Microplastics: Proposed EU Rules on Small Particles Could Lead to Big Implications

 Microplastics: Proposed EU Rules on Small Particles Could Lead to Big Implications
Pilvi Jalonen, 
Bayer Consumer Care AG 

Chris Moreton,* 
FinnBrit Consulting 

Meera Raghuram,* 
Lubrizol Advanced Materials Inc. 

*IPEC-Americas


Less than 100 years after the dawn of plastics in the 1950s, its tiny byproducts can be found on every continent and in every ocean. Studies are showing that microplastics—defined as any solid synthetic polymer particle with a size <5 mm— are impacting marine life, and may also contribute to human health issues. 

There is ongoing discussion and considerations of regulatory and legislative actions to minimize and mitigate plastic pollution in a variety of areas—all warranted, considering the magnitude of this problem. In the European Union, measures are planned to restrict the use of intentionally added microplastics, which aff ects a range of industries including the pharmaceutical sector. Perspective is key; one European Chemicals Agency (ECHA) estimate suggest that the pharmaceutical sector accounts for less than 4% of all intentionally added microplastics used in various market segments, with a fraction of this resulting in potential releases into the environment.1 

In confronting the microplastics situation, the pharmaceutical industry must navigate several nuances. Is the by-product released from medicinal product formulations considered a “Primary” or “Secondary” microplastic? What are the properties of polymers used in medicines? And how do various drug formulations (immediate, modified release etc.) affect the release of microplastics on excretion based on tablet size or excipient/polymer properties? 

Of ‘Primary’ Importance 

First, we must recognize the distinction between primary and secondary microplastics. “Primary” microplastics are particles intentionally manufactured to serve a function—for instance, dermabrasion in a lotion. “Secondary” microplastics result from a product breaking down—for instance, the ubiquitous single-use plastic shopping bag deteriorating into smaller pieces. 

The distinction is paramount, since the ECHA proposes restricting intentionally added microplastics—in other words, primary microplastics—under the Restriction, Evaluation and Authorization (REACH) chemical regulation, expected to be adopted later this year. As part of the European Green Deal and the Circular Economy Action Plan, initiatives have been published in recent years to address both microplastics that are intentionally added to products (including medicinal products) and microplastics that are unintentionally released into the environment (such as released from textiles, tires and plastic pellets). Microplastics resulting from the fragmentation of macroplastics such as plastic bags and bottles are already addressed by existing EU policy and legislation (e.g. EU Plastics Strategy, the Single Use Plastic Directive, the Waste Framework and Marine Strategy Framework Directives). The ECHA proposal covers medicinal products in controlled release applications primarily due to use of polymeric ingredients (excipients and active ingredients), which fall under the EC

HA’s definition of microplastics. 

While it’s tempting to say that this regulation is only an EU issue, it’s important to recognize its wider impact. Medicinal product development and supply chains are global and any company importing and/or exporting medicinal products into or out of Europe will be impacted. Other countries will also likely take on similar rules. 

Chemical Considerations The next nuance is chemical in nature. Polymeric materials considered microplastics can continue to be used in medicinal products subject to labeling and reporting requirements. Polymers that are natural, soluble or biodegradable are considered out of scope from classification as a microplastic. Additionally, polymers where properties are permanently modified during use (swellable polymers that are no longer solid and permanently modified etc.) are no longer considered microplastics, and derogated. 

Here’s where it gets complicated. In the current microplastic restriction proposal,2 excipients and actives—that are polymers, solid and have all dimensions ≤5 mm—are considered microplastics. The ECHA’s assumption appears to be that particles released from these medicinal components will eventually make their way into the environment essentially unchanged after excretion. Similarly, a polymer-coated tablet is assumed to be a microplastic if it is <5 mm in size. The above assumptions do not account for certain excipient properties, formulation and tablet characteristics that may result in changing the microplastic characteristics during formulation an

d ingestion of the medicinal product, thereby minimizing releases of primary microplastics into the environment. Hydrophilic polymers like certain acrylates, carbomers etc. are hygroscopic and are transformed into a gel in use and permanently lose their solid particulate state and are not excreted as microplastics. Some of the synthetic excipients--like povidone--are water soluble and are out of scope of the regulation. 

