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

Adeline Siew, PhD

The pulmonary route is gaining increasing popularity as a fast and effective way of delivering drugs to the lungs both locally and systemically. There are several reasons for this interest, noted Conrad Winters, PhD, director, and Filipe Neves, PhD, group leader, both from the Drug Product Development Group at Hovione. “Firstly, advances in device technology have made inhalation drug delivery more convenient and patient-friendly. Secondly, from a therapeutic angle, the lungs provide a high absorption area with extensive vascularization, leading to rapid delivery of the drug. Moreover, because it circumvents first-pass metabolism, lower doses can be administered compared with the oral route.” 

The pharmaceutical industry has now realized that the potential of inhaled therapies goes beyond asthma and chronic obstructive pulmonary disease (COPD), and therefore, offers opportunities for growth and product differentiation. “Pharmaceutical scientists are increasingly using the pulmonary route as an effective mechanism for systemic drug delivery,” observed Gonçalo Andrade, PhD, business development manager, Hovione. “The greatest interest appears to be in antibiotic delivery, with two products already approved—Tobi (tobramycin, Novartis) and Cayston (aztreonam, Gilead)—and at least three others in Phase II-III clinical trials (i.e., amikacin, vancomycin, and levofloxacin).”

Another key driver has been the development in the delivery of macromolecules, added Peter Villax, vice-president of Hovione. “While the lungs are highly permeable to small molecules, therapeutic peptides, and proteins (that would be deactivated or are too large for absorption via the oral route) are also extensively absorbed from the lungs. This advantage provides for the delivery of molecules previously only administered via the parenteral route, such as vaccines and gene therapy.”

The three types of devices used for pulmonary drug delivery include nebulizers, pressurized metered-dose inhalers (pMDIs), and dry-powder inhalers (DPIs), explained Peter York, chief scientist, and Lyn Daintree, development director, both at CrystecPharma. “While nebulization is used in cases where pMDIs and DPIs are not appropriate, such as for treating small children or infirm patients, or in severe cases of respiratory disease, pMDIs and DPIs offer distinct advantages for patients, prescribers and manufacturers.”

“Patients are much more willing to be placed on an inhalation product than on an injectable product, especially when it’s self administered. And for that reason, we can expect patient compliance to be better,” said Bill Schachtner, associate director, Small Molecule and Inhalation Product Testing Services, PPD. “Moreover, unlike injectable products, pMDI and DPI products do not require sterile manufacturing or cold-chain storage. In contrast to injectable products, which are often limited in the ability to provide multiple doses due to sterility issues, pMDIs and DPIs are usually designed as multidose products.” 

To gain insight into the role of particle engineering in the formulation of inhaled therapeutics, 

 spoke with Daintree and York (both referred to as CrystecPharma thereafter); Andrade, Neves, Villax, Winters (collectively referred to as Hovione); and Schachtner in a roundtable discussion. 

What factors control drug delivery to the lungs?

 Inhaled drug delivery is different from other types of administration because in addition to biological factors, the function of the inhaler and its interaction with both patient and drug dose are key to delivery success.

The physiology of the lungs is designed to keep particles out of the body. Pulmonary drug delivery must, therefore, overcome these barriers. The epithelium of the respiratory system varies in thickness and corresponding permeability from the comparatively thick trachea to the more permeable alveoli. Hydrophobic molecules can be absorbed through the transcellular pathway of the lipid bilayer around cells. More hydrophilic molecules are subject to paracellular absorption through the aqueous pores in the intercellular tight junctions. Some molecules are also subject to an active transport mechanism. The absorption profile of an inhaled molecule is the culmination of all these routes of absorption.

In terms of the technology, pulmonary drug delivery is determined by the nature of the API, the formulation, the device, and their functional performance in aerosolization. An important feature of inhaled drugs is the particle size of the dose components, particularly the active molecule. Particles that are too large will not reach the deep lung tissue whereas particles that are too small risk being exhaled. 

In simple terms, particles between 1 and 5 microns will be deposited in the lungs. A number of particle size-reduction and particle-engineering technologies (e.g., air jet milling, spray drying and wet polishing) can be used to generate particles with aerodynamic particle sizes within this range. The problem is that very small particles have strong cohesive and adhesive forces, and therefore, tend to form agglomerates, which need to be dispersed for effective delivery. Because the particles are often formulated with coarser lactose, they also need to separate from these carrier particles for correct deposition in the lung.

Developing solutions to these challenges requires close cooperation between the device engineer, the formulator, and the particle engineer. The device expert needs to develop an inhaler that efficiently delivers the dose. For DPIs, inhalation delivery is driven by the patient’s inspiratory effort, therefore, the device must efficiently convert this source of energy into effective dispersion forces (to break up the agglomerates, separate particles of active and carrier, and aerosolize the dose) and entrainment forces (to move the aerosol cloud out of the device through the mouth and pharynx into the lungs). The challenge for the engineer is to make sure that this dispersion and entrainment happens in a way that is not affected by changes in inspiratory effort and air flow. In other words, the performance of powder inhalers must be as flow independent as possible, and this is usually done by engineering devices to achieve their peak performance at a low flow rate that most patients will be able to achieve.

As the aerosol cloud leaves the inhaler (i.e., the emitted dose), the device will have dispersed the dose into inhalation-sized particles (i.e., the fine-particle dose). Several factors affect this performance in a complex manner requiring multidisciplinary solutions. For instance, particle adhesion to inhaler surfaces, which affects the emitted dose, can be minimized by choosing the right polymer, followed by engineering of the charge potential of the particles, and finally, by understanding the powder relaxation times needed prior to blending and filling. It is a rather delicate balance that requires a very high level of cooperation between various disciplines. 

 Drug delivery to the lungs is affected by many factors between the formulation, device, patient, and disease. The formulation can affect the delivery through the percent drug load, excipient type/amount. and even the manufacturing process to incorporate the drug and excipients. Changing the grade and size of lactose used in a DPI can affect initial blending of the drug with the lactose as well as the ability of the DPI to de-aggregate the drug from the lactose. The use of a lower-pressure propellant for a pMDI can change the ability to adequately disperse the suspended drug when actuated through the same metering valve and actuator orifice. 

Device differences can significantly affect delivery given that the selection of a low- versus high-resistance DPI device can alter delivery profiles. At the same time, the use of a high-volume versus low-volume metering valve on a pMDI matched with a large or small orifice size on the actuator can change the product delivery characteristics dramatically. Each of these differences requires formulation and device optimization to deliver the needed amount of medication to the lungs.

With inhalation products also comes the human factor, especially for patient-operated devices. Passive DPI uses the patient’s inspiration to pull the drug through the device and de-agglomerate the drug particles from the lactose carrier. The patient’s ability to maintain inhalation throughout the process is crucial for proper delivery of the medication. Newer DPI devices in both passive and active designs have been able to overcome some of the issues associated with patient use.

