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

Adeline Siew, PhD

	Multilayer tablets deliver a combination of therapeutic payloads in a single dosage form. An added advantage is that the API contained in each layer of the tablet can be designed to have different release profiles. The manufacturing of multilayer tablets is, however, more challenging compared with single-layer tablets, observes Jean-Yves Balfin, product manager at Korsch AG. “At first glance, it seems to be simple duplications of the classical single-layer compression cycle, one after the other in the same tablet press, but in reality, only the beginning of the process is classical, up to the dosing of the first layer,” he explains. “From that point onwards, the differences become more obvious.” 

	According to Balfin, the addition of further layers in a tablet creates several complexities. “For example, the previous layer has to be prepared in such a way that it allows bonding with the next layer while having a perfect separation line between the layers. Filling of the next layer has to be done without pulling down the lower punch during this step as is the case in a classical compression cycle using a filling cam,” he says. “In addition, the product dosed out of the feeder must not be recirculated, otherwise cross-contamination would occur between layers. The individual weight in each layer must be regulated, while having several layers in the die.” Balfin spoke to 

about the ins and outs of multilayer tableting.

 What are the key considerations in the production of multilayer tablets? 

There are several key considerations in the manufacturing process of multilayer tablets. 

The filling of the first layer is classically done using a fill cam that pulls the lower punch down, but for the second and subsequent layers, it is only the upper punch penetration at the tamping stage of the previous layer that creates space inside the die. This space is then used to fill the next layer. It is not possible to use a fill cam after the first layer, because the tamped first layer may remain in place in the die due to radial die-wall forces. For this reason, the upper punch penetration is required to make space in the die and to push the tamped first layer deeper in the die to facilitate the next layer fill. 

A low tamping force, between 100 N and 1000 N, is typically applied to the intermediate layers with a minimum densification effect, so that a flat surface is created for the next layer filling space. The tamping force is then used for the weight regulation of the corresponding layer. 

There are different ways to keep each layer from passing into the next layer feeder. The best way is to contain the material in each feeder and to incorporate an integrated dust extraction nozzle to capture any fines or residue that may escape each feeder. 

Final tablet weight is controlled by the main compression force. Single-layer weight control is based on the same principle, but it is adapted to the tamping forces and single-layer sampling. Due to lower forces applied when tamping multilayer tablets, the force measurement transducers may need to have increased sensitivity. 

How can we sample a single layer if it is only tamped (not tableted) and the compression cycle has not finished? Intermediate layer sampling can be achieved by increasing the tamping force during sampling to produce a sample that is hard enough to permit a weight measurement. Some tablet presses can eject every single layer through an additional outlet channel located just after tamping. Others are equipped with retractable feeders, and the layer is ejected through the general discharge chute. In this case, the layer hardening is executed at the final compression station, and the tamping force remains under automatic control during layer sampling. 

What are the critical process parameters, and how do these affect the critical quality attributes of multilayer tablets?

The following process parameters are crucial in multilayer tableting: 

The multi-layer compression cycle is more complex than that for single-layer tablets and, thus, requires a very precise setup. Turret speed and the related dwell times for filling and pressing are, therefore, critical parameters for achieving the targeted layer weight and hardness.

The time and space dedicated to the filling of the successive layers are more limited than when manufacturing single tablets, and there is limited fill space for the second and subsequent layers. All parameters related to the filling of the different layers are, therefore, critical for achieving weight uniformity of the layers and final tablets. The feeder paddle configurations and speeds of the successive feeders, as well as the settings of the upper punch penetrations, will greatly influence the ability to achieve target parameters (weight uniformity and hardness).

A tamping force study is generally recommended to establish the maximum force at which delamination (i.e., layer separation after tableting) will occur. The maximum force is balanced on the low end by the force necessary to create a clear and horizontal dividing line between the layers. Due to lower forces applied when tamping, the force measurement transducers may need to have increased sensitivity. 

Effective layer separation is crucial for multilayer tablets, not only for aesthetic reasons, but also for chemical and pharmacological purposes (such as incompatibilities between the APIs, the different release profiles, etc.). The vacuum should, therefore, be high enough to avoid any cross-contamination between the layers but not high enough to adversely impact the production yields. Excessive dust extraction may also impact layer weight uniformity.  

What are the solutions available for addressing the typical challenges in the production of multilayer tablets? 

The important thing is to achieve enough upper punch penetration to produce the required layer weight. There are upper punches adapted to multilayer compression (i.e., the upper punch tip has to be longer than the maximum insertion depth, while the lower punch and the die are the same as for single-layer tableting). There are also some tablet presses with a ‘deep fill’ option. 

	There’s also the need to achieve the right flow of the different layers with less space and time to fill the die. For this requirement, there are several configurations of feeders available.

	Low tamping forces have to be measured with high accuracy. In this case, special compression rollers with strain gauges adapted to low force range are available.

	Manufacturers also have to address delamination risk. The formulation and lubrication with excipients especially adapted to multilayer applications play a key role in avoiding delamination risk. The right setting of tamping force and the possibilities to increase the dwell time will further help.

	And lastly, steps should be taken to avoid cross-contamination between two or more different products handled at the same time in the same machine. This can be prevented by special execution of the feeders with a sealing of the gap between feeder plate and die table, optimized die table scraping, and dust extraction before each feeder.

