NEWS

‘Materials of concern’ and the rapidly changing environmental and sustainability regulatory environment

25 May 2023
Drug Substance
Fill Finish
Supply Partner
Sustainability
Bob Brooks
Phorum Director

Since the end of the Covid-19 pandemic and COP26 and 27, there has been even more focus on the environmental and sustainability agenda at a global level. BioPhorum Supply Partner is a closely networked community of suppliers and biopharmaceutical manufacturers with links to BioPhorum Sustainability and other external organizations and agencies. Through our network, we have been made aware of several issues raised by the changing environmental and sustainability regulatory environment around several ‘materials of concern’.

Here we discuss the high-level issues and their impact – and what BioPhorum Supply Partner is doing about them.

Per- and polyfluoroalkyl substances (PFAS)

PFAS chemicals are a large class of commonly used synthetic polymers. They have some amazing properties around inertness and hydrophobicity and are widely used in the biopharmaceutical industry, e.g., in filter membranes, gaskets, seals, etc.

However, they are known as ‘forever chemicals’ because they are inert, do not degrade, and are increasingly considered environmental pollutants. Some are also absorbed by the body and can cause illnesses such as cancer. There are reports that almost every human on the planet may have detectable levels of PFAS in their bodies.

There is therefore a strong drive to stop making and using them. The European Commission has started a regulatory process through the European Chemicals Agency (ECHA) to do this under the REACH Regulations (see here and here) and has issued a proposal referencing several industries. The aim is to identify where some of these key materials are being used and give a timeline to find alternative solutions before they are banned.

However, the biopharmaceutical industry is conspicuous by its absence in the ECHA’s Annex XV Restriction Report Proposal For A Restriction on Per- And Polyfluoroalkyl Substances, and the European Commission has not fully considered the impacts its PFAS proposals will have on us, our industry, patients and their families, and the current and future communities that we are serving. These impacts are likely to be significant as almost all biomanufacturing equipment processes and equipment contain PFAS. The issue may also impact packaging and distribution in the forward supply chain.

Moving away from PFAS is also likely to impact regulatory filings. For example, any component change, such as installing a non-PFAS filter, will require a change notification and a potential revalidation activity on a production-batch scale with associated costs, time, and potential quality issues (if the substituted materials are not as effective as PFAS for the purpose selected). Can industry handle the number of changes that may need to happen quickly? And can regulatory agencies?

Hopefully, with consultation, our industry will probably be given a derogation period of a few years to implement PFAS alternatives. This would be similar to the periods proposed for other industries that have been recognized as being impacted, including the medical devices sector where derogation periods of up to 12 years post the 18-month transition period have been proposed (see the ECHA’s Annex XV Report, Section 2.4.3.3 Environmental impacts of restriction options, Sub-section h).

Identifying a need to replace a PFAS item raises many questions. Will the new parts or materials be available? Will the alternative materials have their own environmental and safety issues? Will they be a potential candidate for obsolescence in the not-too-distant future too? And if we introduce a new base material, must we re-look at extractables and leachables profiling? This would be expensive and time-consuming, and laboratories would be even more constrained by extra testing work. These are just some areas that industry must consider when replacing PFAS.

The European Commission is running a consultation that ends in September 2023 looking at restricting the manufacture, placing on the market, and use of PFAS. Those most likely to be interested are companies, organizations representing industry or civil society, and authorities. Stakeholders from the EU and outside are invited to submit comments.

We recognize that a full assessment of the impact of removing PFAS chemicals from the biopharmaceutical manufacturing industry and supporting the inbound supply chain is impossible in the consultation timeframe. However, since March 2023, BioPhorum has been working on a considered response leveraging the understanding of our community of members from across the supplier base and biopharmaceutical manufacturing value chain (BioPhorum response to the Annex XV report on the proposal for universal PFAS restrictions). These are represented by our Supply Partner, Drug Substance, Fill Finish and Cell & Gene Therapy Phorums and aided by BioPhorum Sustainability.

The use of PFAS is a global issue. Europe is leading the charge, but some states in the US have already enacted legislation to restrict the use or manufacture of PFAS. We also know that the US Environmental Protection Agency is also looking at PFAS levels in water and planning to set quite low allowable levels for the top six substances, which will impact other PFAS associated with them.

Ethylene oxide (EtO)

This gas is used to sterilize medical devices and some elements of single-use system technologies. However, there have been instances of leaks at sterilization facilities, EtO emissions, and perceived cancer clusters around these facilities. Emissions control technologies have improved and management of EtO is deemed to be essential to reduce the overall cancer threat to those who live near facilities.

The US Environment Protection Agency wants industry to stop using this gas and is trying to tighten the acceptable emission levels and increase the requirements for personal protective equipment that operators must wear. The issue is not the intent here but the timeframe in which these changes are being proposed to become legislation, which is too short for industry to react and plan a safe, appropriate, and economically viable transition.