Patient use also is important with pMDI products as the coordination of patient inhalation with actuation of the device will determine whether the proper amount of medication is delivered into the lungs. To address this issue, there are auto-inhalation devices for a limited number of products that are self-actuated once the patient starts to inhale from the device. Additionally, the use of spacers has helped meet the need for paediatric administration where it is difficult to not only coordinate the actuation with inspiration but also to obtain the required attention from a young child.

Of course the severity of the disease also affects the ability to administer the medication properly. The only way to understand its impact on the drug/device system is through proper clinical trials using patients with the target disease state. 

What are the key formulation considerations when developing an inhalation drug product?

The primary consideration in pulmonary drug delivery is generating droplets or particles in the 1-5 micron size range during the patient dosing stage and maintaining that delivery throughout the product shelf-life. For nebulized drug products, the main factor is the solubility and stability of the drug being delivered in an aqueous solution and the nebulizer being used to create the fine droplets being delivered. As with all inhalation products, there are differences between jet nebulizers and the newer vibrating mesh nebulizers in the delivery efficiency and droplet sizes formed.

For a DPI, the ability to create stable, fine particles of the drug will determine the overall formulation development process. Conventional particle sie reduction techniques, such as jet milling, works on most of the asthma/COPD drug substances on the market but other particle-generation techniques, such as spray drying, controlled crystallization, or microfluidisers, allow for drug substances that are not amenable to jet milling to be converted to respirable particles. 

The particle size-reduction technique used can drive the type of device used as a technology. For example, spray drying can incorporate bulking agents directly into the finished particle, thus, eliminating the need for blending the fine drug substance with excipients such as lactose. These techniques allow for long-term drug-product stability as well as drug dispersion during patient dosing. Lactose blends are the majority of currently marketed dry-powder formulations but they require much more energy to disrupt the fine drug-substance particles from the larger lactose particle’s surface; therefore, the device to deliver such a blend needs to have incorporated technology for this higher-energy input. Engineered particles, such as spray-dried materials, can create particles that can be readily dispersed without the need for de-aggregation. This allows for a much simpler device on the back end but a higher technical input on the front end of the product development.

pMDIs can work with either solubilized or suspended drug substances depending on the properties of the drug substance being developed. Formulations for water-soluble drug substances are usually developed as suspensions due to the low water content of the hydrofluoroalkane (HFA) propellants used. These formulations can use the same particle size-reduction techniques used for DPIs but will be suspended in a HFA-propellant formulation for dispersion. The delivery of the drug product to the lung is mainly controlled by the incoming particle size of the drug substance; however, other factors such as the propellant, excipients, amount metered from the valve, and actuator orifice size play added roles in the overall final particle size distribution.

For pMDI solution formulations, the solubility of the drug substance is enhanced through the use of cosolvents. Since there are no drug particles to deliver, the delivery to the lung is controlled by the solution formulation (drug content, excipients, cosolvent, propellant type) as well as the amount metered from the valve and actuator orifice size to create droplets containing the medication within the 1–5 micron size range.

For each of these product types, the formulation must show chemical stability. For DPI and pMDI suspension products, these formulations must also maintain physical stability of the fine particles and their delivery from the device.

Pulmonary drug delivery is achieved through an understanding of the complex relationship between particle engineering, formulation and device. There are many goals for a formulation scientist when preparing a pulmonary drug-delivery system. First and foremost, the formulation must be stable. Stability has many influences including temperature, humidity, residual solvents, and solid-state form (i.e., amorphous versus crystalline). The bulk powder properties of the formulation can change with time, leading to differences in the dispersivity of the formulation. For a given aerodynamic force generated by the inhaler, an increase in the agglomeration strength of a powder will lead to decreased dispersion and reduced lung deposition. 

Another key consideration is the target dose. The target doses may vary widely during the early stages of a development process and different approaches are suited to different dose ranges. Ultralow doses, in the order of a few micrograms, may benefit from a combination approach of composite particles with a conventional lactose carrier. For doses up to 5 mg of active, a carrier-based approach using combinations of coarse and fine lactose is appropriate and widely used. For higher doses, engineered particles that comprise a drug-alone formulation are the preferred path forward.

The inhalation formulation scientist must also consider drug targeting. It may be appropriate to proceed with a unimodal distribution for a mono-directed approach, for example if you are targeting the alveoli, or to proceed with a multimodal distribution for a multitargeting approach. Through control of particle size, it is possible to target different regions of the respiratory tract. Larger particles target the upper airways while smaller particles are required for deep lung delivery.

If blended with lactose, the uniformity of the blended batch is crucial, not just because this is good practice, but also because unit doses tend to be very low, making precise blending even more important. For instance, the smallest dose of Advair formulation contains 50 µg of salmeterol, 100 µg of fluticasone and 12.35 mg of lactose (for a total fill weight of 12.5 mg). The difficulty of getting the right blend is further compounded by the fact that mixing parameters (e.g., time, speed) may also affect the carrier/drug adhesion and thus, the fine-particle dose. Composite particles are not subject to this constraint, hence, their applicability to very low doses. In any case, poor reproducibility needs to be actively addressed at every step of the manufacturing process because the inhaler will itself introduce variability during the delivery of the dose. 

From a methodological perspective, developing an inhaled drug formulation starts with the maximization of the emitted dose. Drug material that does not exit the device will not benefit the patient and is a source of variability. Achieving emitted doses in excess of 90% is a development goal. Once a high emitted dose is achieved, the focus turns to maximising the fine-particle dose through the combination of drug particle size, formulation material selection, formulation process control, adequate filling technology and device efficacy. Depending on how these factors are combined and on the drug properties, fine particle fractions of 30% to 80% (in relation to the emitted dose) can be achieved.

Finally, the careful selection of packaging materials ensures minimal change to the formulation over the shelf life, with the balance between cost and protection driving the selection.

 Why is particle engineering important in pulmonary drug delivery? 

Particle engineering has brought a new toolbox to pulmonary drug delivery. These new techniques can induce changes in the material characteristics of the drug and the excipients, modifying size, shape, morphology, and surface, which therefore, have an impact on their delivery characteristics. It is through the application of particle-engineering technologies that we can achieve tailored particles with the appropriate particle size properties designed to achieve maximum lung deposition. 

