USP Plastic Packaging General Chapters: An Overview

Transcription

1 USP Plastic Packaging General Chapters: An Overview Dennis R. Jenke a and Daniel L. Norwood a a Packaging, Storage, and Distribution Expert Committee, USP. ABSTRACT The purpose of this Stimuli article is to provide an overview of the official or planned general chapters in a suite of Plastic Packaging General Chapters in the United States Pharmacopeia (USP). Together these chapters are designed to delineate a general and chemistrybased approach for establishing the safety and quality of packaging systems and their materials of construction for pharmaceutical products. Key topics discussed include a) the selection of suitable, safe plastic materials of construction; b) the importance of characterizing both the materials of construction and the packaging system; and c) extractables and leachables. The various USP chapters discussed are based on the concept that the most definitive way to establish the packaging system s suitability for use with a particular pharmaceutical drug product is to test the packaged drug product, the packaging system and the packaging system s materials of construction and obtain evidence that any interaction, potential or real, between the drug product and the packaging system is within acceptable limits. INTRODUCTION The stated mission of the United States Pharmacopeial Convention (USP) is To improve global health through public standards and related programs that help ensure the quality, safety and benefit of medicines and foods. USP accomplishes this mission by publishing monographs and referenced general chapters with allied reference materials (standards) that include tests, procedures, and acceptance criteria. The published test procedures provide definitive results for food and drug articles under evaluation; such results are used to support accept/reject decisions. The Packaging, Storage, and Distribution Expert (PSD) Committee in USP s Council of Experts is responsible for developing and revising USP standards related to packaging. During the revision cycle, the Expert Committee has worked to delineate a general chemistry-based approach for establishing the safety and quality of packaging systems and their materials of 1

2 construction. The purpose of this Stimuli article is to provide insights into and explanations for the content of the following revised and new general chapters: <661> Plastic Packaging Systems and Their Materials of Construction; <661.1> Plastic Materials of Construction; <661.2> Plastic Packaging Systems for Pharmaceutical Use; <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems; <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems; and <1664.1> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems: Orally Inhaled and Nasal Drug Products. These General Chapters appear in PF 39(5) [September- October 2013]. Many pharmaceutical products and their ingredients are manufactured, packaged, stored, delivered, and/or administered using packaging systems. Interactions between the products and/or ingredients and their packaging systems can affect the quality of the product, or less frequently, the quality of the packaging systems themselves. These interactions are either additive, reductive, or transformative. If the interaction is additive, a constituent of the packaging system is added to the product due to the interaction. If reductive, a product constituent is reduced, in either level or action, due to its uptake into the packaging system. If the interaction is transformative, the product is transformed (for example, loss of stability) due to a physicochemical interaction with the packaging system. An additive, and sometimes transformation, interaction can reflect a single physicochemical process where extractables, organic and/or inorganic chemical entities, migrate out of the packaging system and accumulate as leachables in the product. Leachables in a pharmaceutical product can affect safety and/or efficacy. Regulatory guidances on this subject include recommendations for the chemical 2

3 analysis and the toxicological safety assessment (qualification) of leachables (1-4). The combination of chemical analysis and impact assessment establishes that a packaging system is suited for its intended use. To comply with regulations and to establish the quality and safety impact of a packaging system, numerous medical polymers and elastomers have been characterized for their extractable substances. Similarly, many pharmaceutical products have been characterized for polymer- and elastomer-related leachables. The scientific and practical issues associated with chemical safety assessment in general, and extractables or leachables in particular, have been enumerated, considered, and discussed (5,6). Nevertheless, consistency in the design and execution of the various chemical assessment studies is sometimes lacking. While the studies are driven by the general principles of good science, it is not clear which principles and practices establish or otherwise reflect good scientific methods, processes, and practices. GENERAL PRINCIPLES Packaging systems are constructed from materials of construction that can interact with a pharmaceutical product that contacts these systems at some point during manufacturing, storage or administration. In general, the materials of construction most commonly utilized in these systems include glass, metals, plastics and elastomers. Thus standards that address the safety and efficacy impact of interactions between packaging systems and pharmaceutical products they contact must consider these diverse materials of construction and should include relevant and appropriate test methods and specifications for these materials. The PSD Expert Committee is currently focusing on revising General Chapter <661>. This is necessary and appropriate as (1) <661> has historically been linked to plastic materials and systems, and (2) USP has individual 3

