[Pharmwaste] Chemicals Leach From Packaging

[Tenace, Laurie]

A little off topic, but this demonstrates another exposure pathway to
consider.
Laurie

http://pubs.acs.org/cen/coverstory/87/8735cover.html


Chemicals Leach From Packaging=20
Food and drugs just can=A1=AFt leave their wrappings behind
Sarah Everts =20

  =20
Earlier this year, when Germans were cracking open boxes of chocolate
muesli=A1=AAa common breakfast cereal in their country=A1=AAit=A1=AFs =
unlikely their
thoughts slid to the chemical 4-methylbenzophenone, much less to the =
fact
that this component of printing ink had slipped from the outside of the
cardboard box and into the cereal. That is, until the European Food =
Safety
Authority (EFSA) was asked to look into the matter.

Open a cereal box or a carton of juice, breathe in an asthma drug from =
an
inhaler, or pop an antihistamine pill out of a plastic pouch=A1=AFs =
metal foil.
You are probably thinking about the product you=A1=AFre about to consume =
and not
about its packaging=A1=AAexcept, perhaps, for a twinge of regret about
contributing to landfill waste. But here=A1=AFs something to keep in =
mind: Even
when the wrapping comes off, you inevitably ingest some of the =
container.

Plastic, rubber, cardboard, metal, and glass packaging act as a barrier
against all sorts of contamination, but they are also a source of
contamination. Speak with anyone who produces, studies, or regulates
packaging, and you will hear this point repeated: It is not a question =
of
whether packaging components will leach into a product, it=A1=AFs a =
question of
how much. =A1=B0If you have a material in contact with food, and if =
it=A1=AFs not
completely inert=A1=AAand there are no completely inert =
materials=A1=AAsomething in
the packaging will end up in the food,=A1=B1 says Dimitrios Spyropoulos, =
a
regulator at EFSA.

The same holds true for pharmaceuticals. =A1=B0You will always have =
leachables,=A1=B1
says Guirag Poochikian, a retired U.S. Food & Drug Administration =
regulator
who used to evaluate leachables from inhaler devices. =A1=B0The question =
is
=A1=AEWhat are they, and what is their safety margin=A1=AF =A1=B1 in =
humans?

As analytical technology improves=A1=AAin some cases allowing =
parts-per-trillion
levels of detection=A1=AAtrace, and sometimes not-so-trace, levels of =
thousands
of different leachables can be measured in food and pharmaceuticals. =
More
challenging is tracking down the source of migrating compounds and =
figuring
out what levels are harmful to human health. Controversies over what
migration levels constitute harmful human exposure continue to simmer. =
And
even as researchers come up with new strategies for reducing leachables,
cases of unexpected packaging chemicals migrating into food or drug
formulations point to the need for further diligence.

=20
Packaging leachables have a daunting number of potential sources: They =
can
originate from the molecular makeup of the container or from chemicals a
container encounters during manufacturing, sterilization, or shipping.

Plastic is by far the most common packaging material=A1=AAthink food and =
pill
bottles, plastic wrap, prefilled syringes that carry units of injectable
drugs, or even intravenous-fluid bags.

Leachables from plastics can include everything from leftover monomer
building blocks to additives used to make plastic strong or malleable.
Probably the most infamous leachable from plastics is bisphenol A (BPA),
which is used as a building block in polycarbonate bottles and in the
epoxy-resin liners of metal cans.

Last year, the Canadian government banned the use of BPA in baby bottles =
as a
precautionary measure against the risk that its presence could cause
endocrine disruption in children=A1=AAa risk that other regulatory =
agencies such
as FDA dispute (C&EN, Nov. 17, 2008, page 42). But BPA is just one of
hundreds of molecules that can migrate out of plastics. That group also
includes di(2-ethylhexyl) phthalate, a potential carcinogen and =
endocrine
disrupter that helps make plastics such as polyvinyl chloride (PVC) =
supple
and bendable; phenolic antioxidants such as Irganox 1076; and =
benzophenone
light stabilizers.

