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

Adeline Siew, PhD

Former AstraZeneca engineer and serialization specialist, Ian Haynes, looks at the first practical step contract manufacturing organizations need to take to implement a compliance strategy ahead of the impending serialization deadline.

	Increasing concerns are being expressed by industry observers and top-tier pharmaceutical manufacturers that contract manufacturing organizations (CMOs) will not be ready to comply with emerging track-and-trace requirements.

	This is a major worry for big pharma, and indeed any marketing authorization holders who depend on the CMO sector to manufacture their products. Their ability to comply with the emerging requirements is not only contingent upon in-house capability, but on the capability established within their extended supply chain, contract manufacturing, and indeed third-party logistics providers.

	With more than 80% of sales for a typical pharma company being affected by these requirements by 2018, pharma companies are taking steps to protect their business by identifying and evaluating the risks within their supply chains. This situation highlights the role CMOs play and the importance of dealing with the risk they present.

	CMOs are typically graded in terms of the likelihood that they will establish capability in time-some are held to ransom with early compliance deadlines set to force action. For others, where risk of failure is considered too high, plans are laid to move manufacture to more capable suppliers. In the case of low-value products, where capability is doubtful and tech transfer cannot be justified, range rationalization can be the chosen solution: the product may be manufactured until the deadline is reached and then abandoned.

	In all three instances, the impact on the CMOs is significant, and whilst a small number of the more enterprising CMOs are identifying the business opportunity this situation presents and establishing capability early, it seems inevitable that some, maybe many, of those delaying implementation will fall by the wayside.

	So why the delay? A roundtable meeting held earlier this year in Pennsylvania, to gauge the readiness of the drug industry, suggested a range of reasons. Amongst these was the suggestion that manufacturers may simply be at a loss as to how to get started with their implementation programs, and the solution proposed was to create a serialization tutorial/best practice guide. Similar arguments about a lack of useful guidance have been raised in other circles and industry working parties.

	Detailed guidance and training events are, however, already available. A lack of guidance cannot be cited as the reason for the failure to enact a timely and credible response. We believe that the real reason is more fundamental.

	The well-known change equation, refined by Kathie Dannemiller in the 1980s, informs us that even with a clear vision of a serialization-compliant future, clarity about the first practical steps is critical. Stakeholder engagement has long been cited by experienced industry commentators as the first, most important, and most difficult step.

	Breaking down the unwillingness of senior stakeholders to engage in the challenge of serialization and indeed keeping them engaged through the twists and turns of the implementation program turns out to be the biggest challenge facing program managers today. We believe this is where the problems lie.

	A recent LinkedIn discussion about serialization events asked 

“Which ones are useful and which ones are not?”

 Clearly, those that recognize the issue of stakeholder engagement and give clear practical advice on how to achieve it should be top of the list.

	So the question is: are your stakeholders engaged yet? And if not, it’s high time to get them to that position-time is rapidly running out.

Ian Haynes is a serialization expert and thought leader in coding and serialization for the pharmaceutical industry. Along with partner Christoph Krähenbühl, he runs 

, a specialist consulting firm that currently offers two-day training programs to fully prepare pharma companies of all sizes for implementation.

Articles

Increasing concerns are being expressed by industry observers and top-tier pharmaceutical manufacturers that contract manufacturing organizations (CMOs) will not be ready to comply with emerging track-and-trace requirements.

CMOs and the Track-and-Trace Race: Are You Engaged Yet?

Poor solubility remains an ongoing challenge in formulation development. “The abundance of poorly soluble drugs is often attributed to the manner by which companies build large compound libraries (usually via combinatorial chemistry techniques) and/or the use of high-throughput screening assays to identify potential candidates,” explain Eduardo Jule, PhD, senior manager, and Hywel Williams, PhD, senior scientist, both with Capsugel’s Dosage Form Solutions business unit. “In the latter, the identification of potential hits will often be measured by how readily a particular compound binds to a receptor. Because receptor binding will involve a level of hydrophobic interactions between the drug and receptor, these assays may, therefore, preferentially select those drugs that are intrinsically hydrophobic.”

	Julien Meissonnier, R&D platform director, Pharmaceutical Softgel Europe, Catalent, notes that while poorly soluble drugs are here to stay, this issue is, however, not currently addressed appropriately due to the multiple existing
	and emerging technologies arising in the area, as well as the lack of clarity around the benefits and options that these technologies can provide to formulation scientists. “Also, a large portion of the current solubility-enhancing technologies bring incremental development complexity (such as increased incompatibilities, complex scale-up, and clinical acceptability) resulting in loss of time and additional risks,” says Meissonnier. “As a result, achieving a clear picture of the solubility-enhancement space has become increasingly complex.”

	There is a growing interest in lipid-based drug-delivery systems as a means to improve the bioavailability of poorly soluble drugs. Jule, Williams, and Meissonnier discuss the advantages of this approach and the challenges in
	developing lipid-based formulations.

: First of all, what is the rationale of using lipid-based drug-delivery systems?

: Lipid-based drug-delivery systems have the proven capacity to improve the oral bioavailability of a drug via several mechanisms, with the unique potential to address both physicochemical and biological obstacles to systemic exposure. It is, therefore, appropriate to describe these mechanisms in relation to the fate of a lipid-based formulation in the gastrointestinal (GI) tract:

. Lipid-based formulations containing the drug, either dissolved or suspended, are typically administered via hard or soft capsules. Following rupture and disintegration of the capsule shell in the stomach, the formulation mixes with gastric fluid to an extent that is governed by formulation composition and stomach contents. In the fasted state (which is usually more challenging for poorly soluble drugs than fed-state conditions), those formulations containing a mixture of oil and surfactant(s) will self-emulsify before entering the small intestine--the primary site of drug absorption.

. Here, a high dissolved drug concentration at the intestinal wall will promote passive drug diffusion across the enterocyte membrane. For a poorly soluble drug, enabling technologies are required to increase solubility and dissolution so that a high dissolved concentration that drives intestinal absorption can be attained. This may be achieved via lipid-based formulations, wherein the potential to administer the drug pre-dissolved in the formulation matrix is such that dissolution can be bypassed altogether, while the lipidic components of the formulation (dispersed and/or digested) mix with endogenous bile salts and phospholipids to form a range of colloidal species that increase drug solubility and present the drug in a well-dispersed and readily absorbable form. Small colloidal species formed by lipidic excipients and endogenous solubilizers will also enhance drug transport through the unstirred water layer, which can be slow and potentially limiting to absorption when the drug is lipophilic.

. Lipid-based formulations may also impact post-absorption events to improve bioavailability of drugs that are subject to:

		intestinal efflux-fatty acids and nonionic surfactants commonly used in lipid-based technologies have been shown to reversibly inhibit P-glycoprotein and breast cancer resistance protein (BCRP) efflux transporters or increase transcellular permeability.

		high first-pass metabolism-surfactants have been shown to inhibit cytochrome P450 enzymes known to extensively metabolize drugs in the intestinal wall, while lipidic excipients can, for highly lipophilic drugs, increase the fraction of absorbed drug that enters into the lymphatic system where hepatic metabolic pathways are avoided.

: Lipid-based formulations of poorly soluble drugs generally exist during development where drug substance solutions remain in a solution form in the GI fluids prior to facing the GI walls. This means the formulation must first resist its dispersion in the GI fluids by maintaining the drug in solution. Upon dispersion, the formulation could be present in different states, ranging from coarse emulsions to thermodynamically stable microemulsions, which present different features. After the lipid components of the formulation are subjected to the action of the lipase (pancreatic lipase being the primary contributor), which acts specifically at the oil/water interface, the lipids undergo de-esterification into fatty acids and partial glycerides. Again upon digestion, it is important to ensure that the poorly soluble drugs remains in solution form before facing the enterocytes.

	Lipid systems have the advantage in that they can present the drug as a stable liquid solution, but the term ‘lipid formulation’ has come to mean one of a large group of formulations that share some common features. Lipid systems may include triglycerides, mono- and diglycerides, lipophilic surfactants, hydrophilic surfactants and cosolvents--excipients with a wide variety of physicochemical properties.

