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

1-7.The ICH Q8 “Minimal Approach” to
Pharmaceutical Development
Satish Mallya
January , 2011
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.
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Satish Mallya January
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2011
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.
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Satish Mallya January
January 20-22,
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2011
ICHQ8
Empirical (Minimal)
Essential product
development for
all products
vs
Enhanced (QbD)
Quality by Design
Critical understanding
of product and
process
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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
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Satish Mallya January
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Quality over product life cycle managed through
preventive action and continuous improvement
“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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
“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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
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.
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Satish Mallya January
January 20-22,
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2011
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)
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Satish Mallya January
January 20-22,
19-22, 2010
2011
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.
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Satish Mallya January
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
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Satish Mallya January
January 20-22,
19-22, 2010
2011
“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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
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.
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Satish Mallya January
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2011
Critical Quality Attribute (CQA)
Pertain To
API
Excipients
In-process PP
Affect
Potency
Purity
Drug release
Stability
Sterility
 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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
“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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
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
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Satish Mallya January
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2011
API Characterization
 Physical properties:
– Appearance
– Particle size
– Bulk and tap densities
– Crystalline form
– Hygroscopicity & water content
– Solubility and pH profile of solution/dispersion
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Satish Mallya January
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API Characterization
 Chemical properties
– Stability
• temperature
• humidity
• oxidative
• photolytic
 Biological properties
– permeability
– partition coefficient
– BCS
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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
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Satish Mallya January
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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
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2011
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
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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.
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Satish Mallya January
January 20-22,
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2011
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
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Satish Mallya January
January 20-22,
19-22, 2010
2011
“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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
Manufacturing Process Development
 Justification for the selection of the manufacturing process and inprocess 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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
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.
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Satish Mallya January
January 20-22,
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2011
Critical Process Parameter (CPP)
 Blending
 Granulation
 Drying (LOD)
 Compression
 Filtration
 Sterilization
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Satish Mallya January
January 20-22,
19-22, 2010
2011
“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.
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Satish Mallya January
January 20-22,
19-22, 2010
2011
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
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Satish Mallya January
January 20-22,
19-22, 2010
2011
Thanks