WVTR, EXTRACTABLES, LEACHABLES

Pseudo-empirical modeling is a technique that uses empirically derived data from the packaging
materials, including moisture vapor transmission rate (MVTR) through the bottle, surface area of
the bottle, sorbent adsorption isotherms and drug product adsorption/desorption isotherms.
Linking these variables together mathematically will pseudo-empirically predict the relative
humidity of a pharmaceutical package’s headspace and drug product hydration level over time.

This resulting information will ultimately determine the means by which manufacturers can
maintain a drug’s chemical and physical characteristics throughout its shelf life.

Customized Moisture Management

Pharmaceuticals can be subject to chemical and physical degradation through interaction with
moisture. This is because free moisture increases the molecular mobility within drug product
formulations that can directly affect the rate of all chemical degradation pathways.

Desiccants are used to reduce free moisture within the drug product and thereby curb molecular
mobility while reducing the potential for further hydration from moisture ingress through its
primary packaging. There are a wide range of desiccants available to maintain pharmaceutical
integrity, but it is important to choose the right desiccant type, amount and format for each drug
product. Determining the best combination requires a precise analysis that takes into account the
drug characteristics and packaging materials as well as the sorbent’s functionality.

Pseudo-empirical modeling can be especially helpful because engineers first define the
adsorption properties of a particular drug product and then simulate the effect of that formulation
in combination with a given packaging presentation with varying amounts and types of
desiccants. This approach takes into account conditions during all stages of drug processing,
from formulation to the packaging environment and throughout distribution.

After running this analysis, engineers can provide specifications for the best product/packaging
combinations. Simulations can be performed for many types of pharmaceutical packaging in
accordance with the guidelines for stability testing set by the International Conference on
Harmonization for accelerated test conditions (six months at 40°C and 75% relative humidity
(RH)) or real-time (room temperature) test conditions (two years, typically at 25°C and 60%
RH).

Simulations at either condition require specific input criteria (e.g., isotherms, MVTR, etc.) to
account for the effect that temperature has on polymers and drug products. Because of the ability
to perform testing under accelerated conditions, simulations can help drug makers find a stability
solution quickly, reducing sorbent ranging studies and testing time by at least six months, thus
speeding regulatory filings, subsequent approvals, product launches and ultimately cash flow. It
can also result in cost savings, as it enables manufacturers to purchase the precise amount of
sorbent they will need for a given drug product’s packaging requirements.
Finding the Right Combination

Today’s sorbents are often described as “active packaging components” because they respond to
changes in the headspace of packaging relative to outside conditions. The goals of stability
testing for drug packages are: 1) to determine what the internal conditions of a drug package will
be under given conditions, and 2) to predict equilibrium relative humidity (ERH) and drug
product hydration over the course of the product’s shelf life.

The calculations take into account the humidity levels both inside and outside the package, as
well as the drug’s and desiccant’s respective affinities for moisture at varying humidity and/or
temperature levels and the rate of transfer of moisture and vapor through the package wall.

In essence, the modeling approach simulates how the interdependent variables — drug, desiccant
and package — will affect one another over time. With this information, it is possible for drug
makers to ensure the stability of their formulations and set appropriate expectations for their
shelf lives. For example, a simulation of a solid drug packaged in a high-density polyethylene
bottle and subject to moisture degradation would take into account three interdependent
parameters: the moisture vapor transmission rate through the bottle wall; the adsorption isotherm
for the drug (Figure 1), and finally, the adsorption isotherm for the desiccant (also in Figure 1).

The analysis would also have to calculate the surface area and thickness of the bottle to
determine possible moisture ingression through its walls. Given its performance advantages in
reducing total moisture ingress, the use of a foil-laminate heat-induction seal is always assumed.

The combination of drug product and desiccant functions as a system and will reach equilibrium
relative humidity (ERH) over time. When you first drop a desiccant into a bottle, it acts on all
available sources of moisture, pulling moisture out of both the air and the drug. The impact on
the drug product is to reduce molecular mobility as well as chemical degradation.

In this manner, the desiccant will reduce the ERH inside the headspace of the bottle, and
consequently the ERH and moisture content of the drug product. For this reason, the simulation
model has to calculate the required amount of desiccant to process moisture out of the drug
product in order to establish a protective “envelope” of relative humidity inside the bottle.

