Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
Slide 1
April 2007
Regulatory Aspects of
Pharmaceutical Product Development and the
Need for Registration Prior to Marketing
Presenter:
Joy van Oudtshoorn
Industrial Pharmacy Section
International Pharmaceutical Federation (FIP)
+27 12 347 1392; +27 83 460 5534; joyvo@icon.co.za
Executive Director:
Scientific and Medical Affairs,
J & B Pharmaceutical Consultants
Slide 2
April 2007
Outline
Slide 3
April 2007
Slide 4
April 2007
Outline
 Need for registration prior to marketing
 Guidelines
 CTD
 Pharmaceutical Development
 Regulatory points to consider
 Summary and Conclusions
Slide 5
April 2007
Need for registration prior to marketing
 Approve medicines based on quality, safety and
efficacy and the ability to subsequently adhere to
these
 As result of e.g.
– Diethylene glycol
USA 1930s lacquer, cosmetics, anti-freeze, lubricants, softening
agent, lubricant - preparation of sulfanilamide 105/353 deaths - 1938 Food Drug and Cosmetic Act < seize
mislabelled and adulterated products
– Thalidomide
late 50s early 60s hypnotic, sedative, ‘non-toxic’ teratognic
– “Mishaps”
actives, excipients, manufacturing, packaging, distribution and storage
– Counterfeit and fraud
Slide 6
April 2007
Guidelines
–
–
–
–
–
–
Slide 7
April 2007
CTD
Q8
Q6A and Q6B
Q9
Country specific guidelines
WHO TRS 937 Annexes 7 and 8
CTD Overall Table of Contents (ToC)
2.1
ToC of the CTD
(Mod 2,3,4,5)
Module 1
1.1
ToC of Module 1
or overall ToC,
including Module 1
2.1
2.2
Module 2
2.4
2.5
2.3
2.6
Module 3
3.1
ToC for Module 3
Slide 8
April 2007
Module 4
4.1
ToC for Module 4
2.7
Module 5
5.1
ToC for Module 5
Implementation Coordination Group
June 2002
CTD Numbering System
Module 1
Module 2
1.0 Regional Administrative Information
1.1 ToC of Module 1 or overall ToC,
including Module 1
1.0
2.1 ToC of the CTD (Mod 2,3,4,5)
2.1
2.2 Introduction
2.2
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.4
2.5
2.3
2.6
Module 3
Quality
Slide 9
April 2007
Module 4
Nonclinical
Study Reports
2.5 Clinical Overview
2.7
2.6 Nonclinical Written and
Tabulated Summaries
Module 5
2.7 Clinical Summary
Clinical
Study Reports
Implementation Coordination Group
June 2002
Pharmaceutical Development :
Q8 guideline
– Objective to describe the suggested contents and provide
guidance of the Pharmaceutical Development in ICH CTD
format
– Indicates where demonstration of greater understanding of
pharmaceutical and manufacturing sciences can create a
basis for flexible regulatory approaches, degree of which
is predicated on level of relevant scientific knowledge
gained
– Applicable to products defined in module 3, possibly also
others, not applicable during clinical research stages of
development
Slide 10
April 2007
Pharmaceutical Development Section of CTD:
Q8 Guideline
– opportunity to provide comprehensive understanding of the
product and its manufacturing process for reviewers and
inspectors and also for company personnel
– should describe the knowledge that establishes the dosage form
and formulation suitable for the intended use
– should include sufficient information to provide an understanding
of the development of the product and its manufacturing process
– determine aspects critical to product quality
– justify control strategies
Slide 11
April 2007
Pharmaceutical Development Section of CTD continued
– including an expanded design space and demonstrating an
enhanced knowledge of product performance over range of
attributes, options and parameters could facilitate
• risk-based regulatory decisions
• manufacturing process improvements without further regulatory
review
• reduction of post approval submissions
• real-time quality control leading to reduction of end-product release
testing
– Level of knowledge, not volume of data provides basis for
science based submissions
Slide 12
April 2007
Pharmaceutical Development
Purpose and Scope
 Aim: to design a quality product and
manufacturing process to
consistently deliver the intended performance
of the product
 Knowledge gained:
– provides scientific understanding to establish
design space, specifications and manufacturing
controls
– basis for quality risk management - quality built in by
design
– from changes in formulation and processes during
development and life-cycle management, and prior
information
Slide 13
April 2007
Q8 Aspects to consider
 Innovator or multisource finished pharmaceutical product
 Product components
– Active substance (physicochemical and biological properties,
equivalence of different sources)
– Excipients (characteristics and concentration that can influence drug
performance, compatibility with active and each other)
Slide 14
April 2007
Q8 Aspects to consider continued
HPLC profiles of trimethoprim from different manufacturers of
China (A, B) Israel (C) USA (D, E)
Impurities, any of
– products of incomplete reaction
– products of over reaction
– impurities in starting materials
– impurities from the solvents of the reaction
– impurities from catalysts
– products of side reactions
– degradation products
– residual solvents
– enantiomeric impurities
– inorganic impurities
– impurities in excipients
– polymorphs as impurities
R Nageswara Rao, V.Nagaraju J.Pharm. Biomed.Anal. 33 (2003) 335 -377
Slide 15
April 2007
Q8 Aspects to consider continued
 Dosage form, finished pharmaceutical product
Appropriate paediatric dosage forms for
long term / chronic administration
– Injections, syrups, suspensions, solutions, tablets, capsules ?
