Grant Playter

When one thinks of medicine, the first image that comes to mind will likely be a small white pill, or perhaps an orange bottle full of them. While biologic therapies and various parenterals have experienced significant advances in recent years, the ubiquity of oral solid dosage (OSD) drugs —whether pills, tablets, capsules, soft gels, effervescence, gummies, or any other variant— remains at the forefront of the industry.

“OSD drug delivery systems are predominantly preferred over a parenteral (injection or drip) intravenous drug delivery for many reasons,” says Paul DiMarco, vice-president of Global Commercial Operations, BioSpectra. “Not the least of which being ease of use, lower purity demands due to the acidic environment of the stomach, and little or no medical supervision during administration.”

The popularity of OSD puts it at the heart of the pharmaceutical industry, and it is particularly susceptible to emerging trends or market forces. This article examines the latest technologies and trends unique to OSD, as well as takes a look at the greater market forces influencing its production.

One process that the pharmaceutical industry as a whole has been attempting to adopt, where possible, is continuous manufacturing, due to the decreased resource drain and increased flexibility continuous processes provide. However, while continuous manufacturing has seen steady growth, OSD has faced some difficulties in switching over due to the nature of its manufacturing process—the first oral solid dosage drug manufactured via a continuous approach was not approved until 2015 (1). Largely, these difficulties resulted from the equipment being designed with downtime in mind.

In this regard, various equipment suppliers have stepped in to try to ease continuous manufacturing hiccups. For instance, L.B. Bohle’s QbCon1, a continuous dryer and granulator, uses a novel process to allow for infinite operation without needing to stop the machine for cleaning (2). Similarly, Herma US released modules for its 132M HC Wrap-around Labeler that allow for it to be integrated into a continuous manufacturing process without needing downtime for replacement paper (3). In this vein, companies have come to the understanding that facilities must be designed with continuous “powder-to-tablet” capabilities in mind.

On the client end, there has also been increased demand for other new approaches, as Robert Sedlock, director at Natoli Scientific, notes.

“In the past few years there has been a push for collecting data in a more scientific approach. USP [United States Pharmacopeia] published a new chapter (4) concerning tablet characterization methods, which require instrumented tablet presses,” says Sedlock. “There is now a higher demand for instrumented single-station machines, rotary tablet presses, and compaction emulators/simulators. Understanding material mechanical properties is now a standard in the OSD industry.”

This standard is a natural evolution of the current pharmaceutical industry: as data integration becomes more pronounced, client companies are going to want more detailed information to refine their processes. Savvy manufacturers will build and design processes with this in mind as a means of satisfying ever-increasing data demands, which will in turn continually influence the technologies and approaches of OSD manufacturing.

A striking dichotomy has emerged in sourcing for the two components of oral solid dosage drugs, excipients and APIs. Excipients are typically considered more complex than APIs, largely as a result of their multi-component nature. This characteristic often results in the performance impact of the various components being not well understood; in a similar vein, the composition profiles of complex mixtures may not be well-defined. In contrast, APIs are comparatively simple mixtures—they are improved by reducing the presence of all other chemicals, which can render them inert or result in unintended side effects (5).

However, the stark difference in relative complexity has shaped who is producing them. Because excipients are relatively complex formulations, they require significant regulatory oversight to ensure consumer safety. Consequently, they are largely manufactured in countries with well-regarded, overarching regulations; North America holds the largest share in the pharmaceutical excipient market, followed by Europe (6).

“Pharmaceutical companies in the United States and Europe are held to a rightful standard by [FDA]—one that is not equally experienced by their counterparts in China and India,” says DiMarco. “These companies use higher purity ingredients and fine chemicals sourced from local manufacturers and, consequently, produce higher quality [and] more consistent, more sophisticated finished drug products.”