It also has to compensate for the increased ingress of moisture that results from the use of a
desiccant itself. Consider a scenario in which drug filling takes place in a test chamber at 40°C
and 75% RH, and the bottle headspace conditions are at 40°C and 10% RH. The differing
humidity levels will create a relative humidity gradient. Because the inside of the bottle wants to
reach a point of equilibrium with the outside environment, it will essentially create a driving
force for moisture to come into the bottle until said equilibrium is achieved.

Some drugs have some hygroscopic value; that is, they tend to absorb moisture from the
humidity in the air. Such drugs could contribute to added moisture ingress as well, though to a
lesser degree than a sorbent. An extremely low ERH and related state of disequilibrium can be
observed when molecular sieve desiccants are used. In the above example, permeation takes
place relative to the adsorption properties of both the drug product and desiccant. As the products
adsorb moisture and the RH inside the bottle rises and begins to approach 75%, the rate of
permeation slows down.

Carefully tracking this rate enables one to gauge the exact capacity that will be required from a
desiccant. Additionally, the modeling technique can indicate the conditions of a specific drug
product formulation if packaged without a desiccant.

Multiple Applications

Pseudo-empirical modeling can be used for a range of drug formulations, including oral solid
doses, oral suspensions, powdered drugs, parenteral solutions, and active and passive
transdermal technologies. Appropriate moisture management can extend the shelf life of existing
drugs and make possible innovative delivery methods or drug formulations.

Consider a respiratory drug delivery device used with powdered drugs. By regulating the
moisture levels inside such devices, sorbents facilitate the smooth flow of drug particles and
ensure that the device works effectively and accurately each time it is used. Modeling the precise
amount and type of sorbent needed for such a system to best manage moisture can streamline the
design and production processes, thus reducing time to market.

Careful moisture management in respiratory drug delivery systems is critical to balancing the
opposing challenges of triboelectrification [1] and particle agglomeration and resulting dosing
problems. Many of today’s most innovative drug formulations are also unstable in that they are
highly sensitive to both moisture and oxygen. In some cases, customized sorbent and packaging
solutions developed through pseudoempirical modeling can make drug formulations viable that
may once have been deemed too difficult to market.

Pseudo-empirical modeling and subsequent proofof- concept stability testing offer valuable tools
to formulation chemists and packaging engineers. The information resulting from such testing
enables drug makers to customize moisture management strategies to meet product needs.
Stability tests also provide important evidence to regulators that pharmaceutical products will
remain safe and effective throughout the supply chain.

Innovative modeling techniques bring precision and predictability to the process of choosing a
desiccant and packaging solution. Registration stability testing can now be done on an
accelerated time scale, speeding time to market. This, in turn, can help drug makers enhance
product stability and ensure brand integrity.

Applying the Final Touches

Bringing a new biological drug to market requires a huge financial commitment and entails risks
in every stage of the development process. The risk associated with selecting a vial/stopper/seal
system for packaging the drug may not be in the forefront of early-stage thinking, but the risks
are real nonetheless and can have profound impact on the drug product.
Selecting packaging for a parenteral drug is critical for a successful market launch. Packaging
components must meet functional requirements to help ensure safety at the point of
administration and must protect the purity of the packaged drug product for its shelf-life, usually
a minimum of two years. Packaged drugs, especially highly sensitive biopharmaceuticals, can be
harmed if the administration system and packaging components are not selected carefully to
ensure compatibility with the drug.

With all that is invested in drug research and development, biopharmaceutical researchers must
include packaging and administration system selection in their product development planning.
Requirements for product purity, activity and shelf-life dictate a very high standard for injectible
drug packaging, particularly for highly sensitive biopharmaceuticals.

The Food and Drug Administration’s (FDA) Guidance for Industry – Container Closure Systems
for Packaging Human Drugs and Biologics (May 1999), states that pharmaceutical
manufacturers should conduct extractables and leachables testing on their container closure
systems and drug product. The guidance recommends that each New Drug Application (NDA) or
Abbreviated New Drug Application (ANDA) contain enough information to demonstrate that a
proposed package and its components are suitable for their intended use.

What’s more, FDA’s current thinking on Quality by Design (QbD) has implications for the
biopharmaceutical industry. The Agency has stated that drug product quality should be designed
into the process (using QbD, that is), not achieved by testing drug products into compliance.
Controls should be in place as far upstream as possible. A QbD initiative for biopharmaceutical
manufacturing is designed in terms of risk assessment, risk analysis and risk control.

Risk assessment should be integrated into product development and

process development activities, which includes selection of the
product’s packaging and administration system. To connect the drug
administration system to the manufacturing process in a QbD
environment, the biopharmaceutical company should conduct a risk
assessment of the container closure system components during the
early stages of product development.

