乙酰辅酶A
CONCLUSIONS
Evaluation of the internal surface of glass containers begins with the Surface Glass Test, which us water as the extracting medium. A low value is not always an indicator of a durable inner surface if the results are obtained using surface treatments (e.g., ammonium sulfate). Such treatments can lead to a silica-rich inner surface layer that reprents a weakened glass struc-ture, and risk of delamination increas when the vial is filled with formulations that contain aggressive agents such as organic acids, EDTA, or solutions that have high ionic strength or high pH. The screening methods and strategies described in this chapter can assist in the evaluation of glass containers from different suppliers or on a lot-to-lot basis and can provide an indi-cation of the propensity of the lected formulation to cau delamination over time. Selection of glass vials intended to con-tain a drug product with one or more of the formulation risk factors identified in Table 2 should undergo particular scrutiny. Add the following:
▲á1661ñ EVALUATION OF PLASTIC PACKAGING SYSTEMS AND THEIR MATERIALS OF CONSTRUCTION WITH RESPECT TO THEIR USER
SAFETY IMPACT
INTRODUCTION
Drug products can chemically interact with their associated packaging systems and/or the system's plastic materials and components of construction while the product is being manufactured, shipped, stored, and administered. The magnitude of the interactions must not be such that the interactions adverly affect the suitability for u of the drug product or the pack-aging system. While suitability for u includes veral quality aspects of the packaged drug product and its performance, the suitability for u aspect addresd in this chapter is patient safety.
The potential patient safety impact of interactions between a drug product and its packaging is assd and established via the appropriate testing of the packaging systems and its materials and components of construction. Plastic Packaging Systems and Their Materials of Construction á661ñ establishes the tests and specifications that are necessary and appropriate for ensuring that such systems are suitable for u, specifically safe for u. Chapter á661ñ consists of two sub-chapters, Plastic Materials of Construction á661.1ñ and Plastic Packaging Systems for Pharmaceutical U á661.2ñ.
SCOPE
The purpo of this chapter is to communicate the key concepts behind á661ñ and its related sub-chapters, á661.1ñ
and
á661.2ñ, and to provide additional information and guidance regarding the application and applicability of this t of chapters. Given the large and diver nature of the pharmaceutical marketplace, the proper u and application of the á661ñ suite of chapters may not be intuitive to some stakeholders. Therefore, this chapter is intended to assist urs in understanding and utilizing the chapters.
GENERAL PRINCIPLES
收拾行李The Overall Asssment Process
诘难The objective of USP packaging systems standards is to establish the tests and specifications that ensure packaging systems do not materially impact the safety or effectiveness of pharmaceutical products. Given the complex nature of packaging sys-tems and their manufacturing and development process, multiple testing procedures are needed to establish their suitability for u with a specific pharmaceutical product. The logical development and manufacturing process progression for packaged drug products, starting with the packaging system's materials of construction, continuing with the packaging system itlf, and ending with the packaged drug product, forms the basis of a three-stage approach to packaging systems qualification, as illustrated in Figure 1.
construction.
The process for establishing a packaging system's suitability for u includes: characterization of its materials of construction
(ingredients); testing and asssment of the system itlf (extractables); and testing and asssment of the packaged pharma-ceutical product (leachables). The initial step of the process involves chemically characterizing candidate materials of construc-tion to the extent that the choice of materials to u in the construction of a packaging system can be rationally made and scientifically j
ustified. The intermediate step of system asssment is uful and necessary as it bridges the risk asssment gap between testing starting materials and testing finished product, while providing a means for optimizing pharmaceutical prod-uct testing. The intermediate test is necessary as materials of construction undergo considerable stress, such as exposure to high temperatures, while they are being converted into either components of the packaging system or the packaging system itlf. Furthermore, processing aids and additional additives may be introduced during the manufacturing process for a pack-aging 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 asssment of risk made in material lec-tion is appropriately revisited by testing and qualification of the overall packaging system itlf.
Ultimately, the effect that packaging may have on the drug product ur is mediated by packaging-derived substances that are prent in the drug product. The third stage of the process is product asssment, specifically leachables testing of the packaged product and impact asssment, which
considers the ur's exposure to the leachables.
