Extractables and Leachables
How have recent advancements in mass spectrometry improved the detection and identification of extractable and leachables in pharmaceutical packaging?
As analytical evaluation thresholds (AETs) continue to decrease, advancements in mass spectrometry have enabled us to keep pace with these changes. We can now screen at much lower levels than before, reliably detecting and identifying compounds that are close to the AET. High-resolution mass spectrometry both in the LC and GC space has significantly advanced extractable and leachable testing.
The increased sensitivity and specificity of mass spectrometry have also significantly improved targeted analysis, particularly for compounds like PFAS and nitrosamines.
What are the key differences between targeted and non-targeted screening approaches in extractable and leachable studies, and how do they complement each other?
In non-targeted screening, we aim to detect a broad range of compounds across various analytical techniques, often at unknown concentrations. Non-targeted screening is typically applied in extractable studies, where the resulting data informs targeted analysis and method validation for leachable studies. In leachable studies, both targeted analysis and non-targeted screening are required. For targeted analysis, we focus on identifying compounds likely to be present as leachables and those of toxicological concern. These targets are also used in method validation to ensure that our sample preparation and analysis are suitable for the drug product and that we can detect compounds at levels relevant to toxicological thresholds. In non-targeted screening for leachables, we look for any leachable that is new or not previously identified as a target.
How has the implementation of artificial intelligence and machine learning enhanced data analysis in extractable and leachables testing?
Our industry is closely monitoring these advancements and how regulatory bodies respond to them. While it’s essential to remain mindful of electronic record-keeping and quality compliance, the potential within the E&L space is quite promising. There have already been some initial applications of this technology in data analysis deconvolution and database utilization. We are currently exploring opportunities within our process where AI and machine learning can be integrated.
What are the latest developments in sample preparation techniques for extractable and leachables studies, and how do they improve analytical sensitivity?
The primary challenge in sample preparation currently lies in concentrating samples to meet detection limits at the AET. Most sample enrichment techniques are specific which is a challenge for non-targeted screening, we have to retain extractable and leachables while removing sample matrix components that contribute to analytical interferences.
Advancements in automated liquid sample handling systems continue to improve, but headspace analysis remains difficult. Techniques like purge and trap and SPME have been effective for targeted analysis, but for non-targeted screening, the industry seems to be moving towards dynamic headspace sampling as a method for concentrating headspace samples.
How are regulatory agencies adapting their guidelines to keep pace with advancements in extractables and leachables analytical techniques?
We anticipate that the FDA will release an industry guidance document following the publication of ICH Q3E, along with more specific guidance on leachables from the USP. Regulatory agencies are increasingly emphasizing the need for precise quantitation and identification of extractables and leachables. They are also pushing for the establishment of robust processes and requiring comprehensive data to support the accuracy of quantitation and identification efforts.
Rapid Microbiology
What are the advantages and limitations of ATP bioluminescence technology in rapid microbial detection compared to traditional culture methods?
ATP bioluminescence technology has been used for decades, with advancements in its technology contributing to the evolution of its utilization. In the 1950s, the technology was developed by NASA to detect life on other planets, in the 80s, it became a popular choice for food testing – today its application has included rapid microbial detection in the pharmaceutical industry.
The advantages of ATP Bioluminescence technology have led to its utilization in the industry, at times used over traditional culture methods. The two major reasons for this are clear; it has fast results (for sterility tests, in 7 days or less) and it is easy to use. Additional advantages it has is that it is less subjective than human assessments (done by visual inspection), and it can have automated steps that reduce mistakes caused by human error.
Although there are some hallmark advantages to using ATP bioluminescence, it also has drawbacks. One drawback is that it can be difficult in products that use cells to differentiate between cells and microbes. In that same vein, it can be difficult for the technology to differentiate dead cells and organisms from living microbes as well. In some applications, if products are not filterable, the time to results may increase.
How has the development of MALDI-TOF mass spectrometry revolutionized microbial identification in pharmaceutical quality control?
The development of MALDI-TOF mass spectrometry has revolutionized microbial identification in pharmaceutical quality control by providing a means for more accurate yet cost-effective identification of microorganisms. Additionally, MALDI-TOF mass spectrometry is significantly faster than the traditional methods of identification. This has significant implications in evaluating quality control situations, especially regarding risk assessments and decision-making.
MALDI-TOF mass spectrometry has revolutionized microbial identification in pharmaceutical quality control by providing a significantly faster, more accurate, and cost-effective method for identifying microorganisms compared to traditional techniques, allowing for rapid detection of potential contaminants in pharmaceutical products, enabling faster decision-making and improved quality control procedures with minimal turnaround time; essentially streamlining the process of identifying microbes in a production environment. Where traditional methods may take days for microbial identification – this rapid technology may take minutes. This has huge implications where identification of pathogens could potentially save lives – by providing accurate identification of a microorganism, the appropriate intervention and treatment of infections may be used. Although this is a promising technology, it still has limitations in differentiating between closely related microbial species.
What role does flow cytometry play in rapid microbiology, and how has it evolved to meet the needs of the pharmaceutical industry?
Flow cytometry has an ever-growing role in rapid microbiology. As a rapid method, flow cytometry presents several key advantages, especially in response to the needs of the pharmaceutical industry: it has rapid detection, phenotyping, and automation. With current trends favoring automation over manual methods, flow cytometry has proven valuable in otherwise labor-intensive and time-consuming, traditional methods. Regarding microbial detection, flow cytometry has the potential to quickly detect microorganisms, especially in biological fluids. In the case of microbial identification and sorting, flow cytometry does present some advantages over growth-based identification, especially in cases where organisms are not culturable. Previously, many methods relied on biochemical or microscopic methods for use in identification. Flow cytometry presents an alternative to these methods; one that is fast and automated. These are developments that are especially well-suited for ATMPs.
How are advancements in PCR and next-generation sequencing technologies improving the speed and accuracy of microbial detection and identification?
PCR is another technology that has been around for decades and has only grown in popularity and application. In addition to PCR, next-generation sequencing technology is also pushing the boundaries of rapid tools with cost-effective benefits. These technologies are improving the speed and accuracy of microbial detection and identification by having smaller sample requirements needed for testing, with accurate results even when microbial load may be at low concentrations. With technology and databases improving and growing, error rates in identification are decreasing, with detection and monitoring of microorganisms improving and surpassing traditional methods of detection.
What are the latest developments in automated rapid microbiology systems, and how do they impact workflow efficiency in pharmaceutical quality control laboratories?
There is a growing demand for automation in rapid microbiology systems and rightfully so. Automation in rapid microbiology has several key advantages that address the crux of the industry – the demand for continuous improvement, the need for traceability and data integrity, and the critical need for shorter turnaround times. Many of the technologies discussed, MALDI-TOF mass spectroscopy, PCR, and flow cytometry – all have elements of automation in their processes. Many microbial detection systems, such as those that measure CO2 in a sample, use automated machines that constantly monitor and record samples’ CO2. This provides real-time results with minimal “babysitting” from analysts. With the evolution of robotics, many processes may be more consistent and more standardized. By having consistent processes, automation may have significant benefits to the lab in terms of workflow efficiency and quality control.
Author Details
Sarah Brophy, Global Scientific Director, E&L- Element; Melisa Byrd, Microbiology Supervisor- Element
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 6Sept/Oct 2024Pages: 68-70
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