Transcript Pharmaceutical development

2-3. Pharmaceutical Development
Satish Mallya
Quality Workshop, Copenhagen May 18-21, 2014
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2010
Satish Mallya January
May20-22,
18-21,2014
Outline
 Focus on immediate release solid dosage forms
 Guidance
 Elements
 Case Studies
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2010
Satish Mallya January
May20-22,
18-21,2014
TRS970 Annex 4
 Overarching Principles:
– The Pharmaceutical development section should contain information on the
development studies conducted to establish that the dosage form, the
formulation, manufacturing process, container-closure system,
microbiological attributes and usage instructions are appropriate for the
purpose specified in the product dossier.
– Additionally, this section should identify and describe the formulation and
process attributes (critical parameters) that can influence batch
reproducibility, product performance and FPP quality.
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2010
Satish Mallya January
May20-22,
18-21,2014
TRS970 Annex 4/ICH Q8
 Define Quality Target Product Profile (QTPP) as it relates to quality, safety and
efficacy considering, for example, the route of administration, dosage form,
bioavailability, strength and stability;
 Identify Critical Quality Attributes (CQA) of the FPP so as to adequately
control the product characteristics that could have an impact on quality;
 Discuss CQAs of the API(s), excipients and container-closure system(s)
including the selection of the type, grade and amount to deliver drug product of
the desired quality;
 Discuss the selection criteria for the manufacturing process and the
control strategy required to manufacture commercial lots meeting the QTPP in
a consistent manner.
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2010
Satish Mallya January
May20-22,
18-21,2014
QTTP & CQA
 Define Quality Target Product Profile (QTPP) as it relates to quality, safety and
efficacy considering, for example, the route of administration, dosage form,
bioavailability, strength and stability;
 Identify Critical Quality Attributes (CQA) of the FPP so as to adequately
control the product characteristics that could have an impact on quality;
 Discuss CQAs of the API(s), excipients and container-closure system(s)
including the selection of the type, grade and amount to deliver drug product of
the desired quality;
 Discuss the selection criteria for the manufacturing process and the
control strategy required to manufacture commercial lots meeting the QTPP in
a consistent manner
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2010
Satish Mallya January
May20-22,
18-21,2014
QTPP & CQA
 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.
 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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2010
Satish Mallya January
May20-22,
18-21,2014
Case Study #1
 Identify the QTPPs and CQAs in the following table (product: 100mg IR tablets)
Element/Attribute
Target
Identification
positive
Dosage form
CQA
Element/Attribute
Target
√
Stability
24 M at RT
Tablet
Dissolution
NLT75%/30min
Container/closure
Blisters
Pharmacokinetics
Bioequivalent
to RP
Assay
100% LC
Water content
NMT 4.0%
Content uniformity
USP<905>
Route of administration
Oral
Strength
100 mg
Related substances
Ind -NMT0.2%
Total:- NMT
1.5%
Microbial limits
Ph.Eur
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2010
Satish Mallya January
May20-22,
18-21,2014
QTPP
QTPP
√
CQA
TRS970 Annex 4/ICH Q8
 Define Quality Target Product Profile (QTPP) as it relates to quality, safety and
efficacy considering, for example, the route of administration, dosage form,
bioavailability, strength and stability;
 Identify Critical Quality Attributes (CQA) of the FPP so as to adequately
control the product characteristics that could have an impact on quality;
 Discuss CQAs of the API(s), excipients and container-closure system(s)
including the selection of the type, grade and amount to deliver drug product of
the desired quality;
 Discuss the selection criteria for the manufacturing process and the
control strategy required to manufacture commercial lots meeting the QTPP in
a consistent manner
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2010
Satish Mallya January
May20-22,
18-21,2014
CQAs of the API & Excipients
 Key physicochemical characteristics of the API that can influence the
performance of the FPP:
– Physical properties: particle size distribution, bulk and tap densities,
crystalline form, hygroscopicity,
solubility ;
– Chemical properties: stability under temperature, humidity, oxidative,
photolytic conditions
– Biological properties: permeability, partition coefficient, BCS
 The compatibility of the API(s) with each other (FDCs) and with excipients;
 The choice of excipients, their concentration and their characteristics that can
influence the FPP performance.
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2010
Satish Mallya January
May20-22,
18-21,2014
Processes
Dry Granulation
Direct Compression
Milling
Milling
Milling
Pre-blending
Pre-blending
Blending/lubrication
Addition of binder
Slugging/Roller Compaction
Screening wet mass
Dry screening
Drying
Screening of granules
Blending of lubricant
Blending of lubricant
Tablet compression
Tablet Compression
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2010
Satish Mallya January
May20-22,
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Tablet Compression
What happens to the API
Wet granulation
CQA of the C/C System
 Rationale for selection of the container closure system
 Suitability of the container closure system for storage and
transportation, including the storage and shipping container for bulk
PP
 Safety of packaging materials
 Protection from moisture and light
 Compatibility of the FPP with packaging materials
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2010
Satish Mallya January
May20-22,
18-21,2014
TRS970 Annex 4/ICH Q8
 Define Quality Target Product Profile (QTPP) as it relates to quality, safety and
efficacy considering, for example, the route of administration, dosage form,
bioavailability, strength and stability;
 Identify Critical Quality Attributes (CQA) of the FPP so as to adequately
control the product characteristics that could have an impact on quality;
 Discuss CQAs of the API(s), excipients and container-closure system(s)
including the selection of the type, grade and amount to deliver drug product of
the desired quality;
 Discuss the selection criteria for the manufacturing process and the
control strategy required to manufacture commercial lots meeting the QTPP in
a consistent manner.
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2010
Satish Mallya January
May20-22,
18-21,2014
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.
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2010
Satish Mallya January
May20-22,
18-21,2014
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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Blending
Granulation
Drying (LOD)
Compression
Coating
2010
Satish Mallya January
May20-22,
18-21,2014
Other Considerations
 Justification for overages
 Issues surrounding score line - uniformity testing (i.e. Content uniformity for split
portions containing less than 5 mg or less than 5% of the weight of the dosage
unit portion, or mass uniformity for other situations) should be performed on each
split portion from a minimum of 10 randomly selected whole tablets.
 In-vitro dissolution
– Development of discriminatory method
– Generation of dissolution profiles
 Optimization and Scale-up
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2010
Satish Mallya January
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Optimization Studies
 Studies are undertaken to optimize:
– quantity of binder
– quantity of disintegrant
– LOD
 Different trial batches having varying amounts of disintegrant and binder are
used;
 Results of granule flowability, tablet characteristics and comparative dissolution
profiles are compared;
 Granules with different LOD levels are compressed and results with respect to
flowability and tablet characteristics are used to finalize formulation;
 The formulation so developed is considered to be optimized when there are no
problems (e.g. capping) and the dissolution profile matches the innovator product
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2010
Satish Mallya January
May20-22,
18-21,2014
Case Study #2
 Applicant has developed an IR tablet product containing light and moisture
sensitive API. The API belongs to BCS class 2 and exists in 2 polymorphic forms.
The API constitutes 4% of the formulation. The SmPC reports that the tablets are
uncoated and scored bisected
API/Excipient
Manufacturing
Process
CPP
Others
TOC
Wet Granulation
Blending (BU)
Divisibility: Weight
Variation/Content
Uniformity
XRD
Dry Granulation
Granulation
F2 calculations
PSD
Direct Compression
Drying (LOD)
Geometric dilution
Compatibility
Compression
Coating (spray rate)
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2010
Satish Mallya January
May20-22,
18-21,2014
Thanks
Questions ?
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2010
Satish Mallya January
May20-22,
18-21,2014