The
proper Packaging (Containers)
of Pharmaceutical Products
The proper
packaging and storage of pharmaceutical products are all essential for product
stability and efficacious use.
Containers
Standards for
the packaging of pharmaceuticals by manufacturers are contained in the “Current
Good Manufacturing Practice” section of the Code of Federal
Regulations (1), in the USP–NF (15), and in the FDA’s Guideline for
Submitting Documentation for Packaging for Human Drugs and Biologics
(16). When submitting an NDA, the manufacturer must include all relevant
specifications for packaging the product. During the initial stages of clinical
investigations, the packaging must be shown to provide adequate drug stability
for the duration of the clinical trials. As the clinical trials advance to
their final stage, information on the chemical and physical characteristics of
the container, closure, and other component parts of the package system for the
proposed product must be developed to ensure drug stability for its anticipated
shelf life. Different specifications are required for parenteral,
nonparenteral, pressurized, and bulk containers and for those made of glass,
plastic, and metal. In each instance, the package and closure system must be
shown to be effective for the particular product for which it is intended. Depending
on the intended use and type of container, among the qualities tested are the
following:
• Physicochemical properties
• Light-transmission for glass or plastic
• Drug compatibility
• Leaching and/or migration
• Vapor transmission for plastics
• Moisture barrier
• Toxicity for plastics
• Valve, actuator, metered dose, particle
size, spray characteristics, and leaks for aerosols
• Sterility and permeation for parenteral
containers
• Drug stability for all packaging
Types of Containers
According to the USP, a container is “that which holds the article and is or may
be in direct contact with the article.” The immediate container is “that which is in direct contact with the
article (products) at all times.” The closure is part of the container. The
container must not interact physically or chemically with the drug so as to
alter its strength, quality, or purity beyond the official requirements. The
USP classifies containers according to their ability to protect their contents
from external conditions.
The minimally acceptable container is
termed a well-closed container. It
“protects the contents from extraneous solids and from loss of the article
under ordinary conditions of handling, shipment, storage, and distribution.”
A tight
container “protects the contents from contamination by extraneous liquids,
solids, or vapors, from loss of the article, and from efflorescence,
deliquescence, or evaporation under the ordinary or customary conditions of
handling, shipment, storage, and distribution and is capable of tight
re-closure.”
A hermetic
container “is impervious to air or any other gas under the ordinary or
customary conditions of handling, shipment, storage, and distribution.”
Sterile
hermetic containers
generally hold preparations intended for injection or parenteral
administration.
A single-dose
container is one that holds a quantity of drug intended as a single dose
and when opened, cannot be resealed with assurance that sterility has been
maintained. These containers include fusion sealed ampoules and prefilled
syringes and cartridges.
A multiple-dose
container is a hermetic container that permits withdrawal of successive
portions of the contents without changing the strength or endangering the
quality or purity of the remaining portion. These containers are commonly
called vials.
The packaging materials may be
combinations of paper, foil, plastic, or cellophane. Some drugs must be
packaged in foil-to-foil wrappings to prevent the deteriorating effects of
light or permeation of moisture. The packaging of solid dosage forms in clear
plastic or aluminum blister wells is perhaps the most popular method of
single-unit packaging. Different dosage forms such as oral liquids, suppositories,
powders, ointments, creams, and ophthalmic solutions, are also commonly found
in single-unit packages.
Some pharmaceutical manufacturers use
unit-of- use packaging; that is, the quantity of drug product prescribed is
packaged in a container. For example, if certain antibiotic capsules are usually
prescribed to be taken four times a day for 10 days, unit-of-use packaging
would contain 40 capsules. Many pharmaceutical products require lightresistant containers.
