Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Protein therapeutics are an important class of medicines that are used to treat a variety of diseases. According to market research, the protein therapeutics market is estimated to grow at a compound annual growth rate of 6.86% between 2020 and 2027 (1). This growth is expected to be driven by the rapid rise in chronic disorders, advancements in technologies, broadening awareness of protein therapeutics, increasing adoption of plasma-derived therapies to manage chronic disorders, and mounting government initiatives to develop healthcare sectors (1).

However, therapeutic proteins are notoriously less stable than conventional pharmaceuticals; and due to their complex molecular structures, they can be challenging to develop successfully (2). “Compared to small molecules and peptides, proteins are much more complex,” explains Khanh Courtney, PhD, senior director, Biologics, Element. “Therefore, the understanding of the biophysical and biochemical characteristics of a protein biomolecule is critical in the identification of critical quality attributes (CQAs) to ensure consistent safety and efficacy.”

As proteins are formed by long chains of amino acids that interact with each other, secondary and tertiary molecular structures are formed, notes Courtney. Beyond the tertiary structure, the protein can bind to itself, which results in even higher order structures, such as dimer, trimer, and oligomer, she states.

“Certain amino acids could be post-translationally modified with phosphate groups, methyl groups, simple sugars or complex sugars, and so on, leading to a highly complex protein therapeutic molecule,” Courtney says. “The folding of the protein, the higher order structure, [and] the composition of its post-translational modifications, particularly of the glycans, are all examples of protein characterizations that could impact the potency and function of the molecule.”

“Protein characterization is of [the] highest importance throughout all stages of the value chain from discovery to development, through to quality control,” emphasizes Martin Vollmer, strategic program office lead for Biopharma, Agilent Technologies. “Characterization of a protein provides information about its structure and composition, which is directly linked with its function, leading to a greater understanding of differences and ensuring that quality criteria of developed biopharmaceutical products are met according to regulatory guidelines, ensuring drug efficacy and drug safety.”

For Scott J. Berger, PhD, senior manager, Biopharmaceutical Markets, Waters Corporation, whether making a protein drug via a recombinant or synthetic process, development should start with protein characterization and having as much knowledge as possible about the product. “These processes are imperfect, so they are going to make products with low-level variations that are subject to degradation pathways that further raise product variability,” he specifies. “It’s this complexity that creates reliance on sophisticated analytical tools.”

Tools, such as liquid chromatography (LC) and mass spectrometry (MS), have provided process scientists with the ability to monitor important attributes of a molecule in response to changes in the process, Berger adds. “This [capability] gives scientists the flexibility to incrementally refine their process to improve drug quality and yield by establishing analytical comparability,” he says. “Characterization assays often translate to targeted methods for process monitoring and product release where you are verifying that you have control of your process and product quality.”

A key challenge related to protein characterization is that methods usually require a lot of test material, Courtney stresses. “Ideally, protein characterization is done in the early stages of chemistry, manufacturing, and controls (CMC) program development so that critical attributes are identified early on. Unfortunately, the early stage of CMC, for instance during process development, consists of small-scale productions done at the lab bench and have low yield,” she states. “This challenge can be, and is being, dealt with by the advancement of analytical methodologies that can assess more than one characteristic at a time in a single sample preparation or method.”

An example of how this challenge is being overcome can be found in the use of high resolution, high sensitivity MS. “This approach can be used to decipher the peptide map of the protein, post-translational modifications, deamidation, disulfide bonds, aggregation, molecular mass verification, glycan structure elucidation, and even tertiary structure determination, all in one approach,” Courtney explains. “By packaging multiple attributes into one method, a small yield of protein produced at the lab bench could produce a wealth of data to assess protein characteristics to better inform manufacturing and quality decisions.”

There are several immediate challenges to protein characterization in Berger’s opinion. “First, is the increasing complexity of the molecules,” he says. “We’re seeing the appearance of bi- and tri-specific molecules, antibody-drug conjugates [ADCs], and complex fusion proteins, all of which have more attribute variation than your typical monoclonal antibody, requiring enhanced analytics to define and monitor them.”

Additionally, in light of the increasing number of accelerated reviews by regulatory agencies, a challenge has arisen in the form of being able to fully characterize molecules in a compressed timescale and at the same time as stability studies and formulation development are taking place, Berger points out. “So, there is an increasing need for efficient analytical platform methods that can utilize prior knowledge to accelerate these studies,” he states.

“Another challenge many organizations face is the lack of actionable knowledge during the clone selection stage of product discovery/development,” Berger continues. “Use of LC–MS at this stage can ensure that a biosimilar, for example, matches up to the target analytical profile of the innovator molecule when it comes to a set of key and critical quality attributes.” When used as a part of a quality-by-design (QbD) approach, LC–MS can help to ensure that the desired product attributes are built into the molecule, he notes. If there is insufficient knowledge about a molecule at this stage of development, it is possible that impurities or instabilities won’t be discovered until after the product is placed into clinical production, Berger warns.