	In 2000, Colin Pouton first established an effective classification system for lipid-based formulations, which was completed in 2006 (1). Based upon their qualitative and quantitative composition, the lipid formulations might exhibit different behaviors upon dispersion and digestion. The classification system consists of four broad categories (1) .

	Briefly, Type I formulations are oils that require digestion; Type II formulations include water-insoluble self-emulsifying drug-delivery systems (SEDDS); Type III systems include SEDDS or self-microemulsifying drug-delivery systems (SMEDDS) that contain some water-soluble surfactants and/or cosolvents (Type IIIA) or a greater proportion of water-soluble components (Type IIIB); and Type IV formulations contain no oils and represent the most extremely hydrophilic formulations.

	The advantage of moving from Type I toward Type IV formulations is to enhance the solvent power of the formulation (hence, majority of high-dose anti-proteases have been formulated as Type IV systems). Surfactants offer much greater food solvent capacity on dilution (as a micellar solution) than cosolvents. However, moving in this direction requires increased proportions of hydrophilic surfactants with Macrogol (polyethylene glycol) chains that cover the oil/water interface and provide steric hindrance to pancreatic lipase action, thus inhibiting formulation digestion.

	The application of SMEDDS to oral cyclosporine has revolutionized organ transplantation therapies, which has consequently triggered a strong focus on SMEDDS development. While bringing more complexity, the development of microemulsion concentrates is perfectly suited to enhancing exposure, while resolving variability issues and food effect for drugs with narrow therapeutic windows. Indeed, being thermodynamically stable by definition, those systems are much less sensitive to change in physiological conditions such as food intake, bile salts, and pH. Those requisites, however, do not apply to all target product profiles (TPP) where more simple, fast-to-develop lipid systems would apply.

	Lipid systems enable the resolution of intrinsic solubility issues associated with pharmaceutical actives, but unlike other alternate delivery approaches, enable more complex biopharmaceutical hurdles to be overcome and have the ability to match some more complex TPPs. The proper selection of lipid ingredients can inhibit efflux transporters, extensively affect presystemic metabolism and influence the route of absorption, for example, by enhancing the lymphatic uptake of highly lipophilic actives.

: What are the benefits of using lipid-based drug-delivery systems for solubility/bioavailability enhancement compared with other available methods?

: Lipid systems allow manufacturing operations to progress rapidly, and may accelerate access to early clinical phases and future scale-up steps. Using a rational approach in preformulation operations with
	liquid systems not only enables accelerated predictability of drug/ingredient interactions but also, with the use of in-vitro and in-silico development tools, assists in tailoring the optimum lipid formulation system and increasing predictability of in-vivo performance.

	Working with liquid and semi-solid systems, Catalent has developed a standard procedure, whereby low batch sizes (hundred grams of formulation) are produced under cGMP conditions using commercial encapsulation equipment, enabling quality-by-design integration from the first preclinical batches through to manufacture.

: As mentioned previously, lipid-based technologies offer the possibility to address both physicochemical and biological barriers to bioavailability, which is particularly advantageous when events post-absorption are such that bioavailability remains low, in spite of increased solubility and dissolution rate. Owing to fast capsule rupture and the absence of dissolution, lipid-based formulations also may be designed to provide fast rate of absorption, which is often desirable when a rapid onset of action is needed.

	Aside from performance advantages, lipid-based formulations offer a straightforward way of formulating drugs that are low melting (i.e., < 100 °C) while avoiding process-related issues when attempting to mill, granulate, and produce tablet formulations. The potential to formulate a drug dissolved in a non-aqueous vehicle also circumvents the risk of solid-state polymorphism (during manufacture and/or on storage). Additionally, liquid-filled hard or soft capsules offer an optimal approach for formulating highly potent/low-dose drugs, ensuring dose uniformity and reducing exposure risks associated with handling solids. Lastly, liquid-filled capsules offer an established scale-up route, particularly when working with homogenous solutions.

: Can you describe a stepwise approach for formulation development of lipid-based drug-delivery systems?

: Once a lipid-based approach is determined to be the optimal technology for improving bioavailability, the first step to the development of a robust lipid-based formulation is to further qualify the drug candidate in terms of physicochemical and biopharmaceutical properties. This ensures that a range of lipidic excipients (oils, cosurfactants, surfactants, and cosolvents) is selected based on the drug characteristics. From here, solubility testing is performed to identify excipients toward which the compound exhibits a high affinity. Selected excipients are then progressed into the formulation design phase; this stage of development can often be slow and rate-limiting given that a wide number of potential excipients and excipient combinations can be theoretically explored. To accelerate the formulation design process, Capsugel uses a lipid expert system-an in-silico database based on hundreds of phase diagrams coupled to a decision tree--to identify concept formulations based on drug solubility in lipid excipients, target dose, and the dispersibility of several hundred different placebo formulations across a range of different dilutions.

	Concept formulations are then progressed into a performance testing program. Here, formulations are subjected to dispersion and simulated digestion tests to ascertain the likely fate of the incorporated drug as the lipid formulation is processed via the highly efficient lipid digestion and absorption pathway. The most robust formulations are those that solubilize high compound concentrations in both the dispersed and digested state (i.e., minimizing drug precipitation), with limited change in performance on changing certain experimental factors, such as bile salt concentration and extent of dilution. Our experience tells us that such formulations are less likely to show variable and/or poor performance 

	Alongside a physical and chemical stability program, lead formulation(s) undergo capsule compatibility studies and physical characterization before a technical batch is manufactured. During these latter stages of development, our understanding and capabilities in this area are also leveraged to ensure rapid process development and supply of clinical batches.

: The development of lipid systems encompasses the standard steps found in pharmaceutical development. The state of excellence is reached through the internal development of formulation-specific analytical techniques, enabling access to a more complete and accurate dataset earlier and faster to ensure proper risk mitigation earlier in the development cycle.

	Complementing further drug characterization studies, preformulation studies are based upon the kinetic evaluation of drug solubility in various classes of ingredients, in parallel with chemical
	compatibility screens. These tests are enabled by specific automated platforms and predictive tools.

	When progressing to the formulation development stage, to select a formulation that is resistant to precipitation under dispersion and digestion, Catalent operates proprietary in-vitro and in-silico models, including a computerized database of digestion profiles, and also pseudo-ternary diagrams generated at its five primary global development sites dedicated to lipid-based systems development. These systems improve the efficiency of formulation determination, as well as predictability to progress in further clinical studies. The excipient selectionprocess is also based upon careful selection of the ingredients in light of their global approvability and existing safety status. A wide majority of lipid ingredients are generally recognized as safe (GRAS) and several studies are under way on novel functional lipids to broaden their existing safety data.

Experts from Capsugel and Catalent discuss the rationale of using lipid0basd formulations to improve the oral bioavailability of poorly soluble drugs.

Bioavailability Enhancement with Lipid-Based Drug-Delivery Systems

You may have noticed that our August issue is thicker than usual. Well, it’s because this issue has been specially dedicated to celebrate 

e’s 25th anniversary. The past two and a half decades of charting the progress in pharmaceutical manufacturing has been an exciting journey, filled with ups and downs. The industry has witnessed a surge in mergers and acquisitions, mostly driven by the need to bridge revenue gaps caused by pharmaceutical blockbusters plunging off the patent cliff. And as Big Pharma continues to grapple with its productivity crisis, characterised by a severe drought in innovation, not to mention the weakening R&D pipelines, it looks like the stage is set for the dawning of a new era of biosimilars, particularly in Europe where the approval pathways for this class of medicines are now more clearly defined.

The European regulatory landscape for pharmaceuticals has also evolved over the years. Changing fundamentals, such as globalisation, the rise of emerging markets and the propensity for companies to outsource manufacturing activities, have created an increasingly complex pharmaceutical supply chain that is vulnerable to adulteration, cargo theft, counterfeiting and product diversion. As a result, stakeholders are under pressure to put in place measures to ensure product quality and patient safety. 