In most instances, a container made of a good quality of amber glass or a light-resistant
opaque plastic will reduce light transmission sufficiently to protect a
lightsensitive pharmaceutical. Agents termed ultraviolet absorbers may be added
to plastic to decrease the transmission of short ultraviolet rays. The USP
provides tests and standards for glass and plastic containers with respect to
their ability to prevent the transmission of light. Containers intended to provide
protection from light or those offered as light-resistant containers must meet
the USP standards that define the acceptable limits of light transmission at
any wavelength between 290 and 450 nm. A recent innovation in plastic packaging
is the coextruded two-layer high-density polyethylene bottle, which has an inner
layer of black polyethylene coextruded with an outer layer of white
polyethylene. The container provides light resistance (exceeding amber glass)
and moisture protection. It is increasingly being used in the packaging of
tablets and capsules. The glass used in packaging pharmaceuticals falls into four
categories, depending on the chemical constitution of the glass and its ability
to resist deterioration.
Constitution
of Official Glass Types
Type
General Description
I Highly resistant borosilicate glass
II Treated soda lime glass
III Soda lime glass
NP General purpose soda lime glass
The above Table presents the chemical
makeup of the various glasses; types I, II, and III are intended for parenteral
products, and type NP is intended for other products. Each type is tested
according to its resistance to water attack. The degree of attack is determined
by the amount of alkali released from the glass in the specified test conditions.
Obviously, leaching of alkali from the glass into a pharmaceutical solution or
preparation could alter the pH and thus, the stability of the product.
Pharmaceutical manufacturers must use containers that do not adversely affect the
composition or stability of their products. Type I is the most resistant glass of
the four categories. Today, most pharmaceutical products are packaged in plastic.
The widespread use of plastic containers arose from a number of factors, including
the following:
• Its advantage over glass in lightness
of weight and resistance to impact, which reduces transportation costs and losses
due to container damage
• The versatility in container design and
consumer acceptance
• Consumer preference for plastic squeeze
bottles in administration of ophthalmics, nasal sprays, and lotions
• The popularity of blister packaging and
unitdose dispensing, particularly in health care institutions
Types of Plastic Packing Materials
(Containers)
The term plastic does not apply to
a single type of material but rather to a vast number of materials, each
developed to have desired features. For example, the addition of methyl groups to every other carbon atom in the polymer
chains of polyethylene will give polypropylene, a material that can be
autoclaved, whereas polyethylene cannot.
If a
chlorine atom is added to every other carbon in the polyethylene polymer,
polyvinyl chloride (PVC) is produced. This material is rigid and has good
clarity, making it particularly useful in the blister packaging of tablets and
capsules. However, it has a significant drawback for packaging medical devices
(e.g., syringes): it is unsuitable for gamma sterilization, a method
that is being used increasingly. The
placement of other functional groups on the main chain of polyethylene or added
to other types of polymers can give a variety of alterations to the final plastic
material. Among the newer plastics are polyethylene terephthalate (PET),
amorphous polyethylene terephthalate glycol (APET), and polyethylene
terephthalate glycol (PETG). Both APET and PETG have excellent transparency and
luster and can be sterilized with gamma radiation. Among the problems
encountered in the use of plastics in packaging are
(a)
Permeability of the containers to atmospheric oxygen and to moisture vapor,
(b)
Leaching of the constituents of the container to the internal contents,
(c)
Absorption of drugs from the contents to the container,
(d) Transmission of light through
the container, and
(e)
Alteration of the container upon storage. Agents frequently added to alter the
properties of plastic include plasticizers, stabilizers, antioxidants,
antistatic agents, antifungal agents, colorants, and others.
Permeability of Plastic and Glass
Materials.
Permeability is considered a process of
solution and diffusion, with the penetrant dissolving in the plastic on one
side and diffusing through to the other side. Permeability should not be confused
with porosity, in which minute holes or cracks in the plastic allow gas or
moisture vapor to move through directly. The permeability of a plastic is a
function of several factors, including the nature of the polymer itself; the
amounts and types of plasticizers, fillers, lubricants, pigments and other
additives; pressure; and temperature. Generally, increases in temperature,
pressure, and the use of additives tend to increase the permeability of the plastic.
