Quality by Design (QbD)KVALITET VO DIZAJNOT

na preparatite so modificirano osloboduvanje

VOVED

• Farmacvetskite produkti i procesi se kompleksni i multivarijantni.

• Poradi toa razbiranjeto I razjasnuvanjeto na relevantnite multifaktorijalni medjuzavisnosti (pomedju komponentite na formulacijata, procesot i atributite na kvalitet na FDF) voobicaeno pobaruva primena na multivarijantni pristapi kako sto se: DoE (statisticki dizajn na eksperimenti); RSM (response surface methodologijata); optimizacija i multivarijantna analiza na podatocite ili hemometrija vo kompilacija so solidna baza na znaenja za problemot

Ctd….

• ICH Q8 R(2): The suitability of either a drug substance or a drug product for its intended use

• Quality cannot be tested into products; Quality cannot be tested into products; Quality can only be built into productsQuality can only be built into products

Def.

• Quality by Design “oznacuva deka karakteristikite (performansite, osobinite) na produktot I procesot se naucno dizajnirani zal da se postignaat odredeni celi (soodvetna rastvorlivost, bioraspolozlivost, efikasnost),

• Za da se postignat postavenite QbD celi, karakteristikite na produktot i procesot koi se vazni/kriticni za posakuvanite performanci se deriviraat kako kombinacija na prethodnite znaenja kako i eksperimentalnite rezultati i ispituvanja za vreme na razvojot na produktot.”

• Pharmaceutical Quality = ƒ (Drug substance, excipients, manufacturing, and packaging)

Ctd….

• Se pocnuva od prethodno definiraniot targetiran profil na produktot - predefined target product profile (TPP), posle sto se apliciraat razlicni principi I alatki so cel da se razbere produktot I procesot (ICH, 2008a,b; CMC-IM, 2008; Cook et al., 2009)

Quality Target Product ProfileICH Q8(R2) DefinitionQTPP : A prospective summary of the qualitycharacteristics of a drug product that ideally willbe achieved to ensure the desired quality, takinginto account safety and efficacy of the drug product.

Ctd…. - Alatkite na rizik analizata se apliciraat za da se odredi

preliminarnata lista na potencijalnite kriticni atributi na kvalitet – CQAs (critical quality atributes) i kriticni procesni parametri – CPPS – critical process parameters vo soglasnost so ICHQ9 guidance (ICH, 2005; ICH, 2008a,b).

• Quality risk assessment (QRA) tools:– risk filtering, – fishbone diagram, and – FMEA (failure mode and effect analysis),

Ctd….

• CQAs (critical quality attribute) se odnesuvaat na atributite na kvalitet na surovinite, intermedierniot i/ili finalniot produkt

• The terms, intermediate CQAs and manufacturability CQAs, are interchangeable.

• Posle QRA, moze da se apliciraat nekolku screening DOEs so cel da se reducira listata na CQAs I potencijalni CPPs koi vlijaat vrz kvalitetot na intermedierniot i/ili finalniot proizvod.

Ctd….• DoE vo sklop so multivarijantnata analiza na podatoci se

primenuva za da se postigne podobreno poznavanje na formulacijata I procesot, I istovremeno da se definira dizajn prostorot vo koj ke se naodja optimalnata formulacija so najposakuvanite atributi na kvalitet.

• Pritoa multivarijantnata analiza vo sklop na DoE se primenuva za proucuvanje na kompleksnite zavisnosti na site nezavisni varijabli (faktori) kako sto se na pr. Vidot I kolicestvoto na ekscipiensite ili procesnite parametri vrz osobinite (atributite na kvlitet) na intermedierite i FDF

So, What is QbD

Sistematski, holisticen I praktiven pristap vo farmacevtskiot

Zapocnuva so prethodno definirani celi (TPPS)

Go ovozmozuva detalnoto razbiranje na produktot I

procesot

Se bazira na nauka i rizik analiza na kvalitetot Ref.: ICH Q8 (R2)

How QbD will help improve? Obezbeduva visoko nivo na kvalitet na lekot pred se bidejki se

poznati vlijanijata na klucnite faktori na formulacijata I procesot

od koi zavisi kvalitetot, odnosno kriticnite atributi na kvalitet

Podobreno e razbiranjeto i dizajnot na produktot I procesot

Podobren e monitoringot I pratenjeto na procesot I kvalitetot

na produktot za vreme na proizvodstvoto.

