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

Adeline Siew, PhD

	Multi-tip punches increase the number of tablets produced per turret rotation, which increases production rates of existing presses. Steve Osborn, product design manager at tablet tooling manufacturer I Holland, spoke to 

 about the key considerations for successful implementation of multi-tip tooling in tableting operations.

PTE: Can you provide an example of how multi-tip tooling increases production capacity and lowers running costs in tablet manufacture? 

: Multi-tips have transformed the production of tablets into a process that allows manufacturers to deliver them quickly, efficiently, and at a lower production cost. For example, a customer wanted to increase their tablet output without investing in additional tablet presses. In this case, the tablet press was a Korsch PH800, 77 Station Press, which used single punches and had a maximum tablet output of approximately 831,000 tablet per hour. After some investigation, we found that the machine was only running at 80% of its maximum speed and the output was actually 665,000 tablet per hour. 

	To increase tablet output, we suggested the use of multi-tips. Trials were conducted using multi-two tooling (a tool with two tips). During this test period, tablet output was increased to more than 1 million tablets per hour, with the press running at a speed of 60% capacity. The result was a 66% increase in productivity.

	Following this trial, we saw a further potential for increased productivity and supplied multi-three tooling to be tested. This resulted in an output of nearly 1.5 million tablets per hour, an increase of 125% improvement on the original figure.

	Not only was the output up, but production was also reduced from 14.5 to 8.5 hours. The simple process of adding multi-tips to existing machines can have a huge impact on production through increased output and reduced production time, without the expense of investing in new machinery.

PTE: What are the technical aspects to bear in mind when implementing multi-tip tooling? Can you discuss key considerations in terms of the tablet press, formulation, and tablet design such as size and shape?

: Almost all presses can accommodate multi-tip tooling, but there is a checklist to consider before investment to ensure production runs smoothly. A quality tooling manufacturer can advise you on how you can bring multi-tips into your production process successfully.

	Any press being planned for multi-tip production must be in good working order with no significant wear in the turret area, including punch guides, keyways, and die pockets. The cams should also be replaced if there are signs of excessive wear or degradation to prevent damage to the punch heads.

	You must consider compatibility of the press with multi-tips. The upper turret must have a keyway in the guide to ensure alignment with the tooling. Although the lower turret guide does not require a keyway because the tip remains in the die, a keyway on the lower turret is recommended when using a higher number of tips, as it helps in the setting process and avoids damage to the lower tips.

	Attention should be given to the feeder paddles as they may have to be modified to ensure the amount of formulation is correct for die filling. Also look at the tablet ejection system as it has to receive larger production volumes.

	Press monitoring systems and any equipment associated with them should also be able to provide efficient information and have the capability to be set up for multi tips.

	The formulation being compressed must also be investigated as the increased fill requirement and granulation flow are important to take into account. Granulation that does not flow quickly enough can result in problems. A solution is to modify the feeder mechanism to optimize the press speed, or alternatively, reduce the machine speed to allow time for fill to take place.

	Particle size is another important factor. The particle size must be within certain limits for the tooling to work effectively; however, with modification of tablet design and working tolerances, there are ways to work around it.

	Multi tips can produce most tablet designs, but it is influenced by the press and tool type capabilities. You must look at the tablet size to evaluate the number of tips to fit the punch. Shapes such as ovals can be more challenging to arrange while delivering a robust tool, optimizing die filling, and tablet take-off positions. 

	As mentioned previously, tooling manufactures will look at all factors of the tablet design to develop a multi-tip configuration that ensures all variables are covered from shape and size, to profile, embossing, and break-line details.

	Also important is the use of punch and die treatments and coatings. Using coatings that are correctly matched to the formulation can help to improve corrosion and wear resistance and prevent sticky formulations from adhering to the punch tip faces. When combined with the correct stainless-steel material on the tooling, issues such as corrosion can be prevented.  

PTE: How do you set up multi-tip tooling? How long does implementation take, and what sort of time frames are we looking at?

: The setting of multi-tip tooling is the same as the setting of shaped punches. You should use a fitting tool to ensure that the dies are in the correct alignment and that the guides and die pockets are not out of position or worn. Care must be taken when fitting the tools to the press to avoid causing damage to the tip edges, as this will cause other problems to arise during compression.

	Implementation is not extensive; however, you will have to consider the capability of the tablet press, filling, rejection, ejection, and de-dusting. Advice can be sought from your press and tooling supplier.

	The design and manufacture of the tooling can be completed in a matter of weeks. Implementation and validation may take longer depending on your process and procedural requirements.

PTE: Do you see widespread use of multi-tip tooling? 

: Pharmaceutical manufacturing is an ever-changing environment, which requires changes to respond to this evolvement. To produce tablets cost-effectively, investment in new technologies and processes must be developed, and one of these investments is multi-tip tooling.

	Within modern tablet production, the demand for improved productivity, whilst reducing manufacturing costs, is a dominant factor today, and with the growing demand for increased yield, manufacturers must use a method to meet these requirements.

