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

Felicity Thomas

Various factors have impacted the evolution of drug dosage forms over the years, including the growing complexity of compounds entering the development pipeline, an aging population, increased focus on niche therapeutic markets, and augmented awareness on patient-centricity. Although oral solid dosage forms remain the most popular option within the industry, due to the convenience, cost-effectiveness, and ease-of-use offered by this dosage form, innovative delivery approaches are required to accommodate the rising demand for more customized solutions.

	“Over the past 5–10 years, increased competition in the market, complexity of APIs, and focus on patient-centric products has led to increasing demand for custom drug delivery solutions,” confirms Andriy Kuzmov, drug delivery innovation fellow, science and technology, Catalent. “With increasing competition, it is important for new treatments to differentiate themselves from competitors by meeting the unique needs of the target patient population. This can be achieved by decreasing a patient’s pill burden, improving palatability, eliminating variability due to food effects, improving swallowability, or decreasing the frequency of administration.”

	One key trend affecting drug development has been the rise of biologics and, thus, the need to find novel ways to deliver such complex entities effectively, remarks Jeremy Drummond, senior vice-president, business development, MedPharm. “Biologics create new challenges in terms of packaging, analysis, delivery, and stability,” he says. Drawing on experiences with aptamers, Drummond adds that work has been done to demonstrate the ability of delivering biologics topically, despite the traditional issues with large molecular weight potentially impeding skin penetration (1). 

	As a result of the amplified level of interest in biopharmaceuticals, there has been increased attention by industry in the development of parenteral products, comments Torkel Gren, science and technology officer, Recipharm. “Another driver for the development trend of parenterals is the increasing interest in hospital care products,” he continues. “Finally, people are beginning to see that even though parenteral administration is less convenient than oral administration, it is not that difficult. For many more serious indications, injectable dosage forms are acceptable when looking at the balance between benefit and inconvenience. The development of convenient and reliable autoinjectors is of course contributing to this opinion.”

	In addition, Steve Rode, manager business development, capsules and health ingredients, Lonza, specifies that the growth of biologics as well as small molecules being delivered via alternative routes has been trending in the industry. “Innovation in larger molecules and biotech drugs has also meant increased focus in developing and delivering larger molecules such as proteins, peptides, and monoclonal antibodies orally,” he says. “So, the space is benefiting from both the sustained market focus on continuing to deliver small-molecule APIs orally while developers look to deliver high-value biologics via the same route. More recently, there has been an emergence of live biotherapeutics for which specific dosage forms are essential to ensuring stability and targeted delivery.” 

	The use of more high potency compounds has led to the requirement for low-dose drug products to be developed, which has impacted both formulation development and manufacturing strategies for the targeted dosage form, explains Richard Shook, director, Drug Product Technical Services and Business Integration, Cambrex. “Formulators must utilize a holistic approach to development by integrating the appropriate excipients and ensuring that the final dosage form is stable and uniform in dosing,” he states. “During process development the manufacturing strategy must be robust while balancing efficiency and cost effectiveness.” 

	Harder-to-formulate and manufacture compounds are further permeating the development pipeline, requiring new formulation and/or delivery strategies to ensure that the desired therapeutic effects are achieved, asserts Lonnie Barish, vice-president, business development and marketing, Bora Pharmaceuticals. “The demand for expertise on how to overcome challenges, such as low solubility, low permeability, or short half-life, has soared, and drug developers are increasingly seeking solutions from technical experts, such as contract development and manufacturing organizations (CDMOs), to commercialize these APIs,” he says.

	In concurrence, Paul Kippax, pharmaceutical sector director, Malvern Panalytical, highlights that the move toward delivery of increasingly insoluble APIs has led to the need for evermore complex formulations and processes, even for ‘simple’ oral solid dose products. “Techniques such as API micronization or nano-milling are applied to improve the solubility of APIs,” he says. “Additionally, companies are looking to use amorphous APIs; these are inherently less stable but show higher solubility. As a result of these requirements, there has been a significant increase in the physicochemical characterization tools required to confirm the microstructure and stability of the API within a formulation.”

	According to Rob Lee, president, CDMO division, Lubrizol Life Science Health, the biggest trends impacting drug dosage forms have been the rise in long-acting injectables, implants, and the use of water-insoluble molecules. “Water-insoluble compounds have always been around, but with new drug development technologies, we are better able to formulate them instead of discarding them like formulators used to a few decades ago,” he confirms. “This means that more formulation-challenged compounds stand a greater chance of making it to market and being utilized in breakthrough treatments.”

