Transcript Basic Principles of GMP

Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with a
focus on Paediatric Formulations
Tallinn, Estonia,
15 - 19 October 2007
1
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Pharmaceutical Development
Suitable dosage forms for pediatric medicine
Presenter:
Jean-Marc AIACHE
Emeritus Professor,
Auvergne University,
Faculty of Pharmacy,
28 Place Henri Dunant
63000 Clermont-Ferrand, France
[email protected]
2
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Pharmaceutical Development
Outline and Objectives of presentation
 What are the problems?
 1) Children characteristics:
 2) Prescription and administration of drug products
 Are there suitable dosage forms for paediatric medicines?
 1) Specific dosage forms for long or chronic diseases
 2) Specific dosage forms for acute or common illness
 a) D.F to help the parents for drug administration

b) To help the parents for drug acceptance by children
 c) To help the child to take his medicine
3
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
What are the problems?
 1) Children characteristics:
 Children are “SPECIFIC patients”, and not
“small ADULTS
 Classification
4
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
NEW BORN
INFANTS and
TODDLERS
0 to 27 days
1 to 23 months
5
CHILDREN
2 to 11 years
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
ADOLESCENTS
12 to 16-18 years
What are the problems?
 Their metabolism is different from adults
 Their reaction to drugs may be also different
(pharmacokinetics, pharmacodynamic…..)
 Their preference in term of taste or colour is
quite fundamentally different of adults
6
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
What are the problems?
 2) Prescription and administration of drug products
 The drug product prescription is done by Paediatricians (for heavy
diseases or long or chronic diseases) or more often by a General
Practitioner (for common or acute diseases)
 The administration of drug products to children is made by their
PARENTS
So their role is of most importance in the drug product
acceptability, size, colour, shape, aspect, taste….
Furthermore it is compulsory to treat their stress!
ALL THESE FACTORS CANNOT BE DISSOCIATED
7
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Are there suitable dosage forms for
paediatric medicines?
 There are two different issues in relation to the type of
diseases to be treated.
1) Specific dosage forms for long or chronic diseases
2) Specific dosage forms for acute or common illness
8
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Specific dosage forms for
long or chronic diseases
In a decreasing order:
 Cancers, Aids, Pain
 Pulmonary diseases, Asthma…
 Epilepsies, Depression, psychiatric troubles
 Cardiovascular, Metabolic diseases (diabetes)
 Virus, Orphan diseases
9
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Example : Cancers
 Cancers are rare Disease in the child (1-2 cases/ 10000
< 15 years old)
 The main treatment is made of Cytostatics drugs,
largely used in the treatment of adults cancer, but without
any evaluation in Children neither for conditions of use
nor for safety, furthermore they are not registered for this
use(“off label use”).
10
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Example : cancers
 Dosage forms used:
1)The majority are presented in injectable dosage form
containing a dose for adult treatment and MUST be
DILUTED before injection or infusion.
This is done in the Hospital Pharmacy, until now most
generally manually….Risks!!!
The injection or infusion is painful.
11
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Example : cancers
2)Some solid oral dosage form have been developed for
adult use: tablets or hard gelatin capsules
i.e. Méthotrexate tablet 2.5 mg : The usual maintenance dose is
15 mg per m²!! How many units to be administered??
Some capsules are open and diluted to be administered as
solutions ,but the taste is very Bad.
12
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Improvements
 Better system of catheter to avoid risk of burn by Cytostatics
 More precise pump to select the most adapted dilution for children before
infusion.
 During their illness the most important issue for children is the pain and they
are afraid of all that could be an aggression (injection, perfusion….)
Use of nitrogen protoxide or « fentanyl »patch (manually dose-area
adapted!!) to prevent pain.
Morphine micro pellets are used also as suspension in milk or juice or
water……but the capsules must be opened and the pellets transferred.
13
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
2nd example : Asthma
 The main treatment :AEROSOLS of anti-asthmatic
drugs.
 They are administered with devices ,the aim of which is to
obtain the good number of small particles able to reach
the good lung sites.
14
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
2nd example : Asthma
 Pressurized Metered Dose Inhaler5 (pM.D.I.):
1)First issue for child : Identify the way of use.
2) Second issue : coordination “hand and lung” and
disuse of actuator.
So the need for “spacer” is quite compulsory, if it is accepted
by the child!!
15
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
2nd example : Asthma
 DRUG POWDER INHALERS (D.P.I.)
1)No issue of coordination “hand and lung” and disuse of
actuator.
2) But issue of inspiration pressure to obtain the full dose.
Despite the progress, children have difficulties to use .
New systems, between pMDI and DPI, which delete
inspiration pressure are proposed
16
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
2nd example : Asthma
NEBULIZATION with jet or ultrasonic nebulizer.
 They are made from a solution (no specific children
formula!), more or less diluted and the device( some are
child specific in size and material) is prepared and applied
by the parents who can watch precisely the value and
time of administration duration.
The child has to be “occupied” during the 10 to 15
minutes of administration.
ORAL TREATMENT: Theophyllin solutions cannot be used
as alcohol is the main solvent.
Tablets or capsules SR but to be swallowed ….
17
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Other examples
 Epilepsies, Depression, psychiatric troubles: solutions
administered as drops in? Water, juice: #,taste
