Extractable and leachable studies
Extractable and leachable studies are designed to identify chemicals released or migrated from product or packaging components,
such as rubber, plastic, and glass under various conditions of normal use. Extractables and leachables maybe composed of both
organic substances (packaging raw materials, additives, stabilizers, accelerants, breakdown and reaction products) and inorganic
substances (metal oxides, acids, etc.). These studies are performed on inhalation devices; injectables; implantable devices;
ocular and nasal delivery systems; primary, secondary, and tertiary packaging components; and other products (27).
The presence of extractables is determined through artificial means. Extractable testing studies are recommended even if containers
or closures meet compendial suitability tests. Extensive testing for extractables should be performed as part of the qualification
of the container-closure components. Package component fabricators test for extractables from their materials as part of their
own development and qualification operations. Testing under stressed conditions should demonstrate that the extractable profile
is within acceptable limits for the specific dosage form and that levels observed will not be approached or exceeded during
the shelf life of the drug product (5). More importantly, leachables tests are carried out at the point of use on the actual
drug product. The goal of such testing is to determine that package materials are generally safe, compatible with a given
dosage form, and present an acceptable risk of contamination for particular products (16). Various phases of study include
- Extractable characterization (or controlled extraction study)
- Extractable method optimization
- Extractable method validation
- Routine extractable testing
- Leachable method development
- Leachable method validation
- Leachable testing (stability testing).
Studies are normally conducted in phases that maybe separated by long periods of time, during which, analysis, data reduction,
and risk assessment are performed (10).
"Extractable characterization is the first and probably the most critical one because all other decisions and testing are
based upon it. This process starts with gathering of information and continues with the profiling and characterizing the extractables.
In general, preparation requires both nonpolar and polar solvents. The instrumentation employed includes high-performance
liquid chromatography-photo-diode array detection-mass spectrometry (HPLC-PDA-MS) for organics analysis; gas chromatography-mass
spectrometry (GC-MS) for organics analysis; inductively coupled plasma-optical emission spectroscopy or mass spectrometry
(ICP-OES or ICP-MS) for metals analysis; and sometimes ion chromatography (IC) for inorganics and ion analysis. These techniques
are complementary and provide a wealth of information needed to profile the extractables and leachables that may come from
the packaging component(s)" (11).
"Mass spectrometry is used because it is a powerful tool that elucidates structure. Once the extraction profile is established,
it is crucial that the toxicologists review the data, perform risk assessment, and propose maximum levels based on the total
daily intake defined by the product dosing. After extractables have been characterized and qualified, the analytical methods
are optimized and validated for the compounds of concern. Then, these methods are used for analysis of the components" (10).
Typically, several batches of components are tested, and suitable specifications are proposed for controlling consistency
in the quality of these materials. Once appropriate components are chosen, analytical methods for leachables in the drug product
are developed and validated. Samples of the drug products, which have been in contact with the components for an extended
length of time, are tested. In case such samples are not available, the drug product and component are stressed under appropriate
conditions to generate the leachables. The leachables maybe the same compounds as those identified during extractable studies
or their chemical identity maybe different from the extractables because of drug product interaction. All major compounds
and target compounds that do not have origins in the drug substance or excipients are identified and quantified. These goals
can be accomplished by making a formulation in an inert glass container to exclude the leachables originating from the components
In spite of numerous problems due to leaching, there is also a silver lining. Leaching is being utilized for active packaging
for numerous applications such as antioxidant release from waxed paper packs for breakfast cereals or for release of antimicrobial
agents from wrapping films for preservation of food items (34).
Extractables and leachables are increasingly becoming a cause of major concern for both pharmaceutical industry and regulatory
bodies. The presence of extractables and leachables in the drug product can adversely affect both safety and efficacy. Therefore,
extractables and leachables issues should be investigated and resolved in the early stages of the drug development process.
It has never been more crucial than it is currently, as FDA is seeking more and more information about each and every packaging
component as well as its potential to interact with the drug. A complete characterization is also necessary because extractables
and leachables may have adverse impact on product quality by affecting toxicity or interfering with the desirable characteristics
of the formulation by reducing the potency of the drug, changing the solubility of the drug in the formulation, or causing
other undesirable effects. A systematic and comprehensive approach is the need of the hour for identifying, quantifying and
minimizing impurities emanating from extractables and leachables.
Poonam Kushwaha is a lecturer of pharmacy at Integral University, Lucknow, INDIA, and A. K. Madan* is dean of Pharmaceutical
Sciences at M. D. University, Rohtak-124001, India, +91-9896346211, firstname.lastname@example.org
*To whom all correspondence should be addressed.