Development of Standards for Plastics To Be Used

in Pharmacy and Medicine

JOHN A UTIAN
Drug-Plastic Research Laboratory, The University of Texas, Austin, Texas

The development of standards or specifications for plastic items to be used in medical

and paramedical applications has been the
concern of a small number of individuals and
groups representing the health professions,
pharmaceutical and plastic industries, academic institutions, and governmental agencies. In recent years, articles have appeared
presenting tests or groups of tests that may
be used to insure the safety of a plastic
device.'4 The most recent editions of The
United StatesPharmacopeia and The National
Formulary include a series of biological and
physical-chemical safety tests for plastic
devices that will have contact with parenteral products. Although these tests are now
available, often there is little testing done
on a plastic item before it is placed directly
or indirectly in contact with a patient.
Part of this lack of testing occurs because
of the unawareness of the groups manufacturing plastic medical items or groups
distributing these same items as to the need
for proper evaluation. Generally, these items
are manufactured by groups outside the
medically oriented fields, and a number of
these manufacturers may contribute items
that are only a part of the final, assembled
plastic device. In turn, the distributors may
mistakenly believe that the items they are
marketing have been adequately evaluated
for safety and compatibility with tissue or
with products that may be introduced into
the patient. To these situations must be
added the prevailing trust the physician,
dentist, pharmacist, nurse, and purchasing
agent has in the various plastic devices
available to the hospitals for patient care.
Often they may not recognize that one or
more of the items may cause minor to serious problems if not properly tested.
Several problems in regard to plastic
items will be described in this report to
dramatize that development of standards
1668

along a number of lines is essential if full

advantage is to be taken of these new, manmade materials and the more exotic materials of the future. (Dr. Earl L. Meyers will
review the Food and Drug Administration
role in the use of plastic materials.) Problems pertaining to plastic devices having
short-term contact with tissue, or having
contact with body fluids, drugs, nutritional
or diagnostic products will be considered and
steps will be outlined for groups to follow in
reviewing their possible role and responsibility in developing safe plastic devices or
limiting these devices for a specific use.
Problems in the Use of Plastics
Plastic items used in medical and paramedical applications fall into two classifications,(1) pure plastic (primarily the polymer
with insignificant quantities of additives)
and (2) compounded plastics (polymer and
other agents used to impart certain physicalchemical properties to the item). It generally has been found that devices prepared
from a pure plastic will produce little tissue
effect when implanted for short periods in
animals and human beings. Animal experiments, particularly in rodents, have revealed that these pure, polymeric materials can, however, induce cancerous tissue
changes, depending on the size of the implant and the form of the implant (for instance, plain sheet versus powder or porous
sheet).'-' At present, human experience has
not revealed that these same materials have
induced cancer in man, but man-made materials are of recent vintage to our inner
environment. Perhaps 15 to 30 years must
pass before one can say with assurance that
these pure plastics are noncarcinogenic.
Compounded plastics, since they contain
other ingredients besides the polymer or copolymer, may present more problems. Generally, additives can migrate to tissue and,