APIs, on the other hand, do not need to be quite as closely scrutinized, allowing countries like India and China, who have less stringent regulations and much lower labor costs, to leverage those characteristics to gain a manufacturing stranglehold. While it should be noted that there is some dispute over the precise numbers, in particular because most drug manufacturers do not need to disclose where they source APIs, in 2017 the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) estimated that 40% of global API production was coming from China at the time of the report (7). Similarly, a 2021 report from Mordor Intelligence, a marketing intelligence firm, indicated that approximately 75% to 80% of APIs imported to the US were coming from China or India at the time of their report (8).

This dichotomy in materials sourcing has shaped the landscape of the oral solid dosage manufacturing industry. For instance, while there have been calls to reshore production following the supply chain interruptions brought on by the COVID-19 pandemic, the reliance of the US on these countries for API sourcing complicates that matter; it is particularly exacerbated by desires to reduce drug costs, which necessitates outsourcing to countries who can price relative to their labor costs.

“The supply chain security issues that began with tariff wars between China and the US, followed by the pandemic, continue through this day with strained supply chain logistics and raw material capacity constraints,” says DiMarco. “The worsening relationship between the US and China could quickly lead to more serious conflict and could easily become an existential event that would dwarf in comparison all previous challenges regarding supply chain issues and constraints.”

1. Vertex Pharmaceuticals, “FDA Approves Orkambi,” Press Release, July 2, 2015.

2. L.B. Bohle, “Continuous Granulation and Drying for the Pharmaceutical Industry QbCon 1 – R&D,” 

3. Freudenberg Medical, “Freudenberg Medical Launches HeliFlex TPE Tubing at Bioprocess International Conference,” Press Release, Sept. 29, 2022.

4. USP, “General Chapter <1062> Tablet Compression Characterization,” 

Qualification of Excipients for Use in Pharmaceuticals 

7. MHRA, Medicines and Healthcare products Regulatory Agency International Strategy, www.gov.uk (2017).

Active Pharmaceutical Ingredients (API) Market-Growth, Trends, COVID-19 and Forecasts, (2022 - 2027)

Grant Playter is the Assistant Editor for 


Vol. 46, No. 10
October 2022
Pages: 26-27

When referring to this article, please cite it as G. Playter, "Examining Trends in Oral Solid Dosage Manufacturing," 

Articles

The state of oral solid dose manufacturing is influenced by new approaches, novel technologies, and the structural evolution of the raw materials market.

Examining Trends in Oral Solid Dosage Manufacturing

Cleanroom monitoring is an industry that some reports estimate will be valued at as much as $7.1 billion by 2028 (1). In spite of that massive projected value proposition, however, many questions remain regarding the current (and future) state of the industry. How are recent advances affecting the field? What upcoming changes should we be aware of? Is the industry stable or in flux?

To learn more about the current state of cleanroom monitoring, recent advances in the field, and potential upcoming changes that might impact the industry, 

 spoke with the Alex McDaniel, Environmental Monitoring Program manager, Element; Joe Mundell, chief research officer, Sonicu; and Stephen Tierney, president, XiltriX North America.

When taken together their perspectives provide insight not only into the current state of cleanroom monitoring, but also into changes that may be cresting over the horizon. Topics of discussion include the current state of cleanroom monitoring, recent advances in the industry, upcoming changes, and more.

: Broadly speaking, can you share your thoughts on the current state of cleanroom monitoring? Would you say it is in flux, or a relative state of stability?

: Over the course of the past six years, it has been apparent the current state of cleanroom monitoring is always seemingly in flux. As the industry works to align the methodology, frequency, and validation of a formal environmental monitoring (EM) program, many applicable guidance documents and standards are undergoing revision. This includes 

] General Chapter <797> (2), which is (hopefully) nearing the finish line of its long overdue revision. An increased frequency of surface sampling within the cleanroom suite is anticipated in the 

 <797> revision, in addition to changing the organism identification requirements to be more pragmatic to delivering patient care.

In the current good manufacturing practices sector, the EU Annex 1 revision will emphasize the increasing need for a contamination control strategy, whereas the current version lacks specificity on this. A more consistent and patient-focused approach to EM will be embraced by the industry, as the Annex 1 revisions will impact cleanroom monitoring, especially as it relates to an enhanced focus on conducting a risk assessment of the activities within the facility.

