Ongoing Analytical Procedure Performance Verification Using a Risk-Based Approach to Determine Performance Monitoring Requirements.

The analytical procedure life cycle (APLC) provides a holistic framework to ensure analytical procedure fitness for purpose. USP's general chapter <1220> considers the validation activities that take place across the entire analytical procedure lifecycle and provides a three-stage framework for its implementation. Performing ongoing analytical procedure performance verification (OPPV) (stage 3) ensures that the procedure remains in a state of control across its lifecycle of use post validation (qualification) and involves an ongoing program to collect and analyze data that relate to the performance of the procedure. Knowledge generated during stages 1 (procedure design) and 2 (procedure performance qualification) is used as the basis for the design of the routine monitoring plan to support performance verification (stage 3). The extent of the routine monitoring required should be defined based on risk assessment, considering the complexity of the procedure, its intended purpose, and knowledge about process/procedure variability. The analytical target profile (ATP) can be used to provide or guide the establishment of acceptance criteria used to verify the procedure performance during routine use (e.g., through a system/sample suitability test (SST) or verification criteria applicable to procedure changes or transfers). An ATP however is not essentially required to perform OPPV, and a procedure performance monitoring program can be implemented even if the full APLC framework has not been applied. In these situations, verification criteria can be derived from existing validation or system suitability criteria. Elements of the life cycle approach can also be applied retrospectively if deemed useful.

Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group.

Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharmaceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data management, and utilization of digital technologies are identified as potential solutions that can help meet the challenges of these quality paradigm shifts. Further discussion and collaboration among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development.

Optimization of the water-insoluble procedures for USP General Chapter Residual Solvents <467>.

The water-insoluble procedures in US Pharmacopeia (USP) General Chapter Residual Solvents <467>, which are based on European Pharmacopoeia procedures, were optimized and modified before their inclusion in the chapter to improve their scope, performance, and ruggedness. The optimized procedures use a static headspace introduction system with a gas chromatograph equipped with a flame ionization detector. This article describes some of the key changes made to the USP published procedures, including use of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) as the solvent, addition of 5 mL of water and 1 mL of sample (dissolved in DMSO or DMF) to the headspace vial, use of a 3:1 GC split ratio, and use of new matrix-matched system suitability solutions. These procedures were verified with two different active pharmaceutical ingredients--hydroxyzine pamoate and prednisone. In the investigation, the more polar material (hydroxyzine pamoate) showed greater recoveries for the optimized procedures when prepared in DMSO. The less polar material (prednisone) typically had greater recoveries in DMF for the optimized procedures. During experimentation, insights into sample preparation, additional types of headspace instrumentation, solvent purity, and other parameters were also gained.

Antitumoral activity of a new series of 5,6-dihydrobenzo(a)carbazoles.

The overlapping of three-dimensional structures of 5,6-dihydrobenzo(a)carbazole (DHBC) derivatives over the structure of 4-hydroxytamoxifen (4-OH-TAM), by means of the MDL CHEMLAB 11.0 computational program, shows a reasonable structural and spatial resemblance. This finding raised the hypothesis of their possible antitumoral activity, similar to that of tamoxifen (TAM). A number of DHBCs with an alkyl chain and a second basic nitrogen as substituent were synthesized in our laboratory and their possible antitumoral activity was tested by means of: 1) competitive radioligand assays to determine relative drug affinity for the estrogen receptor (ER); 2) in vivo studies, giving the synthetic drugs subcutaneously (1 mg kg-1 day-1) to Sprague-Dawley rats with N-nitroso-N-methylurea (NMU)-induced mammary tumors; and 3) in vitro cell proliferation experiments employing the soft agar clonogenic technique. Besides, studies on toxicity and histopathological analyses of organs and tumors from treated animals were performed. Results obtained showed that: 1) relative binding affinities (RBA) for the ER were similar to that of TAM; 2) some structures showed significant antitumoral activity and induced tumoral regression similar to TAM; and 3) these compounds had in vitro inhibitory effect on cell proliferation. Even though all the compounds of the series of synthesized DHBCs showed affinity for the ER similar to TAM, the results of in vivo experiments confirmed the crucial role of hydroxyl groups in the molecule and of the interatomic distance between them, similar to that of estradiol, as well as the necessary presence of the aminoalkyl chain on the annular N atom. However, the effect of alkyl chain enlargement in the nitrogen substituent on the biological activity of those drugs is as yet unclear.

A new HPLC method to determine Donepezil hydrochloride in tablets.

A HPLC stability-indicating assay for Donepezil hydrochloride in tablets was developed and validated. Donepezil hydrochloride is a reversible inhibitor of acetylcholinesterase, indicated for the treatment of mild to moderate dementia of the Alzheimer's type. The HPLC method was performed with a reversed phase C18 column, detection at 268 nm and a mixture of methanol, phosphate buffer 0.02 M and triethylamine (50:50:0.5) as mobile phase. Typical retention time for Donepezil was 9 min. The method was statistically validated for linearity, accuracy, precision and selectivity following ICH recommendations. Due to its simplicity and accuracy, the method can be used for routine quality control analysis.