1 Introduction to the packaging of pharmaceuticals

and health care products

Introduction

Pharmaceuticals require more detailed packaging than do other sensitive

products, such as foods, although there are several similarities in their
requirements. Almost every type of modern packaging is used for the wide
range of medications and devices now available, but the quantities
involved are usually smaller than with foods. Security and integrity of the
package are, however, more important and are controlled by licensing
arrangements.

Definition

One of the best general definitions of pharmaceutical packaging was

proposed by Dean [1]:
an economical means of providing protection, presentation, identifica-
tion, information and convenience for a pharmaceutical product from
the moment of production until it is used or administered.
Probably the most important function of pharmaceutical packaging is
protection of the product. Physical damage and chemical deterioration
from mechanical and climatic hazards, as well as changes caused by
microorganisms must be prevented. The product and packaging materials
must be compatible.
Additionally, modern packaging needs to be child resistant and tamper-
evident. Advances in packaging technology have led to more complex
testing requirements and hence a greater in-depth knowledge is required of
traditional as well as newer packaging methods and materials. Convenience
and ease of use, hygiene, package integrity, and new dispensing methods
must now also be provided for patients.
Drugs need more care in their packaging than do most other products,
because any failure in their packaging could result in changes in the drug
that lead either to a failure to cure, to illness, to injury or even to death of
the patient. A drug must be efficacious, for if it is only palliative then the
drug and/or the package is a failure. Potency and bio-availability must both
be demonstrated. Requirements in respect of Good Manufacturing

H. Lockhart et al., Packaging of Pharmaceuticals and Healthcare Products

© Chapman & Hall 1996
2 PACKAGING OF PHARMACEUTICALS AND HEALTHCARE PRODUCTS

Practice (GMP), improved microbiological standards and better ways of

reducing possible contamination all play a part in the package design
process.

Types of product

There are two major types of pharmaceutical product: ethical medicines

and proprietary medicines (also called over-the-counter [OTC] drugs), and
they require different treatment in respect of their packaging.

ETHICAL MEDICINES
Ethical medicines are sold to the public only on a prescription basis. In the
USA, mainland Europe and the UK their sale in any other way is
prohibited by law. There are some countries where such drugs can be
obtained without prescription, but these are few. The principal users of
packaging for ethical medicines are doctors, dentists, nurses, pharmacists
and medical technicians. However, with the introduction of original pack
dispensing (OPD), some ethical drugs are now dispensed to the patient in
the same type of package as is used for over-the-counter products.

Requirements for the packaging of ethical medicines. Special attention is

required, because both the container and closure must protect the
medication from light, water vapour and oxygen, under the conditions of
distribution and storage, which are often for longer periods than in the case
of OTC products. Both the drug and the packaging must be approved by
the regulating authority. While this is also true for OTCs, it is important to
remember that OTCs often come in smaller quantities per pack and, as
they have to meet the retail selling (marketing) challenge, they will require
some display and convenience factors, e.g. transparency and easy opening,
not required for ethical packages. A further difference is that OTCs often
use more packaging per dose, in order to deliver the message and to get
shelf space.
With certain exceptions, all ethical medicines, in whatever form (unit
dose, prescription tablets, capsules, oral liquids, some ointments and some
creams) were, until the introduction of OPD, always supplied to the
pharmacist in bulk packages and repacked for dispensing according to the
doctors' instructions. Fifty years ago, almost all drugs were in liquid form
and were contained in stoppered glass bottles. The great majority were
also administered in hospitals. Currently, there is great emphasis on solid
dosage forms, a decrease in liquid forms and the appearance of many new
forms such as inhalers and transdermal patches. The development of new
forms presents sophisticated challenges for packing developers.
 INTRODUCTION 3

Unit dose packaging. The most significant advance in the packaging of

drugs used in hospitals was the introduction of unit doses for oral
medicines. Although strip packaging for an aspirin-based product (Aspro)
started in 1927, some 20 years elapsed before the concept was widely used.
During the early 1950s, some tablets and capsules were available packaged
individually into pockets in a continuous tube, the pockets being separated
from each other by perforations in the foil strip. From this concept, the
hospital unit dose evolved. The advantages are obvious: this form of
packaging controls the dispensing and administering of a prescribed single
dose of the correct drug at the right time, and it significantly reduced
hospital errors, especially when prefilled disposable syringes came into use
in the USA in the 1960s.
Blister packaging (Figure 1.1), first introduced in American hospitals,
was an even greater improvement in safe dispensing. The tablet or capsule
is visible through the 'blister' and the product can thus be recognised
before the package is opened. In the USA this packaging is also considered
to be cost-effective, mainly because its use can reduce wastage by avoiding
the wrong package being opened.
Today, both strip packs and blister packs are widely used all over the
world. They are more popular in Japan and Europe than in the UK and
USA. The advantages of the unit dose concept are even more clearly

