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

Felicity Thomas

Production of high-quality, defect-free finished products is a top priority in the bio/pharmaceutical industry, primarily to ensure the safety of the end-user—patients. The automation of finished product inspection is leading to gains in efficiency for companies and, as such, is being widely adopted.

To find out more about automated finished product inspection, some of the common tools used, potential pitfalls of approaches, the impact of increasing complexity of therapeutics in development, and regulatory changes, 

 spoke with Tyler Harris, applications engineer, and Oliver Stauffer, CEO, both from PTI—a specialist in packaging inspection technologies.

 Could you provide a little bit of background into automated finished product inspection, its importance, and where the industry currently sits on its use?

 Automated finished product inspection has been widely adopted by the pharmaceutical industry with the use of various test methods. Additionally, not all these test methods are container closure integrity technology (CCIT) methods, non-deterministic, or likely to be accepted by regulatory agencies in the near future.

Visual inspection, torque testing, high-voltage leak detection (HVLD), headspace analysis, vacuum decay, and airborne ultrasound all inspect finished products in some form from label alignment to leak detection, and seal quality. No one test method is suitable for all applications, and more than one test method may be required.

Although methods such as visual inspection are widely adopted by the industry, CCIT methods have not yet become commonplace, although [they are] gaining traction. The newfound increase of CCIT in the automated finished product inspection space comes from the development of scalable test methods and regulatory pressure. Benchtop, offline inspection methods validate automated sampling and 100% inline inspection systems. The practice of offline benchtop quality testing will never dissolve or be replaced by automated inspection; scalability decreases validation time, risk, and analysis time.

 What sort of analytical tools are commonly used in automated finished product inspection?

 The technologies used for automated inspection are application driven and depend heavily on the package format and container contents. Typically, headspace analysis, vacuum decay, or high-voltage leak detection (HVLD) are the go-to inspection technologies for parenterals.

 Are there any pitfalls/analytical shortcomings that need to be addressed?

 The most critical aspect of inspection is selecting the best test method for the application at hand. Some methods are suitable for a variety of applications while others have specific characteristics the applications must have to be effective. In regard to deterministic non-destructive CCIT methods, each have shortcomings that prevent robust, reliable, and repeatable results. Headspace analysis can only test transparent/translucent rigid applications before labeling and the package must have headspace.

One of the more common automated inspection technologies is traditional AC HVLD. Applications suitable for HVLD must be cylindrical, glass or plastic, and conductive liquid with low viscosity. High voltage can have negative effects on active drug product and produce large amounts of ozone.

Over the last half decade, MicroCurrent HVLD (HVLDmc) has been proven to greatly reduce the voltage exposure to the product and reduce ozone to near negligible amounts. Since the mid-1980s, vacuum decay has been utilized to test full container integrity of non-porous flexible and rigid containers. Although widely adopted for benchtop applications, it is not without pitfalls. Vacuum decay is only suitable for non-porous packaging and has difficulty testing large-molecule liquid products. Vacuum decay is often used for automated sampling systems but rarely used for 100% inline testing due to its long test cycles. Shortcomings are overcome by necessary innovation in this regulatory driven climate.

 How has automated finished product inspection adjusted to the increasingly complex therapeutic landscape?

 Therapeutics require far more attention than standard pharmaceutical products. With small batch sizes and costly product, non-destructive methods are mandatory in this market segment. Therapeutics are typically large molecule and sometimes viscous liquids stored in vials, syringes, and intravenous (IV) bags. The increase in large-molecule, high risk products has led to the need for HVLD, and HVLDmc in the automated inspection space, further leading to new innovations in handling, test cycle speed, and reliability.

Although superior to vacuum decay for large-molecule and viscous liquid products, HVLD struggles to effectively test the entirety of an IV bag. During an HVLD test, liquid must cover every interior surface of the package. IV bags are not easily rotated and typically contain a large air bubble. These two issues lead to false negatives and inconsistent results. This is where vacuum decay is highly effective. Although limit of detection (LOD) may be higher due to the molecule size, vacuum decay is able to detect leaks in IV bags in automated sampling inspection systems and offline systems.