	Multi-tip tooling has transformed the way tablets are produced and it is now seen as the most productive form of tablet manufacture. Multi-tip punches allow the number of tablets per turret rotation to be multiplied by the number of tips on the punch. They also require less floor space, because more tablets can be produced with fewer tablet presses, leading to a reduction in overall plant running costs. Ultimately, the development of a technology like multi-tip tooling is beneficial to many end users, and its potential is being increasingly realised with the demand for multi-tip tooling increasing year on year.

Articles

Steve Osborn, product design manager at tablet tooling manufacturer I Holland, spoke to Pharmaceutical Technology Europe about the key considerations for successful implementation of multi-tip tooling in tableting operations.

Increasing Tablet Production with Multi-Tip Tooling

Process analytical technology (PAT) has revolutionized pharmaceutical manufacturing by enabling the design and development of well-understood processes that consistently deliver quality products. The ultimate goal, under the quality-by-design (QbD) initiative, is to build quality into the product rather than traditional batch testing at the end of the manufacturing process. Emil Ciurczak from Doramaxx Consulting; Tim Freeman, managing director of Freeman Technology; and Alon Vaisman, product development manager, process systems at Malvern Instruments, spoke to 

 about the benefits of PAT in solid-dosage manufacturing as well as the strategies for PAT implementation.

 What are the key drivers for the adoption of PAT in pharmaceutical manufacturing and why is uptake slow within the industry?

 The key drivers are and will be the economics of the industry. There is pressure from countries to reduce costs on both generics and proprietaries. New drug introductions in Germany, for example, are allowed to cost more than existing products only if a significant benefit is demonstrated.

	The US Congress is bending to pressures from the largest lobby in the US: AARP. They are demanding lower drug prices and, with our new Republican-controlled Congress, cost-cutting will be the order of the day. PAT, well-executed, is the best way to immediately lower cost of goods sold.

 PAT is a fundamentally important aspect of any modern pharmaceutical processing environment where the need for quality and efficient manufacturing is paramount. As the industry develops new products and processes, it is essential to scrutinize the characteristics of the in-process materials throughout the manufacturing cycle to ensure that quality is met and patient safety is guaranteed. This analysis requires suitable tools applied at each step of the manufacturing process. Significant progress has been made in the past 10 years since the introduction of the PAT initiative, but many processes remain poorly understood and un-optimized.

	Unlike many other powder processing industries, the pharmaceutical sector is challenged by the need for rigorous validation of its processes and measurement techniques, which introduces additional hurdles to the adoption of in-process monitoring and control. This challenge is further exacerbated when implementing real-time release testing, where measurements are taken in real time and a decision about product quality is almost instantaneous.

 One of the key drivers for the adoption of PAT is the growing demand for higher drug quality and efficacy, both from regulators and the public. Within the industry, there is increasing recognition that these demands cannot be met by the traditional approach of relying on final quality-control testing, but rather that a detailed understanding of all aspects of the product and of the associated manufacturing process is required. PAT can provide the information needed to exert and maintain effective process control, and consequently, the necessary assurance of quality and efficacy.

	A second driver is the need to bring products through to market more quickly. Time to commercialization has a major and direct impact on the bottom line, both for generic manufacturers (being first to file) and innovators (time to manufacture under patent). More efficient commercialization calls for the use of enabling tools that produce data faster than can be achieved by applying traditional technologies in an analytical laboratory. Using appropriate PAT makes it quicker to implement the design of experiment (DoE) approach associated with QbD, and to fully scope the impact of critical process parameters (CPPs).

	Several factors are responsible for the relatively slow uptake of PAT in the pharmaceutical industry despite these powerful drivers. Firstly, there are perceived regulatory hurdles, although it would seem that there is little evidence to support this view. Indeed, FDA is actively encouraging and promoting the use of PAT to demonstrate rigorous understanding and control of the manufacturing process and the parameters impacting product quality. In some instances, there is also a concern that the use of PAT will reveal previously unknown quality issues which will then need to be addressed-the potential downside of developing a greater understanding of process and product performance.

	Finally, I would suggest that the scarcity of widely accepted standards for equipment and process design is also an issue, especially against a backdrop of historically low levels of equipment utilization. Almost every PAT implementation is essentially unique, or considered to be so by the end users who also have no clear guidance as to what analytical methods need to be applied in each case. Furthermore, PAT is typically being used to push manufacturing practice towards relatively unfamiliar performance standards. As a result, the introduction of PAT is often associated with demands for customization, increased validation burdens, and substantial engineering efforts on the part of instrument manufacturers and the end users, all of which are barriers to uptake.

Implementing PAT in pharmaceutical processes

 What are the main challenges and key considerations when it comes to implementing PAT in pharmaceutical development and manufacturing?

 In many cases, the challenges of implementing PAT are linked directly with the reasons outlined for its slow uptake. For example, the lack of standards increases the workload associated with producing a fully fit-for-purpose solution for any given application. Engineered solutions are used to adapt available PAT tools to evolving needs, but in the absence of standards, the cost, time, and most importantly, the risk associated with each solution is higher than it should be.

