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

Adeline Siew, PhD

Dissolution testing is an important tool for characterizing the performance of oral solid dosage forms. Its significance is based on the fact that for a drug to be effective, it must first be released from the product and dissolve in the gastrointestinal fluids before absorption into the bloodstream can happen. In other words, the rate and extent of drug absorption are determined by its dissolution from the dosage form.

	For a commercial product, this test is routinely used for quality-control and quality-assurance purposes, to ensure consistency between production batches, or to justify scale-up and post-approval changes made to the manufacturing process (1). In early phase drug development, dissolution testing aids formulation design and drug delivery optimization (2); it is primarily carried out to assess product stability, monitor formulation changes over time, and establish 

 correlations have been demonstrated, dissolution can be used as a surrogate test to predict the 

 performance of drug products (4). From a regulatory perspective, dissolution testing plays a major role in the decision-making process, particularly in the development and approval of generic dosage forms, where unnecessary human studies can be avoided without compromising the quality of the generic drug products (5).

	A dissolution test measures the amount of drug that goes into solution over a period of time under standardized conditions. Factors that affect the dissolution of a drug product include the intrinsic properties of the API (e.g., solubility, wettability, particle size, surface area, morphology, polymorphs), the formulation composition and characteristics (e.g., excipients, hardness, manufacturing process), and the dissolution method used for its assessment (e.g., apparatus, medium, test conditions, sampling, and sample analysis) (6).

	In dissolution testing, the aim is to develop a discriminatory method that is sensitive to variables that affect the dissolution rate, and consequently, the 

 performance of the drug product. The method must be able to distinguish between drug products manufactured under target conditions and formulations with meaningful variations for the most relevant critical manufacturing variables, such as drug substance particle size, compression force, and tablet hardness, for example (7). The dissolution method should also be sufficiently rugged and reproducible for daily operations as well as transferable between laboratories (7).

 describe four different dissolution apparatuses that can be used to develop an appropriate dissolution method for oral solid-dosage forms based on the drug product characteristics (8, 9).

	Apparatus 1 (basket) and Apparatus 2 (paddle) are most commonly used methods in dissolution testing. Apparatus 1 consists of a vessel made of glass or other inert, transparent material and a cylindrical basket attached to the lower part of a rotating stirrer. The set up for Apparatus 2 is generally the same except that a paddle formed from a blade and a shaft is used as the stirring element. Sinkers may be used for dosage forms that would otherwise float. These apparatuses are simple, robust, well standardized, and flexible enough to allow dissolution testing for a wide variety of oral solid-dosage forms (1). Baskets and paddles are recommended for dissolution method development unless they have been shown to be unsatisfactory (1). One disadvantage with the basket and paddle methods is that the volume for dissolution is fixed. In addition, simulation of gastrointestinal transit condition is not easily possible.

	Apparatus 3 (reciprocating cylinder) was develop in recognition of the need for a system that sequentially alters the dissolution conditions to mimic the gastrointestinal tract, so that 

correlations can be established. Apparatus 3 consists of a set of cylindrical, flat-bottomed glass vessels, a set of glass reciprocating cylinders with inert fittings and screens at the top and bottom of the cylinders, and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels; and if desired, the reciprocating cylinders can be moved horizontally to different rows of vessels (8, 9). Unlike the baskets and paddles, agitation in Apparatus 3 comes from dipping within the vessel, rather than through a stirred media approach. The advantages of the reciprocating cylinder include the ability for pH profiling, which enables simulation of pH changes in the gastrointestinal tract; and the system can be programmed to run dissolution in different media and at different speeds at various times (i.e., programmable dip speeds at each interval and programmable interval time). Such flexibility allows for better 

	Apparatus 4 (flow-through cell) consists of a reservoir containing the dissolution medium, a pump that forces the medium upwards through the vertically positioned flow-cell, and a water bath to maintain the temperature of the dissolution medium (8, 9). The flow-through cell apparatus can operate in two different modes-an open system with continuous flow of solvent passing through the cell from the reservoir, and a closed system where a fixed volume of media is recirculated. The open system is suitable for poorly soluble drugs, which require a high volume of media for dissolution. The closed system, on the other hand, is used when a low volume of medium is required.

	Dissolution testing should be carried out under physiological conditions (4). Media selection will be based on the purpose of the dissolution test, taking into account the solubility of the API. Ideally, the dissolution media should meet sink conditions, ensure that the drug is stable for at least 24 hours, preferably avoid the use of surfactants and alcohol where possible, and be biologically relevant for the site of dissolution 

 (i.e., pH 1.2–6.8 for immediate-release dosage forms and pH 1.2–7.5 for modified-release formulations) (3, 10).

