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

Adeline Siew, PhD

Developing fixed-dose combinations (FDCs) is one of the many reformulation strategies used in product lifecycle management. It has the potential to offer quicker commercial returns compared to developing a new chemical entity. For pharmaceutical companies seeking to maximize the value of their drug products, FDCs can provide a means of obtaining supplementary patent protection and differentiating against cheaper generic-drug formulations. These formulations have shown success in the treatment of cardiovascular diseases, diabetes, HIV/AIDS, tuberculosis, and malaria.


	“FDCs can be used either to combine different actives in one single dosage form or to achieve a precise release profile of a specific active-for example, by combining an immediate-release with an extended-release formulation,” explains Stefania Barzanti, marketing manager at IMA Active division. According to her, the success of FDCs is driven by two concurrent needs. “On one side, there is the need for welfare systems to contain healthcare costs; and on the other side, the need for pharmaceutical companies to optimize product lifecycle and exploit the potential of their existing product portfolio,” she says. FDCs are more cost-effective than individual drugs administered separately. They are known for their ability to reduce the pill burden. It is presumed that the simplification of therapy and its convenience lead to better overall patient compliance. The other main advantage of FDCs is the enhanced efficacy and lower incidence of side effects as a result of the synergistic combination of potentially lower doses of the different actives.

	Developing an FDC, however, requires careful assessment of the potential advantages against the possible disadvantages, such as the difficulty or inflexibility of dose titration. “It is true that the flexibility in dosing options is reduced with FDCs, and it becomes more difficult to have fine tuning of the medication prescription to the needs of a specific patient,” Barzanti notes. “That’s why careful evaluation of the pros and cons of developing an FDC should drive the choice between the different solutions on the basis of a patient-centric approach that considers lifestyle needs and the medical condition.”

	Drug developers are required to justify the pharmacological and medical rationale behind each FDC for the intended therapeutic indication. According to the European Medicines Agency, the rationale should consider the posology and dosing frequency of the different components included in the FDC (1).


	“In terms of formulation, the first challenge is to bring together the different pharmacokinetic and target-release profiles,” says Barzanti. “This task, of course, becomes more complex with a higher number of active drugs.” The actives in the FDC must be assessed for physical and chemical compatibility, along with their excipients, to ensure that the different components do not generate new impurities or raise unfavorable drug–drug interactions.

	“From the manufacturing point of view, however, one of the most common challenges is represented by the combination of two chemically incompatible actives that have to be kept separated but included into a single dosage form,” observes Barzanti. She explains that this issue is particularly crucial for layered tablets, where sometimes an intermediate placebo layer has to be created to avoid any interaction. “During tableting, constant checks and frequent replacement of the scraper blade are also important to avoid mixing of the different powders comprising the various layers.”

	Another particularly relevant issue is represented by the control of the dosage of each drug, according to Barzanti. “In a layered tablet, the single layers can be sampled and checked individually on a statistic base, but it is not possible to check them separately in the final complete unit dose,” she says. “During the past four to five years, we have seen a growing interest for hard gelatin capsules, specifically for FDC products. On a capsule filler, different ingredients can be easily combined inside the same capsule shell by simply adding a dosing unit. Besides powder, different product forms can also be dosed, including pellets and minitablets, small tablets or capsules, softgels or liquids, and semi-solids. There are technologies available for in-line check of each single unit produced by the machine.”

	In some cases, FDCs can result in higher manufacturing costs because a more complex dosage form is being produced. Barzanti points out that the total cost to develop an FDC should include the subsequent manufacturing phases up to the final packaging. “But in any case, the final cost reduction from the increased patient compliance and better use of medicines makes FDCs beneficial when considering the cost aspect from a global standpoint,” she says.

	“I see FDCs as one of many opportunities present on the market to innovate oral solid-dosage forms together with the growing interest for multiparticulate formulations and new drug-delivery solutions,” Barzanti continues. “The overall aim is to make better use of existing product portfolios through optimization of pharmacokinetics, improved bioavailability, and enhanced therapeutic effect, as well as minimization of side effects. FDCs can be especially useful to support long-term concurrent therapies in patients affected by chronic diseases that are related to each other. I believe the current aging population is a driver for growth for this type of oral solid-dosage form.”

Guideline on Clinical Development of Fixed Combination Medicinal Products 

When referring to this article, please cite it as A. Siew, “Fixed-Dose Combinations,” 

Articles

The advantages of fixed-dose combinations are well recognized but their formulation and manufacture can be a challenge, Stefania Barzanti from IMA Active explains why.

Fixed-Dose Combinations

	As medicine spending continues to increase, there is a lot of expectation and pressure on the pharmaceutical industry not just to develop new drugs but also to ensure the quality of their products. But challenges such as patent expiries and the death of blockbuster drugs in an increasingly cost-constrained marketplace mean that players both big and small have to adapt with the changing trends if they want to survive and thrive. 

Biotech boom, niche markets, and a smaller batch size

	One of the biggest trends is the move towards biotechnology and personalized medicine, notes Christian Treitel, head of pharma business development and product management at Bosch Packaging Technology. Small-molecule drugs that are chemically synthesized using predictable processes are being replaced by larger, more complex biologics that are produced in living cells and often consist of heterogeneous mixtures. The structure of a chemical API is independent of the manufacturing process but biologics, on the other hand, are defined by the exact manufacturing process, which can be difficult to control from the starting material to the final drug product.

	“While this shift opens up new possibilities in medical diagnosis and therapy, we see batch sizes becoming smaller, derived from the need to treat orphan diseases that affect only a small population of patients worldwide,” says Treitel. FDA has played a crucial role in facilitating the development of orphan drugs through its fast-track program. As a result, the industry is moving away from the one-size-fits-all model and investing more into the development of targeted therapies and finding cures for niche diseases. “The researchers embrace it,” says Treitel, “because there are many areas where you can tap on the potential of targeted therapies; however, for the manufacturers, the complexities of production can be a challenge.”

	Smaller lots mean more frequent changes, Treitel points out, and changeover takes time. “You have to clean your equipment,” he says, “and then, there is also the additional task of documentation because it is important to make sure that everything is properly documented.”

