Pharmaceutical Formulation

and Biopharmaceutics

Aniruddha Roy
Drug Design
 What must a drug do other than bind?
An oral drug must be able to:
 Dissolve
 Survive a range of pHs (1.5
to 8.0)
bladder  Survive intestinal bacteria
 Cross membranes
kidneys  Survive liver metabolism
BBB
 Avoid active transport to
bile
 Avoid excretion by kidneys
bile  Partition into target organ
duct
 Avoid partition into
undesired places (e.g. brain,
foetus)
liver
Why are physical properties important?
 So, before the drug reaches its active site, there are
many hurdles to overcome.

 However, many complicated biological processes can be

modelled using simple physical chemistry models or
properties – and understanding these often drives both
the lead optimisation and lead identification phases of a
drug discovery program forward.

 This lecture will focus on oral therapy, but remember that

there are lots of other methods of administration e.g.
intravenous, inhalation, topical. These will have some of
the same, and some different, hurdles.
 Reducing the complexity
Biological process in Underlying physical Physical chemistry
drug action chemistry model

Energy of dissolution;
Dissolution of drug in Solubility in buffer,
lipophilicity & crystal
gastrointestinal fluids acid or base
packing
logP, logD, polar
Diffusion rate,
Absorption from small surface area,
membrane partition
intestine hydrogen bond counts,
coefficient
MWt

Blood protein Binding affinity to blood Plasma protein

binding proteins e.g. albumin binding, logP and logD

Distribution of Binding affinity to

logP, acid or base
compound in tissues cellular membranes
 Ionisation
 Ionisation = protonation or deprotonation resulting in
charged molecules
 About 85% of marketed drugs contain functional groups that
are ionised to some extent at physiological pH (pH 1.5 – 8).
The acidity or basicity of a compound plays a major role in controlling:
 Absorption and transport to site of action
• Solubility, bioavailability, absorption and cell penetration, plasma
binding, volume of distribution
 Binding of a compound at its site of action
• un-ionised form involved in hydrogen bonding
• ionised form influences strength of salt bridges or H-bonds
 Elimination of compound
• Biliary and renal excretion
• CYP P450 metabolism
 How does pH vary in the body?
Fluid pH So the same compound will
Aqueous humour 7.2 be ionised to different
Blood 7.4 extents in different parts
Colon 5-8 of the body.
Duodenum (fed) 4.4-6.6
Duodenum 5.2-6.2 This means that, for
(fasting) example, basic compounds
Saliva 6.4 will not be so well absorbed
Small intestine 6.5 in the stomach than acidic
Stomach (fed) 1.4-2.1
compounds since it is
generally the unionised form
Stomach (fasting) 3-5
of the drug which diffuses
Sweat 5.4
into the blood stream.
Urine 5.5-7.0
Drugs are only absorbed passively when they are unionised.
This is because the compound has to pass through a lipophilic
membrane and this process will be unfavourable for charged
molecules. In a more acidic medium, such as the stomach,
the percentage ionised for an acidic compound will be less
than at pH 7.4 and so more compound will have the capacity
to be passively absorbed. In comparison, a basic compound in
an acidic medium will be more ionised and so less of the
compound will be in the neutral form and have the capacity
to undergo passive absorption.
 Ionisation of an acid – 2,4-dinitrophenol

OH O
100 NO2 NO2
-H+
90

80

70 NO2 NO2
60
percent

% neutral
50
pKa = 4.1 % anion
40

30

20

10

0
3 4 5 6 7 8 9 10 11
pH
 Ionisation of an base – 4-aminopyridine
NH2 NH2

100 -H+
90 +
80
N N
70 H
60
pKa = 9.1
percent

% neutral
50
% cation
40

30 Do you know why the ring

20 nitrogen protonates
10 rather than the NH2?
0
3 4 5 6 7 8 9 10 11
pH
Effect of ionisation on antibacterial potency
of sulphonamides
6.5
Anion
6 Cation
5.5

