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

Adeline Siew, PhD

	The growing threat and spread of antimicrobial resistance continue to ring alarm bells worldwide. “The most important medicine known to mankind,” as Karl Rotthier, president of DSM Sinochem Pharmaceuticals, calls it, is facing a bleak future. On one hand, there is an increasing sense of urgency to develop new antibacterial drugs, while on the other, it is crucial that we find practical solutions to tackle this problem, such as addressing the misuse and abuse of existing antibiotics.

 from the European Centre for Disease Prevention and Control attribute more than 25,000 deaths in Europe alone to antimicrobial resistance every year. This crisis costs more than EUR1.5 billion in healthcare expenses and productivity losses. The Cabinet Office of the United Kingdom 

 that each year, 80,000 people in the UK could die from antibiotic-resistant infections if no new antibiotics are introduced. The following steps have been recommended in a 

 commissioned by the UK prime minister: 

		Increasing funding to boost the development of new antibiotics

		Implementing measures to ensure efficient use of existing antibiotics, whether by changing the dosing or combining them with other agents or antimicrobials that could slow down the spread of drug resistance and treat resistant infections more effectively

		Supporting the development and use of relevant diagnostic technologies so that more patients are given the right antibiotics for their infections and unnecessary antibiotic prescribing is eliminated or reduced

		Investing in the people who will solve the problem, such as next-generation doctors, scientists, microbiologists, pharmacologists, medical chemists, and biochemists, among others, who will be involved in finding novel approaches and therapies for bacterial infections

		Modernizing the surveillance of drug resistance globally, for example, by using the latest advances in molecular testing and informatics to improve access to real-time global-scale surveillance information.

	With antimicrobial resistance hitting the headlines more frequently than ever, 2014 emerged as a flagship year in the history of antibacterial drug development, according to Frost and Sullivan. FDA approved three new antibiotics in 2014-dalbavancin (Dalvance, Durata Therapeutics), oritavancin (Orbactive, The Medicines Company), and tedizolid phosphate (Sivextro, Cubist Pharmaceuticals). Dalbavancin has received marketing authorization from EMA. European approval for the other two agents are expected in 2015 as the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion on them.

 on antibiotics R&D by Frost and Sullivan found that nearly 80% of drugs in the development pipeline are from smaller pharmaceutical and biotech companies, of which half have had no experience bringing a product to market. GlaxoSmithKline, AstraZeneca, Janssen, and Sanofi-Aventis were among the few big names investing in the antibacterial drug development space. Roche, who exited this market in 1999, recently made a come back in antibiotics R&D and is collaborating with three small biotech companies, Pylor, Discuva, and Spero Therapeutics.

	It goes without saying that R&D is risky business, with high failure rates. Developing new antibiotics is no easy task and the low return on investment is often cited as the main cause for pharma’s lack of interest in this field. But antibiotic incentives are now on the rise, with the European Commission launching action plans such as the Innovative Medicines Initiative (IMI) and FDA implementing the Generating Antibiotic Incentives Now (GAIN) Act. Frost and Sullivan healthcare senior research analyst, Aiswariya Chidambaram believes that “collaborations in the form of public-private partnerships among industry, academia, investors, and key opinion leaders will effectively address the vast unmet clinical and commercial needs in the antibacterial drugs market and quicken the journey towards commercialization.” Moreover, with tax credits for antibiotic R&D now available, we could see five or six new candidates entering the pipeline every year. 

Articles

The growing threat and spread of antimicrobial resistance continue to ring alarm bells worldwide.

Antibiotic Drug Development Makes a Turning Point

	The European Medicines Agency (EMA) and the heads of medicines agencies (HMA) have published a 

 outlining their network strategy for the next five years. This is the first time EMA and HMA have presented a single strategy document that reflects the need for a coordinated approach to address the challenges and opportunities facing the European regulatory system network.

	The document highlights areas in which the network seeks to make an impact on over the next few years leading up to 2020. Four themes were presented as part of the network strategy-human health, animal health, optimization of network operation, and the need for more collaboration in the regulatory environment in response to the increasing globalization of the pharmaceutical industry. 

	With advances in science, it is important for the regulatory framework to evolve accordingly so that new medicines can be developed optimally for the health benefit of European citizens. Antimicrobial resistance was identified as a major threat to public health, creating an urgent need for new antibiotics to treat infectious disease. And with an aging European population, diseases such as dementia have added to the public health burden.