	According to Treitel, customers are now looking for solutions to manage the complexities of modern drug manufacturing, including fast changeovers. “The aim is to make changeover times shorter,” he says. “Basically, you want it to be faster and more convenient for the operators, which is very important.” The new Manesty TPR tablet presses-TPR 200 (for small to medium batches) and TPR 700 (for high production volumes)-from Bosch, for example, have been designed for fast product changeovers, easy cleaning, and simple operation. 

High potency drug manufacturing, isolators, and containment systems

	Another key trend is the rapid growth of high potency APIs, which require specialized containment to ensure that both operators and the environment are protected from exposure, observes Treitel. “You want to really make sure that the product is safe and that the operator is safe.”

	There has been major breakthrough in isolator and containment systems and pharmaceutical manufacturers recognize the advantages of these technologies (e.g., improved aseptic environments and lower operational costs) compared with conventional clean rooms. “Liquid filling lines are becoming more complex and require integration of the filling machine with an isolator and subsequent machines [such as a freeze dryer or an overseal capping machine],” says Treitel. The challenge is to ensure safe functioning of the interfaces, but at the same time, keep the overall controls system simple and be able to easily operate the individual components. Bosch offers everything from a single source, according Treitel.

	For an industry that is highly regulated, quality remains a top priority. “FDA is getting stricter and really checking on pharmaceutical facilities. You often hear of warning letters being issued,” says Treitel. “This means pharmaceutical manufacturers have to work on their quality procedures, and they are looking for support from us-for example, if you are looking to replace your equipment and want certain things to be automated so that manual intervention and human errors can be reduced.”

	The relationship between supplier and the pharmaceutical industry is changing, observes Treitel. “As a supplier, it is no longer about supplying single machines but helping the customer to integrate the different pieces of equipment and providing support in implementing projects.” 

The biotech boom, niche markets, smaller batch sizes, and high potency manufacturing are among the key trends shaping the pharmaceutical industry, and equipment must keep up with features such as fast changeovers and automation.

Pharma Equipment Keeps Up with Trends

Biotech boom, niche markets, smaller batch sizes and high potency manufacturing are among the key trends shaping the pharmaceutical industry of the 21st century, according to Christian Treitel from Bosch Packaging Technology.

Pharma Trends—From Biologics for Niche Patient Populations to Isolators and Containment for HPAPI Manufacturing

Tablets are coated for several reasons, such as to improve appearance; for taste- and odor-masking purposes; to protect the API from moisture, oxygen, or the gastric environment of the stomach (e.g., using acid-resistant enteric coating); to separate incompatible substances; and to control drug release, among others. As the industry continues to explore the advantages of switching from batch manufacturing to continuous processes, 

 spoke to Ali Rajabi-Siahboomi, chief scientific officer at Colorcon; Charlie Cunningham, senior manager, Product Development, Colorcon; Martin Hack, vice-president and general manager, L.B. Bohle; and Hubertus Rehbaum, manager, Scientific Operations, L.B. Bohle, to gain insight on the advances in coating technologies and the potential of continuous coating in the production of solid-dosage forms.

What are the steps involved in a typical tablet coating process? How do you control the different variables affecting the quality attributes of the coated tablets, such as uniformity and functionality of the coating?

The coating processes currently used in the pharmaceutical industry vary from simple taste- or color-masking up to highly complex multilayer functional coatings. But as tablets become more sophisticated therapeutic systems (e.g., with controlled release mechanisms or combined APIs), manufacturers must pay closer attention to the quality of the coating. To achieve the required high-quality standards, process parameters such as air flow, spray rate, spray gun position, and tablet bed movement must be taken into account. By using equipment with reliable hardware components and fine-tuned control loops, those critical process parameters can be kept in the design space, ensuring the targeted product quality. In addition to using laboratory analysis to monitor the process, Raman or near infrared (NIR) spectroscopy will also play an important part in ensuring the final product and process quality.

 In my view, all tablets should be coated, whether for trade-dress purposes or for the functional properties mentioned above. The tablet must have a robust formulation with good mechanical strength to withstand the handling, transport, and film-coating processes. Therefore, robust formulation and physical design of tablets are crucial for film-coating success. Tablets with good hardness, low friability, appropriate shape, and low propensity for moisture uptake are desirable.

	The film coating process is fairly complex but can be broken down into three primary control areas:

 The coating dispersion is delivered to the spray guns and atomized using compressed air into fine droplets for deposition to the tablet surfaces. The viscosity of the coating formulation, number of spray guns (depending on scale of coating pan), atomization, and air-pattern conditions all play a role in how smoothly and uniformly the coating will be applied to the tablet surface. The solids concentration of the dispersion influences coating process time, coating uniformity, and ultimately, the quality of the finished tablet surface.

The drying air parameters of temperature, humidity, and volume (air flow) must be carefully balanced with the spray rates for the liquid-dispersion coating application. As the coating dispersion is applied continuously, maintaining appropriate temperature and air volume versus the coating spray rate is important. The right balance will prevent coating defects related to over-wetting (tablet-to-tablet sticking), or over-dry conditions (spray-drying).

Tablets are typically coated in rotating, perforated drums, ranging in diameter from 10” at laboratory scale to more than 60” at production scale, with batch sizes from a few hundred grams up to several hundred kilograms. The speed of pan rotation governs how many passes an individual tablet will pass through the spray zone in a given coating cycle and has a great influence on coating uniformity. Appropriate design of baffles within the pan also facilitate tablet movement and mixing to influence coating uniformity.

 What about scaling up the coating process?

 When scaling up a coating process, the three unit operations of a film-coating process-which are mixing, spraying/film building, and drying, operated simultaneously within a coating pan during a film-coating process-must be understood. Important parameters are the drum rotation speed, the ratio of the air and liquid flows (as process air flow and coating solution spray rate), and the tablet bed temperature.

	When scaling up, normally, the tablet bed temperature or exhaust air temperature is kept constant. The reason is to have the same film building temperature of the polymer of the coating solution. The spray droplets spread on the tablet surface, and film building is generated with a certain temperature. Also, the ratio between mass flow of process air and mass flow of coating solution (spray rate) should be equal to have the same thermodynamic condition for the drying. The drum rotation speed should be scaled in a way that the tablet velocity-while tablets move through the spray zone-is almost the same in laboratory scale, pilot scale, and production scale. Other parameters such as atomizing air flow and pattern air flow and the distance of the spray nozzle tips to the tablet bed surface need to be adjusted properly for even spray performance in each scale.

