Transcript Rat + Non-Rodt

NON CLINICAL DEVELOPMENT OF
DRUG SPECIALITIES
________________________
Bernard MARCHAND
Explo
Preclinical
Stage A
Project
Bio
Pharmaceutical
Research
Phase I
Preclinical
Stage B
Phase II
Toxicological and kinetics
Expertises
PK/PD
TOXICO
ADME
Salt Selection
Phase I
Formulation
Phase III
PK
Interactions
PB/PK
Up scaled
Formulation
Population
Kinetic
Interspecies
metabolism
comparison
Pharmaceutical
File
NDA
Post
NDA
New
Formulation
Pharmaceutical
Support
Regulatory
Affairs
Pharmacopoeia
Copy
Analysis
RESEARCH
PHARMACOLOGY
CHEMISTRY
BIOPHARMACEUTICAL
SCREENING
DEPARTMENT
New targets
New tools coming
from development
Hits Identification
Lead Optimisation
Structure
Activity
Relationships
Candidat Selection
Preclinical
Development
Analytical methods,
Absorption
Metabolic stability
Solubility,Specific
questions...
Pharmacokinetic
Toxicology
Physicochemistry
DISCOVERY PROCESS & BIOPHARMACY DESCRIPTORS
Lead Optimisation
HTS
SDS
Back-up
Preclinical
Development
1- 3 drugs
300 - 30 drugs