	Sink conditions are described as the volume of the media being at least three times of that required to form a saturated solution of the drug substance. Sink conditions ensure that the amount of drug already dissolved in the media does not affect the dissolution rate as the run progresses. If sink conditions are not met, the dissolution rate will artificially slow down as the API nears the saturated solution state, making the dissolution test overly discriminatory and not reflective of 

 environment (10). However, although recommended, sink conditions are not always an essential requirement; failing to provide sink conditions may be justifiable in some cases. For example, when dissolution testing is used to indicate the biopharmaceutical properties of the dosage form, it is more important that the proposed biorelevant test closely simulate the gastrointestinal environment than necessarily produce sink conditions (3).

	The use of surfactants has to be justified, including the type and concentration of surfactant added into the dissolution media. For poorly soluble drugs, it may not be possible to achieve sufficient dissolution with aqueous solutions within physiological pH ranges; therefore, for these compounds, a surfactant may be required to enhance the drug solubility (3).   

	Once a dissolution test has been developed, it is important to have a good understanding of the method’s characteristics and ruggedness. It generally involves testing the method with different lots of the drug product and anticipating the variations that can be expected (1). 

 17 (1) 8-11 (2011). 
	2. X. Lu, “Filling in the Gaps for 

 Release and Dissolution Testing of Solid Oral Dosage Formulations,” AAPS Blog, Aug. 16, 2016.
	3. C. Brown et al., 

Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms

 (Rockville, MD, Aug. 1997)
	5. O. Anand et al., 

13 (3) 328-335 (2011). 
	6. J. Kochling, “Approaches to the Investigation of Dissolution Testing Changes and Failures,” AAPS Webinar, May 23, 2013. 
	7.

 General Chapter <1092>, “The Dissolution Procedure: Development and Validation,” (US Pharmacopeial Convention, Rockville, MD, 2013).
	8. 

 General Chapter <711>, “Dissolution,” (US Pharmacopeial Convention, Rockville, MD, 2011).
	9. 

, Chapter 2.9.3, “Dissolution Test for Solid Dosage Forms,” (EDQM, Strasbourg, France, 2008).
	10. K. Boda, “

Transferring Dissolution Methods--Building a Robust Dissiolution Method

	When referring to this article, please cite it as A. Siew, "Dissolution Testing,” 

Articles

A dissolution method should have adequate discriminatory power to detect formulation changes that affect the dissolution rate of a drug product.

Dissolution Testing

	The proliferation of counterfeit medicines is nothing new to pharma; however, the scale of the problem seems to be escalating, especially with the Internet providing an easy means for fraudsters to dispense their fakes. Counterfeiting has a devastating impact on public health and the economy. Not only are consumers paying for products of inferior quality, but their wellbeing is also put at risk. For genuine drugmakers, profits are diluted, but the repercussions extend beyond that.

	The European Union Intellectual Property Office (EUIPO) reported in September 2016 that the pharmaceutical industry is stripped of approximately €10 billion of revenue every year because of counterfeit medicines; this figure accounts for 4.4% of the sector’s sales (1). EUIPO noted that the lost sales translate into 37,700 jobs lost across the pharmaceutical sector in the EU as a result of legitimate manufacturers and distributors employing fewer people than they would do had this problem not existed (1). 

	According to the report by EUIPO, the United Kingdom’s pharmaceutical sector lost €605 million of sales due to counterfeiting, with 2940 direct jobs lost (1). Germany, France, Spain, and Italy took an even bigger hit, losing more than €1 billion of pharmaceutical sales, which correspond to 6951 employment opportunities lost in Germany, 3945 direct jobs lost in Italy, 3667 in France, and 3223 in Spain (1). 

	It is not difficult to see what feeds the unfortunate growth of the counterfeit market. It is a highly profitable activity. The demand for medicines coupled with the cost of prescription drugs make vulnerable patients an easy target that can be lured by lower prices. On a brighter note, regulators worldwide are taking measures to crack down on counterfeits. With serialization and track-and trace legislations being rolled out over the next few years, pharma is doing its part to secure its supply chain. The problem will be an ongoing challenge for the industry, but with advances in technology, it will become easier to detect the fakes in the near future.

	1. EUIPO, “The Economic Cost of IPR Infringement in the Pharmaceutical Industry” (September 2016).

	When referring to this article, please cite it as A. Siew, "The Cost of Counterfeits,"

The proliferation of counterfeit medicines is nothing new to pharma; however, the scale of the problem seems to be escalating.

The Cost of Counterfeits

The pharmaceutical contract manufacturing market is expected to hit revenues of $80.5 billion in 2019, according to a report by business intelligence provider Visiongain (1). A notable trend is that pharmaceutical companies will continue to outsource more drug production operations. For several years, API manufacturing has formed the largest share of the pharmaceutical contract manufacturing market, driven by the increased use of generic drugs worldwide, the rise of biologics and biosimilars, and the growth of emerging markets such as India and China (1).