Figure 1.1 Blister packaging. A push-through vinyl blister with foil back. Either vinyl or foil
can be printed.
4 PACKAGING OF PHARMACEUTICALS AND HEALTHCARE PRODUCTS

demonstrated in medicaments for the eyes, ears and nose, as well as for
enemas, where the accuracy of dosage and simpler formulation plus the
much reduced risk of cross infection are even more relevant.
The main plastics used for blister packaging are PVC, PVDC coated
PVC, and PCTFE/PVC laminates. These have some differences in
moisture resistance, the last being 10 times as good as PVC which is three
times less effective than the coated material. Many blister packs are backed
with 18-20 micron aluminium foil with a heat-seal coating.

Unit-of-use packages. While unit dose packs are particularly valuable for
hospital in-patients the unit-of-use package is devised for out-patients and
prescription customers. The pack contains sufficient drug to provide the
patient with his needs for a particular time (usually up to 30 days). It is
dispensed and labelled by the pharmacist, indicating the doctor's instruc-
tions and other necessary information.

PROPRIETARY MEDICINES OTCs

Unlike ethical medicines which are provided to professional healthcare
personnel for dispensing to the patient, proprietary medicines (OTCs) are
designed and produced for self-medication purposes to the actual
consumer, and are available not only through prescription outlets but also
in supermarkets, department stores, corner shops and even from vending
machines. Structural and graphic design are both required to appeal to the
consumer and to assist in selling the product. In the USA, the UK and
some other countries there are different safety regulations concerning the
use of child-resistant and tamper-evident packaging for certain drugs. For
example, in the USA the law permits the sale of one size of package
without the use of a child-resistant closure, while in the UK the purchaser
may request that a plain closure is used.
Unit dose packaging is used extensively for OTC medications as blister
packaging in particular has the further advantage of providing more space
for instructions and even a diagram of how to take the dose.

Other classifications
There are other possible classifications for medicines than ethical prepara-
tions and OTCs. For example, products may be classified by their use -
health care, eye care, oral hygiene, etc. They may also be grouped
according to the manner in which they are administered - local or topical
products (those applied externally to the body, such as creams, ointments,
lotions, talcum powder), oral products (entering by mouth) and parenterals
(this is the medical term for 'outside of the intestine' and usually refers to
sterile products entering the body by injection or infusion into veins (IV),
 INTRODUCTION 5
arteries or muscles (1M». Parenterals can be further sub-divided into large
and small volume parenterals (LVPs and SVPs). The former include
intravenous (IV) solutions and irrigation fluids, which involve volumes
between 500 millilitres and 3 litres and the latter (the SVPs) single and
multi-dose injections usually with volumes below 100 millilitres. Origin-
ally, parenteral products were invariably packed into glass containers
(ampoules, rubber-stoppered or sealed vials, and rubber-stoppered
bottles). The rubber compounds have always had to be specially made,
often compounded specifically for one or a narrow class of product. By
their method of use IV solutions can be considered as a form of unit dose.
Although used for years, glass is not completely inert even when the
surface is specially treated. It is also, of course, heavy and fragile and
containers may require rubber stoppers, from which there is the risk of
extractives and other contaminantion. Hence, the plastic package for IV
solutions was developed and has been approved. These are made
preformed from PE, PP or PVC and of the form-fill-seal type from PE or
PP, although preformed PVC containers are generally preferred.
Currently, plastic ampoules, vials and bottles are appearing for other types
of parenteral product.
Table 1.1 illustrates the wide range of complaints for which Ethicals and
OTC products are available.

Table 1.1 Therapeutic areas and the drugs available (UK) divided between ethical medicines
and proprietary medicines

Ethical medicines Proprietary medicines

Alimentary Aches and pains

Allergies Acne
Asthma
Baby care
Chilbains Cardiovascular
Constipation Central nervous system
Coughs and colds
Dandruff
Diarrhoea
Dietary disorders
Family planning Genito-urinary system
Haemorrhoids Hormones
Hay fever
Incontinence Infections and infestations
Indigestion Muscular skeletal disorders
Nausea/vomiting Nutrition
Oral hygiene
Parasites Respiration
Skin Skin
Sunburn/sunscreen Surgical
Vitamins and tonics

Source: Institute of Packaging (UK), correspondence course notes.