Clinical
Trial
1 drug
30 - 3 drugs
Intestinal absorption
 P450 Isoenzymes
Metabolic Stability
 Inhibition
Metabolic pathway
 Induction
Other parameters  BBB permeation/Cell toxicity
MAJOR TECHNICAL EVOLUTIONS IN BIOPHARMACY
LC/MS/MS
DETECTION
Cassette Dosing
HPLC
* * ** ** * * * * * * * * * * * * * *
**
ANALYTICAL
SAMPLE PREPARATION
SUBCELLULAR
MODELS
CELLLULAR MODELS
(Caco2, hepatocytes)
Hepatic
Microsomes
(animal + man)
Automation (96 wells)
GENETIC TOOLS
BIO INFORMATIC
(Human DNA)
Data Analysis
Modelisation
ABSORBED FRACTION
PERMEABILITY
Molecular Weight
Nitrogen
Oxygene
Hydrogen Bonds
Ionisation
ABSORBED
FRACTION
SOLUBILITY
PERMEABILITY SOLUBILITY
LIPOPHILY
Fraction of the dose
solubilised
in the intestin
Caco2 PERMEABILITY MODEL
HUMAN ENTEROCYTE CELLS
Different Transport
Mechanisms
- Transcellular (passive)
(lipophilic)
- Paracellular (passive)
(hydrophilic)
- Transcellular (active)
(transportors)
- Efflux Process
(PGP)
HEPATIC BARRIER
Metabolism Rate
Component of the
terminal half time
Liver
General
Circulation
Metabolism
rapidity
LIPOPHILY
Metabolic Bioavailability
(first pass effect)
PREDICTION OF IN VIVO METABOLIC
BIOAVAILABILITY
Km vitro
Vm vitro
Km vivo
Vm vivo
g prot/g liver and g liver/animal
Metabolic
Biovailability
Q*fu*Vm*S/(Km+S)
Concentration
OUT
Metabolites
Concentration
Blood
Flow
Q+fu*Vm*S/(Km+S)
Plasma
Proteins
Concentration
IN
Ka
Dose
SIMULATION IN RELATION TO DOSE
SimLin
SimLin
Dose (mg/kg)
40%
+
20%
+
Dose (mg/kg)
2621,44
327,68
40,96
0%
5,12
0%
0,64
10%
10%
0,08
20%
+
30%
0,01
30%
2621,44
20971,52
2621,44
40,96
5,12
+ +
0,64
0%
0,08
10%
327,68
20%
40%
327,68
30%
50%
50%
5,12
40%
60%
60%
40,96
50%
70%
70%
0,64
60%
80%
80%
0,08
70%
90%
90%
0,01
80%
SimLin
100%
100%
90%
0,01
Metabolic Bioavailability
100%
MAN
Biodisponibilité métabolique
DOG
Biodisponibilité métabolique
RAT
Dose (mg/kg)
predicted clinical doses
In vivo/In vitrocorrelation in one species :
Mixture of products (cassette dosing 5/Rat - 50/Dog
NATURE AND NUMBER OF INVOLVED P450
3A4
43%
Metabolic
Stability
± specific
inhibitors
1A2
6%
2A6
2%
2C9
10%
2C19
4%
2E1
5%
2D6
30%
Interest in screening :
- Avoid one polymorphic enzyme
- Avoid metabolism by only one P450
Enterocyte humain : transport et métabolisme
Jonctions serrées
S
A
N
G
BCRP
hOATP-B(?)
ISBT
I
LRP
MRP-3
V
E
I
N
E
MRP-1(?)
Noyau
1A1
3A4
MRP-1
1A2
UGT
1A6
3A4
UGT
2B27
3A4
MRP-2
P-gp (MDR1)
T
E
PepT1
S
ASBT
MCT
(drug/H+cotransporter) +
Na /SLGT1
MRP-(5?)
N
T
I
SPNT1
P
O
R
T
E
Dipeptide
Tripeptide
Transporters
Jonctions serrées
N
BLOOD BRAIN BARRIER MODELE
Co-culture of Bovin Brain Capillary Endothelial Cells
with rat astrocytes (Pr Ceccheli - Lille)
6 wales plates
Transport Study
(filter +/- cells)
Drug
BBCE
(confluent and
differenciated
in 1 week and ready
to use for 5 days)
Apical
Basolateral
LC-MS-MS
Quantitation
(10, 15, 20, 30, 45
min)
Astrocytes
(confluent in 3
weeks)
Ringer HEPES
CORRELATION Caco2/BHE
-6
Log Papp Caco2
-7
-8
-9
R = 0.74
Diazepam
Phenytoin
Cafeine
Hydrocortisone
Pindolol
Propanolol
Dexamethazone
Nicotine
Dopamine
Ac Acetylsalicylique
-10
Sucrose
Urée
-11
-12
Terbutaline
Pipenzepine
Mannitol
-13
-10
-9
-8
-7
-6
Log Papp BBB
-5
-4
SCREENING IN TOXICOLOGY
Mutagenesis
Ames II
Automatised Micronucleus ?
Cellular Toxicology with cryopreserved hepatocytes ?
Morphology, Viability, Glutathion level
In vitro model answering in vivo issues
Ex : vacuolisation on cultured fibroblastes
Toxicogenomics ?
TOXICOGENOMICS
Global approach
Cells / Tissues
RNA
Hybridization
Image analysis
Significant gene
induction or repression
Database mining and
mecanistic interpretation
RESULTS
CYP2B
CYP3A
min
Control
max
Phenobarbital
175 human genes involved in drug metabolism at the
hepatic level
Gene Category
Selected Genes
•Apoptosis
