Quality of New Domestic Hand Sanitizer Drug Product Manufacturers During COVID-19.

The FDA initiated a cross-sectional, statistically based sampling and testing study to characterize the quality of marketed alcohol-based hand sanitizer (ABHS) by evaluating the alcohol content and impurities present in ABHS products manufactured by establishments that registered with the FDA during March-April 2020. A stratified sampling design divided the population of manufacturers into independent groups based on each establishment's level of experience with FDA oversight and its geographic location. ABHS products were collected and analyzed by spatially offset Raman spectroscopy and gas chromatography with mass spectrometry (GC-MS). The GC-MS results for 310 products, from 196 newly registered domestic manufacturers, showed that 71.6% (± 5.7%) of these manufacturers had violative products. In 104 (33.5%) cases, the alcohol content did not meet label claim assay specifications but still fell within CDC efficacy ranges. Ethanol ABHS products failed more often overall (assay and impurities) (84.3%) and for impurities (84.3%), than isopropanol ABHS products (11.2% and 6.2%, respectively). Differences in test results across active ingredients were statistically significant. Ethanol ABHS products often (63.5% of cases) failed due to the presence of acetal or acetaldehyde, particularly in products with pH ≤ 6. Other impurities were also detected in several ABHS products, suggesting the use of low-grade alcohol in the manufacture of these products. Evidence was insufficient to conclude that having experience manufacturing FDA-regulated products, or lack thereof, influenced product-level violative results. This study highlights the importance of sourcing and testing active pharmaceutical ingredients to produce quality drug products.

The Effect of Sampling Cannula on In Vitro Dissolution Testing with USP Paddle Method.

In vitro dissolution tests are widely used as quality control tools for drug products in development and manufacturing. Dissolution acceptance criteria are one of the important factors assessed during the regulatory review process. Understanding potential sources of variability is critical and a key to assuring reliable results are obtained when using a standardized system for in vitro dissolution testing. Sampling cannulas are commonly used to withdraw sample aliquots from dissolution medium and are potentially one of the testing factors that can contribute to variabilities in dissolution testing. However, there are still no clear requirements on the size or setting (intermittent or stationary) of sampling cannulas for dissolution testing. Thus, the objective of this study is to evaluate whether various sizes and sampling cannula settings yield different dissolution results using the USP 2 apparatus. Sampling cannulas with outer diameter (OD) ranging from 1.6 mm to 9.0 mm were used in dissolution testing with either intermittent or stationary setting to collect sample aliquots at multiple time points. The dissolution results at each time point were statistically analyzed for effects of both OD and setting of sampling cannula on drug release from 10 mg prednisone disintegrating tablets. Dissolution results indicated both size and setting of the sampling cannula may cause significant systematic errors, even though the dissolution apparatus has been calibrated. The degree of interference in dissolution results was directly related to the OD of the sampling cannula. Size of sampling cannula and setting of sampling procedure should be documented in standard operating procedures (SOP)  for dissolution testing during method development.

Analysis of bead sizes for MR capsules labeled for sprinkle.

The bead sizes used in approved modified release capsules labeled for sprinkling on food was investigated to generate bead size guidelines for generic products labeled for sprinkling. The conclusions from a survey of FDA databases were corroborated with experimental data obtained by measuring the bead sizes of several reference-listed drugs on the market labeled for administration by sprinkling on food. The experimental data show that majority of the marketed products were found to have bead sizes of less than 1,500 microm (1.5 mm). Based on this information, a bead size of less than 1,500 microm should generally be considered acceptable for use in generic products labeled for sprinkling.

In vitro dissolution of oral modified-release tablets and capsules in ethanolic media.