With change being the only constant, we are seeing a move away from batch processing as the industry embraces continuous manufacturing. And although adoption has been slow, the overarching paradigm of quality by design and process analytical technology is now making significant inroads into pharmaceutical development. Single-use systems that eliminate cleaning validation steps and reduce the risk of cross contamination are also changing the face of bioprocessing both upstream and downstream. 

To mark 25 years of tracking the pulse of the pharmaceutical industry, our editors have put together a special anniversary section, written by the industry, for the industry. Experts share their retrospective and prospective viewpoints on trends and advances in pharmaceutical manufacturing. So sit back, relax and enjoy!


  Adeline Siew, PhD
  Editor of Pharmaceutical Technology Europe
  asiew@advanstar.com

Pharmaceutical Technology Europe marks its 25th anniversary.

Tracking the Pulse of the Pharmaceutical Industry

	The performance of a drug can often be optimized by controlling the rate and extent of its release in the body. As controlled-release (CR) drug-delivery systems continue to play an important role in the treatment of diseases, 

 brought together a panel of industry experts to discuss the challenges involved when developing CR formulations and the advances made in this field. Participating in the roundtable were Randy Wald, senior research fellow at Bend Research, part of Capsugel’s Dosage Form Solutions Business Unit; Ali Rajabi-Siahboomi, PhD, vice-president and chief scientific officer, Colorcon; Leah Appel, PhD, managing partner, Green Ridge Consulting; Ninad Deshpanday, PhD, president of R&D, and Vinod Gupta, PhD, vice-president of pharmaceutical development, both at Kemwell; Anshul Gupte, PhD, Michael DeHart, PhD, and Joe Cobb, CPIP, all three from Metrics; and Anil Kane, PhD, MBA, executive director and global head of formulation sciences at Patheon.

 What do you see as the top three challenges in the development of CR formulations?

The three main challenges in the development of CR formulations include: the intersection of market expectations for once-daily dosing and the prevalence of lower-solubility, higher-dose compounds for the development of oral solid CR products; the development of CR dosage forms that impart abuse resistance; and the increasing need for pediatric CR dosage forms.

	Many compounds do not have sufficient colonic absorption for conventional CR formulations. Absorption technologies such as nanoparticles, amorphous-drug, and lipid-formulation technologies are needed to provide sufficient driving force for adequate absorption, especially in the lower part of the gastrointestinal (GI) tract. These absorption technologies have matured over the past two decades for immediate-release (IR) dosage forms, but substantial research is required to couple them with the processing technologies needed for CR capsules and tablets. This research requires a fundamental understanding of the 

absorption and biotransformation using the ‘high-energy’ formulations as well as an understanding of the process-engineering fundamentals required for manufacturing with capsules (e.g., based on lipids and/or multiparticulates); tablets (e.g., based on gel matrix, osmotic, or compressed multiparticulates); and sachets or other bulk oral solid presentations. One additional challenge of coupling enabling technologies with CR technologies is achieving adequate drug loading and the desired dosage form size. The use of absorption-enabling technologies that also have intrinsic modified-release properties is, therefore, desirable. Two examples include the use of amorphous solid dispersions using enteric or controlled-release polymers and lipid-based systems-both of which can be used in monolithic and multiparticulate dose forms.

	The second challenge involves the development of CR dosage forms that impart abuse resistance, an increasingly important and legislated requirement for opioids and other controlled substances. Designing an effective approach for deterring abuse requires understanding the typical approach an abuser may use to extract the drug inappropriately. The approaches have been novel and vary greatly using physical, chemical, and pharmacological approaches. Formulation scientists and dosage-form solution providers have devised an array of approaches that facilitate meeting target pharmacokinetic profiles while providing abuse resistance (e.g., waxy excipients, high melting point and viscosity modifiers, and others).

	The third challenge surrounds the urgent and increasing need for pediatric CR dosage forms. This is a challenge because fewer excipients are deemed acceptable for pediatric use by regulatory agencies and/or have precedence of use for pediatric formulations than for adult formulations. Dosage forms for infants and very young children are especially challenging because these patients may not be able to swallow a solid-dosage capsule or tablet, and/or concern for dose dumping is of crucial importance. In these situations, sachets, sprinkles, and other suspendable dosage-form intermediates are preferred, although texture and taste constraints must be overcome. Generally, multiparticulates (e.g., 100- to 300-µm micropellets or lipid multiparticulates, coated or uncoated) offer the most viable path forward when designed properly for the target patient population. Nevertheless, the challenges remain high for designing pediatric formulations that meet target pharmacokinetic profiles, which has driven our development of a multiparticulate platform that includes multiple bead-layering approaches, mini-tablets, lipid multiparticulates, and specialized capsules for delivery.

The top challenge for the development of CR formulations is in the area of biopharmaceutics, namely, establishing desired release profiles for new chemical entities, and for generics, matching the originator release profile 

 (i.e., bioequivalence). One of the other challenges for CR dosage forms is the risk management of dose dumping under different GI tract conditions. Most CR formulations contain a higher concentration of the drug within the dosage form compared to a single dose of an IR formulation; the risk of dose dumping from CR dosage forms is, therefore, higher. It is the responsibility of the formulators and drug manufacturers to have an indepth understanding of the potential risks involved and have strategies to mitigate them.

	Maintaining the quality and consistency of CR dosage forms from batch-to-batch during manufacturing is also key. This can be a critical challenge for generic companies, whereby competitive pressures may lead to use of lower-grade (lower-cost) raw materials, which could result in quality issues and batch-to-batch variability of CR drug products.  Colorcon, through the Controlled Release Alliance with Dow Pharma and Food Solutions, helps manufacturers to optimize their process and minimize any risks, leading to predictable outcomes and greater manufacturing efficiency. There has been a specific focus on quality-by-design (QbD) initiatives for the robust design of products and manufacturing processes of hydrophilic matrices, given that these are still the most widely marketed dosage form for CR products.

 The delivery of a CR high-dose drug formulation has always been a challenge due to the relatively large amount of excipients generally needed to provide a specific delivery profile. This issue, combined with the currently large percentage of poorly soluble drugs, is especially problematic in the development of CR dosage forms. Technologies to address poor solubility also tend to require a significant amount of excipients, making CR formulations of high-dose poorly-soluble compounds significantly challenging.

	CR formulations continue to take longer and cost more to develop than IR formulations. Generally, several prototypes spanning a range of release profiles are taken into initial clinical trials, and there may be several iterations needed to obtain the desired pharmacokinetic profile. This issue continues to hamper development efforts.

In spite of the many advances in controlled-release research, establishing 

 correlation (IVIVC) is still one of the biggest challenges. Other challenges include the selection of biocompatible and biodegradable materials with desired controlled-release properties to achieve therapeutic concentrations at the target site and designing CR delivery systems for biologic drugs, bearing in mind their susceptibility to degradation.

 The challenges for CR formulations can be divided into four categories:

-APIs with short half-life and the need for high-dose delivery

-Often need solvent-handling capabilities because most polymers need to be solubilized in organic solvents before coating the CR formulations (i.e., tablets, capsules, granules)  

-Increased complexity of patient-to-patient variability and IVIVC in the formulations

-Enhanced scrutiny and requirements of CR formulations.  

 The top three challenges when developing CR formulations include understanding the target release rate, the target extent of release (i.e., total dose and fraction of dose released over the targeted time), and the mechanism of CR formulation that will meet the rate and extent of release over the targeted time period.

		The development of CR formulations is usually undertaken as a lifecycle management strategy. At this stage of the development program, the pharmacokinetic parameters such as peak concentration (Cmax), time to peak concentration (Tmax), half-life (T1/2), area under the curve (AUC), and the absorption, distribution, metabolism, and excretion (ADME) profile of an IR dosage form of the drug are well defined. The dosing interval required to obtain the required plasma levels of the drug that result in a therapeutic effect should be well understood. These data are crucial in defining the range of dose required to be administered over a defined period of time. For example, clinicians would define that a 100-mg dose is required to be released over a 12-hour period with approximately 20-40% in the first 2 hours, 40-60% in the next 4 hours, and more than 80% released between 8 and 12 hours to achieve the clinical effect.