•Bax, Bcl-2, Bcl-X, c-myc, c-fos, caspase 7-8,CD 27, TNF, Smp30
•Cell cycle
•Cyclin A-B1- D1/2/3-E1, cdK 2-4-6,JNK-1, Telomerase
•DNA damage/Repair
•GADD45, GADD153, MGMT, p16, poly(ADP-ribose) synthetase
•Inflammation
•IL 1, IL-6 ,IL11, IL-15, cyclooxygenase-2
•Oncogene
•c-jun, c-myc, elk-1
•Stress response
•Oxidative stress genes, ApoJ, Hsp70, Heme oxygenase 2, SOD
•Peroxisome Proliferators
•Enoyl coA hydratase, PPAR , Acyl coA oxidase
•Transcription factors, growth factors
•C/EBP, IB-, NFB, erk-1, p38, HGF, TGFB RII
•Plasma transport
•albumin, transferrin
•Phase I
•CYP P450s (22), FMO, EH, MAO
•Phase II
•GST (4), UGT(10), SULT(4)
•Phase 0/III
•MDR1, MRP (6), BSEP, OATP (4), OAT (2), OCT (2)
•CYPs regulating nuclear factors
•CAR, PXR, RXR, GR
HANDLING THE DATA
Tools for rapid assessment of metabolism are available but how
we handle the data has not yet been completely mastered
Back up
Theoretical
approach
HTS
Log K ’Calculated
LogP, Rate of
metabolism
Data base
Sorting molecules
with Warnings
and Metabolic SAR
SDS
Preclinical
development
Solubility, LogP Caco-2
Papp Microsomal
Km/Vm IC50 inhibition
n-in-one dosing
1st administration
to Man
CYP450 Km, Vm Ki
inhibition constant
induction potential
n-in-one dosing
in Man ?
Sorting molecules with
in vivo scaled up data
and Metabolic QSAR
Sorting molecules
with partial or total
rebuilding of the
entire population
Databases for correct data use, the new challenge for tomorrow ?
PRECLINICAL STUDY PROGRAMME
Stage A
Stage B
4 months
- Dose Ranging (3-7d) Rat + Non-Rodt
- Ames test
- Mouse Lymph.
- Drug Subst. Analyt. Chem.
- Degradation
-
6 months
- 4 wk Tox Rat + Non-Rodt
- Acute studies
Rat + Mouse PO & IP or IV
- Rat Bone Marrow
micronucleus
- Choice of Salt
- Tablet Formul. + Stability
Assay developt
TK DoseRanging Rat+ Non-Rodt
PK Rat
Prel. PK Non-Rodt
Blood/Pl.Ratio
Prel. Metab. in vivo Rat
Prel. Prot. Bind.
Inhib. Potential
Intersp. Comp.
Feasibility label. cpd
200 g
-
Assay Validation
Plasma Stability
TK 4 wk Rat
TK 4 wk Non-Rodt
TK Micronucleus
Def. PK Non-Rodt
Induct. Potential Rat + Non-Rdt*
* if Rat positive
- Enzymes identif. (human)
- Intersp. Comp. 14C
-  Label. Cpd
2.5 kg
Regulatory Toxicology – Early Programme #
 Phase I requirements *
Single dose toxicity
Repeat dose toxicity studies
Genotoxicity studies
Reproductive toxicity studies
* Other requirements
Pharmacology (actions relevant to the proposed route)
Safety pharmacology
Pharmacokinetics (preliminary studies on absorption,
distribution, metabolism and excretion) and in vitro
metabolism studies
# ICH M3 : Nonclinical Safety Studies
Regulatory Toxicology – Later Programme #
 Phase II, III marketing application requirements *
Chronic dose toxicity studies
Carcinogenicity studies
Reproductive toxicity studies
Appropriate toxicity/genotoxicity studies on metabolites,
impurities and/or excipient
*
Other requirements
Additional safety pharmacology (if necessary)
Additional genotoxicity studies (if necessary)
Phamacokinetics (studies on absorption, distribution,
metabolism and excretion)
# ICH M3 : Nonclinical Safety Studies
Duration of Toxicity Studies #
To support phase I and II trials in EU and phase I, II and III trials
Minimum duration of toxicity
Duration of clinical trials
*
Rodent
Non –rodent
Single dose
2 weeks*
2 weeks
Up to 2 weeks
2-4 weeks*
2 weeks
Up to one month
one month
one month
Up to 3 months
3 months
3 months
Up to 6 months
6 months
6 months - 1year
> 6 months
6 months
1 year
NOTE in US and EU, as an alternative to repeat dose studies, single dose
toxicity studies with extended examinations may support single dose human
trials
# ICH M3 : Nonclinical Safety Studies
PRECLINICAL STUDIES
GENOTOXICITY : Standard Test Battery