	To remain competitive in an increasingly demanding pharmaceutical market, contract service providers are constantly striving to increase the capacity and efficiency of their manufacturing activities. 

spoke to industry experts about process optimization in API manufacturing. Participants in this roundtable discussion include Joshua P. Van Kley, corporate sales and sales operations manager, Cambrex; David Goeddel, PhD, group leader, Process Development, MilliporeSigma; 
	Andreas Stolle, vice-president, Process Development Services API, and Peter Poechlauer, innovation manager, who are both based in Linz, Austria, which is currently Patheon’s largest API manufacturing site.

 What factors should be taken into account when developing an API manufacturing process? What guidelines have regulators provided?

 When developing an API manufacturing process, there are a number of important considerations from a practical and logistical standpoint. Firstly, can the chemistry be performed at the manufacturing site in terms of handling the necessary solvents and reagents, and does the plant have the capabilities to accommodate the temperature ranges of the process? It is also important to evaluate the specific hazards and safety implications of undertaking the process.

	Availability of key raw materials must be evaluated to ensure that they are readily available from existing suppliers, or whether new suppliers can be established, to avoid a situation where you are limited by supply of a key raw material or unable to import it.

	It is also important to look at the process from an environmental point of view, to ensure that all waste can be handled and disposed of properly, and also to ensure that the process is scalable from laboratory through to the commercially projected scale. Hazards, by-products, and waste products that are not as consequential at smaller scale can become major issues at large scale, thus, it is important to factor these considerations in from the beginning.

	There are also many other considerations that come into play, such as clinical phase, cycle time, the control of the product’s particle size, polymorphism, and handling issues such as the filterability of steps within the process. All these factors can have an impact on the quality of the product as well as cost of goods, therefore, it is important to bear them in mind when providing a quality product as well as meeting the customer pricing demands.

 Several factors should be taken into account when developing the manufacturing process for an API. Careful focus should be placed on ensuring that the overall purity, purity profile, and individual impurity levels are at acceptable levels to ensure the safety of the patient. Guidance has been provided in this area by the International Council for Harmonization (ICH) on threshold limits for impurity identification and qualification in API drug substances--ICH Q3A. In addition to organic impurities, process chemists should also pay close attention to residual solvent levels and elemental impurities when developing a process for API manufacturing. This factor is particularly important when metal catalysts are used in the API synthesis, and remediation techniques (scavengers, charcoal, or crystallization) are often required to reduce these impurities to the acceptable levels outlined in ICH Q3D.

	In addition to impurities, another aspect that needs to be taken into consideration when developing an API process is the potential reactive hazards. Performing a thorough safety evaluation and modifying the chemistry as appropriate will enable the API to be made safely, which will help prevent operator injuries, plant or equipment damage, and potential supply-chain interruptions. The raw material supply chain is another important factor. Not only does the vendor need to be qualified, but they must also be able to ensure the long-term timely delivery of needed raw material quantities in the required quality.

	Finally, throughput is another important factor that should be taken into account when developing a process. Improvement in yield lowers API cost and reduces waste, which will consequently benefit the patient, company, and the environment.

	API purity, impurity levels, raw material supply chain, yield, and process safety are all important factors that should be taken into account when developing a process for API manufacturing. Focusing on those key areas will help secure both patient and employee safety while completing efficient chemical syntheses that reduce cost and minimize the impact on the environment during API production.

The development of a 
	pharmaceutical manufacturing process has to meet different requirements depending on the development phase of the product:

		In early clinical development (CT I), the primary goal is to deliver the required amounts of material quickly and in reproducible quality.

		Later on (in CT II), when the route is frozen, the production process must be reliable, well understood, and again deliver the product in the required quality. The appearance of potentially genotoxic byproducts in the final product must be excluded in a safe and scientifically sound way.

		Finally, the process for the final clinical trials (CT III) and launch of the product must be scalable to deliver the required product volumes with predictable quality, and it has to be environmentally benign and economical on resources.

		After product launch, the process must have room for continuous improvement without major changes.

	In addition to the process figures, the following factors must be taken into account:

		Availability and safe supply of starting materials in constant quality

		Investments in equipment to operate the envisaged process at the desired scale

		Start-up time and time demand for capacity changes

		Easy process transfer between different manufacturing sites to meet local demand and support supply-chain optimization.

	The current regulatory environment supports advancing regulatory science and innovation, which may include abandoning some traditional manufacturing 
	practices in favor of cleaner, more flexible, and more efficient continuous manufacturing. Regulatory authorities in the three ICH regions and beyond are encouraging the industry to adopt new technology as supported by ICH Q8(R2), Q9, Q10, and Q11; and the introduction of quality-by-design (QbD) concepts, emphasizing science and risk-based approaches to assure product quality. The regulatory expectations for assurance of reliable and predictive processing, which is technically sound, risk-based, and relevant to product quality in a commercial setting, are the same for batch and continuous processing.

