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

Felicity Thomas

Potential elemental impurities in drug products have been analyzed for many years, with various methods presented in pharmacopeias across the globe. As the world has become more connected, safety and quality compliance within the pharmaceutical

industry has begun to harmonize. For elemental impurities testing, this harmonized work is apparent in the International Council for Harmonisation’s (ICH’s) Q3D guidance documents (1,2).

To learn more about elemental impurities analysis, including the importance of this analytical process, the techniques that are commonly employed, limitations of current techniques, and potential next steps, 

 spoke with Alan Cross, technical specialist at RSSL.

 Why is the analysis of elemental impurities so important in bio/pharma?

 Any analytical testing performed on pharmaceutical and biopharmaceutical materials is primarily to ensure that patient safety is maintained. This is performed either by confirmation that the correct dose of the correct drug substance is being administered or that the dose has no physical or chemical contaminants that may cause harm, or if there are contaminants, that they are below a defined acceptable exposure level. Elemental impurities are no different from any other contaminant, but until recently, the control of these potentially harmful species has been somewhat lacking.

The current elemental testing requirements came into force in 2018 in both the European and United States pharmacopeias following the ICH Q3D document on elemental impurities. This document defined permissible daily exposure (PDE) limits for 24 elements based on robust medical data, which considered the toxicity of the elements and route of administration, and it is written as such to allow for consistent evolution of potential elemental impurity contamination across all pharmaceutical and biopharmaceutical products. This approach has greatly improved patient safety, as it allows for a common approach to controlling elemental impurities based on health risks. Prior to this, elemental testing and limits were often based on the analytical capabilities of the instrumentation or reliance on a colorimetric ‘Heavy Metals’ test, which was insensitive, unspecific, and prone to poor recoveries (500 parts per million [ppm] of mercury in a sample could still give a passing result).

 What analytical techniques are commonly employed to measure elemental impurities in bio/pharmaceutical products?

 Although ICH guidelines do not include any specific recommendations on instrumental methods, the following analytical procedures are suggested in United States Pharmacopeia (USP) <233> dependent on the expected concentration of the elemental impurity in the product or component: inductively coupled plasma–mass spectroscopy (ICP–MS)—parts-per-billion (ppb) concentrations; and inductively coupled plasma–optical emission spectroscopy (ICP–OES)—ppm concentrations. The chapter also sets out recommended analytic procedures for measuring elemental impurities to these methods.

Both techniques are ideally suited to elemental impurity analysis, as they are able to measure multiple elements simultaneously. Therefore, if a full analysis of the 24 elements is required, these techniques are ideal. Both ICP–MS and ICP–OES also allow for a simple screen to take place whereby samples are analyzed against a simplified calibration. This can be powerful in performing risk assessments on samples, as described in the ICH Q3D guideline in which 30% of PDE can be set on a product. If three lots of in-production or six lots of development product tested by the screening method and are shown to be below this level, then further testing may not be required.

As the regulations insist that methods are validated prior to use, this allows flexibility for alternative methods to be used. These methods may be considered based on existing capability, specific chemistry of samples, or simplification of analysis if only one or two elements require testing. Examples might include, atomic absorption spectroscopy (AAS), typically a flame AAS would struggle to achieve the required levels of detection for elemental impurities control but for some elements other forms of AAS can be used which will provide the required detection limits. Vapor generation AAS is sensitive to ppb levels for elements such as arsenic and mercury, and graphite furnace AAS is easily applied to detect lead and cadmium at low levels.

Other techniques that may be employed might be microwave plasma atomic emission spectroscopy, a relatively new technique to the market which uses nitrogen as a plasma gas so has relatively low running costs, when compared to ICP-OES which uses expensive argon as a plasma gas.

Specific mercury analyzers utilize the volatile nature of mercury to allow untreated whole samples as solids or liquids to be analyzed directly by heating and measuring the mercury gas evolved, this simplifies testing and reduces analysis time and preparation costs.

 Could you share any best practices in terms of analyzing elemental impurities in development?

 Preparation of the samples is as important as the analysis itself. Understanding the behavior of the analytes and the sample matrix will allow for robust methods to be developed.

 Are there any limitations with current analytical techniques for the analysis of elemental impurities?

 Traditionally, the main issue with elemental analysis, particularly in ICP–MS with chemical interferences affecting the accuracy of the results, is that over time many modifications to the basic ICP–MS system have allowed for better resolution—with systems such as collision cells and kinetic energy discrimination to remove interferences from the samples. These methods are now also commonly being combined into triple quadrupole systems, which allow for even greater discrimination and reduction in detection limits.