	Key considerations to address when it comes to using PAT include the need to rigorously assess what information is required and the ability of a proposed PAT tool to deliver it reliably. PAT brings value by enabling faster experimentation, more efficient scale-up, and/or by increasing confidence in the quality and stability of the manufacturing process, and ultimately, the end product. However, it will only deliver these benefits by measuring relevant data in a timely and robust way. Scalability is also an important factor to be considered within this context because ideally, the same PAT tool will deliver all of these benefits by transferring with the product, from R&D through scale-up into commercial manufacture.

	Finally, method development is an important consideration when it comes to PAT because it affects how the information generated by the PAT device will relate to results measured using established quality control (QC) techniques. Correlations between QC and PAT data can be vital to the acceptance of a PAT tool.

 There are now many examples of spectroscopic techniques being successfully applied to blending, granulation, and drying processes, as well as measurements such as in-line particle sizing and more traditional measurements of properties like temperature and moisture. However, a significant outstanding challenge, particularly within powder processing, is the rationalization of which material properties, for both raw materials and intermediates, are important in determining the quality of the finished product.

	Attaining this information is the basis for improved product development and formulation, but also as a driver for the development of new or better process analytical technologies. Whilst there have been a great deal of solutions through the application of in-line spectroscopic techniques and particle sizing methods, there are other attributes of particles, such as density, flow, morphology and permeability, to name a few, that are currently not measured in-line and yet are broadly recognized as being influential in the critical quality attributes (CQAs) of the final product, whether this is weight variation or dissolution of a tablet, or delivery performance of an API from a dry powder inhaler.

 Quite simply, lack of experience in a very conservative industry gives managers pause before attempting anything new and not already being done. In other words, it is a lot simpler to convince a director to buy six new high-performance liquid chromatography (HPLC) systems than one new Raman or near infrared (NIR) unit. Adding more people and more equipment always worked in the past, so why not keep doing the same thing that made money before? The instrument manufacturers need to assure the producers of drugs that they will ‘hold hands’ throughout the early attempts at PAT and then follow through by having knowledgeable staff available.

 What are the strategies for successful implementation of PAT in pharmaceutical development and manufacturing?

 The implementation of a robust and appropriate PAT toolkit should be based on understanding the material properties and process parameters that are important in influencing the quality of the finished product. Some of these tools will be readily available, such as NIR, and others are still emerging or have yet to be commercialized, such as the ability to measure in-line particle morphology or granule density following a batch granulation process. A sensible approach would, therefore, be one whereby the identification of these variables is first achieved and the selection of available PATs is made.

	Bear in mind though, that there may still be important material properties that cannot be measured in real time. Hence, the control strategy for the process needs to account for this absent information, either by retrospective testing or by showing through a QbD approach that such a material property will not vary outside of the acceptable criteria (defined perhaps by off-line measurements) as long as certain process parameters are controlled within a specific predefined range.

 Regulatory documents relating to PAT and QbD, which is covered in detail in the International Conference on Harmonization (ICH) guidance, provide a framework for the successful implementation of PAT. The application of QbD involves the systematic identification of all CQAs and CPPs using a risk-based approach, thereby highlighting those variables that can be productively measured using PAT. The next step is to determine where in the process stream the measurement should be made to provide most value. Potential PAT solutions can then be usefully evaluated by considering the following questions:

		How suitable is the analytical method? Does the PAT measure the parameter that you need it to?

		Can you trust and validate the results that are generated? Does the method robustly report data that are representative of the process stream and allow you to securely differentiate between poor and acceptable process performance?

		What calibration procedures are required to ensure data quality? How easy is it to store and use the generated data?

		Is the technology suitable for its working environment? Are the materials of construction compatible with the process stream and are requirements for cleanliness/avoidance of product contamination met?

		Does the proposed solution address user requirements? How easy is the hardware and software to use? What routine maintenance is needed?

		Are any requirements for versatility met? Can the technology be used for more than one product if necessary?

	Alongside this technical assessment, it is also essential to conduct a business-value review to determine the economic value that an investment in PAT will deliver to offset its cost. An important part of this review includes rigorous assessment of the cost of implementation-the investment associated with the equipment and any associated installation, qualification, and validation work.

Applying PAT in solid-dosage manufacturing

 PAT has been used across many types of operations in the solid-dosage manufacturing process. Can you provide some examples of how PAT has been applied?

 In raw materials testing (i.e., every container of every lot), for example, there have been a number of cases where improper particle sizes were delivered. In one specific case, the micronized drug was delivered instead of 100-mesh, granular material; and it would have been a disaster if used for a suppository batch had the problem not been detected by NIR. The United States Pharmacopeia (USP) testing had already approved the lot-sieving only required that there be ‘no less than 1% on a 100 mesh screen.’ There wasn’t an allowance for smaller sizes being sent.