4 general chapters that deal with the other materials of construction (for example <381> Elastomeric Closures for Injection, <660> Container Glass, and <662> Containers Metal (which is under development)). Thus, this Article, which is focused on the <661> revision, addresses plastic packaging systems and plastic materials of construction to the exclusion of the other materials of construction. This Article also discusses general chapters on extractables and leachables <1663> and <1664> series specifically. While <661> focuses on plastics, <1663> and the <1664> series are relevant and applicable to all packaging systems, regardless of their materials of construction. Plastic materials of construction are generated from reagents that are reacted to produce a base polymer, which is then compounded with various additives to produce a base resin. Individual base resins are combined with additional additives and processing aids to form a specified plastic material of construction. Individual plastic materials of construction are combined to form components of the packaging system, which is completed by assembling its various components into a final form. Assembled packaging systems are filled with a pharmaceutical product by various means and at various points in the packaging system manufacturing process, thereby generating the packaged product. Given the complex nature of packaging systems and their manufacturing processes, multiple testing procedures are needed to establish their suitability for use with a specific pharmaceutical product. Furthermore, simply testing the plastic system itself is not the most effective way to establish its suitability. When considering packaging systems, for example, the single most important step in ensuring that a packaging system is suited for its intended use is to select 4

5 materials of construction which themselves are suited for the intended use in the packaging system. Thus, testing materials of construction for attributes that are relevant to their suitability for use provides a rational basis for material selection in designing a packaging system. Proper selection of materials minimizes the risk that a system made from those materials will be unsuitable for its intended use. Considering safety specifically, selection of materials that have the propensity to be safe will increase the likelihood that packaging made from those materials will be safe. While this reductionist approach is practical and widely applied, a further definitive measure of a packaging system s suitability for use is obtained by testing the packaged pharmaceutical product, looking for evidence that one of the three types of interaction has occurred. Taking these comments into account, an effective and efficient process for establishing a packaging system s suitability for use includes characterization of its materials of construction, characterization of the systems itself and testing of the packaged pharmaceutical product. The intermediate step of system characterization is useful and necessary as it bridges the risk assessment gap between originating materials and finished product testing, and also provides a means for optimizing pharmaceutical product testing. Materials of construction undergo considerable stress, such as exposure to high temperatures, while they are being converted into components of and/or finished packaging systems. Furthermore, processing aids and additional additives may be introduced during the manufacturing process for a packaging system. Thus, the extractables profile of a system is likely to be different from, and potentially more complex than, the sum of the extractables profiles of its materials of construction. Therefore, the initial 5

6 assessment of risk made in material selection is appropriately revisited by testing and qualification of the overall packaging system itself. Information about a packaging system s extractables can be used in several ways to optimize finished product testing for leachables. Consideration of the potential quality and/or safety or impact of extractables may facilitate identification of leachables that might adversely affect product quality. Such leachables of potential concern would necessarily be among the targeted analytes in testing of a final pharmaceutical product either alone or in its packaging system. The targeting of specific leachables, as opposed to the screening of pharmaceutical products for unspecified leachables, has significant analytical benefits, including the ability to develop, validate, and utilize test procedures that are sensitive, specific, and accurate. Further, extractables (and their accumulation levels in extracts) can be predictive of the levels of leachables in the finished product, depending on how well the extraction conditions mimic the pharmaceutical product s actual conditions of clinical use. If the extraction conditions are such that they accelerate and modestly exaggerate the product s clinical use conditions, then the extractables and their levels in the extracts can be extrapolated to estimate the maximum levels of leachables in the finished product. If such extractables are assessed for their safety or quality impact, the results of that assessment can be extrapolated as well to the pharmaceutical product. If no adverse impact is found based on the extractables data, then no adverse impact can be inferred with confidence for the leachables in the pharmaceutical product either alone or in its packaging system. 6

7 This three-step process for the qualification of finished products, packaging systems, and materials of construction has been illustrated in Figure 1, the Chemical Assessment Triad (7). SAFETY AND QUALITY QUALIFICATION OF PACKAGING SYSTEMS In the previous discussion, a three-stage process was established for suitability-for-use assessment of packaging, administration, and manufacturing systems, focusing on safety and quality. These stages included material-of-construction characterization, packaging system characterization, and pharmaceutical product characterization. Although such a process establishes the general strategy for suitability-for-use assessment, it lacks the details which establish how to perform such an assessment. These details are delineated in a comprehensive approach entitled Chemical Assessment of Pharmaceutical Products, Packaging Systems and their Materials of Construction (Figure 2). Via the combination of mandatory and informational General Chapters, the PSD Expert Committee intends to provide a means for qualifying the suitability of use for a plastic system. The purpose of official USP general chapter <661> Containers Plastics is to provide standards for plastic materials and components used to package medical articles (pharmaceuticals, biologics, dietary supplements, and devices). Resin-specific tests for polyethylene, polypropylene, polyethylene terephthalate, and polyethylene terephthalate G are provided in this chapter. Although the chapter has served a useful purpose, it is lacking in its ability to meet the objective of assessing and assuring the safety and quality impact of plastic systems used in the manufacture, packaging, storage, delivery of a pharmaceutical product. The current chapter s shortcomings include the following: 7