	Innovative advanced therapies are emerging, with personalized medicines representing an increasing part of the armamentarium. However, the costs and complexities of drug development continue to present hurdles. While the European regulatory framework offers some degree of flexibility in drug approval pathways, more work needs to be done to enable patient access to promising new drug at the earliest opportunity. The situation calls for the concept of adaptive licensing to be explored and a lifespan approach with drug development, licensing, reimbursement, clinical application, and drug monitoring as to be viewed a continuum. 

	The following objectives were outlined in the chapter pertaining to human health:

		The network will focus on key public health priorities such as antimicrobial resistance and review measures to ensure the continuity of medicines supply.

		The network will look at ways to enable timely access to novel treatments for patients, for example, by moving forward with the adaptive licensing pathways and working in close collaboration with health technology assessment (HTA) bodies, pricing and reimbursement bodies, healthcare professionals, and patient representative bodies.

		The network will implement optimal clinical trial regulation to support patient-focused innovation and consider further incentives to create a vibrant life-science sector in Europe.

		The network will strengthen its capabilities to ensure that the regulatory framework is appropriate for the assessment and surveillance of new innovative medicines. There are also plans to increase transparency concerning data that underpin regulatory decision as well as to consider greater use of real world databases.

	The European Commission, in proposing a new legal framework for veterinary medicines, identified four principle objectives-to increase the availability of veterinary medicines, to reduce the administrative burden on regulators and the industry, to improve the functioning of the European veterinary medicines market, and to minimize the risks from antimicrobial use in the veterinary domain.

	The same four objectives will drive the network strategy in the run up to the new legislation:

		increase availability of veterinary medicines and promote the development of innovative medicines for veterinary use

		promote better regulation to reduce the regulatory burden on the veterinary pharmaceutical industry while maintaining the existing high standards for the protection of human and animal health and of the environment

		improve the functioning of the single market for veterinary medicines within the EU

		focus on key public and animal health priorities including antimicrobial resistance.

	The EU recognizes that collaboration and cooperation between all parties in the network are key to a successful regulatory framework. There are, however, a number of challenges, such as health issues, progress in regulatory science, societal trends, upcoming legislative and political changes, and the impact of further globalization, which must be addressed to ensure efficient operation of the network.

	It has been noted that high-quality scientific and regulatory expertise will play a crucial role in facilitating the progress of regulatory science. The network also wants to ensure that scientific and operational procedures carried out by single or various players within the network are efficient and cost-effective, thereby, minimizing as much as possible the administrative burden for pharmaceutical industry commensurate with public and animal health.

	Over the next five years, the network will undertake initiatives to achieve the following objectives:

		reinforce the scientific and regulatory capacity and capability of the network to cope with changing demands

		strive for operational excellence on regulatory procedures and continuously improve on the quality of scientific output within the current framework

		ensure effective communication of and within the network

		improve interaction with stakeholders and strengthen collaboration with other authorities involved in the decision making process for medicines.

Contributing to the global regulatory environment

	Globalization of pharmaceutical activities has resulted in increased reliance of manufacturers from developing countries, which has brought with it the challenge of protecting the supply chain from counterfeit operations. Moreover, data from clinical trials conducted outside the EU will need to be properly monitored.

	One of the priorities of the network is to contribute to the global regulatory environment and enhance greater collaboration with parties outside the EU. The emergence of new international coalitions where there is a coordinated and consistent approach, which avoids duplication, will have implications on the European network.

	The following objectives were outlined in this chapter of the network strategy document:

		assure product supply chain and data integrity

		convergence of global standards and contribution to international fora

		ensure best use of resources by promoting mutual reliance and work sharing

		support training and capacity building and promote the EU regulatory model.

EU Medicines Agencies Network Strategy to 2020

This is the first time a single strategy document for both EMA and HMA is presented, reflecting the need for a coordinated approach to address the challenges and opportunities facing the European regulatory system network.

EMA and HMA Reveal Network Strategy for Next Five Years

	Indonesia is believed to be pharma’s next hot economy, according to a recent CPhI Pharma Insights 

 based on research conducted by CPhI in collaboration with 

. The study will be available free of charge at 

, which is due to take place at the Jakarta International Expo, Indonesia, from April 8–10.