Glass is about as inert a packaging as can be, but the material can =
sometimes
leach minerals or metals, particularly if it is recycled. Despite its
low-leachability profile, glass containers typically require some form =
of a
cap, which often contains rubber, arguably the most problematic source =
of
migrating chemicals.

Rubber turns up in the seals or stoppers of glass jars used to hold both =
food
and drugs, in elastomeric components in the valves of inhaler devices, =
and in
stoppers at the ends of plungers found in prefilled syringes. Many =
rubber
leachables come from chemicals used in or produced during processing, =
such as
N-nitrosamines, which can sometimes be carcinogenic, or
2-mercaptobenzothiazole. Carbon black=A1=AAeffectively soot=A1=AAwas =
used as an
additive to make rubber supple until the mid-1980s, when it was shown =
that
cancer-causing polynuclear aromatic hydrocarbons leached from
carbon-black-containing rubber used in products such as asthma inhalers =
and
baby-bottle nipples, Poochikian says.

Other specialized packaging materials include the waxy wrapping that =
covers
hamburgers or lines the inside of microwavable popcorn bags. Recently, =
Scott
Mabury, a chemist at the University of Toronto, showed that this kind of
packaging leaches polyfluoroalkyl phosphoric acids (PAPs), which are =
then
absorbed by humans and accumulate in the body. These compounds can be
metabolized in the body to perfluorinated carboxylic acids, which may be
carcinogenic and hormone disrupting.

=20
And then there is ink. Most packaging is covered with some form of =
print, be
it branding or a bar code. Unfortunately, the chemicals used for =
printing
have an uncanny ability to wind up in food and pharmaceuticals. Besides =
this
year=A1=AFs muesli case, millions of liters of infant formula were =
recalled in
2005 in Italy, Portugal, Spain, and France when another printing-ink
component called isopropylthioxanthone was found in the product. Tetra =
Pak,
the firm that supplied the formula=A1=AFs packaging to Nestl=A8=A6, has =
since phased
out the chemical=A1=AFs use.

Contamination such as that in the baby formula case is often caused by a
manufacturing =A1=B0off-set problem,=A1=B1 says Timothy Begley, a =
chemist involved in
leachable evaluation at FDA. Materials such as snack-food bags or
coated-paper cartons used for juice or baby formula are printed and then
rolled up. But in the rolling-up process, =A1=B0the printed layer comes =
in
contact with the food-contact layer,=A1=B1 Begley says. =A1=B0In the =
roll there is a
transfer of ink components into the food-contact layer.=A1=B1 When the =
packaging
is unrolled to make the bag, ink components can transfer to whatever is
stored inside.

But ink can also percolate directly through some plastic packaging, such =
as
prefilled syringes or IV bags. =A1=B0In our experience, materials such =
as
polypropylene and polyethylene do not pose a significant migration =
barrier to
the low-molecular-weight ingredients of printing ink,=A1=B1 Michael Jahn =
said at
the Conference on Leachables & Extractables for Pharmaceutical Products =
in
Barcelona in May. Jahn does contract research work on leachables for
specialty chemical maker Ciba, now part of BASF. In fact, ink can even
migrate through two layers of packaging, noted Kumudini Nicholas, a =
regulator
for Health Canada=A1=AFs Therapeutic Products Directorate, at the same
conference. She said that her agency initiated a product recall after a =
drug
solution in a plastic pouch became contaminated with printing chemicals =
from
the outside of a second plastic-overpouch.

Aside from the direct migration of chemicals from containers, packaging =
can
also be exposed to problematic materials during its production, storage, =
and
transport. The chemicals can later leach into the product stored in the
container.