8 The test methods and specifications are not necessarily precise and complete indicators, or predictors, of the safety and quality impact of plastic packaging, administration systems, and manufacturing suites. The test methods could benefit from modernization and harmonization. For example, the current chapter addresses elemental extractables via the Heavy Metals test described in <231>, which is being replaced by an instrumental method captured in <232> and <233>. The chapter could be expanded to include additional plastics of pharmaceutical interest. The chapter could be expanded to include plastic pharmaceutical systems other than packaging, such as administration systems, medical devices, and manufacturing suites. Although <661> will remain the chapter that does the heavy lifting in terms of suitability-foruse assessment, it will be revised to address these shortcomings. The proposed revision to <661> consists of subchapters that are relevant for a particular type of test article (materials of construction and/or packaging system). Introductory information contained in <661> is augmented with testing protocols and specifications for Plastic Materials of Construction, <661.1>; Plastic Packaging Systems for Pharmaceutical Use, <661.2>; Plastic Systems Used for Manufacturing Pharmaceutical Products, <661.3>; and Plastic Medical Devices Used to Deliver or Administer Pharmaceutical Products, <661.4>. Of these sections, <661.3> and <661.4> are currently under development and will be published at a later date. As shown in Figure 2, <661.1> serves as the nexus for the other three related chapters (<661.2>, <661.3>, <661.4>), because the suitability for use requirements for plastic materials of construction used in any pharmaceutical application are independent of the application. Thus, when considering a specific material of construction, the safety and quality assessment of the material is addressed in the same manner, regardless of its particular application in a packaging system. Although differentiation between the approaches used to address these different 8

9 applications is ultimately necessary, this differentiation is most relevant and appropriate at the system level. The objective of <661.1> is to provide tests, test procedures and acceptance criteria for plastic materials of construction used in packaging systems for pharmaceutical products. The intent of this testing is to ensure that materials of construction selected for study are well-characterized, because proper characterization of materials of construction facilitates the identification and use of appropriate materials in pharmaceutical systems. Operationally, <661.1> includes separate sections for individual plastic materials of construction used in pharmaceutical systems. Although the test procedures and acceptance criteria for different individual materials will be similar in some ways, e.g., the dimensions or characteristics of the materials that are tested, they could also differ based on the specific material involved. For example, while all individual materials of construction will be tested for extracted metals, the relevant metals to target and their associated specifications may be material-dependent. Plastic packaging systems are specifically considered in <661.2>. This chapter notes that plastic packaging systems for pharmaceutical use must be suitable for their intended use. The applicant who seeks regulatory approval of a packaging system or packaged pharmaceutical product is responsible for establishing that the product s packaging system meets these expectations. These expectations are met and systems are shown to be suited for their intended use by ensuring that the packaging system itself and/or the packaged pharmaceutical product have been appropriately tested. Chapter <661.2> establishes what is meant by appropriately tested, including the requirement that the packaging system has been established to be safe by means of the 9

10 appropriate chemical testing, where appropriate chemical testing could include extractables testing, leachables testing, and appropriate toxicological assessment. Although <661.2> refers to extractables and leachables testing and toxicological assessment, it does not provide details or insights into how such testing or assessment is performed. Rather, the PSD Expert Committee has developed and will further develop chapters on these topics. Both <1663> and <1664> present a framework for the design, justification, and execution of either an extractables assessment for pharmaceutical packaging systems or an assessment for a pharmaceutical product s leachables derived from packaging/delivery systems. The chapters establish the critical dimensions for assessment of extractables and leachables and discuss the practical and technical aspects of each individual dimension. Although these chapters are intended to be informational, helpful and generally applicable, they do not establish specific experimental conditions, specific tests, analytical procedures, or acceptance criteria for particular packaging systems or pharmaceutical products. They also do not delineate every situation in which an extractables or leachables assessment is required. Rather, these informational chapters are intended to address the question, If an extractables (or leachables) assessment is required, what are the scientific principles and best demonstrated practices under which it should be accomplished? Accompanying chapter <1664> is <1664.1>, which addresses specific considerations for leachables in metered dose inhalers (MDIs), nasal sprays, dry powder inhalers (DPIs) and inhalation solutions, suspensions, and sprays. Chapter <1664.1> is intended to bring into USP s general chapters specific best practice recommendations of the Product Quality Research 10

