Extractables and Leachables: An Overview of Emerging Challenges

Extractables and leachables are a growing concern for pharmaceutical manufacturers and regulatory bodies. The development of unique packaging, novel formulations and delivery systems, and drug-coated medical devices has exacerbated this issue due to the growing possibilities of foreign materials coming into contact with drug products.

In the pharmaceutical industry, it is essential that a selected package adequately preserves the integrity of a product. But sometimes the packaging of pharmaceutical dosages forms can invalidate the most stable formulation. The selection of a package therefore begins with a determination of the product s physical and chemical characteristics, its protective needs and its marketing requirements (1, 2). Proper packaging maintains the integrity of a drug contents and preserves product ingredients at their listed concentrations until the expiration date, maintains the original purity of the drug, and delivers and dispenses the drug (3). Consequently, it is essential that the choice of the packaging materials for any particular product be made only after a thorough evaluation (2).

Primary container-closure systems, as well as other packaging components, have the potential to interact with the dosage form. Potential interaction between the drug product and the package has always been an important issue. It has never been more crucial than it is currently, as the US Food and Drug Administration demands more and more information about every packaging component and its potential to interact with the drug product. Interaction happens mainly in two ways: leachables from the package can get into the drug product, causing contamination, or the drug can be absorbed by the package, causing the package to compromise its barrier characteristics or the drug to lose some of its potency (4).

Packaging regulations and guidances

Factors that must be considered in evaluating container-closure systems are materials of construction of the systems, surface treatments and/or processing aids, dosage form active ingredients and excipients, sterilization and/or other related processing, and storage conditions (5). A number of regulatory guidances address the evaluations of packaging and delivery systems for pharmaceutical drug products (see Table I). These include those issued by FDA's Committee for Proprietary Medicinal Products (CPMP) and documents related to topics on the development of pharmaceutical packaging components (6).

Table I: Regulation for extractables and leachables in materials and components

The United States Pharmacopoeia (USP) and FDA have been and continue to be the driving force behind the safety evaluation of materials and container-closure systems in the US. An important step in such evaluations is characterizing the materials and the chemicals that can migrate or extract from container-closure system components to the drug product. Such basic information is critical to understanding the biological safety and suitability of a container.

A number of tests can be used to establish initial qualification of the container-closure system, and a quality-control plan can help ensure compatibility and safety. FDA's guidance document requires evaluation to establish suitability: protection, compatibility, safety, and performance/drug delivery. This document also provides a structured approach to ranking packaging concerns according to the route of drug administration and likelihood of packaging component-dosage form interaction. A container-closure system found acceptable for one drug product cannot be assumed to be appropriate for another. Each product should have sufficient information to establish that a primary container and its components are right for their intended use (7).

FDA's requirements, as spelled out in the guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics, describe understanding the levels of extractables and leachables, the test methods related to these contaminants, and other considerations relating to packaging components (8). This guidance also addresses the review and evaluation of packaging requirements. According to this document,

"each new drug application (NDA) or abbreviated new drug application (ANDA) should contain enough information to demonstrate that a proposed container-closure system and its components are suitable for its intended use. The type and extent of information required will depend on the dosage form and route of administration. Qualification and quality review is applied to packaging materials and to the actual dosage form. Packaging suitability is based on four attributes: protection, safety, compatibility and performance (function and/or drug delivery). For injectable dosage forms, the document outlines the tests required to show that interaction is not a problem. Associated components, such as those used only at the time a dosage is administered, self-adhesive labels and secondary packaging materials are also included in the review process" (5, 9).

The guidance also specifies that:

"... packaging components should be constructed of materials that will not leach harmful or undesirable amounts of substances to which a patient will be exposed when being treated with a drug product. These applications should contain an extraction study on the packaging component to determine which chemicals and/or residues may migrate into the dosage form, and second a toxicological evaluation of the substances..." (9, 14).

Drug manufacturers invest a tremendous amount of time and money to identify, quantify, and minimize impurities related to their drug products so that FDA can make appropriate decisions regarding drug product purity and safety. An area of increasing concern and scrutiny for FDA's Center for Drug Evaluation and Research (CDER) is the potential adulteration of drug products by extractable and leachable compounds that enter a drug product from a container, closure system, disposable, or device (10, 11).

