Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

It is well-documented that many APIs are bitter in taste and as a result need to be taste-masked to improve palatability and acceptability for the patient population. “Taste is a critical attribute that determines the palatability of oral dosage forms and patient compliance,” emphasizes Jin Zhao, principle investigator, DuPont.

As taste can be such a key attribute to ensuring a successful drug product is developed, there is a vast array of options available to developers to mask any unwanted bitterness or taste of the ingredients. A common approach, and possibly the simplest of all, is the addition of sweeteners, sugar coating, or flavors. “This approach is suitable for some of the less bitter compounds as the perception of the sweetener or flavor will be stronger than the taste of the drug,” notes Andrew Mound, application development and innovation scientist, DuPont.

“A judicious selection of excipients can enable formulation strategies utilizing flavors, sweeteners, and bitter blockers,” adds Bing Xun Tan, pharmaceutical application laboratory manager at Roquette’s Asia Pacific Innovation Center in Singapore. “Pleasant-tasting, highly viscous, or lipophilic vehicles can also provide an effective taste-masking effect.”

However, for APIs that are extremely bitter or have a complex aversive taste profile, the addition of sweeteners or flavors becomes less viable as their effective taste-masking amount will either increase the overall size of the dosage form which decrease the swallowability of the dosage or will erode the therapeutic dose amount in the dosage form. Another option is to coat the drug, which is possible to do on the tablet, capsule, granule, or API itself, continues Zhao.

“Coating or microencapsulation provide a barrier membrane to prevent the drug from dissolving in the mouth, which is a requisite for taste perception, and depending on the drug properties, coating can be applied in several ways,” says Zhao. “Water insoluble polymers, such as ETHOCEL and Aquacoat ECD, can effectively create barrier membranes and the polymer amount can be adjusted to ensure taste perception is minimized without affecting the release profile.”

Coating can be considered an efficient method, notes Tan; however, the coating process efficiency and coat homogeneity require careful optimization and can be dependent on factors such as the API particle morphology. “Also, depending on the administration technique, interaction of the taste-masking coat and potential food-based dosing vehicles may lead to premature failure of the coating and unmasking of the bitter taste,” he says.

A matrix granulation can be employed to trap a bitter API in a matrix formulation, asserts Zhao. “The matrix may contain gelling or lipid polymers,” she explains. “In granulation-based approaches, the amount of API on the surface of the dosage form is reduced, thereby limiting the amount available to dissolve in the mouth. These approaches work more effectively for drugs with lower solubility or higher taste thresholds.”

Advanced processing techniques such as spray drying or hot-melt extrusion can be used to create a matrix formulation with ethyl cellulose, hydroxypropyl methyl cellulose, or acrylate polymers. “Using these processes, a dispersion can be created in a matrix that is insoluble in the mouth, which will prevent the interaction of drug with taste buds,” explains Zhao. “However, solid dispersion is often less effective as the drug is in a highly soluble state and may be present on the surface of the spray dried or extruded articles.”

Chemically modifying the API is another way to reduce the bitter taste of drugs, adds Tan. “For this approach, the originally bitter APIs are chemically modified to develop prodrug or salt forms with a reduced bitter taste,” he says.

“Complexation with an API, creating a stable complex with ion exchange resin or cyclodextrin, which reduces taste exposure, and a prodrug or salt formation approach can also be useful for taste-masking,” agrees Vinay Muley, technology and innovation leader, India, DuPont.

Tan reveals that an excipient, made from a pea maltodextrin, is available that has been primarily designed for taste-masking and solubility enhancement applications. “The KLEPTOSE Linecaps excipient can decrease the exposure of API to the taste buds through a different mechanism of action to complement the current range of taste-masking excipients available to formulators,” he specifies. “The pea maltodextrin has been reported to exhibit a taste-masking effect on model APIs, such as loperamide hydrochloride and dextromethorphan hydrobromide” (1).

A technique that is rapidly advancing and finding use for taste-masking is 3D printing, according to Zhao. “Personalized medicine is seeing growth opportunities and has the potential to revolutionize the health system,” she says. “Three-dimensional printing is a key enabling technology for personalized medicine and, therefore, there is a need to develop tailor-made taste-masking techniques in conjunction with 3D printed medicine.”

Taste-masking is particularly important for dosage forms and drug products that are targeted to geriatric and pediatric patient populations. “Overall, drug products and dosage forms targeted to pediatric and geriatric populations need to pay particular attention to sensory attributes. Clearly children can be picky and need an appealing dosage form to take the required medicine or vitamin,” confirms Mound. “For older populations with difficulty in swallowing or chewing, taste-masking plays a role in the overall experience of taking medicines.”

Common dosage forms for these target patient populations include chewable tablets, orally disintegrating tablets, gummies, and liquid dosage forms, which are prime for taste-masking and sensory improvement, adds Mound. “These formats are growing in popularity, making them ripe for innovation in the application,” he says.

“The pediatric patient population has a big need for taste-masking solutions that is not yet fully met today,” asserts Tan. “As the pediatric population cannot swallow oral tablets, most pediatric drug products are either liquid, particulate, or orodispersible dosage forms where the bitter APIs can have a prolonged and direct exposure to taste buds in the buccal cavity.”

However, excipient options for pediatrics are limited, and are less well defined or understood in terms of safety, Tan continues. “Hence, current taste-masking approaches for adults may not be feasible and suited for children,” he notes. “The relatively lower commercial value of pediatric products also means that developers generally prefer simple and cost-effective taste-masking strategies, so complex processing is less desirable.”

Formulation difficulties can arise when taste-masking strongly bitter APIs, ingredients that have high solubility in the buccal cavity, or when high doses of active ingredients are required, Tan emphasizes. “In such situations, the application and efficacy of flavors and sweeteners is greatly limited, and so other methods need to be employed, as explained earlier,” he says.

