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 1981-2002

were natural products or derived from them (2).
- 26 plant based drugs were approved during 2000-2006,
including novel-molecular based drugs (3).
- In the future multicomponent botanical therapeutics will
experience an increasing interest in biomedicine (4).

2) Newman, J Nat Pr 2002. 3) Saklani & Kutty, Drug Disc Today 2008. 4) Schmidt et al., Nature Chem
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 Extraction solvent

material
Extractio
n
Miscella (Liquid raw
extract)

Dry extract Liquid extract, Encapsulatable

tincture mass
Tablets, Liquids, Soft capsules
hard capsules drops,
ointments
 II. HIT GENERATION
A) RESEARCH AND DEVELOPMENT

Development of the test substance

Define: - Active substance (in phytopharmacy: native extract)

- Dosage form

Establish: - Physico-chemical profile (active compounds, marker)

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 ?

Pay attention to: - Continuous availability

- 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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Minutes
 II. HIT GENERATION
C) MARKETING AUTHORISATION PROCESS

CTD documentation

Common Technical Document:

Harmonised format for applications Structure of the CTD
for preparing marketing authorisation Module 1:
in the three ICH* regions (Europe, Information
Japan, USA)
Module 2:
Summaries
*ICH: International
conference for harmonisation
of technical requirements for
registration of Module 3: Module 4: Module 5:
pharmaceuticals for human Quality Non clinical Clinical
use.
study study
reports reports
 II. HIT GENERATION
C) MARKETING AUTHORISATION PROCESS

CTD documentation

Prepare Module 3: Quality

- Monograph
- Specification Module 1:
Information
- Development report (on going)

Module 2:
Summaries

Module 3: Module 4: Module 5:

Quality Non clinical Clinical
study study
reports 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 Medium and culture flasks for Medium for cell cultures is
nitrogen. cell cultures. pipetted into a culture flask.

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.
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 What does the body to the

drug ?
Investigate: - Liberation
- Absorption
- Distribution
- Metabolism
- Excretion

Pharmacodynamic studies What does the drug to the body ?

Investigate: - Physiological effects
- Drug action
- Relationship between drug concentration and effect
 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 Module 1:
- Manufacturing protocol Information
- Development report (on going)
Module 2:
Summaries
Prepare Module 4: Non clinical
study reports
Module 3: Module 4: Module 5:
Quality 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: - Safety and tolerability

- Pharmacokinetics
- Pharmacodynamics
Example:
Dose titration - first application in humans

toxic
Dosage

therapeutic
(mg)

subtherapeuti
c

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 - Provide appropriate sample quantities (Phase I, II,

III)
- 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:

1: Administrative information Information
2: CTD summaries
5: Clinical study reports Module 2:
Summaries

- Compile the whole CTD

Module 3: Module 4: Module 5:
Quality Non clinical Clinical
study study
Regulatory Authorities reports 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 - Drug is approved for marketing by the Authorities

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 !