• Aspects to consider:
taste, sugar, colourant, flavours or preservative content, mass and
breakages transport, logistics o/s ttt regimen products
– Formulation development
– Overages
– Physicochemical and biological properties
Slide 16
April 2007
Q8 Aspects to consider continued
 Manufacturing Process Development
selection, control, any improvements of the process, critical attributes, process
options, appropriateness of equipment, process validation, process control
requirements, product specifications, ability of process to reliably produce
quality product under different operating systems
 Container Closure System
choice and rationale for selection
 Microbiological Attributes
choice and rationale for selection
 Compatibility of product, labelling information
with constitution diluents, admixtures or dilution prior to administration
(precipitation and stability)
Slide 17
April 2007
Glossary
 Continuous Process Verification: An alternative approach to
process validation in which manufacturing process performance is
continuously monitored and evaluated
 Design Space: The multidimensional combination and interaction of
input variables (e.g. material attributes) and process parameters that have
been demonstrated to proved assurance of quality. Working within the
design space is not considered as a change. Movement out of the design
space is considered to be a change and would normally initiate a regulatory
post approval change process. Design space is proposed by the applicant
and is subject to regulatory assessment and approval
Slide 18
April 2007
Glossary
continued
 Formal Experimental Design: A structured organised method for
determining the relationship between factors affecting a process and the
output of that process. “Design of experiments”
 Process Analytical Technology (PAT): A system for designing,
analysing and controlling manufacturing through timely measurements (i.e.
during processing) of critical quality and performance attributes of raw and inprocess materials and processes with the goal en ensuring final product
quality
 Process Robustness: Ability of a process to tolerate variability of
materials and changes of the process and equipment without negative impact
on quality
Slide 19
April 2007
Quality Risk Management (QRM) Q9
 Introduction
 Scope
 Principles of Quality Risk management
 General Quality Risk Management Process
 Risk Management Methodology
– Annex I
Risk Management Methods and Tools
 Integration of QRM process into Industry and Regulatory operations
– Annex II
 Definitions
 References
Slide 20
April 2007
Potential Applications for QRM
Quality Risk Management (QRM) Q9
continued
Q9 Guideline
 Risk : the combination of the probability of
occurrence of harm and the severity of that harm
 Guideline provides principles and examples of tools for QRM
 Principles of Quality Risk management
– The evaluation of risk to quality should be based on scientific knowledge
and ultimately link to the protection of the patient
– the level of effort, formality and documentation of the QRM process should
be commensurate with the level of risk
Slide 21
April 2007
Q9 Guideline continued
 General Quality Risk Management Process
– Risk Assessment
• identification - what might go wrong
• analysis - what is the likelihood and what are the consequences (severity)
• evaluation - comparison of the identified and analysed risk against given criteria
– Risk Control
• reduction
• acceptance
– Risk Communication
– Risk Review
• review events
Slide 22
April 2007
General Quality Risk Management Process continued
Initiate
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Ri s k Com munic ation
Risk Control
Risk Reduction
Risk Acceptance
Ri sk Ma nage ment t ools
unacceptable
Initiate Quality
Risk Management Process
Output / Result of the
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Review
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Review Events
Slide 23
April 2007
Risk Review
Review Events
R i s k M a n a g e m e nt t o ol s
Ri s k C o m m u ni c a t i o n
Risk Evaluation
Risk Management Methodology

Annex I
Risk Management Methods and Tools
– Basic Methods
[flowcharts, check sheets process mapping,
cause & effect diagrams (fishbone diagram)]
– Failure Mode Effects Analysis (FMEA)
– Failure Mode, Effects and Criticality Analysis (FMECA)
– Fault Tree Analysis (FTA)
– Hazard Analysis and Critical Control Points (HACCP)
– Hazard Operability Analysis (HAZOP)
– Preliminary Hazard Analysis (PHA)
– Risk Ranking and Filtering
– Supporting Statistical Tools
Slide 24
April 2007
Simple explanations of some tools
 Failure Mode Effects Analysis (FMEA)
– Break down large complex processes into manageable steps
 Failure Mode, Effects and Criticality Analysis (FMECA)
– FMEA & links severity, probability & detectability to criticality
 Fault Tree Analysis (FTA)
– Tree of failure modes combinations with logical operators
 Hazard Analysis and Critical Control Points (HACCP)
– Systematic, proactive, and preventive method on criticality
 Hazard Operability Analysis (HAZOP)
– Brainstorming technique
Slide 25
April 2007
Initiate Quality
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Ri s k C o m m u ni c a t i o n
Risk Evaluation
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the Quality
Risk Management Process
Risk Review
Review Events
R i s k M a n a g e m e nt t o ol s
 Preliminary Hazard Analysis (PHA)
– Possibilities that the risk event happens
 Risk ranking and filtering
– Compare and prioritize risks with factors for each risk
Q9 Guideline continued

Integration of QRM process into Industry and Regulatory
operations
Annex II
Potential Applications for QRM
Integrated Quality Management, Regulatory Operations, Development,
Facilities, Equipment and Utilities, Materials Management, Production,
Laboratory Control and Stability Studies, Packaging and Labelling,
Frequently Asked Questions (Q&A)

Definitions

References
Slide 26
April 2007
Basic risk management facilitation methods
Cause and Effect Diagrams (Ishikawa / fish bone)
Environment
People
Materials
Problem
statement
Equipment
Measurement
System
Methods
Prepare by members of ICH Q9 EWG of example only July 2006
Slide 27
April 2007
Basic risk management facilitation methods continued
Cause and Effect Diagrams (Ishikawa / fish bone)
 To associate multiple possible causes with a single effect
 Constructed to identify and organize possible causes for it
 Primary branch: represents the effect
 Major branch:
corresponds to a major cause
 Minor branch:
correspond to more detailed causal factors
Prepare by members of ICH Q9 EWG of example only July 2006
Slide 28
April 2007
Basic risk management facilitation methods
Cause and Effect Diagrams (Ishikawa / fish bone)continued
How to perform?