垂钓古诗Materials Asssment: Characterization, Screening, and Selection, USPá661.1ñ
To ensure that a packaging system is suited for its intended u, it is important to lect materials of construction which are suited for u in packaging systems. Testing and characterizing materials of construction for attributes relevant to their suitabil-ity provides a rational basis for material lection in designing a packaging system. The intentional lection of well-character-ized materials minimizes the risk that a system made from tho materials will be unsuitable. Considering safety specifically, lection of materials that have the tendency to be safe increas the likelihood that packaging systems made from tho ma-terials will be safe. Therefore, the characterization of materials of construction is the first step in the process of developing and qualifying safe packaging materials. Additionally, chemical characterization data may also provide the basis for effective and appropriate change control.
The intent of á661.1ñ is to establish, with a degree of confidence, whether potential material candidates could adverly af-fect the quality and safety of pharmaceutical products. The basic tenet of materials asssment, as reflected in á661.1ñ, is that knowing the general composition and certai
n general characteristics of a material of construction allows one to:•Rationally asss the potential safety impact of the materials with a degree of certainty that is appropriate for early prod-uct development and/or manufacturing.
•Forecast with some degree of accuracy the identity of the extractables from that material of construction and from sys-tems that u that material of construction.
•U the asssment and forecast to establish and justify the u (or non-u) of a particular material in a particular packag-ing system.
To this end, á661.1ñ defines a well-characterized material of construction as one who:
•Identity has been definitively established.
•Biocompatibility (biological reactivity) has been established.
•General physicochemical properties have been established.
•Additives and extractable metals have been quantified.
Chapter á661.1ñ testing is not a guarantee that plastic systems constructed from materials meeting á661.1ñ specifications will be suitable for their intended u as it is not always the ca that testing of a system's materials of construction directly and completely correlates with subquent testing of the plastic system. Characterization of a material using á661.1ñ merely estab-lishes the composition or characteristics of the material and enables the decision as to whether the material is an appropriate candidate for u in a packaging system. Nevertheless,
á661.1ñ testing leverages the logical connection between material addi-tives, material extractables, and system extractables, and thus provides a uful indication of the probable suitability-for-u issues for materials and systems. The actual qualification of the material occurs when the entire system is qualified for u in a particular application via á661.2ñ testing.
Packaging System Asssment and Qualification, USPá661.2ñ
The impact of packaging systems on the chemical composition of packaged drug products can be established in two ways. The packaging system itlf can be characterized with respect to substances that can be extracted from it (extractables). Sec-ondly, the packaged drug product can be tested for packaging-derived substances that have leached into it (leachables). In the ca of extractables asssment, the impact is predicted bad on a relationship which is established (or inferred) between ex-tractables and leachables. In the ca of leachables asssment, the impact is specifically measurable, assuming that all the rele-vant leachables can be discovered, identified, and quantified in the packaged product. In either ca, á661.2ñ establishes the tests and specifications for the packaging system, while referring urs to relevant informational chapters (e.g., Asssment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems á1663ñ for extractables and Asssment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems á1664ñ for leachables) for insights on how to design and execute relevant studies.
Considering the packaging system as the test article, the intent of á661.2ñ is to define and delineate the testing needed to produce the data required for establishing the packaging system's safety. Chap
ter á661.2ñ refers to this process of establishing the safety of packaging systems as chemical asssment and notes that a packaging system is chemically suited for its intended u if:
•The packaging system is constructed from well-characterized materials, as established by testing according to á661.1ñ.
•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 asssment.白馒头图片
•The packaging system is chemically compatible with the packaged product, as established by appropriate compatibility asssments (e.g., stability studies).
get的音标Considering the fourth bullet point, á661.2ñ notes that appropriate chemical testing includes performing extractables test-ing, leachables testing, and the relevant toxicological asssment of the extractables and/or leachables results. In addition to being the basis for toxicological safety asssments, information about a packaging system's extractables can be ud in veral ways to o
有奖游戏ptimize finished product testing for leachables. The potential quality and/or safety or impact of extractables may fa-cilitate identification of leachables that might adverly affect product quality. Such leachables of potential concern would nec-essarily be among the targeted analytes in testing of a final pharmaceutical product within its packaging system. The targeting of specific leachables, as oppod to the screening of pharmaceutical products for unspecified leachables, has significant ana-lytical benefits, including the ability to develop, validate, and utilize test procedures that are appropriately nsitive, specific,and accurate. Further, extractables (and their accumulation levels in extracts) can be ud to forecast the levels of leachables in the finished product, depending on how well the extraction conditions mimic the pharmaceutical product's composition and actual conditions of clinical u. If the extraction conditions are such that they accelerate and modestly exaggerate the pro-duct's clinical u conditions, then the extractables and their levels in the extracts can be extrapolated to estimate the maxi-mum levels of leachables in the finished product. Additionally, if such extractables are assd for their safety or quality im-pact, the results of that asssment can also be extrapolated to, and deemed to be relevant for, the pharmaceutical product.Finally, if no adver impact is found bad on the extractables data, then no adver impact can be inferred for the leachables in the packaged pharmaceutical product. Consistent with certain regulatory guidelines, leachables studies may not be required when extractables studies establish the maximu
m amount of individual leachables that may be prent in the active substance/medicinal product and when such maximum levels have been demonstrated to be toxicologically safe. However, should a
leachable study be deemed to be unnecessary, a justification should be provided.