5
potency

4.5

3.5

2.5

2
2 3 4 5 6 7 8 9 10 11
pH
pKa
Identify functional groups
in drugs:

Basic
A useful formula for calculating the % ionisation of a
compound at a particular pH from its pKa is

(Where charge = 1 for bases and -1 for acids)

 Distribution Coefficient

Distribution Coefficient

LogD is related to LogP and the pKa by the following

equations:
 Lipophilicity
Lipophilicity (‘fat-liking’) is the most important physical property of
a drug in relation to its absorption, distribution, potency, and
elimination.
Lipophilicity is often an important factor in all of the following,
which include both biological and physicochemical properties:

 Solubility  Biliary and renal clearance

 Absorption
 Plasma protein binding
 Metabolic clearance
 Volume of distribution
 Enzyme / receptor binding
 CNS penetration
 Storage in tissues
 Bioavailability
 Toxicity
 The hydrophobic effect
Molecular interactions – why don’t oil and water mix?
H

H O O H H
H H H
H O H H
H O H O O H H

H H H H
H H
H
O O O H O H H
H H
H H H H H
O O O
H H
H H H H H H
O

 This is entropy driven. Hydrophobic molecules are encouraged to

associate with each other in water.
 Placing a non-polar surface into water disturbs network of water-
water hydrogen bonds. This causes a reorientation of the network
of hydrogen bonds to give fewer, but stronger, water-water H-
bonds close to the non-polar surface.
 Water molecules close to a non-polar surface consequently exhibit
much greater orientational ordering and hence lower entropy than
bulk water.
 The hydrophobic effect
This principle also applies to the physical properties of drug molecules.

If a compound is too lipophilic, it may

 be insoluble in aqueous media (e.g. gastrointestinal fluid or blood)
 bind too strongly to plasma proteins and therefore the free blood
concentration will be too low to produce the desired effect
 distribute into lipid bilayers and be unable to reach the inside of
the cell

Conversely, if the compound is too polar, it may not be absorbed

through the gut wall due to lack of membrane solubility.

So it is important that the lipophilicity of a potential drug molecule is

correct.
 What else does logP affect?

Binding to Aqueous Binding to Absorption Binding to Binding to

logP enzyme / solubility P450 through blood / hERG heart
receptor metabolising membrane tissue ion channel -
enzymes proteins – cardiotoxicit
less drug y risk
free to act

So log P needs to be optimised

What do Log P values mean in practice?
From a survey of the literature, it is possible to
obtain some general guidelines about the optimum
Log P values for certain classes of drugs. When
designing drug molecules some thought should be
given to the following:
Studies have found:
• Optimum CNS penetration around Log P = 2 +/- 0.7 (Hansch)
• Optimum Oral absorption around Log P = 1.8
• Optimum Intestinal absorption Log P =1.35
• Optimum Colonic absorption LogP = 1.32
• Optimum Sub lingual absorption Log P = 5.5
• Optimum Percutaneous Log P = 2.6 (& low mw)
Formulation and dosing forms:
• Low Log P (below 0) Injectable
• Medium (0-3) Oral
• High (3-4) Transdermal
• Very High (4-7) Toxic build up in fatty tissues
Drug Clearance and Toxicity

 Increasing LogD7.4 above 0 will decrease renal clearance and

increase metabolic clearance.

 High Log D7.4 compounds will tend to be metabolized by

P450 enzymes in the liver.

 A high degree of ionization keeps drugs out of cells and

decreases systemic toxicity.

 pKa in range 6 to 8 is advantageous for membrane

penetration.