 How do you optimize process chemistry in API manufacturing? What are the key considerations?

 Our key considerations in optimizing process chemistry are driven by optimizing the service to our clients. This approach comprises considerations such as:

		Are the involved chemicals and reagents reliably available?

		Is their price acceptable in view of the target product price?

		Does the generated waste pose a problem?

		Can we develop a sufficiently detailed process 

		Do the chosen conditions allow quick and safe scale-up?

		Is the process easily transferable between sites or does it require specialized equipment?

Batch-wise versus continuous processing concept:

		Will the process yield/throughput profit from continuous manufacturing techniques?

		Will process control profit from continuous manufacturing?

		Can we develop a sufficiently quick and easy process control system?

		Are the chosen analytical methods reliable and easily transferable?

		Does the process control system support continuous process verification?

	Our optimization strategy comprises both classical determination of proven acceptable ranges (PAR) values and, in tight collaboration with clients, strategies of multivariate analysis and other elements of process analytical technologies. In addition to technical aspects of optimization, there are aspects related to client requirements, such as use of innovative but proven technologies to provide maximum value.

 Initially, the process is carried out in its current state using the conditions provided by our clients. This approach allows us to observe the chemistry and get a feel for how it performs. From there, the next stages of development investigate ways to reduce solvent volumes, increase yields, reduce cycle times, lower raw material costs, and lower waste costs. These steps are crucial to improving product quality and the economics of the process, which allows us to pass efficiencies and qualityon to our clients. Most of this work is undertaken in the chemical development laboratory prior to going into production. Once in production, the chemist and engineer assigned to the program will further work on optimization of the process based on observations made during production. In addition, our continuous improvement/six sigma group will also contribute to the optimization process once the program is in validation or commercial launch. The group will help in managing the lifecycle of the program along with looking at ways to continually improve the efficiency of production by data mining.

	Typically, we will see programs that have chromatography steps within the process, high volume issues, filtration issues, and/or long cycle times. Our development efforts are centered on removal of any chromatography processes if present for scaling purposes, volume reductions, faster filtrations, and cycle time reduction, either for efficiency or the possibility of telescoping steps to reduce unnecessary isolation steps if the process lends itself.

 We strive to perform phase-appropriate process optimization for API manufacturing. Process optimization means very different things for Phase I clinical programs compared with programs that are entering validation. For an API that will be entering Phase I, the key objective is usually to rapidly develop a process that can safely yield the required API with the necessary quality attributes. This way, clinical evaluation of the API can begin quickly, which is important for both drug developers and patients who seek successful treatment. As the program advances toward validation and commercial launch, greater emphasis is placed on improving yield and gaining greater process understanding to support process validation and eventual launch.

	No two programs are the same, but there are some consistent factors that generally apply to most programs. We consider several factors when deciding whether the incoming synthetic route can be used or if a new synthesis should be developed. Raw material supply chain, process safety, projected future API manufacturing costs, likely commercial scale, and timing all play an important role in the decision-making process. After a route is selected, proof-of-concept studies are performed to determine whether or not the proposed route can generate the API. We then optimize the process to reliably and safely generate API in adequate quality. This objective is achieved by building process understanding through many techniques, including impurity origin and control, identifying critical parameters, and setting appropriate limits on operating ranges. We develop this chemistry with an eye on the intended commercial manufacturing scale, because APIs that will be manufactured on a smaller scale will have more processing options available than those that will be made on a larger scale. During the final phase of optimization, experimentation is performed to determine if the API can consistently be manufactured with the required quality attributes. Statistical design of experiments is a particularly useful technique for these studies, because interdependent variables can readily be identified. The successful completion of these phase-appropriate process optimization efforts enables us to deliver high-quality clinical batches and commercial supply in a timely manner, which is important for our customers and their patients.

 How can manufacturers ensure that APIs of the intended quality are consistently produced?

 Manufacturers take steps that span from early research and development through commercial manufacture to ensure that APIs of consistent quality are produced. The general pathway for this process is outlined by FDA and involves three phases: process design, process qualification, and continued process verification.

	During the process design phase in development, great effort is made to understand what parameters are critical. Building upon that knowledge, the process is optimized as necessary to enable the desired quality attributes to be consistently achieved. Manufacturers then perform a failure modes effects analysis (FMEA) on the process to identify processing risks that could impact quality attributes. From that exercise, additional experiments can be designed to address risks identified in the FMEA to ensure that the critical quality attributes are reliably met. During this stage of development, manufacturers perform stress testing, stability studies, design of experiments, and range-finding studies to help ensure that the intended quality is 
	consistently produced in subsequent manufacturing.