	“The last few years have seen an increase in the demand for advanced dosage forms, such as controlled-release products, multiparticulates, orally disintegrating tablets, intranasal dosage forms, or new fixed-dose combinations,” adds Kuzmov. “The new dosage forms address key challenges for patients by improving adherence, ensuring proper administration of the dose, or improving the quality of life for the patient.”

	For Manuel Leal, business development director, Idifarma, the biggest trend in drug dosage forms has been the development of hybrid drugs, involving the re-purposing of existing molecules into new indications or dosage forms. “These drugs take advantage of the hybrid regulatory pathways enabled by FDA-505(b)(2)-and the European Medicines Agency (EMA)-10(3),” he explains. “This trend uses innovative technologies to achieve the required dosage form, and can be very beneficial to certain groups of patients (pediatric and geriatric), and can also help sustain healthcare systems.”

	Other areas of change for drug developers is the expansion of the orphan drug market, which is anticipated to be twice that of the overall prescription drug market by 2024 (2), due in part to the implementation of FDA’s orphan drug modernization plan. “Personalized medicine principles are being applied ito tailor treatments to individual patients or to their subpopulation to minimize side effects and to achieve the best possible therapeutic effect,” notes Barish. “Genetic profiling and epigenetics, the study of heritable phenotype changes, are providing insights into different patient populations and the pharmacokinetic and pharmacodynamic effects of various drugs. With these understandings, it is hoped that doctors can be more selective in their choice of pharmaceutical products for their patients, taking into consideration their efficacy in certain subsets of the population.”

	“Development pipelines are moving away from blockbuster drugs with one-size-fits all dosage forms into more personalized medicines,” agrees Frederique Bordes-Picard, manager business development for innovative products, Capsules and Health Ingredients, Lonza. “More targeted actives are the focus in areas like oncology, thus addressing more specific and smaller patient populations.”

	Furthermore, increased regulatory scrutiny has amplified the industry’s efforts into risk-based approaches and increased the need for integration of quality-by-design methodology during drug development, stresses Shook. “To apply this methodology appropriately, a clearer determination of the critical quality attributes of a dosage form and what factors impact those attributes is needed,” he adds.

	“To help meet the demand for complex drug delivery solutions, manufacturers have been investing in the infrastructure and capacity to successfully produce, at scale, the novel dosage forms that are required by next generation treatments,” says Kuzmov. “Along with capital investments, manufacturers need to ensure they have the right personnel and expertise within their network to handle a variety of development projects.”

	There has been continuous improvement of existing development approaches over the years, asserts Gren, with devices offering an excellent example of advancements. “Inhalation devices have been around for decades; however, new devices are much easier to use. The same is true for injection devices,” he notes. “Many technologies for modified release, such as coated pellets, were also developed decades ago but are now easier to use as we have more experience in how to apply them.” 

	Bordes-Picard adds that there has also been the wider use of personal devices, such as mobile phones and wearables, to improve treatment management and support patient compliance in a number of therapeutic areas. “There’s also been greater exploration of nasal, pulmonary, and transdermal routes as alternatives to injection and oral dose innovation as manufacturers look to develop increasingly patient-centric doses,” she states.

	Excipient development has also impacted formulation approaches, with novel excipients and innovative technologies aiding formulation scientists in the development of better injectable dosage forms for insoluble compounds, confirms Lee. “Innovations in excipient development have had a significant impact on low-dose drug products,” adds Shook. “Formulators can identify critical material attributes of the drug substance and work with manufacturers to ensure that excipient specifications align with those attributes.”  

	Additionally, functional excipients have been made available that improve stability and solubility of biopharmaceutical compounds or that enable targeted delivery, which has removed some of the potential barriers to oral bioavailability, reveals Rode. “To improve the opportunities and potential for drug candidates with low solubility or bioavailability, we’ve seen increased utilization of techniques such as spray dried dispersions,” he continues. “There’s also been a greater adoption of equipment that more accurately fills neat API into capsules allowing developers to speed up first-in-human clinical studies.”

	According to Leal, innovative technologies, such as spray drying, have been instrumental for the development and repurposing of many drugs with solubility problems. “Spray drying is one of the most suitable technologies to improve the solubility, and hence the bioavailability of low soluble compounds,” he says. “Solving this complex problem opens a wide range of potential applications and innovations.”

