1. Quality by Design (QbD) in Product Development
Regulatory Compliance for
Global Pharma Market
Quality by Design (QbD) in Product Development
Dr. Nitin Dharmadhikari
Sun Pharma Advanced Research Company Ltd., Mumbai

2. What is QbD?
Systematic, holistic and proactive approach to pharmaceutical development.
Begins with predefined objectives
Emphasizes product and process understanding and process control
Based on sound science and quality risk management
Ref.: ICH Q8 (R2)

3. Why QbD? Generic industry business model: Regulator’s perspective
File first, learn later
Major amendments during review process
- Exhibit batch stability failure, formulation revision
Longer time for generic product approval
Approved product may not be marketed
Post approval changes – prior approval supplements

4. How QbD will help improve?
Ensure higher level of assurance of product quality for patient
Improved product and process design & understanding
Monitoring, tracking & trending of product & process.
More efficient regulatory oversight
Efficiency and cost saving for industry
Increase efficiency of manufacturing process
Minimize / eliminate potential compliance actions

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

6. Elements of QbD Quality Target Product Profile (QTPP)
Define Critical Quality Attributes (CQAs)
Perform risk assessment
Link raw material attributes and process parameters to CQAs
Design and implement a control strategy
Manage product lifecycle, including continuous improvement

7. Quality Target Product Profile-QTPP
What is QTPP?
A set of elements that defines the drug product
The target or goal set in advance
A guide to Drug Product development
What forms the basis for QTPP?
The RLD and its label
Applicable regulatory guidelines
When to define QTPP?
At the start of development
Knowledge gained in development may change some elements

8. Components of QTPP
Components related to safety, efficacy, identity, purity and potency
Critical and non-critical components, e.g.
Critical: Assay, content uniformity
Non-critical: Appearance
Fixed and variable components
Fixed elements must be present
e.g. Dosage form, strength
Variable elements may have a range of acceptable values
e.g. Tablet weight, assay

9. QTPP components for IR tablet - Example
Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents

10. Specific requirements in QTPP
Scored tablets
Weight variation between two halves
Dissolution of half tablet
Orally Disintegrating tablets
Hardness
Disintegration time
Container closure
Extended Release products
Alcohol induced dose dumping

11. Critical Quality Attributes – CQAs
CQAs are a subset of the QTPP
Include critical parameters that are likely to change based upon variations in raw materials and processes
-Identity test for dosage form – Not a CQA
-Assay, Content uniformity – CQAs
CQAs are monitored throughout the DP development.
CQAs ensure that DP remains within safe and effective levels.

12. Route of administration Dissolution (efficacy)
QTPP and CQAs
QTPP components
Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
CQAs
Assay (efficacy)
Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)

13. QTPP and 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
Defining a QTPP does not mean setting all acceptance criteria
or the product specifications before development work begins.

14. QbD Tools – Risk Assessment
Why risk assessment in product development?
To identify relative risk levels at the beginning of product development
To prioritize limited development resources
To document the decision making process throughout development
To assess the needs of additional studies for scale up and technology transfer
To identify appropriate specifications, critical process parameters and manufacturing controls
To decrease variability of critical quality attributes

15. Risk Assessment Risk assessment for
Formulation – starting material properties, levels of components
Manufacturing process
Steps for risk assessment
List out all components / processes
Prepare the process flow chart
Identify all potential failure modes for each item with risk query (what might go wrong?)
Risk analysis
Risk evaluation

16. Risk Assessment
Various formal methodologies available for risk assessment
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!

17. Risk Assessment Quality by Design for ANDAs:
An Example for Immediate-Release Dosage Forms
Generic product development for Acetriptan Tablets, 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.

18. Risk assessment for formulation components Formulation Variables
Drug Product CQA
Formulation Variables
Drug Substance PSD
MCC/Lactose Ratio
CCS Level
Talc Level
Magnesium Stearate Level
Assay
MEDIUM
LOW
Content Uniformity
HIGH
Dissolution
Degradation Products

19. Risk assessment of DP manufacturing process
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
* RC: Roller compaction

20. 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
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.

21. 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

22. 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

23. CPPs Risk assessment of manufacturing process
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

24. Process Step: Compression Justification and Strategy
CPPs
Process Step: Compression
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.

25. 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.

26. Control Strategy

27. 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

28. 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.

29. 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

30. 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

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

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

33. 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

34. QbD

35. QbD

36. 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