	The process qualification phase involves an assessment of whether or not the process is reproducible. There are two major components to process qualification. The first part involves the qualification of the plant and equipment to ensure everything works as intended. The second part involves the qualification of the process itself through an activity known as process performance qualification (PPQ). PPQ involves drafting a protocol, execution of the protocol for the specified number of batches under current good manufacturing practices (cGMPs), and issuance of a report. Following successful completion of the process qualification, the process can be used for commercial supply of the API.

	The process to ensure product quality does not end with product launch. Manufacturers use systems that enable them to track process data and identify any sort of trend that may require intervention. Furthermore, an adequate facility and equipment maintenance program ensures that the plant and equipment are functioning at the desired level. By performing all of the aforementioned activities, manufacturers can ensure that APIs of the intended quality are consistently produced.

 The key to consistent quality product is a sound process understanding combined with effective process control. Process understanding suffers if the features of the processing equipment mix with features of the actual chemical reaction, blurring them and interfering with precise process control. Consistent production of APIs of intended quality starts with a kinetic and thermodynamic analysis of the synthesis reaction. The rate, energy balance, and kinetics of by-product formation and factors such as equilibria of phase distribution determine the requirements of the process. They in turn determine the features of the processing equipment and ultimately the equipment selection. They also determine the control strategy to effectively safeguard consistent product quality. A sound process understanding allows the 
	conscious choice of proven acceptable ranges for reaction parameters and intermediate product quality. It avoids overly narrow parameter ranges or unnecessary tight intermediate product specifications and thus allows for continuous improvement without putting API quality at risk. In many cases, continuous processing simplifies the precise control of process conditions even for processes that are very exothermic or require quick mixing to establish the correct stoichiometry and avoid byproduct formation.

	Continuous processing equipment can be tailored to meet the respective requirements of a chemical reaction or work-up section with moderate effort. Its combination with state-of-the art methods of continuous analytics allows precise and reliable control of product quality.

	There appears to be a paradigm change: instead of slowing down the chemistry to a degree to allow large-scale batch processing equipment to cope with heat evolution etc., the developer determines ideal conditions for the respective chemical transformation and defines (or if necessary constructs) suitable processing equipment and control instruments. This approach leads to more modern ways of processing and, as the PAT guideline (2) stipulates, ‘development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance.’

 An important step is performing critical process parameter studies. A critical process parameter study is initiated to identify those critical parameters in the process that affect the final product quality and reproducibility. Typical critical parameters to be investigated at each step requiring validation may include: temperature, charge ratios, pressure, vacuum, time (duration), flow rate, cooling rate, and agitation speed, among others.

	Critical process parameters are usually identified and studied after initial laboratory work, or after initial manufacturing campaigns, when the chemists can observe the behavior of the chemistry at scale. Our customers typically dictate when they want this work to be performed to tighten up the operating parameters.

	From a quality perspective, Cambrex follows ICH Q7 guidelines. In addition, we have a strong analytical method validation program in place for all analytical methods, including cleanout methods for each isolated intermediate as well as finished goods. The validated cleanout methods not only ensure quality for the current product being manufactured, but also ensure the quality and integrity of the plant for the next product to be produced, as we operate a multipurpose facility with non-dedicated production streams.

Pharma Contract Manufacturing Services Market Will Reach $80.5 Billion in 2019

,” accessed July 19, 2016. 
	2. FDA, Guidance for Industry, PAT--A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004).

Contract service providers stay competitive by increasing the capacity and efficiency of their manufacturing activities.

API Manufacturers Compete through Process Optimization

Excipients are typically the major components of a solid dosage form. These non-active substances have well-defined roles in the development of tablets and capsules, and are included for a number of reasons such as to aid the manufacturing process or to add functionality to the formulation. 

	Excipients can be divided into several broad processing categories for functionality, notes Paul Skultety, vice-president, Pharmaceutical Development Services, Xcelience, a division of Capsugel. Bulking agents such as lactose, dibasic calcium phosphate, or microcrystalline cellulose are used to make the dosage form bigger in size, he says, firstly, so that it is easier to manufacture, and secondly, to achieve a practical tablet weight for patients to handle. The minimum tablet weight is typically approximately 50 mg.

	Binders such as pregelatinized starch, microcrystalline cellulose, and various polymers are included to facilitate the granulation step. Binders hold the granules together, making the powders easier to compress. Glidants (e.g., colloidal silica) promote powder flow by reducing interparticulate friction and cohesion, enabling the powder to flow better in the hopper and when filling the tablet or capsule dies. Good bulk powder flowability is essential in high-speed processing and reduces problems associated with content uniformity, which can happen if the powders do not flow uniformly, explains Skultety. Lubricants, such as magnesium stearate or stearic acid, are often used in combination with glidants to reduce the tackiness of the powders. Lubricants prevent sticking of the granules or powders to the dies or punches during compression.