For bench scientists, experimental bias can be a significant challenge, Berger highlights. “A top reason why assay-to-assay test results vary from one scientist to another has to do with complicated and multi-step sample preparation methods,” he says. “For multi-attribute monitoring of biomolecules by LC–MS, it’s important that you have a very high-quality and reproducible sample for meaningful results. To address this need automated sample prep technologies are being investigated by many groups as a tool to improve sample quality and reproducibility by eliminating the human factor from potentially biasing assay results.”

Undesirable secondary interactions can adversely impact analytical data when analyzing organic acids, organophosphates, oligonucleotides, phosphopeptides, acidic glycans, and phospholipids, Berger notes. “One example of a secondary interaction is the non-specific adsorption by certain biomolecules to the metal surfaces—or even to bio-compatible materials like titanium—of liquid chromatographs and chromatographic columns,” he states. “Another type of secondary interaction is caused by the highly active surfaces of proteins which have a propensity to interact with the hydrophobic and electrostatically-active sites on the silica and hybrid silica chromatographic particles in the UHPLC [ultra-high performance LC] or UPLC [Ultra-Performance LC] column.”

These secondary interactions cause difficulties when characterizing and monitoring drug products by size exclusion chromatography (SEC), which is used to determine protein sample size variants claims Bill Warren, Principal Bioseparation product manager, Waters Corporation. If these attributes are not carefully controlled then the safety and efficacy of the product can be adversely affected, Warren specifies. “It’s for this reason that regulatory agencies require drug firms to accurately quantify the protein size variants like mAb aggregates, monomers and fragments in protein drug products,” he says.

Vollmer emphasizes that protein characterization is highly complex and is only becoming more complex over time. “In the past, it was mainly monoclonal antibodies (mAbs), hormones, vaccines, modified human proteins, and similar therapeutic proteins. Now with the discovery of antibody [drug conjugates (ADCs) fusion-proteins, bi-specific Abs, and other modalities, the task of protein characterization now requires a much more flexible approach,” he asserts.

This increasing complexity is then also tied to the skill of the analytical scientist that needs to perform the characterization, Vollmer stresses. “There are a multitude of assays that need to be performed and the instrumentation required is more sophisticated, but costly,” he explains. “Big hurdles are, therefore, the cost of implementation, operation, and skilled personnel.”

“Another important challenge is the large amount of data that needs to be analyzed for meaningful information and further action,” Vollmer continues. “More broadly, regulatory hurdles and inertia in the industry are often roadblocks for fast innovation.”

“LC and MS have been the empowering technologies for the well-characterized biotherapeutic,” Warren says. “LC is essential for fully analyzing an intact protein or its sub-units for glycan profiling or peptide mapping or for looking at protein charge or size variants.”

A technique that is useful for characterizing protein size variants is SEC, Warren adds. There have been several new SEC columns that have been brought to the market recently, he states, that address “the problem of secondary interactions (both ionic and hydrophobic) when separating protein aggregates, monomers, and fragments over a molecular weight range of 10,000 to 6,500,000 Daltons.”

Berger also notes that through combining LC and MS, it is possible to establish the primary structure (product sequence), which is a regulatory filing requirement. “With LC–MS, you get to explore the product variation, its stability, and degradation pathways, which ‘hot spots’ to monitor to ensure that the product qualities and your processes are under your control,” he says. “LC–MS is also ideal for looking at a molecule’s higher order structure, which relates to the folding and stability of these biotherapeutics, and how they interact with their protein targets, or themselves when it comes to things like molecular aggregation.”

The structural information obtained by LC–MS can drive product development and can also form the basis of intellectual property, Berger points out. “Understanding higher order structure and stability dynamics may require the use of techniques like hydrogen deuterium exchange or ion mobility mass spectrometry (IMS-MS) and more recent techniques, such as collision-induced unfolding (CIU). CIU is an approach where the mass spectrometer is almost like a calorimeter, adding energy to the protein molecule and seeing how it unfolds within the IMS-MS,” he says. “These techniques allow you to ask questions that go beyond primary structure to understanding the dynamics of its folded structure and interactions with its protein target.”

Courtney highlights three techniques that are important for protein characterization: “High resolution, high sensitivity, orbitrap MS for protein and glycan identification, and structural elucidations; capillary electrophoresis to determine charge heterogeneity; and circular dichroism for secondary structures.”

Although there is no single standard technique to characterize proteins, Vollmer concurs that LC and high-resolution MS are regarded as the gold-standard thanks to the “rich” information such techniques offer on physiochemical properties of the protein. “Other alternative techniques are capillary electrophoresis (CE) and CE–MS because they can provide excellent resolution,” he adds.

“Spectroscopy, such as ultraviolet, Raman, near infrared, or fluorescence, are also widely applied to determine more specific requirements, such as concentration or purity. These techniques are fast and can even be applied inline,” Vollmer concludes. “Cell analysis technologies, such as metabolic analyzers, real-time cell analyzers, cell-imagers, and cell counters are applied to characterize suitable clones and host cells for protein manufacturing.”

Protein Therapeutics Market Research Report: by Type, Application, Protein Function, End User—Forecast to 2027

, Market Report (February 2021).
2. A. Bolje and S. Gobec, 

Felicity Thomas is the European editor for the Pharmaceutical Technology Group.