 Cardiovascular: drops, crushed tablets:" Viagra” in
newborn infant….
 Metabolic diseases (diabetes): injection of insulin or use
of implanted pumps, but difficult. Perhaps the “Exhubera”
 Virus, Orphan diseases: Solutions for injection or oral
route as simple as possible…..
 Ocular systematic control at birth: ocular insert
18
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Acute or common illness:
The most important prescriptions
Bones
Hormones
Eyes….
Respiratory dis.
2%
Dermatology
4%
3%
4%
6%
Digestive tract.
Metabolism
32%
13%
14%
22%
Nervous.C.S
19
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Antibiotics
Acute or common illness
 For of these prescribed drugs,80% are reported to be
used in accordance with their label and with conventional
DF, not at all specifically adapted to the children use.
 The dose of API is fixed by using empirically established
dosage regimen and the dose combination is sometimes
largely used, which is not really convenient.
 The DF used and the ones to be developed in the future
can be classified according to their use by the parents or
the children compliance (patient-child”, age, kind of
illness, etc…)
 :
20
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
newborns, infants ,toddlers (0-23 months)
 a) D.F to help the parents for drug administration:
 Passive administration to : i.e. drugs in powder form or
encapsulated, suspended in milk in the baby bottle,
eventually with sugar,
 Issues:# milk and drugs (adsorption, precipitation), taste
 Suppositories: size and dose adapted.
21
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
newborns, infants ,toddlers
 a) D.F to help the parents for drug administration:
 Active administration : powders, solutions, suspensions
introduced in pacifiers, teats, double teat or pacifier
(reservoir) with which the child can play and in the same
time takes a dose of drug.
 BIG ISSUE : these “devices” have to be different or to
present a special design to be different of the common
device .
 The issue of the choice of dilution liquid remains!!!!
22
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
newborns, infants ,toddlers
The majority of D.F for Respiratory diseases (common
cold, cough, etc )as well as for Digestive tract,
Metabolism ,and Fever or small pains are liquids.
They are presented as solutions containing sugar or
sweeteners, as suspensions or suspensions easy to
prepare from powders or granulates.
2.
Another issue is the method of delivery of the liquids
and the accuracy of the device used for measuring the
dose. In the EP an essay has to be done.
3. Graduated Glasses, Syringes, Burettes for dosing oral
liquids, “Med-T-Spoon”, Intelligent” single doses. The
graduations are presented in Kg, body area in m²,age
(day ,month, years)
1.
23
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
children(2-11 years)
b) TO HELP THE PARENTS FOR DRUG ACCEPTANCE BY
CHILDREN
Passive Administration to children with a taste not
completely elaborated or to children who refuse
systematically every new taste…
Examples : Suppositories or powder for mixing with food :basic
(and quite compulsory) dosage forms !
24
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
children(2-11 years)
Active Administration :
 Its goal is to increase the interest of the child for the
drug administration system.
 For other routes of administration than oral, the D.F
are conventional, with doses adapted to children,
improvements come from packaging.
 But for the oral route, the taste will represent the main
issue of all the developed D.F..
25
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
children(2-11 years)
 The problem of the TASTE has to be solved.
2 issues :
1)The use of specific tasty and masking substances used for
children or special techniques for coating the bitter substances.
It has been proposed special new dosage form adapted to a
quick release of the drug in solution or suspension form.
26
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
children(2-11 years)
2) Taste evaluation studies in children have to be
improved for evaluation and above all, have to be
allowed and done systematically for every new
drug under ethical comity supervision with large
group of subjects.
Creation of taste class-room to teach the taste…..
27
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for
children(2-11 years)
 So for active administration ,the dosage form
could be presented as :
*a special (and delicious) food
*a very famous sweet
*a toy or something which tell a story
28
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for adolescents
(12-16-18 years)
 To help the child to take his medicine (from teenager to
young adult…)
Passive administration :the drug is contained in a
reservoir or neutral device implantable or hidden so that
the child receive the drug in a constant and regular way
but overall does not show at school or in a stadium that
he is ill .He must look like a normal child as his school
friends.!
29
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Dosage forms for adolescents
(12-16-18 years)
Active Administration
The child is responsible (as far as he can !!) of the
time of the drug product administration
*either by a memory recall, which tells the evolution of
the illness
*either by his toy, an intelligent “Game-Boy”, which by
a bell, indicates the precise time of dosing
30
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
But all these developments must
be under the control of two very
important factors :
31
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
NON-OBSERVANCE FACTORS
KIDS-DRIVEN
SUPER SERVICE
EMPOWERMENT
PARADOXE
ENABLING
EXPECTATIONS
SECURITY
FACTORS
INCOHERENT
EXPECTATIONS
REMINDER
EFFECT
OBSERVANCE
FACTORS
MOSAIC
FAMILY
EXPERT-USER
SYNDROME
SUB-ATTENTION
DISPERSION
PHENOMENON
RISK BLINDNESS
NON-SECURITY FACTORS
32
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
Pharmaceutical Development
Summary and conclusion
A very big effort has to be made for
changing the mentality, and also the
methods of drug development in view
of adapting the dosage to the right
patients by taking in account all their
physiologic and pathologic conditions.
33
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
References
 Symposium «Médicament pédiatrique et ses spécificités - Design moi un
médicament.» 21-22/03/2002, Vichy, France