	Geometrical similarity of the selected coating drum from laboratory to production size is useful too. Special spray nozzles (laboratory, pilot, or production coater) designed for different coater sizes (spray rates and droplet sizes) are recommended for successful scale up.

 Can you tell us more about the recent advances in coating technologies and their impact on continuous coating?

In the past, continuous coaters were most often employed for high-volume products with tablet throughput rates in the range of 500 kg to over 1000 kg per hour. The scale of equipment is now being modified to meet lower production capacity demands, ranging from 50 kg to 500 kg per hour. New mechanisms have also been developed to eliminate the start-up and shut-down product losses associated with earlier continuous coater equipment. Studies evaluating these improvements conducted in an O’Hara Fastcoat continuous coating system showed consistent color uniformity for all tablets from start-up through shut-down. Some machine manufacturers have developed novel approaches to coating in semi-continuous modes. In one example, the GEA ConsiGma coater is able to coat small, 3-kg sub-batches rapidly, with a high degree of accuracy. Using this method, each sub-batch is able to be tracked from the upstream continuous tableting process, and critical coating attributes can be monitored in real-time. Use of in-line, process analytical technology (PAT)-based Raman analytics during coating ensures product quality of each sub-batch.

	Film-coating formulation technology is also advancing with the use of lower-viscosity polymers that provide significantly improved process efficiency compared with more traditional hypromellose-based coating systems. A benefit of low-viscosity coating formulations is the ability for application of the coating dispersion at significantly higher solids concentration compared to traditional coatings, resulting in considerably shorter process times.

For the coating process, two different approaches are currently being applied. Some vendors have presented truly continuous coaters, for which a continuous product flow into the long coating drum and a continuous product flow out of the drum is characteristic. R&D at L.B. Bohle, however, has shown that at this point, a truly continuous coating process does not meet the requirements for functional coatings. For tablet coating, the time that each tablet is exposed to the process directly affects the quality of the coating. Therefore, a narrow residence time distribution, ideally a spike, is the key to achieving an outstanding coating uniformity. As the travel time of all tablet cores through a truly continuous coater cannot be controlled sufficiently using inserts or other guiding elements inside the drum, L.B. Bohle has decided to follow the concept of a fast-batch coating design with our KOCO machine family. In this approach, by optimizing the charging and discharging as well as the coating process in terms of spray rate, air flow, and tablet-bed formation, we are able to achieve a high throughput at constant, spike-shaped residence time distributions.

	There is another reason to decouple the coating process from the upstream continuous manufacturing of the tablet core, which is the tablet core relaxation time. For the majority of products, the core needs to be given a sufficient time to expand after the compression process. Feeding the tablet cores from the de-duster directly into a truly continuous coater does not allow the cores to expand before applying the film coat. This implies that the expansion of the tablet core will continue with the film coat in place, leading to cracks in the coating layer. For functional coating, such defects are unacceptable. As a result, the tablet core expansion step, which interrupts the continuous product stream of a continuous production line between the tablet press and the coater, makes the advantage of a truly continuous coater to keep the product stream continuous obsolete.

How does continuous coating compare with the traditional batch coating?

Compared to batch coaters, the commercially available continuous coating machines have pan diameters that are half, or less, than the diameter of manufacturing-scale batch coaters; but the length of the pan can be as long as 15 feet. However, the resultant tablet-bed depth, which is low, is more consistent with laboratory or pilot-scale batch coating pans; this shallower bed depth ensures greater frequency of tablet presentation to the spray zone.

	In recent work, Colorcon studied the effect of tablet residence time and uniformity of tablet progression and coating variability in a Thomas Engineering Flex CTC continuous coater. We were able to conclude that individual tablets progressed uniformly through the continuous process at production rates of up to 850 kg per hour with relatively small variability in transit times and superior coating weight and color uniformity compared to the traditional batch coater process.

	In another study conducted in a Driam Driaconti-T continuous cycled coater, we evaluated the performance of a novel film-coating formulation developed by Colorcon capable of application at solids concentrations up to 35% w/w solids. Although this coater employs elongated rotating drum technology, the drum is divided into individual coating segments, giving it the advantages of small-scale batch production. In this coater, with production rates of 110–180 kg/hour, we also found that coating uniformity was significantly improved over batch coaters.

	The common theme around all currently available continuous and semi-continuous coater technology is a significantly reduced coating cycle time and reduced exposure of the tablets to the coating environment.

 At this point, we do not see advantages in truly continuous coating, as indicated previously. However, based on experience with our KOCO machine family, we can achieve shorter cycle times and higher throughput, while maintaining the coating uniformity.

What aspects of continuous coating still need to be addressed by the industry?

 With continued innovation in equipment design, some of the past limitations in throughput rate are being addressed. Equipment is now available to meet a wide range of production capacity demands. Although current film-coating formulation technology provides satisfactory results in these machines, new, low-viscosity coating formulations are being developed to maximize coating efficiency. Linking continuous coating processes to newly evolving continuous tablet manufacturing lines is underway, and continued technology development is needed for ‘real-time’ PAT monitoring of coated tablet quality attributes to ensure seamless quality from start to finish in continuous tablet manufacture. Although there may not be an issue with the regulators, another aspect to be considered is the definition of a batch while manufacturing using continuous processing. A batch can be defined on a time or material lot basis, depending on specific product manufacturing flows. These may be related to a mindset change for manufacturers as well as the need for clarification from the regulators.

Currently, truly continuous coating from our perspective is limited to simple taste masking or color coatings, as long as the tablet core is not required to expand or the film coating has highly elastic properties. One of the limitations is because of the wide residence time distribution, which results in poor coating uniformity. To be able to overcome this limitation, new ways to control the flow of all (100%) tablet cores are needed. Some vendors have suggested solutions with compartments and mechanical barriers or inserts to guide the tablet bed flow. Unfortunately, from our experience, none of these measures can ensure a spike-shaped residence time distribution. The efforts to overcome this limitation only provide benefits if the coating process can be an integral part of the continuous material flow. If the expansion behavior of the tablet cores forestalls the seamless transfer of the core from tablet press/de-duster to the coating process, there is no benefit in using truly continuous coaters.