	In another example, a granulating/drying process was run to ‘less than 1% moisture’ by Karl Fisher titration. It was discovered that the drug could exist as either a monohydrate or hemihydrate after drying. Both forms were physiologically equivalent, but the hemihydrate had a six-month-shorter stability profile, leading to an earlier recall. This situation is easily controlled by using NIR to control the airflow and temperature.

	Extending to clinical studies, errors in packaging (leading to erroneous correlation) can easily be avoided by scanning 100% of the blister packs with NIR or Raman to assure compliance with the protocol non-destructively. Also, HPLC results may take days, while spectroscopic results are immediate.

 Examples of PAT from Malvern Instruments that has been used to improve solid- dosage manufacturing include: the Parsum in-line particle sizing probe for the optimization and scale-up of granulation processes and the Insitec online laser-diffraction particle-size analyzer that finds application in milling and spray drying control.

	High-shear wet granulation is used routinely to improve the properties of tablet blends ahead of tabletting. Such processes, however, are notoriously difficult to optimize and scale-up because of their sensitivity to small changes in the formulation or in the mixing regime. A QbD approach can be used to develop the knowledge required to minimize and control the risk associated with moving such processes through to commercial manufacture, and real-time PAT is used to facilitate this process. One of the tools deployed by several global pharma companies is a Parsum in-line particle-sizing probe that measures the size of the growing granules 

	Using real-time particle-sizing data, scientists can confirm that a granulation is proceeding identically at different scales to deliver granules with well-controlled properties. Experimental studies have shown that batches of granules identified as being comparable, on the basis of particle-size data, go on to produce tablets of comparable quality. Real-time particle sizing is thus helping to speed up process development and to enable successful scale-up, while at the same time reducing the number of trial runs needed, thereby saving highly valuable API.

	Spiral jet mills are used extensively in the pharmaceutical industry, for example, to control the particle size of active ingredients. Although these mills are seemingly simple in design and easy to operate, micronizing a batch to the right (and often very tight) specification can be challenging due to gradual changes in the performance of the mill and variability of the feed material. Common process optimization by iterative sampling of small sub-batches to find the right parameters and then ‘blind’ processing of the main batch results in a higher risk of failing final QC and of wasting valuable API.

	Using an Insitec laser diffraction analyzer to measure the particle size of the material leaving a jet mill, in real-time, makes it possible to quickly assess the impact of milling parameters such as material feed rate and injector pressure. This information can be used to fully scope a milling process or to identify conditions that will produce a specified particle-size distribution. The continuous analysis of mill output enables a timely response to any deviation from the set specifications during the run. As a result, this PAT can save time and money, by reducing the length of trials and the material required to identify an optimal processing setup, as well as by lowering the overall risk of out-of-specification production.

 The enthusiasm for, and the recent adoption of, continuous manufacturing within the pharmaceutical industry has necessitated the successful implementation of a number of PATs across a range of process steps incorporated within the continuous manufacturing of tablets.

	Work published by Vertex Pharmaceuticals (1) in recent years shows the use of a GEA Pharma Systems ConsiGma continuous manufacturing suite incorporating spectroscopic characterization methods for measuring water content of product in a dryer and blend uniformity of an intermediate prior to compression. It also features an in-line particle sizing technology in the form of a Malvern Insitec for measurement of particles following the milling process.

	Both techniques applied in this appropriate manner provide real-time assessment and the ability to feedback relevant information to permit control of the process should changes need to be made to ensure the product attributes remain within the target specification.

 What recent advances in PAT tools have you seen over the past five years? Or what would you identify as significant advances in PAT for pharmaceutical solid-dosage manufacturing?

I would say without hesitation that continuous manufacturing is the biggest boon to PAT/QbD in the past 20 years. A number of companies are going full bore into this mode of production. Several immediate benefits have been seen:

		The footprint of a continuous production facility is far smaller than a traditional plant set-up, which means lower land costs, lower heating, ventilation, and air conditioning (HVAC) costs, lower warehouse costs (intermediates need not be stored), and less cleaning costs and time.

		There is no scale-up. The experimental batches are the production batch size. This fact alone could add 12–18 months to the patent lifetime.

		Design of experiments, geared to give the design space for QbD and run in a conventional manner, would cost up to 20 times as much as continuous manufacturing and take weeks, whereas in continuous manufacturing this DoE takes days. This approach saves API, cleaning time, allows more experiments, and is run at the level that the final batches will be produced.

		Finally, with constant monitoring, any out-of-specification (OOS) excursion can be immediately spotted and production halted. The amount of product lost is minimized and costs contained.

 There are a number of emerging technologies within the PAT toolkit that include numerical modelling tools as well as techniques for measuring attributes of the in-process material, such as ribbon density of a product leaving a roll compactor. Certain attributes are amenable to in-line measurements, yet others remain challenging to quantify within the process, such as particle morphology and powder flow properties. Nevertheless, both are important powder attributes that have the potential to influence the characteristics of the finished product.