: Cleanroom technology is rapidly evolving as more healthcare and life science customers migrate to the cloud and demand mobile-first solutions that are always on and can be accessed from anywhere. Moreover, clients are looking for monitoring solutions that both integrate with and serve as a multiplier for their BMS/BAS [building management system/building automation system] systems.

: Can you discuss some of the most recent advances in cleanroom monitoring? What makes these technologies fundamentally different from those that came before?

: Some of the recent advances in cleanroom monitoring would be continuous particle counting and measurements, such as volatile organic compounds (VOCs), becoming more and more ‘the norm’. Technologies never fundamentally change because it’s evolution, not revolution. Legislation and regulation would not be able to keep up if it were the latter.

[Increasingly] sensors [are being seen] in a single system. For example, analog magnehelic differential pressure sensors can now be digitally integrated into an [environmental monitoring system] alongside a room’s conditions and particle counters, as well as the equipment stored inside.

: Rapid microbiology has garnered a great deal of interest, yet it remains an unknown quantity and certainly does not look to unseat conventional microbiological testing methods in the near future. The turnaround time for traditional incubation of viable media is its primary pain point, as it takes a minimum of (roughly) a week to 10 days, depending on duration of media dual incubation conditions. This does not include the time microbial identification and reporting takes. Rapid test methods allow for quicker batch release and insight into the state of microbial control, as firms can receive insight into potential growth of bioburden much sooner (some within minutes or hours).

Fundamentally, the validation process for this is not necessarily as straightforward as traditional methods. Guidance documents like 

 <1223> Alternative Microbiological Methods (3) are a good starting point to consult when considering validation of this system. The data comparison is not ‘apples to apples’, as the rapid method employs the use of technologies like ATP [adenosine triphosphate] bioluminescence and viability staining to detect the presence of viable organisms. Rapid forms can cover a wide range of assays, from bioburden of raw materials to sterility confirmation, water monitoring, and active air sampling. However, it is important to ensure that rapid methods are of equal or better quality than traditional testing.

: Has there been any recent changes in what customers want in their environmental monitoring systems? If so, how has the industry changed to accommodate it?

: Data security is continuously becoming more stringent every year. Since the pandemic, life science facilities have been in greater need of remote accessibility; to have full insight into everything going on in a facility, no matter where the staff are located. [Facilities’ operators] want their electronic management systems more integrated with other critical systems like LIMS [laboratory information management system], building management systems, electronic lab notebooks, batch records, asset management, [and so on].

: Along with automation, clients are asking for trended data from their monitoring projects. While trending is a wide-ranging regulatory requirement, it is currently performed via a very manual process. To produce better reports that feature trended data as a standard inclusion, [Element implements and uses] LIMS.

Compressed gas testing is also more frequently requested in the industry. Including secondary points, such line drops within the building that are not routinely monitored, can provide a holistic diagnosis of how the entire system is performing versus a fragmented approach of selecting only certain locations. [It is expected that there will be a] significant increase in this [request] moving forward, especially in terms of validating a previously installed system.

Within the next several years, the momentum will likely swing towards systems that can provide continuous and automated sample collection during a production run. Some processes are still performed in a very manual way and require a great deal of human intervention, from differential pressure monitoring, temperature, and humidity data, or non-viables. Some manufacturers of monitoring devices are also developing viable particle counting units to provide real-time data of colony forming unit (cfu) counts with the use of laser technology similarly used for non-viable particle count testing.

: As the EU GMP Annex 1 revisions edge closer to publication, what changes, if any, will this make to environmental monitoring specifically? If we’re anticipating significant change, what future-proofing (if any) are you seeing in customer orders?

: There is an increased onus on manufacturers to implement and document a contamination control strategy and a vigorous risk assessment within the pharmaceutical quality system. Manufacturers may need to completely overhaul their program to include additional sampling locations if a formal monitoring program was not previously established, or the original program was not updated to reflect current processes or was based upon previous facility designs. An increase in EM performance qualifications conducted on existing cleanroom areas to align with an updated and more modern approach to the documented risk assessment [is expected].