	The Indonesian pharma market is valued at $6.5 billion. The sector recorded 85% growth from 2007 to 2013, with domestic companies holding 70% of the market share compared to the 30% owned by multinationals. The Indonesian pharma market is set for huge growth, says the report. It is, therefore, anticipated that overseas companies will soon be flocking into the region with foreign investments that could lead to innovative partnerships with domestic manufacturers in the long term. Investment from the local government will also help boost drug development.

	During the next two years, domestic players will benefit from the increasing demand for over-the-counter (OTC) drugs. The report, however, predicts that the growth curve for OTCs will gradually become more linear. Consumption of prescription generic drugs, on the other hand, will see a sharp increase over the coming three to five years. This move towards prescription generic drugs is perceived to be driven by new government initiatives as they take on the financial burden of drug sourcing from the private sector.

	The report, however, highlights that most of the local manufacturers are already operating at full capacity, and this could hinder the industry’s ability to cater for the rapidly rising demand for high-quality, low-cost generic drugs. Roy Sparring, chairman of Badan Pengawas Obat and Makanan (BPOM), which is Indonesia’s National Agency for Drug and Food Control, commented in the report that “BPOM welcomes investment into Indonesia’s pharmaceutical industry.” As foreign investments are important in ensuring that supply meets demand, the report postulates that this situation will result in more acquisitions and innovative partnering models. 

	It is likely that more international pharma firms will buy domestic facilities in Indonesia to help navigate the landscape as the demand for prescription generic drugs escalates. The fact that 83% of the local companies are cGMP certified makes it even more appealing to overseas multinationals looking to penetrate the Indonesian market.

	However, foreign investors cannot acquire 100% of an Indonesian firm; their maximum ownership stake 75%. Consequently, there will be more innovative forms of collaboration between local and foreign companies with partial or equal ownership and risk sharing. Such partnerships allow local players to move their businesses towards operating as regional CDMOs and give overseas manufacturers the ability to navigate Indonesia’s challenging distribution pathways.

	Domestic players are currently driving the pharma market in Indonesia, but as the industry evolves, Indonesian manufacturers could so be exporting to other ASEAN countries. Sparringa believes that this progression could occur within the next five years if there is increased harmonization across the region and provided standardized regulations are established.

	The Indonesian pharma market is on the brink of a regional manufacturing boom. According to Chris Kilbee, group director of pharma, “partnership are set to play a major role in advancing this market into a major international drug exporter for ASEAN countries.” He adds that “foreign-domestic partnering will allow local manufacturers access to new technologies and provide the opportunity for companies to develop into regional CDMOs.”

CPhI report notes that the Indonesian pharma market is on the brink of a regional manufacturing boom, with market capitalizations and company values rising.

Indonesian Pharma Market Poised for Strong Growth

	Controlled-release formulations may be more challenging to formulate than traditional dosage forms, but they offer a number of distinct advantages, including:

		Prolonged duration of therapeutic effect

		Reduced adverse reactions due to the maintenance of drug concentration within a desired range without exposing the patient to potentially toxic drug levels

		Better patient compliance, as a result of reduced dosing frequency, especially in cases of chronic diseases where complex drug regimens are involved.

	For pharmaceutical companies, controlled-release formulations are developed as part of a lifecycle management strategy to differentiate their products from generic drug competition and thereby extend market exclusivity. Technologies for controlled-release drug delivery continue to advance, driven by increasing demand. This article looks at some of new developments in the field.
	
	

IntelliCap, an electronic drug delivery and monitoring device


	Medimetrics’ electronic controlled-release oral drug-delivery system, IntelliCap, is a drug-delivery and monitoring device that consists of a cap containing the drug reservoir and a body containing a microcomputer and wireless data exchange unit (1, 2). The ingestable, single-use electronic device has built-in functionalities such as pH and temperature sensors. IntelliCap can be programmed to the desired drug release profile, and the drug can be targeted to specified regions of the gastrointestinal tract. An interesting feature is its ability to achieve real-time control and adjustment of drug delivery while the capsule is in the body (1, 2).

 assessment of pharmacokinetics and gastrointestinal transit times of controlled-release formulations. For example, the device has been used to quantify regional drug absorption in human gastrointestinal tract. In this study (3), an Intellicap system containing diltiazem (i.e., the model drug) was programmed to have the same drug release profile (based on 

 dissolution data) as the commercial extended-release formulation of diltiazem, marketed by Mylan Pharmaceuticals. Results showed that the mean pharmacokinetic data of both formulations were similar. However, a higher peak plasma concentration (C

