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

Features

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

Pharmaceutical Quality/Manufacturing Standards (CGMP) Data Integrity and Compliance With CGMP

, FDA began discussing its remit with a foreboding introduction stating that, “In recent years, FDA has increasingly observed CGMP [current good manufacturing practice] violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s ability to protect the public health. These data integrity-related CGMP violations have led to numerous regulatory actions, including warning letters, import alerts, and consent decrees” (1). The context and consequences of those warning letters was made clear in com- mentary by Peter Zipfell, product marketing manager at Thermo Fisher Scientific, who spelled out that “... based on findings from a 2019 report on drug shortages, of 163 drug shortages in the US between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality problems” (2).

 (updated February 2020), the second recommendation was to “create a rating system to incentivize drug manufacturers to invest in achieving quality management system maturity... as the market does not recognize and reward mature quality management systems. This recommendation aims to rectify this failure by suggesting the development of a system to measure and rate the quality management maturity (QMM) of individual manufacturing facilities based on specific objective indicators” (3). This new framework appears near introduction as FDA issued a white paper last month (March 2022) on the QMM program and will be holding two workshops in May to gain further input from stakeholders.

The drug shortages report goes on to say that, “A rating system could be used to inform purchasers, Group Purchasing Organizations (GPO) and even consumers about the state of, and commitment to, the quality management system maturity of the facility making the drugs they are buying. Pharmaceutical companies could, at their discretion, disclose the rating of the facilities where their drugs are manufactured. GPOs and purchasers could require disclosure of the rating in their contracts with manufacturers. This effort would introduce transparency into the market, and provide firms committed to quality management maturity with a competitive advantage, potentially enabling them to obtain sustainable prices as well as grow market share” (3). So, change is coming, and with it the requirement to tighten up on how data are collected, collated, and shared.

Because past is prologue, BioPharm International asked Edita Botonjic-Sehic, director, Global Analytics, Pall Life Sciences if the original push by FDA to promote process analytical technology (PAT) adoption was helpful in setting expectations and in creating a new tools and services ecosystem. “Yes,” Botonjic-Sehic says, “advanced technologies and computation modeling has contributed significantly to making this capability come to life. By utilizing PAT into integrated bioprocessing, better process understanding is gained, production cycle time is reduced, improvement of yield is achieved, efficiency is improved, and cost reduction is achieved by the reduction of waste and energy consumption resulting from the real-time release of a batch with improved quality.” She goes on to explain, “Biotech processes consist of several unit operations, with each unit operation serving a defined purpose. The need for appropriate control of each step and continuous evaluation of its performance is critical. To date, there are still gaps in the area of advanced analytics for the process; however, computational modeling has slowly started to contribute towards process characterization. The goal is to have both process technologies and advanced computing used in real-time for process control.” So along with the rest of the world, pharmaceutical manufacturing is becoming a digital undertaking.

When asked if increasing compliance and validation requirements lead to more processes and documentation burden, Botonjic-Sehic responded that, “Data driven frameworks and transformation to digitalization will lead to a new future state. There are still many challenges in bringing technological innovation and advancement due to lack of adoption and change in processes ... FDA has been very much involved with the industry to support the adoption of the advancements in the process. It may seem as if it is complex at this given moment; however, the ultimate goal is to make the process and filing seamless and putting in the effort upfront is a necessity in order to make the future of manufacturing much easier.”

Measuring complex product quality attributes

For the future of the industry, does biological complexity require a more diverse set of scientists and wider array of team members? Botonjic-Sehic consid- ers a “lack of advanced process analytical technologies capable of measuring product quality attributes in real-time [as] a change today; however, Pall Life Sciences and many other companies have been investing in making these technologies available to customers that support biotherapeutics manufacturing. Computational techniques supporting predictive outputs of the process are also at the early stages; however, we have seen a much larger uptake of such innovations being utilized in the bioprocess. Integration of process technologies and advanced analytics will support Industry 4.0 and provide bioprocessing manufacturing with real-time process monitoring and control. As far as scientific experts— many of the process analytical scientist and chemometricians (data scientist) come from small molecules manufacturing industry and there is a growing need for these skills sets to move forward faster as we progress in providing advanced technologies for biomanufacturing processes,” concludes Botonjic-Sehic.