Addressing this concern, 21 CFR 211.94(a) states: "Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirement" (11, 12). In addition to FDA's 21 CFR 211, regulations governing primary packaging are contained in the FDA guidance, Container Closure Systems for Packaging Human Drugs and Biologics—Chemistry, Manufacturing and Controls Documentations, and the United States Pharmacopoeia's General Chapter 25 (9, 12, 13).

In May of 2005, the European Agency for the Evaluation of Medical Products (EMEA) issued the Guideline on Plastic Immediate Packaging Materials, which indicates that

"the aim of extraction studies is to determine those additives (such as antioxidants, plasticizers, catalysts, initiators, etc.) that might be extracted by the active substance in contact with the plastic material. Extraction studies are considered necessary for plastic materials used for container systems of nonsolid active substances and nonsolid dosage forms."

EMEA specifies that interaction studies between the plastic packaging material and the active substance should be evaluated. In addition, migration studies are deemed "necessary when extraction studies have resulted in one or several extractables" (14).

The qualification and quality control of all components coming into contact with the drug formulation has become an integral part of any FDA application process. Investigation of potential extractables and leachables must be carried out under International Conference on Harmonization (ICH) and USP guidelines in a current Good Manufacturing Practices (CGMP)-compliant laboratory. These activities may be very time consuming and require a wide array of analytical techniques and expertise (6, 10, 11, 14).

By using clean raw materials with minimal processing additives, extractables and leachables are minimized. FDA levels of concern for extractables and leachables vary for different pharmaceutical products, depending on the route of administration and the dosage form. As the level of concern increases, so do the requirements for characterizing extractables and leachables (10).

Inhalation and injectable drug products have stringent requirements. There are product-specific draft guidelines for metered dose inhalers (MDIs), dry powder inhalers (DPIs), nasal sprays, inhalation solutions, suspensions, and sprays. The identity and concentration of leachables in inhalation and nasal drug products must be monitored throughout the products' shelf life since the product consists of the dosage form and the container/closure system (6).

FDA's interest in this area is believed to be in response to a particular incident in the late-1990s in which an MDI was found to contain harmful leachables (15). Leachables in inhaled drug products tend to arise from polymers, elastomers, adhesives and curing agents, metal components, dyes and pigments, and mold release agents (17, 20). In another case, the supplier of the rubber O-ring in a device wasn't accustomed to the standards of the pharmaceutical industry and formulated the rubber using some polynuclear aromatics (PNAs), creating a health risk. Since then, the agency has asked for more analysis with submissions (15). Some other cases are reports of PNAs in elastomers, PNAs in MDIs, volatile N-nitrosamines were reported to be present in baby bottle rubber nipples, and mercaptobenzothiazole (2 MBT) in elastomers (20, 33).

Extractables and leachables in container-closure systems

All primary package components contain constituents such as ingredients, impurities, contaminants, and degradants that have the potential to accumulate in the product. These constituents are typically referred to as extractables or leachables. They may also include compounds present on the surface of the packaging that simply solubilize in the product. In pharmaceutical products, the extractables from the container-closure system and the components of the container-closure system that can leach into the product formulation are important to understand (23). See Table II for a list of common extractables and leachables.

"Extractables are compounds which can be extracted from the container/closure component under extreme conditions such as the presence of harsh solvents or elevated temperature. These compounds can contaminate the drug product. Leachables are compounds that are released into the drug product from the container/closure component as a result of direct contact with the drug product under normal conditions^" (11).

Table II: Common extractables and leachables

Extractables are chemical species released from a primary container or component material that has the potential to contaminate a pharmaceutical product. Extractables are frequently generated by interaction between products and their packaging over time, depending on solvent and temperature conditions. The organic chemical entities into the drug product. Fortunately, information on potential leachables maybe obtained from the known ingredients of the rubber and plastic materials, as well as the fabrication process of the valve (16). For example, thiurams, dithiocarbamates, and mercaptobenzothiazoles are commonly used sulfur-containing curing agents in rubber manufacturing, hence, they are potential leachables in the drug product where sulfur-cured rubber is used. Polybutylene terephthalate (PBT) is a widely used polyester plastic in medical device and MDI valve components. PBT oligomers and other residuals or degradants can be similarly leached from the valve components fabricated from this material (19).