	For example, a blend may be defined as having acceptable content uniformity as it exits a continuous blender, as measured by an NIR probe, and it may have a suitable particle size distribution following a milling process. However, neither of these measurements ensures that the powder has the same particle-shape characteristics as a previous functional ‘batch,’ nor that it has suitable flow properties. Given that both morphology and flow can lead to capping, weight variation, and hardness problems, the absence of this information explains why variation in product CQAs is still observed, even for processes employing a number of PATs. In this circumstance, the ability to predict and to control all of the CQAs has not been achieved.

	Whilst there have been many advances in PAT, there are still a significant number of material attributes that need to be understood in regard to their influence on CQAs. Once these relationships are established, the next challenge is to develop on-line measurement techniques that permit the measurement of these additional properties to further interrogate and control the complex processes employed.

 Over the past five years, there has been an increasing push for ‘information rich,’ multi-parametric analysis, especially in batch unit operations prone to variability, such as blending and granulation. The term PAT is often synonymous with on- or in-line measurement, because of the value of such instrumentation for process monitoring and control. PAT, however, is actually defined more broadly as ‘a mechanism to design, analyze, and control manufacturing processes…’ (2). So, for example, we are finding that there is appetite to use our Morphologi G3-ID, a laboratory-based instrument, as a PAT, because of the relevant data and insight it is able to provide. The Morphologi G3-ID enables particle size and shape measurement and chemical identification, by combining automated imaging with Raman spectroscopy. It can, therefore, be used to assess, for example, the homogeneity with which an active is distributed within a blend or to assess changes in the size and shape of an active caused by specific processing steps.

	A second trend is the drive towards continuous manufacture now that the successful, cost-effective implementation of this approach has been amply demonstrated. Because continuous manufacture calls for analyzers to work together and for automated process control, it has helped to stimulate the development of new software solutions that simplify analyzer integration, such as Malvern Link II. In addition, new instrumentation such as the Parsum IPP80 probe has been developed for easy data transfer and use to enable the more complex control strategies required for continuous manufacture.

Guidance for Industry PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

 When referring to this article, please cite it as A Siew, “Unlocking the Vast Potential of PAT in Solid-Dosage Manufacturing,” 

PAT holds the key to real-time quality assurance and consistent product quality in pharmaceutical manufacturing.

Unlocking the Vast Potential of PAT in Solid-Dosage Manufacturing

	There is an increasing need for efficient formulation development techniques in the pharmaceutical and biotech industry. Companies typically spend up to $1.6 billion to develop a drug and bring it to market, according to the consulting firm, CRA International. Efficient systems for automated formulation development can save time and reduce cost, while producing better outcomes, notes an 

 on this subject. They can also reduce materials consumption. Automated systems are widely used in the pharmaceutical and chemical industries, such as in drug discovery and in the development of coatings.

 highlights information from Bosch, which indicates that lab process automation can increase lab efficiency by a factor of 2.5, producing time and cost savings of up to 60%. Trials comparing manual and automated formulation development have shown different outcomes. A manual process, for example, would identify certain excipients as unsuitable for a product but in automated trials, the very same compounds could prove useful when combined with other substances.

	There are suppliers who offer special development platforms designed to run simple or complex automatable development processes. Whether it is a modular system or a complete robotic platforms, these tools can be adapted to suit the different requirements in the development process, from design of experiments to sample selection and processing as well as evaluation, analysis, and data mining.

	BASF has a robotic high-throughput screening system, used to measure particle size during the development of multiphase systems, such as emulsions and dispersions. The system fully supports automatic screening of formulations, including the constituents that characterize them, and enables accurate qualitative formulation assessment.

	Siegfried Holding provides tailored formulation development solutions, with its portfolio ranging from API development and production through to delivering complex dosage forms and the final product. Evonik offers a variety of products for pharmaceutical applications and provides formulation development services for oral and parenteral preparations. The company claims that its labs are equipped with cutting-edge technologies and infrastructure for formulation development.  

	Pharmaceutical companies are constantly aiming for shorter drug-development cycles and advances in formulation development produce significant benefits. A wide of technologies and services will be showcased at ACHEMA. The “laboratory and analytical techniques” exhibition group will be located in Hall 4.  

ACHEMA trend report on formulation development

Pharmaceutical companies are constantly aiming for shorter drug-development cycles and advances in formulation development produce significant benefits.

Automation Saves Times and Reduces Cost in Formulation Development

Transdermal patches are designed to deliver drugs through the skin, principally by diffusion, for a systemic effect. As an alternative to the oral route, transdermal drug delivery offers a number of advantages such as the avoidance of first metabolism and gastrointestinal toxicity. It allows for the administration of drugs with narrow therapeutic window, can prolong the activity of drugs with short half-lives, and eliminates the need for hypodermic injections. Patient compliance is also improved because of the ease of administration.

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

	Beyond patient preference, transdermal patches offer efficacy benefits, Schaefer continues. “For instance, instead of the ‘peak and trough’ effect often seen with pills and injections, transdermal patches can maintain a steady blood level of medication,” he explains. “This technology also has the potential to deliver a drug for up to seven days.”