 When referring to this article, please cite it as A. Siew, “Exploring the Potential of Continuous Coating,”

Industry experts share insights on the advances in tablet coating technologies and the potential of continuous coating in solid-dosage manufacturing.

Exploring the Potential of Continuous Coating

	Antibody-drug conjugates (ADCs) have revolutionized the field of cancer treatment by enhancing the selectivity of traditional chemotherapeutic agents while limiting systemic exposure. “ADCs synergistically combine a specific anticancer antibody or antibody fragment linked to a cytotoxic drug,” explains Dave Simpson, PhD, CEO of biotech company Glythera. “The aim is to achieve better tumour penetration and killing properties with lower side effects for cancer patients.”

	Despite the rapidly growing clinical pipeline of these targeted therapies, developing an ADC is no easy task. The challenge of optimal ADC design lies in the overall complexity of these molecules and the increasingly clear requirement to optimize each aspect relative to any given antibody–toxin pair and its target, according to Jennifer L. Mitcham, PhD, SMARTag Business Development, Catalent Biologics. “Conceptually, combining the targeting power of a monoclonal antibody (mAb) with the potency of a cytotoxic molecule should produce a drug with high efficacy relative to its toxicity (known as the therapeutic index),” she says. “However, there are significant hurdles to overcome when developing effective and safe ADCs. The first ADC was generated more than 30 years ago, yet today, there are only two FDA-approved ADCs on the market.”

	There are a number of parameters that must be taken into account when designing an ADC, observes Albert Garofalo, PhD, group leader, Chemistry, Catalent Biologics. “The antibody is set based on the target antigen, and the payload might be set based on intellectual property considerations or the desired mechanism of action. This leaves the linker as the one area of the ADC that can be chemically manipulated to affect physicochemical properties such as solubility, protein aggregation, therapeutic index, and efficacy,” he remarks. 

	To begin, the choice of target for the antibody is a key consideration, notes Cynthia Wooge, PhD, Global Strategic Marketing at SAFC. “The chosen cell-surface antigen should be over-expressed in the tumour cell and relatively non-expressed in normal tissue,” she highlights. This is because the tolerability of an ADC is affected by the specificity of antigen expression in cancerous tissue versus normal tissue, Simpson adds. “Non-specific expression results in toxicity and reduced efficacy due to a reduction in the dose of conjugate available to the tumour,” he explains. “Therefore, the ideal tumour antigen must be specifically localized to the tumour cell surface to allow ADC binding and, preferably, display differential expression between tumour and normal tissue, with increased expression in cancer cells.”

	Ian Evetts, PhD, commercial director of Glythera, points out that antigen choice is also dictated by its ability to internalize upon ADC binding. “Internalization of an ADC occurs through receptor-mediated endocytosis, followed by ADC degradation in the lysosome, which leads to free drug release for effective cell killing,” he says. “However, endocytosis is not guaranteed for all cell-surface antigens, and the rate of internalization can vary considerably. Optimal drug release into the cell requires minimal recycling of the ADC to the cell surface as well as enhanced delivery of an internalized antigen/ADC to the lysosome. The ideal tumour antigen then should be cell-surface expressed, highly upregulated in cancer tissue, internalized upon ADC binding, and able to release the cytotoxic agent inside the cell.”

	“As the cytotoxic payloads need to be internalized, the conjugated antibody should be amenable to this [prerequisite], as well as exhibiting any other effector functions desired,” Wooge reiterates. “The payload needs to deliver the desired cytotoxic effect once released within the cell, [which means that] the linker needs to have the necessary stability to maintain the payload until delivered to the target cell,” she asserts.

	Once the target antigen has been identified, it is important to select a suitable antibody. Antibody selection plays a crucial part in the successful development of an ADC, observes Evetts. “Among the key attributes, high specificity for the tumour antigen is essential because an antibody that binds non-specifically or cross-reacts with other antigens can be taken up in normal tissues, thereby, inducing toxicity as well as elimination of the ADC before it can reach the tumour.” He adds that efficiency of uptake requires high-affinity binding to the target antigen (Kd < 10 nM). “Antibodies should also be minimally immunogenic,” Evetts highlights. “And ideally, antibodies should possess optimal pharmacokinetic properties including relatively long half-lives and slower clearance in the plasma.”

	Currently, the drugs being used to construct ADCs generally fall into two categories: the microtubule inhibitors and the DNA-damaging agents, says Simpson, although he notes that other drugs such as polymerase II inhibitors are also being investigated. “Microtubule inhibitors bind tubulin, destabilize microtubules, and cause G2/M phase cell-cycle arrest,” Simpson explains. “DNA-damaging agents include anthracyclines, calicheamicins, duocarmycins, and pyrrolobenzodiazepines (PBDs). These drugs function by binding the minor groove of DNA and causing DNA stand scission, alkylation, or cross-linking. The cytotoxins are highly potent, with free drug IC50 of <10-9 M.” He cautions that drugs associated with neurotoxicity (such as platinum-based therapies or vinca alkaloids and first-generation taxanes) should be avoided.

	A key consideration, according to Simpson, is that the drug selected for construction of an ADC must contain a suitable functional group for conjugation and be stable under physiological condition. “It is important that therapeutically appropriate amounts of the cytotoxic are linked to the mAb to optimize the potential effectiveness of the ADC once it reaches the target cancer cell,” he stresses. “The cytotoxic should also be chemically tractable and stable while bound to the mAb.” Simpson lists the following criteria as attributes of an ideal cytotoxic drug: 

		Sensitivity of the cancer type to the class of the cytotoxic (e.g., antitubulin agents are frequently used in breast cancer)

		Ability to induce cell death-high toxicity.

	A crucial part in ADC development is choosing the right linker and method of attachment. The linker connects the small-molecule API to the large-molecule antibody that is engineered to bind to the target antigens on specific cell types.

	To be effective, the ADC must remain stable in the bloodstream until it reaches the target cell, whereupon following internalization, the cytotoxic payload is delivered. Any premature drug release will be detrimental to normal cells. The first-generation ADCs had limitations because the early linkers used were either too stable, resulting in low potency and reduced efficacy, or suffered instability while in circulation, causing poor targeting and high systemic toxicity similar to that of an unconjugated chemotherapeutic.