 Drugs should be designed with the lowest possible Log P,

to reduce toxicity, non-specific binding, increase ease of
formulation and bioavailability. Drugs should also be as low
mw as possible to lower the risk of allergic reactions.
Principle of minimum hydrophobicity
"Both parabolic and bilinear relationships allow one to derive
the optimum value of log P for transport to a given location,
within the time of a biological assay. Evidence for an optimum
lipophilicity for CNS depressants was found by 1968. Hancsh
was then able to assert that in order for drugs to gain rapid
access to the CNS, they should preferably have a logP value
near 2.0. Subsequently, studies on anesthetics, hypnotics and
other CNS agents have lead to the "Principle of Minimum
Hydrophobicity in Drug Design” The thrust of this is to keep
drugs out of the CNS, and thereby avoid CNS related side
effects such as depression, weird dreams and sedation, one
should design drugs so that logP is considerably lower than 2.0.
This ploy has been successful in the new generation of non-
sedative antihistamines.
That we require drugs to have lower rather than higher lipophilicity
depends also on other observations made over the past 30 years. Many
studies on plants animals, fish various organelles such as liver
microsomes, and enzymes have shown a linear increase in toxicity or
inhibitory action in a series of compounds as LogP or pi increases.

A very high lipophilicity should also be avoided because of adverse

effects on protein binding and on drug absorption, including solubility.

Linear and sometimes parabolic relationships have been found between

lipophilicity and drug metabolism, either in whole animals, in liver
microsomes, or by specific enzymes such as cytochrome P450.
Metabolism can be undesirable for two reasons; it may limit drug
bioavailability, or it may produce toxic metabolites.

The ideal drug candidate, going into human studies, should have already
been designed with the idea of keeping lipophilicity as low as possible,
provided this can be done without loss of affinity to the target
receptor."
 Hydrogen bonding and bioavailability
Remember: Most oral drugs are absorbed through the gut wall
by transcellular absorption.
H
H
H O O
O H
H H O
O H O
O
H O H H N H
N H O
O H H
O H + H H N N
H N N
O
O H H O H O H
O H H
H H H H
O O O
H H H
H

 De-solvation and formation of a neutral molecule is unfavourable if

the compound forms many hydrogen or ionic bonds with water.
 So, as a good rule of thumb, you don’t want too many hydrogen
bond donors or acceptors, otherwise the drug won’t get from the
gut into the blood.
 There are some exceptions to this – sugars, for example, but these
have special transport mechanisms.
 Molecular size
Molecular size is one of the most important factors
affecting biological activity, but it’s also one of the most
difficult to measure.

There are various ways of investigating the molecular

size, including measurement of:

 Molecular weight
 Electron density
 Polar surface area
 Van der Waals surface
 Molar refractivity
 25
Molecular weight

20

Plot of frequency of occurrence

15
against molecular weight for 594
frequency %

marketed oral drugs

10

0
0

00
15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

10
0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-

0-
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95
Molecular Weight

Most oral drugs have molecular weight < 500

 Number of rotatable bonds
A rotatable bond is defined as any single non-ring bond,
attached to a non-terminal, non-hydrogen atom. Amide
C-N bonds are not counted because of their high barrier to
rotation.
No. of rotatable
OH
H bonds
O N
O
Atenolol
H2N

OH
H
O N
Propranolol
 Number of rotatable bonds
A rotatable bond is defined as any single non-ring bond,
attached to a non-terminal, non-hydrogen atom. Amide
C-N bonds are not counted because of their high barrier to
rotation.
No. of rotatable Bioavailability
OH
H bonds
O N
O
Atenolol 8 50%
H2N

OH
H
O N
Propranolol 6 90%

The number of rotatable bonds influences, in particular,

bioavailability and binding potency. Why should this be so?
In the case of flexible drug molecules, there is a loss of
entropy on binding due to conformational restriction, so if a
molecule is more rigid to start off with, less entropy is lost on
binding. Of course, the problem with removing rotatable bonds
from a molecule to make it more rigid is that potentially you will
lose all potency as you may have restricted the molecule into the
wrong conformation.