	When referring to this article, please cite it as A. Siew, “Key Considerations in Multilayer Tableting,” 

Articles

Jean-Yves Balfin, product manager at Korsch AG, speaks to Pharmaceutical Technology about the ins and outs of multilayer tableting. 

Key Considerations in Multilayer Tableting

Oral delivery has long been regarded as the most preferred route of drug administration and over the years, research in this field has made significant strides despite the numerous challenges. Barriers limiting effective oral drug delivery include poor solubility, membrane permeability, hydrolysis or enzymatic degradation in the gastrointestinal (GI) tract, pre-systemic metabolism, and excretion of the active, among others. Drug developers and formulators, however, now recognize that better dosage form design can be achieved with proper characterization of the API’s physicochemical properties and an assessment of the potential formulation and manufacturing challenges during an early stage. Advances in oral drug delivery continue to open up new avenues for more patient-centric drug design that offer improved outcomes. 

	On Nov. 13, 2017, FDA announced the approval of the first digital pill that has a sensor embedded in it to track if patients with schizophrenia, bipolar disorder episodes, and depressionhave ingested their antipsychotic medication (1). Abilify MyCite (aripiprazole), marketed by Otsuka Pharmaceutical, was hailed as a revolution in addressing the adherence gap.Mitchell Mathis, MD, director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, noted in a press statement (1) that the ability to track ingestion of medications prescribed for mental illness could prove useful for some patients.

	The ingestible sensor, the size of a grain of sand, is embedded at the point of manufacture. It is activated when the tablet dissolves in the stomach and it communicates with a patch worn on the abdomen, which then transmits the date and time of tablet ingestion to the patient’s smartphone to track adherence (2). Patients can allow their physicians or caregivers to view their data through a web-based portal and the information can be useful in documenting improved patient outcomes and demonstrating treatment effectiveness (2, 3). 

	The sensor, composed of a silicon chip coated with minerals that form part of the human diet, is digested and eliminated from the body. Both the sensor and the patch are manufactured by Proteus Digital Health. Nik Leist, senior director of Ingestible Sensor Manufacturing and site leader for Proteus Digital Health, highlighted in a keynote address at CPhI North America on April 25, 2018 that the company has developed an efficient way to manufacture the sensors, as well as a process-based on existing solid-dosage manufacturing technology-for inserting them into a drug tablet or capsule to create a digital-medicine combination drug product (3). 

Robotic pill injects drug into the intestinal wall

	Another innovation that has been grabbing headlines is the breakthrough pill developed by Rani Therapeutics, an InCube Labs company, which injects drugs directly into the small intestine (4). The idea behind the Rani Pill was to eliminate the need for injections, which is known to be one of the biggest hurdles to patient compliance, and provide a safe and pain-free alternative for the delivery of injectable drugs. The technology could potentially be the key to solving oral delivery challenges for biologics such as insulin, antibodies, human growth hormones, peptides, and proteins (5). 

	Rani’s robotic pill is a sophisticated device where the solid drug is placed inside tiny, hollow, dissolvable needles, assembled into a balloon-like structure and folded in the capsule. This ensures that the active is not exposed to the digestive enzymes of the GI tract. The capsule has a pH-sensitive enteric coating, enabling it to pass through the stomach without being degraded. Upon reaching the duodenum, the rise in pH causes the enteric coating to dissolve, which then initiates a chemical reaction to produce gas inside the balloon. Balloon inflation is triggered when citric acid reacts with sodium bicarbonate and this reaction creates the pressure needed to push the drug-loaded needles into the intestinal wall (4, 5). The high vascularity of the intestinal wall facilitates quick absorption and because there are no pain receptors in the intestine, injection is painless. According to the company, the components used in the robotic pill are FDA-approved injectable and ingestible materials that are safely absorbed and easily passed out of the body (4, 5). 

	The technology, which Rani Therapeutics says can be applied to any biologics of any molecular weight, regardless of structure or properties, has attracted the interest of a number of pharmaceutical companies, including Novartis and AstraZeneca. Biotech company, Shire announced in December 2017 that it has entered into a collaboration with Rani Therapeutics to evaluate the use of the Rani Pill technology for the oral delivery of factor VIII therapy for patients with hemophilia A (6). Under the terms of the agreement, Shire has exclusive rights to the development and commercialization of a novel technology for the oral delivery of factor VIII. As part of the collaboration, Shire has also made an equity investment into Rani Therapeutics. In February 2018, Rani Therapeutics secured $53 million to fund the manufacturing of its robotic pill for clinical trials. It is currently working with a manufacturing automation company to develop the aseptic manufacturing line needed for human testing (7). 

Star-shaped structure extends drug delivery

	Researchers from the Massachusetts Institute of Technology (MIT) have developed an oral pill that can remain in the stomach for seven days, allowing once-weekly dosing for antiretroviral drugs for HIV treatment. Studies in pigs have demonstrated that week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine, and cabotegravir could be achieved after a single administration of this novel oral dosage form (8). 

	The pill, which consists of distinct drug–polymer matrices, looks like a normal capsule, but when it reaches the stomach, the coating dissolves and a star-shaped structure that has been packed inside the capsule unfolds and starts to slowly release its cargo of drugs. The structure has six arms joined by a linker to a central core made of an elastomeric material that enables folding of the dosage form into a capsule and its recoil upon dissolution of the capsule shell in the acidic environment of the stomach (8). Drugs are loaded into the arms of the star-shaped structure, which will then degrade after drug release is completed and pass through the digestive. Prolonged gastric residenceis achieved because of its geometry, whereby the expanded star-shaped structure is too large to move out of the stomach but will not cause blockage to food journeying through the GI tract. This approach is applicable to other diseases. The group previously demonstrated that the capsule technology provided extended release of the antimalarial drug ivermectin over a period of two weeks in pigs (9).