DEVELOPMENT OF STANDARDS FOR PLASTICS 1669

45, 1966
5. The pH solvent and other agents in
depending on the chemical agent, can cause
various tissue responses.8-10 Compounded the medium, if a solution.
6. Transfer of various gases from the
materials may have from two to ten additives and, in turn, these additives may them- surroundings through the walls of the conselves contain various levels of impurities, tainer or device into the product.
giving a potentially large number of comMost drug-plastic problems can be initialpounds available for diffusion into tissue or ly categorized into one of five classes:
1. Permeation.
into a drug solvent system.
2. Leaching.
As important as the biological response
3. Sorption (including both adsorption
elicited by a plastic material is the converse problem of the corrosive effect that and absorption).
4. Chemical reactivity.
tissue environments may have on a par5. Alteration of the plastic.
ticular material. In our own experience with
Often one problem, however, can lead to
animals and a group of diverse plastic
materials, this effect has been noticed. Un- a second or third problem. Thus, an initial
fortunately, this type of information is not problem may easily fall into several of these
readily available, and much effort in this categories. Each of these problems will be
area must be expended in the future to considered briefly.
PERMEATION.-The transfer of a gas from
predict the best possible materials for shortthe environment into a product through the
term and long-term implantations.
Still to be reckoned with is the fabrica- plastic container or device can alter the
tion of the material into specific devices such product by catalyzing a reaction that would
as a heart valve, vascular vessel, or artificial lead to degradation of the product. As often
organs. As an example, when the device has happens, the degradation may be slight, but
contact with blood, thrombogenic activities a change in color or aroma may detract from
of the plastic become of paramount im- the product and cause the user to discard
portance. Mechanical movements of such the product. In one study in this laboratory,
rapidity as occurs, for example, in leaflet a number of incompatibilities were noticed
types of heart valves, place an unusual stress with parenteral products in contact with a
on the material and in time might lead to a new plastic administration device."i Analysis
complete breakdown of the valve. It is pos- of the results revealed that these incomsible that the same plastic device will pro- patibilities resulted from the permeation of
duce a serious problem in one instance and air (oxygen) into the drug system, not from
the plastic itself. Product alterations also
will function perfectly in another.
have been noticed when certain liquid oral
Drug-Plastic Consideration
drug products have been stored in polyethylene containers. In these instances, the flavor
It is understood that any device used for has
changed because one of the aromatic inthe collection, storage, transfer, and ad- gredients
has migrated out of the product
ministration of drugs, biological products, through the
plastic walls.
diagnostic agents, and nutritional suppleThe transfer of water vapor through a
ments should not interact directly or in- plastic film or container can initiate drug
directly with the system in contact with it, degradation, even of solid dosage forms such
thereby altering the product. A number of as tablets and capsules, if these products are
factors, besides the plastic material per se, stored at high temperatures and high huwill influence the tendency for a product to midities. Conversely, water vapor or other
become adulterated when in contact with a solvents transferred from a liquid product
plastic item. The more important factors through a plastic device or container can
concentrate the active ingredient. Should
are:
1. The physical state of the product (gas, this product be administered, a large overdose of the drug may be given.
liquid, solid).
2. The time of contact of the product
The permeation problem, in regard to
with the device.
chemicals used as preservatives in drug and
3. The temperature.
biological products, may decrease the ef4. Presence of other ingredients in the fective concentration of the preservative
product.
to such an extent that the product no longer

Vol.

1670 A UTIAN

has any protection from fungus or bacterial

contaminates. Examples of these problems
have been noticed in a study of the loss of
the preservatives in a group of plastic containers."2
Consideration must also be given to the
possibility that inks or compounds making
up an adhesive used for bottle labels may
migrate through the walls of the container
and into the drug product. This reaction
generally is not noticed, since the quantities
entering the product are quite small. If the
product is a diagnostic agent, however, it
may produce erroneous results when various
clinical chemical tests are performed.
LEACHING.-The migration of an ingredient from the plastic item to a product can
present several minor to serious problems.
In one instance, the leached compound may
introduce an ingredient that in itself can
elicit a pharmacologic response. In another
instance, the leached ingredient may not
have any appreciable biological activity,
but it may interact with one of the components in the product. It has been observed in this laboratory that selected plastic containers and devices can, under proper
conditions, release a constituent into a
solution. Recently, these observations also
have been reported by Kordan and Inchiosa.13' 14 Perhaps it is pertinent to reveal
that certain plastic containers used for
serum, antiserum, and allergenic products
may release a constituent to the product.
Again, if these products are used in diagnostic tests, false results may be recorded that
can lead to serious consequences to the

patient.
Although plastic piping may be out of the
realm of devices to be included in this presentation, it is important to note that new
hospital units as well as industrial laboratories may include plastic piping systems
for transporting water and perhaps drug
products from one room to another or from
one vat to another. In one instance, a rigid
polyvinyl chloride (PVC) tubing in a hospital was to be used to transfer parenteral
products. An examination and an analysis of
this piping revealed a heavy concentration
of an organo-tin compound used as a stabilizer in the piping which, if released into the
drug system, could produce a dangerous
product. Parenteral toxicity studies in our
laboratories on a group of organo-tin compounds that have and may be used as