Consider these two seemingly intractable cases encountered by =
pharmaceutical
companies that had packaged their liquid-protein drugs in prefilled =
syringes
and then later found that the protein solution they hoped to sell had
aggregated into clumps. In one case, a syringe manufacturer was using =
epoxy
glue to attach the metal needle to the syringe=A1=AFs barrel, said =
Ingrid
Markovic, a regulator at FDA=A1=AFs Center for Drug Evaluation & =
Research, at the
leachables conference in Barcelona. Unfortunately, a solvent from the
partially dried epoxy glue leached into the liquid-drug product, =
oxidized the
protein, and caused it to aggregate. In the second case, a tungsten =
filament
used to poke a hole through the tip of the syringe needle left tungsten =
oxide
salt residue that later percolated into the liquid-drug formulation, =
also
causing protein aggregation.

Even packaging sterilization=A1=AAsuch as gamma radiation, steam, or =
ethylene
oxide treatments=A1=AAcan introduce leachables. For example, gamma =
radiation is
particularly notorious for severing carbon-chlorine bonds found in PVC
plastics and some additives, forming breakdown products that can then
percolate into food and drugs.

Shipping is also an issue, according to Steve Lovatt, a scientist with
Bespak, a British manufacturer of valves for inhalers. =A1=B0What was =
the truck
shipping the day before? What if it was pesticides?=A1=B1 he asked at =
the
Barcelona workshop. It=A1=AFs important to check the cleanliness of the =
truck=A1=AFs
lining and any off-loaded equipment, he said.

Ultimately, =A1=B0the problem in this business is that material is =
acquired from
tertiary or quaternary sources,=A1=B1 Poochikian says. These distant =
sources
supply a variety of industries, some of which may not have as stringent
cleanliness requirements as the food and drug industries do. Consider
pressurized metered-dose inhalers, such as those used by asthmatics. The
medicine is suspended in a liquid, and the whole solution is stored in a
plastic-lined metal canister that lies in contact with a valve that =
contains
rubber. Large portions of the overall container, including the =
mouthpiece,
are made of plastic. The pharmaceutical company is ultimately =
responsible for
the product consumed by the patient, but the firm doesn=A1=AFt typically =
make the
packaging itself. Instead, a device manufacturer puts everything =
together,
after sourcing the plastic, rubber, and metal from different companies.
Chemicals used for polymerization, softening, and durability of the =
packaging
typically come from another set of suppliers.

The logistics of placing controls throughout the supply chain can be a
challenge, but spending the time to get through =A1=B0the education =
phase=A1=B1 with
suppliers is essential to ensure safe products, says Gerallt Williams,
director of R&D at Valois Pharmaceuticals, which produces inhaler =
devices.

Cheryl Stults, a senior fellow at Novartis, concurs. At the Barcelona
conference, she noted that during drug development it is important to
consider packaging as early as possible=A1=AAand definitely before =
starting
clinical trials. =A1=B0Phase III is not a time to start thinking about =
leachables
and extractables,=A1=B1 she said. No one wants to have to restart =
product
development because a packaging compound has migrated unexpectedly into =
the
formulation and caused some sort of problem, she added.

Even when the packaging supply chain is under control, drug companies =
can
make a small change in drug formulation that might lead to problems. For
example, when a background component of a liquid drug given to people
suffering from kidney problems was switched from human albumin serum to
polysorbate, the polysorbate enhanced leaching of chemicals from rubber =
used
in the packaging. These leachables were at least partially responsible =
for a
dangerous syndrome called pure red cell aplasia, which arose in patients
receiving the drug (Kidney Int. 2008, 74, 1617).

Only after leachables have been identified, quantified, and sourced does =
the
most critical step occur: determining what levels of leachables in food =
or
drugs pose a risk to human health. Regulatory agencies have entirely
different approaches to assessing the risk in food versus =
pharmaceuticals.

Let=A1=AFs start with food. In the U.S., the Code of Federal Regulations =
lists
ingredients that manufacturers may use to make packaging that contacts =
food,
including a limit of how much of the additive can be present in the
packaging. If a company wants to get a new additive approved, it must =
figure
out how much leaches out of the packaging and into the food over 30 =
days;
further migration for the remainder of the product=A1=AFs shelf life is
extrapolated, Begley says. In some cases, migration is assumed to be =
100%, he
adds.