APPLICABILITY AND APPLICATION OF á661.1ñ
Applicability 1.The holder of the drug product application and drug product manufacturer [in the ca of many over-the-counter prod-ucts (OTCs), where there is no application] bear primary responsibility and accountability for ensuring the requirements of
the chapter are met. The means by which the holder of the drug product application and drug product manufacturer
obtains information to meet the requirement is at the discretion of the holder.
2.The testing required and specifications for materials of construction contained within á661.1ñ are relevant to and applica-ble for all drug dosage forms, as it is the universal expectation that packaging materials be constructed from well-charac-terized materials, regardless of the potential interaction between a dosage form. However, the u of risk-management principles and concepts to address the potential product safety risk associated with leachables (and extractables as poten-tial leachables) is a cornerstone of global regulatory and industry thinking on this topic. Industrial scientists and regulators agree that the concepts and principles of risk management have a definite strategic role in terms of designing, imple-menting, and interpreting effective and efficient asssments of extractables and/or leachables. Oversimplifying some-what, it is well-established that risk-management tools and principles can be ud to define the nature and magnitude of asssment (including testing), where low-risk situations require reduced or alternate asssment (t
esting) versus high-risk situations. Thus, as noted in its Tables 1 and 2, á661.1ñ establishes biological reactivity and chemical tests that differ some-what for low-risk dosage forms (such as oral and topical) versus high-risk dosage forms (such as inhalation and injections).Moreover, an esntial principle reflected in á661.2ñ is that packaging systems be tested for extractables and that the ap-proach be consistent with the nature of the interaction between the drug product and its packaging. This includes con-sideration of the drug product contact condition (e.g., liquid vs dry) and the potential interaction between the dosage form and its packaging system. By referencing á1663ñ for extractables testing, á661.2ñ provides the means by which ex-tractables studies relevant for specific dosage forms can be designed, implemented, and interpreted. By allowing for study designs that reflect the nature and clinical u of various dosage forms, á661.2ñ supports and us risk-bad strategies and asssments.
3.The outcome of á661.1ñ testing is that the tested construction material has been well-characterized. Characterization data generated during á661.1ñ testing can be ud to support decisions on the proper u of the tested material. However, the characterization data does not specifically or universally qualify the material for u in packaging systems, as the material's u can vary depending on the packaging applications. It is the responsibility of the developer or ur of the t
ested mate-rial to decide if the material is appropriate for their intended application. Thus, it is the developer's or ur's expert review of the á661.1ñ test results, coupled with additional information as necessary and appropriate, that establishes whether a well-characterized material is suitable for u in a specific application.
Alternatively, the outcome of testing plastic packaging systems via á661.2ñ is an asssment of the probable safety impact of that system on the packaged drug product. This asssment is bad on the biological reactivity testing, the physioco-chemical testing, and the extractable/leachables testing that are required by á661.2ñ. Thus, a packaging system that has been tested per á661.2ñ and which meets the specifications contained within á661.2ñ, including a toxicological safety as-ssment of the extractables and/or leachables data, is qualified for u consistent with the conditions under which it was tested, subject to review by the appropriate regulatory authority.
4.There are two means for demonstrating a material of construction has met the requirements of á661.1ñ. The first means is
direct testing and meeting the requirements in á661.1ñ. The cond means is the u of the material with a currently ap-proved finished drug product.
5.Application of á661.1ñ and á661.2ñ to materials of construction or systems other than packaging systems for finished drug
products is beyond the scope of the chapters, but the concepts and principles of the chapters may be applicable and relevant to other systems (and their materials for construction) such as medical devices for drug product administration, manufacturing systems for pharmaceutical products, and packaging/storage systems for drug substances. It is the expect-ation that future compendial chapters will be developed to address the other pharmaceutically important systems.