Particle size distribution is only one aspect of the characterization of a particle for pulmonary delivery. A narrow span is desirable not just to improve the targeting and dose reproducibility but also to bring extra IP protection to an old product.
  Certain particle-engineering approaches can induce changes in the material characteristics, resulting in the generation of amorphous material, particularly in the case of conventional air jet milling and spray drying from a solution. Whether this is intentional or an implicit result of the process, it is important to understand the crystalline/amorphous components, the stability of the system, and whether recrystallization will occur during the shelf life of the product.
  Particle-engineering technologies applied to particle size reduction can induce changes in surface properties of the particles. Hygroscopicity is an aspect that may change with decreasing particle size. After size reduction, the increased surface area affords for greater water absorption so size-reduced material may behave differently to the starting material. Morphology of the drug substance can affect processing and pulmonary delivery at many points. A different habit of the starting material will determine how the material mills. Particle size measurements are determinant on the technique used for calculation and prisms and needles can be determined as having equivalent particle sizes but behave quite differently during downstream processing. 

Surface chemistry of the drug substance can be greatly influenced by the particle-engineering method. Air jet-mill micronization produces many surface defects and dislocations while microfluidization processes result in smoother surfaces for equivalent sized particles. Surface properties will impact the cohesive and adhesive nature of the engineered materials (regardless of the formulation approach employed) with potential impact on the aerodynamic performance. The surface fractal dimension is a useful value given that geometric details are more important than the bulk picture when addressing particles for pulmonary delivery.

Increasing the surface area enhances the aqueous solubility of materials in accordance with the Noyes-Whitney equation so inhalation size particles can dissolve to a greater extent and faster than those sized for oral delivery, thereby taking advantage of the rapid drug absorption commonly seen with pulmonary delivery.

While controlled drug particle size is crucial because of the dimensional challenges posed by the architecture of the airways of the nasal cavity and lungs, other physicochemical characteristics are also extremely important. These include particle morphology and shape, particle surface topography, and charge (or energy), solid-state chemistry (polymorphic form, crystalline or amorphous state), and hygroscopicity. The quality of the final formulation, in terms of the aerosolization performance, physical and chemical stability, dissolution and absorption in the lungs, will be a consequence of an integration of all these contributing factors. This is a complex situation increasingly recognized by pharmaceutical industrial scientists as well as by regulatory authorities who require appropriate data and evidence on these issues to demonstrate the quality, safety and performance of inhaled products presented for approval. The goal is to design and engineer drug particles with preferred and selected physical, chemical, solid state and particle surface characteristics for a specific drug substance to provide optimal aerodynamic performance when formulated or used as a drug-alone system and delivered via an inhaler. Batch-to-batch consistency is also a prerequisite so that data from guiding studies in animal respiratory toxicology and bioavailability, in-vitro aerosolization and dissolution studies can be used in the knowledge that future batches will behave in the same manner. 

As for the disadvantages, to a great extent, due to the cumbersome and expensive nature of nebulisers, and in many cases, dependency on a healthcare worker for assistance, wide use of this group of inhalers has been bypassed through the advent of pMDIs and DPIs. For pMDIs, issues were focused until recently on the chemical type of propellants used and related environmental concerns; however, the advent of newer propellants has removed this specific challenge while at the same time leading to formulation challenges in some instances. The limited number of regulatory-approved functional excipients, such as wetting and suspending agents, which are routinely required to ensure efficient in-use performance and uniformity of individual doses on activation of the pMDI, can also be problematic.

 What techniques are used in particle engineering for inhalation formulations. Can you tell us the pros and cons of each technology and how they compare with one another?

 In preparing the necessary fine particle size for drug substances for inhalation medicines, there is almost a total reliance upon a ‘top-down’ high-energy milling operation--micronization or fluid energy milling. While this established method provides fine-sized material in the respirable range for low molecular weight drug substances, it is well recognized that the uncontrolled breakage of larger particles to smaller particles frequently causes other undesirable effects. Among these effects that have been reported are the generation of small but variable amounts of hygroscopic amorphous domains within a crystalline phase and highly energized and electrostatically charged surfaces. Process yields can be disappointing, especially when processing materials are expensive, or of limited availability, and batch-to-batch variability is frequently observed. 

In some cases, it has been reported that it is necessary to ‘stabilise’ drug powders after milling for a period of time under controlled temperature and humidity to reduce downstream handling and secondary processing challenges as well as minimise problems of diminished chemical and physical stability, especially those related to particle size growth on storage. 

It follows from previous comments, together with a forward-look to the likely demands for next-generation inhalable medicines, that alternative and more controlled processes for preparing inhalable-sized particles, for biotech and larger molecular weight drugs as well as the low molecular weight materials, are required. 

Over recent years, there have been exciting developments based on a ‘bottom-up’ approach to preparing the fine-sized particles from drugs in solutions. These processes focus on alternative methods of drying the solution to generate the required inhalable-sized particles without the negative features frequently induced by high-energy milling, and include spray drying, freeze-spray drying, and supercritical fluid (SCF) processing. Perhaps an ‘ideal’ process can be defined as one that is a single-step operation (i.e., from solution to inhalable drug particle) that can be ‘tuned’ to produce particles with the desired and targeted size and size distribution, morphology, physicochemical characteristics and related aerodynamic properties. The process and technology should be capable of providing excellent batch-to-batch consistency, delivering high product yield, be financially competitive, be readily scaled under GMP specifications and be suitable for regulatory approval.

Experience and evidence with SCF technologies have indicated that this technology can meet these ideal requirements. Based on an antisolvent principle using supercritical carbon dioxide as the antisolvent and introducing a drug solution to a flow of the antisolvent under supercritical conditions, dry, respirable-sized drug particles form very rapidly, which are retained in and subsequently collected from a particle formation vessel. Particle physical and chemical properties can be tuned by changing the process conditions and the undesirable features frequently seen for micronized material are eliminated. Batches of material with different and tight particle size fractions within the respirable range have been produced, making possible studies for targeting drug particles to different regions of the lungs. The SCF process has also shown to be viable for a range of biotech and larger molecular weight therapeutic agents. The other processing demands of consistency, high yield, facile scale-up, GMP operation and competitive costing have all been demonstrated.

The Levadex MDI product (Allergan) for acute treatment of migraine, is an example of the “new version” of pulmonary drug delivery. The product is expected to be launched following FDA approval this year. SCF technology was chosen, following comparison with other particle-generation approaches, to prepare (at development and for manufacturing GMP scale) dihydroergotamine mesylate drug particles according to an extremely tight physicochemical specification. The MDI device uses a “soft-mist” principle to aid patient compliance. When inhaled, the drug, an off-patent small molecule, is absorbed rapidly from the lungs into the systemic circulation to provide rapid relief for the patient from recognized onset of symptoms of a migraine attack, thereby enabling patients to minimize or avoid a severe event.  This product demonstrates the benefits of adopting alternative technologies to create a “new vision” for an old drug and the innovative approach of systemic distribution via absorption using the pulmonary route, in this case, for treating migraine and for drug delivery the lungs for a rapid neurological effect.   

Commonly used techniques in particle design include emulsion systems, micronization, spray drying, and supercritical antisolvent systems. Other systems, such as wet polishing, use a combination of size-reduction technologies and isolation approaches.