	Excipients are also included to protect the API. Antioxidants such as ascorbic acid, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) are used with compounds that may be susceptible to oxidation, says Skultety. In cases where it is necessary to control the pH of the local environment, pH modifiers such as citric acid or sodium acetate can be added. These agents can help if solubility or stability is better in a certain pH range, he explains. Wetting agents such as polysorbates or sodium lauryl sulfate can be added to help wet the API and get it into solution faster.

	In recent years, the term “functional excipient” has been used more often to describe an excipient that can provide an added function or quality over and above the “conventional” excipients, observes Rob Harris, chief technical officer at Juniper Pharma Services. For instance, powder flow for direct compression formulations may be improved with the inclusion of co-processed silicified microcrystalline cellulose, he says.

	According to Andrew Bulpin, head of Process Solutions Strategic Marketing and Innovation at MilliporeSigma, an ongoing trend in the industry is toward direct compression for oral solid-dose forms to reduce process complexity. As a result, there are specific requirements regarding the particle structure of the excipient that excipient manufacturers have to address. JRS Pharma’s silicified microcrystalline cellulose (Prosolv SMCC) is a unique combination of microcrystalline cellulose (MCC) and colloidal silicon dioxide (CSD). This functional excipient was developed to address common problems of conventional binders such as low bulk density, poor flow, loss of compatibility, stickiness, and sensitivity to lubricants (1). According to the excipients manufacturer, the production process of Prosolv SMCC leads to homogenous and much finer CSD particle size distribution. Surface area is increased as a result, which enables better flowability and compactibility, and subsequently improves the content uniformity and stability of the formulation. It can be used for direct compression, in which it reduces the number of required excipients and use levels (1).

	Ensuring sufficient API bioavailability is a prevalent challenge for formulators, Bulpin highlights. While there are various solutions available, one approach is to use functional excipients to improve solubility, which will in turn lead to bioavailability enhancement. Inert drug carriers can be used as a vehicle for poorly soluble APIs, he says, and Parteck SLC, a silica carrier with unique pore structure, is well suited for this application.

	Mesoporous silica grades, such as MilliporeSigma’s Parteck SLC, are a relatively recent addition to the excipient listing, observes Harris. According to him, they are becoming popular in formulations due to their highly porous structure, which can be used to hold liquids (effectively converting liquids into free-flowing solids) or to hold poorly-soluble drugs in the amorphous form, thus enhancing solubility of the drug. Parteck SLC’s mesopores provide a surface area of up to 1000 m

/g for depositing an API, and the API is kept stable. A user-friendly particle size of 5-25 μm and bulk density of 0.32 g/mL allow easy loading, tableting, or capsule creation (2).

	Polymers and copolymers--such as cellulosics (e.g., hydroxypropyl methylcellulose [HPMC], hydroxypropyl methylcellulose acetate succinate [HPMCAS]), polyvinylpyrrolidone (PVP), acrylates and methacrylates, polyethylene glycol (PEG), and polyethylene oxide (PEO)--also play a crucial role as solubilizing excipients, particularly in the formulation of amorphous solid dispersions. These polymers are amphiphilic in nature; the hydrophobic and hydrophilic sites enable them to interact favorably with the lipophilic drug and yet disperse and dissolve in aqueous environments such as the gastrointestinal tract. The specific interactions of the polymer with itself, the API, and the aqueous medium can result in a range of solubilizing structures, including micelles, colloids, and ionic complexes (3). Examples of such solubilizers include Soluplus (BASF), Affinisol (Dow), Eudragit E, and Eudragit L 100-55 (Evonik).

	The cyclodextrins form another class of functional excipients that are widely used for solubility enhancement purposes. Cyclodextrins are cyclic oligosaccharides derived from starch that take the shape of a truncated cone consisting of a lipophilic central cavity and an outer hydrophilic shell. The mechanism of solubilization is based on the ability of the cyclodextrin to form water-soluble inclusion complexes with the poorly soluble drug. Besides enhancing solubility, formulation with cyclodextrins has also been shown to improve the physical and chemical stability of some APIs (4). A number of cyclodextrin-based products are already on the market, for example, Takeda’s cefotiam-hexetil hydrochloride tablet (Pansporin T), Novartis’ nimesulide tablets (Nimedex), and Janssen’s itraconazole capsules (Sporanox), to name a few (4).

	To increase patient compliance, it is crucial to tailor an API release profile to maximize API efficacy and at the same time reduce side effects, as well as dose frequency, Bulpin points out. Modified-release, functional film-coating systems can be used to delay or extend the drug release from the dosage form, says Pankaj Rege, general manager, Manufactured Excipients, Colorcon. He adds that besides providing product differentiation and branding, film coating can help improve patient compliance by aiding swallowability and taste-masking unpleasant APIs.