Dr. J-L STEPHAN, Difficulté de la prescription pédiatrique en cancérologie
Pr J-M AIACHE, Médicaments et enfants, point de vue du formulateur
galénique

F. JEGOU, Médicaments et enfants, avis du designer

P. GAUTHIER, Résultats d’une enquête réalisée auprès des pédiatres
34
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
References
EMEA GUIDELINES:
 Reflection Paper: Formulations of Choice for the Paediatric Population (Sept
2006)Guideline on conduct of Pharmacovigilance for medicines used by the paediatric
population (June 2006) Guideline on the Role of Pharmacokinetics in the Development of
Medicinal Products in the Paediatric Population (June 2006) Discussion paper on the
impact of renal immaturity when investigating medicinal products intended for paediatric
use (Dec 2004) Note for guidance on evaluation of anticancer medicinal products in man
(addendum on paediatric oncology) (Jan 2004) . Better Medicines for Children. European
Commission [on-line] 2002; http://pharmacos.eudra.org/F2/pharmacos/medchild.htm
(November 2002, date last accessed).
 FDA publications:
 . Guidance for industry. Pediatric oncology studies, in response to a written request. Food
and Drug Administration—Center for Drug Evaluation and Research [on-line] 2001;
http://www.fda.gov/cder/guidance/3756dft.htm (November 2002, date last accessed).
 . Food and Drug Administration Modernization Act of 1997. Food and Drug
Administration—Center for Drug Evaluation and Research [on-line] 1997;
http://www.fda.gov/cder/guidance/105-115.htm (November 2002, date last accessed).
35
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007