The United States Pharmacopeia (USP) has released a new series of draft proposals in Pharmacopeial Forum 51(3), continuing to strengthen analytical standards, risk-based quality systems, and lifecycle-based approaches across pharmaceutical manufacturing.
Below is an overview of the most prominent revisions proposed and how they may affect GMP operations.
〈1037〉 Process Analytical Technology (PAT)
The proposed Chapter 〈1037〉 introduces a comprehensive guide for implementing PAT systems across the pharmaceutical lifecycle, aligning with quality-by-design (QbD) and continuous manufacturing initiatives.
Key Elements
- Definition and Significance: Introduces the evolution of PAT and its role in optimizing manufacturing control, product quality, and efficiency.
- Core Attributes: Highlights key PAT features such as sampling relevance, timeliness, regulatory alignment, measurement integration, and connection to product and process attributes.
- Technologies: Covers the application of chemometrics, machine learning, AI, real-time analyzers, automated sampling tools, IT system integration, DoE (Design of Experiments), and risk assessment tools like FMEA (Failure Mode Effect Analysis).
- Lifecycle Management: Emphasizes PAT method development, performance monitoring, and data-driven adjustment strategies based on product lifecycle stage and risk profile.
- Regulatory Alignment: Maps PAT principles to current regulatory guidance, reinforcing their role in submissions, validation, and ongoing compliance.
- Future Outlook: Discusses potential directions for PAT evolution, including digital twins, advanced modeling, and predictive analytics.
GMP Impact
This chapter encourages a shift from static validation models toward real-time quality control. Firms may need to revise SOPs, integrate PAT with existing control strategies, and align with ICH Q8–Q12 frameworks to enhance process understanding and efficiency.
〈1099〉 Limit on Number of Large Deviations in Content Uniformity
Chapter 〈1099〉 offers a refined approach to managing content uniformity evaluations in datasets exceeding 30 units. It clarifies its independence from Chapter 〈905〉-Uniformity of Dosage Units, and provides an adaptable framework based on confidence intervals and proportion-based calculations.
Key Elements
- Scope Clarification: Not intended for batch release or regulatory acceptance criteria, but rather for internal assessments.
- Critique of ZTC: Acknowledges the limitations of the Zero Tolerance Criterion (ZTC) in large samples and provides alternatives.
- New Evaluation Method:
- Updated Table 1 to define allowable deviations.
- Formulas for calculating confidence intervals and sample sizes.
- Updated Table 1 to define allowable deviations.
- Proportion-Based Alternative: A generalized approach for evaluating the proportion of large deviations in any dataset.
- Jeffreys’ UCB Methodology: A statistically robust method to set acceptance thresholds.
GMP Impact
The chapter is particularly useful in continuous manufacturing, trend analysis, and process improvement. QA and QC teams can leverage this framework to better assess uniformity during investigations and capability studies without the constraints of traditional pass/fail criteria.
〈1664.2〉 Parenteral Drug Products (Intramuscular, Intravenous, and Subcutaneous)
This new chapter supplements 〈1664〉 by focusing specifically on organic leachables in parenteral drug products (PDPs), including both synthetic and biologic formulations administered via IM, IV, or SC routes.
Key Elements
- Scope and Focus: Addresses high-risk routes and organic leachables from packaging, delivery, and manufacturing equipment, especially single-use systems (SUS).
- Study Requirements:
- Extractables testing for commercial packaging and manufacturing components.
- Leachables stability studies on registration batches.
- Analytical methods (targeted and untargeted) with justifiable AETs (Antimicrobial Effectiveness Tests).
- Extractables testing for commercial packaging and manufacturing components.
- AET Calculations:
- Provides worked examples across multiple container systems (prefilled syringes, vials, IV bags).
- AET values derived from SCT thresholds (typically 1.5 µg/day).
- Provides worked examples across multiple container systems (prefilled syringes, vials, IV bags).
- Managing Low AETs:
- Emphasis on simulation studies and extractables correlation when analytical limits are exceeded.
- Use of alternative thresholds when justified by toxicology.
- Emphasis on simulation studies and extractables correlation when analytical limits are exceeded.
- Analytical Uncertainty:
- Introduces the concept of uncertainty factors (UFs) to adjust AETs in cases where compound-specific variability or matrix effects compromise detection.
- Introduces the concept of uncertainty factors (UFs) to adjust AETs in cases where compound-specific variability or matrix effects compromise detection.
- Biologic Product Considerations:
- Highlights risks of leachables-mediated aggregation, degradation, or immunogenicity.
- Recommends early packaging qualification and iterative compatibility studies throughout development.
- Highlights risks of leachables-mediated aggregation, degradation, or immunogenicity.
- Manufacturing Components:
- Risk analysis for SUS materials (tubing, connectors, bioreactor bags).
- Guidance on component-specific leachables and material compatibility studies.
- Risk analysis for SUS materials (tubing, connectors, bioreactor bags).
GMP Impact
PDP manufacturers—especially those handling biologics—will need to implement comprehensive E&L programs, justify toxicological thresholds, and anticipate the impact of leachables on protein structure, stability, and safety. Compatibility studies must span both packaging and manufacturing components throughout the lifecycle.
Cannabidiol (New USP Monograph)
With increasing pharmaceutical interest in cannabinoids, USP now proposes a monograph for Cannabidiol (CBD) derived from Cannabis sativa L., establishing analytical and quality criteria for plant-derived, highly purified CBD.
Key Elements
- Scope: Applies exclusively to CBD from botanical sources; synthetic CBD is excluded due to differing impurity profiles.
- Assay Requirements: 98.0–102.0% CBD content (anhydrous basis).
- Impurity Limits:
- Δ9-THC: NMT 0.10%
- CBDV: NMT 1.0%
- Total unspecified impurities: NMT 0.50%
- Total impurities: NMT 1.5%
- Δ9-THC: NMT 0.10%
- Chromatographic Conditions: HPLC with L11 column and UV detection at 210 nm.
- Additional Tests:
- Water content: NMT 0.3%
- Residue on ignition: NMT 0.2%
- Melting range: 65–67 °C
- Water content: NMT 0.3%
GMP Impact
This monograph provides an official standard for pharmaceutical-grade CBD, offering a clear pathway for method validation and regulatory alignment. Developers working with botanically sourced APIs must demonstrate conformance with the defined assay and impurity thresholds.
Implementation and Industry Feedback
The USP–NF PF 51(3) proposals reflect a broader regulatory trend toward data-driven, risk-based quality systems that evolve throughout the product lifecycle. Industry stakeholders are encouraged to:
- Review the complete proposals on the USP Pharmacopeial Forum.
- Submit formal comments during the open review period.
- Reevaluate internal SOPs, testing methods, and qualification procedures in light of the new expectations.
- Monitor official adoption timelines and prepare for integration into GMP systems.
GMP Insiders will continue to provide detailed guidance and implementation strategies as these chapters evolve. Contact us directly for consulting support, training workshops, or documentation updates aligned with USP changes.