) and longer time to reach peak plasma concentration (T

) were observed with the commercial formulation. This variation was due to the different dosage forms. IntelliCap is a monolithic unit while the commercial formulation is a multiparticulate system, which is known to take longer to travel through the small intestine, accounting for the longer T

Chronocort, controlled release that mimics the circadian rhythm


	Chronocort, developed by Diurnal, a spin-out company from the University of Sheffield, United Kingdom, is a controlled-release, oral formulation of hydrocortisone (cortisol) for the treatment of adrenal insufficiency and congenital adrenal hyperplasia. The multiparticulate formulation has been designed to release the hormone in a manner that mimics the body’s natural circadian rhythm (4).

	Cortisol, more often known as the “stress hormone,” is a steroid hormone secreted by the adrenal gland. Cortisol levels in the body follow a circadian rhythm that is regulated by the main circadian oscillator (pacemaker) in the suprachiasmatic nucleus, located in the hypothalamus. In healthy individuals, cortisol levels build up overnight, reaching a peak in the morning. They slowly decline throughout the day, falling to low or undetectable levels towards midnight (5). The management of adrenal insufficiency has always been a challenge because hydrocortisone has a short plasma half life and patients taking the hormone will only achieve peak cortisol levels one hour after consuming the tablet. Furthermore, it is difficult to replicate physiological cortisol release with immediate-release hydrocortisone tablets.

	A Phase II study of Chronocort in 16 adults with congenital adrenal hyperplasia showed positive results in demonstrating that Diurnal’s controlled-release formulation provided cortisol levels that mimic the circadian rhythm observed in healthy people (6, 7). Patients treated with Chronocort woke up with normal cortisol levels in the morning, and their cortisol profiles matched physiologic cortisol secretion.

A microchip-based implant for pre-programmed dosing schedules


	Microchips Biotech has developed a proprietary microchip-based implant that can store and release precise doses of a drug on-demand or at scheduled intervals for up to 16 years (8, 9). The physician first places the implant under the skin of the patient, using a simple procedure performed under local anesthesia. Once implanted, the device can be activated or deactivated through wireless signals by the physician or patient. The physician can also wirelessly tailor the frequency and dose of the drug to suit the individual patient’s needs without having to remove the implant.

	The microchip-based implant contains 200 micro-reservoirs in small hermetically sealed compartments, each storing up to 1 mg of drug (9). Activation by a wireless signal triggers drug release from the micro-reservoirs according to a pre-programmed dosing schedule. The implant can be built with sensors that release the drug in response to physiological or metabolic changes in the patients. There are control electronics within the implant, such as radio frequency communications, a clock for accurate timing of drug release, a custom circuitry that is electrically connected to individual doses to allow independent dispensing of each dose at any time or in any sequence, and a microcontroller that provides control of all necessary functions. Instructions from an external device (which can be a cell phone, a tablet, or a custom transceiver connected to a computer) are communicated to the implant through radio frequency. The distance between the external device and the body with the implant must be within 3 m for communication to be established (10).

	The technology is being explored as a potential treatment for diabetes and osteoporosis as well as female contraception. The first human trial (11) was conducted in women with osteoporosis. The microchip-based implant was used to deliver teriparatide, an approved anabolic osteoporosis treatment that requires daily subcutaneous injections. The device was implanted in eight osteoporotic postmenopausal women for four months, with the microchip programmed to release the drug, once daily, in escalating doses, for up to 20 days (11). Pharmacokinetic evaluation demonstrated that the drug release profile of the implant was comparable to that of the standard daily injections of teriparatide, but with less variation in pharmacokinetic parameters because of the consistent dosing intervals delivered by the implant. Moreover, bone marker evaluation showed increased bone formation in the study subjects. Changes in serum calcium, N-terminal propeptide of type 1 procollagen (P1NP, marker for bone formation), and C-terminal telopeptide of type 1 collagen (CTX, marker for bone resorption), resulting from the implant, were found to be qualitatively and quantitatively similar to those observed with daily subcutaneous injections of teriparatide. No adverse reactions due to the implant were reported (11).