		The plasma levels that may cause undesirable side effects would also be known. It is, therefore, important to ensure that the drug is released from the dosage form in a controlled rate and not to an extent that it causes side effects.

		Several principles of controlling the release of the drug are used to formulate the dosage form-erosion, diffusion, and release based on concentration gradient through osmosis among others. The choice of the formulation design strategy is based on the target release rate and extent as well as properties of the drug molecule.

 What would you identify as the most significant advances in CR drug delivery over the past 10 years?

Probably the most significant advances have been around collective fundamental understanding of CR dosage forms amongst medical professions, pharmaceutical scientists, manufacturers, and regulators. Realizing the potential clinical advantages of CR products has refined the treatment approach to certain conditions such as cardiovascular and central nervous system diseases. In addition, these learnings have helped formulation scientists to design CR dosage forms in a way that are most closely related to the therapeutic challenges and needs of disease conditions.

		Through review of clinical needs and drug physicochemical properties, different CR platform technologies, such as hydrophilic matrices, multiparticulate reservoir-type systems, and push-pull osmotic pumps, have been commonly used to effectively deliver drugs over time. These approaches have enhanced patient experience and compliance, as well as enabling challenging drugs (e.g., drugs with side effects due to high Cmax) to be formulated and successfully marketed.

		Improved understanding has also led to the development of more complex formulations, such as fixed-dose combinations (FDC), in which two or more drugs with the same or different release profiles are formulated into one dosage form. FDCs offer several advantages, such as increased patient compliance for chronic diseases (e.g., better disease management of diabetes and hypertension due to the synergistic effect of two or more drugs), patient convenience (e.g., in the treatment of AIDS and cardiovascular diseases), reduced cost to the patient (one co-pay), and an opportunity for lifecycle management of marketed drug products.

 The success of oral, parenteral, ocular, and topical routes has been established through several marketed CR systems such as osmotic CR tablets, coated granules/beads/particulates for release over time, poly(lactic-co-glycolic acid) microparticles, liposomes, matrix or reservoir transdermal delivery, iontophoresis patches, and ocular inserts. During the past few years, significant advances have been made in the area of targeted drug-delivery systems, in which drugs are targeted to specific organs and tissues. Examples include dendrimers, polymeric nanoparticles, solid lipid nanoparticles, nanoemulsions, and vesicular systems such as liposomes and virosomes. Another advancing field is the combination of regenerative medicines and tissue/genetic engineering including the use of DNA or siRNA in CR systems for regeneration of bone, cartilage, and osteochondral interface.

 Significant advances include advances in polymer chemistry, specifically pH-dependent and pH-independent release from polymer systems and the availability of specific grades of the polymers; advances in 

 models to understand the release mechanism of the API from the formulation; the co-delivery of IR and CR systems; advancement in engineering of manufacturing equipment to support scale up of CR formulations; and the development of targeted delivery systems or delivery of medications directly to the affected area as opposed to systemic delivery.

Targeted drug delivery has been made possible by use of novel polymers, formulation, and analytical techniques, such as imaging to control the level of coating to obtain the required performance of the dosage form. Advances in polymer systems to control drug delivery and techniques to identify critical material properties that can impact drug product quality and dosage form performance have resulted in the development of better controlled systems.

		There has been significant progress in the importance of understanding the API properties and its influence in development of dosage forms. The concept of risk assessment and use of QbD principles have helped in developing robust drug formulations for controlled release. The use of medical devices to administer CR formulations has also increased due to advances in technology in the transdermal, topical, ocular, and parenteral routes of administration.

 One big change in the past 10 years has been the increased number of FDC products that employ various combinations of IR and CR technologies. These products often require once-daily dosing and have introduced a new set of challenges, ranging from clinical and regulatory challenges to the direct chemistry and formulation/process challenges. Naturally, FDC products that include one or more CR profiles provide the biggest challenges. Nevertheless, a significant number of products have progressed to the market and offer important advances in the controlled-release arena using monolithic (e.g., bilayer tablets with active coatings) and multiparticulate (e.g., blends of coated pellets in capsules) approaches.

		Further areas that have matured are pulsatile-release approaches and chronotherapeutic delivery. Concerta (methylphenidate extended-release tablets) represents a good example in which drug delivery is designed for known daily cyclic needs of the patient. The extension of this concept sets the stage for the personalized medicine genre, an area that appears poised for substantial growth, and enabling technologies integrated into the pharmaceutical development area.

Nanotechnology and personalized medicines

 How are the advent of nanotechnology and the paradigm shift towards personalized medicines changing the way novel CR technologies are developed?

 Nanotechnologies (e.g., nanoparticles, nanorobots) are enabling the development of new drug-delivery approaches in many areas. For example, the development of high surface area mesoporous silica substrates, which offer the ability to provide bioavailability enhancement and deliver a high drug payload, may have broad utility in the development of oral CR formulations of poorly soluble compounds.

		Nanorobots can either be MEMS based (microelectromechanical systems) or biochemically based (e.g., DNA nanobots) and can offer the ability to deliver specific, complex release profiles, and/or target specific cells. This technology may enable customization of dose regimens for a specific patient and disease state.

Developing drug-delivery techniques that help minimize toxicity and improve efficacy offer great benefits to patients and open up new markets for pharmaceutical companies. Nanotechnology offers both diagnostic and therapeutic advantages. The assimilation of biomarkers into delivery systems focuses on tailored therapy for a patient based on gene sequencing, metabolites, and proteins. Prognostic biomarkers can be used for predicting the pathway of a disease as well as deciding the therapeutic approach and dose for a patient. Activatable CR systems are based on the concept of activating the specific biomarker once the drug reaches the therapeutic site. This approach decreases the toxicity associated with potent drugs. The three technologies can be utilized together for efficient diagnostic, therapeutic, and specific delivery. Nanotechnology has already been adopted in several fields such as gene delivery, imaging, and diagnostics.

 The impact of nanotechnology is probably felt more in the parenteral area for targeted delivery. Nevertheless, the use of submicron- or nanometer-sized drug crystals has also affected oral CR dosage forms. In reality, nanotechnology is being used in IR and CR dosage forms but is not recognized 

 rather than as part of the packaged dosage form. For example, colloidal, nanometer-sized species are formed in situ in many amorphous, lipid, and occasionally salt drug forms, as they pass through the GI tract and the components interact with the GI fluids, dissolved buffer, bile salts, and lipoproteins. Research in nanotechnology remains strong and the likelihood of a nanotechnology being reduced to practice in commercial-scale oral CR pharmaceuticals seems eminent.

		The use of companion diagnostics and genomics to drive personalized medicine into pharmaceutical dosage-form development would also appear imminent. It can be argued that the increase of the orphan drug market-where subpopulations and treatment modalities are identified from genomics, diagnostics, and specific biomarkers-is a broader-scale form of personalized medicine. In these cases, CR dosage forms may be the enabling technology given that the range of active molecules offers less latitude for design (e.g., half-life, solubility). At an individual level, the use of personalized flexible doses, dosing regimens, and combinations of drugs has gained momentum in the treatment of cardiovascular disease and diabetes. Since the concept of personalized medicine implies compliance, the new paradigm requires flexible dosage forms amenable to assurance of dosing. Likely examples include CR dosage forms integrated with electronics and personalized dispensing devices that enable customized dosing.

		Lastly, while not personalized medicine per se, there has been a shifting paradigm in drug-development clinical trials that can be considered near personalized medicine. It involves custom manufacturing (e.g., to achieve the desired dose or drug release rate) by a compounding pharmacist or a contract research organization (CRO) that has a closely integrated small-/miniature-scale manufacturing facility. The former-commonly called extemporaneous preparation or manufacture-has recently been used to prepare some CR dosage forms, bypassing the costs and time associated with the manufacture of bulk clinical-trial material (CTM), extended stability, and providing dosing customization based on quick bioanalysis or biomarker feedback. As an example, Quotient Biosciences has been a pioneer in small-/miniature-scale manufacturing as a combined contract development manufacturing organization/contract manufacturing organization (CDMO/CMO) in the same facility focused on customized dosing and evaluation of dosage-form performance.