6 PACKAGING OF PHARMACEUTICALS AND HEALTHCARE PRODUCTS

Drug development and design

To better understand the nature of pharmaceutical packaging design and

the use of packaging for medical products in general, it is useful to have
some idea of the way in which drugs themselves are developed. The
pharmaceutical industry is unique in respect both of its technology and its
economics. It has been estimated that the cost of putting a new drug on the
market is very high (in excess of $200M). Throughout its history
development in pharmaceuticals has been closely associated with
developments in organic chemistry. Before 1900 most medicines were
derived from naturally occurring products extracted from plants or
synthesised as pure compounds. Even today it is estimated that some 64%
of the world's population are almost entirely dependent on medicines
derived from plants, and over 100 drugs are still extracted from natural
sources mainly for use in Western medicine. Natural products are also of
great importance as models (leads) for the synthesis of superior active
compounds.
The discovery of the anti-bacterial sulphonamides in the 1930s was a
major advance in the history of drug discovery and heralded the beginning
of the synthetic drug era. Development was fed by advances in the
synthesis of organic chemicals and in understanding the electronic theory
of organic chemistry. In the 1970s, as a result of advances in biology, drugs
began to be designed on the basis of quantitative experimental studies of
tissue biochemistry. Biological sciences have continued their advances and
today lead the search for innovative drugs. New drugs are now discovered
by groups of highly skilled, well motivated people working in small
interdisciplinary teams.
The pharmaceutical industry is increasingly multi-national and the larger
organisations have almost a third of the world market (see Table 1.2) and
their R&D and manufacturing is located where it is politically, technically
and economically beneficial.
Table 1.2 Leading pharmaceutical companies worldwide

Company % of world market

Merck & Co 4.2

Glaxo 3.6
Bristol-Myers-Squibb 3.4
Ciba-Geigy 2.7
Smith-Kline-Beecham 2.7
Hoechst 2.7
American Home 2.3
Lilly 2.3
Roche 2.3
Johnson & Johnson 2.3

Source: Glaxo Estimates, September 1991.

 INTRODUCTION 7

The Design Process

The process of designing a new drug involves two stages [2]: lead
generation and lead optimisation. Lead generation consists of finding a
novel compound with interesting possibilities, while lead optimisation
involves the synthesis of a series of related compounds to find one that has
not only the desired level of activity but also other needed attributes such
as any possible lead compound not being commercially patented by a
competitor.
In the search for novel active compounds two approaches are possible.
The first is Random Screening, i.e. testing compounds at random until a
suitable one is found. This is time consuming and involves an element of
chance. Increasing economic restraints and competition have made the
second, Rational Drug Design, more efficient and cost-effective. The action
of most drugs is explainable in terms of what is called 'receptor theory'. In
broad outline this postulates that there are chemically receptive sites in the
human body that can combine with certain functional groups in a chemical.
Such chemicals are either produced naturally by the body itself or can be
introduced as a drug. If the structure of receptive sites can be discovered, a
drug may be designed to specifically interact with them. This is the basis of
rational drug design.
Human ailments and diseases may be classified under some 50 or so
'therapeutic areas' but each pharmaceutical producer in its research efforts
will usually limit their studies to between five and seven areas only. At
present, some of the major efforts are concentrated on anti-ulcerants,
respiratory and cardio-vascular medicines, anti-infectives and anti-
arthritics.
The time taken to develop a new medication rose from about 6 or 7 years
in the 1970s to between 10 and 12 years in 1993. R&D is, moreover, a
high-risk and costly activity; only three out of every 10 compounds which
make it to the extent of being marketed ever earn enough to cover the cost
of their development.
The introduction of a new medicine is therefore a long and complex
process involving several well defined stages:

• Initial discovery, development testing and registration

• Development of a viable production process for efficient and high-
quality manufacture
• Development of suitable drug delivery systems and the packaging
required for dispensing or self administration
• Marketing and worldwide distribution

During this process the company has to work with governments and public
authorities and these relationships are well worth consideration. First,
industry expects governments to arrange that competition and access to
8 PACKAGING OF PHARMACEUTICALS AND HEALTHCARE PRODUCTS