Examples of insoluble excipients include crospovidone and croscarmellose sodium where their size is within the range of the microplastics. While they may swell in aqueous media, they will not swell sufficiently to no longer be microplastics, and they will pass out of the body as intact particles. 

Release Mechanisms 

The final nuance concerns how and when medicines release their active ingredients. Because of the above complexities, it’s essential to assess each excipient and formulation on its own chemical characteristics, rather than the more simplified categories of “Primary” and “Secondary” microplastics. It’s also necessary to include formulation characteristics in the analysis. Modified release formulations include delayed release and extended/controlled release products. Immediate-release formulations disintegrate and free their active ingredient(s) during or after ingestion, while modified release formulations are designed to release these ingredients over a prolonged time period or after a delay. 

Immediate-release tablets and capsules of all dimensions (larger and smaller than 5 mm) may contain excipients that fall into ECHA’s definition of microplastic either in the tablet/capsule core or in the coating, for example certain synthetic excipients. As described above, these formulations disintegrate either in the mouth or in the stomach after ingestion. Formulations with soluble polymers in the coating or in the core will completely disintegrate, the polymer will dissolve and will not result in release of microplastic particles. Most immediate-release formulations have dimensions >5 mm, and are thus not microplastics. However, the question that remains is, if insoluble polymer particles present in the tablet core are excreted, would they be considered secondary microplastics? 

The assumption in ECHA’s restriction report that a tablet with a solid coating is always excreted unchanged as a microplastic is incorrect. Modified release tablets and capsules can be of two main types: membrane-controlled or matrix-controlled release. The tablet characteristics in this case would determine if a tablet/ polymer is released as a microplastic as illustrated below. In membrane-controlled release, the control of dissolution and release of the drug is achieved using a coating. The coating may be applied to whole tablets, or minitablets or spheroids that are then filled into capsules or compressed into tablets. If a regular-sized tablet is coated, it is most likely that the formulation will be outside the definition of a microplastic, since at least one dimension typically will be >5 mm, and the tablet will likely pass out of the body intact. 

Coated spheroids and minitablets fall within the size range of microplastics. However, they are typically administered either filled into hard capsules or compressed, along with other excipients, into tablets. The coated spheroids and minitablets would also pass out of the body very close to their original size. Since they are not administered as individual units, it can be argued that they become secondary microplastics on excretion from the body. 

In delayed-release membrane-controlled products, a polymer coating dissolves at a particular pH in the gastrointestinal tract for gastro-resistant coating and colonic delivery. Chronotherapeutic release is typically achieved by means of a thick hydrophilic colloid coating around the tablet core, which takes a certain time to dissolve and thus allows the drug to be released for absorption. In this case, the tablet would not be released as a microplastic as the coating would dissolve and the tablet core would disintegrate. 

Matrix-controlled release formulations are most usually tablets and can have hydrophilic or hydrophobic matrices. Typically, matrix-controlled release tablets do not fall within the definition of a microplastic, since they will have one dimension >5 mm. Hydrophilic matrices are formed from hydrophilic polymers that hydrate and swell in contact with aqueous media. The drug release is governed by the diffusion of water into the matrix, hydration and swelling of the hydrophilic colloid matrix forming material, dissolution of the active drug, diffusion of the dissolved drug out of the tablet and its release into the gastrointestinal tract. Such tablets will swell in aqueous media; however, as the outer layers become more dilute, they are eroded by the action of the gastrointestinal tract. When sufficiently dilute, these polymers are typically water-soluble and would not be released as microplastics. 

