Quality by Design (QbD) KVALITET VO DIZAJNOT na preparatite so modificirano osloboduvanje

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Quality by Design (QbD)KVALITET VO DIZAJNOTna
preparatite so modificirano osloboduvanje
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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

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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
  can only be built into products

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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)

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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 Profile ICH Q8(R2)
Definition QTPP A prospective summary of the
quality characteristics of a drug product that
ideally will be achieved to ensure the desired
quality, taking into account safety and efficacy
of the drug product.
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• - 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),

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• 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.

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• 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

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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)

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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

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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 polovini
• Disolucija na sekoja polovina
• Brzo dezintegriracki tbl
• Tvrdina
• Vreme na dezintegracija
• Zatvaranje na kontejnerot
• Preparati so modificirano osloboduvanje
• Dislucija 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
CQAs
Assay (efficacy)
Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)
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QTPP and SpecificationsSpecifikacijata na FDF?

• 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

• 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

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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
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Risk Assessment

• Quality by Design for ANDAs
• An Example for Immediate-Release Dosage Forms
• PRIMER 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

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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.

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Risk assessment

• Risk assessment for formulation components

Drug Product CQA Formulation Variables Formulation Variables Formulation Variables Formulation Variables Formulation Variables
Drug Product CQA 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)

CPPs2
CPPs1
CMAs1
CQAs
CMAs2
Unit Operation 1
Unit Operation 2
Product
Input Materials
Output Materials
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Critical Material Attributes (CMAs)
Risk Assessment of the drug substance attributes
Drug Product CQAs Drug Substance Attributes Drug Substance Attributes Drug Substance Attributes Drug Substance Attributes Drug Substance Attributes Drug Substance Attributes
Drug Product CQAs Solid State Form Hygroscopicity Particle Size Residual 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
Solid state form and particle size of DS are CMAs
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Risk assessment

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

Drug Product CQAs Process Steps Process Steps Process Steps Process Steps Process Steps
Drug Product CQAs Pre-RC Blending and Lubrication Roller Compaction Milling Final 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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Justification for assigned risks
Process Step Pre-Roller Compaction Blending and
Lubrication
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.
Pre-Roller Compaction Blending and Lubrication 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.
Pre-Roller Compaction Blending and Lubrication 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.
Pre-Roller Compaction Blending and Lubrication Degradation Products LOW Blending process variables are unrelated to the degradation products of Generic Acetriptan Tablets, 20 mg.
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Justification for assigned risks
Process Step Compression as CPP
CPPs DP CQAs Risk Assessment Justification and Strategy
Main compression force Content Uniformity LOW CU is dominated by BU and flowability and is unrelated to main compression force.
Main compression force Dissolution HIGH Suboptimal compression force may affect tablet hardness and friability and, ultimately, dissolution.
Press speed (dwell time) Content Uniformity HIGH A 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.
Press speed (dwell time) Dissolution HIGH A 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.
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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
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
Traditional Approach
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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
Stage Technique Measurement
Dispensing NIR / Raman Identification of raw materials
Wet Granulation NIR Moisture distribution
Drying NIR Moisture content
Blending NIR Blend Uniformity
Compression Strain gauges Compression force
Compression NIR Content Uniformity
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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
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Modified-Release QbD Example

• Developed by the Office of Generic Drugs
  (2009-2011)
• http//www.gphaonline.org/sites/default/files/Draf
  tExampleQbDforMRTablet20April2026.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

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QbD scheme
TARGET - DESIGN - IMPLEMENTATION
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Raw, Lionberger, and Yu, Pharmaceutical Research
28 (7) 2011
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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)

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QTPP for Modified Release Product
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Formulation Development
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Conclusion
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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