Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

 We often hear that globalization of the pharmaceutical industry has added new challenges to the management of the end-to-end supply chain. What are the key trends shaping the pharmaceutical supply chain? How can an organization effectively manage its supply chain to meet increasingly demanding customer requirements? What are the best practices?

 I should start by slaying the myth that globalization has been responsible for the challenges and difficulties experienced in the pharmaceutical supply chain. New markets opening up across the developing world did not have to result in the globe spanning, multi-party, multi-handover supply chains of today. The industry’s tactical approach towards outsourcing and offshoring did the damage; and 30 years after it all started, the pharma supply chain is in crisis.

	This is both good and bad news for the industry. Bad, in that pharmaceutical manufacturers have a mountain to climb if they are to regain proper control of their supply chains. On a more positive note though, the situation has forced many senior executives in the industry to realize that “globalization” is not responsible for this problem. With the right strategic approach, this crisis can be fixed. The quality by design (QbD) paradigm puts emphasis on designing and developing products with the end user, manufacturing process, and supply chain in mind. This approach must be taken by any company if it is to operate a sustainable business model. Janet Woodcock, head of CDER at FDA, has been advocating this approach for nearly 15 years, along with experts from the International Conference on Harmonization (ICH), and many other industry bodies and commentators. Sadly, the industry misunderstood the intention.

	If some of the initial enthusiasm for QbD has been lost in the sands of time, its spirit must be resurrected in its original form. Instead of calling the approach QbD, let’s call it design for manufacture. Rather than having discovery and research teams throw new compounds over the wall for development to make the best of, why not make a committed effort to pressure test prospective compounds? This means being willing to jettison those that do not pass muster, and won’t result in manufacturable molecules. It also means working more closely with suppliers of APIs and excipients in the development process, so that their deep knowledge of processes and material performance can be leveraged to a point where it can make a difference.

	In short, pharmaceutical supply chains have suffered from decades of neglect that can only be reversed if the pharmaceutical industry develops new paradigms for product development based on practices well proven in other industries such as the electronics sector. Semiconductor manufacturing is an example of design for manufacturing that drugmakers could emulate.

Articles

Hedley Rees, managing director at PharmaFlow Ltd and a member of the CPhI expert panel, shares his views on pharmaceutical supply chain issues.

Pharma’s Supply Chain Crisis and the Myth of Globalization

	The personalized medicines era is shifting the focus of pharmaceutical development and manufacturing activities from small molecules to biologic drug products. The formulation of these complex macromolecules, however, is not as straightforward as their small-molecule counterparts. The high patient doses required for biologic therapeutics, for example, present significant drug-delivery challenges, according to Johann Stasny, director, Global Sales Development, Bioavailability Enhancement & Custom API, Merck Millipore KGaA, Darmstadt, Germany. “On average, a dose of 0.1 mg to 3 mg per kg of patient body weight is required,” Stasny notes. Because of their nature, biopharmaceuticals are not easy to deliver via the oral route, explains Kate Hudson-Farmer, market insight strategist, Drug Delivery, Cambridge Consultants. A large proportion of these drugs are currently injected using intravenous infusion in the hospital, or increasingly in the home, she says.

	Most biologic products for parenteral administration are freeze-dried in vials to help maintain drug stability and increase shelf life. But interest is growing in the development of liquid formulations in prefilled syringes and autoinjectors, which offer convenience and ease of administration in a home setting. Stasny observes a shift for certain biologics-especially those indicated for chronic conditions such as inflammatory diseases-toward prefilled syringes for subcutaneous administration. “This delivery method has better patient compliance and efficiency in cases where a high concentration of the drug is required due to the low dosage volume that can be administered,” he says.

	“The trend in self-administration continues to grow,” Hudson-Farmer notes. Claus Feussner, PhD, senior vice-president, Development Service, Vetter, attributes it to the expanding home healthcare market, which he says is a direct reflection of a constantly aging population, particularly in the more established countries. And as a means to control costs and avoid expensive therapies in either a hospital or a doctor’s office, healthcare authorities are putting pressure on the industry to develop medicines that patients can self-administer in a private setting, according to Feussner.