	The majority of modified-release technologies are based on the use of polymers to encapsulate the API and control its rate of release. Ethylcellulose polymer has long been used as a coating material for such applications. Colorcon’s Surelease and FMC Biopolymer’s Aquacoat ECD, for example, are aqueous coating systems in which ethylcellulose works as the rate-controlling polymer for drug release. The principle is based on drug diffusion across a water-insoluble membrane. Ethylcellulose aqueous dispersion provides a stable, reproducible, pH-independent drug-release profile with similar dissolution profiles in both fed and fasted states (5). The drug-release profile can be tailored by adjusting three critical formulation attributes--plasticizer, pore former concentration, and film thickness.

	According to Kathrin Nollenberger, director of Formulations and Polymers, Evonik, recent developments focus on further improvements of existing excipients, for example, to simplify the use or increase the efficiency of coating systems by easy-to-use or ready-to-use premixes (e.g., Eudragit E PO ReadyMix). Applying such coating systems reduces the risk for failures, as well as saves production and storage costs, she says.

	Another focus is to address new challenges such as alcohol-induced dose dumping (ADD) from modified-release formulations, Nollenberger highlights. Dose dumping may occur if the polymer matrix or film coating, which controls drug release, is compromised through dissolution in hydro-alcoholic liquids. Dose dumping is the rapid release of the entire dose or a significant fraction thereof in a short period of time.

	One solution to ADD, according to Nollenberger, is to combine the use of existing excipients to novel formulation systems. “An example for such an enabling formulation system is Evonik’s technology platform Eudratec ADD, which offers a portfolio of novel coating formulations for extended- and delayed-release formulations using combinations of existing functional polymers for ensuring alcohol-resistant coatings for monolithic and multiparticulate dosage forms,” she says. “Reaching this target without any chemical modification of approved and monographed polymers allows an easy and direct application without additional regulatory hurdles.”

	An immediate-release dosage form of a moisture-sensitive API will require measures to protect the drug from humidity, both from the excipients and during processing, Harris highlights. Excipients chosen would either be anhydrous or have low water activity, he says, adding that a “dry” process for manufacture would be required, either by powder blending/direct compression or dry granulation by roller compaction.

	According to Rege, formulation development of a moisture-sensitive API requires selecting excipients that mitigate moisture migration as well as applying a moisture-barrier film coating. The low water activity of Starch 1500, a partially pregelatinized maize starch from Colorcon, makes it a good choice as a filler and disintegrant for moisture-sensitive formulations, he notes. Starch 1500 acts as a moisture scavenger, and when used in combination with microcrystalline cellulose, it produces a great mix of good tablet hardness and rapid disintegration, Rege observes. In addition, moisture-barrier film coatings such as Opadry amb II (Colorcon) have been reliably used and are proven to improve the stability of the product in-use and in long-term accelerated stability studies, he says.

	“The selection of excipients is crucial to ensure you end up with components that provide a stable drug product with the desired pharmacokinetic properties,” says Skultety. “For example, if the dosage form is a gelatin capsule, it may be best to avoid excipients that are very hygroscopic as they will have a tendency to adsorb moisture from the capsule shell, which can make the capsule shell brittle.” HPMC capsule shells, which contain much less moisture, can be used as an alternative. According to Skultety, these shells are more flexible and are resistant to crosslinking, which provides a better formulation option for hygroscopic and moisture-sensitive ingredients.

	Before starting any design-of-experiments (DOE) work to support the quality-by-design (QbD) approach, Skultety recommends reviewing all the excipients to determine which ones may be critical to the formulation. Upon identification, formulation optimization work and varying the quantities of critical excipients to determine the robustness of the formulation should be performed. “For controlled-release formulations, it is best to do some DOE work around the release-controlling excipients,” he says. “DOE will help to define what the critical parameters are and provide a design space in which the formulation can be successfully manufactured.” Skultety also stresses that the polymer being used to control the release of the active ingredient needs to be consistent so that the drug release from the dosage form will be consistent from lot to lot of polymer used.

	Nollenberger points out that the variation of polymer properties is of particular relevance for polymers taken from natural sources such as cellulose derivatives, starch, or carrageenan. “For these naturally derived polymers, small changes in the raw material source can lead to significant changes in the drug product performance,” she explains. “However, for excipients manufactured by fully synthetic processes (such as, the Eudragit polymers), variations of properties are typically much less pronounced, leading to a defined performance and a better control and prediction of their behavior in the formulation.”

	As a rule of thumb, Nollenberger asserts that the development of an oral-dosage form should always be based on at least three different batches of the determining excipients, as the performance of the drug product is an interplay between API, excipients, and the manufacturing processes applied. DOE studies are crucial to determine the optimum parameters for ensuring a robust process, she says. During development, each excipient should be selected on a sound justification of its function in the formulation. Control measures to ensure the functionality need to be developed and thoroughly assessed. Also, the selected quantities need to be determined and justified by meaningful DOE studies, says Nollenberger.

