Grant Playter is the Assistant Editor for 

Grant Playter

In this episode of the Drug Solutions podcast, Grant Playter, Assistant Editor, talks with Rosalind Beasley, vice president, Digital Innovation, Dot Compliance, on the current landscape surrounding compliance and validation. Topics of discussion include frequently overlooked factors in the validation process, under-the-radar innovations, the evolving role of the cloud in quality management systems, and much more.

LabVantage Solutions, a leader in intelligent laboratory informatics serving Top 20 pharma.

 is the Vice President of Digital Innovation at Dot Compliance, a quality management software provider designing solutions specifically for the life science industry. A senior executive with more than 20 years of experience focused on digital transformation within highly regulated industries, Beasley helps companies maximize their investment in enterprise cloud solutions.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

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In this episode, Grant Playter, assistant editor, sits down with Rosalind Beasley, vice president, Digital Innovation, Dot Compliance, to discuss the current state of the compliance and validation industry.

Drug Solutions Podcast: The Current State of Compliance and Validation

Like most sectors of the pharmaceutical industry, the dissolution testing space is in a constant state of flux and evolution. With everything from real-time release testing to automated regulatory audit trail software continuing to gain
prominence in the sector, an in-depth look toward the future of dissolution testing is needed for those seeking comprehensive understanding of the industry.

 spoke with Ishai Nir, small-molecule products manager at Distek, a manufacturer of dissolution and related laboratory testing instruments, to get a perspective from an industry insider on the state of dissolutions technology. The discussion touches on recent innovations, ongoing trends, and the future of the dissolutions testing industry.

What are some recent innovations you have observed in the dissolution testing space, if any? How would you describe their impact?

 Dissolution is a well-defined test with both instrumentation and testing methodology specified in great detail by the USP [US Pharmacopeia). So, for existing formulations there is not a lot of opportunity for innovation. However, as the expression goes ‘all the BCS class 1 and 3 drugs have already been discovered.’ This leaves new, challenging formulations with poor solubility or permeability which in turn require new formulation and delivery methods that may require changes in their corresponding performance tests.

For example, solubility is inversely related to particle size. This has led to multiple submicron dosage forms. However, conventional dissolution methodology breaks down at this scale because it becomes impossible to use conventional filtering techniques to remove undissolved API from collected dissolution samples waiting to be analyzed.

 addressed all the new non-compendial techniques being employed to address this problem. Some of these have already been commercialized as accessories to existing dissolution equipment. There are other novel dosage forms that will be delivered other than orally, such as long acting parenterals, transdermal microneedles, inhalation, etc. that will equally require some new or modified dissolution testing solutions (1).

 Are there any trends you see occurring in this space? Are there any trends that you’ve seen ending?

There are two major trends that will strongly affect dissolution testing. The first is the inclusion of dissolution testing into the comprehensive data integrity solution used by the lab, and with it true 21

Part 11 compliance. As dissolution instrumentation moves away from error-prone manual operations to software driven automation, more and more steps of the process, such as media preparation and dissolution testing and sampling, will join sample analysis as falling under the auspices of these data controls. This will mean that some of the current testing industry band-aids and ‘partially compliant’ solutions will have to be replaced by robust systems.

The second is a push by FDA to move away from a simple single or a few measurements of a straight 

 dissolution test and towards testing that is more biorelevant. This takes two forms. First, increasinglythere will be a move towards creating 

tests that will be more sensitive to changes that will affect 

 behavior. At least in development stages, there is already an increasing requirement to show that a test is not only sensitive to manufacturing variation, but sensitivity to parameters which can affect bioequivalence.

We recently passed the two-year anniversary of the COVID-19 pandemic. Now that we have a clearer idea of its short-term/immediate impacts, are there any longitudinal effects you see it having on your industry?

As with many other industries, one thing that COVID has led to is a rethinking by the pharmaceutical industry of the acceptability of remote access. Pre COVID, most companies would have not even considered allowing any kind of external Internet access to any of their machines or data. Similarly, any cloud-based solutions that would have been entertained would have had to be locally hosted.