Emulsion-based systems generate solid composite particles of high density with a narrow particle size distribution. They are complex to produce at large scale requiring large quantities of solvents and significant effort in the removal of residual solvents.

Micronization by air-jet milling often produces irregularly shaped, predominantly crystalline particles. It is the established method of size reduction in the pulmonary drug delivery field and is a solvent-free process. The resulting particles are typically cohesive and possibly contain amorphous domains that will crystallise over time, resulting in physicochemical instability of the particle size-reduced material. In this case, conditioning strategies are used to accommodate and account for this instability. The material is typically difficult to disperse and blend due to electrostatic charges generated during the process.

Spray-dried particles are highly tuneable. Low-density and solid higher-density particles can be produced. Crystalline particle are obtained mainly when spray drying is used as an isolation step (isolating dry powders from milled suspensions) while amorphous composite particles are obtained when spray drying solutions in which the drug is dissolved together with excipients. Scale up is not without its challenges but as inhalation APIs are usually very potent, it is normal to have rather small batches ranging from kilos to tens of kilos. Thermal sensitivity precludes the use of spray drying for some materials and it is important to understand the solid state of drug-excipient systems before proceeding with amorphous materials.

Wet polishing is a new category of particle-engineering technologies developed by Hovione, which employs a range of particle-size technologies, using suspensions as well as bottom-up techniques combined with a suitable isolating method, often using spray-drying technology. It is highly tuneable in terms of particle size generation, resulting in median particle sizes with a precision of ± 0.1 µm and narrow size distribution. Spans of less than 1.0 are achievable and the inclusion of a size classification step in the wet polishing can reduce the span even further. Wet polishing generates highly crystalline particles with low cohesivity. The particles obtained can then be formulated or blended to improve delivery performance. 

Articles

Experts discuss factors affecting drug delivery to the lungs and key considerations when developing inhalation formulations.

Pulmonary Drug Delivery—Particle Engineering for Inhaled Therapeutics

Generic-drug competition has become increasingly aggressive, especially in an environment where healthcare policies are placing stronger emphasis on pharmacoeconomics and demanding better treatment outcomes at a lower cost. A 2012 analysis by IMS Health estimated that patent expiries will reduce brand spending in developed markets by $127 billion through 2016 (1). With drug-development expenditures escalating at an alarming rate while R&D productivity continues to decline, branded drug-makers are under pressure to maximize the value of their products throughout their lifecycles. 

“Although the development of new drugs to address unmet patient needs remains the single most important goal of any pharmaceutical company, effective lifecycle management (LCM) is invaluable for getting the greatest possible value from existing brands,” says Anil Kane, PhD, executive director and global head of formulation sciences, Patheon. 

“The challenge, however, is in the development of creative and unique strategies that will generate intellectual property and provide additional mid- to long-term exclusivity for the product,” notes Ninad Deshpanday, PhD, president, R&D, Cirrus Pharmaceuticals, a Kemwell company. “The competition among innovators developing similar strategies has increased, and generics have become smarter; therefore, the window to succeed with novel lifecycle products has become much narrower today.”

LCM strategies include identifying new indications, developing modified formulations, finding new routes of administration, combining more than one drug into a single product, producing the drug as a single enantiomer if the original drug substance was a racemic mixture, and switching from a prescription product to over-the-counter (OTC) status, among others. According to Kane, the key issue facing pharmaceutical companies is the selection of one or more of these LCM options by understanding the opportunities and competitor landscape, potential return on investment, and the ability of timely implementation. “Adopting a proactive LCM strategy, such as line extension into pediatrics, changing the dosing regimen by using modified-release formulations or improving clinical benefits and patient compliance by combination products, can offer a broad patent coverage and enhance the value of the brand,” Kane adds.

Thomas Hein, PhD, director of sales & business development, at Hermes Pharma, emphasizes that LCM should start as early as possible and be part of an overall product portfolio strategy. “However, from our experience, most companies tend to consider line extensions after the product has been marketed for several years with the aim of prolonging the product lifecycle when it is under threat or when looking to target new customer segments such as children or the elderly.”


Over the years, pharmaceutical companies have found formulation strategies to be an effective LCM tool in preserving revenue streams following patent expirations of their blockbusters. “Formulation strategies fall into two core groups based on their target patient populations,” says Neal Hansen, managing director of the consulting firm Hansen Strategy. “Switch-and-grow formulations seek to bring improvement to core user populations, for example, greater convenience, better compliance, improved outcomes, and/or reduced side effects. These formulations will typically need to compete head-to-head with generic versions of the original formulations and, therefore, must deliver demonstrable advantage to drive switching and minimize back-leakage. Examples of the switch-and-grow strategy include once-weekly bisphosphonates for the treatment of osteoporosis, once-daily attention deficit hyperactivity disorder agents and new device/formulation combinations in diabetes, asthma, chronic obstructive pulmonary disease, and inflammatory diseases.”

“Expand-and-grow formulations seek to unlock either new or unsatisfied patient pools that are not well addressed by available market formulations. As such, these approaches are already well differentiated from the original, generic-threatened formulations, and therefore, have a degree of competitive protection although such approaches offer no protection to the mass-market side of the business,” continues Hansen. “Classic examples of this approach include pediatric and geriatric formulations, fast-melts for ‘on-the-go’ patients, and intravenous/intramuscular forms for acute use in hospitals.”


  Developing and patenting new modified-release formulations, which include controlled-release, sustained-release, extended-release, and long-acting preparations, has been a route favored by pharmaceutical companies in their quest to extend the lifecycle of their products. These formulations are mainly designed to increase the duration of drug action by providing a gradual and continuous release of a drug substance from its dosage form, and thereby, decrease dosing frequency. The advantages of modified-release drug delivery include enhanced patient compliance, improved treatment efficacy, and a lower incidence of adverse reactions due to more uniform drug levels in the blood or plasma, among others.

A well-known case is with Pfizer’s cardiovascular drug, Procardia (nifedipine), when it lost its patent. Pfizer went on to introduce Procardia XL, an extended-release formulation designed for once-daily administration as opposed to three times a day with the conventional tablet. The improved formulation consists of a semipermeable membrane surrounding an osmotically active drug core. The drug core is divided into two layers: an active layer containing the drug and a push layer containing osmotically active but pharmacologically inert components. Once ingested, water enters the tablet and the increased pressure in the osmotic layer pushes against the drug layer, releasing the drug through a laser-drilled orifice at a constant rate over 24 hours (2). 