Vol. 46, No. 3
March 2022
Pages: 36–39

When referring to this article, please cite it as F. Thomas, “Empowering Protein Characterization,” 

Articles

Scientists can work to overcome the challenges associated with protein characterization through empowering technologies.

Empowering Protein Characterization

The COVID-19 pandemic highlighted how vital cold chain is for the pharmaceutical industry, particularly as some vaccines needed to be produced, transported, and stored at –70 °C. Market projections for cold chain logistics of pharmaceuticals are projected to grow at a compound annual growth rate of 9.03% by 2025, which is reported to be driven by greater global demand for pharmaceuticals, increasing initiatives to promote cold chain, and more demand for reefer containers from the pharma industry (1).

To meet the increase in demand for temperature-controlled solutions, logistics providers are being required to adapt their approaches and employ more advanced technological solutions, while still adhering to strict regulatory requirements. 

 spoke with Nick Gilmore, Global Head of Sales and Marketing, Tower Cold Chain, to learn more about how cold chain solutions have changed, what the regulatory landscape is looking like for logistics providers, and potential future trends for the sector.

 How have cold chain solutions had to adapt to meet the growing demands for cold chain logistics?

 Putting the European success of the COVID-19 vaccine rollout to one side, the demand for effective temperature-controlled packaging solutions in the pharmaceutical supply chain has increased significantly in recent years. Indeed, with a growing prominence for personalized medicines, we are now beginning to see the advancements of precision therapies in the pharmaceutical cold chain industry. There is no longer a ‘one-size-fits-all’ approach to medical intervention. Instead, we’re seeing a move towards bio-specific treatments, tailored to a particular individual’s needs based on their genome. And, with manufacturing adjusting to smaller batch, precision medicines, the vendors, and outsourcing partners must adapt too as the need for transparent, closely controlled global supply chains rise.

It is critical for pharmaceutical manufacturers to partner with a cold chain expert that is committed to continually expanding and evolving, to keep pace with the growth and complexities of transporting temperature-sensitive pharmaceuticals. Cold chain shipping providers should have the technology, resources, and network in place for handling lower volumes of products with tight manufacturing-to-patient timeframes. Delivering a consistent customer outcome, is a need not a want. Put simply, manufacturers will choose partners who offer both proximity and availability assuring products will arrive on time, undamaged, and with no temperature excursions.

Where historically pharmaceutical products were manufactured in one central factory, today they are more often produced, mixed, filled, and packaged in separate locations, thus demanding greater distribution and movement. It is no longer just about the final leg of the journey to patients. Logistic organizations who can offer customers a network of fully stocked hubs and service centres, located across multiple countries, can maximize their proximity and availability, and offer localized sourcing, will be in a strong position to become a partner of choice.

Factoring in the high value of pharmaceutical goods, their perishable nature, and susceptibility to temperature changes, manufacturers require not just optimized networking, but assurance of product integrity for patients and businesses alike. It is here that the choice of the most appropriate cold chain solution makes all the difference.

 As cold chain technologies advance to accommodate industry demands, are European regulations changing appropriately to address the novel technologies being used?

 The pressure is on for logistics players, manufacturers, governments, and non-governmental organizations to improve their capabilities in supporting the life sciences industry, whilst adhering to standards enforced by regulatory bodies to ensure product quality and safety. One solution to meet this industry need is through digitalization.

The volatility of the pharmaceutical market combined with today’s increasingly connected, fast-paced, customer-focused world means data is no longer a bonus feature, but a vital part of cold chain operations. Smart packaging which delivers end-to-end traceability and precise shipment tracking is now a cornerstone of supply chain fulfilment.

Dataloggers, designed to monitor external and internal temperatures throughout the containers journey, can be built into containers, which is an aspect included in those provided by Tower. Using Bluetooth Low Energy Technology, each logger communicates wirelessly, sending real time, accurate data to the cloud. This data communication allows for in-transit compliance checks and on-delivery sign-off, establishing a complete electronic and hard-copy audit trail across the entire logistics process providing complete visibility and transparency to customers.

Assurance of product integrity is paramount in cold chain which is why reliability is a key foundation for logistics providers, such as Tower. Data downloaded from over 15,000 shipments demonstrates fewer than 0.1% of temperature excursions on average, a vital indicator in the maintenance of the cold chain.

 The European Commission is driving more ‘sustainability’ issues within its pharmaceutical strategy, how might/is this aspect impacting cold chain for pharmaceuticals in Europe? Are there similar demands for more sustainable solutions being demanded from countries outside the European Union too, such as the United Kingdom?

 The EU’s pharmaceutical strategy (2) holds significant potential to drive sustainability in the pharmaceutical sector—and is an opportunity not to be missed. The strategy’s key goal is to reduce the impact of pharmaceutical substances on the environment and pave a way for the pharmaceutical industry to contribute to climate neutrality in the EU, with a focus on reducing greenhouse emissions along the value chain.

With such demand for greener supply chain management not just in the UK and EU but globally, many pharmaceutical organizations are reassessing their processes, seeking out external partners with sustainability-first mindsets. In line with government and consumer efforts to address single-use plastics, manufacturers have been compelled to look for sustainable packaging alternatives to ship products. As such, reusable cold storage containers are growing in reputation as a sustainable method for medical logistics. All players in the cold chain have a role to play in sustainability.

