In a recent Pharmacopeial Forum two revised USP general chapters have been published for comment. With these drafts, the USP expert committee is removing the requirement for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms. Read more about the draft chapters of <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.testing for packaging materials and systems for oral and topical dosage forms. Read more about the draft chapters of <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.
In Pharmacopeial Forum 42(4) [Jun-Jul 2016] drafts of two revised USP general chapters <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use have been published for comment. Deadline for comments is September 30, 2016. With these drafts, the USP General Chapters – Packaging and Distribution Expert Committee is removing the requirement for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms.
The Expert Committee is removing the requirement for <87> testing at this time, while the effort to revise the general chapters <87> and Biological Reactivity Tests, In Vivo <88> proceeds. Depending on the revisions of <87> and <88> the two packaging chapters may be revised to align with those chapters.
The new requirement (since May 2016) for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms has been highly discussed, since this testing is not required for the mentioned dosage forms according to EMA guideline on plastic immediate packaging materials (December 2005) and US FDA container closure guidance (May 1999). In case of oral and topical dosage forms both guidances require “only” compliance to food regulations (EU: regulation 10/2011, US: indirect food additives guidelines) or, if applicable, (preferably) to pharmacopoeial monographs (if the material or system is described in a pharmacopoeial chapter).
The principle of these two guidances is that materials considered safe for food contact are also safe for topical and oral dosage form packaging systems.
The new requirement (Biological Reactivity Tests, In Vitro) could have led to delays in releasing new oral or topical products on the market. Additionally, one might have had to re-evaluate already existing oral and topical products packaging systems on the market. Therefore, the present decision to revise the two packaging chapters regarding the requirement for <87>Biological Reactivity Tests, In Vitro seems to be justified.
Furthermore, the Expert Committee is proposing the addition of four new polymers [polyamide 6, polycarbonate, poly(ethylene-vinyl acetate), and polyvinyl chloride, plasticized] with test methods and specifications to general chapter <661.1>. To support the addition of these new polymers, polymer descriptions have been added to Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact <1661>, which appeared in PF 42(3) [May–June 2016].
In addition, the test for Spectral Transmission in Containers—Performance Testing <671> is being moved into general chapter <661.2> as requirement for light resistant containers.
On the basis of comments received, the scope of both chapters was revised for clarification.
After registration on the USP Pharmacopeial Forum website you can read the complete drafts of the two general chapters <661.1> and <661.2>.
Frequently Asked Questions: Plastic Materials of Construction <661.1> and Plastic Packaging Systems for Pharmaceutical Use <661.2>
- How do the newly revised General Chapters <661.1> and <661.2> impact currently marketed packaged pharmaceutical products?
- If a packaging system or component that gained regulatory approval with one product is used as a packaging system for a new product, would <661.1> and/or <661.2> testing be required?
- If a material of construction for a packaging system or component that has received regulatory approval is changed, is <661.1> and/or <661.2> testing required?
- Why does USP require <87> Biological Reactivity Tests, In Vitro testing for solid oral dosage forms?
How do the newly revised General Chapters <661.1> and <661.2> impact currently marketed packaged pharmaceutical products?
In order to market a drug product, defined as a dosage form plus its associated packaging system, the product must be evaluated for its suitability for use by the relevant regulatory authority. The purpose of <661.1> is to increase the likelihood that a packaging system will be suited for use by providing data about its material(s) of construction, whereas the purpose of <661.2> is to establish that the packaging system is suited for use. Because suitability for use has already been established for marketed products via regulatory review, <661.1> and <661.2> testing has no additional value in terms of establishing suitability for use. Thus, a packaging system and its materials of construction that have been evaluated by a regulatory authority and are used with a marketed dosage form are considered to already meet the requirements of <661.2> and <661.1> (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).
If a packaging system or component that gained regulatory approval with one product is used as a packaging system for a new product, would <661.1> and/or <661.2> testing be required?
If a packaging system (and its materials of construction) that is used with one marketed dosage form is used with a second, compositionally similar dosage form, and if the conditions of use are similar for the two dosage forms, neither <661.1> nor <661.2> testing is required. This is because the information used to establish the suitability for use with the approved product is relevant to and is typically sufficient for establishing the suitability for use with the new product.
If the new drug product is compositionally different from the approved product, and/or the conditions of use are different, then <661.1> testing would not be required. This is because generally, <661.1> testing is not dependent on the dosage form composition or the conditions of use.
The exception to this statement is when a packaging system for a marketed “low-risk” dosage form is used for a new “high-risk” dosage form. A dramatic change in the nature of the dosage form would require <661.1> testing. This is because <661.1> testing of materials used with “high-risk” dosage forms is more extensive than <661.1> testing of materials used with “low-risk” dosage forms. In this scenario, those tests that are required for both low- and high-risk dosage forms do not need to be repeated (for example, Identity, Physicochemical Tests, Extractable Metals, and <87> Biological Reactivity Tests, In Vitro). Those tests that are unique to the high-risk dosage forms (e.g., <88> Biological Reactivity Tests, In Vivo as appropriate and Plastic Additives) would need to be performed.