Sources of extractables and leachables

Sources of these compounds include plastic components, elastomers, coatings, accelerants, antioxidants, inks, colors, and vulcanizing agents. Phthalates are one specific example. These carcinogens are added to plastics to make them more flexible and can be found throughout the manufacturing process and in packaging materials. Other examples are nitrosamines and polynuclear aromatic hydrocarbons (PAHs), which are classes of carcinogenic compounds found in rubber (17). Many drug products are distributed or administered in packages made of plastic and rubber components, and, therefore, phthalates, PAHs, or nitrosamines could potentially come into contact with the drug product and be passed on to the patient. MDIs, DPIs, and nebulizers can be complex because they may be constructed from a myriad of plastic, rubber, and stainless steel components. Nevertheless, these devices have many advantages (e.g., rapid absorption and onset of activity and reduced dosing) for effective drug delivery (18).

Extractables and leachables can have considerable influence on the efficacy and safety of drug products, especially highly active biopharmaceutical drug formulations, which may contain extremely small amounts of the active ingredient. Perhaps more important than the toxicology of such materials is their potential to elicit serious immunologic responses, even at extremely small dosages. Extractables and leachables pose problems at every stage: they may interfere with drug product assays, or medical diagnostic tests; they may increase the impurity level of a drug product to an unacceptable level; and they may react with one or more drug product components (18).

Materials used for container-closure systems

The materials most commonly used as primary-container components for pharmaceutical preparations include glass, metal, plastic and rubber. Out of these four materials, glass has been the primary container of choice for pharmaceutical dosage forms owing to its relative inertness and availability of glass in various compositions for different purposes. The excellent barrier characteristics of glass render it as an ideal packaging material for parenteral/liquid products. Glass

has normally been considered far less reactive than plastic with regard to parenteral/liquid products. It also has much lower levels of leachables and extractables. Glass exhibits numerous advantages over other packaging materials, and the problem of release of alkali and flakes is mainly confined to lime-soda glass.

The stability of numerous drugs can be adversely affected by the release of soluble alkali from the glass containers. As a matter of safety, liquid preparations maybe buffered to eliminate or minimize any adverse effect due to possible change in pH following release of alkali from the glass container. Release of alkali from borosilicate glass is negligible but it is relatively expensive. Sometimes, insoluble flakes have been found to appear in solutions stored in glass containers. Flake formation may occur in non-borosilicate glass immediately after autoclaving, whereas in borosilicate glass, it occurs at temperatures much higher than those used for autoclaving. Pure glass that is made from silicon dioxide alone is known for its inertness, but its high melting point and excessive cost prohibit its use in packaging. Several manufacturers produce glass containers in various formulations that comply with USP Type I requirements. Compendial standardization of Type I glass facilitates ease in any necessary vendor changes even after market approval. [1, 2, 22].

Plastics are the fastest growing segment in packaging and have already captured market shares from all other packaging materials, converting glass bottles to plastic bottles, paper bags to plastic bags, fiberboard boxes to plastic wraps, and steel drums to plastic drums. Plastics are synthetic high-molecular-weight polymers of diverse nature, and a wide range of plastics is currently in use. High strength and thin walls amalgamated with low density and transparency render plastics increasingly popular owing to their capacity to withstand mechanical shocks. This leads to steep decrease in breakage losses during routine handling and transportation when compared to glass. Plastic containers, closures, and films generally use less material, are less costly to fabricate and weigh less, thus reducing cost of transportation and handling.

Some of the plastics that are currently in use include: polythene, polypropylene, polystyrene, polyvinylchloride, polyamide, polycarbonate, polytetrafluoroethylene (PTFE), phenol-formaldehyde, urea-formaldehyde, melamine-formaldehyde and several others. Moreover, availability of numerous plastics of diverse nature provides ease in formulating packages of desired flexibility, rigidity, and other characteristics. As a consequence, plastics packages range from flexible packages such as collapsible tubes, strip packs, blister packs, pouches, and stand-up pouches for injectables, to rigid containers meant for solid, semisolid, and liquid products.

A wide range of additives such as plasticizers, lubricants, anti-static agents, antimicrobial agents, antiblocking agents, colorants, antioxidants, coupling agents, flame retardants, impact modifiers, fragrance enhancer agents, nucleating component materials that have potential extractables include glass, plastic, rubber, labeling and bulk packaging and process equipment. Each material or area has factors that can affect the extent of the extractables (5, 6,8, 10, 11, 17, 18).