What future innovations in CR drug delivery do you expect to see in the next five to 10 years?

 I believe there will be a lot more work in pharmacokinetic modeling and simulation techniques to predict the drug-release performance in the development phase of CR formulations. We will also see the use of advanced medical devices to administer drugs for controlled delivery via transdermal, subcutaneous, ocular, and parenteral routes.

Several areas continue to receive investment, and further innovation is expected over the coming years. These areas can be broadly classed into public health, large molecules, and the manufacturing of finished dosage forms.

 Two public health areas for oral CR innovation are pediatric and abuse-deterrent CR dosage forms. Direct financial incentives exist for innovation in both areas. The need for abuse-deterrent formulations has been prominently discussed in the United States medical and media arenas, which includes not only direct opioid extraction abuse, but also ethanol-retardant technologies. There are a number of abuse-resistant formulation approaches available today, and these approaches will continue to be refined and expanded.

		Pediatric studies are now required for product approval and are crucially important because dosing challenges, flexibility, GI transit, and ADME are often different for pediatric patients than for adults. Similarly, the need for innovation to better serve the growing geriatric population is strong. Examples include FDC products, easier-to-swallow dose units, and devices to assist with compliance and compliance monitoring.

 Despite significant efforts over the past decades, oral delivery of high molecular-weight molecules, peptides, and proteins using immediate-release or modified-/delayed-release approaches remains an ongoing challenge. This problem is exacerbated by a growing percentage of molecules in this category and the growing importance of such molecules to the pharmaceutical industry. While exceptions exist, this area remains almost entirely an unmet need. Innovation in new materials and associated dosage forms is an ongoing area of research to address this need. While early in development, orally delivered microelectronics and devices show promise to assist in the protection, absorption, and controlled-release delivery of pharmaceuticals.

 Two areas in the manufacturing arena that require innovation to meet increasing economic and environmental health and safety (EH&S) drivers are continuous manufacturing processes and improved and new approaches for containing high-potency actives. While there is opportunity for synergy in these two areas-since continuous unit operations often have smaller control volumes and, thus, smaller containment volumes-these research areas generally are independent. Continuous processing has advanced further for IR and straightforward CR dosage forms (e.g., hydrophilic gel-matrix CR tablets), but continuous-processing and containment innovations are still required in key controlled-release unit operations such as fluid-bed coating and functional tablet pan coating.

One possible outcome of the QbD initiative is to be able to use continuous processing in the manufacture of CR formulations. While there is interest and some successes, the continuous or semi-continuous processing/manufacturing requires innovation not only in the platform technologies, but also in the processing equipment. A potential area for future innovation is research into complex release profiles for one or more drugs with biologically responsive delivery platforms in combination with biomarkers. Although oral drug delivery is the most desired route of administration, some of the new molecules are only available through injection or implant. Of course, innovations in these areas are also something to watch for.

 There are significant advances being made in targeted drug delivery to deliver drugs to specific cell types (e.g., tumors) and minimize systemic exposure. It is probable that some of these approaches will be demonstrated clinically and become commercially viable. Another area that is poised for significant advancement is the use of drug/device combinations. One example is the combination of a specific drug and a more sophisticated micropump (similar to those currently used for insulin delivery) for more complex delivery profiles. This approach would enable facile clinical evaluation of different dosing regimens and may ultimately lead to the customization of delivery profiles for a specific patient and disease state.

 Although there continues to be significant innovation in the development of CR drug-delivery technologies, we can expect to see efforts focused on converting these ideas from concept to practical use. Examples include customized/personalized delivery technologies for diseases affecting daily life of patients and conditions requiring frequent dose adjustment depending on stage of the disease (e.g., Parkinson’s and Alzheimer’s), chrono-pharmacokinetic delivery systems, use of newer and better controlled-release polymers, and improved targeting leading to site-specific controlled-release delivery of pharmaceuticals and biologics.

 Continued research in polymer chemistry would mean that polymers of the future would be able to respond better to the circadian cycles of different individuals, thereby, resulting in appropriate dose of the API being released over time to maintain an appropriate API concentration in the patient.

Adeline Siew, PhD, is the scientific editor for 

Industry experts share their perspectives on key advances in controlled-release drug delivery and future innovations in this arena.

Advances in Controlled-Release Drug Delivery

The risks posed by extractables and leachables (E&Ls) on product quality and patient safety is an ongoing challenge for the pharmaceutical industry. In this roundtable discussion, industry experts provide insight on E&L testing using a risk-based approach, including how acceptance limits are set. The participants were Diane Paskiet, director, Scientific Affairs, West Pharmaceutical Services, and chair of the Product Quality Research Institute (PQRI) Parenteral and Opthalmic Leachables and Extractables Working Group; Andreas Nixdorf, team manager, Extractables & Leachables Testing, and Chris Harbach, CSci CChem FRSC, manager, Chemical Services, both at the laboratory services division of SGS Life Science Services; and Karl Abele, project manager, Extractables & Leachables Testing, Solvias AG. 

PharmTech: What are the common sources of E&Ls and what measures can you take to reduce such risk? 

Any material in direct contact with a drug solution could potentially cause contamination through leaching. This change in the product’s composition can impact its therapeutic effectiveness—E&Ls may reduce stability, alter impurity profiles, inactivate the active ingredient, alter the smell, taste or color of the product, and cause it to fail quality-control assays. Regulations in both the United States and the European Union state that production equipment should not introduce hazards to the product. In addition, chemical compatibility (regarding E&Ls) of packaging and product must be evaluated. Production equipment, such as filters, single-use bags, and tubes, have large contact surfaces, and the materials used to make them must be carefully tested for suitability. There is, however, often a lack of extractables data from materials manufacturers, and without detailed knowledge and control over all the ingredients, obtaining a reliable E&Ls profile is difficult. The selection of a good supplier is as important as the selection of a good material.

 Polymers are the most common source, whether plastics or rubbers, but they can also arise from glass, metal, adhesives, printing inks, and cardboard packaging. The supply chain is the main problem given that the materials are processed in several locations with additives added at each stage, and full composition information is often not available to the end-user. In the past, additives were included to impart specific properties with no consideration of E&L potential. This issue is compounded by the fact that the pharma sector only uses a tiny amount of worldwide production volumes.

Risk can be reduced if there is good communication throughout the supply chain, and the end-user is informed of all changes. Ideally, the end-user will develop a close relationship with a polymer supplier who specializes in pharmaceutical container/closure systems, and will be aware of the issues around E&Ls, and supply extractables profiles. Non-polymer-related risks can be reduced, for example, by using high-quality glass, avoiding problematic ink formulations, and selecting adhesive with low E&L potential.

 Materials that come into direct or indirect contact with a drug or biologic product have the potential to leach substances into the final pharmaceutical product. Substances that may leach can originate from various materials at any point in the pharmaceutical supply chain and throughout the product lifecycle. Constituents that leach from primary packaging into the final product when manufactured and stored under its normal conditions are referred to as leachables. Typically, leachable compounds are found in trace amounts but can have a negative impact on pharmaceutical quality with potential to compromise patient safety. Any component used during drug or biologic manufacture, storage, shipping, and administration to the patient can be implicated as a source of E&Ls. 

Manufacturing and delivery systems consist of multiple components. In addition to being compatible with the drug product and safe for patient use, suitable materials must protect the drug product, as well as perform and function properly. Primary classes of materials used to manufacture and store drugs and biologics include rubbers, plastics, glass, metal, and paper components. A pharmaceutical product can be affected by leached substances with distinct outcomes—for instance, the leachable entity can be toxic, or the leached substance can react with the APIs or excipients to form a new chemical entity or affect the stability of the final pharmaceutical. The risk to the patient needs to be assessed and mitigated based on understanding the potential for leaching, and this is accomplished by designing systematic studies to identify and quantitate extractable substances. 