COVID forced many companies to accelerate acceptance and implementation of these external access strategies. As a result, things like remote instrument monitoring, maintenance, validation, and possibly repair, software as a service, etc. start becoming subjects of discussion. Together with the move to software control discussed previously, this may make these concepts palatable and applicable to pharma the way they are accepted as 

 in many other industries. Obviously, this is not unique to dissolution testing, but pharma manufacturing as a whole.

 Regarding the future of your industry, what do you see as the next big change? Do you have any predictions in particular?

 One paradigm shift gaining some traction in the not-too-distant future is an increase in the implementation of continuous manufacturing. This is a shift from batch manufacturing, where dissolution testing can be done between batches, to truly continuous manufacturing where all of the characterization of samples needs to be somehow done in real time. This may require a shift to using inline process analytical technologies based on correlation modeling with traditional destructive offline physical tests.

Grant Playter is the Assistant Editor at 

Articles

Dissolution testing has seen recent trends that have led to increased data integrity solutions as well as an increase in biorelevant testing techniques.

Dissolution Testing Sees Advances

While a conclusive ‘end’ to the pandemic remains elusive, the transition to a post-pandemic economic model has been defined by a mass ramp-up of various means of digital communication. Digital training tools are one such solution, often allowing companies to effectively prepare employees for the job before they even set foot on-site. While these tools can take on many forms, of particular prominence are augmented reality (AR) and virtual reality (VR) visualization technologies.

Pharmaceutical Technology's Trends in Manufacturing eBook

When referring to this article, please cite it as G. Playter, "Embracing New Realities," 

Pharmaceutical Technology's Trends in Manufacturing 

Virtual and augmented reality have emerged as critical digital training tools.

Embracing New Realities

When referring to this article, please cite it as G. Playter, “Advances in Dissolution Testing,” 

Recent trends in dissolution testing have led to increased use of data integrity solutions and more biorelevant testing techniques.

Advances in Dissolution Testing

Computer system validation (CSV), also known as software validation, is required by regulatory agencies throughout the development timeline. Pharmaceutical Technology reached out to various experts associated with the FDA-Industry Computer Software Assurance (FISCA) team to discuss computer validation and add context to the ongoing discussion surrounding its use and importance in the greater regulatory landscape.

Pharmaceutical Technology's March 2022 Quality and Regulatory Sourcebook eBook.

Pharmaceutical Technology's Quality and Regulatory Sourcebook eBook

When referring to this article, please cite it as G. Playter, “Contextualizing Computer Validation," 

Experts weigh in on the current state of computer validation and its role in the greater regulatory landscape.

Contextualizing Computer Validation

Revolutionary therapies and innovative drugs can largely be attributed to the research, development, and manufacturing work conducted by the bio/pharm industry. Contributing to that success, however, are the contributions of laboratory technology manufacturers.

As much as new therapeutics are continually discovered, researched, and developed, innovative laboratory equipment is continually being developed, improved upon, and intro- duced to the market. A primary goal of these lab equipment innovations is to improve the efficiency of the drug develop- ment cycle or unlock as yet unknown benefits for researchers. A summary of some of the most recent product innovations to hit the laboratory scene are highlighted below.

Announced in January 2022, Refeyn’s SamuxMP mass photometer is designed to be used with only basic train- ing. Intended for use in adeno-associated virus (AAV) analytics, it has a mass range tailored for AAV analy- sis and provides accurate results in less than five min- utes from sample loading to final result. Combined with low-operational costs and a small footprint, the SamuxMP enables routine quantification of empty/full AAV capsid ratios, even in smaller labs, to set a new stan- dard in AAV characterization.

The SamuxMP is designed to overcome the drawbacks of the current analytical methods by enabling users to rapidly and cost-effectively determine empty/full capsid ratios for AAVs of any serotype at the bench using very low sample volumes and concentrations with minimal sample preparation. This is intended to enhance produc- tivity and speed up workflows through more frequent analyses in-house, making R&D and process development of gene therapies and AAV-based therapeutics signifi- cantly more efficient (1).

