PACKAGING UPDATE: REQUIREMENTS ON PACKAGING AND MATERIALS - PART I
Primary packaging for medicinal products and materials for the manufacture of primary packaging must be developed with great care or chosen from offers already on the market. The main reasons are the possible interactions with the content as well as the protection of the content and safety aspects during the following application. A comprehensive knowledge or characterisation of the packaging material is prerequisite for the subsequent use.
According to the FDA Guideline "Container Closure Systems for Packaging Human Drugs and Biologics" (May 1999) each application should contain enough information to show that each proposed container system and its components are suitable for its intended use. This comprises:
- Protection (light, oxygen, humidity etc.)
- Compatibility
- Safety (extraction study, toxicological evaluation)
- Performance and functionality
Packaging material is at the focus of some regulatory developments at the moment. These developments are summarised in the following.
Glass
The Chapters on glass of the Ph. Eur. (chapter 3.2.1 Glass containers for pharmaceutical use) and the USP (<660> Containers-Glass) were changed or newly introduced (<1660> Evaluation of the inner surface durability of glass containers) in order to integrate the consideration of a possible delamination. The recalls of medicinal products in vials (glass type 1) because of glass flakes due to delamination that occurred in the USA in the past have shown that glass is not absolutely inert. This has to be taken into consideration when deciding on the type of packaging, the type of use (especially parenteral use) and depending on certain risk factors of the formulation (such as formulations with organic acids, EDTA, high pH-value). A delamination potentially occurring during storage should be examined particularly within the scope of stability tests or by means of tests under stress conditions during development.
Plastics
The revised USP chapter <661> (Containers-Plastics) came into effect on 1 May 2016 (USP 39-NF34). Apart from changing the title (new title of chapter <661>: Plastic packaging systems and their materials of construction) parts of chapter <661> were transferred into two new USP chapters
- <661.1> (Plastic materials of construction) and
- <661.2> (Plastic packaging systems for pharmaceutical use)
Chapter <661.1> contains information on how to determine whether a plastic material is characterised comprehensively. Chapter <661.2> describes test methods and standards for plastic packaging systems.
Furthermore, the new USP chapter <1661> (Evaluation of plastic packaging systems and their materials of construction with respect to their user safety impact) came into effect on 1 May 2016.
Besides, the new chapter <661.1> contains the requirement to test the materials for plastic packaging systems according to USP <87> (Biological reactivity tests, in vitro), also for oral and topical preparations. The former chapter <661> did not require a test according to <87> for these dosage forms as long as the materials were in conformity with the US FDA "indirect food additive guideline".
The European "Guideline on plastic immediate packaging materials" (December 2005) and the FDA "Container Closure Guideline" already mentioned do not require this test for packaging material for oral and topical dosage forms. In general they consider compliance with the requirements of the food legislations (EU Regulation on plastic No. 10/2011, USA: CFR 21 Indirect Food Additives) as being sufficient. According to the principles of both regulations materials that are considered to be save for food contact are also safe for packaging materials for oral and topical dosage forms. There seems to be a discrepancy between the rules at the moment.
With the drafts for <661.1> and <661.2> in PF 42(4) [July 2016] the USP has just removed again the requirements for a test according to <87> for packaging materials and systems for oral and topical dosage forms. The reason lies in the actual revision of the USP General Chapters <87> and <88> (Biological Reactivity Tests, In Vivo) that has priority. Depending on the revisions of <87> and <88> the two chapters on packaging (<661.1> and <661.2>) could be revised subsequently for harmonisation.
Furthermore, the USP General Chapters - Packaging and Distribution Expert Committee proposes a new chapter in the Pharmacopoeial Forum (PF) 42(3), May-June 2016: This new chapter <661.3> with the title "Plastic components and systems used in pharmaceutical manufacturing" is supposed to address the qualification of plastic components and systems used in the manufacture of active pharmaceutical ingredients and medicinal products.
The manufacturers of active pharmaceutical ingredients and medicinal products are responsible for guaranteeing that the plastic components and systems used are suited for their intended use. It is possible that raw materials, production intermediates, process streams, active pharmaceutical ingredients, and medicinal products will come into contact with one or more plastic components of the manufacturing suite during the manufacturing process, resulting in process-related impurities (PrIs). PrIs have the potential to alter a quality attribute of the intermediates and also the finished medicinal product, if the PrIs persist through the manufacturing process.
The chapter is applicable solely to processes that involve liquid process streams and process intermediates due to the expected increased degree of interaction with liquids. Plastic manufacturing systems for pharmaceutical use include, but are not limited to, bags, cassettes, chromatographic columns, connectors, filling needles, filters, sensors, tanks, tubing, and valves. Elastomeric parts such as diaphragms, gaskets, and Orings are outside of the scope of this chapter.