In 2005, Palladone, an extended-release capsule, was withdrawn from the market after clinical testing showed subjects who took the product with alcohol had increased levels of drug in their blood. To better understand this phenomenon, we studied the in vitro drug release of 27 oral modified-release products in alcohol-containing media. In 40% alcoholic medium, 9 of 10 capsules and 2 of 17 tablets show accelerated drug release. When a high percentage of the total dose is released in a short period of time, the extended-release product is then performing like an immediate release formulation. Products were also tested in 5% and 20% alcoholic media and in simulated gastric fluid (without enzyme) containing 20% alcohol. No tested capsules or tablets exhibited a significant increase in drug release in media containing only 5% alcohol. The current study indicates that in vitro dissolution may provide evidence regarding the ruggedness of formulations to ingested alcohol.

Generic omeprazole delayed-release capsules: in vitro performance evaluations.

BACKGROUND: After the patent on omeprazole delayed-release capsules expired, Food and Drug Administration (FDA) approved several generic omeprazole delayed-release capsule applications. FDA has received some complaints concerning a lack of therapeutic effect of the generic omeprazole delayed-release capsules. AIM: To investigate the quality of five different marketed generic omeprazole delayed-release capsules. METHOD: The dissolution characteristics of these generic omeprazole delayed-release capsules were determined according to the United States Pharmacopeia (USP). Additional dissolution studies under simulated in vivo physiological conditions were also conducted to determine whether generic omeprazole capsules would perform similarly under these conditions. RESULTS: The experimental data show that all the generic omeprazole delayed-release capsules met the USP standards. The in vitro dissolution of generic drugs is similar to that of the brand omeprazole product. CONCLUSIONS: There is no scientific evidence to support the claims that the generic omeprazole delayed-release capsules perform differently from the brand omeprazole product in vitro.

Studies of variability in dissolution testing with USP apparatus 2.

In this study, gauge repeatability and reproducibility (gauge R&R) was used to analyze variability for USP apparatus 2 dissolution measurement systems. Experiments were designed to assess the variability due to apparatus, operator, and sample tablet. Since dissolution testing is a destructive test, a nested model was used for data analysis. Additionally, perturbation tests with both disintegrating and nondisintegrating tablets were performed to study the variability due to sample position within the dissolution vessel. For the gauge R&R study, two well-trained chemists used two mechanically calibrated USP apparatus 2 units. Six tests were performed by each operator on each apparatus. Evaluation of dissolution test results at 30 min using an internal DPA calibrator tablet NCDA#2 (10 mg prednisone) indicates that the main contribution to the total variance, approximately 70%, is due to the sample tablets, approximately 25% is from the apparatus and approximately 5% is due to the operators. There is no significant difference between operators and apparatuses as shown by the gauge R&R studies. In addition, dissolution results can be strongly affected by the position of the tablet within the vessel. Similarity (f1) and dissimilarity (f2) factors were calculated to statistically evaluate differences between perturbed and normal dissolution tests.

Quality assessment of internet pharmaceutical products using traditional and non-traditional analytical techniques.

This work investigated the use of non-traditional analytical methods to evaluate the quality of a variety of pharmaceutical products purchased via internet sites from foreign sources and compared the results with those obtained from conventional quality assurance methods. Traditional analytical techniques employing HPLC for potency, content uniformity, chromatographic purity and drug release profiles were used to evaluate the quality of five selected drug products (fluoxetine hydrochloride, levothyroxine sodium, metformin hydrochloride, phenytoin sodium, and warfarin sodium). Non-traditional techniques, such as near infrared spectroscopy (NIR), NIR imaging and thermogravimetric analysis (TGA), were employed to verify the results and investigate their potential as alternative testing methods. Two of 20 samples failed USP monographs for quality attributes. The additional analytical methods found 11 of 20 samples had different formulations when compared to the U.S. product. Seven of the 20 samples arrived in questionable containers, and 19 of 20 had incomplete labeling. Only 1 of the 20 samples had final packaging similar to the U.S. products. The non-traditional techniques complemented the traditional techniques used and highlighted additional quality issues for the products tested. For example, these methods detected suspect manufacturing issues (such as blending), which were not evident from traditional testing alone.