	Hudson-Farmer, nonetheless, points out that self-administration has its challenges. Patients require training and education to ensure that these drug-delivery systems are used correctly. “But this is not the only problem,” she asserts, “because self-injection, whichever way you look at it, is not a pleasant thing to have to do, and adherence and compliance to such drugs is often a problem.”

	In addition, drug companies are faced with the challenge of having to deliver larger volumes of biologic formulations, often beyond the capacity allowed by a syringe or an autoinjector. “This is in part due to the trend towards less frequent injection and in part, to drug formulation issues,” says Hudson-Farmer. Patch pumps or on-body injectors that can deliver the drugs in a subcutaneous manner are being developed, she adds. “There have been some interesting advances in this area including the pre-timed, worn-on-body injector that Amgen launched for its Neulasta drug using Omnipod’s on-body injector,” Hudson-Farmer highlights.

	Andy Fry, founder of Team Consulting, notes that wearable devices, which provide an alternative to prefilled syringes and autoinjectors, are attracting a great deal of interest. “A wearable device allows drug delivery over a significantly longer period than the typical 10- to 20-second window associated with an autoinjector. Because of this feature, a wearable device can enable large-volume doses, or high-viscosity formulations, or even larger-volume payloads at high viscosity, to be delivered at acceptable levels of patient discomfort,” he explains. “There has also been renewed interest in all-in-one dual-chamber devices, which aim to take the fiddle and complication out of reconstitution of lyophilized products for self-injection while avoiding the necessity of cold-chain transportation and storage.”

	Graham Reynolds, vice-president of marketing and communications, Delivery Systems, West Pharmaceutical Services, sees an increased need for innovative and effective drug packaging and delivery of biopharmaceuticals. “Additionally, as biologics begin to come off patent, demand for delivery systems that can safely contain and deliver biosimilars should continue to rise, especially as easy-to-use delivery systems can help differentiate drug products,” he says.

	The industry also continues to seek alternatives to glass, such as polymer-based systems, for drug packaging and delivery systems, according to Reynolds. “This is particularly true for biologics, which can be sensitive to their containers,” he observes. “Glass-related risks, such as delamination, breakage, and chemical incompatibility with the drug product do not exist with the newer polymer offerings. These platforms offer a range of options for dose volume and injection time and are designed to help improve patient compliance and outcomes, while meeting the challenges of injectable drug products.”

	Biologics are sensitive drug products, and therefore, require ultra-clean packaging components to ensure low risk of contamination or particulate-which is why manufacturers are, in turn, demanding that drug containment and delivery systems from suppliers offer the highest levels of quality possible to maintain the purity of their biopharmaceuticals. 

There is growing interest in the development of liquid formulations in prefilled syringes and autoinjectors, which offer convenience and ease of administration in a home setting.

Trends in Biologics Drug Delivery

The taste of an oral dosage form has significant impact on patient compliance. As a result, there is increasing interest in taste masking as the pharmaceutical industry invests more resources into the development of palatable and pleasant tasting formulations. Matt Shaffer, manager, formulation development, Bend Research, a division of Capsugel’s Dosage Form Solutions business, and Martin Koeberle, PhD, head of analytical development and stability testing, Hermes Pharma, spoke to 

 about the different approaches used in taste masking and the challenges involved.

Can you discuss the challenges in taste masking, particularly when developing formulations for the pediatric and geriatric populations?

The overall challenge stems from trying to meet diverse product attributes in a narrow formulation space. Palatability is a subjective metric that has shown significant dependence on more than just patient age, making it difficult to quantify and be predictive of patient compliance, even within specifically designed studies.