A similar analysis is true for <661.2> testing of the packaging system. Biological Reactivity and Physicochemical Tests are not specifically linked to a dosage form or conditions of contact, thus the packaging system would not need to be tested for these attributes regardless of any differences in the composition or conditions of use between the approved and new drug products. However, as the generation and toxicological safety assessment of an extractables profile is influenced by the composition of the dosage form and the conditions of use, it may be necessary to perform the Chemical Safety Assessment (extractables profiling and toxicological safety) in <661.2>. Under <661.2>, any decision not to perform this Chemical Safety Assessment would need to be justified on a case-by-case basis.
When a packaging system for a marketed “high-risk” dosage form is used for a new “low-risk” dosage form, <661.1> and <661.2> testing is not necessary. In this case, whatever information was used to establish the suitability for use with the “high-risk” dosage form would also establish the suitability for use with the “low-risk” dosage form, as the “high-risk” information would generally represent a worst case scenario for the “low-risk” situation (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).
If a material of construction for a packaging system or component that has received regulatory approval is changed, is <661.1> and/or <661.2> testing required?
As all materials of construction are required to meet <661.1>, it is expected that the new, different material would have to have been tested per <661.1>. Note that the new material would not be one of the legacy materials whose <661.1> compliance is “covered” by the fact that the product is being marketed.
Use of a new and different material of construction in a packaging system can reasonably be anticipated to have an effect on the suitability for use of that packaging system. Thus, the new packaging system should be tested per <661.2>.
Nevertheless, neither <661.1> nor <661.2> is intended to establish prescriptive requirements associated with exercising change control. Organizations are responsible for establishing their own change control practices, subject to approval by the appropriate regulatory authority. It is expected that those change control practices that do not specifically utilize <661.1> and <661.2> will include a justification for such practices, specifically focusing on the potential effect(s) that the change may have on user safety and product quality (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).
Situation Required Testing General Situation Specific Circumstances <661.1> <661.2> Packaging system used with a currently marketed pharmaceutical product — No No New packaging system that has not gained regulatory approval for use with a to-be-marketed pharmaceutical product — Yes Yes Changes to a packaging system used with a currently marketed pharmaceutical product A new material is introduced into the packaging system Yes (for the new material) Yes A material of construction in the packaging system is changed in either composition or process Yes (for the changed material) Yes The packaging system is changed, in either composition or process, in a manner that does not involve a change in its materials or to its materials (for example, changing the thicknesses of individual layers in a multi-layered film) No Yes Packaging system used with a currently marketed pharmaceutical product is to be applied to a different pharmaceutical product Dosage form and conditions of use are similar for the current and different pharmaceutical products No No Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from a “high risk” to “low risk” dosage form) No No Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from a “low risk” to “high risk” dosage form) Yes Yes
Note: The provisions in <661.2> for packaging systems must be met for components whose testing has been deemed to be necessary.
Why does USP require <87> Biological Reactivity Tests, In Vitro testing for solid oral dosage forms?
In general, the amount and type of testing required to verify the suitability of packaging systems and their materials of construction should be consistent with the risk that the system or material could be unsuitable. In addition, the risk that packaging systems would be unsuited for use for solid oral dosage forms is lower than the risk associated with other dosage forms. Recognizing these generalizations, <661.1> has different testing requirements and/or specifications for these two groups of dosage forms. Because some of the tests required in <661.1> are applicable regardless of dosage form (for example, Identity, Physicochemical Tests, and Extractable Metals), such tests are applied with no difference to both groups of dosage forms. Although both groups of dosage forms are required to address Biological Reactivity, <661.1> requires only Biological Reactivity Tests, In Vitro <87> for oral and topical dosage forms while requiring both Biological Reactivity Tests, In Vitro <87> and Biological Reactivity Tests, In Vivo <88> (as applicable) for all other dosage forms. Both groups are required to address Plastic Additives, but solid oral dosage forms address this aspect by making proper reference to FDA’s Indirect Food Additive regulations while the other dosage forms address this issue by specified Plastic Additives testing.
A cornerstone of suitability for use assessment of packaging systems and their materials of construction is the concept of orthogonal assessment. This is because individual means of assessment are generally insufficiently robust or broad enough in scope to provide rigorous and complete assessments on their own. Thus orthogonal assessments are performed to essentially “fill in the gaps” in the individual assessments.
Q: What types of “plastic packaging systems” are used in the pharmaceutical industry?
A: Plastic packaging systems for pharmaceutical use include bags, bottles, vials, cartridges, metered-dose inhalers, prefillable syringes, pouches and closures for capsules and tablets. Plastic materials commonly used in these systems include polyethylene, polypropylene, polyolefins, and polyvinyl chloride, among others.
Plastic packaging systems can include—not only the container that holds a particular drug product—but also gaskets, rubber stoppers, tubing and other components that may be part of the overall system used to store and/or deliver a drug to the patient.
Q: What are the key quality considerations for manufacturers of plastic packaging systems for drug products?