Allowable levels for a given packaging ingredient are based on =
estimating the
=A1=B0cumulative estimated daily intake=A1=B1 that a person will have of =
that
leachable ingredient, Begley says. As the estimated intake increases, =
the
company must provide more extensive toxicological data. Because the =
migration
of leachables can be enhanced or hampered by the chemical nature of the
product inside=A1=AAwhether it is, say, watery, acidic, or oily=A1=AAthe =
limits are
sometimes set differently for different foods.

In the European Union, a specific list of food-allowable components =
exists
only for plastic packaging. All other components of packaging are =
subject to
a general rule that food-contact materials should =A1=B0not transfer =
their
constituents to food in quantities which could endanger human =
health,=A1=B1
Spyropoulos says. When evaluating the possible health risk of =
food-packaging
constituents, EFSA assumes a consumer will eat 1 kg of food containing =
the
ingredient in question and sets limits on the basis of toxicological =
concerns
of that consumption.

When it comes to pharmaceuticals, governments worldwide have not made =
any
regulations on leachables. Instead, regulators, including those in the =
U.S.
and the EU, evaluate the risk of leachables from a new drug=A1=AFs =
packaging on a
case-by-case basis as the drug traverses regulatory approval. Although =
there
are no set rules for drugs, some of the elements of pharmaceutical =
packaging
evaluation are more stringent than for food. For example, FDA requires =
data
on pharmaceutical leachables throughout the entire shelf life of the =
product,
instead of just the 30 days for food. =A1=B0Pharmaceutical companies =
often look
to packaging components that are allowed in food as starting points for
drug-packaging design,=A1=B1 Stults said at the conference.

When assessing the health risk of drug-packaging leachables, regulators
typically triage on the basis of how often the drug will be consumed or =
how
it will be delivered, Markovic notes. For example, leachables from drugs =
that
are inhaled into the lungs, sniffed up the nose, or injected into the
bloodstream are considered higher risk than those in a drug that is =
swallowed
and has the relative luxury of the digestive track to protect the body =
from
harm.

Then there is the frequency of use. Drugs taken on a daily basis are
considered riskier than infrequently used drugs because any leachables
present will be more regularly ingested.

Another area of concern is drugs in liquid formulations because =
solutions can
elicit more leachables than a pill or a powder.

Because of the lack of specific regulations for pharmaceutical =
packaging, a
working group composed of industry scientists, regulators, and academics =
was
formed in 2001 under the auspices of the Product Quality Research =
Institute
(PQRI). The group spent six years developing guidelines for doing =
extractable
and leachable studies of inhalable drugs that U.S. and European =
regulators
now endorse as a guideline=A1=AAalthough they still reserve the right to =
evaluate
each case individually. The guidelines establish two important =
thresholds for
leachables in inhalable drugs.

The first is an analytical basement called the Safety Concern Threshold,
below which a leachable=A1=AFs presence is considered too small to worry =
about
(0.15 =A6=CCg per day). They also developed a second threshold (5 =
=A6=CCg per day),
below which any leachable is considered tolerable to humans=A1=AAas long =
as the
leachable isn=A1=AFt a known toxicant or doesn=A1=AFt have a chemical =
structure
similar to one. Finally, toxicological studies must be done for any
leachables present above 5 =A6=CCg per day.

Another PQRI working group is now developing guidelines for leachables =
in
ophthalmic and injectable drugs. They aim to have guidelines in a couple =
of
years.

Generating toxicological data for a given leachable, which is expensive
because it often involves animal studies, can lag behind the =
leachable=A1=AFs
identification. For example, in the case of contamination of infant =
formula
by the ink compound isopropylthioxanthone, EFSA had to work with a =
limited
amount of toxicological data for the compound. In the end, the agency
concluded that the levels of isopropylthioxanthone didn=A1=AFt pose =
problems to
infants, but, =A1=B0We said to industry that if it was going to be used, =
we would
need more toxicological data,=A1=B1 EFSA=A1=AFs Spyropoulos says. =
=A1=B0Industry
preferred not to use more money to do the studies but to abandon its =
use.=A1=B1

Sometimes the limits of known leachables set by regulators are =
controversial,
as illustrated by the debate over BPA. Scientists such as biomedical
researcher Wade Welshons of the University of Missouri, Columbia, argue =
that
their data show that both FDA=A1=AFs and the European Commission=A1=AFs =
allowable
level of the molecule in food can cause endocrine disruption in humans =
and
that regulators have been basing their decisions on just four
industry-sponsored studies. Regulators and industry continue to argue =
that
BPA is present in food packaging at levels that are safe and that they =
base
their evaluation on sound science.