	One of the first challenges is to define taste and the need for taste masking-which, ideally, would stem from sensory information gathered early in clinical development that could aid in assigning risk to the compliance challenge for special populations. Furthermore, formulation and technology selection for easy-to-swallow dosage forms are constrained by the desire to maintain similar bio-performance of established drug products. The constraints are further compounded when you consider using a short list of excipients with precedence in oral products and acceptable safety profiles. The last element is to arrive at a final presentation that is stable and ideally preservative-free, yet amenable to flexible, uniform dosing across a broad patient population. These challenges present the opportunity for the development of a platform approach to taste masking that fundamentally produces a neutral-tasting drug form that is easy to administer.

 There are several technologies that can be used to cover the poor taste inherent with many APIs. Depending on the API and dosage form, one option is to work with specific flavors to cover the unpleasant taste. A primary challenge here is the specific knowledge required to combine each individual API with the best-suited flavor, taking into consideration the taste characteristics of the API. As each poor tasting API has a different combination of tastes-for example, sour, bitter, or metallic-there is no universal flavor for all products. If flavoring is insufficient to create a palatable and appealing product, then we mostly rely on hot-melt coating (HMC) to taste mask the API. HMC is a cost-efficient and economic coating technology suitable for tablets, capsules, and orally disintegrating granules (ODGs).

	Developing formulations for children and the elderly has its own challenges
	because taste sensations differ between age groups. While older people prefer sweeter and more intense flavors, nuances of bitterness and sourness are acceptable. Infants and children, on the other hand, are far more sensitive to sour and bitter tastes. It should be noted that taste masking is essential in an oral dosage form such as ODGs, effervescent tablets, chewable tablets, and lozenges because these dosage forms spend more time in the mouth and are tasted more thoroughly.

What are the main approaches used in taste masking?

The three most commonly used approaches to masking the taste of pharmaceuticals include taste modification, drug complexation, and functional coating.

	The category of taste modification includes formulating a combination of sweeteners, flavors, and viscosity modifiers to manipulate the perception of taste through competition of taste receptor sites without changing the concentration of free, or unbound, drug in solution.

	In the case of complexation, the goal is to preferentially bind the drug to a substrate that effectively reduces the concentration of free drug in the use environment, preferably below the taste-detectable limit.

	The final category, and our current approach to taste masking, is to apply functional coatings that modify the release of drug to control the concentration of free drug below a threshold value for a time period relevant to preparation and the administration of the dose. We take a risk-based approach to excipient selection-which includes using components with supporting safety data at levels that achieve the desired performance and stability attributes. Within our multiparticulate platform, these excipients include sugar, cellulose-based derivatives, lipids, and limited amounts of surfactants for drug-containing cores and polymethacrylates, cellulose-derived polymers, and small quantities of plasticizer for functional coatings.

One of the technologies we use for taste masking is HMC, which we often apply to ODGs. In this process, the API particles are suspended in a fluid bed coater while the excipients are heated until they are molten, and then sprayed directly onto the seed particles. Once this process is complete, additional excipients and/or flavors are blended in to create the final formulation, ready for use. Lipids are most often our excipients of choice for HMC, primarily the triglycerides and partial glycerides. As many of these lipids are naturally derived compounds or already found in foodstuffs, the body usually shows a good tolerance for them.

	Over the years, we have developed a range of customized flavoring excipients, such as cappuccino, cream-banana, chocolate, and cherry-mint flavors, including a pomegranate flavor for cough and cold effervescent tablets. We use these flavoring excipients for a range of dosage forms beyond those that have undergone HMC, including chewable tablets and instant drinks.

What are the pros and cons of the different taste-masking strategies? How do you decide on method selection?

 The taste-masking strategy depends on the combination of the dosage form and the API. Although adding sweeteners and suitable flavors might be sufficient for effervescent tablets, this approach may not work for dosage forms such as ODGs or extremely bitter-tasting APIs. With ODGs, the complete dose is taken at once and tasted thoroughly, unlike effervescent tablets that are first dissolved in water, resulting in a far lower concentration of API to be tasted in the mouth. Therefore, HMC is our method of choice for ODGs. HMC has an efficient batch throughput and eliminates the need for expensive and potentially toxic solvents typically required for other coating processes.

