Satish Mallya January 20- 22, 2010 1 | 2-3. Pharmaceutical Development Satish Mallya Quality Workshop, Copenhagen May 18-21, 2014 May 18-21,2014
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Satish Mallya January 20-22, 20101 |
2-3. Pharmaceutical Development2-3. Pharmaceutical Development
Satish Mallya
Quality Workshop, Copenhagen May 18-21, 2014
May 18-21,2014
Satish Mallya January 20-22, 20102 |
OutlineOutline
Focus on immediate release solid dosage forms
Guidance
Elements
Case Studies
May 18-21,2014
Satish Mallya January 20-22, 20103 |
TRS970 Annex 4TRS970 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.
May 18-21,2014
Satish Mallya January 20-22, 20104 |
TRS970 Annex 4/ICH Q8TRS970 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.
May 18-21,2014
Satish Mallya January 20-22, 20105 |
QTTP & CQAQTTP & 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
May 18-21,2014
Satish Mallya January 20-22, 20106 |
QTPP & CQAQTPP & 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.
May 18-21,2014
Satish Mallya January 20-22, 20107 |
Case Study #1Case Study #1
Identify the QTPPs and CQAs in the following table (product: 100mg IR tablets)
May 18-21,2014
Element/AttributeTargetQTPPCQAElement/AttributeTargetQTPPCQA
Identificationpositive√Stability24 M at RT
Dosage formTabletDissolutionNLT75%/30min
Container/closureBlistersPharmacokineticsBioequivalent to RP
Assay100% LCWater contentNMT 4.0%
Content uniformityUSP<905>
Route of administrationOral√
Strength100 mgRelated substancesInd -NMT0.2%Total:- NMT 1.5%
Microbial limitsPh.Eur
Satish Mallya January 20-22, 20108 |
TRS970 Annex 4/ICH Q8TRS970 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
May 18-21,2014
Satish Mallya January 20-22, 20109 |
CQAs of the API & ExcipientsCQAs 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.
May 18-21,2014
Satish Mallya January 20-22, 201010 |
ProcessesProcesses
Wet granulation 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 Tablet Compression
May 18-21,2014
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Satish Mallya January 20-22, 201011 |
CQA of the C/C SystemCQA 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
May 18-21,2014
Satish Mallya January 20-22, 201012 |
TRS970 Annex 4/ICH Q8TRS970 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.
May 18-21,2014
Satish Mallya January 20-22, 201013 |
Manufacturing Process DevelopmentManufacturing 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.
May 18-21,2014
Satish Mallya January 20-22, 201014 |
Critical Process Parameter (CPP)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
– Blending– Granulation– Drying (LOD)– Compression– Coating
May 18-21,2014
Satish Mallya January 20-22, 201015 |
Other ConsiderationsOther 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
May 18-21,2014
Satish Mallya January 20-22, 201016 |
Optimization StudiesOptimization 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
May 18-21,2014
Satish Mallya January 20-22, 201017 |
Case Study #2Case 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
May 18-21,2014
API/ExcipientManufacturing Process
CPPOthers
TOCWet GranulationBlending (BU)Divisibility: Weight Variation/Content Uniformity
XRDDry GranulationGranulation F2 calculations
PSD Direct CompressionDrying (LOD)Geometric dilution
Compatibility Compression
Coating (spray rate)
Satish Mallya January 20-22, 201018 |
ThanksThanks
Questions?
May 18-21,2014
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