 AMES TEST: detection of reverse mutation on
S. typhimurium and E. coli (= procaryotes)
 MOUSE LYMPHOMA : detection of forward
mutation on cell lineage (= eucaryotes)
can also detect clastogenic effects
 MICRONUCLEUS on rat bone marrow: detection of
chromosome breaks = clastogenicity
The battery can be completed with additional test(s) when
necessary.
Should permit to discard at the beginning of development
potential genotoxic carcinogen compounds
PRECLINICAL STUDIES
GENERAL TOXICOLOGY
- ACUTE :
Route:
intended for human -If oral route for human :
ORAL + PARENTERAL (IV or IP)
Species: MOUSE and RAT
Examinations :
MORTALITY
CLINICAL SIGNS/ BEHAVIOR
GROSS OBSERVATION AT NECROPSY
(Histopathology for gross lesions)
 Acute toxicology profile
MNLD = Maximal non-lethal dose
MLD = Minimal lethal dose
PRECLINICAL STUDIES
GENERAL TOXICOLOGY
- SUBCHRONIC and CHRONIC
Route :
intended for human
Species : Rodent = RAT
Non-Rodent = DOG or MONKEY
Dosing : daily (or twice daily), 3 doses + control
Duration : up to 6 months (rodents)
9 to 12 months (non-rodents)
Investigations : pluridisciplinary contributions
 Define NOEL : No Effect Level or
NOAEL: No Adverse Effect Level
TARGET ORGANS - BIOMARKERS
STANDARD TOXICOLOGY EVALUATIONS
Blood
Hematology
red, white cells and
platelet counts
Biochemistry
20 to 25 parameters
Clinical observations
behavior
Bodyweight
Food/Water intakes
Urinalysis
Toxicokinetic/Metabolism (enzyme induction/inhibition)
Necropsy
Gross observations
 40 organs/tissue samples
Histology process
Histopathology
Electron
microscopy
PRECLINICAL STUDIES
REPRODUCTIVE TOXICOLOGY
- FERTILITY : Reproductive performance
Male : sperm analysis
+ histopathology of gonads
and accessory glands
Female : oestrus cycle
- EMBRYOFETAL TOXICOLOGY :
Hysterectomy
- uterus content: implantations, resorptions…
- external
- visceral
examinations of fetus
- skeletal
 Teratogenic effect?
PRECLINICAL STUDIES
REPRODUCTIVE TOXICOLOGY (contld)
- PERI-and POSTNATAL TOXICOLOGY
Parturition
Lactation
Physical, sensory and behavioral development of pups
Second generation study
Species : Rodent = RAT
+ Non Rodent = RABBIT (Lagomorph)
for embryofetal studies
PRECLINICAL STUDIES
CARCINOGENESIS
These studies remain necessary to detect non-genotoxic
carcinogens.
Two species:
RAT and MOUSE
Two-year duration: LIFE SPAN for these species
Investigations :
. Clinical observations and mortality
. Feed and water intakes
. Palpations: for detection of masses (subcutaneous, mammary
glands,…)
. Necropsy
gross observations
organ weights
histomorphologic evaluations
 40 tissues or organs + masses
. Statistical analysis  Conclusion about carcinogenic potential
TOXICOLOGY
Plasma
Concentration
Peak effect
Toxicokinetics
Toxic effects 1000
Toxicity
treshold
Pharmacologic
effects
100
10
Pharmacokinetics
0
1
5
2
3
Time (h)
4
Toxicological Requirement
 Depending on toxicity, a frequently used “safety margin” for
volunteer studies is 10 fold between dose which produces
toxicity in animals and dose given to humans
 First dose can be 1/100 of NOAEL
 Final dose can be 1/10 of NOAEL
 Plasma data on drug will give levels at which toxic effects may
be expected and so must not be exceeded
 Awareness that animal data not necessarily predict clinical
toxicity
PRECLINICAL STUDY PROGRAMME
4 months
6 months
1 month
Preclinical Research
- 4 wk Tox Rat + Non-Rodt
- Acute studies
Rat + Mouse PO & IP or IV
- Rat Bone Marrow
micronucleus
- Drug Subst.
Analyt. Chem.
- Degradation
- Assay developt
- TK DoseRanging Rat+
Non-Rodt
- PK Rat
- Prel. PK Non-Rodt
- Blood/Pl.Ratio
- Prel. Metab. in vivo Rat
- Prel. Prot. Bind.
- Inhib. Potential
- Intersp. Comp.
- Feasibility label. cpd
200 g
Pre- Project
Decision Point
Stage B
Stage A
- Dose Ranging
(3-7d)
Rat + Non-Rodt