All analytical techniques, with the exception of graphite furnace AAS, use solution volumes in excess of 1 mL for analysis. This is not problematic if there is a large amount of sample, but it can cause issues when the amount of drug product or substance produced is very small, which is becoming more typical in the bourgeoning biologics and biosimilars field. This means that novel preparation techniques need to be employed that can work with small sample amounts and final volumes to maintain the required detection limits, as well as further use of sample introduction systems that can work with small volumes, which are currently employed in some instrumental set‑ups.

 How about the advantages of the current techniques? Could you run through some of those?

 The advantage of the key analytical techniques, such as ICP–MS, ICP–OES, and AAS, is that they are truly multi-elemental techniques. These systems can analyze, either simultaneously or sequentially, the majority of the periodic table. The instrumentation manufacturers are constantly working towards lower detection limits and better resolution, as well as interference control.

 What trends do you foresee impacting elemental impurity analysis in the future?

 The food industry has had a particular interest in the speciation of certain elements, such as arsenic and mercury, where the form (organic or inorganic) has a big impact on the toxicity, and this consideration is also included in the USP/EP/ICH guidance. If a drug product is found to have levels of arsenic or mercury exceeding the PDE levels, speciation could be used to discriminate between toxic and less toxic forms to demonstrate compliance with the regulations.

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Articles

To ensure patient safety, drug products must be tested for elemental impurities that pose risk.

Elemental Impurity Analysis Crucial to Patient Safety

Pharmaceutical packaging is a multifaceted segment, providing essential protection for the important and sensitive materials housed within, while also delivering key information and advertising to patients. According to market research, the pharmaceutical packaging sector is expected to grow at a compound annual rate of 7.4% between 2022 and 2031, reaching an estimated $178.8 billion by the end of the forecast period (1).

Factors driving the growth of the pharmaceutical packaging market include a developing preference for single-dose packaging formats, a rise in drug development in general, and the growth of e-Commerce (1). Obviously, the COVID‑19 pandemic has impacted the whole bio/pharma industry, but given the rapid approval of the therapies to tackle the virus, such as the messenger RNA (mRNA) vaccines, drug packaging very quickly became a priority issue.

“During the pandemic, new drug categories and more precisely mRNA drugs entered the market in record-breaking time,” confirms Andreas Reisse, executive vice-president of SCHOTT Pharma. “The new drugs played a key role in the fight against COVID-19. As complete game-changers, they also affect the drug containment solutions, which have to withstand the specific requirements, such as ultra-cold storage temperatures.”

Furthermore, packaging companies had to surmount the challenge of providing drug containment solutions rapidly to ensure the vaccines could be rolled out in a suitably quick timescale. To this point, Stefan Verheyden, global vice-president of the Gx Biological Solutions Team, Gerresheimer, explains that it was necessary to quickly free-up capacity and utilize the intense cooperation with customers to be able to provide the required capacities to the market.

For Patrick Ferguson, managing director, Tjoapack US, COVID-19 provided the industry with an opportunity to accelerate the regulatory approval process in certain aspects, allowing products to reach the market more quickly, yet also demonstrated some shortcomings. “On the downside,” he says, “[accelerated approvals] have further contributed to the observed supply chain challenges.”

“The disruption the pandemic has caused to global supply chains has magnified shortcomings that have existed for years,” agrees Rich Quelch, global head of marketing, Origin. “The solution is creating a more resilient, collaborative, and networked operation moving forwards.”

“One of the most important and current trends is sustainability,” specifies Verheyden. “Even during the development of drug delivery devices and packaging solutions, customers pay attention to how sustainability is integrated in the packaging ecosystem.” As a company, Gerresheimer has set itself sustainability targets, such as cutting carbon dioxide (CO2) emission by half by 2030, Verheyden notes. The new strategy, based on three pillars, sets targets that are to be achieved within a tight timeframe.

“Pharma, as one of the largest global industries, is both part of the problem and the solution when it comes to minimizing the adverse effects of climate change,” adds Quelch. “Pharmaceutical waste continues to be a huge problem, so to eliminate non-biodegradable and single-use plastics from the supply chain, more research is taking place around bio-based PET [polyethylene terephthalate]. It’s made from ethylene derived from sugarcane which has a negative carbon footprint, using CO2 and releasing oxygen when cultivated.” Additionally, Quelch points out that research is currently being performed on a pioneering technology that can convert PET waste back to virgin-grade material for re-use.