Given the push to take a comprehensive look at processes to identify failure points and consequences of those failures in the upcoming Annex 1, using the failure mode and effects analysis (FMEA) tool has worked out well for clients looking to future-proof their risk assessments.

: Do you have any final thoughts on the topic that you can share with our readers?

: [A] greater attention from larger healthcare systems to include air pressure differential and humidity as well as O2, CO2, and VOCs [is being witnessed]. Infection control experts are driving the conversation as part of their risk management focus while construction firms are being consulted on both new build and retrofit projects to work collaboratively on these projects. [Additionally, a] significant demand relative to pre-COVID [is being seen] and [this is] expected to continue accelerating.

: [From personal experience, it is apparent that] critical gaps within an operation may not be identified until it is too late. Downtime can be eliminated, back-end costs reduced, and production lines will stay in operation if those within the industry tasked with maintaining compliance to these standards establish documented protocols in partnership with a subject matter expert (SME) and team of microbiologists.

As professionals, [there is] a responsibility to seek out continual education, as well as educate others in the industry. Establishing a partnership with a collaborative organization with a consultative team invested in teaching others is vital to staying on top of these dynamic requirements—and that is only the beginning. Selecting a firm that has a robust scope of service offerings and quality procedures that can look at processes, provide a gap analysis, establish methods to help mitigate contamination control before it becomes problematic, and even assist in validating a cleaning and disinfection program is a gamechanger when the FDA walks through the door.

USP, General Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” 

USP, General Chapter <1223>, “Alternative Microbiological Methods,” 

Grant Playter is the Assistant Editor at Pharmaceutical Technology.

Recent technological advancements may have put cleanroom monitoring into a state of flux.

Environmental Monitoring Advances

While the debate between stainless steel and single-use systems (SUS) will continue to rage for the foreseeable future, most would agree that there is a time and place for either approach. Naturally, however, this raises the question: when is it ideal to utilize an SUS approach? What advantages does it confer? How are they being used in the current manufacturing environment?

spoke with SUS experts Nick Johnson, director of Product Management, Biopharma, CPC, Wolfgang Walcher, chief commercial officer, Single Use Support; and Helene Pora, vice-president, Technical Communication & Regulatory Strategy, Pall, to get their perspective on the current benefits of single-use systems.

Can you share your thoughts, broadly speaking, on the merits of single-use systems, consumables, etc., in manufacturing? Is there any aspect that you feel is under or over-emphasized in this discussion?

 Think about the flexibility single-use systems allowed during the pandemic. Manufacturers urgently reallocated new therapy and other capacities to commercial vaccine production. The capability to quickly switch from one kind of production to another is a huge benefit that SUS affords in everyday practice. Single-use technologies (SUT) definitely contribute to speed and efficiency by allowing multiple products to be produced in one manufacturing suite with relative ease.

SUT’s flexibility and sterility also has made it simpler to ‘fail fast’ in clinical trials, too, compared to traditional stainless steel. The impact on bioprocessing from early-stage development through commercial manufacture has been an industry game changer.

 SUS offer a level of flexibility, scalability, and cleanliness that is near impossible to achieve with glass and stainless-steel counterparts. Lines can be repurposed more easily, and there is no need for cleaning and cleaning validation. This saves a great deal of time and money while making the process safer for operators. SUS can also reduce the time to build a plant and lower overall capital expenses. And from an environmental perspective, there is a lower carbon footprint, less water, and less chemicals despite higher solid plastic waste.

Unfortunately, the amount of solid waste is frequently overstated compared to the benefits. In 2020, ISPE released a review showing that SUS is responsible for .01% of all global plastic waste, which is largely driven by consumers. This does not mean that the industry does not see the use of plastic as a problem—we are actively investing in recyclability and overall process impacts—however, it does not deserve the level of criticism it gets.

: Single-use systems are trending for a reason:

They help to improve safety, cost-efficiency, and sustainability in comparison with the use of durable stainless-steel manufacturing facilities.