11 Institute (PQRI) related to leachables in Orally Inhaled and Nasal Drug Products (OINDP) 8, including the first safety-based thresholds for leachables characterization and safety qualification. Both the extractables and leachables assessments addressed in <1663> and <1664> are exercises in producing analytical data about the composition of an extract or pharmaceutical product. This body of data is not, in and of itself, an indication of the potential safety or quality impact of the extractables or leachables. Rather, these data must be interpreted to infer their safety or quality implications. Thus the PSD Expert Committee plans a general chapter, <1665>, which will address the toxicological safety assessment of extractables and leachables. As was the case with the extractables and leachables chapters, <1665> is expected to provide a framework for performing a toxicological safety assessment, consistent with existing regulatory guidance 9. As with <1663> and <1664>, <1665> is not expected to provide specific protocols or specifications, nor would it delineate every situation in which a toxicological safety assessment is required. However, developments in regulatory requirements or in the theory and practice of toxicological science may facilitate or require such inclusions. Lastly, the PSD Expert Committee recognizes the possibility that establishing the safety and quality of drugs products would be facilitated by testing those products for leachables, and that this requirement could appear in the compendial monographs for a specific drug product. INDIVIDUAL USP CHAPTERS ON CHEMICAL SAFETY AND QUALITY ASSESSMENT: RATIONALE AND DISCUSSION 11

12 <661> Plastic Packaging Systems and Their Materials of Construction The purpose of general chapter <661> is to establish the rationale behind the testing requirements and specifications that appear in its subsequent sections. The overarching issue that is addressed by general chapter <661> in its entirety is established in its Introduction: Therapeutic products come into direct contact with packaging systems and their plastic materials of construction as the product is manufactured, stored and administered. Such contact may result in an interaction between the therapeutic products and the packaging systems and its materials or components of construction. These interactions must be such that the suitability for use (including its safety and efficacy) of the therapeutic product and the packaging systems is not adversely impacted by the interaction. Obtaining such a necessary and desirable outcome is facilitated by the use of well-characterized plastic materials of construction in components, containers and packaging systems and by the appropriate testing of packaging systems. In its section titled Scope, <661> defines the general process by which suitability for use is established. Establishing the suitability of plastic packaging systems for therapeutic products involves multiple tests and testing procedures, as briefly outlined below: material screening: characterization of a packaging system s materials of construction to evaluate ingredients as probable extractables and tentative leachables. Such a characterization facilitates the identification of materials that are suitable for use in packaging systems system assessment: controlled extraction (simulation) study: worst-case controlled extraction (simulation) study to determine the extent to which extractables may become probable leachables product assessment: actual-case measurement of confirmed leachables. Lastly, <661> maps these activities to specific general chapters within the USP-NF: Testing of these plastic materials of construction to establish that they are wellcharacterized and suitable for use in packaging systems is addressed in <661.1> Plastic Materials of Construction. Testing of packaging systems to establish that they are suited for their intended use is within the scope of this chapter and is addressed in <661.2> Plastic Packaging Systems for Pharmaceutical Use. Testing of packaged therapeutic products to establish that they are suited for their intended use is addressed in compendial monographs relevant to the specific therapeutic product and falls outside of the scope of this chapter. 12

13 <661.1> Plastic Materials of Construction GENERAL The basic tenet of this section of <661> is that knowing the general composition and characteristics of a material of construction allows one to: rationally select appropriate materials of construction for use in systems forecast with some degree of accuracy the identity of the extractables from that material of construction and from systems that use that material of construction. Thus, <661.1> defines a well-characterized material of construction as one whose identity has been definitively established; biocompatibility (biological reactivity) has been established; general physicochemical properties have been established; and additives and extractable metals have been quantified (see Figure 3). The intent of <661.1> is to establish the testing that is necessary to characterize a material based on these dimensions (each of which will be addressed in greater detail) and also to provide general specifications that provide some degree of confidence that the materials will not adversely affect the quality and safety of pharmaceutical products that are contacted by the material. <661.1> testing cannot be construed as a guarantee that plastic systems constructed from materials that meet the <661.1> specifications will be suitable for their intended use as it is not always the case that the testing of a system s materials of construction directly and completely translates to testing of the plastic system. Nevertheless, <661.1> testing leverages the logical connection between material additives, material extractables, and system extractables and thus provides a useful indication of the probable suitability-for-use issues for materials and systems. 13