	Enable Injections is developing wearable bolus injectors for the delivery of high-viscosity and high-volume drugs in development (12, 13). The technology is currently available for investigational purposes and is particularly applicable for large molecules such as biologics, which often present challenges in drug delivery due to their high-viscosity, high-volume formulations. As the system is fully automated, patients can self-administer their medication. The injector has the capacity to deliver payloads of up to 20 mL to the subcutaneous tissue over a time frame that can range from minutes to hours. The system is designed to offer patients a safe, simple, and discrete device that provides a controlled and comfortable flow of drug at a rate that adapts to the wearer. Operation is simple, requiring only one push of a button. A “pause function” has been incorporated into the injector, allowing users to stop the injection at any time.


	1.    Medimetrics, “Controlled Drug Release,” http://medimetrics.com/Controlled-Drug-Release, accessed Mar. 13, 2015.
	2.    C. Wanke and J. Shimizu, 

 4 (5) 276-279 (2014).
	3.    D. Becker et al., 

. 15 (6) 1490-1497 (2014).
	4.    M.J. Whitaker et al., 

. 80 (4) 554-561 (2014).
	5.    S. Chan and M. Debono, 

. 1 (3) 129-138 (2010).
	6.    Diurnal, “Diurnal Reports Positive Results from a Phase 2 Study in Congenital Adrenal Hyperplasia Patients,” Press Release, June 23, 2014.
	7.    A. Mallappa et al., 

. 100 (3) 1137-1145 (2015).
	8.    Microchips Biotech, “Microchips Biotech, Inc. Completes Development and Clinical Demonstration of Proprietary Drug Delivery Platform and Advances Commercialization Efforts in Diabetes, Contraception and Osteoporosis,” Press Release, Dec. 15, 2014.
	9.    Microchips Biotech, “

,” accessed Mar. 13, 2015.
	10.    CRS, “

Wireless Medication: MicroCHIP’s Delivery of Future Medicines

,” accessed Mar. 13, 2015.
	11.    R. Farra et al., 

, accessed Mar. 13, 2015.
	13.    PR Newswire, “Enable Injections Presents A New Class of Injectors for Drug Delivery at PEPTalk, Drug Delivery Partnership Meetings, ” Press Release, Jan. 15, 2014.

 When referring to this article, please cite it as A. Siew, “Will Advances in Controlled Release Open Up New Drug Delivery Opportunities?” 

Emerging controlled-release technologies could lead to more effective therapies in the near future.

Will Advances in Controlled Release Open Up New Drug Delivery Opportunities?

	
	
	This year marked the 14th edition of Pharmapack Europe. The event, which took place at Paris Expo Porte de Versailles on 11 and 12 Feb. 2015, is known for its focus on cutting edge innovation in pharmaceutical packaging and drug delivery solutions. “The industry is constantly innovating,” commented event director, Aurore Domange, and Pharmapack Europe serves as a platform for exhibitors to showcase their new products.
	
	

Aptar Stelmi unveiled a new range of coated stoppers, PremiumCoat (see 

), designed for sensitive and high-value injectables, such as biotech drugs (1). Joel Cotten, business development director of Aptar Stelmi, pointed out that “biopharmaceuticals are very sensitive in nature and prone to interaction with the rubber of the stopper.” The challenge, therefore, is to maintain the integrity of the container closure while minimizing interaction between the formulation and the components of the elastomeric closure system. “To meet this demand, Aptar Stelmi developed the PremiumCoat range of elastomeric stoppers,” Cotten remarked. “The surface of the elastomer is coated with a barrier film (i.e., a thin fluoropolymer film) that effectively prevents extractables and leachables from contaminating the drug product.”

	Catalent’s Advasept technology forms a glass-free container closure system, offering an alternative to glass vials for injectable drug products (2). According to Bill Hartzel, director strategic execution, Advanced Delivery Technologies, Catalent, the advanced aseptic processing of blow fill seal (BFS) mitigates the risk associated with aseptic manufacturing of injectables. “The process is fully automated, reducing the potential of foreign particulates and providing sterility assurance. The vial is constructed using medical grade polypropylene resin. Of course, with plastic, the risk of breakage is reduced. And because it is glass-free, you eliminate delamination issues.” Hartzel added. “It is a simple process in which the vials are formed, filled, stoppered, and sealed.” However, there are considerations that must be taken into account as BFS creates a container closure system, noted Hartzel. “Extractables and leachables will be different, and stability needs to be evaluated because plastic is not impervious.” Catalent has evaluated the stability profile of a monoclonal antibody formulation in its Advasept vial, and the results of six months storage were comparable to that in glass vials (2). Catalent’s Advasept technology could mean a shift away from traditional glass vial paradigm.