With single-use assemblies, bioprocess containers, and other sterile consumables operators can transfer liquids in closed systems and as customized options.

They are adaptable to changing requirements of system setups.

Usually, the systems are designed to minimize manual interventions, thus preventing human errors which can result in quarantined or even rejected batches.

The most under-emphasized aspect is probably sustainability. Different life-cycle assessment studies have proven that single-use systems can be more sustainable than stainless-steel solutions (1). However, there is still room for improvement, and we’ll drive innovation to further improve sustainability in the pharmaceutical industry.

What are the costs of using single-use systems, consumables, etc.? What factors should be considered when deciding whether or not to employ them?

 There are different factors that come into play to influence costs of single-use systems because of the wide range of consumables on the market, which offers a wide span of prices.

The answer is strongly dependent on the application/use of single use systems. For example, in API primary packaging the alternative to single use systems is shipping hundreds of kilograms of cryo-vessels worth millions of dollars and causing tons of CO2 [carbon dioxide] emissions; alternatively, SUS, like bags, are low at cost, easy to store, and safe to ship.

For other applications, [such as] sampling or bioprocess containers, it is a question of flexibility, and people forget that stainless-steel multi-use vessels require a high amount of resources—producing, repairing and maintenance, cooling, etc. 

: Ease of use, flexibility, reliable sterility, production efficiency—these are all factors to be considered. Thanks to SUT, it’s economically feasible to manufacture therapies for diseases that affect small patient populations that have the kinds of numbers that might not justify an investment in a traditional stainless-steel operation.

Modular, purpose-built SUS can be optimized for specific processes so they’re ready when needed. The production suite can be changed over quickly to accommodate the next process. There’s no downtime between production runs because SUS don’t require cleaning or equipment requalification in between batches. The ability of SUS to eliminate the risk of cross-contamination between processes is significant. All of this contributes to more streamlined operations.

Also, SUT is the most cost-effective way for manufacturers to make a wide range of drugs from vaccines, to mAbs [monoclonal antibodies], to cell and gene therapies.

SUS are priced more affordably than traditional equipment. However, SUS require bags and connectors that will generate consumable costs over the life of each process. The cost of consumables and security of supply is very important to consider. Working with trusted suppliers that have taken steps to secure sourcing is paramount in today’s market.

It is, of course, important to consider batch size and the number of batches that will be needed per year. With size constraints usually hovering around 2000 L, any high-volume drug would require a parallel processing approach. And whether the plant will be multi-product or single product is also critical.

Though it can be argued that the ability to changeover is only valuable if it is needed, it is always a smart investment. Having the flexibility, even in a single product environment, is a good backup if anything were to go wrong (e.g., clinical failure) along the way to commercialization.

What trends have you seen occurring as it pertains to single-use manufacturing? Do you anticipate them continuing for the foreseeable future, or is the end in sight?

If you looked back a decade ago, the discussion was still, ‘will this work?’ We are so far past that now, and SUS have helped to enable an era of innovation in this industry that is unmatched. We see a diverse range of modalities, which continues to grow, and a move towards more efficacious or even curative products.

The technologies needed to support the continuous high growth projections in the industry will rely on SUS in many cases. As we’ve seen through the pandemic, SUS not only enable innovation, but they allow for the type of rapid response needed for vaccines. Undoubtedly, the COVID-19 vaccines would not have been introduced and produced so quickly without SUS.

The growth may not be as high as we have seen throughout the last two years of the pandemic, but it will continue. A new product mix with an emphasis on biologicals and smaller indications will keep that demand growing over time. We also cannot ignore that SUS will be the backbone of existing processes (pending the patient population), creating sustainable demand in those areas.

Additionally, the scope of SUS use is continuing to expand, with more critical applications than ever before like formulation and final filling.

SUS will play a vital role in pharmaceutical and biopharmaceutical manufacturing and supply chain in future. The more personal medicines and low volume high potency medication (e.g., gene therapeutics, mRNA [messenger RNA], small interfering RNA, etc.) is progressing, the more important single use system will be. Challenges [such as] recycling of single-use systems will be solved in the near future and [will], therefore, significantly improve the environmental sustainability and CO2 footprints of systems used.