Component profiles have many levels of complexity, which may become more varied once the component is formed, washed, sterilized, and assembled. Common sources of extractables include residuals and by-products from the material. Processing aids and additives, such as stabilizers, antioxidants, lubricants, curatives, and breakdown products, are all examples of species contributing to the chemical profile. 

An extractable study will establish the chemical profile, which reflects risks relative to potential toxicity and incompatibility. Toxicity will depend on the leachable concentration in the final product and patient total daily intake. Incompatibility is fundamentally dependent upon the pharmaceutical matrix and conditions of use. Compatibility issues are often manifested by different end points such as pH shift, degradation, oxidation, aggregation, foreign articles, and other impurities that become evident over time. 

All materials will leach to some degree under certain conditions. The goal is to provide evidence that the materials are suitable for intended use by understanding how risk for leaching correlates to patient harm and eliminating or mitigating that risk. 

PharmTech: What are the key considerations when designing E&L studies? Can you describe a risk-based approach to E&L testing? 

 An E&L strategy consists of multiple steps in which voluminous information is acquired and builds until the final drug product stability studies are completed. It can span a period of five years or more from discovery to confirmation. Formal risk assessment tools such as flow diagrams, control charts, risk ranking/filtering or hazard analysis, and critical control points can add value, although these tools are not required. 

The objective of an E&L study is to identify risk by conducting controlled extractable studies, which can be correlated to drug/biologic safety and quality. The first step in designing a study is to identify the various components to be evaluated and the degree of evaluation. Criticality should be assessed based on the likelihood of component interaction with the drug/biologic product during manufacture, storage, or when in contact with a patient. 
Once the components are deemed critical for evaluation, the chemical make-up of each material should be understood. This chemical profile will feed into the component sampling, preparation of extracts, and analysis techniques. Multiple solvents that encompass organic as well as aqueous solutions should be employed to explore a comprehensive chemical profile. Multiple analytical techniques that are orthogonal are recommended to detect and confirm a wide range of extractable species with a wide range of sensitivities. Analytical methods should be fit for purpose--that is, having a system capable of detecting certain predetermined targets at specified levels as well as detecting unexpected extractables. 

A material’s chemical profile should be generated using aggressive solvents under exaggerated conditions to indicate the basic chemical characterization; however, this approach is often not indicative of actual leachables. Understanding the chemical profile is necessary because trace leachables are easily masked and difficult to detect in a complex matrix. Spiking and recovery studies are necessary to confirm the presence or absence of target compounds. In certain applications, it can be an advantage to simulate or mimic the final product subjected under exaggerated conditions to better define targets. The purpose of extractable studies is to provide comprehensive data to indicate risk for leaching and guide a leachables assessment. Correlation of the component extractables with confirmed leachables under worst-case conditions will lead to the necessary control strategy. 

Harbach (SGS): The key consideration when designing an E&L study is patient safety. For small-molecule pharmaceuticals, the concern is over leachables from the container/closure system. For biopharmaceuticals, an additional concern is any interaction of leachables with the biopharmaceutical product that can adversely affect its potency and efficacy, or cause immunomodulatory effects. These attributes should be monitored in addition to any leachables.

When designing an E&L study, there is no ‘one-size-fits-all’ approach. In a risk-based approach, due consideration should be given to the nature of the drug product, the dosing regimen, the container/closure system, and the nature of the treatment. Risk/benefit should also be considered; higher levels of leachables would be acceptable in a drug used for the treatment of cancer than in, for example, aspirin.

Extraction solvents for controlled extraction studies should be chosen to mimic, as closely as possible, the nature of the drug product. While a controlled extraction study should be designed for the worst-case scenario, it should not use overly harsh solvents compared with those in the drug product. For example, an aqueous-based drug product could be mimicked with water at varying pH values and a water/isopropanol mixture. On the other hand, for a drug product, such as an oral or nasal spray with an organic propellant, solvents such as n-hexane and dichloromethane would be more appropriate. 

Contact time and temperature are also key considerations when designing a controlled extraction study. PQRI recommendations give appropriate extraction methods, temperatures, and times for orally inhaled and nasal drug products (OINDP), such as reflux and Soxhlet extraction. For parenteral and ophthalmic drug products (POPD) with water-based extraction solvents, methods such as autoclaving and migration (e.g., 55 °C for 72 hours) are more appropriate.

The resulting extracts should be concentrated and analyzed by a wide range of analytical techniques in an attempt to detect all potential leachables. It is important to ensure that any extractables (and potential leachables) can be detected down to an appropriate level--the PQRI recommends 0.15 µg per day for OINDPs (1), while a level of 1.5 µg per day can be used for POPDs (2). These values need to be converted into an analytical evaluation threshold (AET) (e.g., µg/mL) using information on amount dosed, doses per day, and doses per container/closure system. Allowance (usually 50%) should also be made for analytical uncertainty. If the drug product is to be given over a shorter period than a lifetime, then the stepped thresholds described in ICH M7 may be used (3).

Once extractables (potential leachables) have been identified and quantified, an experienced toxicologist should review the data and recommend which compounds are of sufficient concern that they should be monitored as leachables in the stability trial samples of the drug product. The choice of potential leachables to monitor is dependent on their toxicity at the maximum dose likely to be received by the patient. These leachables should then be analyzed using validated methods (ICH Q2) (4). It is important that an end-of-shelf-life sample is monitored as part of this process. Following the leachables analysis, the data should again be reviewed by a toxicologist to ensure none of the leachables are at a level that would have an adverse effect on a patient.

The key quality criterion is the absence, or a minimal level, of extractables that become leachables. Common sense implies that selecting component materials based on extractables profiles is very difficult without comprehensive data, and controlled extractables testing and toxicological assessment of observed extractables is essential.

When designing studies, solvent and extraction parameters such as time and temperature should not be so harsh they damage the polymer, and vendor information about the additives a polymer contains is a good starting point for determining decomposition pathways.

It is advisable to start a risk-based E&L assessment program based on a comprehensive knowledge of the process, including R&D studies, process descriptions, batch records, standard operating procedures (SOPs), technical reports, batch testing, data trending, and operating parameters. A list of product contact materials should include any material with the potential to migrate into the product at any point in the process. For each material, risk factors (scoring of risk should be documented) include material compatibility, location in the process, nature of the product, surface area, contact temperature and time, and pre-treatment steps. 

Multiple analytical techniques must be selected to ensure no E&Ls are missed, and any that are found can be identified. Results should be assessed by a toxicologist. The route of patient administration and whether the product is for acute or chronic use should be included in the assessment because the risk levels differ—the concentration of a leachable in the drug product is less important than the amount accumulated by the patient. 

Principally, two different E&L strategies are currently being used. The classical approach is based on defining the targets expected by conducting an analysis of the materials used in the device tested. In particular, non-volatile compounds, which are not accessible by gas chromatography-mass spectrometry (GC–MS), are monitored by simple liquid chromatography with diode-array detection (LC–DAD) or LC–triple-quadrupole target methods, with a limited number of target compounds. As the material information provided by manufacturers is often incomplete, this approach has a significant risk of missing toxicologically relevant compounds. 

The advances in analytical technology (in particular, the improved availability of LC/MS/MS systems with accurate mass capability) have opened up an alternative route, which is based on non-target analysis of larger additives (e.g., bisphenol A diglycidyl ether-type coatings, pentathiaethylenethioglycol oligomers, and hindered-amine light stabilizer-type additives). At Solvias, we have developed a database (EXLEA) comprising accurate mass LC/MS/MS data of nearly 6000 polymer additives and their degradation products. 

We perform target analysis for all EXLEA compounds by monitoring all extracted ion chromatograms (extracted ± 5 mDa) above a defined threshold, thus increasing the sensitivity for compounds in our database by typically three orders of magnitude compared to visual inspection of base-peak chromatograms (BPCs). In addition, BPCs are manually inspected for compounds currently not contained in our database. Our approach typically results in the identification or semi-quantification of 20–50 hits per extract, which would have been missed using a simpler, target-based study layout without accurate mass LC/MS/MS screening. 