With small batch sizes and high risk of therapeutic products, benchtop systems are capable of successfully testing product to ensure sterile barrier is intact and no leaks in the package are present. With small batch sizes and frequent changes to the production process/line, validation must be completed with every change. Automated inspection system validation can stretch across multiple weeks and hold up processing of time sensitive live product. Benchtop offline testing stretches across a few days and can be easily completed by a trained operator without the need for validation of the automated handling mechanisms. Testing offline allows for increased attention to the package and lower machine costs. Additionally, many of these therapeutic products are manufactured in a manual process which does not warrant a need for automated inspection.

 What regulatory changes have impacted automated finished product inspection, in your expert opinion?

 Foundational regulatory guidance documents have been updated in both the [United States] and European market space. United States Pharmacopeia (USP) <1207> was recently updated and reflects the shift away from probabilistic test methods to more reliable and traceable deterministic methods. USP <1207> is prescriptive about the technologies that should be considered as improved alternatives to traditional, less effective methods such as dye ingress.

In Europe, the European Medicines Agency (EMA) is updating its Annex 1 guidance, which is less prescriptive around the suggested technologies, but with guidance that frequency of testing and the method of testing should be scientifically appropriate for the commensurate level of risk associated with the application. The need to test fused containers still stands, and the proposed language further clarifies that IV bags also fall within that category. The final draft will most likely have some leniency related to that requirement. Regardless, in both the US and Europe, the regulatory guidance documents are driving towards increased testing frequency using deterministic test methods.

 Are there further regulatory changes, particularly pertaining to analytical analysis, in the near future that you believe will impact automated finished product inspection?

 The regulatory space is forever in a constant state of flux. The most recent proposed changes revolve around the European Union’s (EU’s) Annex 1 and its drafted revisions. The proposed changes call for 100% testing and deterministic test methods for package integrity on all fused containers. This refers to products such as ampoules, pre-filled syringes, and IV bags. The draft specifies that visual inspection alone is not suitable for these types of packages and must be used in conjunction with a deterministic method. At this moment, IV bags are the most difficult application to test whether automated or benchtop and there are two possible outcomes to the final revision of EU Annex 1. Regulatory demands can force innovation, or regulation must wait for further development of the aforementioned deterministic inspection methods.

 Could you highlight any future trends that you deem to be important within automated finished product inspection in terms of analytics?

 Inspection trends are driven by reliability, [regulations], and most commonly, cost. An uptick in automated sampling systems and scalable test methods is on the horizon. The ability to have the same technology in an automated format and in a laboratory setting is critical in being able to compare results, analyze data, validate, and ensure automated systems are functioning properly. Automated sampling systems allow for less human interaction, rapid inspection, and a decrease in inspection time. These benefits ultimately lead to a decrease in cost despite a larger capital expense.

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


Vol. 46, No. 8
August 2022
Pages: 42–43

When referring to this article, please cite it as F. Thomas, “Inspecting Finished Products with Precision,” 

Articles

Automated finished product inspection has been widely adopted in the bio/pharmaceutical industry.

Inspecting Finished Products with Precision

In this episode of the Drug Solutions podcast, Felicity Thomas, European/Senior Editor, talks to Fernando Muzzio, Distinguished Professor, Chemical and Biochemical Engineering, Rutgers University, about a novel approach to improving drug solubility—continuous melt coating. Fernando talks about the technique in some detail, a little about some of the results that have been achieved in research, and provides information about the current patent filing and what companies can do to start working with this new approach.

Curia is a global contract research, development, and manufacturing organization offering products and services across the drug development spectrum to help their partners turn ideas into real-world impact—from curiosity to cure.

Fernando J. Muzzio, Distinguished Professor, Chemical and Biochemical Engineering, Rutgers University.

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

Podcasts

In this episode, Fernando Muzzio provides greater insight into a novel approach to improving drug solubility—continuous melt coating.

Drug Solutions Podcast: Overcoming Poor Solubility Through Accelerated Dissolution

In mid-July 2022, GSK announced the completion of its demerger from the consumer healthcare business, now formed under the moniker of the Haleon Group (1). However, market conditions and an overriding concern about inflation have proven less than favourable for Haleon’s listing debut on the London Stock Exchange, the biggest listing for a decade, with a small but rapid drop in share price seen (2). Shares in the newly reduced company GSK, which is now solely focused on biopharmaceuticals, also experienced a drop, but through consolidation, the price was roughly brought back in-line with that seen before the demerger (2).