	Today, the industry has a wide variety of excipients compared to past years, notes Anil Kane, global head of Formulation Sciences at Patheon. The excipients used in solid oral-dosage forms are available from various sources and a variety of grades, he says. Although the selection of excipients with the proper functionality and their corresponding levels in the drug product formulation are crucial to drug product performance, a deeper understanding of how variability in the excipients can affect drug product performance and the proposed control strategy is also an important component of improved drug product development (6).

	According to Kane, a number of drug product recalls identified excipient variability, and therefore, a lack of an adequate control strategy, as a key contributor to why the drug product failed. This problem further underscores the need for improved excipient variability understanding, he asserts. However, evaluating the impact of excipient variability on drug product performance has presented a greater challenge to date than evaluating API and process impacts on drug product performance. This difficulty is partially due to the pharmaceutical manufacturer having more internal capability to manipulate the API and the manufacturing process for experimental study, he explains.

	For excipients, the observed lot-to-lot variability for an individual grade is a function of the control strategy put in place by the excipient supplier, Kane notes. Due to the scales of excipient manufacture and the broader industrial application of many of the materials used as pharmaceutical excipients, it can be difficult for pharmaceutical manufacturers to easily obtain an ideal set of samples to adequately investigate the impact of excipient material properties on drug product performance. Furthermore, the number of excipient material properties combined with the number of excipients in a drug product formulation presents a financial and logistical challenge for executing manageable experimental designs, he says. Risk-based approaches to identify the most impactful excipient material properties have been previously examined as a way to streamline experimental evaluation of excipient variability impacts of drug product performance (7). In addition, Kane believes that a data-based analytical method, which uses quantitative physicochemical property data included in vendor certificates of analysis to further evaluate excipient lot-to-lot variability for a larger number of excipient properties reported by the excipient vendor, could be useful (8).

, accessed Sept. 15, 2016. 
	2. Merck Millipore, “Merck Millipore Introduces Parteck SLC, 
	Silica-based Excipient for Enhanced Drug Solubility and 
	Bioavailability,” Press Release, Oct. 22, 2013. 
	3. A. Siew, 

, s6-211. 
	4. M.E. Brewster and T. Loftsson, 

59, 645-666 (2007). 
	5. S. Muschert et al., 

36 (2) 173-179 (2010).
	6. C.M.V. Moore, “An FDA Perspective on Drug Development and the Global Regulatory Landscape, presentation at the AAPS Annual Meeting, Washington,” DC (Oct. 12, 2010).
	7. J. Kushner et al., 

 100 (6) 2222-2239 (2011).
	8. J. Kushner, 

	When referring to this article, please cite it as A. Siew, "Excipients for Formulation Success,” 

Excipients play a crucial role in the manufacturing of solid-dosage forms and the performance of the finished drug product.

Excipients for Formulation Success

	I was catching up with some friends over the weekend, and at some point, our conversation drifted to the EpiPen outrage, which appears to be making headlines on a daily basis in the United States. The manufacturer Mylan is currently under fire for hiking the price of its lifesaving allergy treatment from less than $100 to more than $600, a 460% increase since 2007. 

	Mylan’s response to the situation did not go down very well, unfortunately. Its efforts to alleviate the cost burden by offering discounts and even promising to launch a generic version of EpiPen at half the price only seem to spark further criticisms. Once again, the general public can’t help but question pharma’s priorities. Between their investors and the patient, who comes first? And why does it always look as though drugmakers are more interested in making money than saving lives? 

	Of course, the only reason Mylan could get away with this epic price hike was because of the lack of competition. Mylan was handed virtual monopoly of EpiPen after its rival, Sanofi, recalled Auvi-Q over dosage delivery problems in October 2015. Another competitor, Teva Pharmaceuticals, failed to obtain regulatory approval for its generic epinephrine autoinjector, with the US Food and Drug Administration citing major deficiencies as grounds for its rejection.

	Epinephrine is well past its patent protection, hence, the drug itself is cheap. Mylan’s secret weapon lies in the EpiPen drug-delivery system. The one-cap device, which provides a convenient means of delivering a precise dose of epinephrine, is protected by patent until 2025. CEO of Mylan, Heather Bresch, is now seen as the villain who enjoyed a salary jump of 671% as a result of the unjustified price increase of EpiPen while the inventor of the autoinjector hardly gets any mention in the press. So my friends and I decided we should raise our glass to toast the late Sheldon Kaplan, who designed EpiPen and probably didn’t get a single royalty from its sales. Where would Mylan be without his innovation, which has saved the lives of many? 

	When referring to this article, please cite it as A. Siew, “Of Price and Pen,” 

Pricing of a lifesaving allergy treatment raises concerns.

Of Price and Pen

 Supplement
	September 2016
	Pages: s6–s10

	When referring to this article, please cite it as A. Siew, " Optimizing API Manufacturing," 

Sound process understanding and having effective controls in place are crucial in ensuring that consistent product quality is obtained during API manufacturing.