The USP (United States Pharmacopeia) General Chapter <467> applies to existing drug substances, excipients, and products. The norm describes how to obtain a quantification of residual solvents and MDL.

Residual Solvents (RS), formerly called Organic Volatile Impurities (OVIs), are defined as organic volatile chemicals that are used or produced in the manufacture of active substances or excipients, or in the preparation of drug products. These products may also be contaminated by such solvents from packaging, storage in warehouse, or from shipping and transporation. Because residual solvents do not provide any therapeutic benefit, but may be a potential toxic risk to human health and the environment, it must be ensured that they are either not present in products or are present only below recommended acceptable levels.

As claimed by the norm, solvents that are known to cause unacceptable toxicities should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. These types of solvents are grouped in “Class 1 Residual Solvents“ that includes solvents to be avoided as known human carcinogens, strongly suspected human carcinogens, environmental hazards.

The “Class 2 Residual Solvents” includes solvents associated with less severe toxicity that need to be limited in order to protect patients from potential adverse effects. These are: nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity, such as neurotoxicity or teratogenicity, and solvents suspected of other significant but reversible toxicities.

Pharmaceutical manufacturers may face various challenges when attempting to meet the USP requirements.

The norm requires the use of a static headspace sampler coupled with a GC-FID system in order to recognize and quantify organic volatile impurities. Particularly, the “Valve&Loop” sampling system ensures the best results in terms of repeatability and, for this reason, it is the technique of choice for

this application.

In the present work, the data obtained using the innovative Master SHS Static Headspace Sampler coupled with the Master GC Fast Gas Chromatograph are presented. The methodology was optimized to reduce total analysis and cycle times. Maximum laboratory productivity is thus guaranteed, thanks also to the widest sample capacity of the vial tray.

Moreover, the advanced capability of controlling both the pressure of the vial, and the pressure of the loop provided by the Master SHS were exploited producing unmatched performances. DANI Master SHS, in fact, improved repeatability and precision for residual solvents analysis compared also to other market leaders.

Furthermore, as it’s well known, regulated pharmaceutical arenas are currently striving to meet compliance with 21 CFR part 11, the FDA’s rule governing electronic records and electronic signatures. Matching Part 11 compliance remains challenging. The technical controls for 21 CFR Part 11 compliance are built into the Empower™ (trademark of Waters(R))software. Control of DANI’s Master SHS-GC system is now available through a collaboration between Waters® and DANI Instruments. This control enables the use of the best-in-class USP <467> Solution, which features the world’s highest performance in terms of repeatability, sensibility, and precision, in an Empower™ environment.

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