This coincides nicely with comments from Dr. Natalia Vtyurina, senior quality assurance officer at HALIX B.V., who, in a blog post for the International Society for Pharmaceutical Engineering (ISPE) emphasized that in every highly regulated industry there are specific rules and regulations that when embedded in guidelines, help shape both culture and data collection while streamlining future planning and optimization. Dr. Vtyurina points out that “a data integrity (DI) maturity program uses standard rules and procedures that will take the organization through all aspects of DI. It will support your organization towards a safe environment and a strong culture by properly managing data, ensuring high-quality standards, and improving efficiency. On top of ensuring a high-quality product, your business’s core processes’ costs will be significantly reduced. A DI program will also help you to identify, remediate, and manage potential risks to DI” (4).

To round out the discussion, BioPharm International asked Stefan Holzner, vice president R&D, Pall Life Sciences, if momentum toward modular manufacturing with continuous adjustments and improvements creates a premium for real-time feedback, and has the industry hit a rate limiting bottleneck or bottlenecks. Stefan’s position is that there is a need to get real-time data and make it actionable. “This requires state-of-the-art sensors to cover a wide array of parameters (including different types of metabolites etc.). The data needs to be transferred into insights to make them actionable. Multivariate data analysis could be a tool to achieve this. However, it does (seem) like we have reached a bottleneck as new sensors are required that enable better real time data as well as the proper ecosystem to process this data in real time and allow insights to act accordingly,” Holzner says. Some growing pains allows us some room to grow into, it seems. Data are now how business performance is officially measured and recorded. The sooner DI is controlled for, and firmly established, the earlier organizations will reap its rewards.

Guidance to Industry, Data Integrity and Compliance With cGMP

2. P. Zipfell, “Strengthening Data Integrity and Traceability,” 

Drug Shortages–Root Causes and Potential Solutions

, 2019, updated Feb. 21, 2020 (FDA, 2019). 

4. N. N. Vtyurina, “Why is Data Integrity Critical in the Pharma Industry,” iSpeak Blog, 

Chris Spivey is the Editorial Director of 

FDA continues efforts to incentivize drug manufacturers to follow higher data integrity requirements.

Ensuring CGMP Standards for Data Integrity

Thermo Fisher Scientific is teaming up with biotech incubator LabShares Newton to provide support to the biotech ecosystem in Boston. Through the collaboration, the partners will provide instruments, lab equipment, and consumables to help early-stage life sciences companies accelerate drug discovery efforts, according to a May 19, 2022 company press release.

LabShares provides fully furnished lab space, services, and equipment to more than 25 biotech companies, which alleviates logistics constraints in bringing novel therapeutics to market. Under the agreement, Thermo Fisher will outfit the shared lab space with equipment, including ultra-low temperature freezers, cell culture incubators, microscopes, and polymerase chain reaction instruments.

Although investment in the biotech industry continues to climb, the high cost of bringing drugs through R&D to market is limiting for many early-stage companies. By offering alternative lab space and more tailored support and resources, LabShares and its partners aim to aid emerging biotech companies clear hurdles that previously hindered growth for smaller companies trying to break through to the market, according to the press release.

“Thermo Fisher Scientific is incredibly excited to partner with LabShares in support of the emerging life science and biotech companies in Newton,” said Angela N. Hokanson, vice-president, corporate accounts, Thermo Fisher Scientific, in the press release. “In line with our mission to enable our customers to make the world healthier, cleaner, and safer, we look forward to collaborating with LabShares and their members to innovate, validate, and commercialize the next generation of life-saving therapies.”

“With little lab space available in historic biotech hubs such as Cambridge [Mass.], emerging companies are looking to the suburbs for more accessible and affordable lab space,” said Jeff Behrens, CEO and founder, LabShares, in the press release. “Working with partners such as Thermo Fisher allows LabShares to provide a caliber of equipment that smaller companies may not otherwise have access to, empowering promising biotech startups to hit the ground running.”

News

Through the Thermo Fisher Scientific and LabShares Newton partnership, life science startups can accelerate early-stage discovery and development with shared lab spaces.

