A regulatory change can force the entire pharmaceutical manufacturing industry into a race to become compliant and come to grips with the new reality. When those new rules apply to an emerging trend in a previously unregulated part of the manufacturing process, the challenge becomes even more significant. The increase in the prevalence of single-use systems (SUS) has created precisely that scenario.
United States Pharmacopeia (USP) has been developing chapter <665> since 2015, reacting to the increased use of SUS over stainless steel containers. A final version of the guidance was published in 2022 and is scheduled to become official in 2026, allowing manufacturers time to generate, assess and validate the data they’ll need.
USP <665> has already given the industry plenty to think about and will make an even larger impact once it becomes mandatory. Therefore, manufacturers must understand how the chapter was developed, what it looks like now and how it might change.
The introduction of single-use systems
Drugs were traditionally manufactured in stainless steel containers, which require meticulous cleaning after use. These containers must also be painstakingly tested for contaminants before they can be reused. The entire process is resource intensive and lacks the flexibility required to change the size of a drug batch between cases. The containers themselves take up valuable real estate in manufacturing facilities.
To address this problem, the industry adopted SUS — i.e., plastic components that can be used once and discarded. SUS don’t need cleaning and testing between uses, and they allow drug manufacturers to scale batch sizes according to specifications. By making the switch, manufacturers reduced costs and decreased the footprint in their facilities.
However, by adopting these new systems, manufacturers introduced a significant amount of plastic into their processes. Plastic has a far greater chance of interacting with the drugs these SUS are used to help manufacture compared to the old stainless steel units. This interaction is not just a concern for the integrity of the drug itself; it also raises significant issues regarding patient safety. This move from stainless steel to plastics led to an increased reliance on extractables/leachables (E/L) testing, but regulation lagged. Without proper guidance, there were few standardized methods to ensure chemicals from plastics in SUS were not leaching into final drug products.
A solution emerges
As manufacturers switched from old-school stainless steel to SUS, regulators scrambled to catch up. Most regulatory bodies asked for E/L data as part of their submission process, but there was no uniformity to the requirements, including how testing should be carried out and which data should be included.
The BioPhorum Operations Group (BPOG) attempted to address this need in 2014 when it introduced the first standardized extractables protocol. The BPOG protocol is based on the extraction capabilities of various solvents over recommended periods and was updated in 2020. However, following BPOG's protocol was not required or enforceable, which limited its effectiveness in uniformly addressing the risks associated with extractables and leachables in pharma manufacturing.
Manufacturers and regulators still needed a standardized method to collect E/L data. Manufacturers needed reliable data to select the components they used in SUS and justify that selection. Regulators needed to collect standardized data on component extractables from manufacturers to make sure manufacturing equipment was safe for patients. Both sides required this data to be generated in the most consistent, risk-based way possible.
USP aimed to close this gap when it introduced USP <665> and USP <1665> in the USP Packaging and Distribution Expert Committee’s 2015-2020 cycle. USP chapters above <1000> are generally informational, and those below <1000> are enforceable. In this case, USP <1665> was written as informational, containing principles and concepts relevant to the other chapter, serving as a guide to USP <665>.
Both chapters were published in the Pharmaceutical Forum four times between 2016 and 2020, each time opening them up to public comment. After substantial comments were submitted in response to all four drafts, general themes emerged and were incorporated into a final draft. The final versions of USP <665> and USP <1665> were published in May 2022, with the latter becoming official the same day. USP announced later that chapter <665> would become official on May 1, 2026, giving the industry enough time to generate and assess data.
Highlighting the purpose of USP <665>
The manufacturing industry has used SUSs for some time, proving they can be deployed safely and effectively. However, USP <665> aims to address any concerns by outlining the considerations for characterizing and qualifying plastic components. USP <665> and the accompanying USP <1665> were brought into existence based on three principles.
First, the rigor of extractables testing should be related to the risk of unsafe leachables in the final drug product. This means that the greater the risk, the more extensive and rigorous testing should be undertaken. The second principle states that extractables testing should be performed comprehensively and standardized, producing data sets comparable across component vendors. The final principle states that properly designed, executed and justified extractables testing could qualify a component as safe to use without testing manufactured drug products for manufacturing-related leachables.
What does USP <665> cover?
Even before USP <665> is made mandatory, it’s important to understand what is in it and out of the chapter’s scope.