	For Barish, the use of extrusion spheronization offers even and predictable distribution and transportation of API in the gastrointestinal tract. “Because of its simple and fast processing and its ability for high drug loading capacity, this manufacturing technology is gaining more attention,” he asserts. “It is incredibly versatile so that pellets composed of different drugs can be blended and formulated together to deliver two or more APIs to the same or different sites in GI tract in a single capsule.”  Additionally, the technique can improve the safety and efficiency of the API and help increase the APIs bioavailability by controlling or modifying the release characteristics.  The technique has been widely utilized to formulate sustained and controlled release delivery systems as well. 

	“One key innovation over the past 10 years has been the growing acceptance by regulators of 

physicochemical analysis methods for assessing bioavailability and/or bioequivalence,” says Kippax. “Application of these methods provides a possible means of avoiding complicated clinical studies to show equivalence for complex dosage forms. This has been a significant enabler for the development of complex drug products by generic companies.”

	Further to opportunities within the field of generics, the 

 approaches can offer development opportunities for novel drug products, Kippax continues. Combining physicochemical analysis with the application of new modeling approaches and digital design tools, it is possible to predict the drug product properties that will be required to achieve bioavailability. “This can be an enabler in the selection of the most appropriate dosage form, and in ensuring the development of a robust processing route,” Kippax says.

	Particularly focusing on locally acting products, Drummond adds that major advances have been seen in the use of 

 models that are based on fresh human tissue, which can optimize the activity of drug formulations. “These models are now used not only to measure permeation but also monitor the activity of formulations and de-risk the decision to enter clinical trials through the use of fresh human tissue,” he notes.

	As access to healthcare increases, so too will demand for all kinds of therapeutics, exclaims Barish. “There is already a greater demand for the treatment of more novel and niche diseases, prompting even more development of new modalities, techniques, materials, and excipients to ensure the safety, efficacy, and stability of future challenging drug substances,” he says. 

	Patient-centricity and the increasingly complex nature of molecules in the development pipeline are drivers for demand in advanced dosage forms and formulation techniques, confirms Kuzmov. “The trend of patient-centric dosage forms will continue in the development of parenteral formulations as well through the development of long-acting injectable products or the use of devices to simplify injection procedures for patients,” he notes. “At the same time, researchers will continue the push to develop non-invasive methods for the delivery of biologics and other treatments that are not readily absorbed after oral administration.”

	The growth in biologics is a big driver for Lee. “With more biologics on the market, the preferred delivery routes for those could reshape the status quo. There is already more interest in long-acting injectables for biologic compounds, and this is expected to continue,” he says. However, oral dosage forms will continue to grow in the marketplace, although there may be further exploration into alternative delivery routes, such as nasal, facilitated by regulatory pathways like FDA’s 505(b)(2), Lee adds. 

	Having the ability to dose active molecules with precision while minimizing adverse systemic impact on patient is an important future trend according to Shook. “The further development of modified-release dosage forms will enable the delivery of active molecules to a specific site of treatment,” he says. “This will ensure that the therapy is introduced and actively initiated at right time and place to disrupt the disease with precision and minimal impact to the patient.”

	Personalized medicines are anticipated to drive change in how companies approach dosage forms. “In my opinion, it is likely that the industry will continue to move away from a high volume, one-dosage-form-fits-all approach towards smaller, fully customized dosage forms,” reveals Bordes-Picard.

	This drive toward precision medicines for smaller patient populations could have many implications, adds Gren. “Three-dimensional printing is a technology that may allow a very high degree of individual adaption of the medicine. However, a number of issues regarding quality assurance and cost may limit the use of 3D printing over the next 10 years,” he continues. “Instead, adapting conventional manufacturing technology, making it more flexible and allowing smaller batches may be very useful.”

	Changes in how companies select candidate drugs will be prominent for Kippax, who believes that companies will seek to select drugs that reduce risks associated with scale-up and manufacture. “The paradigm is shifting from the development of specific processes designed to create a single drug product, towards the application of standardized continuous-manufacturing approaches. Selection of candidate APIs and formulations will therefore increasingly be based on their fit with these processes,” he explains.

	Furthermore, Kippax highlights the fact that additive manufacturing approaches are being employed in the design of new dosage forms. “These are exciting developments, perhaps providing a means of delivering truly personalized dosage forms, created to simplify the dosing regimens required to meet a patient’s needs,” he says. “Achieving this will require greater understanding of the link between API and formulation physical properties and the requirements for safe, effective drug delivery.”