14 Specific test methods and specifications that appear in <661.1> were identified and adopted on the basis of three fundamental criteria: where possible, the tests and specifications should be harmonized with other sources of regulatory guidance (e.g., Pharm. Eur., ISO 10993) where possible, the exact test methodologies should be those that are specified in appropriate compendial sources. While it may be appropriate and necessary to revisit and modify or modernize the test methodologies contained in <661.1>, it was not the purpose of the current revision to both require certain testing and then specify test methodologies that are new in the sense that they do not currently appear in compendial sources. This situation notwithstanding, <661.1> allows for the use of alternate but equivalent test methods and establishes criteria for demonstrating equivalency where possible, the specifications are consistent with those that appear in the appropriate regulatory guidance documents and compendial sources. While it may be appropriate and necessary to revisit and modify or update the specifications contained in <661.1>, it was not the purpose of the current revision to establish specifications that have not already been adopted in regulatory guidelines or compendial sources. IDENTIFICATION Individual materials of construction are classified on the basis of their generic identity, and are covered separately in <661.1>. Each material needs to be classified so it can be tested appropriately and compared with the relevant specifications. This is why identification of materials is a necessary aspect of material characterization. Infrared spectrometry and thermal analysis are the identification methods currently specified in <661.1>; however, alternate methods of identification can be utilized if the alternate methods can be justified and if specifications for the alternate method are provided and justified. Because the sole purpose of identification is classification, the identification only needs to be sufficiently precise to accomplish this objective. Although it is well known that thermal and spectroscopic properties may vary among the individual members of a polymer class (e.g., as a 14

15 function of their absolute composition or method of production), it is typically the case that all members of the polymer class will exhibit behavior that is sufficiently consistent to allow proper classification of the individual member. Thus, while the infrared spectra of plasticized polyvinyl chloride (PVC) materials may vary somewhat depending on the amount of the plasticizer, the infrared spectra of all plasticized PVCs will be sufficiently similar that they can be differentiated from a polyolefin, for example. For this reason, specifications in the USP-NF around material identification utilize the concept of substantial equivalence. For example, instead of requiring that the IR spectrum of a sample contains all rigorously specified peaks at rigorously specified wavenumbers, the specification makes some allowance for minor spectral differences arising from the natural compositional and/or physical variation among polymers of this variation. BIOLOGICAL REACTIVITY Use of chemical testing to assess the safety and quality impact of plastic materials in pharmaceutical systems is necessary, but it is generally neither sufficiently comprehensive nor definitive approach to be the only approach. Although chemical assessment is an indicator of safety and quality, it is not a guarantee of safety and quality. Thus, the chemical assessment should be augmented by orthogonal assessment procedures. Biocompatibility testing is one such orthogonal procedure. The expectation that plastic materials of construction meet the requirements of the in vitro biological activity tests (see USP chapter <87>) has historically been a part of chapter <661> and remains so in the proposed revision. In addition, if it is desired that a particular material of construction or plastic system be designated as a member of a specific USP plastic class, then the appropriate biological testing specified in USP chapter <88> is necessary and appropriate. 15

16 PHYSIOCHEMICAL TESTS Physiochemical tests themselves do not provide direct evidence of safety or quality impact because they do not produce the type of information that can be safety- or quality-assessed (that is, the identity and concentration of specific extractables). Nevertheless, certain physiochemical tests can be indicative of potential safety and/or quality issues and can provide insights into the nature of extracted substances. For example, the total organic carbon (TOC) content of an extract reflects the total amount of extracted organic compounds. The UV absorbance of an extract provides some indication of the chemical nature of organic extractables and also provides a semi-quantitative indication of the levels of organic extractable. Finally, an acidity/alkalinity titration can provide some insight into the acidic or basic extractables. Thus these tests are included in <661.1>. Other historically relevant physiochemical tests, such as non-volatile residue, residue on ignition, and buffering capacity, are less useful as indictors of safety and quality and thus are no longer included in the revised <661>. USP s replacement of the Heavy Metals Test (based on sulfide precipitation) with instrumental methods for measuring elemental impurities prompted modification of <661> to address this change. EXTRACTABLE METALS A relevant safety and quality attribute of a packaging system is its propensity to leach metals and other substances that are measured as elemental impurities. The chemical literature documents numerous instances wherein metallic or elemental leachables had a discernible and sometimes undesirable effect on product safety and/or quality. Thus the question for the Packaging, Storage and Distribution EC is not whether to include extractable metals testing and specifications in 16