 After Brexit, are there any specific considerations that you must take into account for cold chain logistics across the continent now?

 With post-Brexit consequences still impacting supply chain shortages and labour capacity, pharmaceutical logistics providers are focusing on developing strategic solutions to mitigate the effect of ongoing difficulties. For example, Tower is seeking to mitigate the potential impact of Brexit by expanding its international hub network, with service centres opening not just in Europe, but also throughout other global regions. By optimizing the global network for localized delivery, it is possible for logistics providers to react even more quickly to customer requests.

Reports of bounced loads by carriers are causing major disruptions in the logistics industry, with Brexit as its catalyst (3). Local customs procedures require the broker to move between local and national government customers offices and then to the Ministry of Health for approval before pharmaceutical products can be released for import. Add Brexit regulations into the mix, and the risk of delay has increased massively.

To alleviate the threat of temperature excursion, pharmaceutical organizations require temperature-controlled containers, robust enough to protect products, and reliable enough to reduce the risk of wastage. Passive containers are a beneficial solution to this demand as they can provide temperature consistency and external security for the product without the need of an external source of electricity or manual checks—passive systems operate using phase change materials, utilizing water, ice, or dry ice to maintain thermal accuracy.

 Could you provide your expert opinion on possible future trends that will be influential to cold chain logistics in Europe?

 With its capital-intensive equipment, strict temperature requirements, and energy dependence, the cold chain has always been a demanding logistics segment. Today, the cold chain is grappling with additional challenges: serving a global market, driving out costs and waste, addressing capacity and resource constraints, and dealing with continually mounting regulations—all whilst handling valuable pharmaceutical cargo. It is vital that cold chain logistics service providers adapt and thrive, to futureproof themselves in an ever-complex industry.

An international market. With the amount of sensitive biopharmaceutical and biologic products expanding, coupled with the demand for advanced pharmaceuticals in middle to low-income countries, cold chains will continue to be pushed to globalize in the coming years. Pharmaceutical organizations are increasingly relying on their external suppliers to operate lean supply chains, with extended distances to ship products quickly and efficiently. Logistic providers must ensure these needs are met, offering a global network for localized deliveries—all whilst complying with each country’s regulations to maintain the strictest requirements.

Technological investment remains critical. Like all supply chains, cold chain operators must continually upgrade technology to ensure efficiency, integrity, and safety. Demand for increased visibility will drive cold chain third-party logistics to innovate and add value to services. Cold chain logistics providers must invest in the latest on-board equipment built into containers to track temperature and location, and to make data available to partners and customers in real time, to prevent or mitigate loss.

Digitalization and the Internet of Things, which are being assessed by Tower, can provide operators with the ability to work faster and better, through both automating and optimizing processes to provide the highest quality and consistency to customers. Systems are integral to the way cold chain operators work and these technologies will help to deliver new ‘SMART’ solutions to the market.

Competition continues to intensify. While the demand for cold chain logistics services is increasing, competition has also intensified. Providers are introducing new, innovative services or are upgrading existing solutions for cold chain logistics. As a result, there are more choices as well as more competition in the market.

Pharmaceutical organizations are also facing competition from generics and biosimilars (less expensive versions of biologics with expired patents). Whilst reliability is still the number one priority in cold chain services, there is an increased focus on cost-efficiency.

The total cost focus in the pharmaceutical industry, coupled with the increased competition and digital self-service means that customers have more choices when selecting solutions to meet their needs. Suppliers to the pharmaceutical sector must be proactive and continuously look to update their services to stay ahead.

The example of the last few years underlines how turbulent and fast changing the pharmaceutical supply chain can be. With demand set to increase further, this complexity isn’t going to go away. That’s why it’s vital to anchor cold chain decisions in the essential elements that won’t change.

Cold Chain Logistics Market for Pharmaceuticals Industry by Service and Geography—Forecast and Analysis 2021–2025

, Market Report (July 2021).
2. European Commission, “

 [Accessed 1 March 2022].
3. S. Clarke, “Road Freight Between Britain and EU is Down by a Third, Data Shows,” 

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 34, No. 3
March 2022
Pages: 25–27

When referring to this article, please cite it as F. Thomas, “Cold Comfort for Bio/Pharma,” 

Continuous improvements in technologies and services will help cold chain operators meet future industry demand.

Cold Comfort for Bio/Pharma

In February 2022, Russia commenced its invasion of neighbouring country Ukraine, in the largest military attack on the continent of Europe since World War II. Shortly thereafter, business leaders from the life sciences industry called on their peers to take immediate action by stopping work with any Russian companies and rejecting investments from Russian funds (1). The open letter garnered a monumental response and currently features, at the time of writing, 860 signatories.

Globally, sanctions—considered to be the toughest actions possible before going to war—have been placed on Russia by numerous governments. Although these sanctions, which include the removal of Russian banks from the international financial system and bans on Russian flights, are not applicable to medicine and medical equipment, there are concerns that there will still be significant disruptions to supply (2).