Bio-Rad's Bio-Plex Pro Human SARS-CoV Variant Neutralizing Antibody Assays

Bio-Rad Laboratories announced in December 2021 that it would be offering new Bio-Plex Pro Human SARS-CoV Variant Neutralizing Antibody Assays for use in measuring neutralizing antibodies. The product con- sists of a ready-to-use 96-well kit containing premixed magnetic capture beads, a detection converting enzyme (ACE)-2 receptor, a standard and positive control, and buffers that measure levels of neutralizing antibodies and percentage inhibition of the ACE-2 receptor binding the viral antigens coupled on the beads.

The assays are being offered in an 11-plex complete all-in-one kit format that consists of wild-type receptor-binding domain and S1 and 9 variant antigens, customizable sin- gleplex assays, and 2-plex Delta variant coupled beads. Additionally, a custom Assay Developer Kit to create assays for any new SARS-CoV-2 variant—such as Omicron—is included. This customizability may prove invaluable as mutant strains of COVID-19 continue to develop (2).

In November 2021, BioChromato released data supporting the notion that its Smart Evaporator C1, designed for preparing microbial degradation culture media for analysis, can utilize a novel bioremediation technique to improve the detoxification process for persistent organic pollutants (POPs) that cannot be decomposed by natural processes in soil.

According to an interview the company had with an anonymous researcher, various advantages were found relative to rotary evaporators:

The Smart Evaporator C1 can evaporate culture medium samples without azeotroping, saving a significant amount of time relative to rotary evaporators.

Rotary evaporators are at risk of water contamination from the steam adsorbed from the water heating bath. The CI instrument avoids this risk because it does not need water.

Researchers no longer have to monitor the process to avoid solvent bumping— because the C1 instrument operates under normal pressure, samples can be left unattended (3).

OpenEye, in a partnership with Specifca, launched the Orion Antibody Discovery Suite, a jointly developed software, in December 2021. Orion is designed to identify diverse antibody sets with better properties for down- stream therapeutics development. The product exclusively features Specifica’s AbXtract software, an antibody discovery module that uses proprietary artificial intelligence methods to analyze large amounts of sequence data.

OpenEye claims that Orion is the only cloud-native fully integrated software-as-a-service molecular modeling platform. Orion uses Amazon Web Services, which provides it with unlimited storage and computational scal- ability in tandem with its data sharing, visualization, and analysis tools (4).

MilliporeSigma's ColorWheel Flow Cytometry Antibodies and Dye

Announced in November 2021, MilliporeSigma’s ColorWheel Flow Cytometry Antibodies and Dyes present the latest advancements in cytometry profile technology. The product allows users to select antibodies and dyes for assembly in any desired combination, resulting in an output of mix-and-match antibodies and dyes analogous to a primary conjugated antibody.

According to MilliporeSigma, multiplexing in flow cytometry can be difficult because researchers must consider instrument configuration, antigen expression and dye brightness balance, and antibody–dye combination avail- ability. In this regard, the ColorWheel is designed to overcome these constraints by making it easier to build a new multiplex assay for samples with varying expression levels of antigen.

Other notable features of the ColorWheel include:

Flexibility to pair any antibody with any dye in a ready-to-use, convenient format

Can be used in five minutes of hands-on time, minimizing necessary time and effort

Preservative-free presentation that promotes sustainability and wider sample type compatibility

Lyophilized product, enhancing stability and allowing for ambient shipping (5).

Satrotius' Sartolab RF|BT 150–1000 Vacuum Filtration Units

Sartorius introduced the new Sartolab RF|BT 150–1000 Vacuum Filtration Units in November 2021. Designed to offer faster and higher capacity filtra- tion, the new filtration units also allow for enhanced physical stability for a wide range of sample types through a newly optimized center of gravity.

The RF|BT 150–1000 has an increased membrane surface area designed to facilitate optimal filtration. Additionally, there is an 0.45- μm polyethersulfone membrane in place of the 0.45-μm cellulose acetate membrane, which increases flow rate while keeping the same low-protein binding properties.

The new units can be directly used on the Sartolab Multistation for par- allel filtration. Additionally, the new vacuum filtration units are available in three different pore sizes to meet the needs of most applications:

: sterile filtration of cell culture media, buffers, and reagents

: clarification of aqueous and viscous solutions (6).