	When selecting a taste-masking method, it is important to consider not only the development process but also commercial production. The goal is to mask the taste of the API sufficiently and cost-effectively.

	The main current trend in taste masking is the move towards developing more efficient and economical coating processes that lead to higher quality products. HMC is a prime example of what many are hoping to achieve. This method allows manufacturers to develop coated products with optimized characteristics that avoid unwanted effects during storage, such as aging or polymorphic changes.

Before pros and cons of the methods are considered, the target product profile should be reviewed along with historical data to evaluate the different strategies against a probability of success. In addition to criteria for vision of the final dosage form presentation, the desired attributes should be considered and tailored to the specific drug and its properties. Commonly, performance attributes such as taste/palatability and bio-performance are first to be considered. However, physical, chemical, and in-use stability should not be ignored, nor should the manufacturing processes, which should be reproducible, scalable, and have a clear path to commercialization. For pediatric populations in particular, excipient safety needs move formulations to higher drug loading spaces. This formulation effort is a balance of minimizing the ratio of any given excipient relative to the active dose, without constraining the final dosage form with respect to uniformity or processability.

	Although some of the taste-masking strategies previously described may have the advantage of rapid development, they fundamentally may not be able to mask compounds that have a challenging taste profile. These compounds can be categorized by the dimensionless ratio of drug solubility to taste threshold concentration. For example, a compound having a solubility of 10 mg/mL would present different challenges if the taste threshold was 1 mg/mL (ratio of 10) versus 1 µg/mL (ratio of 10,000). For taste modification, gains are made by altering the threshold for perceived taste. In the case of complexation (for which cyclodextrins, their derivatives, and ion exchange resins are commonly used), the advantage comes from reducing the available drug below the intrinsic solubility as indicated by binding constants.

	For functional coatings, the drug release can be controlled with respect to time below the threshold concentration, and the resulting intermediate is adaptable-not only can the particles be used in an array of several dosage forms, they can also be used in conjunction with the masking strategies described above. The fundamental functionality and the versatility is the premise for our taste-masking approach for easy-to-swallow dosage forms. We use a development platform of functionally coated, small multiparticulates (0.1 to 0.4 mm in diameter) for palatable, taste-neutral drug forms that can accommodate flexible dosing options in a variety of dosage form presentations, including sprinkles, suspensions, sachets, and orally disintegrating tablets. This trend toward a platform for formulation and process development is driven by the need for a streamlined approach that produces a product that is representative of a commercial presentation and achieves patient compliance without iteration.

How do you evaluate a taste-masked formulation? For example, what tests do you carry out for taste assessment? And what are the quality-control parameters?

 It is important to ensure that a poor-tasting API has been efficiently taste masked and that this effect remains stable after production. At Hermes Pharma, we use modified dissolution testing across the formulation process, from early development through to routine production. Such continuous dissolution testing forms part of our quality control parameters so that consistent endpoints can be achieved throughout development.

	Our assessment of taste masking begins with an initial round of modified dissolution testing that is carried out over a period of one minute, because this is the time that an ODG would typically remain in the mouth. This first testing allows us to filter the number of prototypes down to just a few high-performance candidates. Then, when it comes to assessing the taste of products such as food supplements, we make use of a panel of internal formulation experts, capable of providing very informed feedback about taste and mouthfeel.

	It should be noted that taste is a highly subjective experience. Organoleptic survey data, for example, can be heavily influenced by age, gender, race, smoking preferences, and even mood. There are also ethical concerns to be aware of when assessing the taste of any medicine, because this type of study will require approval by an ethics committee. An alternative is the use of an electronic tongue, although this technology is limited by an inability to account for olfactory input.

Dissolution is the primary in-vitro test for the taste performance of formulations, with the goal of delaying the release of the drug for the time it takes to deliver the dose. The premise for our multiparticulate platform for taste masking is to provide multiple taste-neutral particles as the primary component of the final dosage form. These taste-neutral particles limit drug dissolution in the mouth below a taste threshold over the time course relevant to prepare, administer, and swallow the dose; typically ranging from a few minutes to 30 minutes depending on the dosing regimen.