	“Until now, oral drugs would almost never last for more than a day,” Robert Langer, the David H. Koch Institute Professor at 

“This [technology] really opens the door to ultra-long-lasting oral systems, which could have an effect on all kinds of diseases, such as Alzheimer’s or mental health disorders.”

Dual-trigger coating technology for precise, fail-safe drug release in the colon

	Oral drug delivery targeting the colon is another field that has made significant progress over the years. Intract Pharma has developed a dual-coating technology, known as Phloral, for precise and consistent delivery to the colon. It is well recognized that the colon can serve as an optimal site of absorption and provide a pathway for entering the systemic circulation. The challenge, however, is the ability to achieve consistent, site-specific release in this region of the gut, Professor Abdul Basit, founder of Intract Pharma, pointed out at a formulation seminar held at University College London, United Kingdom on June 22, 2017 at University College London, United Kingdom. Approaches based on the use of pH-sensitive polymers dissolving at higher pH towards the terminal ileum have been associated with high variability and failure 

. The drug is either released prematurely or not at all in some cases (11). 

	Phloral comprises of a pH-sensitive polymer and a natural polyssacharide that is digested by the colonic microbiota. The system exploits changes in gastrointestinal pH in combination with the enzymatic activity of the microbiota as independent but complementary release mechanisms to facilitate site-specific release (12). Basit explained that should there be pH variation in the gut, the polysaccharide component is independently digested by the bacteria residing in the colon, hence, providing a fail-safe mechanism that overcomes the limitations of conventional polymer coatings (11). According to Intract Pharma, the first Phloral product has successfully completed Phase III trials (12).

FDA Approves Pill with Sensor that Digitally Tracks if Patients Have Ingested Their Medication, 

Press Release, Nov. 13, 2017.
	2. Proteus Digital Health, 

Otsuka and Proteus Announce the First US FDA Approval of a Digital Medicine System: Abilify MyCite (Aripiprazole Tablets with Sensor), 

Press Release, Nov. 14, 2017.
	3. PharmTech, Proteus is Extending the Reach of the Digital Pill, 

www.pharmtech.com/proteus-extending-reach-digital-pill

, accessed May 9, 2018.
	4. Rani Therapeutics, Rani Technology, 

Shire and Rani Therapeutics Enter into Collaboration to Evaluate Use of the Rani Pill Technology for the Oral Delivery of Factor Therapy,

Press Release, Dec. 5, 2017.
	7. Rani Therapeutics, 

Global Investors Back Rani Therapeutics with $53 Million as Company Moves to Clinical Trials, Press Release, 

published online Jan. 9, 2018, doi:10.1038/s41467-017-02294-6.
	9. A.M. Bellinger et al., 

published online Nov. 16, 2016, doi:10.1126/scitranslmed.aag2374.
	10. MIT News, 

New Capsule Achieves Long-Term Drug Delivery, 

Press Release, Nov. 16, 2016.
	11. Intract Pharma, 

, accessed May 9, 2018.
	12. A. Basit, “Advanced Gastrointestinal Targeting Technologies-DuoCoat and Phloral,” presentation at 1

Seminar on Formulation Designs for Challenging Needs (London, UK, June 2017).


	Vol. 42, No. 6
	June 2018
	Pages: 18–20

	When referring to this article, please cite it as A. Siew, “Emerging Technologies Advance Oral Drug Delivery,” 

New approaches enable more patient-centric drug design that offers improved outcomes.

Emerging Technologies Advance Oral Drug Delivery

	The CUREfilm technology, developed by Cure Pharmaceutical, delivers drugs through a dissolvable strip that can be applied in the oral cavity or onto the skin. It replaces the need for swallowing or injecting medicines. The film has the ability to hold multiple active ingredients on one dissolvable strip, hence, eliminating the need to take multiple medications for daily treatments. 

	“CUREfilm products are designed to optimize drug release profiles and achieve a target product profile,” says Jessica Rousset, COO at CURE Pharmaceutical. “Unlike traditional oral drug delivery, CUREfilm can be designed to bypass the gastrointestinal (GI) tract, avoiding GI-related side effects and inactivation in the gut or liver.” Rousset explains that the nanoencapsulation of active ingredients within the film further protects them from degradation during the manufacturing process and as they navigate the biological environment, thereby, prolonging the drug’s presence in the circulatory system as needed. Rousset spoke to 

about the advantages of CUREfilm and its applications in drug delivery.

What drug delivery challenges does CUREfilm solve or address?

There are two facets to this answer: bioavailability and patient experience. Regarding bioavailability, recent figures suggest that 30% of marketed drugs have high permeability but low solubility (1). This number jumps to 70% for investigational drugs in the pipeline (2). CUREfilm drives more rapid solubilization of medicines in biological fluids, whether through the GI tract or the oral mucosal membrane. Drug delivery through the mucosal membrane has the advantage of immediate absorption by the cheek, gum, or sublingual vasculature, bypassing the digestive tract where medication can get metabolized and inactivated, or cause GI toxicities. 

	From the patient perspective, approximately 40% of patients struggle swallowing pills, and injections are unpleasant, especially when self-administered. Such experience leads to missed doses, potentially worsening the patient’s health outcomes. CUREfilm can reduce this burden with fewer side effects. 

