How To Avoid The Biggest USP <665> Compliance Trap

By Gilda D'Incerti, CEO & founder, PQE Group

After USP <665> went into effect on May 1, pharmaceutical and biopharmaceutical manufacturers are under increasing pressure to evaluate the polymeric materials used across manufacturing operations. Discussions around the regulation have largely focused on extractables and leachables testing, analytical requirements, and evolving expectations surrounding single-use systems.

But for many organizations, the most difficult part of compliance will be understanding manufacturing systems well enough to know where risk exists.

That challenge is apparent as companies move from high-level regulatory discussions into implementation planning. What initially appears to be a materials evaluation exercise can expand into an operational effort involving engineering, procurement, manufacturing, quality, validation, and supplier management teams simultaneously.

In practice, USP <665> and its companion guideline USP <1665> are forcing organizations to confront a difficult question: How complete is our understanding of the materials, components, and contact surfaces across our manufacturing environment?

For many facilities, the answer is more complicated than expected.

Why Implementation Becomes Operationally Complex

Modern bioprocessing environments contain extensive networks of polymeric materials. Single-use assemblies, tubing systems, filters, connectors, bags, gaskets, seals, and fluid-transfer components may be used across upstream, downstream, and fill/finish operations, sourced from multiple suppliers and introduced over the years of process evolution.

Documentation related to polymeric components exists across disconnected systems, supplier files, engineering records, validation packages, procurement databases, and historical change controls. Material substitutions can occur over time without tracking, and various departments maintain different versions of component information.

As a result, one of the first implementation obstacles companies encounter is simply building a reliable inventory of polymeric materials that come into contact with products throughout the manufacturing process.

Without that visibility, risk assessment becomes difficult to perform consistently.

Supplier Data Is Important  But Insufficient

Another major implementation challenge involves supplier information. Many manufacturers initially expect suppliers to provide all data necessary for compliance assessment. In reality, supplier documentation represents only part of the larger evaluation process.

Polymeric materials contain proprietary formulations that include stabilizers, antioxidants, plasticizers, lubricants, curing agents, and other additives that suppliers can’t disclose because of intellectual property concerns.

At the same time, the actual behavior of materials depends on process-specific operating conditions, including:

• temperature,
• solvent exposure,
• pH,
• contact duration,
• sterilization cycles, and
• mechanical stress.

This means manufacturers can’t rely solely on supplier certifications or declarations to justify compliance. Instead, supplier information must be integrated into a system-level understanding of how materials behave under actual manufacturing conditions.

That can require greater coordination between procurement, engineering, quality, and process teams than organizations initially anticipate.

Why Companies Risk Over-Testing

One implementation mistake is defaulting to extensive testing programs before completing a risk assessment, which involves several steps. For example, the process leader must identify all polymeric materials in contact with products, map their locations and functions in the manufacturing process, evaluate extractables and leachables based on process-specific conditions, prioritize their risk profiles, and document findings to inform testing strategies.

This occurs for understandable reasons: Organizations erroneously assume that testing creates a safer compliance position, but in practice, excessive testing can strain resources without improving any process or understanding of them.

Facilities operating large single-use systems may contain hundreds of polymeric components. Testing every component independently can rapidly increase analytical workload, documentation complexity, and overall compliance costs. More importantly, it can distract teams from identifying which systems actually present meaningful risk.

USP <665> and USP <1665> were designed for phased, risk-based evaluation to prevent unnecessary testing where low risk is justified. Therefore, establishing assessments is usually better positioned to prioritize resources, such as compiling a material inventory, mapping contact points, evaluating process conditions, assessing the likelihood and impact of extractables and leachables, and documenting the rationale behind prioritization decisions.

Cross-Functional Coordination Is Becoming Essential

Another operational reality emerging from USP <665>/<1665> implementation is that no single department fully owns the problem.

Engineering teams understand system configuration and operating conditions. Procurement teams manage supplier relationships and material sourcing. Quality and regulatory groups oversee compliance expectations and documentation requirements. Manufacturing teams understand operational circumstances and process variability.

Without coordination across those functions, gaps can remain hidden. For example:

• Procurement approves supplier substitutions without visibility into process impact.
• Engineering evaluates functionality without the extractables context.
• During assessment activities, quality teams inherit incomplete material histories.

As implementation efforts accelerate, many discover that polymeric material risk management requires more integrated operational oversight than traditional qualification activities.

Preparing Operationally For Implementation

The companies most likely to navigate USP <665>/<1665> successfully are not necessarily those performing the most testing, but rather those building the clearest operational understanding of their systems.

In practical terms, that means focusing early efforts on mapping polymeric contact surfaces, organizing supplier and material data, identifying high-risk process conditions, introducing standardized evaluation methodologies, and creating cross-functional governance around material-related decisions.

Comparator and bracketing strategies can also help reduce burden when supported by sound scientific justification and complete system visibility. Most importantly, leaders should recognize that implementation is not purely a regulatory exercise but also an exercise in operational maturity.

The regulation is ultimately pushing manufacturers toward understanding how materials, systems, and process conditions interact across modern manufacturing environments. That level of understanding is more important as manufacturing systems grow more complex, more material-intensive, and more dependent on single-use technologies.

About The Author:

Gilda D'Incerti is CEO and cofounder at PQE Group, a compliance and regulatory consulting group founded in 1998 to supporting the life sciences industry based in Florence, Italy. Before founding PQE, she worked in operations management and IT positions. She's a member of the Forbes Business Council and received her master's degree from Universitat Politècnica de Catalunya.