“Cutting-edge manufacturing methods like 3D visualization and printing are also helping to reduce waste by eliminating the need for multiple prototype designs,” Quelch says. Utilizing a knowledge-based design or taking a quality-by-design (QbD) approach can help to improve sustainability and reduce waste, he explains. “By designing a product’s primary and secondary packaging well from the outset (including investing ample resources into the process), manufacturers can reduce the amount of materials used and wasted, test new eco materials, ensure safety compliance and efficacy, and benefit from cheaper transportation costs,” Quelch surmises.

Drug development pipelines are becoming increasingly saturated with biological drugs, stresses Reisse. “These [drugs] are typically highly sensitive and are oftentimes filled in low-fill dosages under 1 mL,” he notes. “Subsequently, these types of drugs require high-end containment solutions, which protect the sensitive formulations from unwanted drug/container interactions.”

The highly complex and sensitive biologic formulations also have the potential of contamination via leachables, Reisse continues. “In such cases, unique product development, such as EVERIC care vials that feature a special inner coating for protection, provide a suitable solution to minimize the risk of drug-container interaction,” he says. SCHOTT’s EVERIC care vials feature an inner single-layer plasma-impulse chemical vapor deposition barrier coating with hydrophobic surface, which allows for low leachable levels especially in the alkaline pH range.

Delamination control is another technological advancement that is interesting for biologics, Reisse confirms. Despite the fact that delamination is rare and occurs under certain circumstances, there is still a potential risk for patients. By way of example of a solution to this risk, Reisse refers to a delamination controlled forming process used by SCHOTT, which means that the company can offer vials with a high chemical stability and homogenous surface near the bottom heel area.

Further exciting innovations in packaging for biologics is a trend to watch out for in Quelch’s opinion. “Fluoropolymers—which don’t use any leachable or degradable stabilizing additives—are increasingly being used to form a resistant barrier to eliminate biodegradation issues. So too are cyclic olefin plastics (very rigid thermoplastics), which are intrinsically very inert, composed of just carbon and hydrogen,” he says. “These next-generation packaging materials, amongst others, are helping to deliver the next generation of medicines.”

“Newly developed biological drugs require containers, syringes, and devices that are tailored to the drug and its molecular properties,” concurs Verheyden. A way to help the customer overcome the specific challenges encountered with packaging of biological drugs is to employ a guide, such as Gerresheimer’s ‘g guide’, which can lead the customer to the most suitable solution within the respective therapeutic class or disease area, he states.

Although these new, small-batch, biological medicines represent an exciting era for pharma, there is also a potential pitfall in the supply chain, which will be inherently more complex than the traditional medicines, Quelch warns.

Supply chain challenges are one of the most disruptive issues, in a negative way, for the pharma industry, reveals Ferguson. “The supply chain challenges are negatively impacting the packaging industry both upstream and down,” he notes. “Price increases, delayed delivery, and material shortages at all levels of the supply chain are impacting the industry daily.”

It is not all doom and gloom, however, as a trend that has been apparent for Ferguson has been an increasing uptick in the adoption of a packaging outsourcing model by drug manufacturers in the United States when compared with historical rates. “This [trend] has created opportunities for organizations such as Tjoapack,” he explains. “Most recently, there have been more opportunities tied to the COVID-19 pandemic, providing some sizeable packaging opportunities as part of the testing or treatment of the disease.”

Numerous factors have challenged existing supply processes, such as the pandemic, the war in Ukraine, and the shortage of shipping containers, Reisse points out. “As a result, pharma companies can benefit from a packaging supplier with a true global footprint,” he says.

Yet, Reisse also believes that in the future, the trend of localization (versus globalization) will potentially have a significant impact on containment and drug delivery solutions. “While the industry has highly structured processes, the recent global developments (both social and political) have taken a toll on the supply chains,” he specifies. “In consequence, the industry is shifting towards more regional approaches to overcome those challenges.”

“From a fill and finish perspective, we are witnessing the industry shifting towards ready-to-use (RTU) solutions,” Reisse reveals. “These [solutions] allow pharma companies to focus on their core competencies of developing and filling valuable medications.” A particular benefit of RTU solutions is that pharma companies can simply start the filling process straight away as the washing and sterilization steps are done by the packaging company, he adds.

Verheyden concurs that the trend for RTU primary packaging is continuing to rise, with a clear move from customers choosing this solution for their packaging needs. “RTU drives flexibility and efficiency, while in parallel it offers a substantial impact on total cost of ownership in filling activities,” he says.