In scope:
- Drug substances and drug products
- Pharmaceuticals, small molecule drug products, biologics
- Single-use systems and multi-use systems
Out of scope:
- Materials of construction
- Components in contact with non-liquid process streams
- Any components used to manufacture APIs, which are deemed suitable for use without testing
- Auxiliary items like scoops, funnels, pipettes, beakers, etc., do not need to be tested
- The container is out of scope and does not need testing when frozen for storage; It’s inside the scope when the drug substance is thawed
A risk-based approach
The chapter states that “the magnitude of testing required to establish that an item is safe should be directly proportional to the risk that the item could be unsafe.” The amount of testing required depends on the following:
- The likelihood that manufacturing equipment is extracted by a process solution under typical manufacturing conditions
- The likelihood that an extracted substance would persist in the process stream and become incorporated into the drug product
As the likelihood of either of those two points increases, so does the testing required for manufacturing components. The initial assessment must determine if a plastic component or system is compliant with its intended use without needing further characterization. The risk assessment classifies the risk level as either low, moderate or high.
Effective testing of an SUS does not mean every component needs to be tested. There are several elements to consider when determining the risk, including:
Proximity to final drug product: An SUS downstream may have a much higher risk of leachables reaching the final product than those used upstream.
Temperature: Higher temperatures during manufacturing should be considered. These conditions can cause more opportunities for leachables to be released from the plastic.
Contact duration and surface area: The amount of time a component is in contact with the drug product should be considered, as should the surface area. The larger the surface area in contact, the more opportunity leachables have to enter the final drug product.
Type of plastic: Single-use plastics are made from several different materials. Softer plastics have more potential for leachables than rigid plastics.
There are also mitigating factors to consider when evaluating risk. For example, the leaching of a component doesn’t necessarily mean the leached substance will harm the production output. Also, if an extractable is subsequently cleared from the process stream in a later step, it cannot affect the safety of a drug product as it will no longer be present. Finally, the dosage form can greatly affect a leachable’s degree of risk. In a low-risk dosage form like liquid oral or topical, the potential to put patient safety at risk is lower than if the same leachable is present in a high-risk dosage form like a liquid injectable.
The future of USP <665>
Although the guideline has not yet been fully implemented, the publication of USP <665> means manufacturers have already generated a vast body of data, which could be used to dictate how the chapter is applied when it does become mandatory and how it may change in the future.
At this stage, manufacturers will likely fall into one of three camps. The first is those who have not previously tested their SUSs and will now build the means to do so from scratch. They may have the most straightforward task and can familiarize themselves with USP <665> properly and construct processes that adhere to the regulation without influence from other systems in place.
Other manufacturers may have filled the regulatory gap with BPOG best practices, and if so, they’ll likely be compliant with USP <665> requirements. However, it is not guaranteed, so they should strive to align with USP <665> now, lest they get caught out when 2026 arrives.
The final group is those who have relied on their internal testing. Likely, this group won’t know how much work is required to comply with USP <665> initially, so they face the most arduous task of becoming familiar with the chapter before 2026.
Regardless of which group manufacturers fall into, they should plan now to ensure they’re prepared for the change. Once USP <665> becomes mandatory, no existing drug products will be grandfathered in. This could create a massive line for manufacturers attempting to get products approved.
If manufacturers wait until 2026, they will likely be scrambling for testing solutions when the change is implemented. There is also the possibility that regulators will expect data outlined in the new requirements earlier than 2026. China has already started to ask for USP <665> compliant data and it’s only a matter of time before the United States and Europe follow suit.
Manufacturers should be concerned with extractables and leachables when using SUS, whatever form the regulation eventually takes. Complete chemical characterization means identifying all chemicals within a SUS and plays a crucial role in safety and toxicological risk assessments. Unknown chemicals are automatically deemed carcinogenic or genotoxic, meaning if toxicologists can’t identify every chemical, they can’t accurately assess safety or risk.
A final thought
USP <665> has come a long way in a relatively short time. The chapter was introduced in response to a rapid shift in how the industry uses SUS, and through feedback and steady progress, evolved to the point of full implementation. More changes may be on the horizon before or after the chapter becomes official. Regardless, manufacturers must be prepared. Any procrastination on this topic could lead to lengthy and costly delays in the future.
Many factors are mitigating the risk of leachables from SUS. For one, vendors have largely designed their components to exude low levels of extractables.
Additionally, many parts are rinsed or flushed before use, reducing the chances of leaching. Manufacturing conditions are also usually gentle, with lower temperatures and shorter durations, greatly reducing risks for many manufacturers. Finally, patient risk is reduced when drugs are administered in low-risk dosage forms or volumes. This means the risk is low for the vast majority of drug manufacturing. However, that won’t be the case for all manufacturers.
Given the winding road of regulatory evolution so far, manufacturers should work with experienced lab partners to ensure they’re following the latest rules, regulations and advice on SUS.
