DRUG DEVELOPMENT

A view on the process from the idea to

the registered pharmaceutical

Dr. Matthias Kreuter

Head of Alpinia Laudanum Institute of Phytopharmaceutical
Sciences AG Walenstadt, Switzerland

Organisation of the presentation

I. DISCOVERY
Identification of target and resource

Organisation of the presentation

II. HIT GENERATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

Organisation of the presentation

III. LEAD GENERATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

Organisation of the presentation

IV. CLINICAL DEVELOPMENT
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

Organisation of the presentation

V. POST REGISTRATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

I. DISCOVERY
Identification of target and resource

I. DISCOVERY

Target identification
- Area of interest in terms of drug indication ?
- Relevant cellular or molecular targets ?
- Appropriate assays established or to be
developed ?
- Available relevant literature ?
- Patent situation in the target area ?

I. DISCOVERY

Resource identification
Potential resources for novel drugs:
- Natural organisms (plants, fungi, bacteria, animals)
- Combinatorial chemistry
- Structure-based drug design
Methods for drug discovery:
- High throughput screening of random samples (HTS):
Including screen development, primary and
secondary screening
- Ethnobiological approach:
Traditional use of natural organisms for medicines

I. DISCOVERY

Resource identification - Alpinia Institute

Natural organisms, in particular plants
Medicinal plants continue to play a significant
role
as a resource for the discovery of novel drugs
(1)

1) Balunas and Koinghorn, Life

Sci 2005.

I. DISCOVERY

Resource identification - Alpinia Institute

Natural organisms, in particular plants
Medicinal plants continue to play a significant
role
as a resource for the discovery of novel drugs
(1)
- 52% of the drugs approved
in the U.S. from 19812002
them (2).

were natural products or derived from

- 26 plant based drugs were approved during 20002006,

including novel-molecular based drugs (3).
- In the future multicomponent botanical
therapeutics will
experience an increasing
2) Newman, J Nat Pr 2002. 3) Saklani & Kutty, Drug Disc Today 2008. 4) Schmidt et al.,
interest
biomedicine
(4).
Nature
Chemin
Biol
2007.

I. DISCOVERY

Method of drug discovery - Alpinia Institute

Ethnobotanical approach
Systematic screening of:
- Published literature on traditional medicinal plant use
(e.g. documented traditional healers
experience)
- Historical texts
(e.g. ancient botanico-medicinal manuscripts)
Advantages: - Preselection of potentially active
resources
- Promising safety profile (age-long
experience)
- Cost-efficient and comparatively fast

II. HIT GENERATION

Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

II. HIT GENERATION

A) RESEARCH AND DEVELOPMENT

Process development in phytopharmacy

Herbal raw
material

Extraction
solvent
Extract
ion
Miscella (Liquid raw
extract)

Dry
extract
Tablets,
hard
capsules

Liquid extract,
tincture
Liquids,
drops,
ointments

Encapsulatable
mass
Soft
capsules

II. HIT GENERATION

A) RESEARCH AND DEVELOPMENT

Development of the test substance

Define:
- Active substance (in phytopharmacy:
native extract)
- Dosage form
Establish:
marker)

- Physico-chemical profile (active compounds,

Investigate:

- Pharmacology
- Mode of action

Prepare:

- Patent draft

II. HIT GENERATION

B) QUALITY CONTROL AND PRODUCTION

Raw material supply

Availability of raw materials, excipients, consumables
Herbal raw material
- Established market product ?
- Contract cultivation ?
- Wild harvesting
?
- Continuous availability
Pay attention to:
- Quality variations
- Sustainable cultivation / harvesting
- Biodiversity regulations
- Existing patent and intellectual property
rights

II. HIT GENERATION

B) QUALITY CONTROL AND PRODUCTION

Identity test, controls

Monographs in pharmacopoeias for:
- Chemical substances
- Herbal raw materials
Organisation of a monograph
Definition:
chemical characterisation
Characters: appearance, solubility
Identification:
microscopy, physico-chemical
tests
Tests:
qualitative analysis
Assay:
quantitative analysis
Impurities:
chemical or microbiological impurities

II. HIT GENERATION

B) QUALITY CONTROL AND PRODUCTION

In house controls
Two standard analytical methods in phytopharmacy:
- TLC = Thin layer chromatography

- HPLC = High performance liquid chromatography

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II. HIT GENERATION

C) MARKETING AUTHORISATION PROCESS

CTD documentation
Common Technical
Document:
Harmonised format for
applications for preparing
marketing authorisation in the
three ICH* regions (Europe,
*ICH: International
Japan,
USA)
conference for
harmonisation of technical
requirements for
registration of
pharmaceuticals for
human use.

Module 1:
Information

Structure of the
CTD

Module 2:
Summaries

Module 3: Module 4:
Quality
Non clinical
study
reports

Module 5:
Clinical
study
reports

II. HIT GENERATION

C) MARKETING AUTHORISATION PROCESS

CTD documentation
Prepare Module 3: Quality
- Monograph
- Specification
- Development report (on
going)

Module 1:
Information
Module 2:
Summaries

Module
3:
Quality

Module 4:
Non clinical
study
reports

Module 5:
Clinical
study
reports

II. HIT GENERATION

A) RESEARCH AND DEVELOPMENT

Preclinical development
In vitro profiling:
- Biochemical assays (e.g. enzyme activity assays)
- Cell culture assays (e.g. cancer cell lines)
- Isolated tissue assays (e.g. mucosa model)
In vitro toxicology:
Investigate potential toxic effects
in bacteria- or cell cultures

II. HIT GENERATION

A) RESEARCH AND DEVELOPMENT

Working with cell cultures

Cells are kept in liquid

nitrogen.