“Another challenge in development is with taste evaluation techniques,” Tan continues. “A human sensory panel is still the most recognized method of taste evaluation. However, sensory evaluations are often more costly and challenging to organize, especially when potent APIs or new chemical entities are involved.” Furthermore, there is some debate over the relevance of human sensory panels for specific patient populations, such as pediatrics, he asserts.

“There is a great need to develop analytical technologies that characterize the taste and correlate well with 

 performance,” comments Zhao. “Advances have been made in electronic tongues, but 

 correlation (IVIVC) of taste is even more challenging than IVIVC of drug release; as simulating taste recognition in the mouth is more challenging than simulating drug absorption in digestive tract.”

Methods such as the electronic tongue are useful for the early screening of formulations during R&D, agrees Tan. “However, there remain technological limitations in these methods, and the sensitivity and reliability of the measurement depends greatly on the API properties and also the excipients used in formulation,” he adds.

“Another challenge is creating an effective taste-masking performance without affecting pharmacokinetics and pharmacodynamics of active ingredients,” asserts Zhao. “Some of the previously mentioned barrier membranes can also modulate release to the point that it changes the absorption profile. For example, ethylcellulose at a low level will provide excellent taste-masking; however, at slightly higher percentages it begins to provide a sustained release profile, which may be undesirable for a given drug and most be monitored during development.”

Additionally, there is still a need to ensure there is a robust measurement system in place that can provide qualitative and quantitative data on the taste attributes—without which optimization of taste-masking technologies is difficult, emphasizes Muley. “Finally, regulatory constraints to reduce the number of excipients in pediatric formulations presents additional challenges in providing an optimized taste-masking approach,” he says.

Industry will continue to see developments and improvements in taste-masking of dosage forms for pediatric and geriatric patient populations, states Mound. “Novel dosage forms such as orally disintegrating tablets and films, chewable tablets, and liquids will continue to evolve to boost taste-masking technology options,” he specifies.

Moreover, as there is an increasing drive from major regulatory agencies for new drug product developments to include pediatric trials, there will be advancements in taste-masking options, highlights Tan. “The Pediatric Research Equity Act (PREA) in the United States and Paediatric Regulation in Europe require submission of a Pediatric Study Plan (PSP) and Paediatric Investigation Plan (PIP), respectively,” he explains. “Because of this regulatory direction, there is a renewed focus from pharmaceutical companies on taste-masking solutions and palatability studies, which can aid development and demonstrate acceptability of the drug product for children.”

The scope of what constitutes taste sensation is also widening, Tan continues. Whereas, traditional taste-masking solutions have been focused on the bitter taste of the drug product, there will be more consideration of other attributes, such as sourness, and also aversive sensory attributes such as odors, texture, and irritation, which contribute to the overall patient experience, he explains.

“Therefore, a combination and synergism of several taste-masking strategies may be required to address different aspects of the sensory challenge,” Tan reveals. “For example, a combination of different excipients, such as a polyol (maltitol) and intense sweetener (sucralose), have been reported to display synergism leading to an optimized taste-masking of the model API, acetaminophen, in chewable tablets (2). Also, excipients that can contribute to more than one aspect of the taste-masking or formulation challenge will be advantageous in reducing formulation complexity.”

The expansion of scope for improvements in sensory attributes will also incorporate over-the-counter (OTC) and dietary supplement segments, which will provide opportunities for taste-masking technologies, highlights Mound. “As consumers continue to gravitate toward the elimination of sugars and other non-clean label sweeteners, formulators will be challenged to deliver a quality product without the traditional options at their disposal,” he says. “Cleaner label taste-masking options are needed in this space.”

Added to this, the competitive nature of the OTC and nutraceutical markets will mean that innovation, particularly in dosage forms and formulation, will be highly sought after to ensure product differentiation, Tan emphasizes. “Interest in innovative oral dosage forms will in turn increase the demand for novel taste-masking solutions,” he states.

“And as innovations, such as 3D printing, enable the development toward personalized medicine, customized taste-masking options will be possible and essential in delivering differentiated products,” summarizes Zhao.

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 44, No. 10
October 2020
Pages: 24–27

When referring to this article, please cite it as F. Thomas, “Masking Taste: A Key Attribute to Success,” 

Articles

Taste-masking can be of significant importance in ensuring success of a drug product, particularly those targeted to pediatric or geriatric populations.

Masking Taste: A Key Attribute to Success

Annex 1, the European Union’s good manufacturing practice (GMP) guide for sterile products, has undergone several updates since its original publication in 1971. The latest revised document, the proposed draft of which was published in February 2020 and has undergone a second consultation period (1), has been comprehensively updated and builds on a significant number of comments submitted to the European Medicines Agency (EMA) by companies and organizations from the pharmaceutical industry.

To find out more about the key revisions to Annex 1 and the impact the changes will have on industry, 

 spoke with Vincent Quiles-Pelletier, director, quality management and head of steriles at Recipharm.

 Could you highlight the key changes of the Annex 1 2020 revision?

 The Annex 1, Manufacture of Sterile Products guideline, was proposed as a new draft in February 2020 for a second consultation period, which ended in July 2020. This document was completely rewritten to organize and describe detailed and comprehensive requirements in 10 specific sections. The scope was enlarged to include non-sterile products where principles of contamination control could apply, using quality risk management (QRM) principles adapted to these products.

The key changes in this new version include: quality management through the introduction of the contamination control strategy (CCS) concept combined with QRM and pharmaceutical quality system (PQS); introduction of new barrier technologies such as restricted access barrier systems (RABS) and isolators, which should be considered as part of the CCS; creation of new sections for form fill and seal, closed systems, and single use systems (SUS); reinforcement of some requirements around areas classification and qualification, including microbial airborne and surface contamination; introduction of detailed measures and/or specifications to prevent any contamination (for example, airlock/changing rooms, continuous monitoring systems for total organic carbon and conductivity on water for injection loops, validated disinfection/decontamination programme including a focus on vacuum, cooling systems, and dry heat tunnels); and introduction of specific requirements regarding personnel, including a strong knowledge and expertise through adapted training, combined with reinforced monitoring and gowning requirements.