17 <661.1>, but rather what form that testing should take and what should be the appropriate specifications. Considering the form of the testing, the two major considerations are the generation of the test samples and the means by which these samples are tested. Regarding generation of the test sample, <661.1> notes that plastic materials used in packaging systems for medical articles do not dissolve under the conditions of use. Rather, substances derived from packaging systems accumulate in the packaged articles by the process of leaching (extraction). Thus the appropriate and relevant sample-preparation process for assessing extractable metals (elemental impurities) in a packaging system s materials of construction is extraction, as opposed to complete digestion, of the plastic material. Considering the means for testing the extract, it is clear that atomic spectroscopy, in general, and inductively coupled plasma spectroscopy or spectrometry in particular, are the methods of choice due to their performance capabilities and their wide application and availability. Regarding the specifications, there are two sides to the question of what are the relevant and appropriate specifications. Both the USP and ICH are developing documents that address elemental impurities in finished drug products. These documents are relevant to plastic systems and their materials of construction because these systems and materials are potential sources of the elemental impurities. However, as the USP and ICH documents are under development, review, or implementation, they cannot serve as meaningful resources for <661.1> at the current time. Additionally, these documents might not specify which of the elemental impurities relevant for finished drug products are also relevant to plastic systems. Lastly, the documents may not clarify the relationship between specifications for elemental impurities in the finished 17

18 drug product and the corresponding specifications for packaging systems. It is likely that a subset of the elemental impurities relevant and appropriate for drug products would be appropriate for plastic systems and that the limit for total elemental impurities in drug products may not translate directly to the limit for total extractable metals in plastic systems. To address the current ambiguity regarding elemental impurities derived from plastic systems, <661.1> establishes the concept of relevant metals, where a relevant metal is one which is a known component of the plastic material or could potentially arise from the plastic s starting materials, additives, or manufacturing residuals. <661.1> requires that plastic materials of construction be tested for those metals that are relevant to that material. These metals include, but are not necessarily limited to, those which appear in the compendial literature (e.g., European Pharmacopeia). Such a list of compendial metals must be augmented with those metals that the user or vendor can reasonably conclude may be present in the material due to its composition and manufacturing process. It is the responsibility of the user of the material to compile and justify the material s list of relevant extractable metals/elemental impurities. Specifications that appear in <661.1> for relevant extractable metals were established in the same way that the list of relevant extractable metals was established. If the relevant extractable metal appears in a material s section 3.1 monograph in Ph. Eur., then the specification for that metal in <661.1> was harmonized with the specification in Ph. Eur. If the relevant extractable metal is established by the material s vendor, then the material s vendor must also specify an appropriate specification for that relevant extractable metal, consistent with the specifications contained in the Ph. Eur. for its listed relevant extractable metals. 18

19 Once a global consensus is reached regarding element impurities in drug products, and once that consensus is interpreted in the context of contributions from plastic systems, it is expected that <661.1> will be modified to reflect that consensus and maintain consistency with it. PLASTIC ADDITIVES Information about the substances that can be extracted from plastic materials of construction is relevant and necessary for ascertaining the material s potential safety and quality impact when it is used in a system. Thus, as noted previously, materials are tested for relevant extractable metals. Following the same logic, one might conclude that materials should also be tested for extractable organics. However this conclusion should be tempered by noting that there is a trade-off between the value of such information and the effort required to obtain it. Extractables testing would be highly valued during material screening and selection if it were the only means of characterizing the material so that appropriate materials of construction could be selected. However, this is not the case. It is noted that suitability for use of the plastic system can be inferred from the suitability for use of its materials of construction and that this inference is sufficiently strong that it can be the basis for material screening and selection. The question is what minimum set of tests is sufficiently complete that it can be used as the basis of material selection? While organic extractables profiling of materials can be the basis of material selection, it does not represent the minimum set of tests that can accomplish this objective. Firstly, screening multiple extracts for an unspecified number of unknown organic extractables using multiple test methods involves a much greater level of effort than profiling a single extract for a list of targeted, relevant metals using a single analytical method. Secondly, it is noted that 19

20 organic extractables related to a packaging system can be inferred from the composition (e.g., list of ingredients or additives) of its constituent materials of construction. Thus, if one knows the composition of a material of construction, one can infer the material s extractables via the clear relationship that exists between ingredients and extractables, specifically that organic extractables are generally derived from a material s constituents. Because ingredient information can be obtained more readily than extractables information and because ingredient information can be used to forecast extractables, <661.1> is based on characterizing materials for their ingredients (additives) versus their extractables. The current state of knowledge about the chemistry of common material ingredients is sufficiently mature that one can establish with confidence the decomposition products and related substances profile of many commonly used polymer additives. Consider, for example, the case of a polyolefin material stabilized with two commonly used antioxidants, Irganox 1010 and Irgafos 168. As shown in Figures 4 and 5, the chemistry of these two antioxidants is well documented, and therefore it is relatively straightforward to compile a list of the antioxidant s degradation products and related substances. It is the antioxidants themselves and their degradation products and related substances that establish the polyolefin s extractables profile. As this example illustrates, if one can establish a material s composition, one can infer the material s organic extractables profile with sufficient accuracy that the inferred profile can be the basis for material selection (or rejection). Thus, materials of construction are characterized for their polymer additives, and not profiled for their organic extractables, for the purpose of material screening and selection. 20