Thermo Fisher Scientific and LabShares Partner to Support Emerging Boston Biotechs

PerkinElmer has introduced its ultrarapid whole genome sequencing (urWGS) services through PerkinElmer Genomics, expanding the company’s portfolio of whole genome sequencing offerings. The urWGS offering provides physicians with comprehensive, meaningful results in five days to help inform clinical management and improve outcomes for critically ill patients in neonatal and pediatric intensive care units (NICUs and PICUs).

urWGS uses a dried blood spot sample to provide phenotype-driven analysis with a mean coverage of 40x a patient’s genome. According to a May 16, 2022 press release, studies suggest that up to 15% of disease-causing genetic variants may be found in the non-coding regions of the genome, which WGS helps identify. In addition to an analysis of the mitochondrial genome, copy number variation detection—which identifies deletions, duplications, other gene- and chromosomal-level events, spinal muscular atrophy, and a repeat disorders screen—the urWGS offering includes a StepOne comprehensive biochemical profile. The StepOne offering screens for more than 70 inherited conditions and disorders, including the recommended universal newborn screening panel as well as many others that may not be found in state-mandated programs.

Rapid WGS tests have been shown to reduce healthcare costs for patients in NICUs and PICUs (1). In addition, these testing services include the elimination of unnecessary tests and procedures and reduced length of hospital stays, according to PerkinElmer in its press release.

“Increasingly, whole genome sequencing is proving its value as a first-tier clinical test for many patients, especially in a NICU and PICU where timely clinical decisions are critical for timely intervention,” said Madhuri Hegde, senior vice-president and chief scientific officer, Global Lab Services, PerkinElmer, in the press release. “By making services such as this urWGS combined with StepOne available to more hospital systems and physicians, our hope is that we may help shorten the diagnostic odyssey for more newborns and their families. With PerkinElmer’s global leadership in newborn screening using dried blood spot card technology, we will continue to enhance urWGS with additional assays.”

New Technology

PerkinElmer has expanded its genomics testing services with the launch of its ultrarapid whole genome sequencing.

PerkinElmer Introduces Ultrarapid Whole Genome Sequencing

Eurofins Scientific signed an agreement in May 2022 with Stichting PAMM Laboratoria voor Pathologie en Medische Microbiologie (PAMM), a medical microbiology and pathology laboratory diagnostics company in The Netherlands. The agreement will see PAMM outsource its laboratory activities to Eurofins.

Under the agreement, Eurofins will invest in the laboratory and in R&D, innovation, employee development, and job security. PAMM serves six hospitals in The Netherlands, including two top-rated clinical oncology centers, general practitioners, and independent treatment centers. The lab specializes in medical microbiology and pathology and was the first in The Netherlands to have implemented full digital pathology, according to a May 9, 2022 press release.

“We are very pleased to welcome PAMM and its team of outstanding specialists and laboratory technicians to the Eurofins Group. This agreement reinforces the Group’s broad innovative test offering to hospitals and practitioners in The Netherlands, strengthens Eurofins geographic offering in the clinical testing market, and enhances our ability to deploy the latest scientific advances to benefit patients,” said Gilles Martin, Eurofins CEO, in the press release.

Eurofins partners with PAMM to strengthen laboratory services for the Dutch healthcare system.

PAMM Foundation Outsources Laboratory Activities to Eurofins

BioGrad Diagnostics, a UK-based diagnostics company, has adopted the Matrix Gemini system from Autoscribe Informatics, a UK-based database management company, as its laboratory information management system (LIMS). BioGrad, which is also a COVID-19 testing laboratory, is focusing on fast turn-around of COVID-19 samples. It intends to manage client and sample data within the LIMS, driving automation and efficiency, the company said in a May 12, 2022 press release.

The company offers rapid, accurate antigen and polymerase chain reaction COVID-19 testing and has been analyzing an increasing number of home test kits posted directly to its lab. BioGrad has also opened several satellite collection sites including Manchester, Warrington, and Liverpool, in the United Kingdom, offering supervised Pre-Travel, Day 2, Day 8, and Test-to-Release testing services for UK travelers and international travelers coming to the UK.

BioGrad chose to replace its old management system with Matrix Gemini LIMS to enable it to better cope with the increasing volume of samples from the SARS-CoV-2 epidemic The new LIMS provides the flexibility to capture data and report that data to Public Health England (PHE) for test and trace purposes. Certificates of analysis are also created for clients to support the various types of testing offered for the UK market, including Fit-to-fly, Day2, Day 8, and Test-to-Release.

Biograd Diagnostics has chosen the Matrix Gemini system by Autoscribe Informatics as its laboratory information management system for managing COVID-19 test samples.