Medium and culture flasks

for cell cultures.

Changes of the cultivated

cells are evaluated under
the micro-scope after the
addition of a test
substance.

Cultivation of cell
cultures in petri-dishes or
cell plates with the
addition of test
substances.

Medium for cell cultures is

pipetted into a culture flask.

III. LEAD GENERATION

Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

III. LEAD GENERATION

A) RESEARCH AND DEVELOPMENT

Preclinical development
In vivo testing

Animal model (mouse or rat)

Drug action:

- Behaviour and reaction

- Physiology
- Histopathology

Toxicology:

Acute toxicity
Subchronic toxicity
Tissue specific toxicity
Tolerability

Consider ethical aspects (e.g. number and kind of

animals used)

III. LEAD GENERATION

A) RESEARCH AND DEVELOPMENT

Preclinical development (continued)

Pharmacokinetic studies
the drug ?
Investigate: - Liberation
- Absorption
- Distribution
- Metabolism
- Excretion

What does the body to

Pharmacodynamic studies
What does the drug to
the body ?
Investigate: - Physiological effects
- Drug action
- Relationship between drug concentration and

III. LEAD GENERATION

A) RESEARCH AND DEVELOPMENT

Preclinical development (continued)

Patent policy
Explore the related patent environment:
Database of the European Patent Office
(espacencet)
Develop a patent strategy:
-

Rationale
Possibilities
Desired strength
Costs

III. LEAD GENERATION

B) QUALITY CONTROL AND PRODUCTION

Scaling up
Scaling up from laboratory to production size
GMP and GLP environments
Validation
Conduct a process validation including various batch sizes
Stability testing
Conduct a stability test under different conditions of
temperature, humidity and exposure time

III. LEAD GENERATION

C) MARKETING AUTHORISATION PROCESS

CTD documentation
Continue Module 3: Quality
-

Validation report
Stability report
Manufacturing protocol
Development report (on
going)
Prepare Module 4: Non clinical
study reports
Module
3:
Quality

Module 1:
Information
Module 2:
Summaries

Module 4: Module 5:
Non
Clinical
clinical
study
study
reports
reports

IV. CLINICAL DEVELOPMENT

Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

IV. CLINICAL DEVELOPMENT

A) RESEARCH AND DEVELOPMENT

Clinical development Linking bench to bedside

Clinical drug studies Research in humans
Subject to ethical concern:
- Qualify to increase existing knowledge
- Respect freedom of decision of volunteers
- Involve a substantiated risk-benefit
assessment
The realisation of a clinical drug study has to be approved by
an
Independent Ethics Commitee (IEC).

IV. CLINICAL DEVELOPMENT

A) RESEARCH AND DEVELOPMENT

Clinical development Linking bench to bedside

Phase I studies

20 to 30 healthy volunteers
Investigate:

Example:
Dose titration - first application in
humans

- Safety and tolerability

- Pharmacokinetics
- Pharmacodynamics

Dosage
(mg)

toxic
therapeut
ic
subtherape
utic
Treatment
groups

IV. CLINICAL DEVELOPMENT

A) RESEARCH AND DEVELOPMENT

Clinical development Linking bench to bedside

(continued)
Phase II studies

100 to 500 patient volunteers

Investigate:

Safety and tolerability

Pharmacokinetics
Pharmacodynamics
Efficiency
Dosage to effect

relationship
Study design: - Dosage comparison
Antitumor drugs: Combination of Phase I and II at an early
stage of drug development is possible.

IV. CLINICAL DEVELOPMENT

A) RESEARCH AND DEVELOPMENT

Overall aim of Phase III: Risk-benefit

evaluation
Phase III studies are pivotal studies = outcome is crucial for
the decision taking of the regulatory authorities.

IV. CLINICAL DEVELOPMENT

B) QUALITY CONTROL AND PRODUCTION

Clinical samples
Production
I, II, III)

- Provide appropriate sample quantities (Phase

- Define sample shipment logistics

Quality control
- Prepare complete batch release
documentation
- Define short and long term storage of
samples
GMP and GLP environments

IV. CLINICAL DEVELOPMENT

C) MARKETING AUTHORISATION PROCESS

CTD documentation
- Prepare Modules:
Module 1:
Information
1: Administrative information
2: CTD summaries
Module 2:
5: Clinical study reports
Summaries

- Compile the whole CTD

Module 3: Module 4:
Quality
Non clinical
study
Regulatory Authorities
reports

Module 5:
Clinical
study
reports

- Submit the completed CTD

- File a New Drug Application with EMEA (Europe) or FDA
(USA)

V. POST REGISTRATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

V. POST REGISTRATION
A) RESEARCH AND DEVELOPMENT

Clinical development after marketing

Phase IV studies

Post marketing testing

Investigate specific questions within the frame of the

approved indication:
- Expanded benefit-risk-profile
- Combination with other drugs
- Optimization (e.g. dosage, application)
E.g.: The worldwide use of the approved drug might lead to
the occurrence of very rare side effects.
Reason for expanded epidemiologic
studies

V. POST REGISTRATION
B) PRODUCTION & QC / C) MARKETING AUTHORISATION

Production and quality control

Manufacture- Manufacturing of the product
- Controls acc. to the established batch release
process
GMP and GLP environments

Marketing authorisation process

Approval
Authorities

- Drug is approved for marketing by the

Summary
I.

DISCOVERY
Identify target and resource

II. HIT GENERATION

Develop process and test substance
Conduct in vitro testing
III. LEAD GENERATION
Conduct in vivo testing
Pharmacokinetic and pharmacodynamic
studies
IV. CLINICAL DEVELOPMENT
Human trials Phase I, II, III
V. POST REGISTRATION
Human trials Phase IV

Thank you for your attention !