markets is fair and that the physical and social infrastructure in the country
will be maintained. Secondly, industry is concerned with the extent to
which research, development and registration are regulated. Regulation is
unavoidable, since the industry deals with materials that can be a matter of
life or death. Governments must assess whether any new medication is safe
as well as effective, and determine the limitations which should be placed
on their use. As technological impacts on society increase so public
authorities' concern will increase, and this will result in increased
regulation of the applications to introduce new drugs.
Under current scientific and regulatory requirements the development
of a drug is a multi-step process in which there are several points at which
the group concerned with package development should be involved. The
earlier in the process this happens the better it is for the eventual success of
the drug/package system. Clinical trials offer an opportunity to test specific
package applications. If this selection of systems and materials is done
without the advice and involvement of personnel conversant with the
economics and technology of packaging, serious packaging mistakes can
interfere with the final development and introduction of the drug. A heavy
commitment of time and money to packaging occurs when the test
programme for stability begins. If packaging is selected which 3 or 4 years
later is found to be either economically or technologically not feasible then
the investment in both time and money is wasted.
Table 1.3 shows a hypothetical drug development programme similar to
several that have been presented previously. It shows the duration and the
character of typical drug development programmes in the USA for a
hypothetical new hypertensive drug. The cumulative time and the activities
are listed. At several points comments show the need for entry of a
package development group into the process. Packaging development
personnel should be included in the process no later than 2 or 2.S years into
the development since at this point the drug is being characterised and the
first documentation is prepared for submission to the licensing authority
(the FDA in the USA). Too often the packaging group is not brought in
until S.S years into development and even as late as year 7. Both are too
late and to wait until year 7 means that there has been no significant
packaging expertise applied to the development programme at all.
Several US industry and government sources have estimated that the
cost of drug development in the USA ranges from a minimim of $12SM
after tax, to $SOOM before tax (Wall Street Journal); and the costs in other
Western countries are unlikely to be very different. This level of
investment is too large to jeopardise by not including expertise concerning
packaging economics and technology in the development process. More
importantly, this knowledge must be applied using the best estimates of
future trends, because the decisions made at the time when stability testing
is initiated will not be activated until 3-S years later.
 INTRODUCTION 9

Table 1.3 Development of a new drug

Cumulative time Stage of development Activities

(years)

0.5 Synthesis/isolation/ Chemists are synthesising a

characterisation new molecule or extracting
and purifying a substance
from a natural source.
1.0 Primary screening Biological testing with animals.
1.5 Secondary screening More biological testing with
animals for characterising
drug action on multiple
species.
2.0 Preliminary toxicity testing Animal experiments to
determine if drug is safe to
test on people.
2.5 Preparation/submission of Report above work to FDA for
IND classification as investigational
new drug (IND)
At this stage the package development staff should be included during the next half-year's
work so that they can know the drug characteristics that will affect package choice. They will
have time to begin package planning for clinical studies and for stability testing, if necessary.

3.0 Phase 1 clinical trials/further Drug administered to healthy

animal studies people and animal studies
continue.
4.0 Phase 2 clinical trials Drug administered to a few
patients with hypertension to
see if it works.
Package development staff can help with design and acquisition of packaging for the clinical
trials. Selection of packaging for stability testing should begin during the 4th year.

5.5 Phase 3 clinical trials Trials with a large number of

hypertensive patients. Drug is
tested in the precise manner
in which it will be used.
Package development staff should be included in package development for the Phase 3 trial.
Large numbers of patients and a closer approach to the market require their participation.
Selection of packages for stability testing must be completed and these tests started during this
18 months if any information is to be available for submission to the FDA.

7.0 Preparation for marketing Prepare labels, design capsules

or tablets. Write package
inserts.
7.5 Preparation/submission of Report all above to FDA as an
NDA NDA.
9.0 New drug ready for market Awaiting FDA approval.
Providing additional
information requested by
FDA. Preparing for
production.
10 PACKAGING OF PHARMACEUTICALS AND HEALTHCARE PRODUCTS

Newer drug delivery systems

Since packaging frequently contributes to the dispensing process and/or the

drug delivery system a brief discussion of recent advances in these areas is
worthwhile. New approaches to drug treatments have involved novel
means of drug delivery. Conventionally, drugs are administered either
orally, by injection into the bloodstream, inserted under the skin or into
the rectum or otherwise distributed throughout the body after absorption
into the blood. This medicates the whole body, rather than the specific
area on which the drug is to have its primary pharmacological effect. This
widespread distribution, although wasteful, is not of great clinical concern
unless side effects are produced or the procedure limits the therapy [3].
One method of improving therapy is to modify the means by which the
drug is delivered. Some of the systems being used are listed in Table 1.4.
Many, such as the use of transdermal patches, depend on controlled
release of the drug. Of all the possible ways of delivering a drug this is one
of the most awkward since the primary function of the skin is to keep
foreign substances out.
There are, however, advantages in transdermal applications. One is that
the digestive system is by-passed and a second is that because application is
easy there is a better chance that the patient will follow the dosage
instructions. But the permeability of the skin is quite low and getting useful
quantities of drugs into the blood by this route is so difficult that, currently,
there are less than 10 drugs which are administered in this way. However,
research on improving the technique is under way and results suggest that
transport through the skin can be improved by applying electrical impulses
to stimulate the nerves.
There is also the important oral administration route, which is still the
most popular, but there are some difficulties in achieving controlled
release or targeting systems. Once a conventional tablet is swallowed
control over it is lost. It disintegrates, dissolves relatively rapidly and