Another LCM example is Bristol-Myers Squibb’s extended-release formulation of its oral antihyperglycemic drug, Glucophage XR (metformin), which permitted once-daily dosing (instead of twice-daily) in the management of Type II diabetes. Glucophage XR consists of a dual hydrophilic polymer matrix system. Metformin is combined with a polymer, which controls drug release, to form an inner phase. This inner phase is then incorporated as discrete particles into an external phase of a second polymer. Following administration, gastrointestinal fluids enter the tablet, causing the polymers to hydrate and swell, thereby releasing the drug slowly by diffusion through the gel matrix. Drug release is independent of pH, and the hydrated polymer system is broken down by peristalsis of the gastrointestinal tract (3). 

Similarly, after the patent of Eli Lilly’s blockbuster antidepressant drug, Prozac (fluoxetine), expired, the company developed a once-weekly sustained-release formulation. Prozac Weekly capsules contain enteric-coated pellets that resist dissolution until the lower region of the gastrointestinal tract where the pH is more than 5.5. The enteric coating delays the onset of absorption of fluoxetine for 1 to 2 hours compared with the immediate-release formulations (4). Compliance with the weekly formulation was better than with once-daily fluoxetine (5).

Janssen Pharmaceuticals also used modified-release formulations to optimize product lifecycle by introducing a once-daily paliperidone palmitate tablet (Invega) and an extended-release injectable suspension for intramuscular use (Invega Sustena), administered once every four weeks, for the treatment of schizophrenia. Invega Sustena incorporates Alkermes’ proprietary technology for nanoparticles. Janssen is now developing a three-month depot injection, and in June 2012, the company initiated a Phase III trial to evaluate the efficacy, safety, and tolerability of the three-month formulation (6). 


  Combining two or more drugs into a single solid dosage unit and marketing it as a whole new product is also becoming increasingly popular as an LCM strategy to extend intellectual property and minimize generic exposure of mature brands. “According to a recent study from IMS Health, about half a trillion dollars could be avoided by improving the use of medicines, which equals to 8% of annual total healthcare costs worldwide,” comments Stefania Barzanti, marketing manager at IMA Active. “These costs are due to many reasons, but nonadherence to prescription regimen and mismanaged polypharmacy account for more than 60% of this avoidable cost opportunity. This is where fixed-dosed combinations (FDC) can offer convenience to patients and encourage compliance and adherence with their medications. At the same time, FDCs allow product differentiation and containment of generic exposure for mature pharmaceutical products.”

For example, Eli Lilly launched Symbyax (olanzapine and fluoxetine) as a means to stall sales erosion following the patent expiry of its antipsychotic blockbuster, Zyprexa (olanzapine). Merck & Co. also pursued this strategy with the development of Fosamax Plus, which is a combination of a bisphosphonate and vitamin D for the treatment of osteoporosis in postmenopausal women, and Juvisync, the FDC formulation of the cholesterol-lowering agent, simvastatin, and the antidiabetic drug, sitagliptin. Other examples include GlaxoSmithKline’s combination treatments for HIV, Combivir (lamivudine and zidovudine), Trizivir (abacavir, lamivudine, and zidovudine), and Epzicom (abacavir and lamivudine); and Gilead’s Truvada (tenofovir and emtricitabine).

FDCs can be developed in different forms, for example, layered tablets, hard gelatin capsules filled with multiple products or multiparticulate tablets, formed through the compression of multiparticulates. In terms of formulation considerations for FDCs, Barzanti explained that the first issue is the challenge of bringing together different pharmacokinectics and target release profiles, which becomes more complex with higher number of actives. “From the manufacturing point of view, however, one of the most common challenges is combining two chemically incompatible actives that need to be kept separated but included in a single dosage form,” says Barzanti. “This issue is particularly crucial for layered tablets, where sometimes, an 
intermediate placebo layer has to be placed to avoid any interaction. Constant check and frequent replacement of the scraper blade are of the utmost importance to avoid the mixing of the different powders comprising the various layers.” 

Another critical issue for all forms of FDC is the in-line control of the single dosages of each drug. “In a layered tablet, the single layers can be sampled and checked individually but it is not possible to check them separately in the final complete unit dose,” notes Barzanti. “On the contrary, manufacturing of FDC in hard gelatin capsules can be easily achieved through subsequent filling unit, and many technical solutions are available for in-line check of each drug dosage.”


  Recently, there has been a growing interest in user-friendly dosage forms, particularly formulations that dissolve quickly in the mouth without water as they eliminate the need to swallow pills. “User-friendly medicines are easier to take, taste better, and can reduce the number of doses required in a day,” says Hein from Hermes Pharma. “These are factors that attract the interest of 
  patients. Adherence is still a major problem today, limiting the effectiveness of treatments, and anything that makes administration easier has the potential to offer significant benefits.”

“Applications of fast-dissolve formulations are expanding across therapeutic areas,” observes Steve Hamlen, global group product manager, Catalent. For example, conventional selegiline tablets had to be taken more than once daily. Not only did the conventional formulation have less than optimal efficacy, but it also presented a safety risk due to first-pass metabolite formation. The fast-dissolve formulation of selegiline, Zelapar, developed using Catalent’s Zydis orally disintegrating tablet technology, is absorbed buccally, thereby, avoiding first-pass metabolism and significantly reducing the potential for side effects. The ability to disintegrate in less than 3 seconds allows for increased bioavailability and a faster onset of action for Zelapar. The maximum blood levels of the drug (Tmax) were achieved in 15 minutes for Zelapar compared with 1 hour for the conventional selegiline pills. Moreover, dosing frequency could be reduced (i.e., 1.25 mg or 2.5 mg once daily compared with 5 mg twice daily for the conventional formulation). 

“In one recent case, we were asked to redesign a life-saving medication that required delivering large quantities of the API. The original medication is administered as multiple tablets taken three times a day,” says Hein. “We reformulated the medicine from a series of solid tablets into three single packages of orally disintegrating granules, allowing us to encapsulate more API per dose, and therefore, simplify the treatment regimen. This innovation not only improved patient compliance but also provided our client with the opportunity to extend patent protection as the new formulation significantly improved the product.”


  In the past, drug-makers have only dedicated modest resources to their off-patent strategies but the changing landscape of the industry, especially with the increasing focus on value, budget management and outcomes in today’s healthcare systems, means that LCM is essential for sustained revenue generation and margin improvement. “The future for successful formulation strategies will most likely lie in hypersegmentation as with the much-hyped death of the blockbuster. Companies that can hypersegment their markets and deliver solutions to the specific needs of different patient and healthcare professional groups will be those that succeed,” comments Hansen. “To win will require both a level of true market insight and continuing innovation in the formulation and services sector to optimize product performance.” With fewer compounds in the development pipeline and more products edging towards the patent cliff, strategies that can extend the commercial life of mature brands are crucial to the success of pharmaceutical companies. 