	“Ultimately, the main role of linkers is to ensure specific release of free drug in the cancer cells,” Simpson adds. “Linker properties are, therefore, crucial for controlling the toxicity of the highly potent drugs used to construct ADCs.” The linker can influence the distribution and pharmacokinetics of an ADC, and hence, its safety and efficacy, Wooge explains. “Depending on the preferred site of attachment on the antibody, linkers utilizing different functional groups or chemistries can be employed.”

	The selection of suitable linkers, however, remains a key challenge in ADC design and manufacture, according to Garofalo. “The long circulating half-life of an ADC demands linkers that have high plasma stability in order to minimize off-target effects,” Mitcham says. “Yet, balancing the need for plasma stability with the need for selective intracellular drug release can be quite challenging.” 

	There are two types of linkers used in ADC development-cleavable and non-cleavable. “As the cytotoxic payload is delivered into the cell, it can either be freed by digestion of the whole antibody, or it can be released by selective cleavage of the linker,” notes Vivek Sharma, CEO, Pharma Solutions, Piramal Enterprises. “You can tailor the drug release inside the target cell through design of the linker.”

	The majority of ADCs in the clinic use cleavable linkers, observes Evetts, in particular, the protease-cleavable valine-citrulline dipeptide linker, originally designed to balance high plasma stability with intracellular protease cleavage. “Protease-sensitive linkers take advantage of the high levels of protease activity inside the lysosomes and include a peptide sequence that is recognized and cleaved by these proteases,” he explains. “Acid-sensitive linkers exploit the low pH within the lysosomal compartment to trigger hydrolysis of an acid-labile group within the linker, such as a hydrazone, to release the drug payload,” Evetts continues, but points out that ADCs using these linkers have yet to deliver successful clinical profiles due to instability-associated toxicity or lack of clinical efficacy. “Glutathione sensitive linkers (e.g., disulfides) utilize the higher concentration of thiols inside the cell relative to the bloodstream,” says Evetts. “Disulfide bonds within the linker are relatively stable while in circulation but are reduced by intracellular glutathione to release the free drug.”

	Cleavable linkers release the free drug in a state that is more likely to permeate from the cell and kill surrounding cells-the by-stander killing effect, observes Mark Wright, site lead at Piramal Healthcare UK. “This comes down to the design of the conjugate,” he adds. “Should a conjugate be required to kill not only the highest expressing cells in the tumour, but also the surrounding ones, a cleavable linker is preferred.”

	The downside is that with cleavable linkers, there is a higher chance of the payload being released into the circulation and causing off-target toxicity, Sharma asserts. “However, larger molecules with a significant charge can limit this off-target toxicity, as the drug is unable to cross through cell membranes and damage other cells,” he says.

	On the other hand, non-cleavable linkers (e.g., thioethers) are more stable in the blood than cleavable linkers, according to Simpson, but they are wholly dependent on internalization, lysosomal delivery, and ADC degradation to release drug payload. “They cannot kill neighbouring tumour cells through the by-stander effect,” he says.

	“Non-cleavable linkers release the drug with the linker still attached to the amino acid,” explains Wright. “These kind of linkers tend to generate active payloads that are charged and can’t escape from the cell easily.”

	“With this approach, the target cell is killed, but nothing leaks out into the general circulation,” adds Sharma. “This approach delivers more tolerable conjugates, which work well with tumours that have very homogenous expression of antigen (although this is not always the case due to different cell classes making up tumours).”

	Currently, there are two marketed ADCs-Roche’s Kadcyla, which is manufactured by Lonza, and Adcetris, jointly developed by Seattle Genetics and Takeda and produced by Piramal. Each of these ADCs use different linker systems, Mitcham and Garofalo remark. “Ado-trastuzumab emtansine (Kadcyla) consists of a maytansinoid payload randomly conjugated to the trastuzumab antibody using a 4-(N-maleimidomethyl)cyclohexanecarboxylic acid N-hydroxysuccinimate (SMCC) linker,” says Mitcham. “This linker is considered to be a non-cleavable linker and as such, once the ADC is internalized within the target cancer cell, the antibody is degraded by proteolysis, leaving the maytansinoid payload still attached to a lysine residue via the SMCC linker. In this case, the payload remains effective because it can still bind to its intracellular target and induce cell death.”

	Brentuximab vedotin (Adcetris) is the other marketed ADC, as Garofalo highlights. “It consists of an auristatin payload randomly conjugated to an anti-CD30 antibody using an enzymatically-cleavable dipeptide linker. This linker is proteolytically degraded in the cell and releases the payload as an unmodified drug. In this case, the cleavable linker was selected because chemical modification of the toxin interferes with its ability to bind its intracellular target.”

	“Adcetris uses partial reduction chemistry, which has proven to be robust and generates consistent products. From a manufacturing perspective, this chemistry remains a good option for simple, trouble-free manufacturing of ADCs,” says Wright. “Partial reduction conjugation may have some drawbacks therapeutically in terms of stability and off target toxicity, but we expect to see more advanced conjugation technologies in future.”

	There are some interesting developments in the newer generation of linkers, according to Sharma, such as the ability to incorporate more payloads, enabling a linker to hold more than one payload, and combining multiple effects from a particular payload. A lot of work is being done on developing the linker itself, observes Wright, adding that the linker choice can have a dramatic effect on the amount of payload that can be loaded onto the antibody. “There is some really interesting new science coming through where changes in the linker can make the payload significantly more effective in terms of killing the target cells, for example, by overcoming multidrug resistance or through enhanced killing of lower antigen-expressing cancer cells,” Sharma and Wright highlight. 

	While linkers are generally selected based on the preferred method of drug release from the antibody, Simpson points out that the attachment chemistry used to link both drug and antibody will determine the overall stability and clinical performance of the ADC.

	Attachment to the polypeptide of the antibody is carried out via reaction with amino acids-cysteine being the most common, followed by lysine. According to Simpson, most approaches use maleimide chemistry, whereby maleimide selectively attaches to exposed or engineered cysteines via a covalent Michael addition. “However, maleimide is inherently associated with (i) deconjugation in physiological conditions via the reverse-Michael reaction, resulting in free drug in circulation and (ii) hydrolysis of the succinimide ring,” he explains, stressing that these factors hamper conjugate stability, ADC stability, and consequently, the therapeutic activity.