Zgolemena e efikasnosta/sigurnosta na industriskoto

proizvodstvo

Podobrena e efikasnosta na rabotata na regulatornite organi

Overview of QbD

Quality Target Product Profile

Product Design and Understanding

Process Design and Understanding

Control Strategy

Continuous Improvement

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Komponenti na QTPP

Komponenti koi se odnesuvaat na bezbednosta, efikasnosta, cistotata I potencijata

Kriticni i ne-kriticni komponenti– Critical: uniformnost na sodrzina, disolucija– Non-critical: izgled

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QTPP components for one tablet formulation- Example

Dosage Form

Route of administration

Strength

Weight

PK/BQ

Appearance

Identity

Assay

Impurities

Content uniformity

Friability

Dissolution

Residual solvents

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Specificni QTPP

Podeleni tableti (Scored tablets)Varijacija na masa na dvete poloviniDisolucija na sekoja polovina

Brzo dezintegriracki tblTvrdinaVreme na dezintegracijaZatvaranje na kontejnerot

Preparati so modificirano osloboduvanjeDislucija vo alkoholen rastvor/Osloboduvanje na

cela doza poradi zemanje so alkohol

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Critical Quality Attributes – CQAs

CQAs poteknuvaat od CTTP

Se vklucuvaat kriticnite parametri koi pretpostavuvame

deka ke se menuvaat so variranje na kolicestvoto na

ekscipiensite I parametrite na procesot ili vv gi pratime

efektite na variranjeto na kolicestvata/vidot na

ekscipiensite i/ili procesnite parametri koi pretpostavuvae

deka ke vlijaat vrz kriticnite atributi na kvalitet-Identity test for dosage form – Not a CQA-Assay, Content uniformity – CQAs

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QTPP and CQAs

QTPP components

Dosage Form

Route of administration

Strength

Weight

PK/BQ

Appearance

Identity

Assay

Impurities

Content uniformity

Friability

Dissolution

Residual solvents

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CQAs

Assay (efficacy)

Impurities (safety)

C.U. (efficacy)

Dissolution (efficacy)

QTPP and SpecificationsSpecifikacijata na FDF?

QTPP

• Desired target for developmental work

• Components of QTPP may or may not

be in specification

- Not in spec – Dosage form, strength

- In spec – Assay, impurities

• Does not include acceptance criteria

Specifications

• Includes all of the CQAs

• Specification is a list of - tests, - references to analytical procedures - acceptance criteria

• Establishes the set of criteria to

which DP should conform to be

considered acceptable for its

intended use

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Alatki na QbD – Aanaliza na rizikQbD Tools – Risk Assessment

Sto e toa rizik analiza za vreme na razvoj na doziranta forma –

farmacevtskiot produkt; zosto ja koristime?

Za identifikacija na nivoata na rizik na pocetokot na razvojot

Za dokumentiranje na procesot na odlucuvanje za vreme na

razvojot

Za da se odredi kolkava e potrebata od dopolnitelni studii na

zgolemuvanje I transfer na tehnologijata

Za odreduvanje na soodvetna specifikcija, kriticnite procesni

parametri i kontrolni tocki pri proizvodstvoto

Za da se namali varijabilnosta na kriticnite atributi na kvalitet

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Rizik analiza – Risk Assessment

Rizik analiza za :

- Formulacijata – pocetna formulaija, nivoa na komponenti

- Proces na proizvodstvo

Cekori pri rizik analizata:- Lista na site komponenti/procesi- Dijagram na procesot- Lista na potencijalnite problemi koi ke rezultirat so

namaluvanje na efikasnosta I sigurnosta na lekot- Postavuvanje na rizik analizata- Evaluacija na rizik analizata

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Rizik analiza - Risk Assessment

Dostapni se poveke metodologii za rizik analiza:

Failure Mode Effects Analysis & Failure Mode Effects & Criticality Analysis

Hazard & Operability Analysis

Supporting statistical tools

•It is neither always appropriate nor always necessary to use a formal risk

management process….. The use of informal risk assessment processes can

also be considered acceptable. – ICH Q9

•A risk-based justification based on experience and data is always necessary!

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PRIMERI

Risk Assessment

Quality by Design for ANDAs: An Example for Immediate-Release Dosage FormsPRIMER ZA FDF SO BRZO OSLDOBODUVANJE I

DELUVANJE

RAZVOJ NA GENERICKI PRODUKT Acetriptan Tableti, 20 mg.

Acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range.

It exists in three different polymorphic forms which may affect dissolution.

Polymorph III is the most stable polymorph.

Drug product is prepared with roller compaction process.

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QTPP

• the quality target product profile (QTPP) was defined based on the properties of the drug substance, characterization of the RLD product, and consideration of the RLD label and intended patient population.

• Pharmaceutical Equivalence + Bioequivalence = Therapeutic Equivalence

CQAs

• Identification of critical quality attributes (CQAs) was based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute of the drug product.

• For generic acetriptan tablets, these CQAs include assay, content uniformity, dissolution and degradation products.

Risk assessment

Risk assessment for formulation components

Drug Product CQA

Formulation Variables

Drug Substance ParticleSizeDist.

MCC/Lactose Ratio

Croscarmelose Sodium Level

Talc Level

Magnesium Stearate Level

Assay MEDIUM MEDIUM LOW LOW LOW

Content Uniformity HIGH HIGH LOW LOW LOW

Dissolution HIGH MEDIUM HIGH LOW HIGH

Degradation Products

LOW LOW LOW LOW MEDIUM

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CMAs, CPPs and CQAs

What factors affect drug product CQAs? Properties of Input Materials- Identify Critical Material Attributes

(CMAs) Properties of in-process materials- CQAs of one step become CMAs

for a downstream unit operation Manufacturing process parameters- Identify Critical Process

Parameters (CPPs)

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Input Materials

CMAs1

Output Materials

ProductCQAs

CPPs1

Unit Operation 1

Unit Operation 2

CMAs2

CPPs2

Critical Material Attributes (CMAs)

Drug Product CQAs

Drug Substance Attributes

Solid State Form

HygroscopicityParticle

SizeResidual Solvents

Process Impurities

Chemical Stability

Physical Attributes (size and splitability)

LOW LOW LOW LOW LOW LOW

Assay LOW LOW LOW LOW LOW LOW

Content Uniformity

LOW LOW LOW LOW LOW LOW

Drug Release HIGH LOW HIGH LOW LOW LOW

Risk Assessment of the drug substance attributes

Solid state form and particle size of DS are CMAs

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Risk assessment

Drug Product CQAs

Process Steps

Pre-RC* Blending and Lubrication

Roller Compaction

MillingFinal Blending

and Lubrication

Compression

Assay MEDIUM LOW MEDIUM LOW MEDIUM

Content Uniformity

HIGH HIGH HIGH LOW HIGH

Dissolution MEDIUM HIGH MEDIUM HIGH HIGH

Degradation Products

LOW LOW LOW LOW LOW

* RC: Roller compaction

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• Risk assessment of manufacturing process - CPP• Identify high risk steps (unit operation) that affect the

CQAs of DP.

Justification for assigned risks

Process Steps

Drug Product CQAs

Assigned Risk

Justification

Pre-Roller

Compaction

Blending and

Lubrication

Assay MEDIUM

Suboptimal pre-roller compaction blending and lubrication

may cause variable flowability of the blend affecting

Assay.

Content Uniformity

HIGH

The PSD and cohesiveness of the drug substance

adversely impact its flowability. If not blended properly

with excipients, it may affect CU.

Dissolution MEDIUM

Blending process variables may impact the distribution of

CCS in the blend which could impact disintegration of the

granules and ultimately, dissolution of the tablets.

Degradation Products

LOW

Blending process variables are unrelated to the

degradation products of Generic Acetriptan Tablets, 20

mg.

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Process Step Pre-Roller Compaction Blending and Lubrication

CPPs DP CQAsRisk

AssessmentJustification and Strategy

Main compression force

Content Uniformity

LOWCU is dominated by BU and flowability and is

unrelated to main compression force.

Dissolution HIGHSuboptimal compression force may affect tablet

hardness and friability and, ultimately, dissolution.

Press speed (dwell time)

Content Uniformity

HIGHA faster than optimal press speed may cause

inconsistent die filling and weight variability which

may then impact CU and dissolution. For efficiency,

the press speed will be set as fast as practically

possible without adversely impacting tablet quality. Dissolution HIGH

Process Step: Compression as CPP

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Justification for assigned risks

QbD Tools – DoE

Design of experiments (DoE) – Useful for screening of variables with significant impact on DP CQAs

– Classical approach uses OFAT (One Factor At A Time)

– Limited number of experiments gives limited information.