“Over the next years, it is likely we will see a move to pharma companies using RTU solutions in mass scale with high demands for vials, syringes, and cartridges,” continues Reisse. “This is a natural step in simplifying the filling process for pharma companies and offering more flexibility when filling different medications or switching from one containment solution to another.”

Pediatrics are a patient population that often requires substantial planning, forethought, and consideration within the drug development life cycle. When formulating a medicine, scientists must consider the useability of a product as children may have difficulties in swallowing medicines, dislike the taste, require smaller doses than adults, and so on. When packaging medicines that are aimed at children, however, it is important to ensure the packaging is ‘child-resistant’ to avoid any potential overdose issues, which could be very harmful or even lethal.

“An increase in legislation and awareness globally about the pervasive issue [of pediatric-appropriate packaging] has led to the growth of the child-resistant packaging market, which is predicted to double over this decade from approximately $20 billion to $40 billion by 2031,” explains Rich Quelch, global head of marketing, Origin. “The emergence of effective packaging solutions is encouraging the industry to challenge the minimum legal requirements for both ethical and commercial advantage, conscious no doubt of the importance of brand value.”

Quelch expects that there will be continued advancements in child-resistant packaging throughout 2022 and that these advancements will be spurred on further by investment and innovation in the expanding cannabidiol market. “The shift towards non-re-closable designs will become more widespread, providing a higher level of protection to the medicine, plus a longer shelf-life,” he says.

Another popular advancement in Quelch’s opinion is ziplock bags, which offer a single-entry design requiring mature dexterity to be able to access the contents. “The bags can easily be opened and re-secured by adults but provide a barrier to entry to children. Many designs even include a flap that covers the zipper when the bag is closed, disguising the entry point as an added layer of security,” he explains. “Other recent packaging developments include visual distraction technologies designed to distort depth perception and cause children difficulty opening the product.”

Technological aides for quality and safety

Quality requirements for packaging have also increased, asserts Verheyden, but more advanced inspections technologies and the use of artificial intelligence (AI) has enabled progression. “Through AI, the glass manufacturing process of the syringe barrels can be monitored, and recommended actions are displayed to the plant operator,” he says.

Disruptive technologies, such as AI, are proving useful in the molding process as well, where many parameters can also be monitored, Verheyden continues. “In concrete terms, using AI can allow for the determination of, among other things, the remaining service lives of molding parts over their period of use and thus, instead of fixed replacement intervals, a precise prediction of lifespan can take place,” he notes. “Monitoring the molding process also makes it much easier to identify defects in a linked process.”

“There has been an increased focus on packaging line automation,” agrees Ferguson. “Equipment and solution providers have done an excellent job in developing various applications and solutions that range from dedicated lines for large commercial operations to highly flexible solutions for small-batch contract packaging operations.”

Additionally, the user is benefiting from some technological advances, such as quick response (QR) codes, which are being implemented on packaging to help with health literacy and patient compliance, states Quelch. “In the area of clinical trials, smart packaging (featuring RFID [radio frequency identification] tags) and wearable devices are promoting greater secure interaction between patient and doctor by using real-time data to monitor compliance, identify side effects faster, and improve health outcomes for both volunteers and, in the longer term, the wider community,” he says.

Technological progress is also helping with tracking and tracing of medicines. “Technological progress in the track-and-trace field are bringing ‘industry 4.0’ to the pharma industry and, most importantly, bringing its benefits to the fill-and-finish operations,” adds Reisse. “For example, using solutions such as SCHOTT Smart Container, it is possible to track and trace drug containment solutions on an individual basis, from production all the way to the end user. Among other benefits, this technology minimizes the risk of mix-ups on the filling line as each container is laser-marked with a data matrix code, which allows for distinct, single-container based traceability throughout the fill-and-finish process and beyond.”

The implementation of serialization, through the Drug Supply Chain Security Act in the US and the Falsified Medicines Directive in Europe, has been a hot topic for years and is generally well rooted in the industry now, explains Ferguson. “The regulations have separated contract packagers who chose to invest in serialization technologies from those who have not, resulting in more opportunities for the pharmaceutical companies such as Tjoapack, that chose to invest in the serialization technologies,” he says. “Keeping up with software and hardware upgrades is a challenge but necessary to stay current with industry expectations and requirements.”