- Ames test
- Mouse Lymph.
2 months
- Choice of Salt
- Tablet Formul.
+ Stability
-
Assay Validation
Plasma Stability
TK 4 wk Rat
TK 4 wk Non-Rodt
TK Micronucleus
Def. PK Non-Rodt
Induct. Potential
Rat + Non-Rdt*
Check List
- Dose Ranging
ReproTox
Preclinical Summary
Board Committee
- Production clinical batch
Phase I (capsule)
-
Development Decision
Clinical Assay
Plasma Stab. (man)
TK assay (transfer to CRO)
TK Dose Ranging
ReproTox
- WBA Rat
- Mass Bal. Rat & in vivo Met.
- Def. Prot. Bind. (label. cpd)
* if Rat positive
- Enzymes identif.
(human)
- Intersp. Comp. 14C
-  Label. Cpd
2.5 kg
IMPD
Investigator brochure
16 kg
PHASE 1 STUDIES
Clinical Pharmacokinetics
Phase I : dose tolerance
10000
20
AUC
15
Concentration
1000
10
5
0
0
30
60
90
120
Dose
100
10
1
0
6
12
18
Time (h)
Dosing 600-900 samples in real time
24
SINGLE DOSE PK
GASTRO INTESTINAL
TRACT
ORAL ROUTE
Administration
Bile
First pass effect
Portal vein
LIVER
TARGET
ORGANS
(TISSUES)
1000 Cmax
Concentration
ABSORPTION
100
DISTRIBUTION
+ ELIMINATION
10
BLOOD
CIRCULATION
AUC Exposure
1
0 tmax4
8
12
16
Time (h)
20
24
EXCRETION
Integration of physiological parameters
and in vitro measurements
Kplung
Qheart
Kpheart
Qtissues
Concentration
1000
100
10
1
Kptissues
0
4
Concentration
1000
12 16 20 24
Time (h)
Qmuscles
100
Kpmuscles
10
Q
1
0
8
4
8
12 16 20 24
Time (h)
Vmax Km
hepatic. a
Kp liver
Q portal v.
fabs
DMPK ISSUES IN DRUG DEVELOPMENT
Bioavailability
Inter/intr
Evaluation of simple
Drug-drug
a subject
drug metabolism
variability interaction
parameters
Intestinal absorption
Metabolic stability
Metabolic pathways
P450 Isoenzymes
Inhibition potential
Prediction of the main
drug characteristics
with respect to the
entire population
Induction potential
Rebuild (predict) of the in vivo situation
PREDICTIONS IN VIVO
Interindividual variability
CYP1A1 CYP1A2
Concentration (µM)
CYP2C9
Extreme
subjects of
the simulation
Time (h)
IN VIVO PREDICTIONS
Drug-drug interactions
1000
+ inhibitor
Concentration
100
10
+
+ inductor
1
0
4
8
12
Time (h)
16
20
24
+
PHASE II PK/PD
Pharmacokinetic / Pharmacodynamic Analysis
700
140
600
120
Effect
500
100
80
Plasma
concentration
Cp
40
20
0
50
Cp
1400
1200
1000
800
600
100
0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
2000
1800
1600
150
60
Effect
200
200
100
400
300
Direct effect
Effect versus Cp
0
0
80
70
Ce
50
100
150
200
250
300
350
400
450
concentration
60
Effect
50
40
30
20
400
200
0
10
0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Delayed effect
Effect versus Ce
Why a modelling approach?
Sustained release
formulation
A clinical study
per formulation
Pharmacodynamic
objectives
PK/PD model :
Relationship between plasma
concentrations and effects
PK model :
Absorption, distribution, elimination
Dissolution model :
Relationship between In vitro and
In vivo dissolution
Simulations
FORMULATION RESEARCH
Oral Route
Transmucosal Route
Tablets and Capsules
Fast Dissolving Forms
Slow Release Formulation
Delayed Formulation
Buccal
Nasal
Pulmonary
Transdermal Route
Injectable Route
Bolus and Infusion
Slow Release Formulation
Patches
Iontophoresis devices
ORAL ROUTE/PROLONGED RELEASE
HYDROPHILIC MATRIX
 Gastro
intestinal
fluids penetrate the
polymer layer which,
consequently, swells
and forms a gel which
controls the release
kinetics of the drug
substance
HPMC
H2O
ORAL ROUTE / HYDROPHILIC MATRIX
In vitro dissolution profile
%
100
50
Prolonged Release
Immediate Release
0
0
4
8
12
16
H
ORAL ROUTE / HYDROPHILIC MATRIX
In Vivo
80
[ng/ml]
Immediate Release
60
Prolonged Release
40
20
0
0
24
48
72
H
ORAL ROUTE / PROLONGED RELEASE
SEMI SOLID LIPOPHILIC MATRIX
• Control of the release kinetics is obtained by
the choice of the excipient and by its
hydrophilic-lipophilic balance (HLB).