Table 1.4 Drug delivery systems (3)

System Feature

Transdermal patches Partial rate control via polymer membrane

Osmotic pumps for oral and rectal delivery Zero-order release determined by drug salt/
osmotic core
Vesicles Targeting and slow release of lipo- and
hydrophilic drugs
Antibody-drug conjugates 'Homing' potential to antigen sites
Complex emulsions Slow release potential
Implants Release over days or years
Microspheres Targeting and slow release
 INTRODUCTION 11

releases the drug into the stomach. To achieve some control over this some
developments have taken place (see Figure 1.2) [3].
Since many drugs are not reliably absorbed from the gut alternatives are
being examined. Insulin for example, has been given via the nose, the
rectum, and even via the eye with varying degrees of success. The ideal
delivery system would sense the levels of drug needed and respond by
releasing the active ingredient into the circulation or the tissue in which it
has been embedded. Work on these possibilities is also under way. All
these advances may have a profound effect on the protection which will
have to be provided by the packaging for these new forms of medication.

l__ Floating system

Disintegrating C;:?~
~Ie~.;l
....: :.; '.>
system
.. ~- '.

Matrix ? ~::~~.
system ~

system
OROS~

Pulsincap .;----;--,
sy~em ~--------- Bacteria
mediated
release
sy~em

Figure 1.2 Oral controlled release systems, both to control descent and rate of release of
drug, sometimes in specific regions of the GI tract [3]. Floating tablets and adhesive
preparations maintain residence in the stomach; disintegrating pelletised systems unload their
granules in the stomach or intestine; matrix systems remain intact, as do osmotic pumps and
the Pulsincap device. Formulations for delivery to the colon can be based on pH-dependent
dissolution of a polymer coating or on breakdown of the azo-polymer barrier membrane by
azo-reductases from the colonic bacterial flora.
12 PACKAGING OF PHARMACEUTICALS AND HEALTHCARE PRODUCTS

Inhalation therapies

Inhalation therapies allow the administration of drugs by atomisation or

finely divided particles. Liquids and solids gain access to the lungs far
better if they are atomised or in powdered form. Products can be so
dispersed when correctly formulated and then dispensed by an appropriate
device. This might be a squeeze pack, a metered dose pump, an inhaler or
a nebulizer. The squeeze pack for a nasal spray has many limitations and is
being replaced by a metered dose pump coupled with a suitable break-up
system.
Powder inhalers (devices such as the Spinhaler and the Inhalator) which
deliver a powder to the lungs after a capsule has been pierced or opened
are particularly successful for asthma sufferers. The Spinhaler® was the
first widely used capsule delivery system. The capsule is inserted into the
device and is then pierced by two needles which are actuated by a sliding
cam arrangement. The drug stays inside the capsule until the user sucks on
the device. At this point, a propeller rotates and the drug exits the capsule.
It then passes over the propeller blades, through a constriction, through a
grid, and into the patient. The Spinhaler delivers only a single dose while
the Inhalator was designed to hold six doses.
Such devices also help to overcome some of the problems of patient
compliance since inhalation ensures entry into the lungs. Many such
devices have been reviewed by Shepherd [4].

References

1. Dean DA. Private communication and many papers.

2. Clark DE. Chem lnd 1993, 19: 444-445.
3. Florence AT. New drug delivery systems. Chem lnd 1993; 1000-1004.
4. Shepherd MT. Dry powder deliver devices for asthma. In: The role of packaging in drug
delivery. Inst. of Packaging conference, Fison Ltd., Loughborough, 8 March 1994.

Further reading

Packaging of Pharmaceuticals. (Products, Sterilisation, Safety.) C.F. Ross, Institute of

Packaging, Sysonby Lodge, Melton Mowbray, Leics. UK, 1983.
Packaging of Pharmaceuticals. (Packages and Closures.) D.A. Dean, Institute of Packaging.
Sysonby Lodge, Melton Mowbray, Leics. UK, 1983.
Drug and Cosmetic Packaging Griffin & ·Sacharow.
Packaging Drugs & Pharmaceuticals. W.A. Jenkins and K.R. Osborn, Technomic Publishing
Co Ltd.
Packaging Design & Performance. F.A. Paine, Pira International. Leatherhead, UK, 1990.