What are the advantages of CUREfilm compared with other drug delivery technologies? 

CUREfilm technology enables high drug loading, whether it is one or multiple active ingredients, while maintaining the film’s desirable properties such as rapid dissolution and a pleasant taste. This feature allows us to improve the delivery of lower potency drugs, such as antibiotics and combination drugs. To date, we have produced at commercial scale, a CUREfilm nutraceutical product with five different active ingredients for a combined dose of 180 mg. In the laboratory, using a next-generation tri-layer film, we have exceeded 500-mg film loads that dissolve rapidly. CUREfilm technology has the potential to advance precision medicine by relegating the ‘one-size-fits-all’ approach to dosing drugs to the past. As we better understand how individuals, both children and adults, metabolize drugs differently, it will become increasingly essential to dispense drug doses with precision, and CUREfilm opens up this possibility. CUREfilm technology is also available to preclinical researchers delivering test compounds to experimental animals, as a more humane and operator friendly alternative to oral gavage. 

What type of drugs and treatments will benefit from CUREfilm?

Currently, we have several ranges of products that are manufactured, in development, or in the research stage. The target indications include neurological conditions, sleep disorders, inflammatory conditions, and cancer. We have several pharmaceutical products that are in the works leveraging the CUREfilm technology: a combination cannabinoid buccal film to treat obstructive sleep apnea, a treatment for erectile dysfunction, and a high dose vitamin D3. 

	CURE is also strategically investing in research on the endocannabinoid system, which is a new frontier in medicine. The endocannabinoid pathway is an important regulator of other physiological systems and plays a role in maintaining homeostasis. When you can regulate the body, you unlock the potential to treat a host of medical conditions, such as cancer, diabetes, multiple sclerosis, and many other conditions. Specifically, we are sponsoring cancer discovery research in the laboratory of Dr. Dedi Meiri at the Technion Institute of Technology to evaluate the antitumor effects of phytocannabinoids and terpenes, on various cancer-driving mutations and pathways and to elucidate the mechanism of cannabinoid-mediated antitumor effects with the goal of delivering these actives to patients using CUREfilm.

	1. Benet L.Z., Broccatelli F., Oprea T.I. 

13 (4) 519–547 (2011).
	2. “Solubility Enhancement in Pharmaceutical Oral Solid Dosage Forms: Global Market Analysis and Opportunities,” Kline & Co. Report Published: March 2015.

	When referring to this article, please cite it as A. Siew, “An alternative to pills and injections: CUREfilm redefines how medicines are delivered and experienced,” 

The CUREfilm technology delivers drugs through a dissolvable strip that can be applied in the oral cavity or onto the skin. 

An Alternative to Pills and Injections: CUREfilm Redefines How Medicines are Delivered and Experienced

The use of capsules loaded into a dry powder inhaler (DPI) to deliver drugs to the lungs is a well-established method for the treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Developing a capsule formulation for inhalation, however, is not nearly the same as an orally administered capsule. For DPI capsules, powder properties not only affect the manufacturing process but also drug delivery to the lungs. Experts from DFE Pharma-Mohit Mehta, scientist; Gerald Hebbink, scientist; and Harry Peters, lactose inhalation specialist-spoke to Pharmaceutical Technologyabout the importance of carrier selection and how the capsule filling process can affect DPI performance. 

Can you tell us about the role of carriers in DPI formulations?

DPI formulations contain micronized drugs. The aerodynamic particle size of these micronized drugs typically ranges between 1–5 μm. The majority of the drugs used for treatment of asthma and chronic obstructive pulmonary disease (COPD) are either beta agonist, anticholinergic, or corticosteroids, which can be formulated in combinations. These drugs have very low doses, usually in the microgram range. The carrier, therefore, provides the bulk, which enables ease of handling during dispensing, manufacturing, and delivery through the device (1). A carrier is an important component of the DPI formulation. Because micronized drugs have poor flow properties, mixing the drug with a suitable carrier enhances the flow behavior and thus improves dosing accuracy and consistency. Furthermore, the carrier facilitates the dispersion of the cohesive micronized drug during the inhalation event. Any change in the physiochemical properties of the carrier has potential to alter the product performance and drug deposition in the lungs; therefore, selecting and optimizing the right carrier is an important step in developing a suitable DPI formulation.

What excipients are commonly used as carriers?

Due to the lack of toxicological data concerning the potential hazard of carriers to lung tissue, the primary carrier currently approved or certified safe by FDA remains limited to lactose. Mannitol has been investigated as a carrier. However, mannitol can trigger issues related to bronchoconstriction, and using it as a carrier for treatment of asthma and COPD could be a regulatory challenge (2). Based on their functional role, there are other excipients, such as magnesium stearate, distearyl phoshatidylcholine (DSPC), and fumaryl diketopiperazine (FDKP), that have also been approved to be used for inhalations. The major commercially available formulations are, however, manufactured using lactose as the carrier (3). Lactose has been thoroughly investigated and described for this purpose. Mostly alpha-monohydrate lactose is used, although there are existing formulations that use beta-anhydrous lactose. 

What are the key considerations when selecting a carrier for a DPI formulation? What are the properties required in a carrier?

Selection of a carrier is typically based on: 

		Functionality: powder flow and dispersion during inhalation

		Stability: physicochemical stability, biocompatibility, biodegradability, and compatibility with the drug substance 

		Safety: it must be inert and non-toxic to lung tissues. 