Additional requirements have also been introduced regarding production and specific technologies, including pre-use post sterilization integrity test (PUPSIT), specific process holding times, container closure integrity, and visual inspection. Further, reinforced sterility test sampling after each critical intervention is also mandatory.

 What were the reasons behind the revisions to the Annex 1 guidance and why has the revised document taken so long to prepare?

 Since the first version was published in 1971, several updates with partial revisions were issued in 1996, 2003, and 2007 to align classification of cleanrooms, to include guidance on media simulations, bioburden monitoring and capping of vials. In 2012, German authorities started to require a complete revision to be handled by the Inspectors Working Group (IWG) from EMA, involving EMA, the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and World Health Organization (WHO) experts. The work began in 2014 and a concept paper was raised on 8 Jan. 2015 (2). Consideration was given to the fact that that the initial document was never completely reviewed despite significant changes in technologies, practices, and in GMP (e.g., International Council for Harmonization [ICH] Q9 and Q10 guidelines adoption).

A first draft of the new Annex 1 was proposed in December 2017 for review until March 2018, and about 6200 comments were received from 140 companies and organizations, showing a significant interest from all actors involved in sterile manufacturing. As a result, this new Annex 1 proposed in 2017 and updated in 2020 is a completely rebuilt document of 50 pages (16 pages for the current version) answering to the concept paper objective from 2015.

 Are there specific changes in the newly revised guidance document that will significantly impact industry?

 Absolutely, the most important challenges will be technical and organizational. From a technical perspective, we have seen that a big prominence was placed on any equipment or premises design that can minimize the risks of potential contamination. If new equipment is completely integrated into the CCS using QRM principles, this can be a challenge, both technically and financially, for old equipment and premises. A good example of this issue is new barrier technologies, which should be considered in the CCS as it offers significant improvements in terms of contamination control.

At an organizational level, the sterility assurance level is based on CCS and PQS is based on QRM principles and continuous improvement. This new concept demands a periodic review of each risk assessment initially raised, and the implementation of a new review of data and trends generated by systems or equipment considered as critical in the CCS.

 Could you describe the principle of a CCS in more detail and how the revised Annex 1 approach to CCS will impact manufacturers?

 The principle of the CCS is to provide a global tool, allowing companies to implement, follow, and maintain an acceptable sterility assurance level. This required level of quality assurance in sterile operations means that each process and product should be assessed to define all critical control points, covering the following areas of contamination risks: viable (microbial) and non-viable (pyrogen as well as other potential particulate matter such as glass, visible and sub‑visible).

The impact for manufacturers will most probably be a significant effort in making a link between measures and the quality systems in place, and to reopen and reassess existing risk assessments periodically based on data generated by all critical control points, checking efficiency, and deciding new adapted preventive actions if justified by these reviews.

 Does the newly revised EU guidance offer a more harmonized approach with other global regulatory requirements?

 Definitively, as EMA, PIC/S, and WHO experts were all involved in the revision process, as well as there being some input from the United States Food and Drug Administration, to provide a more comprehensive document, there is harmonization of approaches. Overall, more than 70 countries provided comments for the revised guidance.

Some reference documents were taken in consideration for the review, such as current monograph of the relevant pharmacopoeia for water (3) or ISO 14644 for cleanroom qualification (4). However, some significant differences remain between US and EU regulations, for example PUPSIT or cleanroom requirements.

The new Annex 1 version, proposed for review and comments, has been the opportunity for targeted stakeholders to give a valuable input in terms of technical feasibility, alignment, and consistency with other guidance, precision and clarity on some of the requirements, and disagreement on specific requirements. This revised document is a good example of what a harmonized approach can achieve, making a link with the mutual recognition process in progress between the US and EU.

Second Targeted Stakeholders’ Consultation on the Revision of Annex 1 on Manufacturing of Sterile Medicinal Products, of Eudralex Volume 4

Concept Paper on the Revision of Annex 1 of the Guidelines on Good Manufacturing Practice—Manufacture of Sterile Medicinal Products

Guideline on the Quality of Water for Pharmaceutical Use

Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness by Particle Concentration


Vol. 32, No. 10
October 2020
Pages: 42–43

When referring to this article, please cite it as F. Thomas, “Unlocking the Key Changes to Annex 1,” 

A comprehensive rewrite of Annex 1 has been proposed and aims to organize and structure requirements in 10 specific sections.

Unlocking the Key Changes to Annex 1

With the United States presidential election merely days away (set to take place on 3 Nov. 2020), the world’s gaze has shifted to the race for the White House and whether there will be a Republican or Democrat taking office. As reported by UBS, the Chief Investment Office, while there is not usually a global interest in national elections, the US presidential election has a significant relevance to many global countries, including those located in Europe (1).

For pharmaceutical companies, there has been a certain level of turbulence for some time over the issue of drug pricing in the US. Donald Trump, the current president (at the time of writing), had pitched the reduction in drug pricing as one of the key pillars of his original presidential campaign back in 2016 and has continued to raise the issue throughout his tenure as president, with it being made a central theme to his 2020 campaign (2).

However, in terms of policies, little has changed over the course of the past four years, despite the signing of four executive orders on 24 July 2020 that Trump had touted as being of great importance in the reduction of drug prices and linking US pricing to that of other nations (2).

The issue of pricing is high on the agenda for the Democrats as well, with the party’s candidate, Joe Biden, advocating several policies that would see drug prices reduced during his campaign. Biden’s policies include the appointment of a government board to set prices, limiting drug price increases, and cracking down on patent manipulation (3). These proposed policies by the Democratic candidate will certainly have ramifications for pharmaceutical companies should they become bills and are voted into legislation.

Currently, the Republican party controls the Senate and the Democratic party controls the House of Representatives. This division basically means that any big legislative change is generally ruled out. However, if this circumstance were to change, there would be potential consequences for European pharma companies that have a presence in or deal with the US.