Others say that regulators approach the study of risk too narrowly. In
particular, regulators evaluate the risk associated with individual =
leachable
chemicals in isolation. This approach neglects the possibility that if =
humans
are exposed to low doses of several chemicals that affect the same organ =
in
the body, the combination may induce harmful effects, even if they are
present below their =A1=B0no-effect concentration=A1=B1 as individual =
chemicals, says
Jane Muncke, a toxicologist at Switzerland-based glass-container =
supplier
Emhart Glass. =A1=B0New approaches need to be put in place to =
characterize
whole-packaging toxicity=A1=AAincluding printing inks, adhesives, and =
secondary
packaging=A1=AAto understand what consumers are actually being exposed =
to and
whether there is a safety issue,=A1=B1 Muncke notes.

In addition, there is concern about the increasing use of nanotechnology =
in
packaging to improve structural integrity and detect and kill microbes.
Regulators lack the tools to characterize and detect such nanoscale =
materials
as well as the materials=A1=AF impact on biological systems (C&EN, Oct. =
6, 2008,
page 38).

At the same time, those producing packaging are looking at ways to =
reduce
leachables. For example, one way the rubber industry has dealt with
problematic leachables is to give rubber a bath. These extraction baths =
take
away a majority of chemicals of concern before the rubber passes on to =
the
manufacturing stage, Valois Pharmaceuticals=A1=AF Williams says. Other =
firms coat
rubber with polytetrafluoroethylene to block leaching or use =
rubber-curing
agents such as peroxide that reduce leaching. Some researchers, such as =
Judit
E. Puskas, a polymer scientist at the University of Akron, are =
developing
thermoplastic elastomers that self-assemble by physical forces. This =
means
there is no need to add rubber-processing chemicals that could later =
leach
out, Puskas says.

To prevent ink leaching, some companies are developing higher molecular
weight, polymerized, or cross-linked ink components. But the formulation =
of
these decreased-migration inks is typically =A1=B0a carefully preserved =
secret,=A1=B1
Jahn said at the conference in Barcelona. Other manufacturers opt to =
insert a
metal foil layer as a physical barrier to ink migration. Although this =
may
successfully block the migration of ink components, adhesives used to =
stick
the foil in place may also be a source of leachables, Jahn warned.

Glass can also play an important role as a physical barrier. For =
example, to
prevent leaching from polyethylene teraphthalate, a plastic that is =
sometimes
used to store wine, some companies use chemical vapor deposition to add =
a
layer of silicon oxide glass in between the plastic and the wine.

The packaging industry is also coming up with new ingredients and =
additives
that leach less but do the same job. For example, after the EU banned =
the use
of di(2-ethylhexyl) phthalate plasticizers in baby toys in 2005, =
companies
developed a cornucopia of substitutes such as pentanediol =
diiso-butyrates,
cyclohexanedicarboxylic acid esters, and monostearate derivatives.

The common feature of all potential solutions to the leachables problem =
is
that they cost money=A1=AAsometimes several times the price of the =
components
they replace. It remains to be seen whether consumers are willing to pay =
more
for expensive packaging that reduces leaching into their food and drugs.

Laurie Tenace
Environmental Specialist
Waste Reduction Section
Florida Department of Environmental Protection
2600 Blair Stone Rd., MS 4555
Tallahassee FL 32399-2400
P: 850.245.8759
F: 850.245.8811
Laurie.Tenace at dep.state.fl.us=20

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