About 65% of fairly rigid compounds (those with seven or fewer

rotatable bonds) exhibited good-to-excellent oral
bioavailability, independent of molecular weight. In contrast,
more than 75% of floppy compounds (those with more than 10
rotatable bonds) had poor oral bioavailability. Compounds of
intermediate rigidity fell somewhere in between.
 70
60
50
Percentage of 40
compounds MW 0-499
with F >20% 30 MW 500+
20
10
0
# Rot 0-7 # Rot 8-10 # Rot 11+

The bar chart shows how the number of rotatable bonds (# Rot)
affects the bioavailability (F) for some compounds. A bioavailability of
20% is chosen as the cut off for an acceptable compound as this is
about the minimum necessary for a good oral drug. As you can see, the
bioavailability decreases as the flexibility of the molecule increases,
and this is independent of molecular weight.
 This seems like a lot to remember!
There are various guidelines to help, the most well-
known of which is the Lipinski Rule of Five
 Molecular weight < 500
 logP < 5
 < 5 H-bond donors (sum of NH and OH)
 < 10 H-bond acceptors (sum of N and O)
 < 10 rotatable bonds
Otherwise absorption and bioavailability are likely to
be poor.

* NB This is for oral drugs only.

Chirality
One of the most silent chemical parameters that define the
pharmacological activity is the type of isomer. Many molecular entities
exist in racemic form, but only one form gives the desirable
pharmacological activity. Other present isomer may be devoid of
pharmacological activity or may exhibit deleterious side effects. Most
of us are known to teratogenic tragedy of thalidomide. Thalidomide
exists as racemic form. It was introduced as a sedative agent. The S-
enantiomer of thalidomide was a teratogenic agent, while R-enantiomer
was effective as a sedative agent. Lack of knowledge about chiral
selectivity leads to disastrous consequence.
Several single enantiomers are preferred over racemic form (e.g.,
levofloxacin (ofloxacin), esomeprazole (omeprazole), escitalopram
(citalopram), and desloratadine (loratadine)).
Overview of the same is given in Table. For better clinical performance
of the molecule, it has become necessity to study the chirality of the
molecule. In most of the cases, it can be studied by optical rotatory
dispersion and circular dichroism.
Read this article: https://www.nature.com/articles/s41598-018-35457-6
Drug in racemic Used active
Advantage offered
form enantiomer
Levofloxacin
Ofloxacin Enhanced activity against pneumococci
S(−)-enantiomer
Levocetirizine
Cetirizine Less sedative action with same activity
R(−)-enantiomer
Dexketoprofen Reduction is dose of ketoprofen (half) with same
Ketoprofen
S(+)-enantiomer effectiveness and lesser GT-related side effects
(S)-ibuprofen is over 100-fold more potent
Ibuprofen S(+)-enantiomer inhibitor of cyclooxygenase. So three times dose
reduction was achieved than racemic mixture
Esomeprazole has lower first-pass metabolism and
Esomeprazole shows better bioavailability than R-eneantiomer
Omeprazole
S(+)-enantiomer and maintains pH above 4 in patients with GERD
with least variability
Racemic for and S-enantiomer
hyperresponsiveness in sensitized patients with
Salbutamol Levalbuterol loss of bronchodilator activity. (R)-salbutamol
produces significantly greater bronchodilation
than the equivalent dose of the racemate
 Biopharmaceutical Classification
System (BCS)
• Biopharmaceutics Classification System (BCS) is a
predictive approach to relate certain physicochemical
characteristics of a drug substance and drug product
to in-vivo bioavailability
• BCS categorized drugs according to two key physico-
chemical parameters:
– Solubility
– Permeability
• These two factors were selected because most orally
administered drugs are absorbed via a passive diffusion
process through the small intestine, where the extent
of oral absorption is largely influenced by a drug’s
membrane permeability and solubility
• According to the FDA guidelines, a high solubility
drug is defined as one that, in the largest dose
strength, fully dissolves in 250 mL of aqueous medium
with the pH ranging from 1 to 7.5 at 37 ° C.
Otherwise, drugs are considered poorly soluble. In
other words, the highest therapeutic dose must
dissolve in 250 mL of water at any physiological pH

• In the same guidance as mentioned above, a drug is

considered highly permeable if the extent of oral
absorption is greater than 90%.
 BCS Classes

