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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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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
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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 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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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
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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
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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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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
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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Formulation Strategies for Phase I/II Clinical Programs
Solid Orals - Excipients
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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Formulation Strategies for Phase I/II Clinical Programs
Solid Orals - Excipients
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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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
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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Formulation Strategies for Phase I/II Clinical Programs
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
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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
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
known or potential impact to CQA
known or potential impact to CQA
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
Example from Case Study
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
Example from Case Study
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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
Example from Case Study
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
Example from Case Study
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
Example from Case Study
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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