1. A view on the process from the idea to the registered pharmaceutical
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

2. Organisation of the presentation
I. DISCOVERY
Identification of target and resource

3. Organisation of the presentation
II. HIT GENERATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

4. Organisation of the presentation
III. LEAD GENERATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

5. Organisation of the presentation
IV. CLINICAL DEVELOPMENT
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

6. Organisation of the presentation
V. POST REGISTRATION
Perspectives: A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation

7. I. DISCOVERY
Identification of target and resource

8. Target identification - Area of interest in terms of drug indication ?
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 ?

9. Resource identification Potential resources for novel drugs:
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

10. Resource identification - Alpinia Institute
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.

11. Resource identification - Alpinia Institute
I. DISCOVERY
Resource identification - Alpinia Institute
Natural organisms, in particular plants
- 52% of the drugs approved in the U.S. from were natural products or derived from them (2).
- 26 plant based drugs were approved during ,
including novel-molecular based drugs (3).
- In the future multicomponent botanical therapeutics will experience an increasing interest in biomedicine (4).
Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs (1)
2) Newman, J Nat Pr ) Saklani & Kutty, Drug Disc Today ) Schmidt et al., Nature Chem Biol 2007.

12. Method of drug discovery - Alpinia Institute Ethnobotanical approach
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

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

14. Process development – in phytopharmacy
II. HIT GENERATION
A) RESEARCH AND DEVELOPMENT
Process development – in phytopharmacy
Herbal raw material
Extraction solvent
Extraction
Miscella (Liquid raw extract)
Encapsulatable mass
Dry extract
Liquid extract, tincture
Soft capsules
Liquids, drops, ointments
Tablets,
hard capsules

15. Development of the test substance
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

16. Availability of raw materials, excipients, consumables
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

17. Identity test, controls Monographs in pharmacopoeias for:
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

18. Two standard analytical methods in phytopharmacy:
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

19. Common Technical Document:
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, Japan, USA)
Module 1:
Information
Module 2:
Summaries
Module 3:
Quality
Module 4:
Non clinical study reports
Module 5:
Clinical study reports
Structure of the CTD
*ICH: International conference for harmonisation of technical requirements for registration of pharmaceuticals for human use.

20. Prepare Module 3: Quality
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

21. Preclinical development In vitro profiling:
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

22. Working with 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.
Medium for cell cultures is 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.

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

24. Preclinical development In vivo testing Animal model (mouse or rat)
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)

25. Preclinical development (continued)
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

26. Preclinical development (continued) Patent policy
III. LEAD GENERATION
A) RESEARCH AND DEVELOPMENT
Preclinical development (continued)
Patent policy
Explore the related patent environment:
Develop a patent strategy:
Database of the European Patent Office (espacencet)
Rationale
Possibilities
- Desired strength
- Costs

27. Scaling up from laboratory to production size GMP and GLP environments
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

28. Continue Module 3: Quality
III. LEAD GENERATION
C) MARKETING AUTHORISATION PROCESS
CTD documentation
Continue Module 3: Quality
Prepare Module 4: Non clinical study reports
Validation report
Stability report
Manufacturing protocol
Development report (on going)
Module 1:
Information
Module 2:
Summaries
Module 3:
Quality
Module 4:
Non clinical study reports
Module 5:
Clinical study reports

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

30. Clinical development – “Linking bench to bedside”
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).

31. Clinical development – “Linking bench to bedside”
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
Treatment groups
toxic
therapeutic
subtherapeutic
Dosage (mg)
Example:
Dose titration - first application in humans

32. Clinical development – “Linking bench to bedside” (continued)
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.

33. Clinical development – “Linking bench to bedside” (continued)
IV. CLINICAL DEVELOPMENT
A) RESEARCH AND DEVELOPMENT
Clinical development – “Linking bench to bedside” (continued)
Phase III studies: Up to 1000 or more patient volunteers
Monitor reaction to long term drug use.
Study design:
- Comparison to placebo or to standard therapy
Multicentre and multinational trials
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.

34. Production - Provide appropriate sample quantities (Phase I, II, III)
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

35. 1: Administrative information 2: CTD summaries
IV. CLINICAL DEVELOPMENT
C) MARKETING AUTHORISATION PROCESS
CTD documentation
- Prepare Modules:
1: Administrative information
2: CTD summaries
5: Clinical study reports
- Compile the whole CTD
Regulatory Authorities
- Submit the completed CTD
- File a New Drug Application with EMEA (Europe) or FDA (USA)
Module 1:
Information
Module 2:
Summaries
Module 3:
Quality
Module 4:
Non clinical study reports
Module 5:
Clinical study reports

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

37. Clinical development after marketing
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

38. Production and quality control
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

39. 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

40. Thank you for your attention !