	Celanese highlighted Hostaform MT SlideX POM, new tribologically modified polymers that enable the production of quiet, smooth-sliding medical devices. “During the past few decades, Celanese has analyzed the tribological behaviour of various thermoplastics and have found that engineering polymers are ideal candidates for use in medical applications,” said Andrew Brown, director, Celanese Global Medical Business. “Manufacturers use engineering polymers as an alternative to metal and ceramics in medical devices that require complex designs such as injection pens and inhalers. These plastics are different from metal because they are light weight, resistant to wear, have low coefficients of friction, and allow for dimensional accuracy through precision molding.” The advantages of inhalers and injection pens manufactured using Hostaform MT SlideX POM include a reduction in force required to activate the device and increased comfort during use because of the easy sliding properties.

	Essentra showcased its portfolio of packaging solutions, which range from cartons, leaflets, and labels to printed primary packaging. ComboPack consists of a pre-assembled leaflet attached inside or outside the flat carton. “It removes the need for in-line insertion equipment, particularly for small to mid-size companies that do not have all the packaging equipment,” explained Tiffany Overstreet, director, category management, Essentra. The company’s Plurium leaflet, on the other hand, is a multipage folded booklet for the communication of high volume of information. “There is an increasing need to have multiple languages on product leaflets, and Plurium provides a realistic way to accommodate all the information required by regulators. You can have one language per page for example, which enables patients to easily find the information relevant to them” said Overstreet.

Gerresheimer introduced an application aid for eye drop bottles (3). The innovation, known as DropAid (see 

), helps users to easily open their eye drop bottles. Its circular aperture fits onto the bottle top, enabling senior patients and children to open the bottle with little effort or pressure. When placed on the neck of an eye drop bottle, DropAid positions the dropper above the eye so that users can apply their eye drops without difficulty.

	Gerresheimer’s Gx MultiShell vials combine an inner and outer layer of cyclic olefin polymer (COP) with a centre polyamide layer (4). This three-layer structure increases resistance to breakage. According to the company, COP minimizes the interaction between highly sensitive biopharmaceuticals and the packaging, which means considerably less adsorption. The special design of the outer layer provides barrier properties that are up to 40 times more effective than other polymers (4). The high level of oxygen impermeability of these vials make them suitable for packaging of reaction-sensitive parenterals.

	Honeywell presented its Aclar films, designed to provide moisture barrier protection for hydroscopic formulations. The increasingly complex and sensitive nature of pharmaceutical products today create physical and chemical stability issues and the only blister packaging material available in the past was the cold formed foil. Aclar is a clear poly-chloro-tri-fluoro-ethylene film that is biochemically inert, chemical resistant, as well as plasticizer- and stabilizer-free. Honeywell’s latest innovation, the Aclar UltRx 6000 film, offers a theoretical 50% increase in moisture barrier protection according to the company (5).

	MegaPlast’s airless dispenser for liquids, creams, and gels, features a child-resistant closure in addition to its ability to dispense the precise dose and maintain formulation integrity by protecting against oxidation (6). This innovation was developed to meet market demand for security measures in packaging solutions. MegaPlast’s airless dispenser consists of a protective band coupled with a press-and-rotate opening system. Opening does not require force, which is especially useful for seniors. This non-pressurized dispensing system combines a mechanically activated pump and container that, after filling and air-tight sealing, delivers the product with no air intake.

Schott has extended its delamination-controlled (DC) product range with the addition of 6-mL and 8-mL vial sizes (7). Schott Vials DC have been developed to minimize the risk of delamination, which is the detachment of glass flakes from the inner glass surface of a pharmaceutical vial as a result of interaction with its contents. The vials are produced using chemically highly resistant glass tubing (Fiolax) coupled with optimized manufacturing processes that ensure the glass surface is more homogenous and thus less susceptible to delamination (see 

). “Production of the vials is routinely monitored for quality using our patented delamination quicktest,” explained Florence Buscke, global product manager, vials and coatings. “We check the sodium content because it correlates with delamination propensity. The aim is to ensure that Schott Vials DC do not exceed the set sodium limit.”