: Most new and upgraded contract development and manufacturing organizations, contract manufacturing organizations, and biopharma companies are incorporating single-use bioprocessing equipment. That’s the way the industry has been moving and will continue to go.

From a big-picture standpoint, it might take five to seven years from groundbreaking to a qualified facility using stainless steel. In contrast, a SUS-based facility might require two to three years. Then, after a facility is operational, SUS allow biomanufacturers to process multiple drugs simultaneously in one space or make rapid equipment changeovers between production runs without compromising sterility. That push for efficiency and modularity within and across sites is a driver.

There’s strong interest in standardizing SUT, which begins with components purchased from SUS equipment suppliers. The same equipment, standard operating procedures, and a shared supply chain create efficiency. SUS components also will need to work in automated equipment as the industry moves away from reliance on operators toward automatic processes.

Are there any unique use cases for single-use consumables, systems, etc. that you have experienced in the industry?

: The SUS component industry is catching up a bit to create solutions specifically for small-bore tubing in small-volume work—applications [such as] sampling, seed train expansion, analytical processing, buffer/media transfers, and early cell-culture processes involving shaker flasks and rocker tables.

A growing number of companies are now engaged in small-volume (< 10 L) aseptic processes, such as early-stage drug development. You’ll also see very small volumes in cell therapy, for example, where cell availability is limited or media is expensive, and in the development of small-batch autologous therapies.

In the past, making reliable sterile connections in these smaller aseptic processes was typically handled using biosafety cabinets or tube welding. But biosafety cabinets can only handle a limited number of processes at one time. Tube welding is labor intensive, and the equipment is expensive—easily $15,000 or more per welder—and takes up valuable cleanroom space. Small companies with limited resources may not have the capital to purchase tube welders.

Until recently, tube welding was the only option for creating sterile closed systems at small volumes. Now there are single-use aseptic micro-connectors designed to sterilely connect small-bore tubing, so that’s new to the industry. Aseptic connections with new micro connectors can be completed in three steps and up to four times faster than an operator using tube welding, which can require a dozen steps or more to get a successful weld.

Also, in our line of work—connection technologies—there’s never been a genderless connector that can both connect and disconnect tubing using one product in bioprocessing until this past spring. Users appreciate genderless products because they’re more convenient. They eliminate mating complexity, reduce inventory requirements, simplify system design and reduce operator error. That genderless convenience factor was taken up a notch by creating a product that connects and disconnects aseptically without the need for ancillary equipment.

: Initially the use of SUS was focused on providing a solution for media and buffer preparation and handling. Over the last decade, we can now leverage the benefit of SUS throughout the process and even into the final filling applications. The use here is very functional—we only use exactly what we need, which is another part of how we keep the volume of waste minimized.

: There is a broad application of SUS established, so you will find all (even exotic) applications of SUS in the industry.

While the broader effects of the COVID-19 pandemic have lessened in public discourse, the supply chain interruptions it brought on remain a concern. Can you discuss the impact this has had on manufacturing? How would a mass return to the just-in-time (JIT) delivery model shift the current landscape?

The industry wasn’t prepared for such a supply chain challenge. The shortages have jeopardized business continuity of major manufacturing sites apart from COVID-19.

The shortage of SUS has therefore made biopharmaceutical manufacturers reflect on their relationship with suppliers. It has shown that it is crucial to have reliable partners, to plan ahead, and to establish reliable forecasts. Suppliers can react accordingly by building stock and procuring it early. Manufacturers and suppliers need a common understanding and common standards across the industry with respect to equipment and consumable design, as this enhances delivery speed.

A JIT delivery model in the pharmaceutical industry needs suppliers who rethink supplier relationships by offering solutions [such as] supplier agnostic solutions for flexibility or various business continuity measures to allow fast delivery times.