	Simpson notes that several groups have focused on enhancing ADC stability through stabilizing conjugation although most have concentrated on next-generation maleimide chemistry approaches. Methods include (i) controlling the microenvironment around the succinimide ether to slow down the retro-Michael reaction and (ii) shifting the equilibrium through hydrolysis and developing more stable ring-opened thioethers.

	“Through controlling microenvironment around the succinimide thioether, stability of maleimide conjugation can be improved since solvent accessible sites slow down retro-Michael. If cysteine is close to positively charged entities, rapid succinimide hydrolysis occurs, preventing further linker-maleimide exchange,” Simpson continues. “Also, modifying maleimide with the insertion of an amine group can shift the reaction through hydrolysis.” Nonetheless, although improved conjugation stability has been demonstrated, Simpson highlights that these approaches have not yet led to better clinical profiles, at least for cleavable linker systems. “Moreover, the processes required are not amenable to large-scale conjugation.”

	Simpson believes that non-maleimide approaches may, therefore, offer a better option for delivering stable conjugation of drug to antibody. Highly stable constructs allow the incorporation of even more potent payloads. According to Simpson, Glythera’s vinyl-pyrridine-based chemistry platform, PermaLink, is associated with more stable ADCs compared with maleimide equivalents, with the potential for delivering superior, better tolerated next-wave options.

	Mitcham and Garofalo from Catalent emphasize that the chemistry employed for conjugation must be compatible with conditions suitable for handling antibodies. “The reaction must proceed in an aqueous environment and must demonstrate chemical selectivity in the context of complex biomolecules that present a number of functional groups,” they say. “For this reason, there are relatively few reaction types that can be used for chemical ligation and even fewer that afford the potential for site-specific placement of the payload and the formation of a stable carbon–carbon bond. The Hydrazino-iso-Pictet-Spengler (HIPS) conjugation chemistry, developed by Catalent and used in conjunction with Catalent’s SMARTag technology, delivers on both of those needs.”

	Recently, there has been an expanded use of a variety of linking technologies that improve the bioavailability and/or stability of the conjugate, according to Wooge. “This is reflected in technologies such as Mersana with its Fleximer backbone, which uses a polymer as a drug carrier,” she says. “Alternatively, there are multiple approaches that synthetically build the linker into the potent payload such as with the first-generation auristatin-peptide drug-linkers of Seattle Genetics and newer ones such as the Polytherics ThioBridge linker.” Wooge notes that Immunogen has remained on the forefront of linker technology, with active development of molecules with differing charges and spacers to allow the optimal match between the linker, payload, and antibody.

	There is a growing body of evidence that a structure–activity relationship approach is required for optimal ADC design, observes Garofalo. “Catalent’s SMARTag technology is one of the newer technologies that allows for a structure–activity relationship study approach to building and testing each design component of the ADC,” Mitcham adds. “These components include programmable toxin placement, controlled drug-to-antibody ratio, stable conjugation chemistry, and novel linker technologies as applied to any given mAb–toxin pair.”

	Given that different ADCs have different characteristics, it is necessary to evaluate the optimal mAb-linker-cytotoxic combination for each cancer type and target antigen under investigation, Simpson reminds. Successful ADC development clearly depends on the optimization and combination of all components-antibodies, payloads, linkers, and the attachment chemistries. 

 When referring to this article, please cite it as A Siew, “Building Safe and Effective Antibody-Drug Conjugates,” 

The development of successful ADCs involves careful selection of drug, antibody, and linker, as well as choosing the right attachment chemistry to link the cytotoxic to the antibody.

Building Safe and Effective Antibody-Drug Conjugates

Reformulation of existing drug products is often seen as the cornerstone of lifecycle management strategies in an increasingly cost-constrained environment. While pharma’s R&D productivity appears to be showing signs of recovery (1), developing a new, innovative molecule is not only a lengthy and expensive process, but the risk of failure is also high. On the other hand, new formulations exploiting advanced drug-delivery technologies-whether aimed at reducing dosing frequency, improving patient experience, or using alternative routes of administration-have the potential to deliver quicker returns on investments.
	
	“Pharmaceutical companies are increasingly reformulating existing compounds, often using the FDA’s NDA [new drug application] 505(b)(2) pathway (2), which is generally faster and more cost effective than bringing new compounds to market,” says James Coward, global head of market development, Capsugel Dosage Form Solutions. “The pathway can provide patent extension for existing compounds that secures continued market exclusivities for several additional years. 505(b)2 product development often targets enhanced bioavailability and/or optimized drug delivery profiles-which can result in reduced pill burden-as well as new indications or specialized formulations for pediatrics.”  

	There are many different approaches to reformulation, depending on the strategic imperative, observes Jon Sutch, PhD, manager of formulation development at Patheon’s Milton Park facility in the United Kingdom. “If the strategy is marketing-driven, a line extension such as a new presentation, for example, changing a capsule to a tablet or reformulating as a softgel, may be used to differentiate it from the original product,” says Sutch. “There may also be a clinical requirement to improve compliance, in which case, an enteric-release or other controlled-release formulation may be developed, or a fixed-dose combination (FDC) may be used to improve therapy in a particular area. Additionally, extensions to the original indication or patient group might lead to reformulation such as solutions, suspensions, or mini-tablets for pediatric or geriatric use as well.”

	According to Sutch, a new presentation must be based on a combination of the target product profile (TPP) and the characteristics of the API. “The TPP, which is driven by the marketing and clinical considerations for the new presentation, must direct the pharmaceutics team in terms of the specifications required-whether it is the dissolution rate for a controlled-release formulation or the dosage levels for FDCs, for example,” he explains. “For more marketing-led line extensions, presentation aspects may also be included to meet the needs of the target population, while the characteristics of the API are important in defining what is practical.”