Of course, the bio/pharma industry has a duty of care to ensure medicines and vaccines are delivered to those in need, a point that was emphasized by the European Federation of Pharmaceutical Industries and Associations (EFPIA): “Our first priority is to ensure that medicines reach the patients that need them in Ukraine, in the neighbouring [European Union] EU Member States, in Russia, and in other countries where access to medicines may be negatively impacted. We call on all parties to facilitate the safe passage of medicines and vaccines to those in need,” EFPIA said in a news release (3).

As was demonstrated by the recent COVID-19 pandemic, the bio/pharma industry has the capacity to act quickly in crisis situations, and this recent emergency is proving no different. Many companies have already made donations and committed their support to humanitarian efforts (2). EFPIA explained the reaction of industry well in their release, which stated, “The research-based pharmaceutical industry in Europe stands in solidarity with the people of Ukraine. We condemn the invasion of their country and express our sorrow at the suffering it has caused. As an industry dedicated to saving and improving lives, we stand for peace” (3).

The thoughts of all at Pharmaceutical Technology Europe and MJH Life Sciences are with those affected, and we hope that a peaceful resolution to this situation will be swift.

1. Business Leaders for Ukraine, “Call for Business Leaders to Economically Disengage from Russian Industry,” 

, Open Letter, 27 Feb. 2022.
2. F. Guarascio, M. Erman, and S. Jacobsen, “Drugmakers, Device Companies Say Sanctions May Hinder Medical Supplies to Russia,” 

, News, 3 March 2022.
3. EFPIA, “Pharmaceutical Industry Response to the War in Ukraine,” 

, News Release [last updated on 11 March 2022].

When referring to this article, please cite it as F. Thomas, “Standing in Solidarity,” 

As Russia’s invasion of Ukraine continues, industry leaders speak out in condemnation of the actions taking place and pledge to provide aid to those in need.

Standing in Solidarity

As the world becomes increasingly data-driven and the need for standardization and transparency between the various sectors of the bio/pharma industry heightens, Europe’s implementation of the International Organization for Standardization (ISO) Identification of Medicinal Products (IDMP) continues to progress apace under the European Medicines Agency’s (EMA’s) substance, product, organization, and referential (SPOR) programme (1). To learn more about the ISO IDMP and the way that data and documents will need to be addressed in the future for bio/pharma companies, 

 spoke with James Kelleher, CEO of Generis; and Frits Stulp, managing director, and Remco Munnik, associate director, both of Iperion Life Sciences, a Deloitte company.

 Could you provide some key details about the ISO IDMP standards and how these will impact bio/pharma companies within Europe (as well as those seeking to do business in the region)?

 The ISO IDMP standards were designed to allow structured data exchange on medicinal products. These standards will ensure consistency of data collected, enabling comparisons, traceability, and that updates to constituent parts are harmonized (for example, update on manufacturer or substance information).

As with any such standard, there is effort required by all companies, small and large, in meeting it. EMA has published an EU IDMP Implementation Guide (EU IG) (2), with several updates, to guide along this process, but while it might seem an easy task, and a goal that will provide a considerable benefit to companies, agencies, and, therefore, ultimately to patients, getting ready for IDMP is not straightforward.

 It is expected that IDMP data standards will be implemented as part of the SPOR programme, which will be used directly by the Digital Application Dataset Integration (DADI) project. Existing electronic application forms (eAFs) will be replaced by this project. This will trigger a huge step forward in the submission of structured data within the regulatory processes.

This change requires companies to control their regulatory data in accordance with the ISO IDMP standards and controlled vocabularies.

 What, in your opinion, could be significant bottlenecks for bio/pharma companies in the future in terms of data and documents?

 ISO IDMP requires data from different departments. For this reason, data governance—clear rules on rights and accountabilities for the data—must be considered and provided for. Due to the tie-in of the submission of structured regulatory data and the regulatory process, companies need to have processes and systems in place to access structured data from the get-go. Authors contributing to the supporting documents for product registration will need direct access to the latest and agreed terms to ensure consistent use. Although this may sound challenging, this requirement provides an opportunity to control the regulatory data end-to-end—from development and across the regulatory process and pharmacovigilance—and achieve benefits (e.g., cross-divisional reporting), harnessing that data as the definitive source for authoring.

 Much of the data required is, of course, already present within company databases—but frequently in multiple databases, which have different data owners and stewards, and are not linked or synchronised. Additionally, data [are] quite often in the wrong format—one key example being items such as dosage strength, where some companies might have a dosage strength as a single value (‘10 mg/100 mL’) and others might have four data items (‘10’, ‘milligrams’, ‘100’, ‘millilitres’). These data items might even be free text in some systems internally, leading to a need for a substantial exercise in data cleaning/consolidation.

As companies look to do business in Europe and meet these standards, they will also find two basic types of vendors on the market: those who provide a dedicated IDMP database (yet another database of separate information), meaning users have to enter data that is potentially duplicated in other systems, and potentially in different formats and not linked to the regulatory documents and applications/registrations; and those who provide regulatory systems where the data [are] captured and applied, in the right format, to documents and submissions as part of the regulatory operations processes, and can then be compiled/extracted to provide the required IDMP submissions, without duplication.