  1. 		IMS Institute for Healthcare Informatics, “The Global Use of Medicines: Outlook Through 2016” (Parsippany, NJ, 2012).
  2. 		Pfizer, “

, accessed Oct. 16, 2013. 
  3. 		Bristol-Myers Squibb, “

,” accessed Oct. 16, 2013.
  4. 		NIH website, “

,” accessed Oct. 16, 2013.
  5. 		E. Clerk, 

, 62 (suppl 22) 43-47 (2001).
  6. 		Alkermes, “Invega Sustenna Three-Month Formulation of Paliperidone Palmitate Enters Phase 3 Clinical Program for Schizophrenia,” Press Release, June 12, 2012. 

Pharmaceutical companies are using formulation strategies as a lifecycle management tool to maximize product value and preserve their revenue streams.

Can Pharma Defy Gravity at the Patent Cliff?

Mass spectrometry is an analytical technique that provides valuable compound identity information, particularly for substances present at low concentrations that may be difficult to obtain using other methods. Unfortunately, mass spectrometry instrumentation is often expensive, usually requires skilled and trained personnel to operate, and generally occupies a large amount of bench space. For many analytical chemists, therefore, mass spectrometry isn’t practical. Many who do require mass spectral data must send their samples out for analysis,  either to a dedicated mass spectrometry laboratory within their company or, alternatively, to an outside laboratory. That could mean long turnaround times and missed deadlines in addition to higher costs. To address the continuing challenges in separations science with mass spectral information, Waters Corporation has developed a mass detector that overcomes the barriers to adoption of mass spectrometry by analytical chemists. The new mass detector is not only affordable, but it can be directly integrated with various chromatographic systems, to provide high quality mass spectral data at the touch of a button.

Real need for simple and affordable mass detection


    “Across numerous markets, including pharmaceuticals, we found that people working in labs,  whether in methods development, sample profiling, synthesis, or purification, there is a real desire for access to mass detection capabilities, but without the cost and complexity of a traditional mass spectrometer,” notes Gary Harland, director for mass spectrometry product management at Waters Corporation. “What is really needed,” he continues,” is a mass detector that is complementary to their existing optical detection techniques, can be easily and repeatedly used, and maintained without extra work. In sum, they want to obtain mass spectral data using a chromatographic-like detector.”

  In liquid chromatography method development, mass spectroscopy is not routinely used by most. While separation techniques have improved significantly in recent years, there are still challenges, according to Harland. A validated chromatographic method is one that completely separates the components of a sample from one another and that identifies components based on their retention time. To develop such a method requires extensive expertise and experience, particularly when there may be a coelution of structurally related compounds and when numerous chromatographic peaks must be completely baseline-resolved. Sample profiling also relies on the accurate identification of compounds in very complex matrices, such as foods and pharmaceutical formulations, that are often at very low concentrations. For synthetic chemists who often rely on mass spectral data to test reactions and verify the intended products or those reactions, the waiting time for mass spectrometry results can be quite long since samples must often must be sent to another lab and analyzed by someone with the proper expertise. Finally, according to Harland, ultraviolet-visible (UV-vis) methods are often used to detect compounds during downstream purification steps. That means that every fraction must be analyzed in order to determine which ones are of interest.

In all of these cases, access to immediate mass spectral data could significantly improve the efficiency of the analytical process.


    To address the need for easy-to-use mass detection as part of a separations system, Waters developed the ACQUITY QDa detector. Based on the same ion physics as a conventional single quadrupole mass spectrometer, it is specially designed for a small footprint and to work synergistically with a variety of chromatographic separation systems, such as liquid chromatography (LC) ultra-performance LC (UPLC) supercritical fluid chromatography (SFC) and conventional detection systems, such as UV-vis spectroscopy and photodiode array (PDA) systems, and do so at a cost closer to those detectors.

 “When developing this technology, our key goals were to create a mass detector that would provide quality mass spectral data but operate with the familiarity of a PDA detector,” Harland notes. In addition, the detector needed to be reliable, require little maintenance, and be compatible and complementary with other chromatographic systems, which meant covering the mass range for the types of molecules that are separated and detected with LC/UV methods. Furthermore, the acquisition speeds needed to match that of very fast UPLC systems, and the ionization of the molecules could not impact the performance and operation of the other separation systems.

Two key features, according to Harland, are its push-button operation and automatic calibration. “Once the system is turned on, it boots up within 30 seconds and is under vacuum within five minutes and pressure tested and ready to use within six-and-a-half minutes. For a cold start, the system also goes through automated calibrations, so it takes a little longer, but operators are still up and running within 20 minutes. At that point, the detector is ready to use in the same time as it takes a PDA to be ready.”

Significant advances in technology were needed to achieve these goals. Many patents have been filed that are related to advances in ease of use and affordability, according to Harland, without compromising the high-quality mass spectral data required. “We had to engineer many new systems in order to achieve robust, high-quality mass detection at a reasonable price.” Two examples include a single-piece, zero-adjustment probe capillary that not only eliminates all the optimization normally required but also minimizes dispersion and preserves the high resolution chromatographic separation, and a new sample cone assembly featuring an inexpensive and disposable sample aperture. “Conventional sample cones for mass spectrometry are expensive, can be damaged if dropped or mishandled, and require regular cleaning involving disassembly and sonication to prevent degradation of the sensitivity of the instrument, which is a time-consuming process. The new disposable system is easy to replace and only needs replacing about as often as the column gets replaced, which saves both time and money while maintaining consistent performance,” Harland observes. 

Key advantages for all chromatographic separations


    With the ability to obtain optical and electrospray (ES) ionization mass spectral data simultaneously, it is possible for scientists to identify compounds at low concentrations in complex mixtures, including co-eluting substances. They can also detect compounds that are “transparent” to UV detectors because they lack chromophores. “For methods development, having access to mass spectral data will enable faster methods development and allow for more rapid and robust methods as well,” asserts Harland. “We expect that, because scientists can get mass spectra immediately, it will have the biggest impact in methods development applications,” he continues.

He also believes that the mass detector will provide greater sensitivity and selectivity for sample profiling, which includes quantifying impurities or additives often at low levels in complex matrices. Meanwhile, synthetic chemists who have tested the detector are considering expanding the use of LC­–MS systems for more immediate results, which can significantly speed up new compound synthesis. In purification processes, the ability to identify the compounds in each fraction means that only the fractions that contain the desired compound need to be processed, which leads to more efficient separations and greater productivity, according to Harland. He adds that there is also interest in the new mass detector from academia, both for research and for undergraduate education. 

The mass detector also has potential applications in the pharmaceutical manufacturing setting. Some possible uses include the profiling of active pharmaceutical ingredients and related compounds, the determination of batch-to-batch variations, and the determination of extractables and leachables.


