1. 1-7.The ICH Q8 “Minimal Approach” to Pharmaceutical Development
Satish Mallya
January , 2011

2. Pharmaceutical Development Q8(R2)
The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product.
The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.
January 19-22, 2011

3. Pharmaceutical Development Q8(R2)
At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified.
Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product.
January 19-22, 2011

4. ICHQ8 Empirical (Minimal) Essential product development for
all products vs
Enhanced (QbD) Quality by Design
Critical understanding of product and process
January 19-22, 2011

5. Approaches & Outcomes Minimal Enhanced
Conducted one variable at a time – minimum product knowledge
Multivariate experiments – extensive product knowledge
Focus on optimization and reproducibility of process
Focus on control strategy and robustness of process
End product testing
On line (PAT) tools utilized
Primary control through FPP specifications
FPP specifications part of overall control strategy
FPP quality controlled by in-process and end product testing
FPP quality ensured through risk based control strategy since product and process are well understood.
Real time release testing with possible reduction of end product testing
Quality over product life cycle managed through problem solving and corrective action
Quality over product life cycle managed through preventive action and continuous improvement
January 19-22, 2011

6. “Minimal” Approach Establish Quality Target Product Profile (QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API and formulation ingredients
Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP).
Outline pertinent control strategies.
January 19-22, 2011

7. “Minimal” Approach Establish Quality Target Product Profile (QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API and formulation ingredients
Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP).
Outline pertinent control strategies.
January 19-22, 2011

8. Quality Target Product Profile (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.
January 19-22, 2011

9. Quality Target Product Profile (QTPP)
QTPP is the basis of design for the development of the product
Considerations for establishing QTPP:
Indication & route of administration
Dosage form & strength(s)
Container closure system
Attributes affecting pharmacokinetic characteristics (e.g., dissolution)
FPP quality criteria (e.g., sterility, purity, stability and drug release)
January 19-22, 2011

10. Quality Target Product Profile (QTPP)
The following are generally identified as elements of QTPP:
Assay of API in the FPP
Purity
Content Uniformity of API in the FPP
Disintegration/Dissolution of FPP
Tablet Friability & Hardness
Stability/Suitability of Container Closure System
Bioequivalence
Various formulations are investigated in order to obtain similar dissolution patterns as for the innovator product and to improve the disintegration time. On achieving satisfactory results in the lab scale batches scale up is undertaken to ensure reproducibility of results on larger scales.
January 19-22, 2011

11. Quality Target Product Profile
QTPP Attribute
Target
Product
IR tablet, 300 mg
Bioequivalence
F2 > 50
Appearance
Film coated scored
Potency
95-105%
Purity
Impurity A – 0.2%
Impurity B – 0.5%
Total – 1.0%
Content Uniformity
Meet Ph. Eur.
Dissolution
NLT 85% in 30 minutes in pH 1.2, 4.5 & 6.8
Stability
24 months at RT in HDPE and blisters
January 19-22, 2011

12. “Minimal” Approach Establish Quality Target Product Profile (QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API and formulation ingredients
Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP).
Outline pertinent control strategies.
January 19-22, 2011

13. Critical Quality Attribute (CQA)
A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
January 19-22, 2011

14. Critical Quality Attribute (CQA)
Additional CQAs for APIs, raw materials and intermediates: properties that affect FPP CQAs (e.g., particle size distribution, bulk density) .
Potential drug product CQAs are utilized to guide the product and process development.
The list of potential CQAs may be modified as product knowledge and process understanding increase.
Pertain To
Affect
API
Excipients
In-process PP
Potency
Purity
Drug release
Stability
Sterility
January 19-22, 2011

15. “Minimal” Approach Establish Quality Target Product Profile (QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API and formulation ingredients
Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP).
Outline pertinent control strategies.
January 19-22, 2011

16. Quality Attributes of the API
API Characterization
Physical
Chemical
Biological
For FDC products, evaluate the compatibility of the APIs with each other.
The knowledge gained from the studies investigating the potential effect of API properties on FPP performance can be used to justify tests in the API specification
January 19-22, 2011

17. API Characterization Physical properties: Appearance Particle size
Bulk and tap densities
Crystalline form
Hygroscopicity & water content
Solubility and pH profile of solution/dispersion
January 19-22, 2011

18. API Characterization Chemical properties Stability temperature
humidity
oxidative
photolytic
Biological properties
permeability
partition coefficient
BCS
January 19-22, 2011

19. Excipients Function in formulation Affect on performance of FPP
Stability
Bioavailability
Affect on manufacturability of FPP
Ability to perform during shelf-life
Disintegrants
Preservatives
Antioxidants
Safety of Novel Excipients
January 19-22, 2011

20. FPP
Identification of attributes critical to the quality of the drug product
Justification for choice of drug product components
properties of the drug substance
Properties of excipients
Suitability of container closure system
Justification for choice of the manufacturing process
Summary of formulations used in bioequivalence studies
justification for changes between the proposed commercial formulation and those formulations used in bioequivalence batches and primary stability batches
Justification for score line
Justification for overages
January 19-22, 2011

21. Container Closure System
Rationale for selection of the container closure system
Safety of packaging material
Suitability of the container closure system for storage and transportation, including the storage and shipping container for bulk PP
Compatibility of the FPP with packaging materials
Integrity of the container and closure
Justification for the use of secondary packaging materials
January 19-22, 2011

22. Compatibility
Compatibility of the drug product with reconstitution diluents
Range of diluents
Range of dilutions
Container types
Storage recommendations
Compatibility and stability of admixtures obtained from further dilution of reconstituted products prior to administration.
January 19-22, 2011

23. Microbiological Attributes
Rationale for performing or not performing microbial limit testing for non sterile drug products
Evidence of effectiveness of preservative
At the lowest specified concentration
Over shelf-life
Antimicrobial effectiveness of products that are inherently antimicrobial
January 19-22, 2011

24. “Minimal” Approach Establish Quality Target Product Profile (QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API and formulation ingredients
Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP).
Outline pertinent control strategies.
January 19-22, 2011

25. Manufacturing Process Development
Justification for the selection of the manufacturing process and in- process controls;
Appropriateness of the equipment used;
Identification of critical process parameters (CPP);
Justification for differences between the manufacturing processes used to produce batches for bioequivalence studies or primary stability studies and the commercial process.
Collection of process monitoring data during the development of the manufacturing process can provide useful information to enhance process understanding.
January 19-22, 2011

26. Critical Process Parameter (CPP)
A process parameter whose variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality.
January 19-22, 2011

27. Critical Process Parameter (CPP)
Blending
Granulation
Drying (LOD)
Compression
Filtration
Sterilization
January 19-22, 2011

28. “Minimal” Approach Establish Quality Target Product Profile (QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API and formulation ingredients
Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP).
Outline pertinent control strategies.
January 19-22, 2011

29. Control Strategy
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.
Is intended to ensure that a product of required quality will be produced consistently
Sources of variability that can impact product quality should be identified, thoroughly understood and appropriately controlled
January 19-22, 2011

30. Thanks