From a supplier perspective, it has driven us to significantly increase our manufacturing footprint and take deeper steps internally to secure our supply chain. Just about a year ago, Danaher announced an investment of $1.5 billion into the Cytiva and Pall lines of business (2). Over $300 million of that has been dedicated to strengthening the SUS line of business. Even as we start to realize some of the benefits of these investments, we remain committed to honing an agile approach to business processes standardization in parallel with our daily activities.

There will be a tradeoff for every approach. JIT will be largely dependent on the capability of biomanufacturers to produce accurate forecasts. While this can be achieved to a certain level with commercial products, it will remain very difficult for clinical manufacturing. Therefore, JIT delivery will be a combination of demand and how much some form of standardization is achieved, together with improved forecasting practices. It will still take some time to reach that level after the pandemic. The goal is really to more reliable and reproducible lead times, regardless of the model.

: From a supply-chain perspective, there’s no question that COVID-19 has disrupted everything from obtaining raw materials used to create components to the ability to ship sterilized equipment in a timely way. This isn’t exclusive to SUS, but it’s had an impact throughout the supply chain.

Supply-chain considerations are especially important when selecting suppliers of single-use assemblies. That’s because no supplier of single-use assemblies manufactures all of the products used in that assembly. For example, the manufacturer of a single-use mixer bag probably sourced the aseptic connectors, tubing, tubing clamps, T or Y connectors, filter capsules, etc., from other companies. Each of those component suppliers has a supply chain that may comprise sub-component suppliers, external assemblers, raw material suppliers, contract manufacturers, and so on. You can see that the SUS supply chain is multi-tiered and complex; the ability of the SUS manufacturer to supply product is 100% dependent upon the robustness of the entire supply chain.

Enhancing sustainability in the pharma industry

Cytiva, “Cytiva and Pall Corporation investing 1.5 billion USD over two years to meet growing demand for biotechnology solutions,” Press Release, July 27, 2021.

Grant Playter is the Assistant Editor at 

Experts outline the benefits of single-use consumables relative to traditional approaches.

Weighing the Benefits of Single-Use Consumables

Preventing contaminants from interfering with pharmaceutical operations is critical for the safety of the workers handling the materials and the consumers to whom the final product is delivered. Apart from the self-evident health risks brought about by contamination, the financial risks can be just as dire; management firm McKinsey found that, on average, recalls cost the industry between $2.5 billion and $5 billion per year through non-routine costs and lost sales of new and existing products (1). Moreover, if product contamination results in a recall, the damage will be more than monetary; latent effects, such as consumer and investor confidence in a company, brand, or product must also be considered.

This naturally raises the question of what is being done to prevent contamination in the pharmaceutical field. The following reviews key areas of the pharmaceutical production process to look at what novel techniques, technologies, and policies are being implemented to mitigate the chance of contamination.

When a process is repeated in stainless steel, sterilization is necessary between batches to ensure product quality. Regardless of how this is done, whenever a system is exposed to multiple batches (and, in the case of manually cleaned systems, human intervention) the chance that the process fails to fully sterilize the system exists. This is especially true for lower-grade systems or ones that require complex clean-in-place/sterilize-in-place (CIP/SIP) procedures that require significant, specialized training to correctly perform.

One way in which the industry has begun addressing this issue is through automation. Not only does this eliminate the need for direct human intervention, it simplifies many of the procedural steps that can indirectly affect the cleaning process. Alex Van Hagen, Life Sciences Sector Specialist at Watson-Marlow Fluid Technology Solutions, discussed the impact this can have on the manufacturing process in the “Sterilization’s Horizon: Improving Automation, Single-Use Technologies, and Annex 1” episode of 

t series (2). Van Hagen specifically highlighted the rise of vaporized hydrogen peroxide (H₂O₂) systems in aseptic processing, which has made key advances in its efficacy as a sterilization tool.

According to Van Hagen, companies historically used open-systems where human operators would go in and sterilize the machinery. However, this process opened the gates to massive amounts of contamination risk.