Class I Class II
Highly permeable Highly permeable
Highly soluble Poorly soluble

Class III Class IV

Poorly permeable Poorly permeable
Highly soluble Poorly soluble
 BCS Class I: High Solubility and High
Permeability
• Compounds belonging to this class are normally expected
to dissolve quickly in gastric and intestinal fluids, and
readily cross the intestinal wall through passive diffusion

• BCS Class I are unlikely to show bioavailability or

bioequivalence issues

• Therefore, for BCS class I drugs, in vitro dissolution

studies are thought to provide sufficient information
to assure in vivo product performance making full in vivo
bioavailability / bioequivalence studies unnecessary.
 BCS Class I: High Solubility and High
Permeability
• Although class I compounds are expected to have
excellent oral absorption, given their high solubility and
high permeability, additional absorption barriers may
exist, which is beyond the scope of the BCS.

• For example, luminal complexation and degradation can

significantly limit the amount of drug available for
absorption. Even after the drug crosses the intestinal
membrane, it may be metabolized within the
enterocytes/hepatocytes and/or pumped out of the
cells due to efflux mechanisms.
 BCS Class II: Poor Solubility and High
Permeability
• By definition, poor solubility and/or slow dissolution are the
rate-limiting steps for oral absorption of BCS class II
compounds

• For compounds with a very large dose-to-solubility ratio, poor

solubility is likely to be the rate-limiting step for absorption.

• In other words, the compounds may dissolve quickly enough to

reach their equilibrium solubility, but the solubility is too low
to establish a wide enough concentration gradient to drive
passive diffusion
 BCS Class II: Poor Solubility and High
Permeability
• Formulations designed to overcome
solubility or dissolution rate problems:
– Salt formation
– Particle size reduction
– Metastable forms
– Solid dispersion
– Complexation
– Lipid based formulations
– Precipitation inhibitors
 BCS Class III: High Solubility and Low
Permeability
• Since passive diffusion is the rate-limiting step
for oral absorption of BCS class III compounds,
the most effective way to improve absorption and
bioavailability of this class of compounds is to
increase the membrane permeability.

• Approaches to improve permeability:

– Prodrugs
– Permeation enhancers
 BCS Class IV: Low Solubility and Low
Permeability
• Class IV compounds exhibit both poor solubility and
poor permeability, and they pose tremendous
challenges to formulation development

• As a result, a substantial investment in dosage form

development with no guarantee of success should
be expected

• A combination of class II and class III

technologies could be used to formulate class IV
compounds, although the success rate is not
expected to be high
 IVIVC Expectations Based on BCS
Class Solubil Permea Absorption IVIVC expectations for
ity bility rate control Immediate release product

I High High Gastric IVIVC expected, if dissolution

emptying rate is slower than gastric
emptying rate, otherwise limited
or no correlations
II Low High Dissolution IVIVC expected, if in vitro
dissolution rate is similar to in
vivo dissolution rate, unless dose
is very high.
III High Low Permeability Absorption (permeability) is rate
determining and limited or no
IVIVC with dissolution.

IV Low Low Case by case Limited or no IVIVC is expected.

 BCS can be used as a key component to guide drug
delivery system design for any route of administration
BCS-based formulation strategies
BCS class Animal formulation strategy
High solubility API in capsule for dog
high permeability Simple suspension for rat and
monkey
Low solubility Surfactant enhanced
high permeability suspension with micronized API
pH modified surfactant
enhanced suspension with
micronized API
Suspension with nanosized API
and surfactant
Non-aqueous solution
High solubility API in capsule for dog
low permeability Aqueous solution for rat and
monkey
Low solubility Combination of BCS 2 and
low permeability absorption enhancers
Human formulation strategy
Simple capsule or tablet
Micronized API and
surfactant
Nano-particle technology
Solid dispersion
Melt granulation/extrusion
Liquid or semisolid filled
capsule
Coating technology
Simple capsule or tablet
Absorption enhancers
Combination of BCS 2 and
absorption enhancers
Example 1

o Aspirin tablet is stable but not as a liquid

dosage form

o How to design liquid form?