An early-stage assessment can identify potential issues related to

system component functionality, machinability and fitness for use
with a specific biological product. It is especially important to
evaluate potential extractables from elastomeric components such as
vial stoppers and syringe plungers. A risk analysis can help identify
Fluorocarbon film coatings a potential adverse effect to the product caused by system
provide protection from components, which helps the biopharmaceutical company to
extractables from the prevent or eliminate the potential risk. Risk control and mitigation
component material while are pertinent to the process scale-up phase of product development.
providing a high level of
barrier protection for the A QbD system strives to reduce risks to product quality by
drug product, therefore managing and controlling the source of materials and the effect of
variability in materials used to manufacture products such as
minimizing leachables.
container closure system components. Biopharmaceutical manufacturers can advance their QbD
process by working with component manufacturers that have appropriate in-process controls in
place.

The potential impact of extractables

Minute particles of metals, plasticizers and other materials from packaging components may
deactivate or denature biopharmaceuticals such as monoclonal antibodies. Whether in liquid or
lyophilized form, biologically derived products possess properties that make them extremely
sensitive to their packaging or delivery system. Proteins and peptides have a tendency to adsorb
onto the surface of packaging containers and closures.

Lyophilized proteins are no less immune to the effect of packaging. Because lyophilized cakes
are sensitive to moisture, an inadequate seal could cause water to enter the package and interfere
with the activity of the drug product. Many biopharmaceuticals are sensitive to silicone oil, a
material commonly used to lubricate elastomeric components so they will track properly on
pharmaceutical filling lines. Component lubricity also facilitates the insertion of stoppers into
vials and plungers into syringes.

Fluorocarbon films on stoppers and plungers provide needed lubricity and create a chemically
inert barrier between the component and the packaged drug. Fluorocarbon films thus serve as
both lubricant and a barrier to improve compatibility between the drug and the rubber closure.
Extractables and leachables can be released into a drug product from a container closure system,
other packaging materials or from the processing equipment.

These chemical entities may have a direct effect on the patient by being toxic, carcinogenic or
immunogenic. They may also indirectly affect the quality of the drug product by introducing
impurities that alter physicochemical properties of the active pharmaceutical ingredient. For
these reasons, extractables and leachables pose significant safety risks for patients and could
result in product recalls or misdirected clinical trials. It is essential to develop appropriate
methods for the detection and continuous monitoring of these compounds and to establish
appropriate acceptance limits.

Leachables are chemical entities that migrate under normal conditions from a container closure
system and other packaging components under recommended conditions of product use and
storage. Extractables, unlike leachables, are generated under extreme temperature and time
conditions in the presence of an appropriate solvent (e.g., polar and non-polar organic solvents,
purified water). Leachables are often a subset of extractables; however, they can also be derived
by chemical modification (e.g. degradation) of extractables.

Evaluation of extractables is considered an essential step in the accurate prediction of leachables,

and in the selection of an adequate container closure system for a drug product. The interaction
of the drug product, the packaging components, manufacturing process, product quality attributes
and storage conditions (e.g., temperature and duration) is critical in determining an extractables/
leachables profile.
Chemical leaching is often detected during product storage and
rarely at the time of release. This emphasizes the need for
comprehensive stability protocols that not only evaluate typical
product quality attributes, but are also capable of detecting
potential leachables. The potential impact of extractables on drug
products is significant, especially with sensitive biopharmaceutical
drug products that may contain extremely small amounts of active
ingredient.

Perhaps more important than these materials’ toxicology is their

potential to elicit serious immunologic responses, even at minute During Phase I, a sponsor
dosages. company should begin
screening for vial closure
Fluorocarbon film protects against extractables
designs and materials. By
Phase II, sponsors should
Fluorocarbon films provide a barrier to protect the drug product
against extractables from the elastomeric material, thereby begin developing precise,
minimizing leachables. When applied to stoppers or plungers, validated methods for
fluorocarbon films significantly reduce adsorption of the drug onto determining extractables
the stopper, which is critical for maintaining the product’s potency and leachables.
and shelf-life. In addition, fluorocarbon films provide lubricity to
enhance performance on pharmaceutical filling lines without the
need for free silicone oil, a potential source of particulate contamination.

The cost of selecting an inappropriate packaging and administration system can be high.
Problems discovered during the drug development process can lead to delays. Problems
discovered after the product is marketed can lead to an expensive recall and may affect the
public’s confidence in the company. Because the stakes are so high, biopharmaceutical
manufacturers should have a development plan for primary packaging.