A Republican president and control over Congress may pave the way for a boost to US drug manufacturers as Trump aims for the population to ‘buy American’ and for there to be less reliance on drugs manufactured offshore. Additionally, Trump has negotiated deals to extend patent protections, as a way of providing an advantage for US manufacturers, which may increase US drug exports but may also delay any price reductions (4).

If the Democrats win the presidency and have control over Congress, it is expected that foreign and generic-drug manufacturers would benefit as a result of lower market entrance barriers. However, patent-holding manufacturers may be exposed to increased competition and would potentially experience revenue loss (4).

Finally, the issue of a COVID-19 vaccine is proving to be divisive for the presidential candidates, as reported by the Financial Times (FT) (5). The tables have almost turned for Trump, who has historically provided a voice for the anti-vaccination movement, FT reported. Now, Trump is pushing for a quick approval of a vaccine for COVID-19, while Biden is urging caution.

However, the political back and forth could lower the public’s confidence in immunizations (5). In response to the rising public concern over vaccines, nine biopharmaceutical companies signed a joint statement committing to uphold regulatory guidelines and scientific principles in vaccine development (6).

In light of the issues in contention and the possible impact on the pharma industry, it is inevitable that the result of the 3 Nov. 2020 election will be eagerly anticipated around the world. But whatever the outcome, be it blue or red, stay alert, stay safe, and stay healthy.

UBS, “The Global Impact of the US Election,” 

S.G. Stolberg and M. Sanger-Katz, “Trump Keeps Promoting a Drug Order That No One Has Seen,” 

, Published 24 Aug. 2020, Updated 23 Sept. 2020.

J. Nathan-Kazis, “The Election Will Have a Significant Impact on Health-Care Stocks. Here’s How,” 

M. Powers, S. Zaidi, and J. Graham, “The 2020—Winners and Losers in Healthcare,” 

K. Stacey and H. Kuchler, “COVID Vaccine Becomes Divisive Issue in US Election Campaign,” 

International Federation of Pharmaceutical Manufacturers & Associations, “COVID-19 Vaccine Maker Pledge,” 

When referring to this article, please cite it as F. Thomas, “The Elephant (or Donkey) in the Room,” 

European pharma companies may have a vested interest in the outcome of the US elections.

The Elephant (or Donkey) in the Room

Capsules are a common oral solid dosage form and are produced in a variety of shapes, materials, and sizes. The popularity of capsules can be somewhat attributed to the ease and simplicity of their manufacture, particularly when compared with other forms. Another benefit of capsules is the potential of shorter development times, which is an ever-increasing priority for developers.

To find out more about the importance of capsules in drug development, innovations that have occurred to the dosage form over time, and the specific challenges facing developers looking to use this dosage form, Pharmaceutical Technology spoke with Sven Stegemann, head of Global Scientific Business Development, ACG.

 What specific formulations are suitable for use in capsules?

 The performance of any pharmaceutical drug product is the result of its single components and the materials that are going into the formulation, the processing, and, finally the packaging. If you understand the material properties and the processing parameters, you can basically use any formulation in capsules today, be it powder, granule, pellet, semi-solid, or liquid.

The capsule formulation can serve oral administration as a single dose, as sprinkles on soft food, or as an orally inhaled dry powder. With the development and introduction of new capsules made from polymers, such as hydroxypropyl methylcellulose (HPMC), it is now possible to provide a capsule with very specific characteristics that can broaden and simplify the use of capsules in product development. To give an example, for therapeutics that are very sensitive to water activity, or head space humidity, such as microbiota, it is possible to specify and guarantee a very narrow humidity range to provide longer shelf life, especially if moisture-protective packing is being used.

Moreover, as microbiota normally requires enteric protection these capsules are also optimized for enteric coating or coating for targeted release. A capsule that already provides a certain degree of enteric protection could be another option, dependent on the specific needs of the therapeutic entity or formulation. In summary, there is no reason to exclude any type of formulation in a capsule dosage form. Working closely with the capsule supplier and using their expertise and capabilities throughout development and manufacturing is encouraged.

 What beneficial features can capsules offer over other dosage forms?

 The most important thing is that you first establish a comprehensive target product profile (TPP). This should also include the targeted patient profile and should take into account, that according to the International Council on Harmonization (ICH) Q8 guideline, ‘in all cases, the product should be designed to meet patients’ needs and the intended product performance’ (1). These TPPs will guide you in selecting the best dosage form for the specific product.

Looking at the actual industrial and regulatory trends, some particular capsule features are gaining importance. For example, 60% of new drug launches in 2019 by the FDA were designated in one or more expedited categories of fast track, breakthrough, priority review, and/or accelerated approval (2). The very tight timelines in development favor the use of simple, yet effective, capsule formulation development.

Increasing focus on a special population, such as pediatric or geriatric patients, require a higher number of different dose strengths, easy to swallow forms like sprinkles, and, to address the issue with increasing polypharmacy, the provision of fixed-dose-combination products. Without compromising on the release characteristics, multiparticulates (e.g., pellets, mini-tablets) manufactured at large scale, can be customized to serve any of these populations and needs by capsule filling. Different sizes, color combinations, and imprints will make these customized products unique. Or, take for example, inhalation drug therapy, where capsule-based dry-powder inhaler (DPI) products are the most cost-effective form, and can be manufactured on standard capsule filling equipment that is available around the world.

 Are there specific disadvantages of capsules over other dosage forms?

 As for any dosage form, there are advantages and disadvantages that need to be balanced against each other during the TPP process. Probably, the most significant disadvantage occurs when formulators are initially requested to develop a tablet formulation. When this dosage form is not feasible due to technical reasons, the formulators are then requested to push the formulation into a capsule. Even though it might work, the formulation is normally suboptimal for capsules, leading to a lot of issues along the commercial phase, which is then perceived as a general capsule dosage form problem.