    The initial development of the new mass detector began about three years ago, according to Harland. At that time, Waters was working with key customers to determine the key properties of the new system. In the last year, that program expanded significantly to include numerous customers across many different markets. “This testing initiative was our largest beta-testing program ever because we wanted to be certain that we would have a very high level of confidence that the mass detector would meet the operability and data performance needs of all possible groups of scientists that could benefit from the technology,” he observes. The program was very valuable, and refinements were made to the detector based on input from these users before it was determined ready for commercial sale. “We definitely want to thank all of the participants in the testing program. They were definitely a key factor in the successful development of the new technology.” 

Mass detection at the push of a button could change the way many laboratories carry out their chromatographic analysis.

New Technology Enables Integrated Chromatographic Separation and Mass Detection

Blow-fill-seal (BFS) aseptic processing in parenteral manufacturing enables the automated formation of a plastic container, aseptic filling of the container with a liquid, and the hermetic sealing of the container, all in a few seconds using one machine. Because packaging of the formulated drug takes place under aseptic conditions without any human intervention, it provides increased product safety. The automated nature of the process leads to lower energy consumption, reduced waste generation, and a lower carbon footprint. In addition, the resins used to form the plastic containers are recyclable, and plastic containers do not shatter like glass. Furthermore, with most advanced BFS systems, numerous different container shapes can be produced, and today premolded, presterilized inserts can be added once the container is filled, allowing for more delivery options. “These advanced aseptic BFS containers and ampuls can deliver precise dosing in disposable formats. The incorporation of a sterile tip-and-cap, a rubber stopper, or a multi-entry insert into the BFS package offers added flexibility in container design and drug delivery methods, as well as enhanced sterility safety,” observes Chuck Reed, director of sales and marketing with Weiler Engineering and leader of the US Parenteral Drug Association (PDA) Blow-Fill-Seal Interest Group.

Today, in fact, FDA characterizes modern BFS technology as an "advanced aseptic process," indicating its use as a preferred technology, according to Reed, director of sales and marketing with Weiler Engineering and leader of the US Parenteral Drug Association (PDA) Blow-Fill-Seal Interest Group. As leader of the PDA BFS Interest Group, and a member of the PDA Task Force, Reed is involved in the development of the BFS Technical Report that will provide science-based support for the use of BFS technology in the pharmaceutical industry.

Cooperation with the BFS International Operators Association (IOA)


    The BFS IOA, founded as a meeting forum for users of BFS technology to get together and discuss topics of interest specifically to users, is celebrating its 25th anniversary in 2013.  This group’s 

 is a template and reference document for its members to use when establishing BFS processes for their products. “The BFS IOA and the PDA have signed a memorandum of understanding (MOU) so that the BFS Technical Report Task Force of the PDA can use the 

 as the basis for development of the PDA BFS Technical Report,” Reed explains.


    Interest in the development of a BFS Technical Report was initiated by subject-matter experts on the PDA Science Advisory Board. “Technical Reports have already been developed on filtration and sterilization processes for parenterals, and it was a natural fit to provide the pharmaceutical industry with a similar document on BFS technology since it is increasing in use as its benefits are realized,” Reed says.

The PDA Task Force was created to develop the report and consists of approximately 20 people, most of whom are current active users of the technology. Two of the invited members, however, are representatives from the European Medicines Agency and FDA. “We felt that this size of a group would be able to work effectively and efficiently to develop a first draft. Involving the key regulatory agencies throughout the process ensures that the document will be in accordance with existing regulations,” explains Reed.

The Technical Report is designed to be an industry reference document in which science supports the use of BFS technology. “Our goal is to present harmonized blow-fill-seal procedures for the US, Europe, and others based on the scientific data that has been obtained to date,” observes Reed. Topics will include, for example, risk analysis, validation protocols, selection of BFS systems for particular types of products, and quality assurance.


    At this point, a table of contents for the PDA BFS Technical Report has been developed and each Task Force member has been assigned specific sections/topics to address. The group has scheduled regular face-to-face and web-based meetings, and the expectation is that a final draft will be ready around the time of the PDA Annual Meeting in April 2014. At that point, there will be an internal PDA committee and staff review, followed by a review by the relevant regulatory agencies. The document will then be available for open review, and input from other interested industry participants will be solicited. Reed anticipates that this open-review period will commence sometime in late 2014, with a hope to publish by year-end.  “The review process takes a while; the value of these PDA Technical Reports lies in the fact that they are science-based and peer-reviewed. It is therefore necessary to ensure that the document is thoroughly and appropriately reviewed before being issued for general use,” Reed asserts.


    The BFS Interest Group (IG) is an active part of the PDA interaction process and meets three to four times per year during relevant PDA meetings and conferences, according to Reed. Joint BFS IG meetings are also occasionally held with the Sterile Processing IG because there are cross-over topics of interest to both groups. Membership in the BFS IG is open to anyone who is a current PDA member and/or conference attendee and includes representatives from all of the major pharmaceutical companies and contract manufacturers that use BFS technology.

The most recent IG meeting was held in September at the 2013 PDA/FDA Joint Regulatory Conference, where much of the discussion focused on FDA-related issues that should be included in the new BFS Technical report. The next formal meeting of the IG is scheduled for the PDA Parenteral Packaging Conference in Brussels in March 2014 while the next domestic meeting will be held at the PDA Annual Meeting in April 2014 in San Antonio. “Topics vary at these meetings and are driven both by industry trends and the particular interests of the attendees at the meeting.  Over the course of the next several months, updates on the progress of the BFS Technical Report Task Force will be one of the main discussion points.

The Parenteral Drug Association has established a task force to develop a peer- and regulatory agency-reviewed Technical Report that will serve as a science-based industry reference document.

Science-Based Technical Report Being Developed to Ensure Effective Use of Blow-Fill-Seal Technology

Single-use bioreactors come in all shapes and sizes that fit the variety of manufacturing conditions required for different biopharmaceutical production processes. WAVE Bioreactor technology, which was first introduced in 1996, has a unique rocking motion that provides for efficient mixing without the need for the use of internal stirrers. The industry has changed a lot in the last 17 years, though, and single-use bioreactor technology has evolved with it. To meet these changing needs of the biopharmaceutical industry, GE Healthcare Life Sciences has updated the WAVE Bioreactor system.


     “We realize that the biopharmaceutical industry today constantly needs to develop to meet new regulatory requirements. It also now relies on many different types of cell-culture processes and is looking to leverage advanced process analytical technology while also increasing product yield and reducing turnover time. To meet these changing needs, we have developed a new WAVE Bioreactor system that builds on the functionality of the original bioreactor but is more advanced and yet easier to use,” says Cecilia Annerén, product manager with GE Healthcare Life Sciences. “Most importantly, she adds, “we have incorporated accurate and intelligent controls for numerous process parameters, many more automated functions, and a user-friendly interface that includes several data analysis and reporting options.”