	Sutch cites ibuprofen as a classic example of how reformulation has been used to extend product lines. “Ibuprofen is a non-steroidal anti-inflammatory drug and, therefore, has applications in many areas of medicine. From the original ibuprofen tablet came a controlled-release version for chronic pain and gastric side-effects prevention. Today, however, ibuprofen can be found in many presentations used in different markets or disease areas,” says Sutch. “For example, the softgel presentation of ibuprofen claims to have a faster onset because its active ingredient is dissolved in the softgel matrix--presenting a potential advantage for acute pain. Other ibuprofen presentations include pediatric suspensions, fast-melt tablets, topical gels, and combination products with analgesics or decongestants. Formulations or presentations and packaging that target specific disease areas (such as menstrual pain or headaches) are also available for this drug, each having a marketable advantage for its particular market or disease area.” 

Reducing dosing frequency with extended-release formulations


	Extended-release drug products, whether they are oral dosage forms or injectable depots, are often developed as part of a pharmaceutical company’s reformulation strategy to differentiate its brand from generic competition and thereby extend market exclusivity.  Although more challenging to formulate, extended-release drug products provide added value and well-recognized advantages such as improved pharmacokinetic profiles, prolonged duration of therapeutic effect, lower incidence of adverse reactions (due to the maintenance of drug concentration within a desired range without exposing the patient to potentially toxic drug levels), and better patient compliance as a result of reduced dosing frequency, especially in cases of chronic diseases where complex drug regimens are involved (3).

	Pfizer, for example, has reformulated its twice-daily, immediate-release 5-mg tablet (tofacitinib citrate, Xeljanz) for rheumatoid arthritis into a once-daily, modified-release formulation. It was announced in July 2015 that FDA has accepted for review Pfizer’s NDA for Xeljanz 11-mg once-daily, modified-release tablet (4).  The NDA was based on data from a clinical pharmacology program that demonstrated pharmacokinetic equivalence in key parameters with Xeljanz 5 mg twice daily.  

	The bisphosphonate ibandronate, marketed as Boniva, was initially approved as a once-daily tablet for the treatment and prevention of osteoporosis in postmenopausal women (5). Roche, in collaboration with GlaxoSmithKline, further reformulated the oral bisphosphonate into a once-monthly formulation. FDA’s approval of the improved formulation made Boniva the first-ever oral treatment to be administered on a monthly basis for any chronic disease (6).

	Oral bisphosphonates, however, have to be taken according to a strict treatment regime, which involves remaining in the upright position and not eating, drinking (except water), or taking other medications for a period of time before and after administration of the drug. As such, oral bisphosphonates may not be suitable for some women, either due to other medical conditions or because the patient is unable to stay upright for the required length of time. To meet this need, Roche and GlaxoSmithKline developed a quarterly intravenous injection of ibandronate (7). Boniva injection comes in a prefilled syringe, which is administered as a 15- to 30-second injection by a healthcare professional once every three months.

Reducing the pill burden with fixed-dose combinations


	Reformulating and combining drugs that have been proven to be safe and effective into FDCs is another popular lifecycle-management strategy for pharmaceutical companies seeking to maximize the value of their products. FDCs can be used either to combine different actives into one, single-dosage form, or to achieve a precise release profile of a specific active (e.g., combining an immediate-release with an extended-release formulation).

	One of the advantages of FDCs is the enhanced efficacy through the synergistic effect of potentially lower doses (8, 9). “In addition to delivering increased therapeutic benefit, FDCs reduce the pill burden and can thereby increase overall patient compliance,” says Coward.

		antihypertensive combinations to provide better blood pressure control-Prestalia (ACE inhibitor perindopril + calcium channel blocker amlodipine); Avelide (angiotensin II receptor antagonists irbesartan + diuretic hydrochlorthiazide)

		antidiabetic combinations for more effective glycemic control-Glucovance (glibenclamide + metformin); Actoplus Met (pioglitazone + metformin)

		antiretroviral combinations for the treatment of HIV/AIDS-Prezcobix (darunavir + cobicistat); Atripla (efavirenz + emtricitabine + tenofovir disoproxil fumarate)

		antitubercular combinations-Voractiv (rifampicin + isoniazid + pyrazinamide + ethambutol)

		antimalarial combinations-Coartem (artemether and lumefantrine) 

		topical combination therapy for acne-Onexton gel (clindamycin + benzoyl peroxide).

Improving patient experience with user-friendly dosage forms


	The increasing focus on patient-centricity is driving the shift towards the development of more user-friendly dosage forms. Martin Koeberle, PhD, senior manager of Analytical Development at Hermes Pharma, defines such formulations as dosage forms that provide a more positive experience compared to traditional tablets and capsules. “User-friendly dosage forms also overcome the widespread problems associated with swallowing traditional solid oral dosage forms,” he highlights. 

	Findings from a 2014 survey revealed that more than 55% of people from all age groups and genders experience swallowing difficulties when taking their pills (10). Various reasons were cited by survey respondents, but the most frequent ones were related to the tablets or capsules being too large, getting stuck in the throat, or having an unpleasant taste or odor.

	Swallowing difficulties are known to have a negative impact on patient compliance. “By offering an active ingredient solely as a tablet or capsule, pharmaceutical and life-sciences companies ignore the needs of more than 50% of their target audience,” said Thomas Hein, PhD, senior vice-president, Commercial and Regulatory Affairs, Hermes Pharma, in a press release (10). “Given the weaknesses exhibited by conventional tablets and capsules, there is a significant opportunity to capture market share by formulating user-friendly dosage forms.”

	Reformulating large tablets, such as paracetamol into effervescent tablets or aspirin into orally disintegrating granules (ODGs), avoids swallowing difficulties and provides a faster onset of action due to the dissolved API, according to Koeberle. “There is also the option to include additional APIs (e.g., caffeine or phenylephrine) due to the removal of tablet-size restrictions,” he adds.

	Lately, there has been a lot of interest in orally disintegrating tablets (ODTs) and ODGs as a solution to the widespread problem of swallowing difficulties. With ODGs, patients pour the granules into their mouths, where they dissolve without the need for water, says Koeberle.

	“ODTs are primarily defined by their performance characteristic of rapid oral disintegration in saliva with no need for chewing or drinking water,” explains Robert Smith, Zydis global R&D director at Catalent. Catalent’s Zydis ODT fast-dissolve formulation is a freeze-dried product that disperses almost instantly in the mouth, usually in about three seconds, according to Smith, and no water is required. Another key feature of the Zydis technology is the ability to formulate peptides, allergens, and vaccines into fast-dissolve ODTs. “Benefits include low-temperature processing, which minimizes manufacturing losses of labile drugs; solution or suspension dosing, which achieves good content uniformity for low-dose actives; the solid dosage form and low water activity, which aid long-term stability; liquid processing, which facilitates containment of potent drugs in production; and the potential for sublingual or buccal absorption,” Smith adds.