Another disadvantage is that for a high dose formulation, the capsule size might become prohibitive. In my experience, patients generally do not want to accept larger, brick-like tablets and, as a result, tend to crush the tablets or capsules for administration. For cases where the largest (size #000) capsule might be required, why not instead consider employing a sprinkle formulation, which can be administered with soft food that the patient prefers?

 How can capsules aid in speeding up drug development timelines?

 More than 25 years ago, when I began my career in capsule science, there was a collaborative effort that led to the formation of group basics for capsule formulations (3), which are absolutely still valid today and have substantially evolved with new types of capsules and excipients. Not surprisingly, drug in a capsule alone, or a simple blend, is still the preferred approach for the first-in-human trials. The majority of these Phase I formulations are already achieving the desired performance and remain in capsules for the fast track or breakthrough therapies through to the market.

And to be a little bit provocative, we as pharmaceutical scientists prefer more challenging formulation programmes than applying a simple blending and encapsulation process. However, with the increasing cost pressure, it is inevitable that we will be increasingly questioned regarding the over-engineering of products in development.

 What are the advantages and disadvantages of soft gel versus hard gel capsules?

 This question suggests that I can use soft gel or hard gel for any type of formulation and that these dosage forms are interchangeable from a technical standpoint, which is not necessarily true. However, looking at the liquid-filled products on the market in soft and hard gels, we see very different portfolios. For example, soft gels are suited for hydrophilic liquids, but they are not suited for hot melt products. Hard capsules can also be filled with combinations of liquids and solids, like pellets, smaller capsules of tablets. Only oily formulations are suitable for both soft and hard gels.

With regard to the capsule polymer, pharmaceutical soft gels are still gelatin-based, while liquids and hot melts can be filled in a hard capsule made of gelatin or HPMC. Whereas, the shell composition of soft gels can be adapted to tailor the shell to certain formulations. When we consider all of this, we are talking about two distinct and complementary technologies and dosage forms, that can generally not be interchanged without reformulation.

 Are there any significant innovations in capsule formulations that you believe have impacted industry or will in the near future?

 Pharmaceutical sciences will continue to be one of the highly dynamic sciences. There are many innovative formulations and drug delivery technologies under investigation, and only clinical evidence and real-world data will give us the final answer.

One of the areas where we see substantial innovation right now is in the field of enhanced therapeutic entities, so-called 505(b)(2) or hybrid applications. Known drugs are being reformulated using advanced drug delivery technology to achieve a better ‘effectiveness’ (efficacy under real-world conditions) and drug safety, by reducing medication errors.

Many innovations are taking place in the field of capsule-based DPI. The delivery of high drug doses and large biomolecules, enabled by particle engineering (e.g., spray drying), provide new avenues to treat now life-threatening diseases, such as cystic fibrosis.

Looking toward microbiome research and the microbiota as the therapeutic entity, capsules will be the preferred choice and become a functional excipient, protecting the sensitive microbiota from moisture, as well as gastric juice, and releasing it at the defined site of the intestinal tract.

 Are there specific regulatory considerations surrounding capsule formulations?

 Capsules are well-known and, regulatory-wise, a well described and accepted dosage form. Nevertheless, regulatory science continues to drive towards more global quality standards, digitalization, and patient focus and centricity. If we just look to digitalization, we see global efforts to combat falsified or substandard medicines by tagging and tracing each box and, soon, each dosage form from the factory through to the patient. The increasing focus on patients and patient centricity stems from the patient’s growing awareness as one of the most important factors in achieving the therapeutic outcomes.

Starting with the geriatric population, the European Medicines Agency (EMA) has put forward another reflection paper on the pharmaceutical development of medicines for use in the older population (4), followed by an FDA initiative of patient-focused drug development (5). All these regulatory and industrial initiatives require much more trans- and multidisciplinary collaboration, including the pharmaceutical supply industry. The next generation of capsule products to serve these emerging regulatory and industrial requirements will definitively benefit from co-development, if not co-creation, in close partnership with capsule manufacturers.

 What impact has the COVID-19 pandemic had on capsule formulation, if any?

 As a result of SARS-CoV-2, the pharmaceutical industry will go through a complete rethink of the pharmaceutical supply chain and the relationship with suppliers over the next two to three years. The revival of more regional and flexible manufacturing, as well as further governmental cost pressure, will raise several questions on investments into efficient manufacturing infrastructure. This manufacturing adjustment will be another opportunity to consider capsules due to the simplicity and flexibility in capsule product manufacturing and other innovative approaches, such as continuous manufacturing.

ICH, Q8(R2) Pharmaceutical Development (August 2009).

FDA, “New Drug Therapy Approvals 2019,” 

S.M.H. Lai, “An Expert System for Development of Powder Filled Hard Gelatin Capsule Formulations,” Thesis submitted to the University of London, Faculty of Medicine (September 1996).

EMA, “Reflection Paper on the Pharmaceutical Development of Medicines for Use in the Older Population,” 

FDA, “CDER Patient-Focused Drug Development,” 


Vol. 44, No. 9
September 2020
Pages: 30–32

When referring to this article, please cite it as F. Thomas, “Capsule Innovations: Speeding Up Drug Development,” 

Tight development timelines and accelerated approval pathways favor simple, cost-effective capsule formulations.

Capsule Innovations: Speeding Up Drug Development

Lyophilization is a well-established technique within the bio/pharmaceutical industry and is a necessity for certain drug products that include unstable ingredients, require longer shelf-lives, or are temperature-sensitive. The lyophilized drug market is expected to grow at a compound annual rate of approximately 7%, according to market research, mainly driven by increasing regulatory approvals for lyophilized formulations (1).

“The primary benefit of lyophilization is improved product stability,” explains Andrew Morbey, associate director of process development, LSNE Contract Manufacturing. “This can manifest as additional shelf-life at frozen, refrigerated, or ambient storage conditions or as equivalent stability at an increased storage temperature. In many cases, this eliminates the need for cold chain shipping and storage, reducing risk during manufacturing.”

