2-3.

Pharmaceutical Development

Satish Mallya

Quality Workshop, Copenhagen May 18-21, 2014

1| Satish Mallya January

May20-22, 2010
18-21,2014
 Outline

 Focus on immediate release solid dosage forms

 Guidance

 Elements

 Case Studies

2| Satish Mallya January

May20-22, 2010
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.

3| Satish Mallya January

May20-22, 2010
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.

4| Satish Mallya January

May20-22, 2010
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

5| Satish Mallya January

May20-22, 2010
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.

6| Satish Mallya January

May20-22, 2010
18-21,2014
 Case Study #1

 Identify the QTPPs and CQAs in the following table (product: 100mg IR tablets)
Element/Attribute Target QTPP CQA Element/Attribute Target QTPP CQA

Identification positive √ Stability 24 M at RT

Dosage form 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

7| Satish Mallya January

May20-22, 2010
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

8| Satish Mallya January

May20-22, 2010
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.

9| Satish Mallya January

May20-22, 2010
18-21,2014
 Processes

Wet granulation Dry Granulation Direct Compression

Milling Milling Milling

What happens to the API

Pre-blending Pre-blending Blending/lubrication

Addition of binder Slugging/Roller Compaction

Screening wet massDry screening

Drying

Screening of granules

Blending of lubricant Blending of lubricant

Tablet compression Tablet Compression Tablet Compression

10 | Satish Mallya January

May20-22, 2010
18-21,2014
 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

11 | Satish Mallya January

May20-22, 2010
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.

12 | Satish Mallya January

May20-22, 2010
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.

13 | Satish Mallya January

May20-22, 2010
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
– Blending
– Granulation
– Drying (LOD)
– Compression
– Coating

14 | Satish Mallya January

May20-22, 2010
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

15 | Satish Mallya January

May20-22, 2010
18-21,2014
 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

16 | Satish Mallya January

May20-22, 2010
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 CPP Others

Process
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)

17 | Satish Mallya January

May20-22, 2010
18-21,2014
 Thanks

?Questions

18 | Satish Mallya January

May20-22, 2010
18-21,2014