Planning an extractables study starts with the definition of the reporting threshold for extractables related to the device tested, which will be based on considerations such as the route and frequency of the drug product administration and the dose applied to the patient. After this, a study protocol will be defined (which includes device definition, reporting threshold of the study planned extractions, screening methods for volatiles, semi-volatiles, non-volatiles, and inorganic compounds).

The extractables study report will contain identification and semi-quantification of any extractables detected above the reporting threshold. Additionally, we may include a toxicological assessment in the study report, which evaluates the complete list of compounds detected by using a software-based quantitative structure activity relationship (QSAR) approach. Compounds classified by the software as Cramer Classes III–V will be further examined by our toxicological experts.

Based on the extractable study report and the toxicological assessments, target compounds for the leachables study will be defined. For these targets, quantitative methods will be developed and validated according to ICH Q2(R1) (4). In most cases, GC/MS/MS and LC/MS/MS target methods will be used. In parallel, stored drug samples will be analyzed with screening methods to monitor secondary leachables (e.g., reaction products of target compounds with the drug formulation).

PharmTech: How do you set acceptance limits? What guidance has regulators provided on this issue?

 Setting acceptance limits involves the extrapolation of agent-induced health effects in animals to human risks. For drug development, the methodologies for threshold-associated exposures are discussed in ICH Q3C (5). This guideline discusses a method for calculating a permissible daily exposure (PDE) for a solvent, although calculating PDEs for mutagens and carcinogens is more complex. Toxicological data are often required to do a risk assessment that can be obtained from rodent lifetime bioassays for example. The data, however, are rarely available for impurities found in drug products, and it is impractical to test all potential carcinogens this way. As a result, toxicologists devised the concept of TTC that represents a level of exposure for a chemical below which there is no appreciable risk to human health. The PQRI’s Leachables and Extractables Working Group has also developed various thresholds and analytical methods for E&Ls to help establish whether testing is necessary. 

The extractables analyses conducted at SGS M-Scan for OINDPs are based on PQRI recommendations, which have been used for submissions to US, European, and Canadian regulators. The recommendations suggest the use of a safety concern threshold (SCT) of 0.15 µg per day for patient exposure (1).

Extractables analyses for other drug products (e.g., PODP) are usually based on the EMA genotoxic limit of 1.5 µg per day for patient exposure (6). The latest information from the PQRI suggests that they will also adopt this level for PODP. FDA, however, recommends particular limits for potential leachables within ophthalmic products and these limits will need to be followed when submitting ophthalmic data to FDA.

 There are limits in various compendia for certain materials used in the pharmaceutical and medical-device industries; however, these limits are considered a starting point to identify materials that might be acceptable. The final drug or biologic product will influence appropriate specifications and acceptance criteria. Acceptance criteria should be set based on the observed range of variation according to FDA and ICH guidance—

Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products (Q6A) and Biological Products (Q6B) 

(7, 8). The guidance establishes the criteria to which a drug and biologic product should conform to be considered acceptable for its intended use. There is a provision for control of extractables from container/closure systems in which parenteral products are considered significantly important. The guidance indicates that where development and stability data show evidence that extractables are consistently below levels demonstrated to be acceptable and safe, the elimination of this test can be accepted but should be reinvestigated if the container/closure system or formulation changes. The guidance also recommends that data should be collected for components as early in the development process as possible. This recommendation is consistent with quality guidelines ICH Q8, ICH Q9, and ICH Q10 (9-11). 

Acquiring appropriate evidence to demonstrate suitability of materials is necessary for each pharmaceutical product. Extractables are a function of the material chemical make-up, physicochemical properties, configuration of the component, various environments, and length of exposure. Risk variables include component proximity to the final product, area of direct contact, dosage form, and conditions of use throughout material processing, manufacturing, filling, and storing. Risk for leachables can be indicated based on identifying those extractable compounds with the highest propensity to leach into the final product. The extraction and analysis methods should be tailored to substantiate that leachable levels are below quality and safety concerns. This approach allows risk of toxicity or poor quality to be identified and mitigated. It is not practical to assume that a standard method, or even suite of methods, can provide the essential evidence. A strategic approach for demonstrating safety thresholds and best practices for E&Ls in OINDPs has been demonstrated by PQRI and is currently in process for PODPs. Recent 

(USP) guidelines <1663> Assessment of Extractables Associated with Pharmaceutical Packaging and Delivery Systems and <1664> Assessment of Leachables Associated with Pharmaceutical Packaging and Delivery Systems were published in 

 in September 2013 and are consistent with PQRI approaches (12, 13).

To set acceptance criteria for E&Ls, relevant data must be collected and assessed. It is important to justify specifications based on impact to the final product and the patient. Control points can be considered early on, but the nature of leaching often occurs over a period of time. Variability will exist from component to component as well as the extractables’ propensity to leach. Control points are not easily derived until there are multiple lots of components representing full shelf-life stability studies. Once an analytical target profile is established for leachables, methods should be optimized and measurements fully validated. Statistically relevant data are necessary to establish acceptance criteria. 

PharmTech: What analytical techniques are used in the identification and quantification of E&Ls?

Identification and quantification of E&Ls covers a broad range of extraction and analytical techniques. The overall goal of the study is to detect and measure leachables and interpret the data with regard to safety risk based on total daily exposure and alerts for incompatibility. The scope of a leachable study includes understanding materials, which begins with an extractable study. 

The objective of an extractable study is to provide evidence to support leachables assessments. Depending on the intended outcome, different methods will be fit for different purposes. The material should be characterized to confirm chemical make-up and establish suitable methodology. The output would indicate general compatibility and potential for a material to leach. In this case, aggressive extraction techniques using multiple solvents of varying polarity are generally employed. Extraction techniques can also be designed to simulate worst-case conditions relative to the actual product or a placebo to indicate probable leachables. If the extraction media is complex, extractables can be masked and method optimization may be necessary. Extractions using complex media for discovery of extractables are not recommended unless known targets for spiking and recovery have been justified. Extractions should not be so mild that information is insufficient, or so overly aggressive that it leads to misleading extractables data. Extractability is influenced by variables of extraction techniques as related to time, temperature, solvent/media, sample surface area, static versus dynamic with consideration of the polymer properties, and diffusion/migration characteristics. 

Solvent-extraction methods include standard Soxhlet, reflux apparatus, shakers, and sonication equipment. Instrument-based extraction techniques include microwave, accelerated solvent extraction (ASE) or supercritical fluid extraction (SFE). A host of methods for volatile organic extraction exist such as headspace samplers, dynamic headspace, thermal desorption, solid-phase microextraction (SPME), stir bar sorptive extraction (SBSE), and thermal desorption techniques. The extraction techniques should be optimized, and in some cases, method development for extractions techniques will be necessary. 

Once the extract is generated, it is possible that dilution, concentration, or solvent exchange is warranted. Depending on chemical species of interest and analytical technique, isolation of trace compounds in complex mixtures or derivitization to increase volatility can be considered. 

There is not a single analytical technique capable of detecting all volatile and non-volatile organics, or inorganic E&Ls. GC or LC techniques are generally employed to separate mixtures of organic compounds. Many chemical species that are likely to migrate are amenable to GC due to the mobility of low molecular weight volatile compounds. High-performance liquid chromatography (HPLC) can separate diverse species with a wide range of molecular weight, polarity, or conductivity. Typically, chromatographic techniques are paired with MS. This method will measure the molecular mass of charged ions providing molecular structure of chemical entities, and is the mainstay of extractable identification. 