	According to Mattias Springfelter, senior formulation scientist at Recipharm Pharmaceutical Development, transdermal patches can be designed to provide prolonged and controlled release of certain drugs, which can be convenient for pain-relief drugs, nicotine, and hormone products. Schaefer cites Sancuso (granisetron transdermal system) as an example of a drug being adapted for transdermal delivery. “The transdermal patch is a good match for this drug; it is used to treat chemotherapy-induced nausea and vomiting. The alternative forms-intravenous injections and oral tablets-both pose challenges for patients, whereas transdermal delivery provides a more comfortable and patient-friendly delivery method.”

Challenges in the development of a transdermal drug delivery system


	One of the key challenges in transdermal delivery is the limited number of drugs that are suitable for administration by this route. As Springfelter points out, achieving sufficient drug absorption can prove to be a challenge for many molecules, given that the skin is such an efficient barrier against the outside environment.

	“The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against the ingress of xenobiotics (including invasion by micro-organisms) and the prevention of the loss of physiologically essential substances such as water,” explains Majella Lane, PhD, senior lecturer in pharmaceutics at University College London, School of Pharmacy. “Notwithstanding this, transdermal therapeutic systems have been designed to provide continuous controlled delivery of drugs via this barrier to the systemic circulation.”

	“The classic candidate for traditional transdermal delivery is a small, lipophilic molecule that can diffuse through the 

and pass into the systemic circulation,” notes Schaefer. “The 

 is made up of dense, hydrophilic structures surrounded by an intercellular lipid matrix, so hydrophilic drugs are typically not good candidates. Most transdermal drugs are relatively hydrophobic molecules that can permeate through the lipid pathway.”

	The permeation of drugs across the skin is influenced by a number of physiological and physicochemical factors (1, 2). The physiological factors that affect drug absorption include skin age, gender, ethnicity, the thickness of the 

(which varies between different anatomical sites), the degree of skin hydration, the presence of hair follicles, skin condition (e.g., disease compromises the natural barrier function of the skin), temperature, and metabolism. In terms of physicochemical factors, properties such as drug solubility, partition coefficient, molecular mass, and whether the drug is in an ionized or unionized form will influence transdermal absorption.


	Transdermal systems include reservoir devices, matrix devices, multiple polymer devices, and multilayer matrix systems. According to Lane, reservoir and matrix systems are the two most common patch systems that are currently available with the matrix patches dominating the field. “The reservoir system is a diffusion-controlled system, which contains a drug reservoir with a rate-controlling polymer membrane. With this device, the membrane that lies between the drug reservoir and the skin controls the rate of release from the drug reservoir to the skin surface,” Lane continues. “For matrix patches, so named because the active is mixed with or contained in a polymer, the drug is released at a rate governed by the components in the matrix. For a drug-in-adhesive matrix, the polymer (in which the drug is dispersed) is an adhesive. The adhesive serves two roles-it acts as the drug reservoir, and it holds the patch on the skin.”

	Neha Singh, PhD, transdermal specialist at Kemwell Biopharma, highlights that adhesives are an integral component of passive transdermal patch systems. She adds that selecting the correct type of adhesive based on its compatibility with the API, biocompatibility with the skin, optimum wear time, and skin type can be a challenge.

	“Crystallization of the API from the patch has posed a challenge for many transdermal systems,” Singh remarks. “Different factors can result in the formation of crystals over the shelf life.” Selecting the formulation components based on extensive physicochemical compatibility studies and well-planned stability studies can provide valuable insight to the formulation behavior, according to Singh. “One of the main concerns for transdermal systems is the high amount of drug loading required in formulations to maintain a constant flux over the stipulated time duration. Potent drug candidates are ideal candidates for transdermal delivery; however, the saturated concentration requirement necessitates addition of larger amounts. This can also lead to abuse and risks of drug transfer from a used patch once it is disposed of.”

	“Skin properties allow the transport of limited drug candidates through passive transdermal delivery,” says Singh. Advances in patch technology have resulted in the surge of first-generation transdermal delivery systems, which form the majority of transdermal patches on the market today. Their clinical use, however, is limited to the delivery of small, lipophilic drugs that are efficacious at low doses (3). The scope of candidates for this route is expanded with the second generation of transdermal delivery systems, which exploits the use of chemical enhancers, iontophoresis, and non-cavitational ultrasound to increase skin permeability (3). Third-generation transdermal delivery systems target the 

using microneedles, thermal ablation, microdermabrasion, electroporation, and cavitational ultrasound to enable more effective transdermal delivery, while still protecting the deeper tissues (3).

Recent advances in transdermal drug delivery


	Lane observes that the concept of supersaturation has been exploited in the development of transdermal spray technology, where supersaturated states are generated because volatile components (e.g., ethanol or isopropanol) evaporate after the spray is applied to skin, with consequent enhancement in skin flux. “Because of the dynamic nature of these systems, we still do not fully understand the extent to which the thermodynamic activity of the enhancer, as opposed to that of the active, contributes to the overall permeation-enhancement process, but products are already on the market,” she adds. “The Australian company, Acrux, pioneered the development of a transdermal testosterone formulation based on this approach and the company has also licensed similar technology for animal health applications.”