	“An important trend in the future is undoubtedly going to be the combination of dosage form delivery with technology, whether that be for monitoring the patient or in aiding the delivery,” summarizes Drummond. “It is an exciting time in the drug development industry, and the COVID-19 pandemic has focused the attention on the value that innovation can bring to patients, as well as the value governments and populations place on health and wellbeing.” 

, 138 (2) 282–290 (2018).
	2. Evaluate Pharma, “Orphan Drug Report 2019,” 


	Vol. 44, No. 7
	July 2020
	Pages: 16–20, 33

	When referring to this article, please cite it as F. Thomas, “Demand for Custom Dosage Forms Fuels Innovation,” 

Articles

Demand for custom drug delivery solutions is increasing and bringing forth an exciting period of valuable, innovative development opportunities.

Demand for Custom Dosage Forms Fuels Innovation

Numerous industries around the world have been significantly impacted by the current global COVID-19 pandemic and have been required to adapt in order to ensure continued commercial success. The bio/pharma sector is an industry that has probably been most affected by the pandemic, not only is there an expectation for bio/pharma companies to step up and develop appropriate treatments quickly, resulting in regulatory flexibility and unprecedented collaborations, but there have also been concerns around supply chain security.

	Focusing on how regulatory authorities have reacted to the COVID-19 pandemic within the bio/pharma sector and the potential ramification of actions taken in a crisis situation for the long-term, Pharmaceutical Technology Europe sat down with a roundtable of experts to get an in-depth view of current regulatory enforcement trends. These experts include Gabriela Marton, regulatory affairs director at Arriello; Remco Munnik, associate director at Iperion; Darren Mansell, regulatory affairs manager, Owen Mumford Pharmaceutical Services; and Denis Gross, vice-president delivery at ProductLife Group.

 In light of the current climate (COVID-19 pandemic), what changes have regulatory authorities been making to accommodate for industry disruption and/or to accelerate any potential treatment development?

 Regulatory authorities around the world started adapting to the COVID-19 pandemic and adjusting ways of working by primarily changing submission conditions. For example, many authorities, which usually require physical submission of documents or parts of documents, have now made submission available by electronic means. It is hoped that these solutions (electronic submission) will be continued in the future.

	Additionally, adapted rules on handling clinical studies and product approvals have been published. Most authorities have adopted a flexible approach regarding product registration; clinical trial rapid review, advice, or management; audits; extending deadlines where needed; readability user tests; and so on. All of the changes being made by regulatory authorities could accelerate solution development for a COVID-19 treatment or help reduce the risk of the infection spreading.

 In the current pandemic situation, industry is facing a reality that most people are working remotely or from home. Regulators, on the European level, did share information that systems are running; however, it is also believed that the current situation demonstrates the need for more transparency within industry. How can real-life information about the availability of medicines be provided? In case one country faces problems with medicines (or medical devices), how can the industry and regulators track products that are registered on a European level and those that are available for supply from another country? The same could apply on an even smaller scale, with information of availability between regions and/or hospitals. The current process of checking availability of medicines involves the appointment of a single contact to collect information by sending out spreadsheets, which need to be filtered and completed (1).  

	With regards to potential treatments, a large number of activities are ongoing to stimulate the development of vaccines and treatments. For pharmacovigilance purposes, at the level of adverse event reporting, new terms for COVID-19 were added to the MedDRA [Medical Dictionary for Regulatory Activities] (2).

 There has been discussion by regulatory authorities on the fast-tracking of particular products that could be used to diagnose or treat the COVID-19 virus. In addition to accelerated pathways, regulatory authorities have been accepting scans of documents instead of ‘original’ paper documents where notarization and legalization services are currently unavailable. 

	However, there have been negative impacts too, where regulatory authorities are either currently short-staffed or prioritizing emergency products, meaning non-emergency products are currently ‘de-prioritized’.

 Regulators in the United States and the European Union, as well as other major authorities, have been focused on streamlining clinical research for potential medical solutions against COVID-19 by prioritizing resources on these activities. Agencies have prioritized protocol consultations, shortened the timelines for clinical trial application review and approvals, and there is some focus on implementing fast-track and priority review processes for the evaluation of marketing authorization applications.

 Have the approaches been vastly different around the world (Europe versus US versus rest of the world)? Or is there general harmonization?

 Members of the European Medicines Agency (EMA) have written a paper asking for a worldwide coalition to concentrate the efforts on the set up of adequate clinical trials to treat COVID-19. They have listed seven points for consideration to achieve streamlined efforts, which, broadly speaking, call for cooperation between all stakeholders-agencies, the research community, ethics committees, the development of infrastructure to support clinical trials, and efforts by patient organizations to encourage clinical trial coordination.