Globally, the size of the fake medicines market is huge and growing, Quelch stresses. “Anti-counterfeiting is a cat and mouse game, which means continuous packaging improvements and advancements are needed to stay one step ahead,” he says. “RFID technology, using electromagnetic fields, is supporting anti-counterfeiting efforts by identifying tampering. Another key development is the application of thermochromic inks, used to print reactive temperature indicators on packaging, as will smart sensors that can detect changes in humidity, light, and temperature.”

Further advances in the field of anti-counterfeiting measures include digital watermarks that are invisible to the human eye and developments in holograms that are only visible behind each capsule or pill cavity on the back of the blister pack, Quelch continues. “Enhanced anti-counterfeiting methods, including cloud-based tracking and perennial encryption technologies, are extending the lifecycle of protection for manufacturers so frequent and costly overhauls are avoided,” he notes. “These methods are also making it easier to spot and eliminate weak links in supply chains that criminals are quick to exploit.”

Ferguson expects that there will be a continued focus on streamlining operations within the bio/pharma industry moving forwards with investments in automation and efficiency improvements. “These investments would also have a positive impact on product quality and delivery to the customer,” he says. “DSCSA will be fully implemented in the US in 2023, but the adaptation of a global serialization standard is needed to build a truly global system.”

As cost becomes an ever more pressing concern, Quelch believes that packaging will be an area where companies can unlock greater financial returns through driving efficiency, quality, and sustainability. “Traditionally, packaging has been an afterthought in the product design process. It starts with a ground-breaking idea, and once this is developed, attention turns to packaging,” he asserts. “However, this is an outdated approach that ignores the vital role packaging plays not just in the delivery stage of product development but in every stage, from conceptualization to dispensing by healthcare professionals or patients.”

Moreover, tackling the packaging too late in the development lifecycle will only serve to prevent companies from being able to take advantage of potential functional design features and could lead to costly mistakes, Quelch adds. “Taking a proactive approach to packaging not only helps avoid the costs associated with fixing future performance or functional problems but also delivers business benefits in improved products, patient satisfaction, and reputation,” he summarizes. “The result is an optimal product that puts user experience at the forefront of design, ensuring effortless patient experience and an improved bottom line for big pharma.”

Pharmaceutical Packaging Market Outlook (2022–2031)

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

When referring to this article, please cite it as F. Thomas, “Getting Proactive with Pharmaceutical Packaging,” 

Technological advances are progressing pharmaceutical packaging to overcome the challenges of the future.

Getting Proactive with Pharma Packaging

The total pharma development pipeline is set to exceed 20,000 drug candidates in 2022, which has grown by 8.22% and seen more than 1500 new drugs added to the pipeline from the prior year (1). When looking at biological versus non-biological drugs, there has been more ground gain for the former type of drug in the pipeline with the proportions coming close to 50:50—biologics are now consuming 44.7% of the development pipeline (1).

This strong development pipeline representation is also translating into impressive growth for the biologics market, which is projected to grow at a rate of 10.7% annually up until 2025 and then 9.6% annually from 2025 until 2030 (2). Driving this growth are factors such as an increasingly geriatric population, rising need for immunology, and more government initiatives (2).

However, the majority of the pipeline drugs are still in preclinical phases (1), which means there are still attrition rates to be wary of and some work to be done for commercial success to be achieved. Formulating a biologic drug is a potentially problematic area, as the molecules are inherently large and complex, and also have stability issues to overcome.

“For a successful biological formulation, choosing the right formula and a process that will ensure the biological stability and activity while also maintaining sufficient drug concentration without aggregation is key,” explains Jim Huang, PhD, founder and CEO of Ascendia Pharmaceuticals. “And using the correct drug delivery system to deliver the biologicals to the target organ while minimizing enzymatic degradation during body circulation 

A common issue encountered when developing biologics is degradation, which can occur due to changes in a variety of external factors, such as temperature and pH. Huang stresses that many formulation errors can occur due to insufficient studies being performed “to test the biologicals under a variety of physical and chemical stresses in order to provide a good understanding of the degradation products and mechanism.”

Although regulatory bodies demand stress testing be performed on all drug substances and drug products, there aren’t well established selection protocols for such tests available (3). This is an area where an outsourcing partner can prove invaluable, as they have access to a greater pool of knowledge and experience than a company typically would in-house.

“Outsourcing partners should not only function as an extension of the client’s chemistry, manufacturing, and control labs, but also can contribute to its in-house proprietary technologies, formulation skills, and know-how to address the issues arising from the development process of complex biologicals,” Huang adds.