	Consequently, it has been stated that the efficiency of a DPI formulation is extremely dependent on the carrier characteristics, and the selection of carrier is a crucial determinant of the overall DPI performance (1). In case of DPI formulations, most of the micronized drug particles adhere to the surface of coarse carrier particles. During inhalation maneuvering, based on the velocity of inspired air flow, these drug particles are detached from the surface of the carrier particles. The larger carrier particles are deposited in the upper airways, while the small drug particles can reach the lower parts of the lungs (1). Detachment of drug from the carrier is based on the balance between inter-particulate adhesive forces and air flow velocity (4). The right cohesive and adhesive balance is, therefore, required between the drug and carrier to produce a stable formulation that at the same time allows easy separation during inhalation.

	Often the question is raised to a lactose producer as to what grade of inhalation lactose should be used. There is, however, no single grade lactose that fits all purposes. One has to determine what kind of functionality needs to be addressed with the lactose. Is it the filling of the device, the mixing of the powder, the metering of the device, the deposition of the drug, or a combination of these?

Can you discuss the differences between lactose for inhaled formulations versus lactose used in oral formulations? 

Lactose for oral formulations is primarily selected based on the manufacturing process, the dosage form (whether tablets, capsules, or sachets), and the nature of the API (e.g., moisture sensitivity). In the case of lactose for inhalation, selection is based on filling of the device, device design, and deposition of drug into the lungs. In both solid oral and inhalation dosage forms, important characteristics to be considered when selecting a lactose are particle size and flow properties. However, in case of inhalation formulations, the particle size of the lactose plays a crucial role in determining drug deposition into the lungs and its pharmacokinetic behavior. For inhalation-grade lactose, health authorities require extra testing and controls, especially for some parameters, where tighter limits are required compared to pharmaceutical-grade lactose. Inhalation-grade lactose has to be manufactured specifically to meet the stringent specifications.

Can you elaborate on how capsule filling affects DPI performance, and what’s the best way to ensure reproducibility and consistency of DPI performance?

Capsules play an important role in delivery of drugs in the case of capsule-based DPIs. The capsule has a significant impact on powder deagglomeration and the detachment of the micronized drug from the carrier during inhalation. Capsule selection should, therefore, be an integral part of DPI product development. In comparison to solid oral formulations, DPI capsules have low fill weights, and hence, it is often more challenging to fill the dry powders with accuracy and consistency. Filling of these powders often requires specialized filling equipment with built-in systems for in-process checks and the ability to reject under- or over-filled capsules based on the required quality specifications. 

	Temperature and humidity play a crucial role. It is important to avoid moisture uptake, as it may lead to powder aggregation and variability in the filling process (5). For accurate powder dosing, there are several mechanisms available, which include dosator filling, vacuum drum filler, and tamping pins. Generally, the filling mechanism is selected based on the amount and the characteristics of powder blend to be filled. Powder flow properties are one of the important parameters of the dry powder blends that can affect capsule filling and the DPI performance. It is important to have a thorough understanding of powder flow properties in combination with the mechanism of filling to optimize the filling parameters, which govern reproducibility and consistency of DPI performance. 

What are the challenges of scaling up DPI capsule production and how do you address them? 

There are several unit operations involved in DPI capsule manufacturing. However, the most important unit operations during scale up are blending and capsule filling. Blending is well established in the pharmaceutical industry, and manufacturing scale-up from bench to factory is generally well understood. However, blending is an important unit operation that plays a crucial role in determining the detachment of micronized drug from the carrier particles. In the case of a capsule filling operation, the major challenge is the unavailability of a defined scalability factor from laboratory scale to commercial scale. Hence, the whole process needs to be optimized based on the batch size, the filling equipment, and powder flow properties at commercial scale. To address these issues, the best approach is to have proper risk assessment done before optimizing the process. Risk assessment should take into consideration powder flow properties, filling process parameters, environmental conditions, storage after filling, and further packaging into blisters.

	1. G. Pilcer, N. Wauthoz, and K. Amighi, 

 64 (3) 233–256 (2012).
	2. S. Anderson, 

8 (1) 53–60 (2011).
	3. P. Tingting et al., 

6 (4) 308–318 (2016).
	4. H. Hamishehka, Y. Rahimpour, and Y. Javadzadeh, “The Role of Carrier in Dry Powder Inhaler,” in 

Recent Advances in Novel Drug Carrier Systems, 

A.D. Sezer Ed. (InTech, Rijeka, Croatia, 2012), pp. 39–66.
	5. D. Edwards, 


	Vol. 42, No. 5
	May 2018
	Pages: 30–33

	When referring to this article, please cite it as A. Siew, "The Role of Carriers in DPI Capsules," 

Choice of carrier can have a significant impact on the capsule filling process as well as the performance of the DPI formulation.

The Role of Carriers in DPI Capsules

Freeze-drying is widely used in the pharmaceutical industry to stabilize drug products. During freeze-drying, solvent is removed from a frozen product by sublimation to produce a dry product that can be readily reconstituted to its original liquid formulation by the addition of solvent. The process prolongs shelf life of the product by inhibiting chemical and physical degradation pathways that occur in the presence of moisture. The process, however, is one of the most expensive unit operations in a complete manufacturing line because of the slow drying rate arising from inefficient heat transfer, and the high investment and operating costs (1, 2). Cycle optimization is, therefore, crucial, especially for products produced on a large scale, where the cost factor increases significantly with time spent in the freeze dryer (1). A fully optimized cycle uses only the energy and time required, resulting in shorter process time and higher product throughput (3). Most importantly, it ensures optimum product quality and consistency between batches. 