6.The scope of á661.1ñ is materials of construction and of á661.2ñ is packaging systems. A third type of test article, compo-
nents, is not directly considered in the Scope of either chapter. In this context, a component is defined as an individual part of a packaging system and is constructed from one or more materials of construction. Thus, a plastic bag consisting of a laminated film is considered to be a component of the packaging system that includes the bag.
Since a component is constructed from materials and is part of a system, if component testing is deemed to be necessary, the relevant testing and specifications for the component are contained within á661.2ñ. The provisions in á661.2ñ for pack-
aging systems must be met for components who testing has been deemed to be necessary. The component must be constructed from materials that meet the requirements of á661.1ñ and the component must be tested by the methods, and meet the specifications, contained in á661.2ñ.
7.Testing of materials of construction via á661.1ñ is predicated on the circumstance that the material will most likely interact
with the packaged drug product when the material is ud in a packaging system. It is not necessary for a material ud in
a packaging system to be well-characterized if there is little or no chance of the material and the packaged drug product
interacting. Under the conditions the materials of construction would be considered non-interacting and would be ex-empt from á661.1ñ testing. The designation of a material of construction as “non-interacting” must be accepted by the appropriate regulatory authority.
Although it is beyond the scope of á661.1ñ to establish the means by which a material of construction is established as “non-interacting”, it is relevant to differentiate between the potentially similar terms “no direct contact” and “non-interacting”, where the term “no direct contact” means that the material and the packaged drug product do not come into direct physical contact under the clinical conditions of u. Although it may well be the ca that in a specific application a “no direct con-tact” material of construction is also a “non-interacting” material of construction, it may also be the ca that “no direct con-tact” does not insure “non-interacting”, especially when the conditions of contact include long durations and/or substantially elevated temperatures.
To explain the concepts of “no direct contact” and “non-interacting”, consider the following example. An aqueous drug product is packaged in a flexible plastic container. The flexible container is further placed in a foil overpouch. The over-pouched product is terminally sterilized. An adhesive label is applied to the outside of the foil overpouch after the product unit has been cooled after terminal sterilization.
In this ca, both the foil overpouch and the label are “no direct contact”, as there is at least one physical barrier (the pri-mary container) between the packaged drug product and the two items. However, if the flexible plastic primary container is permeable, the foil overpouch can be considered to be a “potentially interacting” component, as substances from the over-pouch could migrate through the primary packaging, especially under the high-temperature conditions of terminal steriliza-tion. On the other hand, the label is a “non-interacting” component becau (1) the foil overpouch is impermeable and (2) the label is applied after the thermal stress associated with terminal sterilization.
Thus, the difference between a “potentially interacting” and “non-interacting” “no direct contact” component is the perme-ability of the barrier that parates the “no direct contact” components from the drug product. If the barrier is incomplete, then the component (and its materials of construction) i
s “potentially interacting” and the materials must be tested per
á661.1ñ. If the barrier is complete, then the component (and its materials of construction) is “non-interacting” and the materi-als need not be tested per á661.1ñ.
美丽新城Application
1.There are two means of demonstrating that a material of construction has met the requirements of á661.1ñ. The first
means is to perform the testing contained within á661.1ñ and meet the specifications in á661.1ñ. The cond means is the u of a material in the packaging system of a currently approved finished drug product. Specifically, á661.1ñ states “indi-vidual plastic materials of construction are deemed to be well-characterized and appropriate for u if they are ud in a packaging system that meets the requirements in á661.2ñ or if the packaging system has been deemed appropriate for pharmaceutical u by the appropriate regulatory authority”. However, it is noted that such a conclusion is only valid for the specific packaging system meeting the requirements of á661.2ñ and cannot be extended to other packaging systems using the same material (or materials) of construction. If the same material of construction is ud in another packaging system, then its suita
bility for u in that packaging system must be established.
2.The outcome of á661.1ñ testing is that the tested material of construction has been well-characterized. Characterization
data generated during á661.1ñ testing can be ud to support decisions on the proper u of the tested material. Howev-er, the characterization data do not specifically or universally qualify the material for u in packaging systems, becau the material's u can vary depending on the packaging applications. Alternately, the outcome of testing plastic packag-