Plastic components and systems are chemically suited for their intended use with respect to safety if
- they are constructed from wellcharacterized materials that have been intentionally chosen for use (as established by the test methods included in USP General Chapter <661.1>),
- the general physicochemical properties of the components or systems have been established,
- the biocompatibility (biological reactivity) has been appropriately established,
- they have been established as safe by means of the appropriate chemical testing, such as extractables or leachables profiling and toxicological assessment of the test data.
The chapter provides guidance on the appropriate application of the biological reactivity tests (reference to USP General Chapters <87>, <88>) and physicochemical tests (cross reference to food regulations and USP General Chapter <661.1>) to manufacturing components and systems. A two-stage approach to component characterisation, consisting of an Initial Assessment followed by a Risk Assessment leads to the required level of component characterisation. In the Initial Assessment the factors present are examined for the demonstration of equivalence with a comparator component or system. The following parameters are considered:
- purpose and composition of component or system;
- composition of medicinal product(s);
- processing conditions;
- product dosage form.
Demonstration of equivalence can allow acceptance of the component (or the system) without further characterisation. If equivalence cannot be established between the component (or system) under consideration and the comparator, then a risk assessment should be conducted. The risk assessment matrix is provided in detail in General Chapter <1661>. The outcome of this assessment establishes three levels of risk: low (Level A), moderate (Level B), and high (Level C). These levels are linked to the following test requirements described in the draft chapter <661.3> according to the risk of the single dosage forms (such as "solid oral and liquid oral" and "other than solid oral and liquid oral"). All three risk levels require that the component or system is tested for identity as specified in General Chapter <661.1>. However, the determination of identity is only required for those components or systems that consist of single materials of construction (individual polymers, not mixtures of polymeric compounds). Biological reactivity tests according to USP General Chapter <87> (In Vitro) are required for all levels as well as tests according to Class VI in <88> (In Vivo) for the levels B and C. The levels A and B require that the component or system is tested as specified in General Chapter <661.1> for physicochemical characteristics and extractable metals profile. With regard to the extractables profile components and systems in Risk Level C must be more rigorously characterised than those represented in the Levels A and B (such as use of other extraction solvents, testing for extractable organic compounds).
Additives: For components in Risk Level A a reference to 21 CFR Indirect Food Additive Regulation is sufficient. For components in Risk Level B additives must be determined by testing. In the case of components or systems in the Risk Level C extraction studies must be performed according to the Standard Extraction Protocol in the proposed chapter <661.3>.
A flow diagram that shows a typical biotechnological process of a medicinal product in connection with the possible production system is shown in General Chapter <1661> figure 2. To support the use and understanding of this new General Chapter <661.3> a section has been added to this chapter. The issue PF 42(3) also contains the revision of the General Chapter <1661> (including the changing of the title in Evaluation of plastic packaging and manufacturing systems and their materials of construction with respect to their user safety impact).
Metals
One of the oldest packaging materials used in the food industry is aluminium. It is for example often used to wrap chocolate. A metal packaging system was first used to package pharmaceutical products in the early 1900s due to its lightness and its impermeability to light and moisture. Common metal packaging components include aluminium and its alloys, stainless steel, tin-free steel, and tinplate. Within the pharmaceutical industry, primary metal packaging systems can include aerosols, blister packs, canisters, collapsible tubes, drums and gas cylinders, and secondary packaging systems such as overwraps and seals. Currently there are no compendial standards for metal packaging systems.
The USP Expert Committee "General Chapters-Packaging and Storage" has announced the development of a new General Chapter <662> that will provide test methods and standards for materials of metal packaging systems to help ensure the safety and suitability of metal packaging systems for pharmaceutical products. Its proposed title is "Metal packaging components and their materials of construction". The announcement was published on 26 February 2016, deadline for inputs was 29 March 2016.
Suggested audience of the document are on the one hand suppliers of metal materials and components used for packaging systems (primary packaging components) and on the other hand medicinal product manufacturers using metal primary containers. Scope and applications concern metal materials and components that make up a primary packaging system. The function of this chapter is to help determine the safety and suitability of metal packaging systems for pharmaceutical products. The draft of the new chapter is supposed to be published in the Pharmacopeial Forum (PF) 44 (2018). A stimuli article (Metal Packaging Systems and Their Materials of Construction for Pharmaceutical Products) on the proposed General Chapter <662> has already been published in PF 39(4) in July-August 2013.
Part II of this article in the next GMP Journal issue will cover Extractables and Leachables, Container-Closure Integrity and requirements for sterile packaging as well as defect evaluation lists.
Author:
Dr Andrea Kühn-Hebecker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area pharmaceutics and cosmetics manufacturing, focussed mainly on packaging, development and life cycle management.