 Do you believe there will be an increased demand for digital provisions post-pandemic, and if so, how might this impact the volume of data to be processed by companies?

 The use of digital/virtual solutions will absolutely increase—having been forced to accelerate the implementation of such capabilities during the pandemic, companies are really seeing the benefits in both the speed with which they can perform business processes (and therefore being able to do more in the same time) as well as the consistency of data that it brings, improving compliance, reducing rework and errors.

One emerging trend is the desire to increase automations—having a system that acts as a ‘dump’ of data or documents is no longer sufficient, and companies are looking at systems that have capabilities to automate repetitive processes into a single button click. One great example is around the audits and inspections: previously, setting up an audit, requesting particular documents ahead of time, choosing dates, receiving pre-audit documents, and so on, was all done back and forth by emails. Now, a single audit object can be created which automates the process of notifications, uploads of documents, setting of meetings, and also generating a final audit report.

 Digitalization is the future—to optimize existing processes and data flows. With increased demands as well as expectations around healthcare, the competent authorities will need to be able to do more with the same resources. It’s essential, then, to be able to leverage the potential of digital data/processes. This can only be achieved by adopting standards. The use of standardized and structured data will not only ensure data quality and consistency; it will also help accelerate regulatory processing and assessment by the health authorities. The sky is the limit, and the time is right to shape the future. What’s more, society will expect no less.

 What tools are currently available for companies to deal with this potential increased volume of data?

 Most companies are still struggling with the legacy of data captured and held in documents. For large parts of the portfolio, consistency between the regulatory information and the data stored in documents needs to be checked, extracted, and aligned with ISO IDMP/SPOR data.

Tools exist that can alleviate the burden of the data extraction, and which make use of artificial intelligence (AI). However, experts in the interpretation of the regulatory data have an important role to play too, to assess the data extraction and data transformation requirements.

Biotech companies (with a smaller portfolio) have a potential advantage in being able to leverage processes and systems that work with structured data in a shorter timeframe.

 There is a move towards ‘platforms’ which leverage technology such as Elasticsearch for very rapid searching in massive volumes of data. The concept of data lakes is being married to document/data repositories—for example, our platform can contain all enterprise data, documents, and business processes in a single ‘Information Lake’ to allow the enter-one-and-reuse that ensures data consistency for purposes such as IDMP and digital automations. There are two key aspects to this: to have a platform that does actually consist of a single data source—rather than the older-style platforms that are multiple silos built with the same technology and need connectors and even then, still duplicate data; and to have a platform that doesn’t just act as a data store but provides the place where users can do their entire business process, guided by wizards/automations, and where they have access to all supporting data required, regardless of its provenance or data owners within the company.

 Do you feel industry’s cautious approach to technology advances is changing?

 Interestingly, we have seen a major change in this since the pandemic—the rate at which companies are reaching out for the kinds of automations, AI, single ‘Information Lake’ solutions has really accelerated, and the fear of newer technologies, moving to the cloud, and taking ‘out of the box’ pre-configured solutions has dramatically decreased—companies are looking for ready-made solutions (with pre-packaged validation thrown in) that can set them up for the coming five-year explosion in industry digital requirements and the faster pace of drug development that we have seen start during the pandemic.

 Many bio/pharma companies are looking into ways in which AI might support and increase efficiency internally. Within the regulatory field, the administrative burden has only increased over the last few years, with fewer people having to do more work. We believe that the time is right to do things smarter, quicker… to optimize existing processes via a more data-driven way of working.

1. EMA, “Data on Medicines (ISO IDMP Standards): Overview,” 

 [Accessed 2 Feb. 2022].
2. EMA, “Substance and Product Data Management Services,” 


Vol. 34, No. 2
February 2022
Pages: 31–32

When referring to this article, please cite it as F. Thomas, “The Data Relationship,” 

As Europe moves closer to implementation of ISO IDMP standards, the bio/pharma industry is accelerating efforts to manage its data and documents more effectively.

The Data Relationship

Drug pricing has long been a contentious issue within the bio/pharma industry and has, in fact, provided politicians with good fodder for campaigns. Currently, with some countries ahead of the curve in terms of COVID-19 treatment programmes and others lagging way behind, the issue of pricing is once again peaking.

 An evidence report from the Institute for Clinical and Economic Review (ICER) has found that the prices of four COVID-19 treatments for mild-to-moderate disease were ‘reasonably aligned’ with the benefits they offer patients (1). In the ICER report, cost-effectiveness of the COVID-19 treatments was projected by estimating the relative treatment effectiveness from the pivotal trials of each therapy and then applying those estimations to a common ‘usual care’ comparator arm.

None of the four treatments evaluated (sotrovimab [Xevudy, GlaxoSmithKline and Vir Biotechnology], molnupiravir [Lagevrio, Merck & Co.], nirmatrelvir/ritonavir [Paxlovid, Pfizer], and fluvoxamine [Luvox/Fevarin, Upsher-Smith Laboratories]) had base-case results that exceeded US$100,000 (€87,400) per quality-adjusted life year gained and equal-value life year gained (1). Furthermore, the report authors specify that there may be other benefits afforded by the treatments that could not be fully accounted for within the economic model used.