 Authorities that have more experience in evaluation of data adapted quickly, while other authorities, such as those in the Commonwealth of Independent States area, stopped all activities for a period of time or adapted along the way. The Medicines and Healthcare products Regulatory Agency (MHRA) and EMA are good examples, and they were immediately followed by other EU authorities. 

	The challenge was perhaps greater for authorities in the eastern EU where they needed to adopt reduced contact rules and make it possible for marketing authorization holders (MAH) to approach authorities by virtual means. 

	The US Food and Drug Administration (FDA) started signalling what was happening in the world before the pandemic reached the US and coming up with changes and solutions slightly more openly than EU authorities, but overall, more experienced authorities around the world [have been] harmonized in their approach to the pandemic situation.

 How might the approaches being taken at the moment (whether different or more harmonized) impact regulation of the global pharma industry in the future?

	Mansell (Owen Mumford): There has been discussion of more ‘fast track’ options for devices that need rapid movement to market in the future. There could also be more allowance for electronic regulatory dossiers rather than the old-fashioned paper copies containing legalized documents, as a result of the acceptance of digital documents during the COVID-19 pandemic.

 It is my opinion that the current situation should be used as an opportunity to prepare for the future. As a network, both industry and regulators need to have current information on which products are registered and available on a global level. This requirement is true for products that are new developments (new treatments), and those that are already existing medicines, which are critical in treatment and/or new clinical trials to test medicines for new indications.

 At the moment, as the pandemic is not yet over, it is hoped that some changes will be maintained in the future, but it’s hard to predict if most of the measures will be maintained or if the industry will encourage authorities to maintain some of the new measures and embrace the changes.

	From the perspective of a regulatory affairs and quality professional, I would say that some of the rules, relaxations, or changes in communication adopted during this period are welcome and have accelerated processes. In some cases, especially those related to products proven to have a clinical effect on the virus or on associated symptoms of the virus, it was demonstrated that collaboration between professionals and authorities can be very effective.

	Whereas, I recognize that the pharma industry needs to remain very strictly regulated and legislation needs to fit the times that we live in when the necessity is to have safe, high quality, and efficacious medical products on the market.

	In conclusion, I’m hoping that both regulatory authorities and the industry will learn from this pandemic. 

 There is already some cooperation between the US and Europe, especially in the regulatory development process and in the evaluation process, so it’s possible the current situation could reinforce those efforts and lead to some further joint assessments for clinical trial protocols and marketing authorization reviews. However, there are many issues that would have to be overcome, including the regulatory burden, competition between agencies and countries, as well as economic and political considerations.

 Are there any potential legal ramifications that could arise from the current regulatory approaches?

 There is likely to be a push to relocate manufacturing of certain strategic products-such as vaccines, active substances, and finished products, in addition to medical equipment-to Europe, rather than China and India where most manufacturing currently takes place. There may also be a crackdown on investigator-initiated trials and more control over the design of clinical trials to avoid resource shortages, although this could be difficult to enforce.

 If the question implies potential new legislation being introduced in areas not regulated until now, I would say probably not, but I think that changes resulting from COVID-19 will enrich current legislation in the EU or US. I believe that the pandemic has made both authorities and industry players see that it is possible to speed up some processes by slightly changing the approach, as in the case of clinical trials, and that access to medicine can be improved.

 I would assume that on regional level, more guidance will be made available with regards to working in pandemic situations, which included better tracking on availability and shortages of medicinal products.

 Have any existing regulations been affected by the pandemic?

 The EU’s Medical Device Regulation (MDR) has been delayed by 12 months to May 2021, as a direct result of the COVID-19 pandemic (3).

	Gross (ProductLife): The most obvious one is the MDR, which has been delayed by a year due to the impact of the pandemic. Beyond that, the fact that agency staff can’t work together will have an impact on the development of new guidance documents.

 Many rules set by regulators have been affected by the pandemic because of contact restrictions and because treating COVID-19 infected people was every government’s priority. Setting regulations was affected, as legal work started before the pandemic was postponed. Instead the focus is on adopting measurements to help the population and industry during the COVID-19 pandemic. Probably, during this month, the issues that were raised before the pandemic happened will start to once again become the topic of discussion. 

 Do you believe EMA (and other regulatory authorities) will reassess their approach to ‘health crises’ as a result of lessons learned from COVID-19?