• Manufacturing process, excipient melting,
drug substance dispersion in the molten
mass and, pouring into hard gelatin capsules
ORAL ROUTE
SEMI SOLID MATRIX STABILISATION
Antiparkinson drug - 30°C/60%HR
Without stabilisation
Antiparkinson drug - 30°C/60%HR
With stabilisation (Servier's patent)
100
Drug Substance dissolved, %
Drug Substance dissolved, %
100
75
50
initial
1 month
2 months
3 months
25
75
50
initial
1 month
2 months
3 months
25
0
0
0
4
8
Figure 5 Time (h)
12
16
0
4
8
Time (h)
12
16
ORAL ROUTE / PROLONGED RELEASE
MICROPARTICLES
• Multiparticulate
dosage form as small
spherical reservoir
beads (0.5 à
1.5 mm diameter)
• Dissolution rate
controlled by a semipermeable membrane
PROLONGED RELEASE MICROPARTICLES
Filters
Semi permeable
membrane
Drug substance +
Excipients
Coating solution
Hot air
ORAL ROUTE
SUSTAINED RELEASE MICROPARTICLES
Steady-state plasma concentrations of
the two different dosage forms
IR 3 x day
PR 1 x day
100
Plasma concentration (ng/ml)
Drug Substance dissolved, %
In vitro dissolution rate of two
different dosage forms
75
50
IR
P
R
25
0
0
4
8
12
Time (h)
16
20
24
90
80
70
60
50
40
30
20
10
0
72
78
84
Time (h)
90
96
102
ORAL ROUTE / DELAYED RELEASE
Drug
substance
released (%)
120
100
80
60
40
20
0
0
2
4
6
8
Time (h)
10
12
14
16
18
ORAL ROUTE / DELAYED RELEASE
plasma
concentration
(ng/ml)
8
7
6
5
4
3
2
1
0
IR
DR
0
2
4
6
8
10
12
16
20
24
Time (h)
ORAL ROUTE DELAYED AND PROLONGED RELEASE
MICROPARTICLES
Plasma Concentration
12 ng/ml
8
In vitro dissolution rate
Drug substance released
(%)
100
4
50
0
0
4
8
12
16
Time (h)
0
0
4
8
12
16
Time (h)
20
24
Explo
Preclinical
Stage A
Project
Bio
Pharmaceutical
Research
Phase I
Preclinical
Stage B
Phase II
Toxicological and kinetics
Expertises
PK/PD
TOXICO
ADME
Salt Selection
Phase I
Formulation
Phase III
PK
Interactions
PB/PK
Up scaled
Formulation
Population
Kinetic
Interspecies
metabolism
comparison
Pharmaceutical
File
NDA
Post
NDA
New
Formulation
Pharmaceutical
Support
Regulatory
Affairs
Pharmacopoeia
Copy
Analysis
POPULATION KINETIC
Plasma concentration
CL
Population Analysis
healthy subjects
Time
CL creat
Plasma concentration
plasma concentration
renal impaired subjects
Population simulations
(variability
variability))
Time
Bayesian feedback
Time
Clearance Extrapolation
CL/F (L/h)
41
39
36
33
30
27
24
21
19
16
13
10
7
4
2 98
8
9
7
6
5
88
4
78
68
Age (Years)
58
3
48
38
28
2
18
1
CLcr (L/h)
Pharmacokinetics
Activity - Toxicity
•
•
•
•
•
Therapeutic window
Relation conc. / effects
Side effects
Toxicity
Clinical
etc.
• Absorption
•
•
•
•
PKcs
Distribution
Metabolism
Elimination
etc.
Regimen
OtherFactors
Clinical Factors
•
•
•
•
•
•
•
Status of the patient
Age, weight
Stage of the illness
Associated pathologies
Associated treatments
Compliance
etc.
• Administration routes
•
•
•
•
•
Formulation
Tolerance - addiction
Drug interactions
Genetic Polymorphism
etc.
Explo
Preclinical
Stage A
Project
Bio
Pharmaceutical
Research
Phase I
Preclinical
Stage B
Phase II
Toxicological and kinetics
Expertises
PK/PD
TOXICO
ADME
Salt Selection
Phase I
Formulation
Phase III
PK
Interactions
PB/PK
Up scaled
Formulation
Population
Kinetic
Interspecies
metabolism
comparison
Pharmaceutical
File
NDA
Post
NDA
New
Formulation
Pharmaceutical
Support
Regulatory
Affairs
Pharmacopoeia
Copy
Analysis
COHERENCE
Analytical Methods
Impurities
Degradation products
REGULATORY
CONSTRAINTS
% Qualification
Pharmaceutical File
FORMULATION DESCRIPTION
Diluting and lubrification agents
Added excipients
PHARMACEUTICAL DEVELOPMENT
2 Definitions :
Drug substance = Active substance (New Chemical
Entity or existing drug substance )
Drug product = medicinal product = Finished product
(tablets, capsules, …)
BEGINNING OF PHARMACEUTICAL
DEVELOPMENT (1)