Delivering a drug effectively is key, and, nowadays there are many possibilities for developers to explore. “Non-vector drug delivery technologies such as lipid nanoparticles or polymeric nanoparticles have been applied to delivery of biologicals,” says Huang. “For example, lipid nanoparticle technology has made delivery of COVID-19 vaccines possible.”

“There is a tendency to use more complex drug delivery technologies to address the complex nature of biologicals,” Huang continues. “For example, Ascendia has started to use long acting injectable, in-situ depot, lipid nanoparticles, liposome, and polymeric nano/microparticles to deliver biologicals in order to achieve the pharmacokinetic profiles requested for the biologicals.”

However, nanoparticles are not without their own challenges—safety being a major consideration to factor in (4). When combining a drug with a nanoparticle carrier, it is important to understand whether or not the carrier will impart some side effects for the patient in addition to the potential effects of the active molecule.

The route of administration is, of course, an important factor when considering the delivery of a drug. For the most part, biologic therapies are developed as injectable formulations, mainly because the molecules have poor permeability across the mucosal layer and suffer destruction when introduced to the gastrointestinal (GI) tract (5). However, for patients, non-invasive routes of administration, such as oral, are preferred.

On the matter of oral administration of biologics, Huang points out that it is possible and alludes to the fact that Ascendia has successfully delivered biological-like molecules orally via its EmulSol technology, which increases the molecular bioavailability. “Key to the success of orally administered biologicals is to protect them from GI tract degradation and to enhance the permeability of the biologicals through GI gut membrane,” he summarizes.

Pharma R&D Annual Review 2022 Navigating the Landscape

 (May 2022).
2. Research and Markets, ~, Market Report (February 2022).
3. E. Tamizi and A. Jouyban, 

, 28, 1100–1102 (2022).
5. B. Homayun, X. Lin, and H.-J. Choi, 

When referring to this article, please cite it as F. Thomas, “Formulating Biologics: A Learning Curve,” 

Biologics are forming a greater proportion of the development pipeline, but there are still some formulation difficulties to overcome to ensure clinical and commercial success.

Formulating Biologics: A Learning Curve 

In late June 2022, podcast presenter and campaigner Dame Deborah James passed away after battling stage IV bowel cancer for five years. James was diagnosed at the age of 35 and since that time had championed the cause to raise awareness of bowel cancer and funding to help research in the area (1).

Despite the sad news, James’ efforts in raising the profile of bowel cancer will definitely not go unsung. In fact, since James’ diagnosis in 2016, some promising developments in the field of bowel cancer therapies have already surfaced.

Immunotherapies have been around since 2014 within the oncology sector and have seen therapeutic success in cancer patients, particularly checkpoint inhibitors when combined with chemotherapy (2). However, recent results of a small clinical trial, performed at the Memorial Sloan Kettering Cancer Center in the United States, have shown a 100% complete response rate in 14 patients after being treated with the immunotherapy dostarlimab as a first-line treatment for mismatch repair-deficient (MMRd) locally advanced rectal cancer (3). For this small study, the participants received dostarlimab alone at regular intervals for six months and as all those involved achieved a clinical complete response, none of the patients required follow up chemoradiation or surgery.

Researchers from Queen’s University Belfast have stimulated a viral-like response within tumours to reawaken the body’s own defences, allowing for the immune system to attack the cancer cells and reducing the risk of the disease spreading (4). Currently, this research is in very early stages, but the scientists are designing a clinical trial to test the approach, and it is hoped that it could lead to new treatments that are targeted for bowel cancer in the future.

In a slightly earlier study, the results of which were presented in September 2021, university researchers from the United Kingdom found that it was possible to slow tumour growth in bowel cancer patients through treatment with a small-molecule, protein-inhibitor drug, adavosertib (5). Although this trial was also small and further research in larger patient populations is required, the results are still encouraging because a subset of patients involved had tumours with two common mutations—representing a third of all bowel cancer patients.

Through her work, James has raised millions of pounds, which is continuing to rise posthumously and has reached, at the time of writing, more than £7 million. With the support of Cancer Research UK, the monies raised will be used to fund clinical trials and research into personalized medicine, as well as continuing to raise awareness of cancer.