Certain approaches can help minimize concerns emanating from extractables. The data generated by extractables screening during initial package selection and compatibility studies can be used to help select an appropriate container closure for a drug product. However, low extractables do not ensure compatibility, and compatibility does not ensure low extractables. Both should be assessed as part of a drug product market introduction (6).

Leachables are chemical species that migrate from packaging or other components under normal conditions or use or during the shelf life of a drug product. Extractables are the most common source of leachable contamination arising from a product formulation's contact with its package materials (5,6,10,11,17).

Leachables can be regarded as subsets of extractables (11). These impurities are released from container, closure, and packaging components into the drug product (See Figure 1). Leachables can be found in a variety of drug products, including orally inhaled and nasal drug products (OINDPs), injectables, solid-dosage forms, etc., and they include both organic and inorganic chemical entities. Organic leachables can be monomers or oligomers of the polymeric material, or additives, cross-linking or curing agents, antioxidants, plasticizers, pigments, lubricants, and mold release agents, etc., that are used in the manufacture of the container, closure, and packaging materials. Labels, inks, and adhesives can also leach impurities into the drug product (19, 29). Leachables include both soluble and insoluble chemical entities.

Figure 1. Examples of leachables derived from packaging components

Identification of leachables can be a significant analytical challenge for some dosage forms. For example, in an MDI, the rubber and plastic components of the metering valve are in direct, constant contact with the formulation, which is primarily a propellant, such as a chlorofluorocarbon (CFC) or more ozone-friendly hydrofluoroalkane (HFA), which are both good organic solvents. It is anticipated that these plastic and rubber valve components in the MDI will leach various agents, and ultraviolet stabilizing agents are being incorporated in plastics to obtain container-closure systems of desired characteristics. However, presence of large numbers of ingredients in the plastic container-closure systems pose a serious problem with regard to leaching and sorption.

Because both the drug product and plastic container happen to be formulations, therefore, contact between these two formulations can naturally lead to leaching, sorption and chemical interaction. Problems arise with increasing number of components. This necessitates thorough study of the stability and compatibility of the primary plastic container with the drug product for which it is to be used. A major disadvantage of plastic containers when compared to the glass is the problem of permeability, which may result in loss of component(s) of drug product by volatilization or sublimation, or may facilitate degradation of drug product by allowing contact with atmospheric oxygen or moisture. Materials leached from the primary plastic container or closure into a liquid preparation leads to contamination. Similarly, any component(s) from the drug product can be adsorbed onto or absorbed into primary plastic container or closure system with a possibility of a chemical or physical reaction. The extent of permeation, leaching, sorption, diffusion, and chemical reactivity naturally varies considerably from one plastic composition to another (1, 2, 30, 31).

With few exceptions, compendial standardization of plastics for parenteral product packages does not exist. Therefore, each potential vendor's plastic components must be demonstrated to be compatible with drug product through extensive stability studies (22).

Apart from glass and plastic, certain metals are also being used as primary containers or closures for drug products. Numerous semisolid products such as paste, gel, cream, or ointment can be conveniently packaged into metallic collapsible tubes. Metallic containers and cans are also being used for aerosols and other liquid products. Metals commonly used are tin, plastic-coated tin, tin-coated lead, aluminum, coated aluminum for collapsible tubes, and aluminum- and tin-plated steel for cans/aerosol containers. Single material tubes/cans can be readily tested for stability with drug products. The steel container is not chemically inert and, therefore, can react with environment and its contents. Steel's major ingredient, iron, is a chemically active metal which readily takes part in reactions involving water, oxygen, acids, and other reactive elements or compounds. Though the application of tin to the surface of steel significantly improves its resistance, the potential for corrosion or chemical attack still persists. However, coated tubes/containers present additional problems because any absence of continuity, as well as inertness of the coatings, may lead to chemical interaction or leaching. Moreover, coating should exhibit resistance towards cracking and solvent(s) (1, 2, 32).

Natural and synthetic rubbers of varying compositions are being widely used in pharmaceuticals and allied products as stoppers, cap liners, and parts of dropper assemblies.

The major problems involving use of rubber closures in direct contact with the liquid in the vial pertain to the sorption of active ingredient, preservatives or other substances into the rubber and the extraction of one or more components of the rubber into the vial solution. The presence of rubber extractives in the product could interfere with the chemical analysis of the active ingredient, affect the toxicity or pyrogenicity, interact with the drug or preservative to cause inactivation or loss of stability or sterility, and cause physical instability to the preparation owing to the presence of particulate matter in the solution.

