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.

Lessons from CDER's Quality Management Maturity Pilot Programs.

Between October 2020 and March 2022, FDA's Center for Drug Evaluation and Research (CDER) completed two pilot programs to assess the quality management maturity (QMM) of drug manufacturing establishments. Mature quality systems promote proactive detection of vulnerabilities, prevent problems before they occur, and foster a culture that rewards process and system improvements. A CDER QMM program may help to advance supply chain resiliency and robustness and mitigate drug shortages. One pilot program evaluated seven establishments located within the U.S. that produce finished dosage form products marketed in the U.S. A second pilot program evaluated eight establishments located outside the U.S. that produce active pharmaceutical ingredients used in drug products marketed in the U.S. The execution of these pilot programs afforded FDA the opportunity to learn important lessons about the establishment QMM assessment process, scoring approach, assessor behaviors, and perceptions of the assessment questions, reports, and ratings. Many of the participating establishments reported that the QMM pilot assessments helped to identify their strengths, weaknesses, and new areas for improvement which they had not previously identified through internal audits or CGMP inspections. There has been a great deal of interest in the outcomes of CDER's QMM pilot programs and this paper describes, for the first time, the lessons CDER learned and will continue to heed in the development of a QMM program.

Benchmarking the Quality Practices of Global Pharmaceutical Manufacturing to Advance Supply Chain Resilience.

Over the past several decades, pharmaceutical manufacturing has become increasingly global and supply chains have become longer, more complex, and fragmented. While pharmaceutical products available to patients and customers typically conform with appropriate standards, supply chains are often affected by disruptive events and shocks that impact public health. One approach to assuring the availability of quality pharmaceutical products is to encourage drug manufacturers to invest in quality management maturity (QMM) and promote continual improvement. The interests of patients are served by risk-based drug shortage prevention and mitigation activities that help to proactively manage supply chain complexities and ensure availability of drugs. This paper demonstrates that adherence to certain quality practices enables improved manufacturing performance. Prior research has identified quality practices that are correlated with manufacturing performance. To better understand how these quality practices can be characterized, measured, and analyzed, this research project conducted a voluntary global study of pharmaceutical manufacturing establishments. Over 200 global pharmaceutical manufacturing establishments participated in this Quality Benchmarking Study (QBS) and provided data on manufacturing performance and self-assessments of adherence to quality practices. The analysis of these data found that the implementation level for selected quality management practices correlates positively with certain Key Performance Indicators (KPIs). More specifically, we found a significant positive correlation between (i) Delivery Performance and (ii) Application of QMM principles associated with Technical Production.

Application of a headspace GC-MS method to evaluate the product quality of alcohol-based hand wipe sanitizers.

The investigation of marketed hand wipe sanitizers presented an analytical challenge owing to the need for extraction from the solid matrix of the products. The present work describes the development of a new sample preparation method for the extraction of analytes from the hand wipe sanitizer matrix into dimethyl sulfoxide for analysis using headspace GCMS. Alcohol-based hand sanitizer (ABHS) wipe products labeled to contain ethanol or isopropanol as active ingredients were tested, varying in the size and weight of the wipes. The spike recovery assay was confirmed using spiking solutions containing impurities at concentrations equivalent to 50, 100 and 200% of the interim concentration limits. All of the tested analytes showed recovery within the allowable limits (80-120%). Six marketed ABHS wipe products were tested and no impurities above the FDA interim limits were observed. One product contained ethanol below the 60% v/v limit and another product was mislabeled for isopropanol and was found to contain ethanol instead. Four of the six ABHS products did not meet the label claim, which may affect the product quality. The analytical method and sample preparation procedures will provide the FDA and ABHS manufacturers with the capability to conduct quality assurance testing of hand wipe sanitizers for active ingredient content and impurities.

Development and validation of a headspace GC-MS method to evaluate the interconversion of impurities and the product quality of liquid hand sanitizers.

The COVID-19 pandemic has led to increased usage of hand sanitizer products by the public to prevent the spread of COVID-19 and decrease the likelihood of acquiring the disease. The increase in demand has also led to an increase in the number of manufacturers. This work describes the FDA's Center for Drug Evaluation and Research (CDER) laboratories efforts to develop tests to assess the quality of hand sanitizer products containing ethanol or isopropanol as the primary active ingredient. The products were evaluated for the active ingredient content and determination of the 12 impurities listed in the FDA Hand Sanitizer Temporary Guidance, followed by a spike recovery assay performed to verify the test results. Extensive method development was conducted including an investigation into the stability of ethanol, isopropanol, and the 12 impurities. Stability and kinetic studies confirmed the instability of acetal in acidic liquid hand sanitizer products during spike recovery assay testing. The headspace GC-MS method was validated according to ICH Q2 (R1) guidelines and the spike recovery assay was validated using three concentrations of standards for the drug product. During method application, six liquid hand sanitizer products were tested and all were determined to have ethanol or isopropanol above 70% v/v. Two liquid hand sanitizer products were determined to contain acetaldehyde as an impurity above the FDA recommended safety levels. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41120-021-00049-8.

