI Team



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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

Assay calculation Verify (API assay of blend by HPLC) X (tablet weight)

Tablet weight by automatic weight control (feedback loop), %RSD of 10 tablets

Content Uniformity On-line NIR criteria met for end of blending (blend homogeneity)

Tablet weight control results checked

Dissolution 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

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

Assay calculation (drug product acceptance criteria 95-105% by HPLC) Verify (API assay of blend by HPLC) X (tablet weight)

Tablet weight by automatic weight control (feedback loop) For 10 tablets per sampling point,


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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