o Soluble or dispersible aspirin tablets-to be

dissolved in water

o Note: the resulting solution or suspension

is to be taken immediately
Example 2
o Benzylpenicillin is inactivated by gastric acid

o Susceptible to hydrolysis if stored as a solution

o How to administer to human?

o Formulated for parenteral, rather than for oral

and packed as powder

o Use of sodium or potassium salt which readily

dissolve upon reconstitution
Example 3
o Diclofenac sodium is inactivated in gastric acid

o It is to be taken orally

o How to administer to human?

o Formulated for enteric coated tablet

o Enteric coat protects the tablet from destruction

within the gastric chamber

o Enteric coated dissolves in the small intestine

Phase of Drug Development
Why dosage form?
• Mechanism for the safe and convenient delivery of accurate dosage
• Protection of a drug substance from destructive influences of
atmospheric oxygen or humidity
• Protection from influence of gastric acid after oral administration
• To mask taste of offensive drugs
• To provide liquid preparation of substances that are either insoluble or
unstable
• To provide clear liquid dosage form
• To provide time-controlled release of drug
• To provide optimal topical administration
• To provide for the insertion of a drug into one of the body’s orifices
• Provide for placement of drugs into the blood stream
• Provide for lung inhalation of drug
 The Importance of Product Design
It may seem obvious to state that a new product should be
adequately defined before any serious product development is
undertaken.

In many cases, the value of the design phase is often

underestimated in the rush to start development and get
products to the market quickly.

This can result in much wasted time and valuable resources. It

can also lead to reduced staff motivation if a product is
developed that is not wanted or if the product definition is
constantly changing during development.

The quality of the design activities can strongly influence the

success of development of the right product to the market and
ultimate return on investment (ROI).
The following recent example of inhalable insulin has been described
as “one of the drug industry’s costliest failures ever,” estimated to
be $2.8 billion from the cost of development, closure of dedicated
manufacturing plants, and unsold product (Johnson, 2007).

The idea was that diabetics did not like to prick themselves with
needles several times a day to deliver the insulin.

The biggest hurdle was to deliver insulin by inhaler as consistently

as with a standard needle and syringe.

It took a technological breakthrough to develop and launch the first

inhalable insulin product in July 2006, only to abandon it in October
2007, after the product’s disappointing sales performance.

The company predicted that inhalable insulin would be a $2 billion-a-

year product by 2010, but it only sold $12 million in the first year.
There were several reasons attributed to the poor sales
performance.
The device drew unfavorable reviews from doctors and
investors. Some patients likened it to a bong for smoking
marijuana and were embarrassed to use the device in public.

o It was taking much longer to teach patients how to use

the inhaler device compared with an insulin pen, and
diabetic specialists said it was hard to use.

o There were concerns about safety as only 10% of the

insulin reaches the bloodstream, raising the question
about the long-term effects of the other 90%
remaining in the lungs.

o The inhaled treatment was approximately twice as

expensive per day as the injectable insulin and some
payers refused to accept the inhaled product on costs
alone.
A simple definition of “product design” is “the initial stage of
product development, where ‘global’ agreement is required about
the nature of the product to be developed.”
Effective product design is considered to have the following
important benefits:

o To provide clear direction and objectives for the project team

o To gain buy-in and input from all the key functions at the start of
development (such as pharmaceutical development, safety, clinical,
manufacturing operations, quality assurance, regulatory, and
commercial/marketing)
o To assess the feasibility of the project in commercial and technical
terms
o To identify any risks early and hence manage them
o To avoid wasting valuable resources on developing a product that is
not needed or wanted
o To provide a good reference source for the development plan
 Product Design Considerations
A useful outcome of the initial product design phase is a product
design report. This should document the careful evaluation of the
following key elements:

o Target product profile (TPP)/minimum product profile (MPP)