Physicochemical properties of the new drug
substance
solubility in water at different pH values
kinetics of dissolution as a function of
particle size
........

Stability of the drug substance itself
stress conditions (acidic or basic pH,
oxidation, temperature)
BEGINNING OF PHARMACEUTICAL
DEVELOPMENT (2)
 Choice of salt and cristalin form for development
- Solubility
- Stability
 Chemical compatibility drug substance/excipients
 Formulations for phase I
TYPES OF FORMULATION / ORAL ROUTE
 Release of the drug substance
Immediate release (IR)
Modified release (MR)
prolonged release
delayed release
IMMEDIATE RELEASE TABLET
 Drug substance
 Diluant (lactose, mannitol ....)
 Binder (povidone,HPMC, maltodextrin ....)
 Desintegrating agent (sodium starch glycolate,…)
 Flowing agent (silica, talc ....)
 Lubricant (magnesium stearate, stearic acid ....)
THE IDEAL FORMULATION (1)

Easy to manufacture, with a robust process giving always a
quality product

Delivering the drug substance as needed according
to its intrinsec pharmacokinetic properties (half-life,
site of absorption......) and to the therapeutic needs :
 prolonged release for a once-a-day formulation of a drug
substance with a short half-life
 quick Cmax to get an effect quickly
 lower Cmax to decrease side effects
 ......

