1. Development and Delivery of Pharmaceutical Products
Dr. Colin Minchom
September 23, 2011
1

2. Development
and
delivery
of
pharmaceu4cal
products
Chemistry
manufacturing
and
controls
(CM&C)
Colin
M.
Minchom
PhD
MRPharmS
MaRS
September
2011
colin.minchom@gmail.com
2

3. Topics
• Introduc4on
• The
drug
development
process
• “Drugability”
• Oral
absorp4on
• Biopharmaceu4cs
Classifica4on
System
• Sterile
products
3

4. Colin
M.
Minchom
PhD
MRPharmS
• UK
trained
pharmacist
• 30
years
in
product
development
• Patheon,
start-­‐up
pharma,
Eli
Lilly,
Squibb
• 13
products
launched
in
USA
and
EU
• Chair
-­‐
AAPS
Annual
Mee4ng
Science
CommiTee
• Member
-­‐
U.S.
Pharmacopoeia
CommiTee
of
Experts
4

5. The
drug
development
process
5

6. Discovery
to
launch
-­‐
The
drug
development
process
Discovery/Research
Development
Submission
Launch
Toxicology
Phase
I
Phase
II
Phase
III
Registra4on
Approval
Clinical
Proof
of
Large
safety
and
Safety
Post-­‐
efficacy
efficacy
marke4ng
6

7. Discovery
to
launch
-­‐
The
drug
development
process
Discovery/Research
Development
Submission
Launch
Toxicology
Phase
I
Phase
II
Phase
III
Registra4on
Approval
Toxicology
Chronic
and
reproduc4ve
toxicology
Acute
tes4ng
Line
tes4ng
extensions
7

8. Discovery
to
launch
-­‐
The
drug
development
process
Discovery/Research
Development
Submission
Launch
Toxicology
Phase
I
Phase
II
Phase
III
Registra4on
Approval
Organic
Chemistry
Route
Scale up Scale up and optimisation
identification
8

9. Discovery
to
launch
-­‐
The
drug
development
process
Discovery/Research
Development
Submission
Launch
Toxicology
Phase
I
Phase
II
Phase
III
Registra4on
Approval
Dose
Form
Development
Preformula4on
and
Market
image
formula4on,
Line
early
formula4on
scale
up
and
op4mise
extensions
9

10. Discovery
to
launch
-­‐
The
drug
development
process
Discovery/Research
Development
Submission
Launch
Toxicology
Phase
I
Simple
solu4on/
Phase
II
suspension
Phase
III
Simple
capsule
Registra4on
or
solu4on
/suspension
Approval
Tablet
Market
image
tablet
10

11. “Drugability”
11

12. Drug
product
development
• Facilitation of repeated safe delivery of the
correct quantity of active substance at the
correct rate to desired body compartment
• Guaranteed until the expiry date
12

13. How
product
development
facilitates…
Fred has a headache
Stomach
Liver
13

14. Preformula4on/formula4on
Molecular properties
• Solubility • Hydrophilicity/Lipophilicity (log p)
• pH • Surface active agents – Micelles
• Stability – Chemical
Particle properties
• Morphology/Crystallinity • Surface area
• Melting point • Solution rate
• Stability – physical • Hygroscopicity - Adsorption
isotherms
• Particle Size • Hydration/Solvation state
• Particle Shape • Material Properties
elastic/plastic/brittle
Powder properties
• Odour • Bulk and Tap densities
• Colour • Electrostatics
• Flow Properties
14

15. Oral
Absorp4on
15

16. Oral
delivery
of
drug
to
systema4c
circula4on
16

17. Typical
oral
delivery
pharmacokine4c
profiles
Dose
Xtal
Form
Formn
High
A
A
Med
B
B
Low
C
C
Minimum
toxic
concentra4on
Minimum
effec4ve
concentra4on
Pharmacokinetics (PK): The study of blood levels of a substance over time after dosing/exposure
17

18. Crystal
form
-­‐
Carbamazepine
Form
III
Monoclinic
MP=
~168
C
Stable
at
RT
Good
flow
and
tableeng
proper4es
Form
IV
Trigonal
MP=
~190
C
Thermostable
Poor
flow
and
tableeng
proper4es
18

19. The
biopharmaceu4cs
classifica4on
system
(BCS)
19

20. Biopharmaceu4cs
classifica4on
system
(BCS)
High
Solubility
Low
Solubility
Permeability
Class
I
Class
II
High
High
Solubility
Low
Solubility
High
Permeability
High
Permeability
Permeability
Class
III
Class
IV
Low
High
Solubility
Low
Solubility
Low
Permeability
Low
Permeability
Source: Amidon et al. (Pharm.
Res.
1995,
12
(3):
413–20), adopted by the FDA (2000).
20

21. Trending
in
biopharmaceu4cs
classifica4on
system
New Chemical Entities Top 200 Marketed Drugs
in the U.S.A.
Source: Hauss, Oral Lipid-Based Formulations, 2007
21

22. Bioavailability
enhancement
• Mul4-­‐factorial
challenges
– No
one
solu4on
works
for
all
molecules
• Time
consuming
• Expensive
22

23. Sterile
Products
23

24. When
are
sterile
products
required?
• When
the
route
of
administra4on
is:
– Intravenous
– Intra-­‐muscular
– Sub-­‐cutaneous
– Ophthalmic
– Inhala4on
– Wound
applica4on
24