Biograd Diagnostics Adopts Autoscribe Informatics’ Matrix Gemini LIMS

Foxx Life Sciences, a US-based manufacturer of biotech, pharmaceutical, and diagnostics products, entered into an online distribution agreement with Thomas Scientific in May 2022 to make selling easier for Foxx’s EZBio made-to-order media bottle assemblies (EZBio MTO). The products will be made available for customization and can be ordered through a direct-to-consumer microsite hosted on the Thomas Scientific website.

Foxx launched the EZBio MTO service in February 2021, and the service was previously only available through the Foxx website. The EZBio MTO service allows customers to select individual laboratory media bottle assembly components best suited to their project needs. Components that can be selected include the volume and material of bottle, brand of thermoplastic elastomers tubing, and type of fitting.

Through the agreement with Foxx, Thomas Scientific customers can now gain access to the EZBio service and product portfolio through a unique dedicated microsite. Compared to traditional media bottle assembly ordering, the microsite’s customization provides users with increased flexibility and offers a significant reduction in lead time, according to a May 3, 2022 press release.

EZBio MTO assemblies are available in polyethylene terephthalate glycol-modified and polycarbonate. These assemblies are applicable to bioprocess storage and sterile fluid transfers that typically require regulation. The microsite’s component selectors can be used to select from more than 400 different combinations in seconds, which can cut down the standard eight-to-10-week lead time to four to six weeks in most instances, according to the companies in the press release.

"The Foxx Thomas EZBio MTO program is an SUT [single-use technology] end user game changer,” said Foxx Life Sciences President and CEO Thomas Taylor in the company press release. “A few simple clicks and you have exactly what you are looking for with your tubing, your connectors, etc. Foxx was the first in the world to create this SUT MTO program."

“This partnership with Foxx gives Thomas the ability to offer fast, flexible, single use solutions to all our customers. It significantly broadens our ability to support them in their manufacturing suites,” said Michael Klipstein, Thomas Scientific’s chief commercial officer in the press release.

Foxx Life Sciences and Thomas Scientific collaborate to simplify online ordering access to Foxx’s media bottle assembly offerings.

Foxx Life Sciences and Thomas Scientific Partner to Simplify Media Bottle Ordering

Fluid Air, a division of Spraying Systems, announced that Sferalp, the R&D arm of Micro-Sphere, has selected their PolarDry technology for use in its research laboratory in Monteggio, Switzerland. Sferalp will use the PolarDry technology for powder processing with its commercial food, pharmaceutical, and nutraceutical customers.

“Our Swissmedic-certified laboratory is authorized to perform chemical-physical quality control tests on medicinal products and active substances in accordance with [good manufacturing practices] for medicinal products, and we know that we can count on Fluid Air technology to help achieve superior results for our customers,” said Michele Müller, general manager of Sferalp, in a May 10, 2022 company press release. “Fluid Air is the only provider in the marketplace whose technology can support our lab’s needs and help us meet the highest industry standards for quality and product performance.”

“Fluid Air is pleased to have its PolarDry technology used by an industry influencer [such as] Sferalp [and] is thrilled to have been selected as a key technology contributor to Sferalp[’s] important work,” said Michel Thenin, president, Fluid Air, in the press release.

Sferalp will use Fluid Air’s PolarDry technology for powder processing.

Sferalp to Use Fluid Air Technology for Laboratory Research

Avacta Group, a clinical-stage oncology drug company, announced that it would be relocating its Therapeutics division on May 11, 2022.The division will now be headquartered at Scale Space in Imperial College’s White City Campus, London, United Kingdom. This move follows Avacta’s recent transition of lead candidate AVA600, a tumor-activated form of doxorubicin, into clinical trials in August 2021.

Scale Space is part of the broader White City Innovation District, which is currently home to over 140 companies across a broad range of industries, including pharmaceutical and biotech. According to a company press release, Avacta’s new HQ will be part of a life science cluster at the west London site.

“This move is the result of a clear vision to bring together the research and development teams into one hub to facilitate the translation of our in-house research from bench to bedside,” said Fiona McLaughlin, chief scientific officer of Avacta, in the press release. “We are now at the heart of the innovative White City community in London, readily accessible to our collaborators around the world and poised to take Avacta to the next level in its evolution as a clinical stage biopharmaceutical company.”

Avacta is relocating its therapeutics headquarters to Scale Space in Imperial College’s White City Campus, London, United Kingdom.

Pharmaceutical Technology's In the Lab eNewsletter, June 2022