Stable throughout the storage period
 chemical stability of the drug
 no evolution of the dissolution profile
INTERNATIONAL CONFERENCE OF
HARMONISATION : I.C.H. PROCESS

Since 1990

The aim: to standardize the studies to be performed for the
registration of a new product in the 3 main geographical
areas :
• USA/Canada
• Japon
• European Union

3 topics
• Safety (guidelines S) / Toxicology
• Efficacy (guidelines E) / Clinical development
• Quality (guidelines Q) / Pharmaceutical development
I.C.H. PROCESS
Example : Stability for zone II


Drug substance :
 3 batches
 packaging representative of industrial packaging
Drug product :
 3 batches (the size of 2 out of 3 is more than 1/10
that of industrial batches)
 packaging chosen for the market
Conditions :
 25°C/60%RH throughout shelf-life
 30°C/60%RH (65%RH in 2005) 1 year
 40°C/75%RH 6 months
 Time of analysis :
 0, 3 months, 6 months, 9 months, 1 year,
18 months, 2 years, 3 years

MARKETING AUTHORISATION FILE
DRUG SUBSTANCE

S.2 Preparation/synthesis

S.3 Characterisation (Physico-chemical properties,
structure and qualification of impurities)

S.4 Control of drug substance

S.7 Stability
MARKETING AUTHORISATION FILE
DRUG PRODUCT

P.1 Description and composition

P.2 Process development/validation

P.3 Manufacturing process

P.4 Excipients

P.5 Control of drug product

P.7 Container closure system

P.8 Stability  shelf-life and storage conditions
Change in Production Site
Up dating of the CMC File
New Specifications
F
F
F
Improvment
of Analytical
Technics
Stability
Solvants
Impurities
SETTING THE SPECIFICATION
OF THE ACTIVE PRINCIPLE
PHARMACOPEA
1st WAY
Consensus within competitors
2nd WAY
Before patent issue
Monopole situation
PHARMACOPEA FOR PERINDOPRIL
STRUCTURE
Isomere S S S S S
31 isomeres as potential
impurities
< 0.1 %
H
(3a)
(2)
(7a)
N
COOH
(9)
(11)
CO - CH - NH - CH - C3H7
CH3
COOC2H5
H
N
O
H3C
TRACING IMPURITY
COOH
H
COOC2H5
N
C3H7
H
H
COPIES AND COUNTERFEITS
How to distinguish Real from False ?
1st pathway : Standard analysis criteria :
F
F
F
purity profil
dissolution
content
2nd pathway : Qualitative and Quantitative
Analysis of the Formulation
EX : SUSPECTED DRUG
China
Suspicion of counterfeited Servier drug
Analysis of a whole truck content F official ceremony to
distroy the unlegal product
Indonesia
Suspicion of counterfeit but appeared to be parallel
import through Australia then ???... Indonesia
Malte
Suspicion of parallel import finally proved to be counterfeits
Explo
Preclinical
Stage A
Project
Bio
Pharmaceutical
Research
Phase I
Preclinical
Stage B
Phase II
Toxicological and kinetics
Expertises
PK/PD
TOXICO
ADME
Salt Selection
Phase I
Formulation
Phase III
PK
Interactions
PB/PK
Up scaled
Formulation
Population
Kinetic
Interspecies
metabolism
comparison
Pharmaceutical
File
NDA
Post
NDA
New
Formulation
Pharmaceutical
Support
Regulatory
Affairs
Pharmacopoeia
Copy
Analysis
BIOPHARMACY
PHARMACOKINETICS
PHARMACEUTICAL
DEVELOPMENT
London
Wexham, London
Orléans
Courbevoie
Orléans Vignat
Staff : 150
Analytical methods
Stability & Purity analysis
Formulation
Drug Delivery
Courbevoie
Orléans
TOXICOLOGY
Gidy
Drug Safety Research Center
Gidy
Staff : 109
General Toxicology
Reproductive Toxicology
Mutagenesis
Cancerogenesis
Staff : 136 (3 sites)
Screening
ADME studies
PK/PD Relationships
Population kinetics
Orléans Bel Air