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

2. 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
Quality by design (QbD)
Multivariate data analysis
Design of experiments (DOEs)
Design space
Critical process parameter (CPP)
Critical quality attribute (CQA)

3. 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

5. 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)

6. 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)
 FMEA - Failure Mode and Effects Analysis
Failure Mode, Effects and Criticality Analysis - (FMECA)
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.

7. Ctd…. Quality risk assessment (QRA) tools:
- 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),

8. 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.

9. 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

10. 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)

11. 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

12. Overview of QbD Product Design and Understanding
Quality Target Product Profile
Product Design and Understanding
Process Design and Understanding
Control Strategy
Continuous Improvement

14. 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

15. 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

16. 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

17. 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

18. QTPP and CQAs QTPP components CQAs Assay (efficacy)
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)

19. QTPP and Specifications Specifikacijata na FDF?
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

20. 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

21. 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

22. 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!

23. PRIMERI

24. 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 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.
RLD – REGERENCE LISTED DRUG

25. 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

26. 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.
Acetriptan is a poorly soluble, highly permeable Biopharmaceutics Classification System (BCS)
Class II compound. As such, initial efforts focused on developing a dissolution method that
would be able to predict in vivo performance. The developed in-house dissolution method uses
900 mL of 0.1 N HCl with 1.0% w/v sodium lauryl sulfate (SLS) in USP apparatus 2 stirred at
75 rpm. This method is capable of differentiating between formulations manufactured using
different acetriptan particle size distributions (PSD) and predicting their in vivo performance in
the pilot bioequivalence (BE) study.
Risk assessment was used throughout development to identify potentially high risk formulation
and process variables and to determine which studies were necessary to achieve product and
process understanding in order to develop a control strategy. Each risk assessment was then
updated after development to capture the reduced level of risk based on our improved product
and process understanding.
For formulation development, an in silico simulation was conducted to evaluate the potential
effect of acetriptan PSD on in vivo performance and a d90 of 30 µm or less was selected. Roller
compaction (RC) was selected as the granulation method due to the potential for thermal
degradation of acetriptan during the drying step of a wet granulation process. The same types of
excipients as the RLD product were chosen. Excipient grade selection was based on experience
with previously approved ANDA and ANDA which both used roller
compaction. Initial excipient binary mixture compatibility studies identified a potential
interaction between acetriptan and magnesium stearate. However, at levels representative of the
final formulation, the interaction was found to be negligible. Furthermore, the potential
interaction between acetriptan and magnesium stearate is limited by only including extragranular
magnesium stearate.

27. Risk assessment for formulation components Formulation Variables
Drug Product CQA
Formulation Variables
Drug Substance ParticleSizeDist.
MCC/Lactose Ratio
Croscarmelose Sodium Level
Talc Level
Magnesium Stearate Level
Assay
MEDIUM
LOW
Content Uniformity
HIGH
Dissolution
Degradation Products
Two formulation development design of experiments (DOE) were conducted. The first DOE
investigated the impact of acetriptan PSD and levels of intragranular lactose, microcrystalline
cellulose and croscarmellose sodium on drug product CQAs. The second DOE studied the levels
of extragranular talc and magnesium stearate on drug product CQAs. The formulation composition was finalized based on the knowledge gained from these two DOE studies.

28. 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)
CPPs1
CPPs2
CMAs1
CMAs2
CQAs
Unit Operation 1
Unit Operation 2
Product
Input Materials
Output Materials

29. Critical Material Attributes (CMAs)
Risk Assessment of the drug substance attributes
Drug Product CQAs
Drug Substance Attributes
Solid State Form
Hygroscopicity
Particle Size
Residual Solvents
Process Impurities
Chemical Stability
Physical Attributes (size and splitability)
LOW
Assay
Content Uniformity
Drug Release
HIGH
Solid state form and particle size of DS are CMAs

30. 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
Pre-RC* Blending and Lubrication
Roller Compaction
Milling
Final Blending and Lubrication
Compression
Assay
MEDIUM
LOW
Content Uniformity
HIGH
Dissolution
Degradation Products
An in-line near infrared (NIR) spectrophotometric method was validated and implemented to
monitor blend uniformity and to reduce the risk associated with the pre-roller compaction
blending and lubrication step. Roller pressure, roller gap and mill screen orifice size were
identified as critical process parameters (CPPs) for the roller compaction and integrated milling
process step and acceptable ranges were identified through the DOE. Within the ranges studied
during development of the final blending and lubrication step, magnesium stearate specific
surface area ( m2 /g) and number of revolutions (60-100) did not impact the final product
CQAs. During tablet compression, an acceptable range for compression force was identified and
force adjustments should be made to accommodate the ribbon relative density ( )
variations between batches in order to achieve optimal hardness and dissolution.
Scale-up principles and plans were discussed for scaling up from lab (5.0 kg) to pilot scale (50.0
kg) and then proposed for commercial scale (150.0 kg). A 50.0 kg cGMP exhibit batch was
manufactured at pilot scale and demonstrated bioequivalence in the pivotal BE study. The
operating ranges for identified CPPs at commercial scale were proposed and will be qualified
and continually verified during routine commercial manufacture.
* RC: Roller compaction

31. 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.
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
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.

32. Justification for assigned risks Justification and Strategy
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.
Dissolution
HIGH
Suboptimal compression force may affect tablet hardness and friability and, ultimately, dissolution.
Press speed (dwell time)
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.

33. Design of experiments (DoE)
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.

34. 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.

35. Control Strategy

36. 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

37. 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

38. PAT in Tablet manufacturing
Stage
Technique
Measurement
Dispensing
NIR / Raman
Identification of raw materials
Wet Granulation
NIR
Moisture distribution
Drying
Moisture content
Blending
Blend Uniformity
Compression
Strain gauges
Compression force
Content Uniformity

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

40. Real-time Blend Uniformity by using TruProcess™ Analyzer
PAT Examples
Real-time Blend Uniformity by using TruProcess™ Analyzer

41. QbD: Required or Optional?
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

42. Quality by Design Example for Generic Modified Release Drug Products

43. Modified-Release QbD Example
Developed by the Office of Generic Drugs ( )
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

44. QbD scheme
TARGET - DESIGN - IMPLEMENTATION

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

46. 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)

47. QTPP for Modified Release Product

48. Ctd….

49. Ctd…

50. Ctd…

51. Formulation Development

52. Ctd…

53. Ctd…

67. Conclusion

68. References for QbD
Guidance for Industry: Q8(R2) Pharmaceutical Development
Guidance for Industry: Q9 Quality Risk Management
Guidance for Industry: Q10 Pharmaceutical Quality System
Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance
Quality by Design for ANDAs: An Example for Modified Release Dosage Forms
Quality by Design for ANDAs: An Example for Immediate Release Dosage Forms
GPhA presentations
Draft QbR updated