	West Pharmaceutical Services launched a new sterile, ready-to-use drug vial seal, the Flip-Off Plus seal, designed to help pharmaceutical and biopharmaceutical manufacturers protect the safety and integrity of their drug products (8). “Regulators are constantly pushing for higher standards,” noted Mike Schäfers, vice-president, Global Marketing, Pharmaceutical Packaging Systems, West. “Manufacturers of injectable drug products are required to use clean components for their filling operations.” Seals ensure that the injectable drug product remains sterile in its vial and is free from contamination. According to West, the company’s Flip-Off Plus seals consistently achieve reproducible and safe container integrity for drug products while keeping bioburden and particulates at low levels. “The seals are manufactured under clean environment using prewashed and sterilized components” continued Schäfers. “The production process ensures a clean, certified, and sterilized product that supports clean crimping.”

		Aptar Stelmi, “Aptar Stelmi Unveils PremiumCoat,” Press Release,	

		Bill Hartzel, “Advanced Aseptic Vial Production,” presentation at the ISPE Annual Meeting (Las Vegas, October 2014).	

		Gerresheimer, “Gerresheimer launches an eye opener for easy use of eye droppers,” Press Release, 11 Feb. 2015.	

		Gerresheimer, “Gx MultiShell vials are safe and efficient packaging for	

		Honeywell, “The Aclar Advantage,” www.honeywell-aclar.com/Documentation/Honeywell-Aclar-advantage-overview-brochure.pdf, accessed 1 Mar. 2015.	

		MegaPlast, www.mega-airless.com, accessed 1 Mar. 2015.	

		Schott, “Delamination Under Control,” Press Release, 4 Feb. 2015.

 When referring to this article, please cite it as A. Siew, “Highlights at Pharmapack Europe 2015,” 

A review of some of the latest packaging and drug-delivery innovation presented at Pharmapack Europe.

Highlights at Pharmapack Europe 2015

	Matthias Springfelter, senior formulation scientist at Recipharm Pharmaceutical Development AB, Solna, Sweden, spoke to 

 about the advantages and the key considerations in developing topical formulations. 
	
	

: What advantages do topical formulations offer compared to other dosage forms?
	
	

: Perhaps the most obvious advantage is that topical formulations allow for local treatment of a number of dermatological conditions with very little systemic exposure. A high drug load can be applied on the actual site where the drug is required, with a reduced risk of unwanted side effects. Topical products are easy for the patient to apply and the moisturizing effect of topical formulations, such as creams and ointments, may also be beneficial for several skin conditions.

	Transdermal delivery systems offer an alternative route for systemic administration of various drugs with the benefit of a reduced risk of loss of potency or unwanted variability due to first-pass metabolism. Transdermal delivery systems can be designed to offer prolonged and controlled-release absorption of certain drugs, which can be convenient for pain relief drugs, nicotine, and hormone products.  
	
	

: Can you tell us more about the mechanisms of drug absorption across the skin barrier and how they affect the development of topical drug products?
	
	

: The human skin functions as an efficient barrier against the outside environment. Achieving sufficient drug absorption can, therefore, prove challenging for many molecules. For a drug to reach its target site or to be absorbed into the blood stream, a sufficient amount has to pass through the outer part of the epidermis, the 

, and the epidermis. Even though there are some passages, such as the hair follicles, sweat glands, and active transportation mechanisms, the most important mechanism for drug absorption is by passive diffusion. The rate of diffusion will, to a large extent, depend on the properties of the drug molecule itself. However, formulators can use a number of methods to optimize drug absorption.
	In general, small-sized and relatively lipophilic molecules are most likely to be readily absorbed through the skin, and this aspect must be considered when selecting a drug candidate. Sometimes, it is possible to modify the drug properties or alternatively, choose a pro-drug that is delivered in inactive form and that better matches these criteria. The choice of vehicle depends on the properties of the drug substance, such as the solubility profile and partition coefficient, so that the chemical potential of the drug is maximized. The permeability of the skin is also an important factor--the penetration rate could be increased by an increase in skin hydration, for example, by choosing an occlusive vehicle or patch. A number of penetration enhancers that increase the absorption of a drug by temporarily increasing the permeability of the skin have been evaluated, but there are limitations because of skin irritation or toxicity concerns.

: What are the main components of a topical formulation?