21 In the process of characterizing a plastic material for its additives, it is necessary to establish test methods and specifications for the additives for the individual plastics. As was previously noted, the choice of analytical methods for polymer additives in <661.1> was predicated on the tenet that where possible, the proposed test methodologies should be those that are currently specified in appropriate compendial sources. Similarly, specifications for additives that appear in <661.1> are consistent with those that appear in the appropriate regulatory guidance documents and compendial sources. Although it may be appropriate and necessary to revisit and modify or update the test methods and specifications contained in <661.1>, it is not the purpose of the current revision to establish methods and specifications which have not already been adopted in regulatory guidelines or compendial sources. WHAT IF A SPECIFIC CIRCUMSTANCE IS NOT ADDRESSED IN <661.1>? An important aspect of <661.1> is its recognition that the development, testing, assessment, and registration of materials and systems are not mature activities or sciences, and thus that it is impractical to expect that the <661> chapters will be all-encompassing and fully consistent with the latest developments in material, analytical, toxicological, and regulatory science. For example, <661.1> recognizes that in view of the wide variety of materials and packaging systems available and recognizing possible new developments in materials and packaging systems, it is possible that plastic packaging systems could be constructed from materials that are not specifically addressed in this chapter. Rather than suggesting that if it isn t in the USP, it can t be used, chapter <661.1> notes that the fact that the material of construction is not addressed in this chapter does not preclude its use in the packaging system. However, such a 21

22 material of construction must be characterized by methods equivalent in intent and performance to the methods specified in this chapter. To meet this requirement, such a material of construction must be identified by appropriate methodology, tested for biocompatibility and physicochemical properties by the methodology listed in the chapter, and tested for additives and relevant extracted metals by an appropriate methodology. Additionally, specifications must exist for such materials of construction, and those specifications must be consistent with the specifications listed in the chapter. It is logical and appropriate that a material s vendor or user would be responsible for the development and justification of the necessary test methods and their associated specifications. Furthermore, <661.1> provides a second option for the assessment of materials that do not have corresponding or relevant chapter sections. To wit, <661.1> states that individual plastic materials of construction are deemed to be well characterized and appropriate for use if they are used in a packaging system that meets the relevant specifications in <661.2>. Thus individual materials of construction are deemed to have met the relevant specifications in <661.1> if the packaging system in which they are used meets the relevant specifications of <661.2>, subject to agreement by competent authority. However, this option is limited in its applications because such a conclusion is valid only in the context of the specific packaging system that meets the <661.2> specifications and cannot be extended to other packaging systems that use the same material (or materials) of construction. Thus, a material of construction used in one packaging system that meets the relevant specifications of <661.2> is deemed to have met the specifications of <661.1> only for that one packaging system. If the same material of construction is used in another packaging system, then its suitability for use in that other 22

23 packaging system must be established by another means (for example, the testing specified in this chapter). Chapter <661.1> also considers the possibility that candidate materials of construction for systems may contain additives other than those specified in <661.1>. Clearly, such candidate materials must be tested for these additives that are not specified in <661.1>. Thus, both the procedures and the specifications for additives not specified in the chapter must be established and should be made consistent with those used for materials that are specified in the chapter. The responsibility for establishing such procedures and specifications rests with the material s vendor or user. Lastly, a similar approach is taken for test methods. <661.1> recognizes that the test methods in this chapter are appropriate for these tasks as evidenced by their longstanding inclusion in the compendia, and thus they reflect acceptable practices. Other methods may be equally suitable. Thus, the recommendation of specific tests, test methods, and test parameters does not preclude the use of other suitable methods and procedures, but the conditions presented in this chapter take precedence for official purposes. Should the sponsor take the path of using alternate methods, the chapter provides general performance guidelines, noting that: Alternative test methods and conditions must be demonstrated to be suitable by means of appropriate and sufficient validation data. Important aspects of alternative methods include the completeness of the extraction process and the specificity, sensitivity, and applicability of the analytical test methods. Extraction methods employed must have a demonstrated ability to quantitatively transfer additives from the material to the extracting medium and must do so without modifying the chemical nature of the additive unless such modification is an integral part of the test methodology. Test methods employed must have equivalent ability compared to the test methods contained in this chapter to produce a clear and unambiguous identification of all relevant additives at levels at least as low as the levels specified in this chapter. 23