“If you are going to open it up and have people going in and cleaning it, that’s all [well and good],” said Van Hagen. “However, they’re using their hands. Our hands are [how] we interact with the world, it’s the highest bioburden-laden part of our body except for our mouths.”

This method, risky as it is, was one of the cheapest, fastest ways to sterilize bioreactors. However, when an existing patent that was preventing companies from developing faster ways of using H₂O₂ in aseptic production expired in 2002, H₂O₂ emerged as a potentially viable alternative; to this point, multiple days of cleaning were needed to use the chemical. Now, with the advances that have been made in its usage over the past 20 years, it can be done in as little as 30 minutes, making an automated system a feasible alternative to historical practices (2).

With single-use consumables, the chances of prior batch residue contaminating a fresh batch is removed, but the chances for extractables and leachables (E&L) to enter the product is introduced. Because they are made of various types of plastic, rather than stainless-steel, chemicals may now corrode the system and contaminate it, necessitating highly regulated E&L studies to determine what chemicals can be safely delivered through the system. Technological advancements have largely been in increasing the accuracy and speed of these studies. For instance, high-resolution, accurate-mass mass-spectrometers (HRAM-MS) have gained popularity as a tool to understand the structure of unknown compounds.

That said, the E&L field sees significant change through tightened regulatory oversight, albeit in a somewhat unconventional way. While direct changes to regulatory insight do occur, current guidance is not necessarily prescriptive; often, changes come down to changes in interpretation (3). To keep up with ongoing regulatory interpretations, self-governing bodies issue recommendations for E&L testing.

The Product Quality Research Institute (PQRI), one such institution, pushed for several changes in its most recent recommendations, most notably as it pertains to a justification and outline for toxicological evaluation of leachables in parenteral drug products (PDPs) (4). In addition to various other recommended procedures, the organization recommended that a qualification threshold (QT) of 5 µg/day is appropriate for orally inhaled or nasal drug products in the absence of supporting general toxicology data and an identified potential for irritation or sensitization in PDPs. Apart from PDPs, PQRI also issued guidance for unique considerations necessary for biologics (4).

Lastly, cleanroom technologies have also seen some advancements that are changing how researchers work in the cleanroom. Stephen Tierney, president, XiltriX North America, noted that certain technologies have begun to gain greater prominence in cleanrooms. One example of this is continuous particle counting measurements, such as volatile organic compounds, which are becoming more broadly incorporated. Similarly, he also noted that sensors are being put in a single system; analog magnehelic differential pressure sensors, for example, can now be digitally integrated into an environmental monitoring system alongside a room’s conditions and particle counters (5).

As it concerns cutting edge advancements, there are many promising advances that have not yet crested the horizon for widespread use. Alex McDaniel, Environmental Monitoring Program manager, Element, noted that while conventional microbiology testing methods are set to continue seeing use in the near future, rapid microbiology has begun garnering greater interest. Traditional microbiology methods take between 7–10 days, depending on duration of media dual incubation conditions, a painful timeframe that does not take into account the time it takes to identify and report microbial infection. Rapid methods would allow for quicker insight (hours, or even minutes) into the state of batch release for various forms of assays, including raw materials, sterility confirmation, water monitoring, and active air sampling (5).

The Business Case for Medical Device Quality, 

M. Rivers and F. Thomas, “Drug Digest: Sterilization’s Horizon: Improving Automation, Single-Use Technologies, and Annex 1,” 

F. Thomas, “Meeting E&L Expectations,” 

Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular),

G. Playter, “Advances in Environmental Monitoring,” 


Vol. 46, No. 10
October 2022
Pages: 38-40

When referring to this article, please cite it as G. Playter, "The State of Contamination Control," 

Various advances in contamination control are being utilized to reduce the chance pollutants contaminate a drug product.

The State of Contamination Control

Editor’s Note: This article has been updated from the original version.


Vol. 46, No. 9
September 2022
Pages: 40–43

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

Cleanroom monitoring may be in a state of flux after many recent technological advancements.

Advances in Environmental Monitoring

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

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

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

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

Podcasts

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