	The primary quality-control parameters are the amount of active released over an appropriate time in a volume of media or vehicle relevant to preparation and administration and the amount of active released over an appropriate time in a media relevant to the mouth. The concentration limits for these metrics are set relative to taste threshold concentrations. Human sensory data are the best way to define threshold concentrations; this can be done directly using trained taste panels, or indirectly from recorded palatability experiences of the various dosage forms used during clinical development.

	As for the relevant time, it can be broken out into two scales, each of which entails different strategies for dissolution testing. The first is a combination of the preparation and administration times that are relevant for in-use stability testing, and the second is the range of residence times in the mouth that are relevant for sensory attributes. Dosage form type, label considerations, and patient age are some considerations that guide the initial time metrics. Anyone with children or an elderly grandparent will tell you those times can be long and inherently variable, even for healthy individuals.

	The next step is to build confidence in the 

 dissolution tests by gathering in-vivo sensory data from a human taste evaluation. Given the intrinsic variability in time to deliver a dose to a patient, study designs should consider looking at formulations with multiple release characteristics, as well as different time scales for a single formulation. A taste evaluation can be run separately, and/or run in combination with a pharmacokinetics study designed to answer an equally important question-what is the bioavailability of the new formulation? The data from these studies provide the feedback loop needed to optimize both the formulation and test methodologies required to ensure the quality of the new dosage form.

 When referring to this article, please cite it as A. Siew, "A Matter of Taste," 

Matt Shaffer, manager, formulation development, Bend Research, a division of Capsugel’s Dosage Form Solutions business, and Martin Koeberle, PhD, head of analytical development and stability testing, Hermes Pharma, spoke to Pharmaceutical Technology about the different approaches used in taste-masking and the challenges involved.

A Matter of Taste

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Pharmaceutical Technology APIs, Excipients, and Manufacturing Supplement

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APIs, Excipients, and Manufacturing Supplement

This special issue combines technical articles on leading pharma industry topics and a comprehensive preview of the upcoming CPhI Worldwide trade show

The PharmTech/CPhI Connection

	Advances in combinatorial chemistry and high-throughput screening have led to an increasing number of poorly soluble drugs in the development pipeline and the need to develop technologies that address solubility issues has never been more crucial. One approach that is becoming increasingly popular is the use of amorphous solid dispersions because of their broad applicability, observes Kevin O’Donnell, PhD, Associate Research Scientist at Dow Pharma & Food Solutions. Traditional methods rely on certain API properties to be successful, according to O’Donnell. “For example, salt formation requires the API to be ionizable and complexing agents such as cyclodextrins require the drug to fit within the complexing ring.”

	“For solid dispersions, it is a matter of rendering and maintaining the drug in the amorphous state and/or adequately dispersing it within a carrier matrix using one of many available technologies,” O’Donnell explains. “While drug-carrier incompatibilities may exist, requiring careful excipient selection, there is no distinct property required of the API for formulation into a solid dispersion.”

	“Solid dispersions can often provide a significant increase in solubility compared to other formulation approaches,” O’Donnell adds. “This advantage is largely due to the amorphous state of the API and to the hydrophilic nature of the surrounding matrix material that can aid in wetting once exposed to the aqueous biological media. Furthermore, solid dispersions allow for unique intellectual property to be obtained, thereby aiding in the lifecycle management of existing compounds and maximizing a drug’s economic potential.”

	O’Donnell notes that until recently, the number of methods available to a formulator to generate an amorphous solid dispersion was limited. “However, recent growth in the techniques capable of generating an amorphous solid dispersion-such as spray drying, hot melt extrusion (HME), precipitation methods, co-milling, KinetiSol dispersing, cryogenic methods, and others-has created processing flexibility, allowing almost any API to be formulated into a solid dispersion.”