Fluorocarbon film coatings provide the best combination of protection against extractables from stopper materials while providing a high level of barrier protection for drug products, therefore minimizing leachables concern. When applied to stoppers, fluorocarbon films significantly reduce a drug's adsorption on them, which is critical for maintaining potency and shelf life of the product. Moreover, fluorocarbon films provide additional lubricity for proper vial seating without the need for silicone oil. Fluoroelastomer films made from highly inert materials significantly reduce the possibility of extractables migrating from rubber stoppers into the biopharmaceutical product formulations (1, 2, 8, 24, 25).

"The quality of the rubber components used in prefilled syringes is of vital importance for not only ensuring the functionality of the syringe but also for the shelf life of the product. The rubber composition must have an excellent extractables profile in order to ascertain product quality and efficacy over its intended shelf life. The latter is even more important for prefilled syringes since they usually present a larger rubber surface to product volume ratio than corresponding vials. Pharmaceutical rubber components are increasingly supplied as Ready-for-Sterilization (RfS®), washed and rinsed with WFI and packed in special bags so as to facilitate sterilization by the user without any pre-treatment" (24).

During the past few years, the requirements for the assessment of substances that could leach into the drug product during the course of its life cycle have increased considerably. The kind of leachable one would have to look for can vary from organic oligomers and catalyst residues to heavy metals. Due to the resulting complexity, it is very important to consider the potential risk at a very early stage in process development. Packaging materials have been in the focus for such investigations for a considerable period as the contact period between drug product and packaging material is rather long. Leachables and extractables testing will become a cause of major concern (26).

Industry response

Numerous guidelines mention the appropriate evaluation of packaging components. These guidelines recommend that the safety and compatibility of the dosage form with the primary container-closure system are established early in the drug development process. Specific focus is on the potential for drug or biologic interaction with the container or closure because of leaching or absorption. Industry-based working groups have been established to assess extractable concerns and other scientific issues. The Product Quality Research Institute (PQRI) was established to conduct research that generates scientific information to support the development of regulatory policy. It is driven by its member organizations which include the American Association of Pharmaceutical Scientists (AAPS), the Pharmaceutical Research and Manufacturers Association (PhRMA), the Generic Pharmaceutical Association (GPhA), the Parenteral Drug Association (PDA) and FDA's CDER (11). PQRI serves as a vehicle for FDA, industry and academia to collaborate on key issues in pharmaceutical product quality through research and expert analysis (5).

Another industrial group, the International Pharmaceutical Aerosol Consortium on Regulation and Science and the Inhalation Technology Focus Group of AAPS developed a 'points to consider' document in reference to leachables and extractable testing as defined in the MDI/DPI draft guidance and the nasal spray/inhalation solution draft guidance. It has recommended establishment of identification and qualification thresholds for extractable and leachables, along with other suggested points clarification (5, 16).

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 (10, 11):

• 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).

Study design

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 (10, 11).

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).

Conclusion

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, madan_ak@yahoo.com

*To whom all correspondence should be addressed.

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30. D. Twede and T.W. Downes, "Economics of Packaging" in "The Wiley Encyclopedia of Packaging Technology", Edited by A.L. Brody and K.S. Marsh (John Wiley & Sons, Inc., New York, Second Edition), pp 325-331.

31. D.V. Rosato, "Additives, Plastics" in "The Wiley Encyclopedia of Packaging Technology", Edited by A.L. Brody and K.S. Marsh (John Wiley & Sons, Inc., New York, Second Edition), pp 8-13.

32. F.J. Kraus and G.J. Tarulis, "Cans, Steel", in "The Wiley Encyclopedia of Packaging Technology", Edited by A.L. Brody and K.S. Marsh (John Wiley & Sons, Inc., New York, Second Edition), pp 144-155.

33. A. L. Schroeder, "Leachables and Extractables in OINDP—An FDA perspective" in proceedings of PQRI L/E workshop, Dec. 5-6, 2005.

34. M.L. Roony, "Active Packaging", in "The Wiley Encyclopedia of Packaging Technology", Edited by A.L. Brody and K.S. Marsh (John Wiley & Sons, Inc., New York, Second Edition), pp 2-8.