: The components of a topical product will depend on the type of formulation. It could be as simple as an active ingredient dissolved in a solvent with suitable additives such as pH-buffers, co-solvent, and preservatives to achieve adequate solubility and stability for the formulation. In a topical gel, viscosity modifiers such as cellulose-based or synthetic polymers are added to achieve the desired rheological properties. Ointments are semi-solid preparations of a drug substance dissolved or dispersed in a semisolid ointment base made of paraffin or other hydrocarbons. Emulsions are somewhat more complex because they consist of two liquid phases, one of which is dispersed within the other, usually oil droplets dispersed in water. A number of excipients are often necessary to achieve a physically and chemically stable emulsion. Water and one or more organic compounds, such as mineral or vegetable oils, make up the two liquid phases, and one or more emulsifying agents will be needed to keep the phases apart. The stability of the emulsion can be further improved by the addition of polymers to increase the viscosity of the water phase. Additional excipients such as pH-buffers, antioxidants, and preservatives are usually added as well.

Considerations in formulation development

: What are the key considerations when designing a formulation for topical drug delivery? 

: First of all, the choice of formulation must be made based on the disease or condition to be treated, the type of skin upon which it is to be applied, and the properties of the drug substance. After that, one has to ensure that sufficient amount of the drug reaches its site of action, whether it is  on the skin layer, or systemically. The drug absorption may have to be optimized, for example by adjusting the vehicle or adding penetration enhancers. It is also important to ensure that skin irritation and toxicity are minimized.

	As always in formulation development, the physicochemical properties of the drug product must be well controlled. The stability of the active ingredients and other functional excipients, such as preservatives or antioxidants, will have to be monitored. Phase changes, such as separation or bleeding, must be prevented in emulsions and ointments. The microbial quality control of the drug product needs to be considered, especially in water-rich formulations; in this case, it is often necessary to add preservatives. The viscosity and rheological behavior should be adjusted to fit the type of application and the overall cosmetic properties should be acceptable.

: Can you elaborate more on the selection of a vehicle for topical formulations and how drug properties will affect the choice of a vehicle?

: The selection of a vehicle for a topical formulation is based on several factors, ranging from stability and compatibility, the type of disease and skin to be applied on, to biopharmaceutical considerations.

	In general, the lipophilic type of vehicles, such as ointments and emulsions, are preferred for conditions that involve dry skin. Ointment vehicles are commonly used as they provide a moisturizing effect on dry and flaky skin due to their occlusive properties. In addition, the increase in hydration of the skin can also improve the absorption of the drug. Ointments are also less irritating to sensitive skin than water-based formulations, but they have a greasy feel that patients tend to dislike.

	Emulsion-type vehicles, such as oil-in-water creams, are often preferred for their improved cosmetic properties because they are easy to apply and are less viscous and greasy. Achieving a stable emulsion, however, can prove to be challenging in some cases. Liquid vehicles such as solutions or gels are convenient for application on hairy skin areas such as the scalp and are sometimes preferred in dermal conditions for which a drying effect is desired. For transdermal applications, a suitable patch or other device would have to be evaluated together with the formulation.

: How do you test drug release and drug absorption?

: A number of methods are available for the evaluation of the drug release and absorption of dermal and transdermal products. There is, however, no gold standard and the method used will vary from case to case.

 methods are particularly useful for early studies and screening purposes. For transdermal patches, the paddle-over-disc method described in the 

 dissolution rate. For semi-solids, no compendial methods are available, but the diffusion cell systems, such as Franz or In-Line cells, are widely used and may be fitted with various artificial or animal skin membranes, or even excised human skin. Diffusion cell systems can provide useful information and guidance, for example, when choosing the vehicle for a topical product, but as always, caution should be taken when extrapolating into more complex 

 models and methods are also being developed, and are becoming more useful in the characterization of topical products. 

 studies in different species of animals are often performed, but as animal skin differs from human skin, results should be extrapolated with caution.

: As the pharmaceutical landscape becomes increasingly competitive, drug developers are now focusing more on patient centricity and formulation for specific populations. In your opinion, what is the future outlook for semi-solid drug products and do you expect demand for this type of dosage form to increase?

: We have seen increased interest in semi-solid products in recent years and there may be several reasons for this trend. Where, several years ago, the focus was on blockbuster products, today there is a move toward more niche applications. As demand for personalized products increases, topical administration is gaining popularity. Another key driver is the increasing interest in new products that use existing drug substances. New topical formulations using drugs that were previously administered in another dosage form can offer significant benefits, not only therapeutic benefits, but financial ones, as they reduce development cost and risk.

 When referring to this article, please cite it as A. Siew, “Semi-Solid Dosage Forms,” 

While the skin offers an alternative route of administration for local and systemic drug delivery, developing semi-solid dosage forms can be a challenge.