Some service providers using EtO have said they will find these restrictions so stringent that they will stop using it – but will not retrofit their facilities for other sterilization methods. For example, the US Biomedical Advanced Research and Development Authority (BARDA) has said that of the 86 US facilities using EtO, several are likely to either seriously curtail their operations or close them down. If all 86 sites were to close, this would affect 50% of the capacity for sterilization in the US – with an unthinkable impact on the biopharmaceutical manufacturing industry’s ability to produce vaccines and biotherapeutics.

Even if a smaller percentage of EtO sterilization service providers shutdown, a further concern is that as an alternative, some companies will look to switch sterilization to gamma irradiation. However, gamma is already constrained, and service providers say they will not build any more gamma facilities and are investing in X-ray sterilization facilities. Unfortunately, there are only two X-ray facilities planned to come online in the next few months, versus the much larger number of gamma irradiation facilities already fully loaded for capacity throughput. Therefore, X-ray is not a viable alternative for any volume previously sterilized by EtO. Yet X-ray is already being factored into biopharmaceutical manufacturers’ capacity plans to help relieve the situation with gamma irradiation capacity for their bioprocessing materials requirements – therefore, compromising X-ray capacity is as detrimental as compromising gamma capacity. BioPhorum is working hard to get X-ray adopted as a universal validation package, and this approach has been well received by the FDA and other regulatory agencies but, as stated above, it is not a solution for EtO carry-over capacity requirements. Many questions remain to be resolved, e.g., the issue of EtO regulations being tightened in other regions of the world also needs to be considered.

The need for solutions to EtO is being driven by regulators and at a much faster pace than PFAS. Industry needs a similar approach to the proposal of derogation periods to allow the transition away from using EtO to other modes of sterilization. Considering product redesign and revalidation timelines, the 12 years given for PFAS would seem more appropriate in the case of EtO.

Regulators are looking for a solution in the next 18 months, so industry has less time to find and implement an answer. Working in partnership with regulatory agencies is how BioPhorum hopes to help the transition happen at a pace that industry can handle and without concerns for the availability of the life-changing biopharmaceuticals that so many already rely on.

Nitrosamines

This material of concern gets into feedstocks and our biopharmaceutical manufacturing production and may not get stripped out by the downstream process. They are thought to be genotoxic and carcinogenic. Many are agriculturally derived and may enter the production process as a contaminant or be created during processing when nitrogenous materials are converted into nitrosamines. The European Federation of Pharmaceutical Industry and Associations has produced a Quality Risk Management Workflow to help biopharmaceutical manufacturers identify if there is a potential risk in their manufacturing processes.

We need to understand whether we can better control and manage the biopharmaceutical manufacturing process and how cells metabolize nitrogenous materials during production. We should also consider whether there is a source of nitrogen that is more likely to cause nitrosamines to occur than others and look to minimize the risk.

As a recognized material of concern, the FDA, EMA, and other jurisdictions will be looking to see our industry take the right risk management approaches to minimize the exposure of patients to nitrosamines (Nitrosamines are thought to be genotoxic and carcinogenic and, whilst there is concern, their overall impact needs to be understood – see the EMA’s advice on nitrosamines). It is highly likely that regulations on nitrosamines and raising awareness of them will be increased globally. Once a material gets to a level of profile, it is also picked up by the World Health Organization (WHO), which has produced a publication titled: Initial Note on Nitrosamine Impurities.

We need to understand the timelines established by regulators, which will define how quickly industry needs to act and what we need to do to transition away from these materials. Collaborating with regulatory agencies on this transition is how our industry can demonstrate our duty of care to patients, the planet, and the people involved in our industry.

So how do we tackle these issues?

Whether it is any of the above three materials of concern or the next potential one, we need to develop a high-level approach for managing the transition away from them as an industry. This must consider the impact on the current patient population supported by processes that may need to change. It must also be mindful that we are all global citizens and want to do the right thing for the future without negatively impacting anyone relying on our biotherapeutics in the present.

This is the aim of our BioPhorum, Supply Partner Phorum, Leadership Team, SPP16 conference, where we will develop a high-level approach outlining the actions needed to address these issues in a standardized way based on our ‘one voice’ industry consensus. This way, we can proactively drive the agenda rather than have it forced upon us.

While subtleties will apply to each issue, there are common elements that apply to them all. We will use PFAS, EtO and nitrosamines as test cases on how to develop the ability to investigate our processes and identify where we might need to make an industry-wide change.

This means asking many questions, such as How do we do this? What information should we collect? What systems and processes do we have in place that can be shared? Where are the gaps in our data collection, or what are the processes to use during this transition activity? Can we leverage what we have learned in other areas that have adopted an industry-wide approach, e.g., the move to X-ray?

