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Specification Setting for Biopharmaceuticals: Expert Panel Discussion on Best Practices

by BioQC | May 21, 2025 | Summary

This summary accompanies a recent expert forum discussion organised by BioQC, and we appreciate the panellists for their time and expertise.

This panel focuses on practical aspects of specification setting for biopharmaceuticals under ICH Q6B.

Who Sets Specifications: A Multidisciplinary Effort

Specification setting requires collaborative input across multiple functions. Production and quality control departments must work together on risk assessment and determining which quality attributes warrant inclusion in specifications. Regulatory affairs teams play crucial roles ensuring specifications comply with standards in target markets and facilitating dialogue with regulatory agencies.

Project leadership typically makes final decisions, but requires input from a multidisciplinary team. Technical experts from analytical development, drug substance and drug product development, and process engineering contribute essential knowledge. Statistical teams, whilst perhaps not driving final decisions, provide vital information on current process capability and stability impacts on safety and efficacy. The statistical perspective proves essential yet faces challenges, as biochemists and pharmacists often find statistics difficult, with most education programmes allocating insufficient hours for industry needs.

Release Versus Shelf Life Specifications

Specifications can be identical for release and shelf life provided stability data confirms consistent product quality throughout the shelf life period. However, when product evolution occurs during shelf life, meaning one or more quality attributes change over time whilst remaining within acceptable quality levels, specifications may differ. End of shelf life specifications are set based on product knowledge to ensure safety and efficacy at expiration. Statistical modelling then calculates appropriate release specifications for time zero that guarantee shelf life specification compliance. Internal release limits represent company-specific controls that may differ from official specifications. These limits serve as internal business guarantees and supportive tools for maintaining process control. They help companies understand process trends whilst providing flexibility during storage. Internal limits typically employ narrower thresholds than official specifications, ensuring products survive the shelf life period whilst both must ensure efficacy and safety to patients.

Setting Specifications for Impurities

Two main impurity types require different specification-setting approaches: product-related and process-related impurities.

Product-related impurities derive from product degradation. For therapeutic proteins, these might include clipped forms or aggregates. The specification-setting approach examines preclinical evidence, receptor occupancy, or other efficacy surrogates to determine maximum acceptable impurity levels that do not impact projected drug efficacy.

Most importantly, degraded species must not present safety concerns. This process starts with critical quality attribute assessment, examining which degradation mechanisms occur and assessing whether resulting impurities are critical.

Process-related impurities come from raw materials or solvents used during product preparation. Specification setting begins with safety assessment, examining safety limits for specific chemicals that might remain as residuals. Safety limits provide initial boundaries, and specifications ensure product delivery within these safety-determined ranges. Regulators also consider process control capability for delivering low impurity amounts, though specifications are primarily dictated by safety limits.

Low impurity amounts in well-controlled processes create statistical challenges. A key difficulty involves explaining to stakeholders that measurements cannot yield negative values, requiring data transformation. The process focuses so intensely on producing the main product that impurities become rare events, making comprehensive capture in statistically significant ways challenging.

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