	“The advent of active transdermal systems, such as iontophoresis and microneedles, enables delivery of larger molecules with hydrophilic properties, such as peptides, proteins, and vaccines,” comments Singh. “Microneedles made from a variety of materials, including biodegradable hydrogels that dissolve in the skin, have been designed. Other skin permeabilization techniques, including low-frequency sonophoresis and electroporation, have been studied further to refine their role in enhancing delivery through skin. Modulated delivery (i.e., controlled amount of dose) is possible using iontophoresis when an appropriate amount of current is applied over a stipulated time duration. Physical enhancement techniques have thus expanded the scope of transdermal delivery and have a promising future.” Nonetheless, Singh highlights that the complex nature of these devices, for example, the electronics in iontophoresis and the sterility required for microneedles, could be a challenge for these systems.


	Lane agrees that microneedles have emerged as one of the most promising technologies for the realization of novel dermal and transdermal therapies. “Although microneedles were first described in the 1990s, this technology has advanced exponentially in recent years,” notes Lane. “Microneedles consist of an array of micro-projections generally ranging from 25–2000 μm in height, which are attached to a base support. The application of such arrays to biological membranes creates micron-sized transport pathways.”

	According to Lane, microneedles have been shown to penetrate the skin across the 

and into the viable epidermis, but do not cause pain as they avoid contact with nerve fibres and blood vessels located in the dermal layer. “The early microneedles were fabricated with silicon, but the major development in recent years has been the design of biodegradable and biocompatible microneedles. Drug can be loaded into the microneedle or coated on to the microneedle and a reservoir patch may also be adhered to the array. As well as effectively transporting conventional small actives into skin, promising results have been reported for macromolecular targeting ex vivo and vaccine delivery in humans,” she explains.

	One company that is active in this area, 3M Drug Delivery Systems, is getting closer to introducing its hollow microneedle device on the market. According to Mark Tomai, PhD, head of TLR and MTS Business Development, 3M Drug Delivery Systems Division, the company’s microneedle device consists of polymeric microstructures that utilize one of 3M’s core technologies-microreplication. “This technology was pioneered in the 1960s and first used for applications including roadway signage, but it has now been adapted by 3M Drug Delivery Systems to broaden the scope of drugs that can be delivered transdermally.” 3M has conducted a number of human tolerability studies and design verification tests; and supplies for clinical trials are available for pharmaceutical and biotech companies interested in this technology.

	“There are currently two types of microneedle devices under development,” adds Tomai, “solid microneedles (sMTS), which use a dried coating of a molecule or peptide up to 300 μg on the tips of a microneedle array; and hollow microneedles (hMTS), which are compatible with small molecules as well as biologics such as proteins and peptides, and can deliver liquid formulations up to 2 mL.”

	Tomai further explains that the hMTS offers a patient-friendly intradermal delivery solution. “The device’s hollow microneedles reach into the highly vascularized dermal layer of the skin, making it ideal for delivery of many treatments. The hMTS handheld delivery device contains up to 2 mL API in a conventional glass vial. The API is transmitted via a sterile flow path through the polymeric hollow microneedles. This single-use delivery system is designed for self-administration and has the potential to expand the range of drugs available for in home injections.”

	Researchers from the National University of Singapore (NUS) have developed a microneedle patch that is said to offer a faster, more effective, painless, and non-invasive way to deliver lidocaine (4). A photolithography-based process was used to fabricate this novel transdermal patch. The drug is encapsulated in tiny polymeric needles attached to an adhesive patch. When applied to the skin, the microneedles deliver lidocaine rapidly into the systemic circulation without causing any discomfort to the patient. The technology can also be applied to collagen and used for cosmetic and skincare purposes.

	Studies showed that the microneedle patch could deliver lidocaine within five minutes of application compared with the commercial lidocaine patch, which took 45 minutes for the drug to penetrate the skin. According to the researchers, the miniature needles on the patch create micrometre-sized porous channels in the skin, thereby, enabling rapid drug delivery. Because the needle shafts are approximately 600 µm in length, they do not cause any perceptible pain. The reservoir system in the patch acts as channels for drugs to be encapsulated in the backing layers, circumventing the premature closure of miniaturized pores created by the microneedles and ensuring continued drug permeation.

	Researchers at Queen’s University Belfast have invented a unique and innovative microneedle transdermal system, based on hydrogel materials (5). The microneedles, which are less than 0.5 mm high or smaller, are made of a hydrogel of biocompatible polymers that can safely deliver constant doses of the drug. The microneedles are hard and sharp when dry, but rapidly hydrate when inserted into the skin. The swollen hydrogel projections create a continuous aqueous pathway between the external environment and dermal microcirculation enabling controlled delivery of the API.