However, the report authors also note that there are disadvantages to each treatment to be considered and that the cost-effectiveness of the treatments would be reduced significantly if used in populations with a lower-risk of infection (1).

 Looking at the other side of the argument, and in light of recent announcements of company profits, there has been patter about the potential of ‘pandemic profiteering’ (2). Pfizer has been singled out most recently by the democratic social justice organization, Global Justice Now, after the release of the company’s annual revenue information, which has been stated as being larger than the gross domestic product value of most countries (2).

In a press release, Global Justice Now revealed that Pfizer’s annual revenue has doubled to US$81 billion (€70.8 billion), which has been largely driven by the sales of the vaccine, Comirnaty (2). “It’s nothing short of pandemic profiteering for Pfizer to make a killing while its vaccines have been withheld from so many,” said Tim Bierley, pharma campaigner at Global Justice Now, in the release (2).

1. K. Yeung, et al., Special Assessment of Outpatient Treatments for COVID‑19, 

, Draft Evidence Report, 3 Feb. 2022.
2. Global Justice Now, “Pfizer Accused of ‘Pandemic Profiteering’ Amid Bumper Revenue,” Press Release, 8 Feb. 2022.

When referring to this article, please cite it as F. Thomas, “The Price Debate,” 

As company revenues are gaining a boost from COVID-19, the issue of pricing is being debated once more.

The Price Debate

Toxicology studies are employed in drug development to evaluate the safety and viability of potential drug candidates, and the data from such studies are used to support regulatory submissions. As it is widely known that toxicity is a contributing factor to drug candidate attrition and with demand for faster and cheaper drug development increasing, researchers are looking at ways to perform toxicology studies as efficiently as possible.

To learn more about toxicology studies, including how accelerated timelines impact these studies, the expectations and requirements of regulatory bodies, issues surrounding animal models, and possible alternative assays, 

 spoke with Steven Bulera, PhD, DABT, corporate vice-president, global head of Toxicology, Charles River Laboratories.

 Could you elaborate on the importance of toxicology studies?

 When developing a new therapeutic, the new therapy must demonstrate two simple criteria. First, the therapy must be efficacious: it must treat the disease or improve the quality of life of the patient. Second, the therapy must be safe and not cause additional and/or unacceptable harm to the patient. Toxicology studies are designed and conducted to identify and characterize any potential adverse events or toxicities prior to the new drug being administered to patients or volunteers participating in clinical trials (1). To accomplish this task, a variety of nonclinical toxicology studies are performed in non-human 

 models. Additionally, these studies are required for regulatory submissions around the world and support ‘first-in-human’ clinical trials and clinical trials needed to bring the drug to the market and to patients in need.

In addition to characterizing potential adverse events, toxicology is important in that the studies conducted help identify and remove potentially ‘bad’ drugs from development, which protects patients from potentially harmful drugs and removes drugs from development before large financial investments are made in drugs that have limited or no potential to be a successful new therapy.

 What type of toxicology studies are performed in drug development?

 The types of studies run include general toxicology (various durations), genetic toxicology, safety pharmacology, reproductive toxicology, and carcinogenicity bioassays. Additionally, other specialty studies may be run to identify abuse/seizure liabilities, musculoskeletal toxicities, neuro-toxicities, ocular toxicities, and/or phototoxicities that could potentially be caused by the new therapeutic. The 

 studies are run in a variety of cell types, and the 

 studies are typically run in two species (a rodent and nonrodent species). In general, regardless of the new drug modality (small molecule, monoclonal antibody, gene therapy, oligonucleotide, protein, etc.), the study designs and endpoints are similar.

Where differences are seen are with the specific biomarkers that are included in the study and are based on the specific type of molecule and the target of the new drug. It is important to mention and acknowledge that while many of the toxicology studies use animals, the studies are designed with the 3Rs (reduce, refine, and replace) in mind and that the animals are treated humanely with the highest standards of animal welfare in mind.

 How might accelerated development timelines impact toxicology studies?

 When there is an unmet medical need, the question that is always on a researcher’s mind, is ‘how fast can we get this drug to the patients that need it?’ A common trend in drug development is ‘how do we go faster?’ To support accelerated programs, toxicology has developed faster ways to generate, analyze, and interpret data, as well as faster ways to create the reports needed for regulatory submission. Additionally, some of the best practices that can be called upon involve strong partnerships between clients and contract research organizations (CROs) so that both parties are working together to remove white space from study initiation and reporting timelines. Milestones can then be reached more rapidly.

Also, companies have developed paradigms that require decisions to be made at risk or in parallel with the reporting process to move to the next steps faster. Often, companies wait for final reports to make decisions. To accelerate the toxicology program, companies are encouraged to make decisions on data, and then start the next study/phase before the previous study report is finalized. This [method] can remove weeks if not months from a toxicology program.

 What are the regulatory expectations and requirements for toxicology studies in drug development, both for a regular timescale and an accelerated one?