GSK’s own reported second quarter results demonstrated healthy growth, and as a result of demand in vaccines, the company is increasing its sales growth outlook in this area, with Shingrix, the company’s shingles vaccine, expected to do very well (3). “This is GSK’s first set of results as a newly focused biopharma company, and we have delivered an excellent second quarter performance, with strong growth in Specialty Medicines, including HIV, and a record quarter for our shingles vaccine Shingrix,” said Emma Walmsley, CEO, GSK, in a company press release (3). “With this momentum in sales and operating profit growth, we have raised our full-year guidance and are confident in delivering the long-term growth outlooks we set out for shareholders last year.”

Additionally, GSK announced on 28 July 2022 that it had signed an agreement with the European Commission’s Health Emergency Preparedness and Response Authority (HERA) for the reservation of future production and supply of Adjupanrix (4). This latest agreement follows on from others made by GSK with the United States, the World Health Organization (WHO), and Canada for the pandemic influenza vaccine.

“I’m delighted that HERA has chosen GSK as a key partner in pandemic flu preparedness. This contract follows three other agreements GSK has made, in the US, Canada, and with the WHO,” said Roger Connor, president Vaccines and Global Health, GSK, in a press release (4). “These agreements leverage GSK’s world-class global vaccine manufacturing network to continue our long-standing partnerships on pandemic preparedness and response. We have all seen the devastating human, economic and social consequences of a pandemic and the important part that vaccines are playing in helping us return to normal life. Through this agreement for 85 million doses, we can help the [European Union] and European countries, as well as other countries and regions, be better prepared for future pandemics.”

1. GSK, “Completion of the Demerger of Haleon and Share Consolidation of GSK,” Press Release, 18 July 2022.
2. J. Evans, “Debut of GSK Consumer-Health Spin-Off Haleon Disappoints,” 

, 18 July 2022.
3. GSK, “GSK Delivers Strong Q2 2022 Sales of £6.9 Billion +19% at AER, +13% at CER and Total EPS from Continuing Operations 17.5p -42% AER, -58% CER; Adjusted EPS of 34.7p +23% AER, +6% CER,” Press Release, 27 July 2022.
4. GSK, “GSK Signs Agreement to Support Pandemic Preparedness in Europe,” Press Release, 28 July 2022.

When referring to this article, please cite it as F. Thomas, “Demerger and the Future” 

GSK has completed its demerger of Haleon and has signed an agreement to help support future pandemic preparedness in Europe.

Demerger and the Future

In this episode of the Drug Solutions podcast, Felicity Thomas, European Editor, talks to a couple of experts on drug packaging advances that have been impactful in recent years and those that may have an impact in the future. Some talking points include sustainable packaging, tailored and patient-centric packaging options, the packaging challenges that arise when dealing with biologics, technological advances making packaging more convenient, and some interesting insights from events. The experts involved in this discussion were Aurelio Arias, who is part of the EMEA thought-leadership group at IQVIA, and Josh Brooks, the marketing and community director for a new event called Connect in Pharma.

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

Aurelio Arias, engagement manager, European Thought Leadership, IQVIA

Aurelio creates topical and forward-looking strategic content relevant to pharma executives and publishes articles, blogs and white papers on a regular basis. He is involved in numerous projects related to increasing access to medicine as well as the interface between healthcare and digital technology. He is considered a subject matter expert in these areas and speaks at numerous conferences worldwide, presents at board-level meetings and engages with consulting projects.

Prior to IQVIA, Aurelio has worked in R&D and in various strategy consulting roles. He holds an MSci in Chemistry from Imperial College London.

Josh Brooks, marketing & community director, Packaging at Easyfairs

Josh heads marketing and communication activities across an international portfolio of agenda-setting packaging events in the UK, France, Switzerland and Italy. He joined Easyfairs in 2018 after an early career in business journalism and publishing, where he covered a wide range of sectors including packaging, printing, construction, property and electronics.

In this episode, experts share their insights into important drug packaging advances of the past, present, and future.  

Drug Solutions Podcast: Drug Packaging Advances

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.

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)

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.