This activity is frequently contracted out to firms that specialize in packaging components. Even
if the effort is conducted in-house, team members should work closely with experts who have
specialized knowledge of packaging and administration systems for biopharmaceuticals.

During Phase 1 drug product development, the team should begin screening closure designs and
materials for their drug product. By Phase 2 – or earlier if possible – sponsors should develop
precise, validated methods for determining extractables and leachables. When method
development and validation is completed, testing is carried out using samples stored under in
accordance with International Conference for Harmonization (ICH) guidelines.

Problems may also arise when a contract manufacturer recommends components solely because
they have been validated with the contractor’s filling line. Components must be qualified with
the drug product first, and then with the filling machinery. Requirements for lyophilized drugs
Many biopharmaceuticals come to market in lyophilized form, which presents specialized
process and packaging requirements.
The elastomers used to manufacture stoppers and syringe plungers adsorb and desorb water at
varying rates. Under storage conditions, components that were not properly dehydrated can
release water into the lyophilized product, affecting product stability over time. This can be
especially problematic with lyophilized biopharmaceuticals, which tend to have very small cake
weights when compared with traditional pharmaceuticals following lyophilization.

Because their weight is often in the range of milligrams or less, these cakes are significantly
more sensitive to moisture, pH changes and extractables that migrate from the closure. A small
difference in moisture in the lyophilization cake can make the difference between an active and
denatured protein. Further, pH differences may be caused by contaminants and can seriously
affect protein structure and activity. Fluorocarbon films, because of their barrier properties, can
help reduce the potential of the stopper or syringe plunger as a source of leachables that could
impact pH. Glass vials, however, can also leach ions that can impact pH.

Minimizing risk

Drug developers who underestimate the impact of the packaging and administration system on
their biopharmaceutical products are assuming an unnecessary level of regulatory and product-
related risk. The high value of biopharmaceuticals, coupled with injectible delivery in most
cases, demands a high level of awareness of primary packaging, even in the early stages of drug
development.

Developers should consider a fluorocarbon film for the stoppers and syringe plungers used to
package and administer their drug. Given the long development times and consequences of
selecting inappropriate packaging and administration systems, such measures are prudent and
will lower costs in the long run.

Identification and Risk-Assessment of

Extractables and Leachables
Mass spectroscopic identification

As mentioned previously, mass spectrometry is a powerful tool for structural elucidation. Still, it
is not always possible to make an indisputable identification of every peak (or compound)
detected. Each of the different mass spectrometry techniques has its advantages and
disadvantages. GC–MS data consist of fingerprint patterns that can be compared with large
databases of organic compounds. Identification often can be performed with a high degree of
confidence, and certified standards can be purchased for confirmation. The compounds amenable
to GC, however, only make up a minority of the possible organic compounds that may be present
in a component. Furthermore, some classes of compounds such as alkanes yield very similar
fingerprint patterns or fragments, and thus a specific molecular entity cannot be identified.

LC–MS data typically only provide a few ions, not a fingerprint pattern as those observed with
GC–MS. Other advanced techniques such as tandem mass spectrometry (MS–MS) and TOF can
provide more information such as molecular fragments and accurate mass. Database matching,
however, is not achievable as it is with GC–MS. Orthogonal approaches such as nuclear
magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy also can be used
to try to solve this sometimes complex puzzle.

At some point, the toxicologist should perform a risk assessment. These other analytical
techniques can be time-consuming and expensive and do not always yield answers. Sometimes
the data must be looked at from a different perspective. For example, an extractable is detected at
50 ppb from a component sample exposed to a strong solvent at high temperature for an
extended period of time. The drug product is formulated in an aqueous buffer, exposed to this
component for a relatively short amount of time, and must be kept refrigerated. Therefore, the
extractable would probably not leach into the final product. The effort put into method
development, analytical testing and identification must be weighed against the risk.

Conclusion

Qualification and quality control of components that come into contact with the drug formulation
is an integral part of any US Food and Drug Administration application. Therefore, extractable
and leachable issues should be investigated and resolved early in the process. For a successful
study, it is imperative that the component vendors, laboratories, toxicologists, and the regulatory
agency have open, effective, and timely communication. As new delivery devices, disposables,
and medical devices are developed, it is certain that FDA will continue to demand information
about these components so that the agency can make informed decisions on risk and safety.