24 <661.2> Plastic Packaging Systems for Pharmaceutical Use GENERAL The basic tenet of this section of <661> is that packaging systems must be qualified to establish their suitability for use. A packaging system that is suitable for use should: protect the pharmaceutical product adequately function properly be compatible with the pharmaceutical product (i.e., the product ingredients are not adsorbed onto the surface or into the body of the packaging system and do not migrate through the packaging system; also, the packaging system does not release substances that then accumulate in the product in quantities sufficient to affect its stability) be composed of materials that are safe for use with the pharmaceutical product (i.e., the packaging system does not release substances that then accumulate in the product in quantities that present a risk of toxicity, thereby compromising user safety). Certain of these aspects of suitability for use are mentioned in <661.2> but not covered by <661.2>; these include protection, compatibility, and functionality. The aspects of protection and functionality are more appropriately addressed in chapter <659> Packaging and Storage Requirements, while the compatibility between a packaged drug product and its packaging system is most appropriately addressed by testing the packaged drug product (e.g., over the course of development and stability studies conducted in the commercial plastic packaging). Thus <661.2> focuses on the safety aspects of a packaged drug product s packaging system. The intent of <661.2> is to establish the testing needed to produce the data required for establishing the packaging system s safety and to provide specifications that establish the requirements for safe packaging systems. <661.2> refers to this process of establishing the safety of packaging systems as chemical assessment (Figure 6) and notes that a packaging system is chemically suited for its intended use if: 24

25 the packaging system is constructed from well-characterized materials as established by testing according to Plastic Materials of Construction <661.1> the packaging system s general physicochemical properties have been established the packaging system s biocompatibility (biological reactivity) has been established the packaging system has been established to be safe by means of the appropriate chemical testing and toxicological assessment the packaging system is chemically compatible with the packaged product, as established by appropriate compatibility assessments (e.g., stability studies). Considering the fourth bullet point further, <661.2> notes that appropriate chemical testing involves performing extractables testing, leachables testing, and the relevant toxicological assessment. The specified toxicological safety assessment should be performed for each individual member of the packaging system s extractables profile (or each member of the contained product s leachables profile, as appropriate) to demonstrate that the user safety risk associated with each individual leachable (or extractable as worst case leachable) is acceptable and that the probable safety risk posed by all leachables (or extractables as worst case leachables), considered individually, is within acceptable parameters. As noted previously, the fifth bullet point, which addresses the compatibility of the packaged product and the packaging system, is outside the scope of <661.2>. As was the case with <661.1>, the methods and specifications that appear in <661.2> were identified and adopted based on the fundamental criteria that 1) the methods and specifications should be harmonized, to the extent possible, with existing sources of regulatory guidance; 2) the test methods should be adopted from existing compendial sources (method modifications will be addressed, as is necessary and appropriate, in future revisions of <661.2>), and 3) specifications should be adopted from existing compendial sources and/or regulatory guidance sources. USE OF WELL-CHARACTERIZED MATERIALS OF CONSTRUCTION 25

26 In <661.1> it was proposed that the single most important step in designing a safe packaging system is to use well-characterized materials of construction specifically selected for their anticipated low safety risk (among other properties). <661.2> also requires the use of specifically characterized and judiciously selected materials of construction in packaging systems. BIOLOGICAL REACTIVITY AND PHYSIOCHEMICAL TESTS Performance of biological reactivity and physiochemical testing was justified previously for materials of construction, and the same reasoning is valid for packaging systems. However, because biological reactivity and physiochemical testing was performed on all materials of construction, it may seem redundant to perform such testing again on the packaging system. This perception is inaccurate in three ways. First, materials of construction may be altered when they are processed into packaging systems, e.g., a material could be molded to produce a component of the packaging system, and that component might be sterilized by gamma irradiation prior to being mounted onto the packaging system. Exposure to such stresses (high temperature, ionizing radiation) could have a marked effect on the material s extractables profile. Second, the processes used to convert the materials of construction into components, and the assembling of components into packaging systems, may result in chemicals being added to the system. For example, an auxiliary antioxidant might be added to a resin before its extrusion as a film to ensure its integrity over the anticipated shelf-life of the packaged product. In another example, slip- or mold-release agents might be used to facilitate the manufacturing operation. Bonding agents, glues, or adhesives may be needed to attach component A to component B in 26