	Freeze-drying involves three basic steps-freezing (solidification), primary drying (ice sublimation), and secondary drying (moisture desorption)-which can take several days to complete. A fundamental goal of freeze-drying is to produce a well-dried product with elegant cake appearance, short reconstitution time, long shelf life, and complete recovery of activity on rehydration (3, 4), among other requirements. Two major considerations for optimization of a freeze-drying process are the stability of the drug product, during the process itself and during the storage period after the cycle is terminated (5). Designing an optimized freeze-drying cycle requires identifying the critical properties of the formulation so that the processing conditions can be specifically tailored to the formulation’s freeze-drying characteristics, such as the collapse temperature (T

) (3). As Arnab Ganguly, technology manager, IMA Life North America, underlines, thermal characterization of the product is essential to understand product limits.

	The freezing step is of paramount importance in a freeze-drying cycle because it is a known equivalent dehydration step. Further, it determines the ice crystal morphology and pore size distribution of the product, which in turn affect downstream steps such as primary and secondary drying, observes Paritosh Pande, research scientist, IMA Life North America. Proper freezing creates the foundation for efficient and consistent freeze-drying cycles, according to T.N. Thompson, president of Millrock Technology (6).

	“For freezing, we want to make sure that the product is thoroughly solidified,” says Steven Nail, principal scientist at Baxter Biopharma Solutions. He explains that freezing is often carried out at a shelf temperature of -40 °C to -60 °C for a period of time long enough to establish a steady state. 

	Once freezing is complete, primary drying begins. “The chamber pressure is reduced, and shelf temperature is raised to supply heat for the ice to sublime,” says Vaibhav Kshirsagar, associate scientist, IMA Life North America. “Normally, most of the water is removed at this stage.” 

	Primary drying is usually the longest step, taking up the largest fraction of the freeze-drying cycle time. Optimizing this process step has been shown to have significant economic impact (5). The temperature and pressure during primary drying will determine the rate of solvent removal and product temperature, according to Ganguly. “At or close to the edge of failure, increasing the temperature and pressure will speed up the primary drying process, but it may adversely affect product quality,” he says. 

	“Shelf temperature and chamber pressure are critical because of their influence on heat transfer, mass transfer, and ultimately product temperature-which is the most critical process variable, even though we can’t control it directly,” Nail explains. “Ideally, you want the product temperature to be a safe distance below the upper product temperature limit (usually the collapse temperature), without being so low that it unnecessarily slows down the process.” 

	Pande cautions that drastic increase of the shelf temperature in favor of more rapid ice sublimation during primary drying can lead to the collapse of an amorphous product or result in a eutectic melt for a formulation containing a crystalline product. “Both the collapse and eutectic melt can have significant consequences on product stability as well as for product appearance,” he says. 

	Kshirsagar further adds that heat transfer to the product is not only dependent upon temperature and pressure, but also on the product containments such as whether they are contained in vials or syringes. He notes that increasing the pressure in the chamber will generally increase the heat transfer to the product, thus, increasing the mass transfer to the condenser. 

	The optimal temperature and pressure during primary drying are determined based on the product collapse temperature and the freeze dryer’s capabilities. “The optimum process conditions will prevent loss of pressure control in the chamber and maintain the product temperature below the collapse temperature,” says Kshirsagar. Pande highlights that there are also other variables that can influence the primary drying process such as fill volumes, vial size, freeze dryer geometry, nature of the solvent, and product concentration. 

	“To ensure successful primary drying, the product, process, and equipment characteristics must be factored in when deciding the appropriate conditions,” Ganguly explains. “The process of identifying appropriate conditions for primary drying typically begins with thermal characterization of the product of interest. During thermal characterization, the critical collapse temperature of a product is identified by factoring in its glass transition temperature (T

’), as determined by differential scanning calorimetry, and identifying its collapse temperature through freeze-drying microscopy. The critical collapse temperature determines the maximum temperature that a product can withstand during primary drying without undergoing melt or collapse.”

	From an equipment standpoint, Kshirsagar notes that aggressive cycles may be possible for products with high collapse temperature. “However, such aggressive cycles may sometimes lead to condenser overload or choked flow in the freeze dryer, if not well characterized,” he says. “In such situations, the equipment capability will be a limiting factor, and the temperature and pressure would be chosen accordingly.” 

	According to Pande, appropriate primary drying conditions can be determined with good accuracy using a combination of thermal characterization data and steady-state mathematical modeling performed using first principle methods. “This approach eliminates the need for trial and error,” he says. 

	Baxter’s approach involves constructing a graphical design space to determine primary drying conditions. “For us, that is a plot with sublimation rate on the y-axis, chamber pressure on the x-axis, and two sets of isotherms-one set for shelf temperature and the other for product temperature,” Nail explains. “We do this by measuring the vial heat transfer coefficient as a function of pressure and the resistance of the dried product layer to flow of water vapor. One of the boundaries design space is the upper product temperature limit, and the other is the equipment capability curve. The highest sublimation rate within the resulting ‘space’ gives the optimum shelf temperature and chamber pressure.” 