Stephan Reuter, managing director, Optima Pharma in Gladenbach-Mornshausen emphasizes that the greatest advantage of lyophilization is the stable formulation result, which subsequently impacts the success of a development program. “The development of drugs is a very costly and time-consuming process, and always runs the potential risk of not being successful,” he says. “Many substances would not be stable without freeze-drying technology, which creates a durable product and retains effectiveness.”

Additionally, as the formulation is filled as a liquid, there is compatibility with almost all filling lines and little variability occurs as a liquid formulation is amenable to maintaining proper fill weights, asserts Gregory Sacha, senior research scientist, Baxter BioPharma Solutions. “Sterility of the product can also be maintained and achieved,” he says. “The moving parts of the equipment, such as compressors, are located in an equipment maintenance area on the other side of the aseptic manufacturing area. This keeps the area clean and reduces introduction of foreign particles.”

A further advantage of lyophilization lies in the fact that the process requires low temperature and so is suitable for heat sensitive drug substances or those prone to degradation from hydrolysis, Morbey continues. “Other advantages include the ability to reconstitute to the desired concentration at the time of use and reducing shipping costs due to lower finished product weight compared to liquid products,” he notes.

A challenge for lyophilization is that not all molecules are stable as freeze-dried solids. “For example, some cephalosporins remain amorphous and are less stable than when in the crystalline form,” stresses Sacha.

For Morbey, a major disadvantage of freeze-drying is the development of appropriate formulations that are suitable for lyophilization. “Not all liquid formulations are suitable for lyophilization,” he confirms. “The appropriate buffers, cryoprotectants, bulking agents, and tonicity modifiers need to be carefully selected to provide both stability to the formulated drug substance and properties suitable for lyophilization.”

“Volatile compounds, such as acetate buffers, can be removed by high vacuum, which can result in changes of the final product pH,” notes Sacha. Additionally, he specifies that not all solutes can be dried to a form with an acceptable appearance. “For example, formulations prepared with high salt concentrations have low melting points and are difficult to freeze-dry,” he says.

Development of the lyophilization cycle can also be challenging, requiring extensive expertise, particularly for turnkey projects, highlights Reuter.

Each cycle is unique to the formulation and requires expertise to ensure product quality, agrees Morbey. “Most cycles are 24 to 96 hours; however, some products require conditions that extend the cycle length beyond 192 hours. A consistent challenge to lyophilization is the expertise required to develop a cycle appropriately to fit both equipment and product limitations,” he states. “Some lyophilization cycles are not suitable for commercial scale lyophilizers because there is little consideration for refrigeration capacity, system capabilities, or variation in equipment capabilities. Without the awareness of these challenges, there could be considerable impact to the product.”

Traditional technique but advancing process understanding

“There have been few changes to lyophilization equipment, but there have been large changes in understanding and conducting the lyophilization process,” remarks Sacha. “For example, process development was achieved by trial and error and, in some cases, it still is. However, today process development is often approached using the first principles of heat and mass transfer to understand the process.”

Understanding the process involves a thorough thermal characterization of the formulation so that the failure point during primary drying can be known, continues Sacha. Additionally, an understanding of the capability of the equipment, determining the heat transfer coefficient for the specific vial, and determining the resistance to mass transfer of the drying solid are required. “The data are used to develop a design space for primary drying that identifies the most efficient process conditions, as well as the conditions that may lead to failure of the product,” Sacha adds.

Morbey agrees that despite the lack of changes in the lyophilization process over the past 15 years at a commercial scale, the laboratory and academic settings have seen great advances in the understanding of each individual step of the process and the impact on product critical quality attributes (CQAs). “These advancements include controlled nucleation to improve the thermal treatment phase,” he says. “Understanding of container specific heat transfer coefficients, mass flow and heat flux, and implementation of process analytical technology (PAT) devices to aid in primary and secondary drying end point determination have supplemented the development of the drying phases of lyophilization.”

Significant advancement toward the automatic loading/unloading systems have been seen throughout the supporting manufacturing activities, Morbey continues. These advancements have limited the need for operator intervention and, hence, mitigated risks to sterility. And, isolator technology has also advanced, he adds.

“The development of freeze-drying technology is based on product development, since freeze-drying has a massive influence on the product. Therefore, innovations must be adapted to product development,” reveals Reuter. “This reasoning is why the general principle of freeze-drying has not changed in the last 30 to 40 years, but freeze-dryers have become faster and more effective. They are more accurately adjustable, and alternative, more environmentally friendly refrigerants are increasingly being used.”

It is possible to drastically reduce processing time by building a primary drying design space based on the first principles of heat and mass transfer, emphasizes Sacha. “Data obtained through this design space can also be used to support deviations in shelf temperature and chamber pressure that may occur during routine production,” he says. “The technique also demonstrates that the company has a good understanding of the equipment and how the formulation can affect processing conditions.”

“The simulation of processes during freeze-drying and their influence on each other can give a better understanding of the process itself,” adds Reuter. “The integration of the products’ properties in the simulation, which has to be freeze-dried, allows improvements in the process by predicting what the product quality attributes will be at the end of the freeze-drying. So, nowadays it is theoretically possible to define lyophilization process parameters with very high accuracy. If the freeze-drying parameters are defined correctly, the entire process achieves the best efficiency.”

However, verification and qualification of the process are still required, Reuter continues, which leads on to the instrumentation. “A number of new sensors are available now on the market to monitor and control the lyophilization process with very high accuracy,” he explains. “Through these sensors it is possible to save time and energy, and, hence, make the process more efficient.”

The majority of equipment advancements were created to aid in the development, optimization, and characterization of lyophilization cycles so that it would be possible to effectively transfer cycles to commercial‑scale equipment, emphasizes Morbey. “Most drug product manufacturers do not have the luxury of performing lyophilization cycle development activities on the intended commercial‑scale freeze-dryer. Therefore, a comprehensive understanding of the product’s characteristics and equipment is required to ensure product quality is maintained when scaling up to commercial‑scale production,” he says. “Product characterization using modulated differential scanning calorimetry and freeze-dry microscopy is now standard practice. New technologies are being developed to supplement these tests and better understand the product.”