	Fujifilm’s microneedle array consists of a sheet arrayed with 100–2000 µm projections made of polysaccharides (6). The drug is delivered into the body by simply attaching the sheet onto the skin. These projections dissolve in the skin within minutes as the drug is delivered. According to Fujifilm, array types with non-dissolvable projections pose risks of the projections breaking off and remaining inside the body; however, Fujifilm’s microneedle array has been proven to be safe as the projections do not retain their form. Experiments with a model vaccine administered using the microneedle array showed that it generated the same amount of, or more, antibodies than the injected vaccine (6). 

19 (12) 20780–20807 (2014).
	2. I. Singh and A.P. Morris, 

1 (1) 4–9 (2011).
	3. M.R. Prausnitz and R. Langer, 

26 (11) 1262–1268 (2008).
	4. NUS News, “NUS researchers invent novel microneedle patch for faster and effective delivery of painkiller and collagen,” Press Release, Sept. 5, 2014.
	5. R.F. Donnelly et al., 

22 (23) 4879–4890 (2012).
	6. Fujifilm, “Fujifilm develops the microneedle array,” Press Release, Nov. 14, 2012. 

When referring to this article, please cite it as A Siew, “Transdermal Drug Delivery Gains Traction,” 

Advances in transdermal drug delivery, particularly with microneedles, are enabling a wider range of drugs to be delivered through the skin.

Transdermal Drug Delivery Gains Traction

, a Dutch biotech company, presented data on the potential use of endolysin as an alternative to antibiotics at the Royal Society of Medicine (RSM) Medical Innovations Spring Summit on April 18. The concept is based on a treatment inspired by naturally occurring viruses that attack bacteria using enzymes called endolysins.

	The growing threat of antimicrobial resistance has created an urgent need for new antibiotics to be developed. Micreos believes that endolysin technology could hold the key to the prevention and treatment of bacterial infections, including those caused by superbugs, such as the methicillin-resistant 

	CEO Mark Offerhaus and Bjorn Herpers, a clinical microbiologist and medical advisor at Micreos, presented the concept of the colonization-infection continuum, and explained how endolysin technology can combat pathogenic bacteria before colonization leads to infection, enabling a novel approach to antibacterial therapy.

	Antibiotics are non selective in the bacterial species that they target. Over-prescribing and misuse of antibiotics have caused resistant bacterial strains to emerge. Because bacteria interact with the human body across a spectrum of stages, called the colonization-infection continuum, Micreos argues that antibiotic use should be limited to the infection stage of this continuum.

	The company presented new data at the meeting showing that its endolysin, 

, including MRSA, without inducing bacterial resistance. Endolysins are enzymes produced by phages, the family of viruses that naturally infect and destroy bacteria.

	Staphefekt, the first endolysin available for human use, is specific to its target species and does not harm beneficial bacteria, according to Micreos. This novel approach to treating bacterial infections is, therefore, suitable for long-term maintenance therapy. It can be used in the early stages of the colonization-infection continuum in certain patient populations, for example in 

-related skin conditions, such as eczema, acne, and rosacea. Mircreos showed data demonstrating reduced symptoms of inflammation in these conditions.

	Staphefekt causes lysis of the bacterial cell wall, targeting highly conserved areas, which is why resistance development against endolysins has not been observed and is not expected. These characteristics have been confirmed in 

 studies. Laboratory results have shown that lysis of 

, efficient, and unlikely to induce resistance.

	“Endolysin technology enables us to deal with the bacteria around us in a completely different way, preserving the beneficial species, and the biodiversity of the bacteria on our skin,” said Mark Offerhaus. “This is necessary, and it represents a paradigm shift, allowing for prophylactic and maintenance treatment of bacterial skin diseases at an early stage, alleviating pressure on antibiotics in these indications and preserving antibiotics for when we really need them.”

	Bjorn Herpers added that “the results demonstrate the potential this technology has for effective action in the earlier stages of the colonization-infection continuum. The United Kingdom Five-Year Antimicrobial Resistance Strategy 2013 to 2018 outlines the need for new strategies for the treatment of bacterial infections, and this could be one of the answers.”

Endolysin technology targets unwanted bacteria, including resistant strains

Endolysin Technology Presents an Antibiotic Alternative with Broad Applicability

	The World Health Organization has released a 

 calling for public disclosure of clinical trial results. It reaffirms the ethical imperative of clinical trial data reporting and defines timelines for publishing study results. 

, WHO says that results from clinical trials should be reported within 12 months of completion of the study. WHO is also calling for publication of results from previously unreported trials to be made publicly available, and reiterates that governments and organizations should implement measures to achieve this transparency in clinical trial data. WHO has outlined steps to improve linkages between clinical trial registry entries and their published results.

	The latest version of the Declaration of Helsinki states that all human studies must be registered in a publicly accessible database before recruitment of the first subject begins. It also states that researchers are responsible for making study results available to the public, and this includes negative and inconclusive data.

	WHO’s call for clinical data disclosure builds upon its 2005 statement that “the registration of all interventional trials is a scientific, ethical, and moral responsibility.”

WHO says that results from clinical trials should be reported within 12 months of completion of the study