This approach means we can develop a common framework for addressing future issues that we can take ‘off-the-shelf’ and modify it to a new situation or crisis using a risk-based approach. This will show that we have done our due diligence and have a plan that includes transitioning away from a problem, managing communications, meeting regulatory requirements without swamping agencies, etc.

Industry must come together and demonstrate that we have a consensus solution – we will then be in a strong position when making proposals to regulators. If we do not do this, organizations will try to create their own solutions, which is inefficient and can cause problems for regulators, who will be bombarded with many different proposals.

It seems certain that the need to resolve this type of issue will become more common as environmental and sustainability regulations require a greater understanding of how these materials behave in the environment and how they affect humans. If we can build an approach with some longevity and flexibility, it will be easier to deal with this type of issue in the future.

Part of the answer might be learning from previous work in programs such as those on the REACH Regulations. These aim to provide a high level of protection of human health and the environment from using chemicals and make those who place chemicals on the market responsible for managing the associated risks. They also promote using alternative methods to assess the hazardous properties of substances.
Other industries will be facing similar issues and BioPhorum is open to working with organizations and bodies in other sectors as well as those in our own, such as the European Federation of Pharmaceutical Industries and Associations, the European Chemical Industry Council, the Bio-Process Systems Alliance, the Parenteral Drug Association, and others. We can act as the ‘connective tissue’ to help coordinate best practices for addressing this type of high-level, pan-sector issue. This would create enormous efficiencies, ensure we support each other, and streamline conversations with regulators.

Covid-19

Another subject we will look at during SPP16 is the WHO challenge of ‘Imagining the future of pandemics and epidemics: a 2022 perspective’. We will review what happened during the pandemic and whether we, as companies and an industry, can achieve a state of ‘perpetual pandemic preparedness’. The WHO 2022 report sets out possible scenarios that are not predictions of the future but instead invites us to imagine the different directions that current and future pandemics might take and to expand the range of plausible futures. The scenarios are an opportunity to identify possible risks and solutions, discuss the implications, and propose actions aimed at preventing the occurrence or mitigating the impact of current and future infectious threats. It has a short time horizon (3–5 years) to encourage immediate action.
This means we must reflect on what happened in the inbound supply chain and question whether, if another pandemic happened again soon, would we react in the same way and have the same issues at the same time in the pandemic cycle – or would we be better prepared. If we are not ready, and if vaccines are not as effective the next time, then the global health situation could be even worse than during the Covid-19 pandemic.

We must ask ourselves what fundamental things we must do to make the inbound supply chain more resilient and robust. There is also the risk that another pandemic may go on beyond 1–2 years; we would then be in a very tough position because all forward inventories would be used. And if we cannot manufacture batches, we will have drug shortages with all of the critical effects this would have on patients.

BioPhorum actions

To help overcome these issues, it might be useful to consider the concept of ‘design thinking’. BioPhorum has always used this type of approach, which tries to address difficult problems and ones not easily reconcilable by individual organizations on their own. These are typically global or social problems but are also common in the highly regulated and technically challenging biopharmaceutical manufacturing industry – just look at the PFAS, EtO and Nitrosamines issues above. The idea is not to find an ‘end solution’ to every problem but to improve a situation. We will explore how we, as an industry, achieve a state of perpetual pandemic preparedness using a ‘design thinking’ approach or something similar in SPP16 to investigate solutions to some of the problems discussed in this article.

In the Biopharmaceutical manufacturing industry’s strategic framework, created by the community members of BioPhorum Supply Partner, we have already identified the key five strategic objectives that will help drive operational excellence and improvements needed to address these issues. Our members own the inbound supply chain for our industry and have the expertise to help make change happen. These issues affect us all and our peer-to-peer conversations between biomanufacturers and suppliers are the way to facilitate the transition away from these materials of concern and learn lessons from Covid-19.

Addressing these materials of concern will require coordination with external organizations and internally within BioPhorum. That is why we will be talking to our colleagues in BioPhorum Drug Substance, BioPhorum Fill Finish, BioPhorum CGT, BioPhorum IT, etc., as these issues do not just sit within one Phorum, they are cross-functional and action needs to be coordinated through a central point, i.e., BioPhorum Supply Partner.

These are just some of the exciting and critical subjects we will discuss in SPP 16 on 6–8 June in Barcelona. Do you want to know more, or share your expertise in these materials so that industry can create long-term sustainable solutions?
For this event, we are running end-of-day, online review and workshop sessions to engage with our members who cannot be with us in person. These inclusive sessions mean all our members can participate in the workshop activities during the conference. For more information about SPP16 or BioPhorum’s actions on these issues, contact Bob Brooks, BioPhorum Supply Partner Director, at bob.brooks@biophorum.com

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