– DoE helps study effects of interaction of multiple factors at a time

– Used in optimization studies, enables creation of “design space”

– “Design space” is proposed by the applicant and subject to

regulatory assessment and approval.

– “Design space” developed at lab or pilot scale can be proposed for

commercial scale, but needs to be verified at production scale for

scale dependant parameters.

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Control Strategy

“A planned set of controls, derived from current product and process understanding that ensures process performance and product quality…..”

ICH Q8 (R2) & Q10

Control Strategy includes following elements (but not limited to): – Input material attributes (e.g. drug substance, excipients,

container closure) – Equipment operating conditions (process parameters) – In-process controls – Finished product specifications – Controls for each unit operations – Methods and frequency of monitoring and control.

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Control Strategy

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Control Strategy

Control Strategy Implementation Options

Enhanced Approach

Traditional Approach

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Level 1 Real-time automatic control + Flexible process parameters

Level 2 Reduced end product testing + Flexibility for critical material attributes and critical process parameters within design space

Level 3 End product testing + tightly constrained material attributes and process parameters

Process Analytical Technology (PAT)

Timely measurements during processing

Critical quality and performance attributes

Raw and in-process materials

At-line, on-line or in-line measurements

• Founded on “Process Understanding”

Opportunities for improvement

• More reliable and consistent processes (& product)

– Less failures, less reworks, less recalls

• Flexibility w.r.t. scale and equipment

• Better / faster Quality Systems

• Process Enhancement Opportunities

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PAT in Tablet manufacturing

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Stage Technique Measurement

Dispensing NIR / Raman Identification of raw materials

Wet Granulation NIR Moisture distribution

Drying NIR Moisture content

Blending NIR Blend Uniformity

CompressionStrain gauges Compression force

NIR Content Uniformity

PAT Examples

Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD without any dryer modification.

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PAT Examples

Real-time Blend Uniformity by using TruProcess™ Analyzer

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QbD: Required or Optional?

Required

• Quality target product profile (QTPP) including critical quality attributes (CQAs) of the drug product and including Product design and understanding

• Product design and understanding

– Critical material attributes (CMAs) of the drug substance and excipients

• Process design and understanding

– Critical process parameters (CPPs)

• Control strategy, including justification

Optional

• Design Space

• Process Analytical Technology

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Quality by Design Example forGeneric Modified Release

Drug Products

Modified-Release QbD Example

• Developed by the Office of Generic Drugs (2009-2011)• http://www.gphaonline.org/sites/default/files/DraftExampleQbDforMRTa

blet%20April%2026.pdf• Intended to illustrate the types of development studies ANDA applicants

may use as they implement QbD for these complex products.• Provide a concrete illustration of the QbD principles from ICH Q8(R2)• Development of a real product may differ from the example• Different Products will have Different Issues• There are Scientifically Valid Alternative Approaches• Full-Implementation of QbD in the review assessment by 2013

QbD scheme

TARGET - DESIGN - IMPLEMENTATION

Raw, Lionberger, and Yu, Pharmaceutical Research 28 (7) 2011

Generic MR (10 mg) Tablet

• Label• Active ingredient Z (BCS Class I)• Indication: Immediate onset of effect similar to the IR product, as

well as for maintenance of the effect, for once a day dosing.• PK: MR provides for plasma concentrations of Z comparable to

immediate release product through the first two hours for immediate onset of effect, and a sustained release phase to maintain plasma concentrations of the drug through 24 hours

• Dose: 10 mg Tablet• Conveniently Scored for 5 mg Dose• Taken without Regard to Food (No Food Effect)

QTPP for Modified Release Product

Ctd….

Ctd…

Ctd…

Formulation Development

Ctd…

Ctd…

Conclusion

References for QbD

1. Guidance for Industry: Q8(R2) Pharmaceutical Development

2. Guidance for Industry: Q9 Quality Risk Management

3. Guidance for Industry: Q10 Pharmaceutical Quality System

4. Guidance for Industry PAT: A Framework for Innovative Pharmaceutical

Development, Manufacturing, and Quality Assurance

5. Quality by Design for ANDAs: An Example for Modified Release Dosage

Forms

6. Quality by Design for ANDAs: An Example for Immediate Release Dosage

Forms

7. GPhA presentations

8. Draft QbR updated

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