1. R. Williams, “Dame Deborah James Dies Age 40 After Cancer Battle,” 

, 28 June 2022.
2. D. Crow, “Big Pharma on Mission to Bring Immunotherapy to More Patients,” 

, 1 June 2018.
3. Memorial Sloan Kettering Cancer Center, “ASCO 2022: 100% Complete Response Rate in MMRd Locally Advanced Rectal Cancer Seen in Pivotal ‘Immunoablative’ Neoadjuvant Immunotherapy Clinical Trial,” Press Release, 5 June 2022.
4. Queen’s University Belfast, “Scientists Awaken Viral Response to Target Bowel Cancer,” Press Release, 27 April 2022.
5. NIHR, “New Drug Shows Promise in Slowing Growth of Bowel Cancer,” Press Release, 20 Sep. 2021.

When referring to this article, please cite it as F. Thomas, “Bottoms Up!” 

Dame Deborah James’ legacy and the millions raised through her campaigning will undoubtedly be a big boost to clinical research, ultimately providing new and promising treatments for bowel cancer patients. 

Bottoms Up! Research into Bowel Cancer Therapies Gain Funding Boost

A major component in the success of a therapeutic product is whether the patient actually takes the medicine—an aspect that is particularly pressing in patients with chronic and long-term illnesses. It has been well reported that non-adherence to medication regimens is significantly burdensome on healthcare systems and, ultimately, countries’ economies.

One way to improve patient adherence to medication is by ensuring the dosage form is patient-centric or user-friendly. “Patient centricity is gaining more focus and importance in drug development,” confirms Anil Kane, PhD, MBA, senior director, global technical scientific affairs, pharma services, Thermo Fisher Scientific. “Problems related to polypharmacy and patient non-adherence is critical to healthcare. Patient-centric pharmaceutical drug product is increasingly important to gain patient adherence in pediatrics, adults, and geriatric patients.”

Ideally, a dosage form should incorporate multiple facets to be patient-friendly, notes Anita Solanki, lead—White Papers, Formulation R&D (Pharma and Nutra), ACG Group. “The ideal, patient-friendly, dosage form is one that is easier to swallow, non-invasive, with no taste or odor, has quicker brand recall and is easier to handle and carry, with suitable packaging materials,” she says. “So, throughout the process—right from dosage form selection, through to excipient selection, appearance, packaging, and material selection—every step needs to be considered with the patient in mind.”

Cornell Stamoran, PhD, vice president of Strategy and co-chair of the Catalent Applied Drug Delivery Institute, also agrees that key decisions made during drug development, such as molecule design, formulation, dose form, device selection, and packaging, can have an impact on how successful the therapy will be for patients. Stamoran confirms that through discussions with physicians and payors that were performed at Catalent’s Applied Drug Delivery Institute there is a belief “that those companies that more effectively incorporate patient-focused thinking into drug product design, and provide evidence from the resulting clinical trials, will increasingly have a significant advantage in the market, and ultimately this will benefit patients.”

In terms of dosage form, Thomas B. “Brad” Gold, PhD, vice president, Pharmaceutical Development, Metrics, specifies that oral solid dosage (OSD) forms are preferred by both patients and payers. As such, OSD forms are dominant within drug development and payer schedules. However, despite the fact that OSD forms are preferred there are still issues with compliance, he continues.

“Depending on the formulation and treatment course, orally administering a drug to patients can become problematic and contribute to poor health outcomes,” Gold adds. “Individual dose size, as well as dose frequency all have an impact on the patient centricity of an oral drug. Fortunately, formulation and manufacturing techniques like amorphous solid dispersions, multiple unit particle systems, mini-tablets and other systems are helping to make OSDs more patient centric than ever.”

Kane concurs that OSD forms continue to be market-leading, not least because of the preference by patients, but also due to cost savings and efficiencies afforded by the dosage form in the small molecule market. “Strategies for improving adherence need to consider the characteristics of the individual therapeutic regimens according to the needs of the patients. In particular, geriatric, and pediatric populations have special needs/preferences that should be considered when designing drug products,” Kane continues. “Introducing patient centricity into drug product design offers the opportunity to meet the needs and preferences of patients.”

Providing some examples, Kane explains that through employing taste-masking to create palatable dosage forms will allow for improved patient compliance in geriatric patients with dysphagia, which is a difficulty in swallowing. Other considerations to improve patient centricity of a dosage form for the pediatric segment of the population include the size of the dose, ease of administration, volume of fluid required to be administered, and dosing frequency or frequency of administration, he confirms.

“Innovative ideas and formulation strategies including fixed-dose combinations, modified release dosage forms, orodispersible formulations, multi-particulates, and minitablets in capsules or tablets will support patient-centric drug products,” Kane states.