J. dent. Res. Supplement to No. 6

stabilizers for vinyl products have been

found to be extremely toxic.15
Within the past several months a dermatologist requested help with a problem one
of his patients was having when a particular
cannula was used. This cannula was an
elastomer and on analysis was found to have
low molecular weight fractions of the polymer, which in tissue proved to be toxic. In
another instance, a new plastic in a fine
powder form was evaluated. The powder
had the advantage that a cationic agent
might be incorporated into the material,
and that this could then be injected into a
patient, achieving a slow release of the agent
to the tissue. Results from one of the studies
revealed that the powder was not quite as
inert as claimed. Implantation studies in
animals, lasting several weeks to a month,
clearly demonstrated that the powder was
being eroded away by the biological system. There are many other examples of the
problem of leaching, but these presented
should dramatize the problem.
SORPTION.-The removal of a constituent
from a product in contact with a plastic item
will reduce the concentration of that ingredient in the product and deny the patient
the proper dose of the drug. In the past,
nylon syringes and other items composed of
one of the polyamides have sorbed weak
organic acids and certain cationic agents
(for example, benzalkonium chloride and
dicyclomine HCl) from aqueous mediums.
If the ingredient is sorbed by the plastic, it
will diffuse to the outer surface of the item
and, depending on its vapor pressure, be
released to the atmosphere, bringing about
permeation. Thus, sorption may lead to
permeation into the air or into a new solvent
system in contact with the plastic.
CHEMICAL REACTIVITY.-This classification of chemical reactivity pertains to the
actual reaction of an ingredient with the
plastic, causing an alteration in the physical
appearance of the plastic. Color changes in
plastics have become common when various
solutions have been stored for long periods.
Often, the chemical reaction is not primarily
due to an interaction with the polymer, but
with an additive in the plastic.
ALTERATION OF THE PLASTIC PROPERTIES.
-The four factors just discussed may, if the
course of the action is prolonged, alter the
physical-chemical properties of a plastic item
to such an extent that it no longer protects

DEVELOPMENT OF STANDARDS FOR PLASTICS 1671

Vol. 45, 1966

the product or it prevents proper usage of the

item.
Sterilization by radiation can cause sufficient cross-linking in a polymer to make the
device brittle. In one instance, a polypropylene syringe exposed to cobalt radiation
was so brittle that it could break when
handled. Sterilization by autoclaving and
by ethylene oxide may induce stresses in
the plastic device that at first may be undetectable by physical appearance but that,
under conditions of use, could cause a complete breakdown of the device.
Polystyrene devices (for instance, containers and syringes) kept in an atmosphere
where organic vapors might be present will
be susceptible to stress cracking. Vinyl devices kept in a warm environment will release their plasticizers to the atmosphere
and revert to an unmanagable tubing or
sheeting. Other physical-chemical changes
in plastics may occur in a specific item,
depending on its use and storage.

Special Problems
Minor to perhaps serious consequences
can occur from the use of the "wrong" material and the improper use of the "right"
material for a medical or paramedical application. Why should there be these problems, or at least potential problems, in regard to plastics? The answer is simple, if
not exactly academic. Plastics do not refer
to one specific material composed of a clearly
designated organic molecule having an exact
structure and an exact molecular weight.
Rather, it can refer to any material that
contains long-chain molecules called polymers. A polymer, in turn, can be composed
of subunits of the same chemical structure or
a group of different subunits. The polymer
chains in the material are of various lengths,
some quite short and others quite long.
These chains can be arranged in various
architectural ways, producing some regions
in the plastic that are quite permeable to
certain small molecules and other regions
that will not permit the passage of the same
molecules. As may be surmised, a number of
different physical-chemical and mechanical
properties can be achieved by substituting
new subunits (from different monomers),
altering the molecular weights (for instance,
having many more longer chains than short
chains), and rearranging the architecture of
the polymer chains. These three factors