25. Sterility
and
sterility
tes4ng
– A
product
is
either
sterile
or
non-­‐sterile
– Test
is
destruc4ve
• en4re
product
batch
cannot
be
tested
– The
sterility
test
needs
to
be
developed
and
validated
for
each
formula4on
– Sterility
Assurance
The
probability
that
a
package
will
test
posi4ve
on
sterility
tes4ng.
• Assurance
of
asep@c
processes
is
1
in
1,000
• Heat
steriliza@on
processes
1
in
10,000
• Probability
of
sterility
failure
is
much
lower
when
validated
procedures
are
followed
25

26. Endotoxins
– Sterile
products
MUST
be
low
in
endotoxins
– Endotoxins
(pyrogens)
• Lipo-­‐polysaccharides
from
outer
shell
of
gram
nega4ve
bacteria
• May
cause
reac4ons
in
pa4ents
§ Minor-­‐Moderate:
Fever,
muscle
pain,
joint
pain
§ Life
threatening:
Thrombosis,
inflamma4on,
hypotension
26

27. Steriliza4on
• Methods
– Autoclaving
the
product
in
its
final
container
– Subjec4ng
the
product
to
sterilizing
gases.
§ E.g.
ethylene
oxide
– Subjec4ng
the
product
to
ionizing
radia4on.
– Asep4c
processing.
§ Drug
formula4on
–
sterilized
by
filtra4on
§ Vials,
stoppers,
all
contact
parts
are
sterilized
separately
§ Assembled
in
a
Class
A
(Class
100)
room.
27

28. Heat
steriliza4on
• If
a
product
can
withstand
heat
steriliza4on,
then
it
must
be
heat
sterilized
-­‐
regulatory
requirement
– Heat
sterilized
products
are
sterile
filtered
using
0.2
micron
filters,
before
they
are
sterilized
§ Dead
bacteria,
especially
gram
nega4ve
bacteria,
can
cause
severe
problems
due
to
endotoxins
28

29. Heat
steriliza4on
• Before
a
product
is
heat
sterilized,
a
steriliza4on
cycle
must
be
developed
and
validated
– Heat
sensi4vity
of
bacteria
is
a
func4on
of
the
formula4on
§ Typical
steriliza4on
cycle
–
steam
autoclave
§ 120
Celsius
§ 15
-­‐
30
minutes
29

30. Ascep4c
processing
• Sterile
filtra4on
– Filtra4on
of
product
§ Filter
the
liquid
formula4on
through
0.22
micron
membrane
§ The
product
is
filtered
into
Class
A
room
containing
the
fillers
and
cappers
§ Different
filter
materials
are
used
depending
on
compa4bility
with
the
drug
formula4ons
§ Endotoxins
are
not
removed
by
sterile
filtra8on
– Steriliza4on
/
de-­‐pyrogena4on
of
vials
§ Dry
heat
(
~250
Celsius)
– Stoppers
§ Oqen
siliconized
for
smooth
movement
in
filling
machines
§ Sterilized
in
steam
autoclaves
30

31. Sterile
products
• Sterile
products
can
be
classified
into…
– Liquid
– Lyophilized
(freeze
dried)
– Powder
fills
– Dispersed
§ Emulsions,
suspensions,
liposomes,
lipid
complexes
31

32. Sterile
liquids
• Drugs
are
formulated
as
ready
to
use
liquids:
– If
the
ac4ve
drug
is…
• sufficiently
water
soluble
• stable
in
aqueous
solu4on
for
18-­‐24
months
at
expected
storage
condi4on
Preferred
storage
condi4on
is
room
temperature
~25
Celsius
If
not
refrigera4on
at
2-­‐
8
Celsius
32

33. Lyophiliza4on
– Freeze
drying
removes
water,
preven4ng
hydroly4c
reac4ons
and
extending
shelf
life
– Primary
Drying
• Freeze
the
formula4on
in
vials,
apply
a
vacuum
then
slowly
raise
the
temperature
to
sublime
the
frozen
water
– Secondary
drying
• Bound
water
removed
by
raising
the
temperature
further
Lyophiliza4on
will
add
several
dollars
to
the
cost
of
processing
each
vial
33

34. Sterile
powder
fills
– Used
for
manufacturing
cephalosporins,
and
rarely
for
cytotoxic
drugs
– The
last
stage
of
ac4ve
drug
synthesis
is
asep4c.
§ The
sterile
powder
of
ac4ve
drug
is
then
filled
in
vials
in
Class
A
rooms
§ Compared
to
freeze
drying,
powder
filling
is
rela4vely
inexpensive
§ Excipients
are
not
used
34

35. Dispersed
sterile
dosage
forms
– ~70%
of
all
ac4ve
drugs
are
insoluble
or
poorly
soluble
– These
drugs
may
be
solubilized
using
surfactants
-­‐
possible
adverse
reac4ons
– If
drug
is
oil
soluble,
then
an
emulsion
can
be
prepared
– Alterna4ve
approach
is
to
prepare
liposomes
or
lipid
complexes.
Development
will
be
4me
consuming
(expensive)
35

36. Review
• The
drug
development
process
• “Drugability”
• Oral
absorp4on
• Biopharmaceu4cs
Classifica4on
System
• Sterile
products
Ques4ons?
colin.minchom@gmail.com
36