Equipment process improvement for analytical technologies include tunable diode laser absorption spectrometry, heat flux measurements, end of primary drying determination, and in-line mass spectrometry, Morbey continues. “Implementation of these technologies during the development phase, in most instances, has increased the overall time, energy, and cost of development services. However, the benefit is realized through seamless transitions from development scale to production scale,” he notes. “Complete process and product understanding following quality-by-design principles takes time; however, a standardized approach for lyophilization cycle development together with experienced scientists capable of utilizing the available PAT devices can streamline the development process.”

An additional growth factor for lyophilization is the rising proportion of biologics in development pipelines. “The industry evolution toward biologics is making the need for lyophilization more prevalent,” confirms Morbey. “Many biologics are not stable in solution and, as such, need to be lyophilized.”

Morbey iterates that there are even some instances where lyophilized biologic drug products form aggregates on stability. In such cases, it is necessary to revisit the formulation and add surfactants or additional excipients so that the aggregation is inhibited. Formulation scientists should be able to build upon previous experiences to inform development activities prior to the issues arising, he notes.

“The high cost for biologic drug substance development and manufacture translates to smaller drug product batch sizes in order to reduce risk. For lyophilization development scientists, this enforces the importance of formulation and cycle development to ensure minimal product loss,” Morbey stresses. “Some high-volume parenteral manufacturers may be accepting of 90–95% yield from 200,000+ unit batches when producing 30 million units a year. For low volume, high-value lyophilized biologics every dose is important. Unnecessary manufacturing line loss and rejects caused by inadequate lyophilization practices are not acceptable.”

For Sacha, the increased need for lyophilization as a result of the rising proportion of biologics will be a long-term effect unless combinations of excipients are developed that can offer the same, or better, stability improvements as freeze-drying. “The challenge with freeze-drying biologics is that they can be sensitive to the stresses of freezing and drying” he says. “This issue requires study of the biologics’ sensitivity to interfacial interactions and loss of residual moisture to determine if certain protective agents are needed in the formulation.”

Turning the attention to highly potent compounds in general, Reuter notes that the processing of such pharmaceuticals puts special demands on the cleaning concept and construction of pharmaceutical plants so that safety of both the product and human life can be assured. “It is, therefore, important to develop a comprehensive and holistic process for the filling and processing of highly potent substances, including comprehensive pressure and wastewater concepts, for example,” he adds.

“Many of the highly potent molecules are both poorly soluble in aqueous solutions and unstable in solution. There have been a rising number of requests to lyophilize formulations that consist of 100% organic solvent or co-solvents,” Morbey says. “Lyophilization of organic solvent systems provides unique challenges to the development program and its equipment. The handling of the formulation and compatibilities of the material contact and equipment, need to be fully understood.”

Additionally, the development scientist must comprehend how to remove the organic solvents from the cake to residual levels without affecting other product quality attributes, asserts Morbey. “Hopefully, the trend towards higher value biologics and highly potent drugs translates to an increased understanding of the importance of the development activities. As quality-by-design approaches prove their worth, we expect this trend to continue well into the future.”

Despite the fact that not all vaccines need to be freeze-dried, there is an overall positive impact on the demand for lyophilization happening as a result of the current pandemic situation, highlights Reuter. “Freeze-drying is the best way to safely and quickly achieve a successful formulation and facilitates the transport of pharmaceuticals to warmer regions,” he says. “Whether this is a long-term trend, however, cannot be assessed at this point in time.”

“In the short term, product stability for the COVID-19 vaccines will not be an issue in developed countries with cold supply chain capabilities because doses will likely be administered rapidly after manufacture,” Morbey adds. “However, with the potential for additional waves of the virus and the unknown approval timeline, it will be critical to stockpile both vaccines and therapies in order to have product available to meet future demand. I am quite confident that many vaccines are currently being simultaneously developed as both a liquid and lyophilized dosage form.”

The same principle applies to proven anti-viral products, Morbey asserts. “If the liquid presentation is stable for 12 months but the lyophilized presentation is stable for four years, the current demand does not require more than 12 months of shelf-life,” he explains. “However, once the pandemic is under control, shelf life may become prohibitive for maintaining stockpiles to combat new outbreaks. For under-developed countries without cold supply chain capabilities, stable lyophilized vaccine and therapies are needed.”

Sacha remarks on the development of mRNA platforms, which are not necessarily very stable in solution at room temperature. “These platforms may require cold storage that creates challenges for effective distribution around the world,” he states. “There is a potential that lyophilization can simplify the supply chain for these vaccines and facilitate widespread, global vaccination efforts.”

A further impact of COVID-19 is in the form of manufacturing capacity, which is being exhausted, continues Morbey. “Government agencies have acted quickly to buy manufacturing capacity from large contract manufacturers to support mass production of vaccines,” he says. “With reduced liquid manufacturing capacity, drug developers can look to lyophilized presentations as a first step instead of a last resort.”

Two trends are particularly important in Morbey’s opinion to continue gaining traction within the industry—understanding the importance of product specific lyophilization cycle development, and standardization of lyophilization equipment capabilities, controls, and PAT. “Cycle development is critical to ensure product quality and is dependent on the formulation characteristics and freeze-dryer capabilities,” he notes. “Technologies exist to fully characterize and understand product characteristics and develop cycles appropriately. When cycles are implemented on out-dated equipment or poorly controlled equipment, all the development and optimization efforts can be thrown out the window.”

Increasing system complexity, efficiency, and flexibility is a primary trend for Reuter. “As a result, there is an impulse to implement new technologies in the lyophilization system, for example PAT tools—not only for process monitoring but moreover for process control, making the process parameters adjustable within an allowable range,” he says. “Through better process understanding it is possible to significantly reduce the freeze-drying process duration and in combination with highly flexible fill/finish systems, small batches with rapidly changing container types, formats and ingredients can be processed.”