	Spray drying and HME are currently the most commonly used methods to produce solid dispersions. “Spray drying is highly effective at generating the amorphous form of an API and can be used for APIs that have low degradation temperatures,” says William 'Trey' Porter III, PhD, Associate Research Scientist at Dow Pharma & Food Solutions. “Furthermore, with appropriate polymer and solvent selection, the resulting product will be homogeneous.” Porter adds that HME is also effective in converting a crystalline API into the amorphous form and has the advantage of being a continuous process with significant versatility in the final dosage form.

	An important consideration for solid dispersions is the pairing of the API to the optimal polymer for solubility enhancement, Porter points out. “This, combined with an in-depth understanding of the API physical properties, allows for selection of an appropriate technology for the generation of the amorphous solid dispersion. By letting the API and matched polymer guide the formulator to an optimal technology, rather than force-fitting a formulation to a technology, the likelihood of success increases.”

	Another primary challenge for solid dispersions is the stability of the amorphous drug, according to Porter. “Improperly formulated systems may recrystallize into more thermodynamically stable and less soluble forms, resulting in dramatic changes in the dissolution, absorption, and therapeutic effect of the API,” he explains. “The stability of crystalline formulations is also of great concern if a high energy polymorph is selected because polymorphic transformations can have similar negative effects.”

	A number of tools can be used to improve the likelihood of success of early formulations and for selection of an appropriate technology, says Porter. “A strong understanding of the API including the melting point, glass transition temperature, lipophilicity, and Tm/Tg ratio will provide insight into the propensity for recrystallization of an amorphous API as well as drug loading limitations in the final formulation. Additionally, the organic solubility and thermal decomposition temperatures are important factors in selecting a technology by which to produce the amorphous solid dispersion.”

	“At Dow, our primary screening tools for amorphous solid dispersion formulation include high throughput precipitation inhibition screening for polymer selection,” says Porter. “Furthermore, small-scale spray drying/HME and microcentrifuge dissolution testing are performed on leading candidates to ensure that the proper polymer structure has been selected for maximum dissolution performance and formulation stability.”

	One of the most significant advances in recent years is the introduction of small-scale spray drying and HME equipment capable of reducing API consumption and increasing technology availability for formulators, observes Porter. “However, despite significant advances such as the use of high throughput screening methods for polymer selection and formulation design, the number of available excipients and new excipients entering the market hinders formulation optimization,” says Porter. “With no definitive approval pathway for newly designed excipients, the ability to gain acceptance and broad use of an excipient is reliant upon its use in an approved product, thus creating lengthy timelines to market.”

Experts from Dow Pharma & Food Solutions discuss the versatility of solid dispersions in solubility enhancement and the importance of pairing the active pharmaceutical ingredient to the optimal polymer.

A Case for Solid Dispersions

	Advances in modern medicine have shifted the pharmaceutical market dynamics. As the industry moves towards targeted therapies, drug molecules are becoming more complex, requiring highly specialized manufacturing process.

	“Historically, you have had blockbuster drugs for a broad patient population,” says Andrew Bulpin, executive vice president of EMD Millipore’s Process Solutions Business. “But now, it’s the niche buster era, with smaller patient populations. Ultimately, we are heading towards stratified medicines as our understanding of disease mechanisms improves and we get more sensitive and sophisticated in testing for the different biomarkers,” explains Bulpin in an exclusive interview with 

	Innovation in manufacturing technologies continues to play a key role in ensuring that biopharmaceutical drug products are produced flexibly, economically, and, more importantly, in compliance with the required safety and quality standards.

	“The industry continues to evolve along two fronts,” observes Bulpin. “Let’s start in the upstream space.”

	“In cell culture, one always has to look at what you are putting into the media,” says Bulpin. “In the past, there were no qualms about putting in fractionated proteins or components of animal origins. Fetal bovine serum, for example, was commonly available.” However, following cases of mycoplasma contamination in the 1970s, endotoxin concerns in the 1980s, and bovine spongiform encephalopathy scares in the 1990s (1), the industry started paying closer attention to the origin of raw materials used in drug manufacturing processes and began moving away from media and reagents of animal origin. “While you may still see some legacy processes using animal serum, all the new ones are animal origin free,” Bulpin notes.