 The vast majority, if not all, toxicology studies used for regulatory submissions are run under good laboratory practice (GLP) regulations. These are a series of regulations required by countries that dictate how studies must be conducted to ensure that the studies were conducted with the highest scientific quality. Additionally, these regulations have documentation expectations so that regulatory agencies reviewing the toxicology study package can know how the studies were conducted and that they can accurately recreate the study from what was documented.

Regardless of whether the new drug was conducted under a standard or accelerated timeline, countries have the expectation that the studies were conducted under the auspices of the GLPs. Where there is some potential flexibility for the toxicology program, is what individual studies are needed and the duration of those studies that are required to move the drug to the next development milestone. There are examples for rare and orphan disease therapies, where regulatory agencies have been open to alternative toxicology study designs and customized toxicology packages so that these drugs can get to patients that need them faster.

 Could you run through some of the issues surrounding animal models for toxicology studies and what possible solutions there may be in the pipeline or already being used that could benefit industry for wider adoption?

 Some of the common reasons cited as to why whole animal toxicology models are not appropriate to use in drug development are that animal models do not reliably predict human outcomes, drugs that appear to work well in animal models fail to work when given to humans, and having to use animal models and run animal studies delays the drug development process. Numerous articles exploring the limitations of these models have been published (2–4).

Alternatives to the use of animal models are also continually being discussed and developed. We have seen advances made using 

 models (1D, 2D, 3D cell cultures, tissue slices, organs-on-a chip). As an example, for many years chemical irritancy was tested by administering compounds to the eyes of rabbits (Draize eye irritation assay). However, that assay has been replaced by the 

 Bovine Corneal Opacity and Permeability (BCOP) assay that only uses animal corneas that normally would have been discarded.

Also, researchers continue to look at alternative models for testing the toxicity of compounds. Khabib 

 outline the advantages and disadvantages of using alternative models such as brine shrimp, zebrafish, daphnia, copepods, molluscs, and so on (4). These 

, and alternative animal models are useful for identifying if a compound is toxic, can be used as screens to rank order compounds from more to less toxic, and can be used to determine if a compound impacts a specific cell type or a specific cellular pathway. However, they currently do not capture the complex interactions with organ pathways (i.e., communication pathways between cells and organ systems) that are linked together in a whole animal model.

While the predictiveness of animal toxicology models may not be as predictive of human outcomes as researchers would like, history has shown that the testing performed using these whole animal toxicology models has and continues to protect humans/patients from harmful drugs. In addition, the more that is learned about cellular and biochemical mechanisms, and how organ systems operate and communicate, the predictiveness of our models will also improve. Also, as researchers continue to learn about how to better care for and manage research animals, the reproducibility of results will also improve. Even as the predictability and reproducibility of whole animal models improves, researchers will continue to look for assays/methods to replace animal toxicology models in an effort to reduce animal usage (3Rs), bring drugs to ‘in need’ patients faster, and to appreciate the value that these alternate methods bring to drug development.

 Might the use of computer simulations (or other disruptive technology) become the industry standard for toxicology studies in the near future?

 As new data are obtained about cellular pathways, organ systems, and cellular communication networks, and are combined with information about the new drug (structure data, similarity to previously tested drugs, absorption, distribution, metabolism, and excretion data, 

 data, etc.), it is conceivable to envision a time when it will be possible to employ artificial intelligence and machine learning algorithms to characterize new drugs completely 

. There are numerous examples in the literature, where 

 methods have been used as accepted replacement/substitutes for whole animal models or for examining specific biomarkers. However, as 

 models are developed as replacements/substitutes for whole animal toxicology models, they will need to be thoroughly evaluated before they are accepted and implemented, and the associated whole animal toxicology model discontinued.

One of the main challenges facing the use and implementation of these alternate assays/methods is the validation/predictiveness of these alternate assays/methods. Acceptance of the assays/methods as a substitute by regulatory agencies and by the public will be based on researchers being able to demonstrate that the alternative assays/methods are equivalent or better at predicting human toxicity then the current whole animal toxicity models and that the outcomes of these assays/methods can be used to make drug development decisions that will protect patients and not jeopardize human health and safety.

Additionally, with the concerns about rising drug costs and cost of developing new therapies, researchers will need to be aware of the costs of implementing these alternate assays/methods. Current estimates to develop a drug range from $944 million to as high as $4.54 billion (5). If the cost of these alternative assays/methods substantially increases the cost of a drug’s development, companies will need to acknowledge these costs and still be supportive of these alternative assays/methods.

In the end, the development, implementation, and use of these alternative assays/methods will be a balance of how these assays/methods will decrease drug development timelines, how much faster can needed medicines get to patients, how much better they are at predicting human safety, and the value that these investments/costs bring to the drug development process.

, 31 (1) 19.1.1–19.1.35 (2007).
2. G.A. Van Norman, 

J. Am. Coll. Cardiol. Basic Trans. Science

, 4 (7) 845–854 (2019).
3. G.A. Van Norman, 

, 5 (4) 387–397 (2020).
4. M.N.H. Khabib et al., 

, 465, 153053 (2022).
5. M. Schlander et al., 

Toxicology studies are an important and required aspect of drug development that are performed to ensure that drugs are deemed safe prior to patient administration and use in clinical trials.