Organic compounds can be targeted for quantitative analysis based on results of a basic extractables screen. Some materials have known safety or quality targets to be investigated. There are multiple detectors to consider depending on the intended outcome. MS is compound specific, but there could be a need to measure a specific type of compound with low sensitivity or wide/narrow ranges of concentrations. Different options include: flame-ionization detector, which has a linear response across a wide range; electron-capture detector, which is more suitable for detecting halogenated compounds; and photoionization detector for low level volatile organics. Often LC employs a photodiode-array detector to obtain ultraviolet (UV) and visible spectra. The value depends on specific needs and examples noted are not implied to be all-inclusive. 

Extractable screening studies typically produce numerous unknown and known organic compounds. Equally as important are screenings for inorganics. Even though the number of inorganics is limited to the periodic table, there are unique challenges. Trace levels can interact with drugs or biologics, and in some cases, may be toxic. There is potential for elements to leach, but some of these elements already exist in drug-product excipients whereas others are ubiquitous and difficult to trace to the source. It is the accumulation of all elements in the system that will impact the final dosage form. Most inorganics from component materials are not readily soluble and should not be a significant contributor to the end product but should be realized. A semi-quantitative screen of extracts across the periodic table of the elements is commonly performed using inductively coupled plasma mass spectroscopy (ICP–MS) or atomic emission spectroscopy (ICP–AES). The plasma will atomize/excite atoms that are ionized and detected by MS or, in the case of AES, the photons are detected by optical methods. In certain cases, such as mercury, arsenic, or chromium, speciation may be warranted and may require other excitation and detection techniques. Once a comprehensive list of extractables is derived, selecting the critical extractable is the next challenge. Methods should be robust and have the capability to detect the unexpected E&Ls. 

Modern analytical technology offers a wealth of tools in various combinations. Critical to establishing the extractable profile are the extraction solvents/media and technique. Only the chemicals extracted will be detected, so worst-case scenarios must be considered. An example of detailed extractable protocols can be found at 

The totality of the extractable data will lead to the leachable analytical target profile. Leachable methods often will use the same techniques as those used for extractables. In most case, the techniques need to be optimized to eliminate interferences and achieve appropriate sensitivities.

Accurate and reliable measurements that are fully validated are necessary to provide leachable data. Accelerated leachable data can be useful but will not take the place of shelf-life stability studies. The stability of the final pharmaceutical product over the shelf life should be observed for unexpected leaching resulting in poor quality, which can be in the form of an impurity, particle, or degradants. The multiple and diverse tools of modern analytics provides a means for thorough E&L evaluation. The analytical techniques are abundant but the challenge is choosing an appropriate methodology for the relevant information to link the acquired knowledge to product quality and patient safety. 

 Extraction from container/closure systems is carried out using a range of techniques including Soxhlet extraction, reflux, ultrasonication, autoclaving, and migration testing in ovens for extended periods. These extracts are concentrated and/or solvent exchanged to provide suitable aliquots for analysis.

At SGS M-Scan, we typically performed our analyses using one of more of the following major pieces of equipment:

Triple-quadrupole mass spectrometer fitted with an atmospheric pressure chemical ionization (APCI) ion source and incorporating a HPLC system with a variable wavelength UV detector for the analysis of fluorinated compounds from polytetrafluoroethylene-coated seals.

Single-quadrupole mass spectrometers fitted with a combined electrospray/APCI ionization (ESCi) source and a ultra-performance liquid chromatography (UPLC) system with a diode-array detector (UV) for the analysis of non-volatiles and more polar species. 

Triple-quadrupole mass spectrometer fitted with an ESCi source and a UPLC system with a diode-array detector (UV) for the analysis of non-volatiles and more polar species. 

GC–MS system with headspace autosampler for the analysis of volatile organic compounds. 

GC–MS systems with liquid injection for the analysis of semi-volatile organic species amenable to this method.

GC–MS system with a pyrolyzer for the analysis of polymeric and oligomeric compounds.

LC–UV system for analyzing mercaptobenzothiozole (MBT) from rubber components.

ICP–MS system for the analysis of elements particularly heavy metals.

GC–NCD for the analysis of nitrosamines from rubber components.

GC–MS for the analysis of polycyclic aromatic hydrocarbons from rubber components.

 Numerous analytical techniques are used to detect, identify, and quantitate E&Ls. A combined analytical approach is preferable, using at least two different techniques. HPLC, for example, is a universal separation tool for organic compounds, and can accommodate multiple detection techniques such as UV diode array and mass spectrometry. GC is used for semi-volatile and volatile analytes, and can be used alongside high-resolution mass spectrometry and flame-ionization detectors, among others. GC plus headspace sampling analyzes vaporized volatiles, useful if residual solvents are likely to be present.  Inductively coupled plasma spectroscopy screens for a wide range of metals. Nuclear magnetic resonance (NMR) spectroscopy may also be used if identification is required. 

PharmTech: Have advances in technology have improved E&L testing? What advances do you wish to see in the near future? 

 Advances in technology continue to improve testing for E&Ls. Many OINDPs contain a large number of doses in a relatively small volume, and hence have high AETs. However, some PODPs, particularly those dosed intravenously or those used for dialysis, can have extremely low AETs. The continuing advances in the sensitivity of mass spectrometers are vital to the successful analysis of such drug products. Despite these advances, some AETs in large volume parenterals are still beyond the reach of modern analytical instruments, and alternative approaches are required.

New chromatography techniques also contribute to advances in E&L testing. For example, the use of UPLC rather than HPLC has substantially reduced the time taken for LC–MS analysis of extractables from controlled extraction studies and leachables in drug products.

Ensuring patient safety through sound science is the goal of any E&L study. Newly emerging analytical techniques should be employed where they can advance the detection, identification, and quantitation of E&Ls. 

It is not possible to precisely identify all substances extracted from polymers under harsh conditions. A confirmation must be grounded on fact or a confident attribute to be deemed ‘reliable.’ For this reason, rules are required to specify what constitutes a reliable confirmation. In cases where an authentic reference substance is not available, data must be collected from multiple analytical techniques for a plausibility check.

For example, a UV spectrum might provide some information about a conjugated double bond or aromatic system. Data from electron ionization (EI)–GC/MS could provide spectral information by matching the pattern of two or three substances in a library of spectra. Accurate mass assignments could predict the elemental composition of the peak of interest, and double bond equivalents can be predicted. This is the degree of saturation, and allows for the sum of the number of rings, double bonds, and triple bonds present in the molecule to be determined. The final structure can be verified with the use of NMR, MS, and infrared (IR), as well as a qualitative inspection of all the data. 

A wide range of sophisticated analytical technologies can be employed for E&L testing. While all-purpose methods can be a starting point, these methods will not address distinct applications. Pertinent information is acquired by understanding the materials and intended use to enable specific extraction and analytical methodology to be justified. There continues to be a move to green chemistry, which will influence future use of chemicals and analytical instrumentation but will not have a direct impact on the overall E&L strategy. There is a need for advances in efficiency for acquiring and interpreting appropriate data to meet today’s quality expectations; perhaps novel approaches to proven models will be explored in the future. 

In my opinion, upcoming advances should be a combination of improving technologies for identifying/qualifying leachables along with development of new materials that are engineered to fit a purpose in a quality-by-design (QbD) paradigm. Accurate and precise analytical measurements will be the means to enabling future applications of the right knowledge at the right time to materials used in the manufacture, containment, and delivery of high-quality pharmaceutical products. 

Safety Thresholds and Best Practice for Extractables and Leachables on OINDP

, (September 2006), accessed Mar. 26, 2014. 
  2. 	C.T. Houston, “Extractables and Leachables in Parenteral and Ophthalmic Drug Products: An Evolving Strategy,” presentation at the Extractables & Leachables Conference (Vienna, December 2012).
  3.	ICH, M7, 

Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk

, Step 2 version (February 2013). 
  4. 	ICH, Q2(R1), 

Validation of Analytical Procedures: Text and Methodology

, Step 4 version (November 2005). 
  5. 	ICH, Q3C(R5), 

Impurities: Guideline for Residual Solvents

, Step 5 version (Feb. 2011).
  6. 	EMA, 

Guideline on the Limits of Genotoxic Impurities

Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

Industry experts discuss how extractables and leachables studies are designed using a risk-based approach.