	Capsugel has designed its Coni-Snap Sprinkle capsules to address swallowing difficulties, particularly prevalent in pediatric and geriatric patients. “Our sprinkle capsules feature an innovative closure that makes it easier and safer for patients and/or their caregivers to open the capsule and administer the medication by sprinkling the contents-typically powders, pellets, or granules-onto soft food for oral consumption,” explains Coward.

	“We tested sprinkle capsules with older consumers and caregivers of young children to gauge usability, ease of opening, and user accuracy when sprinkling capsule contents,” he says. “Eighty-one percent of participants described the new design as ‘easy’ or ‘very easy’ to open. The convenience of sprinkle capsules may encourage those with swallowing difficulties to more easily comply with taking their medicine as prescribed. It’s also an easier alternative to using reconstitutable powders administered via sachet/stick-packs or bottles.”  

Using alternative routes of administration


	Reformulation strategies can also include using alternative routes of administration. AstraZeneca’s nasal spray formulation of zolmitriptan (Zomig) for the acute treatment of migraine is one example. It was developed in addition to zolmitriptan tablets and ODTs as a lifecycle management strategy to expand AstraZeneca’s Zomig product line. The nasal spray provides rapid onset of action for migraine sufferers and is a convenient, alternative, non-oral formulation for patients who experience nausea or vomiting in conjunction with their migraine attacks (11). 

	Another alternative to the oral route is transdermal drug delivery, which offers a number of advantages such as the avoidance of first metabolism and gastrointestinal toxicity. It allows the administration of drugs with narrow therapeutic windows, can prolong the activity of drugs with short half-lives, and eliminates the need for hypodermic injections (12).

	“Patient preference is becoming increasingly important,” Simmon Schaefer, director of business development, 3M Drug Delivery Systems, told 

 “and transdermal patches are a great alternative for those who struggle with swallowing pills and want a more comfortable alternative to injections.” Another advantage is that, in the event of adverse reactions or other problems, patients can terminate the therapy rapidly at any point, simply by removing the patch (12).

	The pharmaceutical landscape is becoming more competitive, driving the demand for new drug delivery devices, observes Mark Tomai, head of TLR and MTS Business Development, 3M Drug Delivery Systems. “In general, patient-friendly delivery systems, such as microneedles or passive transdermal patches, are attractive options when considering reformulation as a lifecycle management strategy,” he says. “For instance, reformulating an oral drug into a transdermal patch may be ideally suited for caregiver-intensive conditions. Elderly patients often have difficulty swallowing (dysphagia) or remembering to take their medications. That’s where reformulation into a transdermal system may help, providing a potential to increase compliance, and ultimately treatment outcome.”

	According to Tomai, the 3M Hollow Microstructured Transdermal System offers a number of unique benefits that could be advantageous for lifecycle management strategy, including reproducible intradermal delivery, a proven ability to deliver formulations up to 2 mL with various viscosities, and API-dependent pharmacokinetic profile benefits. “Its patient-friendly features and the ability for patients to self-administer opens new opportunities to move treatments out of the clinic and into the patient’s own home,” he adds.

	The process of developing a transdermal patch is not straightforward, “which is why companies turn to experts in drug delivery for help with selecting the right technology for their drug product, and then developing and manufacturing the final product,” says Tomai. “Product lifecycle management, technological performance, and opportunity to capture additional market share are just a few of the many factors that should be considered when considering a reformulation strategy, such as converting from an oral dosage form to a transdermal patch or from injectable into microneedle administration. It is essential to involve your contract manufacturing organization early on, so they can help avoid unnecessary pitfalls, such as delays in project timelines and/or additional steps during formulation processing.’’


	Reformulation strategies include both technical and commercial objectives, according to Coward. “The first step involves defining the goals of reformulation, whether it is to improve ease-of-swallowing, enhance taste, or offer convenience. The approach can also address specific marketing objectives, helping to strengthen a brand or identifying new target groups and effectively meeting their expectations,” says Koeberle. “Then comes the evaluation of the current product and its requirements: the characteristics and strength of the API, the particular dosage form, and the kind of packaging (e.g., child resistant versus senior-friendly packaging). These are important factors that give users a more positive experience when taking their medication, and will benefit companies and patients alike by improving compliance.” 

Pharma R&D Innovation Showing Signs of Resurgence After A Decade of Decline"

Guidance for Industry, Applications Covered by Section 505(b)(2) 

(Rockville, MD, October 1999).
	3. A. Siew, 

 39 (4) 2015. 
	4. Pfizer, “Pfizer Announces FDA Acceptance for Review of New Drug Application for A Once-Daily Formulation of XELJANZ (tofacitinib citrate) Modified Release Tablets,” Press Release July 2, 2015. 
	5. Roche, “FDA approves new drug application for osteoporosis drug Boniva (ibandronate sodium),” Press Release, May 19, 2003. 
	6. Roche, “FDA approves once-monthly Boniva for osteoporosis,” Press Release, March 29, 2005. 
	7. Roche, “FDA approves first quarterly I.V. injection for postmenopausal osteoporosis in US,” Press Release 9 January 2006. 
	8. A. Siew, 

 38 (4) 2014. 
	9. N. Udupa, A. Gupta, and D. Sreedhar, 

24 (1) 2012. 
	10. Hermes Pharma, “Conventional Tablets May No Longer be the Go-To-Solution,” Press Release, Sept. 2, 2014. 
	11. AstraZeneca, “FDA Approves New ZOMIG (Zolmitriptan) Nasal Spray Formulation,” Press Release, Oct. 1, 2003. 
	12. A. Siew, 

 When referring to this article, please cite it as A. Siew, “Stretching Product Value 
	through Reformulation Strategies,” 

New formulations that enhance bioavailability, optimize drug-delivery profiles, reduce dosing frequency, or improve patient experience have the potential to deliver quicker returns on investments than developing a completely new drug.