o Design specification and critical quality parameters

o Commercial and marketing considerations

o Technical issues and risk assessment

o Safety assessment considerations

o Environmental, health, and safety considerations

o Intellectual property considerations

 Target Product Profile/Minimum Product
Profile
A TPP, which defines the product attributes, should be
established for the intended marketed product based on all
“customer” and “end-user” needs. Customers and end users
include anyone in the supply chain, including both internal and
external customers, such as those in manufacturing and in
sales and marketing, distributors, doctors, nurses,
pharmacists, and patients. Each customer wants the right
product (meeting their quality expectations) at the right time
and at the right price. Additionally, each customer will have
his or her own specific requirements.
 Design Specifications and Critical Quality
Parameters
In addition to the preformulation information, there will be other
considerations in the selection of the excipients and packaging
components for the product.
o The pack will be acceptable to regulatory authorities in the
countries to be marketed.
o Only packs that can be multiple sourced from more than one
supplier/country will be used.
o The pack must have consistency of dimensions and
performance.
o The pack will meet function/user tests and specifications.
o Minimum acceptable shelf life for the product.
Commercial and Marketing Considerations
Any pharmaceutical company’s economic objective must be to
maximize its return on investment (ROI) after launch.

o Development costs

o Timing to market

o Market size (disease prevalence, diagnosis and treatment

rates, market value)

o Competition (current, developing, and impact on future

market)

o Unmet medical need (effectiveness of current treatment,

improvements required)

o Pricing and reimbursement (current and future)

o Cost of goods (CoG)

Advantages and Disadvantages of Outsourcing
Technical Issues and Risk Assessment
There may be a variety of issues that should be documented in the
product design report to highlight the perceived risks involved in
developing the product.

o Technical challenges anticipated in developing a novel or complex

drug delivery system or manufacturing process.

o Lack of in-house expertise

o Lack of in-house facilities or equipment to handle the candidate

drug.

o Sources of excipients and packaging components

The importance of identifying these issues in a product design

report is to make the company aware of the risks it is taking and to
make effective plans to overcome problems and manage the risks.
 Safety Assessment Considerations
In the interests of rapid product development, it is beneficial to
select well-established excipients that already have regulatory
approval in registered products.
According to ICH, an excipient is considered new or novel if it is used
for the first time in a human drug product or by a new route of
administration.
Investment in a new excipient includes the cost of safety testing,
investment in manufacturing facilities, and other development costs,
including stability testing. Safety testing of a new excipient alone
can be expensive.
It may be possible to “piggyback” the safety evaluation of the new
excipient onto the safety evaluation of the candidate drug itself.
There may be lesser considerations for excipient safety testing in
novel treatments, where there is an overwhelming need to treat
patients quickly and effectively, for example, for life-threatening
diseases such as cancer.
Summary of Excipient Safety Testing for Different Routes of Exposure for
Humans (proposal by IPEC Europe and IPEC America)
Environmental, Health, and Safety Considerations

There are increasing pressures on the pharmaceutical industry to

use environmentally friendly materials in products, which are
biodegradable or recyclable and do no harm to the environment.
Examples are the replacement of CFCs in pressurized metered
dose aerosols and the replacement of polyvinyl chloride (PVC) for
alternative packaging materials in some countries.
 Intellectual Property Considerations
Few pharmaceutical companies would venture into a long and
expensive development program without a strategy for effective
patent protection in place to ensure market exclusivity. Patents
are legal property that prevents others using the invention (for
20 years in most countries) in exchange for a full public disclosure
of information.

o Three criteria be met to grant a patent: novelty, presence of

an inventive step, and industrial applicability.

o Although an invention might be novel, it might not be

patentable if it could have been predicted from “prior art,”
that is, knowledge in the public domain. Hence, there is a need
for an inventive step.
At the product design stage of development, the only patent filed
is likely to be for the new candidate drug.

There may be a patent for a candidate drug and further patents

for a new indication or a new pharmaceutical use.

For example, Minoxidil, originally developed as an

antihypertensive, had been discovered subsequently to be useful
for the treatment of male pattern baldness.

Patent protection is stronger if multiple patents can be obtained;

for example, a single product could have patents covering a range
of features from the candidate drug itself to the method of
treatment and the delivery system.