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Why USP <665>/<1665> Matters
USP <665> primarily addresses the evaluation of polymeric materials used in pharmaceutical processing equipment - components that come into direct contact with intermediates, drug substances, or final drug products. From valves and connectors to piping and flexible tubing, these materials are ubiquitous across biotech and API manufacturing environments. Naturally, no manufacturing system is completely free of plastics, particularly in liquid processing, and because plastics are composed of complex polymer matrices combined with small‑molecule additives such as plasticizers, antioxidants, stabilizers, and colorants, they can release impurities under stress conditions that may accumulate throughout multi‑step manufacturing processes.
The regulation is especially significant for biotech facilities, where the sensitivity of biological molecules increases the risk of adverse interactions with impurities, making robust GMP compliance in biotech manufacturing increasingly dependent on a science-based risk assessment approach. Yet, its applicability is broader than it may initially seem. While new biotech facilities will unquestionably fall under the scope of USP <665>, the text leaves room for interpretation regarding existing facilities and API manufacturers. This lack of clarity is already generating confusion. Nevertheless, the safest - and ultimately the most strategic approach is to conduct a structured initial component/system assessment timely, rather than waiting for regulators to define the boundaries through inspections later.
This early evaluation is also aligned with global regulatory trends. As environmental concerns and microplastic contamination gain visibility worldwide, regulatory agencies are strengthening expectations regarding the use, control, and documentation of plastics in the pharmaceutical supply chain. In this sense, USP <665> and the explicative USP<1665> is not an isolated requirement but part of a broader movement toward more sustainable, transparent, and scientifically justified use of polymeric materials in pharma.
Key Risk: Understanding Contaminants from Polymeric Materials
While polymers themselves are long‑chain molecules unlikely to break apart during normal use, concerns arise from the small‑molecule additives necessary to produce or stabilize plastic components. These include plasticizers that improve flexibility, antioxidants that prevent aging, and colorants or functional modifiers that enable specific performance characteristics. Under certain process conditions, such as elevated temperatures, extreme pH, mechanical stress, or prolonged contact, these substances may migrate into the product stream as potential harmful impurities.
For biologics, which are molecularly complex and highly sensitive to impurities, even trace amounts of unexpected molecules can compromise product stability or safety. But the risks extend to any drug product, particularly sterile or parenteral formulations, where contamination thresholds are exceptionally stringent and whose API may be the source of potential impurities.
USP <665>recognizes that contamination may not always be measurable in the final product. Instead, risk may accumulate throughout multi‑step manufacturing processes, making the evaluation of polymer contact surfaces at every stage essential. Therefore, the regulation requires a systematic assessment of the entire process equipment system.
Why Risk Assessment Is the Foundation
The risk assessment phase is the critical pillar of the regulation. It provides a structured way to identify where risks lie and determines whether further testing is required. This is particularly relevant because USP <665> intentionally uses a phased, risk‑based approach designed to avoid unnecessary testing where risk is shown to be low.
The first step, therefore, is an initial component/system assessment across the entire manufacturing process, examining each polymeric component in relation to process conditions, product characteristics, and exposure durations. Although not trivial, this step is relatively straightforward when supported by proper tools and multidisciplinary knowledge. For many facilities, this assessment may be enough to demonstrate low risk, eliminating the need for further investigation.
Where the assessed risk is moderate or high, manufacturers may then identify “comparators.” These are representative components made of the same or similar polymeric materials, with similar geometry and used under comparable conditions. Regulators suggest and accept to identify these systems as a bracketing approach to represent similar systems in the process equipment train. Testing performed on these comparators can then be extended to all equivalent parts, greatly reducing both cost and effort. However, defining these comparators requires in‑depth understanding of polymer chemistry, equipment design, and process engineering.
In medium‑risk cases, standard extraction tests (such as ethanol‑based extractions analysed by HPLC) may be required. High‑risk cases demand more advanced analytical work to identify specific extractables. Thus, without a solid risk assessment, companies cannot accurately determine which path applies, often resulting in overtesting, delayed timelines, or incomplete compliance.
The Challenges Manufacturers Face
Risk assessment may be the foundation of the regulation, but it is also the stage where companies tend to struggle most. One of the biggest obstacles is supplier documentation. Many polymeric formulations are protected under patents, making suppliers reluctant to disclose their full composition. Yet USP <665> is clear: manufacturers cannot rely on suppliers to perform the assessment. The responsibility lies entirely with the manufacturer, and this shifts the burden onto quality and procurement teams who may not be familiar with the technical details of polymer chemistry or extractables behaviour.
Another barrier is the difficulty of mapping all polymeric components within a facility, especially in plants with legacy systems or incomplete technical documentation. Equipment knowledge, process expertise, and a detailed understanding of contact surfaces are all required.
Finally, the multi‑step structure of the regulation, from a global risk overview to comparator identification and targeted testing, requires a blend of skills rarely found within a single internal team.
Preparing for 2026: How PQE Supports Compliance
To meet the 2026 deadline confidently, manufacturers need a structured, multidisciplinary approach. PQE supports companies throughout the process, from the initial global risk assessment to comparator definition, supplier engagement, and advanced testing support when required. With deep experience in process engineering, polymer science, and regulatory compliance, PQE helps clients anticipate challenges, avoid unnecessary testing, and produce the robust documentation needed for inspection readiness.
Most importantly, PQE provides the clarity that regulators will expect once USP <665> becomes enforceable and the related explanatory, not mandatory USP<1665> shall be applied.. Companies that invest in a thorough risk assessment today will streamline compliance, safeguard product quality, reduce long‑term operational risks, and ensure patient safety.