For Ali Rajabi-Siahboomi, vice president—chief innovation officer, Colorcon, another factor to consider is the potential differentiation between tablets, which is being sought by regulators and marketers. “Unique designs are important because they help make medicines memorable to patients, caregivers, and pharmacists, and may also make a tablet easier to take. From an anti-counterfeiting perspective, unique designs also make products more difficult to copy,” he says. “There are production benefits as well. A unique design offers differentiation on the packaging line, making it easier to visually spot a mix-up and prevent product recalls before it even happens.”

Furthermore, Rajabi-Siahboomi reports that the FDA has also acknowledged the advantages of better design, a fact that is apparent through its guidance documents—Safety Considerations for Product Design to Minimize Medication Errors and Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules (1,2). “In essence, too many products and dosages look the same and there’s a risk dispensers may distribute the wrong product, or people taking more than one medicine (increasingly common in our aging population) will get their pills mixed up,” he explains. “Regulators now expect companies to consider aspects such as size, shape, color, and differentiation between dosage strengths before marketing. Similar-looking dosages, especially plain white tablets, may not get through the regulatory process. Your tablet needs to be different.”

Adding to these thoughts, Hanns-Christian Mahler, CEO of ten23 health agrees that regulatory focus on patient-centricity will further increase, albeit to ensure the therapeutic product is being used adequately and to understand potential liabilities when products are used incorrectly. “Additionally, connectivity (to e.g., smartphones) and sustainability are in my view key topics in relation to patient-centricity for drug/device combination products,” he says.

In concurrence, Rajabi-Siabhoomi also points out that the connection with smartphones or smart medicines can provide a significant opportunity with on-dose authentication technology. “Imagine a patient scanning their pill with a smartphone that not only confirms the identity of the medicine but also connects the patient directly to support materials, such as the product leaflet, information that explains the benefits of the medicine, the importance of adherence, what to do if there are side effects, and even the ability to opt into reminders to take the medicine at the right time,” he states.

In March 2022, a panel of experts were interviewed by 

 for a Drug Solutions Podcast episode, focusing on the topic of drug dosage form trends that have had an impact on the bio/pharma industry in recent years.

The panel of experts involved in the discussion were Anita Solanki and Dr. Jnanadeva Bhat, both from ACG Group; Cornell Stamoran, from the Catalent Applied Drug Delivery Institute; Dr. Ali Rajabi-Siahboomi from Colorcon; Brad Gold, from Metrics Contract Services; Hanns-Christian Mahler, from ten23 health; and Anil Kane, from Thermo Fisher Scientific. Amongst the talking points, the panel broached the topic of patient-centricity as well as overarching development trends and the potential effect of novel excipients on dosage forms.

If you would like to listen to the episode in full, visit 

www.PharmTech.com/view/drug‑dosage‑form‑trends

As was specified earlier, poor adherence to a therapeutic regimen not only impacts the effectiveness of a drug but also has a financial impact on healthcare systems, economies, and patients. “Prescription drug medication adherence is a growing concern for public health, and poor adherence to therapy has been associated with poor health outcomes and higher costs for patients,” notes Kane.

Solanki believes that the influence of patient-centricity on the pharma industry will continue to grow and is leading to a big shift in priorities during the development of most dosage forms. “The patient centricity trend is fueling the focus on developing patient-friendly dosage forms. This trend has to be accomplished whilst maintaining optimum therapeutic efficacy and safety,” she says. “Concept transformation has led to the integration of patient-centricity into all aspects of R&D—including formulation design and dosage form development.”

However, there is more work to be done, according to Stamoran. “Through Catalent’s Applied Drug Delivery Institute, we have been advocating for an intentional, patient-focused approach to these areas for the last 10 years. There are important signs of progress, but there remains substantial opportunity to improve patient usability of both new and existing treatments,” he states.

Mahler hopes that patient-centricity and product usability remain priorities for the pharma industry and even that they grow in relevance. “After all, patient-centric drug development all about the patient and to enable them to have an effective and safe treatment,” he concludes.

Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

Safety Considerations for Product Design to Minimize Medication Errors

When referring to this article, please cite it as F. Thomas, “Focusing on the Patient in Drug Development,” 

Putting the patient at the forefront of drug development is essential, particularly to ensure medication compliance is optimized.

Focusing on the Patient in Drug Development

When referring to this article, please cite it as F. Thomas, “Ensuring Patient Safety Through Elemental Impurity Analysis,” 

Analyzing elemental impurities in drug products is—much like other analytical testing—primarily aimed at ensuring patient safety.