Embedding expert knowledge in a decision model: evaluating natural attenuation at TCE sites.

This paper describes a generalized methodology that enables the translation of expert knowledge about any complex process involved in a remedial decision into easy-to-use decision tools. The methodology is applied to evaluate reductive dechlorination as a remedial possibility at sites contaminated with trichloroethene (TCE), building on an existing protocol/scoring system put forth by the US Air Force and the US EPA. An alternate scoring system is proposed, which has two major advantages, namely that it: (i) attributes relative weights to findings based on expert beliefs; and (ii) systematically includes negative weights for negative findings. The ability of the proposed scoring system to assess the bioattenuation potential of TCE is demonstrated using data from extensively studied sites.

Site-specific updating and aggregation of Bayesian belief network models for multiple experts.

A method for combining multiple expert opinions that are encoded in a Bayesian Belief Network (BBN) model is presented and applied to a problem involving the cleanup of hazardous chemicals at a site with contaminated groundwater. The method uses Bayes Rule to update each expert model with the observed evidence, then uses it again to compute posterior probability weights for each model. The weights reflect the consistency of each model with the observed evidence, allowing the aggregate model to be tailored to the particular conditions observed in the site-specific application of the risk model. The Bayesian update is easy to implement, since the likelihood for the set of evidence (observations for selected nodes of the BBN model) is readily computed by sequential execution of the BBN model. The method is demonstrated using a simple pedagogical example and subsequently applied to a groundwater contamination problem using an expert-knowledge BBN model. The BBN model in this application predicts the probability that reductive dechlorination of the contaminant trichlorethene (TCE) is occurring at a site--a critical step in the demonstration of the feasibility of monitored natural attenuation for site cleanup--given information on 14 measurable antecedent and descendant conditions. The predictions for the BBN models for 21 experts are weighted and aggregated using examples of hypothetical and actual site data. The method allows more weight for those expert models that are more reflective of the site conditions, and is shown to yield an aggregate prediction that differs from that of simple model averaging in a potentially significant manner.

What number is "fifty-fifty"?: redistributing excessive 50% responses in elicited probabilities.

Studies using open-ended response modes to elicit probabilistic beliefs have sometimes found an elevated frequency (or blip) at 50 in their response distributions. Our previous research suggests that this is caused by intrusion of the phrase "fifty-fifty," which represents epistemic uncertainty, rather than a true numeric probability of 50%. Such inappropriate responses pose a problem for decision analysts and others relying on probabilistic judgments. Using an explicit numeric probability scale (ranging from 0-100%) reduces thinking about uncertain events in verbal terms like "fifty-fifty," and, with it, exaggerated use of the 50 response. Here, we present two procedures for adjusting response distributions for data already collected with open-ended response modes and hence vulnerable to an exaggerated presence of 50%. Each procedure infers the prevalence of 50s had a numeric probability scale been used, then redistributes the excess. The two procedures are validated on some of our own existing data and then applied to judgments elicited from experts in groundwater pollution and bioremediation.

The Relationship between Historic Industrial Site Use and Environmental Contamination.

A methodology is presented for estimating the probability that particular classes of environmental contaminants will be of concern at brownfield redevelopment sites. These probabilities are predicted by a logistics model that is based on qualitative information about site history and status. This qualitative information comprises data that would be collected through a Phase I Environmental Site Assessment (ESA), including historic site use, current use and ownership status, and the nature of adjacent properties. The model is fit and demonstrated using a set of 59 former industrial sites in southwestern Pennsylvania that were collected from the files of the Pennsylvania Department of Environmental Protection (PADEP). Predictive models are developed for exceedances of contaminants as grouped into the following classes: metals, chlorinated hydrocarbons, fuel hydrocarbons, and PCBs. A procedure for estimating the parametric uncertainty of the model predictions is also illustrated. This method can serve as a starting point for more effective usage of existing Phase I ESA information and for evaluation of the benefit of obtaining additional site information. By increasing the decision-making value of existing (or inexpensive) data, this method can help to reduce the information asymmetry that may be an obstacle to redevelopment.