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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 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 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.
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 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
CQAs
PK/BQ
Assay (efficacy)
Appearance
Identity
Assay
Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
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QTPP and Specifications
Specifikacijata na FDF?
QTPP
Specifications
•
Desired target for developmental work
•
Includes all of the CQAs
•
Components of QTPP may or may not
•
Specification is a list of
be in specification
•
- Not in spec – Dosage form,
strength
- In spec – Assay, impurities
Does not include acceptance criteria
•
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 rizik
QbD 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 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
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
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
Input
Materials
Unit
Operation 1
CMAs2
Output
Materials
CQAs
Unit
Operation 2
Product
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Critical Material Attributes (CMAs)
Risk Assessment of the 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.
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
Assay
MEDIUM
Justification
Suboptimal pre-roller compaction blending and lubrication
may cause variable flowability of the blend affecting Assay.
The PSD and cohesiveness of the drug substance
Pre-Roller
Content
Uniformity
HIGH
adversely impact its flowability. If not blended properly
Compaction
with excipients, it may affect CU.
Blending and
Blending process variables may impact the distribution of
Lubrication
Dissolution
MEDIUM
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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Justification for assigned risks
Process Step: Compression as CPP
CPPs
Main
compression
force
DP CQAs
Risk
Assessment
Content
Uniformity
LOW
Dissolution
HIGH
Justification and Strategy
CU is dominated by BU and flowability and is
unrelated to main compression force.
Suboptimal compression force may affect tablet
hardness and friability and, ultimately, dissolution.
Press speed
(dwell time)
Content
Uniformity
A faster than optimal press speed may cause
HIGH
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
Dissolution
HIGH
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
Traditional Approach
Level 3
End product testing + tightly
constrained material attributes and
process parameters
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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
Strain gauges
Compression force
NIR
Content Uniformity
Compression
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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
40
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 for
Generic Modified Release
Drug Products
Modified-Release QbD Example
• Developed by the Office of Generic Drugs (2009-2011)
• http://www.gphaonline.org/sites/default/files/DraftExampleQbDforMRTab
let%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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