(subunits, molecular weight distribution,

and architecture) in themselves can give a
host of materials having different properties. Further alterations can be achieved
in plastics by the addition of other ingredients, collectively called additives. These
additives may be used as plasticizing agents
(to give flexibility), antioxidants, stabilizing
agents, fillers, ultraviolet filters, pigments,
mold-releasing agents, and antistatic agents.
Each of these ingredients can thus alter a
property in the plastic. Changes in the final
plastic material can also occur when the
various stresses (such as heat, pressure, and
mechanical forces) are imposed on the material as it is being molded into an object in
one of a number of different ways.
The various possibilities for the alteration in physical-chemical as well as mechanical properties of plastics should give some
appreciation as to why even a same-named
plastic can have different properties.
Steps to be Taken to Develop
Standards
There is a need today for consideration
of steps that will lead to the establishment
of suitable standards for plastic items to be
introduced into the medical and paramedical markets. Unfortunately, one set of
standards cannot ever cover all the possible
plastic devices that are presently being used
or will be used in the future. It may be possible, however, to bring some order to the
present state of standards if medical items
could first be classified into basic groups as
shown (Table 1). Five classes are given here:
(1) permanent implants, (2) implants having contact with mucosal tissue, (3) corrective, protective, and supportative devices,
(4) collection and administration devices,
and (5) storage devices.
Specifications, including testing procedures, should be worked out for each of these
classifications by committees representing
the various industrial and health professions, with the help and guidance of selected
governmental agencies under the general
control of the Department of Health, Education and Welfare. Mention was made
earlier that in the present USP and NF
standards are included for plastic containers
for parenteral products. Several workers
have also suggested certain tests that might
be useful in establishing the safety of a particular plastic item, and Committee F-4

1672 A U TIAN

J. dent. Res. Supplement to No. 6

TABLE 1
CLASSES OF PLASTIC DEVICES
ACCORDING TO USE
Class
1

Device

or

Examples

Item

Permanent implants Heart valves, various

vascular grafts, orthopedic implants,
other artificial organs,

etc.

Implants having con- Artificial eyes, contact

tact with mucosal
lens, dentures, intratissue
uterine devices, certain types of cathe-

Corrective, protec- Splints, braces, films,

ters

tive, and supportative devices

protective

clothes,

etc.

Collection and ad- Blood transfusion sets,

ministration devarious types of cathvices
eters, dialysing units,
hypodermic devices
and similar injection
devices, etc.
Containers, bags for
Storage devices
blood, blood products, drug products,
nutritional products,
diagnostic agents,
etc.

of the American Society for Testing and

Materials is currently designing studies in
regard to implants that may lead to establishment of standards for certain implant
devices.
Although most standards test the final
plastic device, there is a need for the establishment of standards at two other levels.
The first level of consideration should be
with the raw materials used to make the
plastic formula. The second level of consideration should deal with the plastic
formula used to produce the final device. In
effect, then, any device that is to enter the
medical market must be viewed from three
levels: (1) Raw materials, (2) plastic formula, and (3) plastic device. Each group thus
involved with one or more steps in the
manufacture, distribution, and use of a
plastic device must become cognizant of
these three levels of consideration; this may
then lead to the establishment of standards
for each level. Unfortunately, certain gaps
will soon develop on each level and will require special studies or research before
meaningful standards can be established.

Some index as to what will be needed for the

establishment of standards at each of the
levels may be surmised by examining Table
2, which includes brief notations, tests, or
information requirements. Some general
comments, however, can be made in regard
to all levels of standards. There must be
established a physical-chemical and biological profile of each agent that is to be
involved in the creation of the plastic device.
The exact purity of each item must be
known. Detailed toxicity data must be
available from a number of routes of administration in groups of animals. Chronic
toxicity data must be assembled and the
possible carcinogenic activity of the ingredients or one of its impurities. The first
level of standards (raw materials) must
precede the second level of standards (plastic formula). It would seem reasonable that
any compound found to elicit undesirable
effects to biological systems might be eliminated as an ingredient in the plastic formula. Exception would be made if it can be
demonstrated that, during the development
of the plastic formula or manufacture of the
final device, the compound has lost its
original character (monomer to polymer) or
will not be released to a product or tissue.
In any event, no ingredient should be used
that has not been thoroughly evaluated
biologically.
Tests or information requirements for
Level 2 standards (plastic formula) follow
somewhat closely those of Level 1, with additional tests to define certain physical
chemical properties of the material. Level 3
deals with the plastic device and will include
a great many more tests, including the tests
for safety as well as tests for performance.
Special testing, such as sterility and pyrogen
testing and compatibility testing of the
plastic device with a specific product, may
be required; at times, these actually may be
short- and long-term studies.