    The ReadyToProcess WAVE 25 single-use bioreactor system consists of a rocker, a gas mixer, and a pump, all operated by software installed on a client computer. The rocker is used together with one of three trays that support disposable bioreactor cultivation chambers with working volumes up to 25 L. As with the original WAVE Bioreactor system, the rocker provides mixing through rocking and temperature and weight measurement through integrated sensors and load cells, respectively. The gas mixer delivers gas of a defined composition to the culture and is used, together with optical sensors in the bioreactor, for online control of culture pH and dissolved oxygen (DO).

    The sensors in the disposable bioreactor and the rocker are very important features of the new system, according to Annerén, because they are combined with advanced feed-back loops for the monitoring and adjustment of process parameters. The system can determine, for example, the appropriate heating rate depending on the culture mass/volume in the bioreactor, and will implement a more aggressive heating rate for large volumes. In addition, the amount of acid or base needed to maintain a particular pH level is automatically determined based on the current pH level, the molarity of the base or acid being used, the size of the tubing, and the feed rate of the pump.   

 In addition, the system has a new tilt position to facilitate sampling and harvest, and its rounded corners make for easier cleaning. “While the new features seem simple, they can have a big impact on the operators using the bioreactor. For example, the tilt position eliminates the need for heavy lifting when harvesting the bag, and the wide top-opening of the lid enables complicated manipulations of the bag without removing the lid,” Annerén notes. Furthermore, it is now possible to adjust the speed, angle, and motion of rocking. The latter parameter is new for the upgraded system and determines the acceleration profile, which at low settings creates a gentler wave motion that is suitable for cells on microcarriers and at higher settings creates the more aggressive waves that are required for robust cells with a higher oxygen uptake rate, according to Annerén.


    In addition to the new design of the tray, the software that comes with the system, which was originally developed for use with GE Healthcare Life Science’s chromatography equipment, has been adapted specifically for operation of the updated rocking bioreactor and incorporates many features that are designed for user friendliness. “It was very important to us that, even though we have incorporated very advanced functionality into the new bioreactor, it continues to be extremely easy to operate, so that anyone can rapidly learn how to use it without the need for extensive training,” Annerén comments. 

    Therefore, the graphical interface was designed to be intuitive and provides real-time information. In addition, a library of predefined control parameters tailored for different cultivation volumes has been included so that suitable parameters can be automatically determined for a run, which can reduce the set-up time and provide accurate and stable control of the process, according to Annerén. She adds that the system can also be set up to automatically monitor reactions and respond to changing reaction conditions in order to optimize performance, and there is a method-development function that allows operators to establish automated operations, such as daily feeding at a given time. Finally, the software allows the setting of alarm conditions for any of several essential parameters (heating, gas flow, carbon dioxide pH, and DO) and can update the user with optional e-mail notifications. “Improving efficiency and productivity are primary goals for many biopharmaceutical manufacturers, and the automated features that have been incorporated into the software for the updated WAVE bioreactor are intended to help achieve these goals,” Annerén notes.  


    While the first-generation WAVE Bioreactor has commonly been used in seed-train applications and small-scale production, there is, according to Annerén, growing interest from the process development community in the newer bioreactor. “Because it is so easy to adjust a wide variety of process parameters and monitor the changes in the culture conditions in real time, it is possible to very rapidly gather a large amount of data and evaluate the performance of a given biopharmaceutical process under numerous different conditions. As a result, process development times can be reduced, which is a major goal for all pharmaceutical manufacturers,” she observes. 

    Another feature of the updated system that is attracting attention for both process development and commercial manufacturing is the ability to carry out perfusion culturing easily and accurately. “Perfusion is definitely being more widely used, so we made a point of developing the new bioreactor so that perfusion can be easily achieved at many scales,” says Annerén. In fact, the optional pump can operate over a very wide range of flow rates from 0.1 L to up to 144 L per day. In addition, there is an optional autocalibration feature that enables automatic calibration of the pump flow rate if desired.

An updated bioreactor based on rocking technology has more advanced controls but is easier for biopharmaceutical manufacturers to use.

New Single-Use Bioreactor Technology Emphasizes Ease-of-Use and Intelligent Process Control

Poor solubility remains a significant problem that the industry continues to battle. Pharmaceutical Technology spoke with Nathalie Knabe, global business communications leader, and Christophe Massip, global marketing director of Dow Pharma & Food Solutions, about the company’s innovations to solve solubility issues.
  
  

 What advances have you seen in solubilization strategies?
  
  

 Solubility enhancement strategies are increasingly utilizing amorphous solid dispersions. To meet this need an increasing number of polymers are being developed to support the creation of amorphous solid dispersions via hot melt extrusion (HME) and spray drying. As examples, Dow has developed AFFINISOL HPMC, a new extrudable grade of HPMC that does not require any additives or plasticizers for extrusion, and AFFINISOL HPMCAS for spray drying applications.
  

 Can you tell us more about your new HPMCAS polymer? How does it address solubilization needs or enhance solubilization performance?
  
  

Dow’s AFFINISOL HPMCAS addresses the solubility enhancement of each individual API through the utilization of tailor-made QbD HPMCAS polymer sets that find the optimal acetyl and succinyl substitution levels as well as the ideal molecular weight of the HPMCAS. Each API is unique and may require an HPMCAS polymer outside of the current commercial offering. AFFINISOL HPMCAS addresses the unique needs of each API and allows for the best performance to be obtained. If required, customized HPMCAS can be scaled in Dow’s pilot plant and later commercially manufactured at CAMBREX for clinical trial and commercial drug needs.
  
  In addition, novel AFFINISOL HPMCAS high productivity facilitates higher solids content in solution for higher throughput in spray-drying while maintaining solubility enhancement from HPMCAS. This innovative solution addresses technology gaps in manufacturability and delivery, offering process scale-up efficiencies and greater drug-product utility with expected solubility enhancement performance.

 Why is structure-property important when designing solubilizing polymers?
  
  

 Structure-property is a key element in the design of polymers for the solubility enhancement of an API. The polymer must balance the ability to be water soluble with the ability to interact and form a stable solid dispersion with a poorly soluble API. Our experience in polymer chemistry allows us to understand and modify the structure polymer performance of our polymers to obtain the most desirable performance for solubility enhancement.
  
  

 Can you discuss the relationship between substitution levels and peak drug concentration and maintaining supersaturated drug concentration?
  


Each API has a unique performance with HPMCAS. This is why it is important to understand the HPMCAS substitution design space and utilize Dow’s QbD AFFINISOL tools to maximize the peak drug concentration and supersaturation maintenance. Often times, there is a balance between peak drug concentration and long term supersaturation of drug maintained in the supersaturated state that requires several HPMCAS substitution levels to be studied to maximize the combined performance of an API.

PharmTech spoke with Dow about innovations in polymers to address poor solubility.