	The most widely used tools to monitor primary drying are pressure sensors, including the capacitance manometer and Pirani gauge. Temperature probes, which include thermocouples, resistance temperature detectors, or wireless sensors, are typically used during engineering runs, observes Ganguly. “Residual gas analysers and mass spectrometers can be used to determine the gas composition inside close environments and have proven to be extremely useful to monitor trace concentrations of contaminants such as silicone oils or even for process monitoring in primary and secondary drying (7). Tunable diode laser absorption spectroscopy is a well-established tool for monitoring the vapor flow rate between the chamber and condenser in real time. Heat flux sensors mounted on the freeze dryer shelves can be used to quantitatively obtain the vapor flow rate if prior heat transfer coefficient (Kv) measurements are performed,” he says. “These process-monitoring techniques gather enormous amount of data that can be used to determine the end point of a primary drying process.”

Shelf temperature during secondary drying 

	The purpose of secondary drying is to remove remaining unfrozen water that is either loosely associated with the crystal surfaces or buried within the glassy phase (1). The relatively small amount of water is removed by desorption, “typically to a final moisture content of 1–3%,” says Pande. “As the moisture content approaches 1%, the choice and concentration of excipients play an important role in preventing damage to the activity of any biological product,” he continues. “Excipients such as trehalose, for example, can better offset the effects of dehydration for a freeze-dried protein like immunoglobulin G by offering better H-bonding and a phase-homogeneous matrix with more suppressed β-relaxation, compared to large-sugar excipients such as dextran or inulin.” 

	Nail highlights that there is only one critical process variable during secondary drying, and that is the shelf temperature. “Both published literature and our own experience show that the chamber pressure doesn’t seem to have any effect on either the rate or the extent of secondary drying, probably because the rate-limiting step in secondary drying is diffusion of water through the glassy mixture of partly-dried solids,” he adds.

	“We nearly always use a secondary drying temperature that is room temperature or above,” Nail says. “As a general rule, we like to keep the secondary drying shelf temperature as high as we can, because it results in a faster rate of secondary drying, and probably a greater extent of secondary drying.” 

	In addition, Kshirsagar points out that the temperature of the product needs to be maintained well below the T

during secondary drying. The rate of water desorption during secondary drying step is sensitive to the specific surface area of solid, he notes, which is impacted by the ice nucleation event occurring in freezing stage. 

	Kshirsagar explains that the rate of water desorption during secondary drying can also be influenced by the primary drying step. “Aggressive primary drying above the glass transition temperature can generate macro- or micro-collapse in the product cake,” he says. “To avoid product collapse during secondary drying, it is imperative that maximum water sublimation is achieved during the preceding primary drying step.” He reiterates the importance of maintaining shelf temperature during secondary drying several degrees below the T

of the product. “Because the primary driver of water removal during secondary drying is the shelf temperature, as one example, it can be optimized by choosing a shelf temperature close to the T

while maintaining a safety buffer,” he says. “In addition, a slow shelf temperature ramp rate is preferred to avoid exceeding the T

and leading to viscous flow in the product.”

	Nail explains that the appropriate combinations of shelf temperature and drying time are determined by taking “thief” samples during secondary drying and measuring the residual moisture content relative to a target residual moisture limit.

	According to Kshirsagar, the Pirani and capacitance manometer pressure sensors alongside thermocouples can be used in the early stage of secondary drying. Pande adds that the use of mass spectrometers can greatly improve the secondary drying process monitoring, by which the exact gas composition in the chamber can be known and potentially related back to the batch average residual moisture (7). 

	Determining the right process conditions for a freeze-drying cycle requires an understanding of the effect of each step on the drug product. A confirmation run should be conducted at the end of cycle design to ensure that the process is robust and efficient and that it produces acceptable products.

	1. J. Schwegman, Technical Note: Basic Cycle Development Techniques for Lyophilized Products (Nov. 11, 2009).
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29 (5) 58–68 (2009).
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26 (3) 46–51 (2013).
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	5. X. Tang and M. Pikal, 

37 (5) 36–40 (2013).
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European Journal of Pharmaceutics and Biopharmaceutics


	Vol. 42, No. 5
	May 2018
	Pages: 18–23

	When referring to this article, please cite it as A. Siew, “Freeze-Drying Process Optimization,” 

Determining the right process conditions for a freeze-drying cycle requires an understanding of the effect of each step on the drug product.

Freeze-Drying Process Optimization

Monoclonal antibodies (mAbs) are typically given as intravenous infusions, but subcutaneous administration is fast becoming the preferred alternative, especially for patients with chronic diseases who require frequent dosing of the mAb over their lifetime. Subcutaneous injection of a drug using a self-administered delivery device such as an autoinjector, pen, or prefilled syringe is not only more convenient for the patient, but it also reduces healthcare costs by minimizing hospital visits.

	When developing mAb formulations for subcutaneous administration, volume and viscosity are crucial considerations. Because the subcutaneous space limits the volume that can be delivered, mAb formulations tend to be developed as highly concentrated solutions, often in the range of hundreds of milligrams per mL, which consequently give rise to high viscosities. “Intermolecular interactions are thought to play a role [in viscosity],” says Nicholas Warne, senior director, Formulations, Pfizer. He explains that the proteins within the mAb molecule have the potential to align themselves at specific domains, causing the solution to form transient, networked structures. The literature has reported that a protein solution’s viscosity can be predicted based on the formulation and protein characteristics such as the shape of the protein molecule (1, 2), charge distribution on the protein, which is formulation-dependent (3, 4), and the kinetics of self-association (5–7).