 Define and agree a precise problem statement
(put as “head” of fish bone)
Think “What could be its causes?” for each node
 Add it to the “fish bone” diagram
 For each line pursue back to its root cause
 Consider splitting up overcrowded sections “bones”
Environment
People
Materials
 Consider which potential root
causes and the need for
further investigation on them
Problem
statement
Equipment
Prepare by members of ICH Q9 EWG of example only July 2006
Slide 29
April 2007
Measurement
System
Methods
Basic risk management facilitation methods
Cause and Effect Diagrams (Ishikawa / fish bone) continued
Basic risk management facilitation methods
Cause and Effect Diagrams (Ishikawa / fish bone)
C. Kingery, The Six Sigma Memory Jogger II
Slide 30
April 2007
Cause and Effect Diagram
for Tablet Hardness
Coating
Drying
Milling
Analytical
Temperature
Spray Rate
Redrying
Pan Speed
Time
Milling
Gun Distance
Temp
RH
Temperature
Screen Size
Air Flow
Atomizing Air Pressure
Mill Speed
Precompressing
Operator
Training
Spray Rate
HPMC
Punch Penetration
Depth
Spray Pattern
Tooling
Plant
Factors
P.S.
Process Conditions
LOD
Temp
Press Speed
P.S.
Feed
Frame
Scrape Down
Compressing
Chopper Speed
Mixer Speed
Methoxyl
Hydroxyl
P.S.
LOD
Other
Syloid
Lactose
Endpoint
Coating
Power
Time
Slide 31
April 2007
Tablet
Hardness
Age
Binder
Feeder Speed
Method
Drug
Substance
Water
Main Compressing
Temp/RH
Sampling
Porosity
Shock Cycle
Operator
Other
Granulation
Raw
Materials
© Alastair Coupe, Pfizer Inc.
Regulatory Points to Consider
Reference product(s)
 FDA strongly recommends that sponsors use the U.S.-approved drug as the reference drug
in BE studies to support FDA approval of a new drug product. If the applicant has right of
reference to information that shows that the brand name products in the United States and
Europe are equivalent formulations, then a 505(b)(2) application could be approved based in
part on a BE study conducted comparing the new product with the European approved
product. The potential use of BE studies comparing a test drug with a European reference
should be discussed with FDA in advance of any submission.1
 EU Test products in an application for a generic product are normally compared with the
corresponding dosage form of an innovator medicinal product (reference product). …
When variations to an essentially similar product are made the reference product for the
bioequivalence study should be the innovator product.2
 WHO The comparator product is a pharmaceutical product with which the multisource
product is intended to be interchangeable in clinical practice. The comparator product will
normally be the innovator product for which efficacy, safety and quality have been
established. The selection of the comparator product is usually made at the national level by
the drug regulatory authority.3
Slide 32
April 2007
Regulatory Points to Consider
 Data
– Appropriateness, compliance
– Optimal use, design space concept
– Assess the need for additional studies
(e.g. bioequivalence, stability) relating to scale up and
technology transfer
– Presentation
– Inspection/audit
Slide 33
April 2007
Summary and Conclusions
 Need for the registration of medicines
 Comprehensive guidelines
 Common interest, the Patient
1
2
3
Slide 34
FDA Guidance for Industry Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously
Approved Antiretrovirals for the Treatment of HIV" October 2006
EU CPMP/EWP/QWP/1401/98: Investigation of Bioavailability and Bioequivalence, 26-Jul-2001
WHO TRS 937 Annex 7, 8
April 2007
Slide 35
April 2007