Thermo Fisher Scientific's Orbitrap Exploris MX Mass Detector

Thermo Fisher Scientific unveiled the Orbitrap Exploris MX Mass Detector at the 69th American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics in October 2021. The new mass detector allows biopharmaceutical laboratories to implement multi-attribute method (MAM), an analytical extraction technique that can extract large amounts of different quality parameters of a protein via a single analytical approach.

In addition to MAM, the Orbitrap can perform intact analysis of monoclonal antibodies, conduct oligonucleotide mass determination, and carry out peptide mapping. According to Thermo Fisher, this instrument simplifies the transition of biotherapeutics from development to manufacturing and enables quality control customers to use the same method established earlier in a molecule’s journey to commercialization. This design is intended to accelerate the overall biopharma development pipeline (7).

CuriRx announced the CuriLytics Platform in September 2021. Designed to support the development of complex biotherapeutics, CuriLytics uses high-resolution mass spectrometry and various orthogonal characterization methods to characterize modern bio- pharmaceutical drugs, including:

Ultimately, the platform can iden- tify quality attributes of protein can- didates at the individual residue level, which can be used to provide context to effects brought about by changes to the process or production of the drug (8).

Bürkert Fluid Control Systems new scalable chemical disinfection system features a compressed air-operated dual-substance nozzle that provides homogenous and fine aerosol formation of hydrogen peroxide with minimal chemical and energy input.

The system is designed for applications such as sterilizing packages, cleaning high efficiency particulate air filters, or disinfecting rooms. In operation, hydrogen peroxide is pumped from a stainless-steel container to a liquid flow controller. Atomizing air is metered to the nozzle through a mass- flow controller, producing a fine mist. The measured material flows enable the control of disinfection time.

The modular preparation system can be customized to suit customer needs to include heaters, integrated flushing, safety devices, or control cabinet integration with programmatic logic controllers (9).

The Lasair Pro Airborne Particle Counter from Particle Measuring Systems, announced in July 2021, supports a range of applications, including clean-area monitoring and classification while meeting international cleanroom certification standards.

The instrument is designed to meet increasing data integrity and regulatory requirements, featuring integrated audit trail capabilities. Sampling activities can be programmed and managed locally or remotely. Collected data are securely saved and transferred to meeting data integrity-related standards such as 21 

The instrument can store up to 10,000 data samples and can be configured for up to 100 users. Unlimited users can access a near field communication card (10).

1. Refeyn, “Refeyn’s New SamuxMP Mass Photometer Promises to Significantly Improve AAV Workflows,” Press Release, Jan. 19, 2021.

2. Bio-Rad Laboratories, “Bio-Rad Introduces Bio-Plex Pro Human SARS-CoV-2 Variant Neutralization Antibody Assays to Quickly Measure Neutralizing Antibodies Against SARS-CoV-2 Virus,” Press Release, Dec. 20, 2021.

3. BioChromato, “Fast & Effective Evaporator Improves Bioremediation Sample Preparation,” Press Release, Nov. 26, 2021.

4. Specifica, “OpenEye Scientific And Specifica Partner To Launch Orion Antibody Discovery Suite Incorporating AbXtract,” Press Release, Dec. 2, 2021.

5. BioPharm International, “MilliporeSigma Unveils ColorWheel Flow Cytometry Portfolio,” 

6. Sartorius, “Sartorius Introduces Faster, Higher Capacity Sartolab RF|BT Vacuum Filtration Units,” Nov. 1, 2021.

7. Thermo Fisher Scientific, “Thermo Fisher Scientific Launches
New Mass Spectrometry and Chromatography Solutions at ASMS 2021,” Press Release, Nov. 1, 2021.

8. CuriRx, “CuriRx Launches CuriLytics Platform to Provide CMC Analytical Services to Support Complex Biotherapeutic Development Using High Resolution Mass Spectrometry,” Press Release, Sep. 21, 2021

9. Pharmaceutical Technology, “Hydrogen Peroxide Dispensing System” 

10. Pharmaceutical Technology, “Airborne Particle Counter,” 

An overview of technologies aiming to improve laboratory processes from the past year.