	“With the second-generation media, they took away the animal origin component, but they were still not defined,” says Bulpin. “Now you have the third-generation media, which are completely chemically defined and you have full traceability of all the components within the media. This is where most of the major manufacturers are heading, if they aren’t already there.”

	Bulpin stresses that in today’s cell culture processes, “it’s all about knowing what’s in the media chemically; it’s all about control; it’s all about traceability.”

	The other big focus in biopharmaceutical manufacturing is yield (g/L), adds Bulpin. “Yield is going to be a product of a specific productivity of an individual cell multiplied by the number of cell, i.e., the cell density,” he explains. “There is a lot of work being done on engineering new and different cell lines that have higher individual specificity-this is one area where people are focusing. Another area is looking at cell lines that are more robust and easier to grow in defined media.”

	The past decade has witnessed significant improvement in upstream processes such that yields produced are now significantly higher. “To give you an example, the first-generation biopharmaceutical drugs were expressed in an order of 200mg/L,” says Bulpin. “With the new expression platforms, the new drugs coming out can be up to 5g/L, which is a 25-fold increase of productivity or yield out of the bioreactor. Manufacturers can now obtain the same amount of antibodies using smaller-scale 1000-L single-use bioreactors, as was historically produced in 15,000-L stainless steel bioreactors. Single-use is, therefore, suitable for production applications today.”

	This increase in upstream efficiency, however, has brought new challenges to downstream purification steps. Because of higher cell densities coming out from the bioreactor, clarification can be a challenge, observes Bulpin. With most high-density processes, the clarification step will often involve centrifugation at some stage. “But for those who want to go purely to single use, and not invest in capital equipment such as centrifuges, one option is to use flocculation treatment,” says Bulpin. Incorporating feed pretreatment, flocculation, and different filtration technologies such as tangential flow filtration into the harvesting and clarification steps can help improve process capacities and filtrate quality (2).

	Moving further downstream, protein A chromatography is one of the more expensive processing steps, and “the notion of having it as single-use is still a bit far off,” according to Bulpin. “Current options will be continuous processing, where you have multiple column systems, and I think that will be an area for further exploration moving forward.”

	Another trend that bodes well with single use is the increasing number of multiproduct facilities. “Historically, you would have a production facility built for a single product,” notes Bulpin. “But with lower demands in the absolute quantities of antibodies because of the diversity of patient phenotypes coupled with higher yields, manufacturers are looking to have multiproduct facilities, and that is why we see an uptake in single use.”

	“There are also other factors that work in favor of single use,” Bulpin adds. “As companies start out on their drug development journey, they tend to want to keep hold of their molecule and take it as far as they possibly can. Because single use is far less capital intensive compared to stainless steel, it enables small companies and start ups to stay in control of their molecules at the early stages, before either investing in the full capital or taking their molecule to a third-party CMO to do larger-scale production.”

	Furthermore, in certain geographies, the local governmental policy requires that for a molecule to be sold in that market, the company must do some manufacturing activities in that country. “In the past, the dynamics of doing a big capital production that is going to cost 1 billion relative to the potential market size has put people off,” explains Bulpin. “But now you can do one of these modular approaches, where you put in a single-use facility, and really all you need is a shell of a building and utilities such as electricity and water.” According to Bulpin, EMD Millipore recently expanded its facility in South France, which is fully single use, due to high demand. The company converted the warehouse building into a new production unit. “From start to finish, the installation took four months,” says Bulpin, “to give you an idea of how quickly you can set it up with single-use.”

Andrew Bulpin, executive vice president of EMD Millipore’s Process Solutions Business, speaks to Pharmaceutical Technology about the trends shaping the biopharmaceutical manufacturing industry.