Another trend highlighted by Sacha is a reduction in the size of the lyophilizer itself so that efficiency can be increased. “Smaller lyophilizers may be needed to accommodate smaller volumes of product,” he states. “Biologic formulations are typically processed in smaller volumes than for many small molecule formulations and the formulations are quite expensive. Operating with smaller equipment will reduce loss of material and may improve handling of the product.”

Replacing currently used refrigerants with more environmentally friendly ones is also a consideration of Reuter. “Furthermore, investigating and implementing alternative heat sources, such as infrared or microwave, may also improve system efficiency and make lyophilization more attractive,” he comments. “For some lyophilized products, continuous manufacturing can be beneficial and spray freeze-drying has a positive future for certain application fields.”

“Manufacturing of lyophilized dosage forms is a tried and true process for organizations with this expertise. Significant changes are not needed; however, continuous improvement of equipment controls, PAT devices, and implementation of process understanding at commercial scale will lead to improvements in lyophilization practices industry wide,” Morbey concludes. “With the right equipment, quality systems, and development expertise, the lyophilization process is a low-risk operation with significant benefits to the product.”

1. Coherent Market Insights, “Lyophilized Drugs Market Analysis,” 

Felicity Thomas is the European editor for 


Vol. 44, No. 9
September 2020
Pages: 44–49

When referring to this article, please cite it as F. Thomas, “Advancing Understanding of a Traditional Technique,” 

The general principle of lyophilization has hardly changed, but significant advances have occurred in process and product attribute understanding.

Advancing Understanding of a Traditional Technique

AstraZeneca has potentially taken the lead in the current COVID-19 vaccine development race, through robust Phase I/II trial results and numerous deals being struck for supply, as well as media hype over a possible ‘fast track’ status in the United States, albeit denied by the company. So, will AstraZeneca’s hope of being able to deliver AZD1222 before the end of 2020 actually come true?

The AZD1222 vaccine is currently in late-stage Phase II/III trials in the United Kingdom, Brazil, and South Africa. Interim results from the Phase I/II trial, led by Oxford University, were released in July 2020 and demonstrated a robust antibody and T-cell response in all participants (1).

“The interim Phase I/II data for our coronavirus vaccine shows that the vaccine did not lead to any unexpected reactions and had a similar safety profile to previous vaccines of this type,” said Professor Andrew Pollard, chief investigator of the Oxford Vaccine Trial at Oxford University and co-author of the trial, in a press release (1). Further results on the immunogenicity and efficacy of the vaccine are expected to be available between September and November 2020.

Since forming the partnership with the University of Oxford for the global development and distribution of the COVID-19 vaccine (2), AstraZeneca has established numerous agreements for the supply of the AZD1222 vaccine globally. For example, AstraZeneca and the European Commission recently concluded an agreement for the supply of up to 400 million doses (3), which adds to a prior arrangement the company had formed with the Inclusive Vaccines Alliance (4).

Additionally, supply and manufacturing agreements for AZD1222 have been set up with several partner companies, including Catalent and Cobra Biologics (5,6). AstraZeneca has been working on manufacturing the vaccine at scale to ensure broad and equitable access in the case of successful late-stage clinical trials and regulatory approval.

US President, Donald Trump, is also reportedly pushing to get AZD1222 fast tracked through approval, so that it will be available to the US population before November’s elections. However, according to a report by 

, who spoke with AstraZeneca on the matter, the company has not been in discussions over emergency use authorization within the US (7).

“It would be premature to speculate on that possibility,” the AstraZeneca spokesperson told 

 (7). “Late-stage Phase II/III trials for AZD1222 are ongoing in the UK and other markets globally, and we do not anticipate efficacy results until later this year.”

Irrespective of the rapid pace at which companies, such as AstraZeneca, have been developing prospective vaccines and treatments to tackle the current COVID-19 crisis, clinical data and ultimately a thorough regulatory review are required. So, in terms of AZD1222, there may well be sufficient data by the end of the year to suggest efficacy and safety, but the regulatory bodies will still need to issue approvals before it can be used.

, Professor Chris Whitty—England’s chief medical officer—has suggested that a vaccine may not be ready until winter in 2021 (8). Oftentimes, it is better to hope for the best, but prepare for the worst, and for vaccine development, sufficient data and regulatory review are critical requirements.

AstraZeneca, “COVID-19 Vaccine AZD1222 Showed Robust Immune Responses in All Participants in Phase I/II Trial,” Press Release, 20 July 2020.

AstraZeneca, “AstraZeneca and Oxford University Announce Landmark Agreement for COVID-19 Vaccine,” Press Release, 30 April 2020.

EC, “Coronavirus: Commission Reaches First Agreement on a Potential Vaccine,” Press Release, 14 Aug. 2020.

AstraZeneca, “AstraZeneca to Supply Europe with up to 400 Million Doses of Oxford University’s Vaccine at No Profit,” Press Release, 13 June 2020.

Catalent, “Catalent Signs Agreement with AstraZeneca to Expand Manufacturing Support for COVID-19 Vaccine AZD1222,” Press Release, 24 Aug. 2020.

Cobra Biologics, “Cobra Signs Supply Agreement with AstraZeneca for Manufacture of COVID-19 Vaccine Candidate,” Press Release, 16 June 2020.

Matt Mathers, “Trump ‘Considering Fast-Tracking UK’s Coronavirus Vaccine Before US Election’,” News Story, 

PA Media, “Whitty Says it Would be Foolish to Count on Having COVID Jab by Winter,” News Story, 

When referring to this article, please cite it as F. Thomas, “Leader of the Pack?” 

AstraZeneca has potentially taken poll position in the race to develop a novel coronavirus vaccine, but will AZD1222 be ready in 2020?