Hydrophobic matrices do not swell, but incorporate soluble channeling agents into the formulation that dissolve due to the influx of water and leave tortuous channels through which the drug diffuses and is released from the tablet. Hydrophobic matrices typically retain their shape during passage through the gastrointestinal tract and will be excreted with approximately the same size as the original tablet. A question that needs to be asked here is, if polymer particles present in the tablet core in a matrix system are excreted, would they be considered secondary microplastic? However, most hydrophobic matrix tablets are >5 mm, and thus not microplastics. 

Osmotic pump devices are also membrane-controlled. In this case, the tablet core is coated with a semi-permeable membrane and a hole is drilled through the membrane using a laser device. After administration, water diffuses into the device through the semi-permeable membrane, dissolving or suspending the drug. As the osmotic pressure builds up, the drug solution or suspension is forced out of the device through the laser-drilled hole. Osmotic pump devices retain their shape during transit down the gastrointestinal tract, and when excreted, are generally a similar size to when they were administered. Typically, oral osmotic pump devices will have at least one dimension >5 mm, and are thus not microplastics. 

Controlled-release aqueous suspensions are based on ion exchange resins whereby the drug is taken up into the ion exchange resin and released over an extended period in the gastrointestinal tract. The ion-exchange resin beads may be further modified to provide for the extended release. The ion-exchange resin particles fall within the definition of microparticles and would be expected to pass out of the body also as microparticles. 

A Path Forward 

The above discussion illustrates the complexity in medicinal products and how both polymer excipient properties and tablet or capsule formulation can impact whether a primary or secondary microplastic is released after use. Reporting releases of microplastics from medicinal products is important, as ECHA has indicated that additional data and information collected in a systematic manner will guide future regulatory actions. Therefore, the pharmaceutical sector—including both excipient and medicinal product manufacturers—must develop guidance on how microplastics are evaluated and potential releases estimated. The information above is also driven by data that includes knowledge of polymer properties and environmental fate to assess if a polymer is within scope and will be subject to derogation based on its properties in use. Similarly, the drug manufacturer must clearly understand the characteristics of the solid dose formulation to determine if a tablet ≤5 mm would eventually be released as a microplastic. The pharmaceutical sector should develop a strategy to ensure that any reported releases are justified and verifiable. Another challenge? Only limited data may be available for excipients related to biodegradation and environmental fate. Excipients are complex and based on the supplier, manufacturing process, and intended use, the physical chemical properties can vary significantly within the same excipient family. A drug manufacturer may get confusing data, depending on the supplier, and that makes a thorough assessment even more complex. 

The pharmaceutical sector should also provide clarity and realistic release estimates to allow a more accurate assessment of the releases from medicinal products. ECHA has stated that reporting requirements for any sector will end once use of microplastics has stopped. Reformulation and approval of drugs can take 5 – 10 years and without workable alternatives, reformulation is not a viable option. The use of polymeric excipients has enabled formulations that have both improved and saved the lives of countless patients. The pharmaceutical sector must educate and inform on the specificities of pharmaceutical formulations and, consequently, realistic estimates of releases into the environment. As it does so, the industry should be proactive in categorizing and reporting what it considers “Primary” microplastics in its formulations. By addressing categorization and reporting issues now, the industry may alleviate over-regulation in the future. 


References 

1. ANNEX XV RESTRICTION REPORT PROPOSAL FOR A RESTRICTION, intentionally added microplastics, European Chemicals Agency (ECHA), Annankatu 18, PO BOX 400, FI-00121, Helsinki, Finland, VERSION NUMBER: 1.2 

2. Annex to the Annex XV Restriction Report, Proposal for a restriction, Substance name: intentionally added microplastics, European Chemicals Agency (ECHA), Annankatu 18, PO BOX 400, FI-00121, Helsinki, Finland. VERSION NUMBER: 1.2 DATE: 22 August 2019 


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