A: As drug products are manufactured, packaged, and stored, they come into direct contact with packaging systems and their plastic materials of construction. Such contact may result in interactions between the drug product and its packaging system. The packaging systems must protect and be compatible with drug products and not compromise their stability, efficacy or safety. In turn, the ingredients of a drug product should not be absorbed onto the surface or migrate into the body of the plastic packaging system.
The use of well-characterized plastic materials of construction and the appropriate testing of packaging systems help to determine if adverse interactions are taking place. Manufacturers should be able to provide a rationale for using a particular raw material of a packaging system and characterize that material to know what can possibly come out of it (e.g., additives, extractable metals). This is key to determining potential interactions with a drug product.
Q: What are extractables and leachables?
A: Extractables are organic and inorganic chemical compounds that can be extracted from packaging material under laboratory conditions. They can be released from a pharmaceutical packaging/delivery system, a packaging component or a packaging material of construction. Depending on the specific purpose of a particular extraction study, laboratory conditions (e.g., solvent, temperature) may accelerate or exaggerate the normal conditions of storage and use for a packaged dosage form. Extractables themselves (or substances derived from extractables) have the potential to leach into a drug product under normal conditions or storage and use and, thus, become leachables.
Leachables are extractables derived from drug packaging or delivery systems that may migrate into the drug product over the course of a drug product’s shelf life. Leachables can affect the stability and efficacy of the drug product, and in some extreme cases, introduce some patient safety risks.
Q: How can USP help?
A: The U.S. Pharmacopeial Convention (USP) is a nonprofit scientific organization that develops and revises public standards that help promote global drug quality. USP’s standards encompass drug substances, excipients, drug products and their delivery and packaging systems. These standards are available for use by industry, academia, regulators, healthcare professionals and other stakeholders.
USP’s published official standards—in the form of specifications for identity, strength, quality and purity in drug product, drug substance and excipient monographs as well as information and procedures in general chapters—appear in the compendia, U.S. Pharmacopeia—National Formulary (USP–NF).
Q: What USP standards are available to support work with plastic packaging systems, as well as extractables and leachables?
A: USP has developed the following standards specifically for plastic packaging systems:
- General Chapter <661> Plastic Packaging Systems and their Materials of Construction: Testing rationale for plastic materials of construction and packaging systems used in the pharmaceutical industry. The use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suitable for its intended use since properties and characteristics of the materials can be matched to the performance requirements of the packaging system. (Current official standard, published in USP 38–NF 33.)
- General Chapter <661.1> Plastic Materials of Construction: Tests, procedures and acceptance criteria for plastic materials of construction used in pharmaceutical packaging systems. Proper characterization of materials of construction facilitates the identification of and use of appropriate materials for pharmaceutical packaging systems. (New standard, becomes official May 1, 2016, published in USP 39–NF 34.)
- General Chapter <661.2> Plastic Packaging Systems for Pharmaceutical Use: Safety aspects of a drug product’s packaging system based on appropriate chemical assessments, includes performing extractables testing, leachables testing, and toxicology assessment. (New standard, becomes official May 1, 2016, published in USP 39–NF 34.)
- General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems*: Framework for the design, justification and execution of an extractables assessment for pharmaceutical packaging and delivery systems. Establishes critical dimensions of an extractables assessment and discusses practical and technical aspects of each. Also examines critical dimensions of an extraction study—laboratory generation of the extract (extraction) and testing the extract (characterization). (Current official standard, published in USP 38–NF 33, S1.)
- General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems*: Framework for the design, justification and implementation of assessments for drug-product leachables derived from pharmaceutical packaging and delivery systems. Covers: 1) the requirement for leachables studies; 2) fundamental concepts for leachables studies; 3) the basis of thresholds for leachables and general guidance and application of these thresholds; 4) design and implementation of leachables studies; 5) leachables method development and validation; 6) correlation of results from extractables assessment and routine extractables testing with leachables studies; and 7) establishment of leachables specification including acceptance criteria. (Current official standard, published in USP 38–NF 33, S1.)
*This chapter is for informational purposes, it does not establish specific conditions, analytical methods, specifications, or acceptance criteria for any particular dosage forms or packaging system or drug product combination. The principles and best practices outlined in this general chapter represent a unified interpretation of sound science and are applicable to situations in which extractables or leachables assessment is required for pharmaceutical application.
Q: Does USP have plans to develop future standards for plastic packaging systems?
A: Yes, USP is currently developing a brand new chapter <661.3> Plastic Materials for Pharmaceutical Manufacturing Systems which will cover plastic components and systems used in the manufacturing of a drug products. The chapter is scheduled to be published for public review and comment in Pharmacopeial Forum 42 (3) May 2016.
In addition, we will be hosting a workshop June 20–21 on Material Biocompatibility and Standard for Plastic Manufacturing Systems/Components at our facility in Rockville, MD.
We encourage all interested parties to take advantage of these two new resources to learn more and contribute to the development of new USP standards for drug packaging systems.
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