A Final Recommendation
Man-made materials are entering our
world at a faster pace than ever before, and
it is certain that this rate will increase greatly in the future. The science of materials,
however, is relatively a new discipline and,
as is often the situation, the art far outstrips the science. A great gap exists be-

TABLE 2
LIST OF TESTS OR INFORMATION REQUIREMENTS FOR DEVELOPMENT OF STANDARDS*
LEVEL 1 STANDARDS-RAW MA TERIALS

A. Physical-Chemical Tests
1. Identification of substances used in the preparation of polymer and in final device.
2. Identification of impurities and concentration
of these impurities in each raw material.
3. Information on the degradation character of
each of the raw materials when stored under
various conditions.
B. Biological Tests
1. Toxicity profile on each of the substances used
in the preparation of polymer and final plastic
device. Toxicity data to be ascertained from
various routes of administration in groups of
animals.
2. Toxicity profile on each of the impurities.
3. Sensitivity potential of each of the ingredients.
4. Carcinogenic activity of each of the ingredients as well as the impurities.
LEVEL 2 STANDARDS-PLASTIC FORMULA

A. Tests or Information Needed on Plastic Directly

1. Physical-Chemical Tests
a. Information on composition of the formula.
b. Various tests for establishing the properties
of the plastic formula.
(1) Molecular weight distribution of the

polymer.

(2) Differential thermal analysis spectrum.

(3) Pyrolysis and gas chromatography
analysis.
(4) Infrared spectrum.
(5) Other tests.
2. Biological Tests
a. Long-term implantation studies in groups
of animals.
b. Short-term implantation studies in groups
of animals.
c. Tissue culture tests.
B. Tests or Information Needed on Eluates (Normal
Saline Solution, Alcoholic Solutions, Nonpolar
Solvents)
1. Physical-Chemical Tests
a. Changes in pH (where applicable).
b. Ultraviolet spectrum.
c. Thin-layer chromatography analysis.

d. Gas chromatography analysis.

e. Separation and identification of the extracted constituents.

*The various tests or information requirements are only

suggestions; other tests and information requirements will be
needed when specific items are considered. Procedures for performance of certain of the physical and chemical tests can be
found in American Society for Testing and Materials publications, and many of the biological tests are given in detail in The
United States Pharmacopeia and The National Formsiary as well

2. Biological Tests
a. Acute toxicity studies by several routes.
b. Chronic toxicity studies by several routes.
c. Tissue culture tests.
d. Tests for tissue sensitivity in animals and
man.
e. Hemolysis tests.
LEVEL 3 STANDARDS-PLASTIc DEVICE OR ITEM

A. General Considerations
1. Complete history of all parts making up the
plastic device.
2. Complete history as to the exact procedure
used to manufacture each part to the final assembly of the final device.
3. All information required for raw materials
and plastic formula should be available.
B. Tests or Information Needed on Plastic Part
1. Physical-chemical tests-same as given in
level 2 standards.
2. Biological tests-same as given in level 2
standards.
C. Tests or Information Needed on Eluates (normal
saline solution, alcoholic solutions, nonpolar
solvents)
1. Physical-chemical tests same as given in
level 2 standards.
2. Biological tests-same as given in level 2
standards.
D. Performance Tests
1. Ascertain if a specific device will function in
proper manner under a number of conditions.
E. Other Tests of Studies
1. Drug-product (including blood, blood products, nutritional products, etc.) compatibility
studies with plastic devices.
2. Sterility and pyrogenicity tests (for products
to be introduced into body or that will have
contact with products to be introduced into

body).

3. Stability profile as to shelf life of device.

F. Package Requirements for the Device
G. Label Requirements for the Device
1. Should include all essential information as to
the specific use of device and contraindica-

tions.

2.7 Should include the proper conditions for

storage of the device.
3. Should include an expiration date.
publications, such as have been cited in the text.
Final establishment of standards on the final item or class of
items must be left to committees representing the industrial
groups manufacturing the items and the health professions, with
guidance from one or more governmental agencies such as the
FDA.

as in specific

1674 A UTIAN

tween art and science in regard to a plastic

item for medical and biomedical use, as has
been implied in this discussion. It should be
clear to those in this field of medical plastics
that both basic and applied research must
be increased to bring to mankind the advantages of polymeric materials, while eliminating or circumventing problems that may
lead to injury or harm the health. The health
professions, and all those supplying directly
or indirectly polymeric materials to these
professions, are in need of a new breed of
scientists to fill the present and future voids
in insuring the safety of materials; scientists
of this new breed perhaps should be called
material science toxicologists. This new discipline must be supported and nurtured if,
in fact, we are sincerely interested in the
welfare and health of mankind. The road to
meaningful standards can be built only
through knowledge generated by those acting in the role of material science toxicologist.

J. dent. Res. Supplement to No.

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