	High viscosity not only presents difficulties in processing and storage, but it is known to pose formulation and delivery challenges, as viscous solutions require high injection force to administer the drug and may also require prolonged injection time. The pain and discomfort experienced by the patient can have a negative impact on compliance and adherence to the medication. For drug developers, it is important to bear in mind the potential product loss that could result from the highly viscous solutions sticking to the contact surface of the primary packaging. If drug delivery is through an autoinjector, the challenge will be to ensure that the device can produce the required force to function properly throughout its shelf life, hence necessitating extensive modeling and accelerated aging to simulate the high stress placed on the device.

	According to Warne, the acceptable viscosity range for subcutaneous injection will depend on the patient population. “For patients with challenged dexterity, we tend to limit viscosity to 10 cps for a 1-mL prefilled syringe,” he says. “[Whereas] for patients with normal dexterity, the limit may be 20 cps. For these higher viscosity solutions, we may choose to implement autoinjectors, which help manage self-administration and reduce injection time to below 10 seconds.”

	With highly concentrated mAb formulations, there are a number of issues to consider. Warne highlights that compounding and mixing must be assessed to ensure a homogeneous solution at the time of mixing and storage. He adds that viscous solutions can affect the filtration process. High-concentration mAb formulations will require the use of filters with higher V

 (i.e., maximum volume that can be filtered through) and larger surface area. “The need for larger membrane area can result in yield losses and slower processing times [due to the higher back pressure on the filtration equipment created by the viscous solution],” he highlights. Moreover, as shear stress can cause proteins to unfold or aggregate, Warne recommends assessing the solution characteristics of the mAb formulation during pumping, transfer, and filling.

	Viscosity challenges can be addressed by controlling the pH of the formulation in relation to the isoelectric point (pI) or by adding excipients, including cations and anions to increase the ionic strength of the formulation (8). In terms of optimizing the viscosity of a mAb formulation, Warne believes that less is more, “the closer to water, the better,” he says. “We are exploring the application of viscosity-reducing formulations including formulating at least two pH units away from the pI, developing proteins and mAbs with favorable electrostatic profiles, assessing the impact of pH on viscosity and the role of ionic strength, and evaluating the potential role of viscosity-reducing excipients such as arginine,” he adds. According to Warne, arginine may occasionally be beneficial in reducing formulation viscosity, but he cautions that using novel innovative excipients carries regulatory and safety risks.

	Despite the challenges associated with delivering highly viscous solutions, Warne observes that there have been advances in the delivery of high-concentration protein formulations, such as the increased comfort level with delivering a 2-mL injection subcutaneously and the development of 2.25-mL prefilled syringes and autoinjectors from multiple vendors. “The ability to tolerate osmolality of up to 600 mOsm/kg in high-concentration solutions has also provided much needed flexibility,” he adds.

	As demonstrated at Pharmapack Europe 2018, held on Feb. 7–8 in Paris, France, the industry continues to innovate and provide patient-centric solutions to drug-delivery challenges. Biocorp’s Onejet autoinjector won the Patient Safety and Convenience Award at this year’s show. According to Biocorp, the device is the first motor-driven, disposable, and Bluetooth-connected autoinjector compatible with standard primary containers (prefilled syringes from 1 mL to 2.25 mL) (9). Its motorization can be adjusted to any biologics density, enabling Onejet to easily deliver highly viscous drugs. Injection speed and force can be calibrated. Another key feature of Onejet is its ability to record injection data such as date, time, and doses administered, which are then transferred to a mobile app via Bluetooth so that treatment can be monitored.

	The SelfDose patient-controlled injector by West Pharmaceutical Services received the award for “Ease-of-Use and Patient Compliance.” The injector has a simple two-step operation where the patient only has to remove the cap and press the device against the skin to deliver a subcutaneous injection. Audible and visual end-of-dose indicators confirm successful administration of the prescribed dose. Erin O’Brien, vice-president of West, noted in a press release that many patients could benefit from a drug-delivery device system that makes the injection experience more user-friendly and less intimidating (10). SelfDose has been ergonomically designed with the patient’s unique needs in mind. In addition, the device has a passive safety system that covers the needle before and after injection to help prevent needlestick injuries to the patient and caregiver. According to West, extensive human factors studies have been performed with the SelfDose injector, confirming the intuitive design and supporting its ease of use and patient acceptance.

 1700 (1) 27–34 (2004).
	3. B.A. Salinas et al.,

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	4. S. Yadav, S.J. Shire, and D.S. Kalonia, 

28 (8) 1973–1983 (2011).
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	7. S. Yadav et al., 

 28 (7) 1750–1764 (2011).
	8. Y. Yang et al., 

 114 (9) 2043–2056 (2017).
	9. Biocorp, “Biocorp Wins Pharmapack Award for Its New Generation Autoinjector Onejet,” Press Release, Feb. 7, 2018.10. West Pharmaceutical Services, “SelfDose Patient-Controlled Injector Named as Recipient of Pharmapack Exhibitor Innovation Award,” Press Release, Feb. 7, 2018.


	Vol. 42, No. 4
	April 2018
	Pages: 30–33

	When referring to this article, please cite it as A. Siew, “Delivering High-Concentration Protein Formulations,” 

The high viscosity of highly concentrated monoclonal antibody formulations not only presents processing and storage difficulties, but also formulation and delivery challenges.