Glass containers are less permeable than plastic containers. The movement of moisture
vapor or gas, especially oxygen, through a pharmaceutical container can pose a
threat to the stability of the product. Most of these adjuncts are
carbohydrates, starches, and natural or synthetic gums, and because of their hygroscopicity,
they hold moisture and may even serve as nutrient media for the growth of microorganisms.
Many of the tablet- disintegrating agents act by swelling, and if they are
exposed to high moisture vapor during storage, they can cause tablet
deterioration. Specially developed high-barrier packaging can provide added
protection to pharmaceutical products against the effects of humidity. Such packaging
meets the drug stability requirements adopted by the International Committee on
Harmonization, which call for testing of packaged products for a minimum for 12
months at 25°C (77°F) at 60% relative humidity (18). Drug substances that are
subject to oxidative degradation may undergo a greater degree of degradation
when packaged in plastic than in glass. In glass, the container’s void space is
confined and presents only a limited amount of oxygen to the drug contents,
whereas a drug packaged in a gas-permeable plastic container may be constantly
exposed to oxygen because of the replenished air supply entering through the container.
Liquid pharmaceuticals packaged in permeable plastic may lose drug molecules or
solvent to the container, altering the concentration of the drug in the product
and affecting its potency.
Leaching &
Sorption
Leaching is a term used to describe the movement
of components of a container into the contents. Compounds leached from plastic containers
are generally the polymer additives, such as the plasticizers, stabilizers, or antioxidants.
The leaching of these additives occurs predominantly when liquids or semisolids
are packaged in plastic. Little leaching occurs when tablets or capsules are
packaged in plastic. Leaching may be influenced by temperature, excessive
agitation of the filled container, and the solubilizing effect of liquid
contents on one or more of the polymer additives. The leaching of polymer
additives from plastic containers of fluids intended for intravenous
administration is a special concern that requires careful selection of the
plastic used. Leached material, whether dissolved in an intravenous fluid or in
minute particles, poses a health hazard to the patient. Thus, studies of the
leaching characteristics of each plastic considered for use are undertaken as a
part of the drug development process. Soft-walled plastic containers of PVC are
used to package intravenous solutions and blood for transfusion.
Sorption, a term used to indicate the binding of
molecules to polymer materials, includes both adsorption and absorption.
Sorption occurs through chemical or physical means due to the chemical
structure of the solute molecules and the physical and chemical properties of
the polymer. Generally, the un-ionized species of a solute has a greater
tendency to be bound than the ionized species. Because the degree of ionization
of a solute may be affected by the pH of a solution, the pH may influence the
sorption tendency of a particular solute. Furthermore, the pH of a solution may
affect the chemical nature of a plastic container so as to increase or decrease
the active bonding sites available to the solute molecules. Plastic materials
with polar groups are particularly prone to sorption. Because sorption depends
on the penetration or diffusion of a solute into the plastic, the
pharmaceutical vehicle or solvent used can also play a role by altering the
integrity of the plastic. Sorption may occur with active pharmacologic
agents or with pharmaceutical excipients.
Thus, each ingredient must be examined in the proposed plastic packaging to
determine its tendency. Sorption may be initiated by the adsorption of a solute
to the inner surface of a plastic container. After saturation of the surface,
the solute may diffuse into the container and be bound within the plastic. The
sorption of an active pharmacologic agent from a pharmaceutical solution would
reduce its effective concentration and render the product’s potency unreliable.
The sorption of pharmaceutical excipients such as colorants, preservatives, or
stabilizers would likewise alter the quality of the product. Methylparaben may
be sorbed to some types of plastics, resulting in a decrease in the available concentration
of the preservative; this may be reflected in a lowering of its preservative
effectiveness. Deformations, softening, hardening, and other physical changes
in plastic containers can be caused by the action of the container’s contents or
external factors, including changes in temperature and the physical stress placed upon the container in handling and shipping.
Source: Ansel’s
Pharmaceutical Dosage Forms and Drug Delivery Systems (Ninth Edition)