 The COVID-19 pandemic has definitely been a lesson of sorts. How much will be learned remains to be seen, as measures that were introduced in a period of change need to be endorsed by both authorities and industry.

	There is no doubt that crisis management, as well as business continuity planning, will be different as a result of the pandemic, and both authorities and industry will have to consider these changes. Plans to support continuity for employees working from home or from adapted working places will trigger the need for change. 

	Furthermore, there has been an immediate response needed in light of COVID-19, with regards to supply, advice, and approval. Everyone-government, authorities, and industry-must be better prepared to take action in the instance of a future crisis.  

 Undoubtedly regulatory authorities should be learning lessons from the current pandemic! There should be efforts made to ensure the latest regulatory status on new clinical trials, as well as existing products and their availability, is available. I do hope that everyone realises the importance of having one (preferably) global set of regulatory data that can be used in crisis situations. 

	It is currently unknown as to how long the impact of COVID-19 will last. In my opinion, it is better to start assessing regulatory approaches to pandemic and crisis situations as soon as possible to make systems future proof.

 It is certainly the hope that lessons will be learned, but success will require harmonization between countries, which is a political issue, and extends beyond the oversight of health products. It is possible regulatory harmonization could start with alignment on certain activities, for example, France and Germany are collaborating on a proposal for a recovery fund for regions and sectors hardest hit by the pandemic, but this still requires agreement from other European countries. 

	One challenge that could undermine clinical research into COVID-19 vaccines and therapies particularly is the proliferation of isolated, poorly controlled clinical trials that create a strain on patient resources. To combat this issue there is a need for greater coordination across agencies, as well as private and public stakeholders, to concentrate their efforts on setting up conclusive, well-designed clinical trials to avoid these patient shortages.

	1. EMA, “Update on EU Actions to Support Availability of Medicines During COVID-19 Pandemic,” 

, Press Release, 10 April 2020.
	2. MedDRA, “MedDRA Version 23.0 Update to be Produced,” 

, Press Release, 10 April 2020.
	3. European Parliament, “Parliament Decides to Postpone New Requirements for Medical Devices,” 


	Vol. 32, No. 7
	July 2020
	Pages: 24–26

	When referring to this article, please cite it as F. Thomas, “Learning Regulatory Lessons in Times of a Crisis,” 

There is much to learn from the COVID-19 pandemic, but future success may hinge upon the capacity for regulatory bodies to harmonize approaches.

Learning Regulatory Lessons in Times of a Crisis

Controlled-release formulations have been around since 1952, after the first introduction by Smith Kline Beecham (1), and have seen continued growth and expansion thanks to technological advancements. According to market research, the controlled-release drug delivery market is anticipated to grow at a compound annual rate of nearly 8% between 2020–2027 (2). A drive in R&D to improve therapeutic efficiency for a variety of chronic diseases and the acknowledged improvements in medication adherence that can be gained through controlled-release formulations are key aspects to market growth in the field. 

	“A distinction of controlled-release, compared with other modified-release formulations, is that it not only prolongs action of the drug but it attempts to maintain drug levels within the therapeutic window to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency,” notes Ali Rajabi-Siahboomi, vice-president and chief scientific officer, Colorcon. “So, controlled release is generally understood to mean where the drug delivery technology delivers the drug at a predetermined rate; other modified release technologies may not have a specific rate defined.”

	There are a multitude of formulation concepts that may be used in order to control drug release and duration, and dependent on the API and its action in the body, tailored solutions are required to gain innovative drug products, explains Thorsten Cech, manager European Pharma Application Lab, BASF Pharma Solutions. “Application concepts range from topical patches to injections, which form subcutaneous pockets (depots) lasting for several hours, or even days. Furthermore, there are implants, which provide application windows of several years, although this is a very specific dosage form requiring trained medical staff for application,” he says. “Drug products that can be applied by the patients themselves are typically found in the field of oral solid dosage forms, meaning they are either delivered as tablet or capsule. Rarely seen are liquid formulations, as this concept is quite demanding and not suitable for many APIs.” 

	There are two main concepts in the formulation of controlled or sustained-release oral solid dosage forms: matrix systems and reservoir systems, specifies Krizia M. Karry, global technical marketing manager, BASF Pharma Solutions. “In matrix systems, the drug is embedded in an insoluble, sometimes swellable excipient core, containing the actual matrix-former and additional components for tailoring the drug release rate. Drug release is either initiated by swelling or erosion of the core and diffusion of the API through the matrix,” she says. “These systems are most straightforward in terms of their formulation and manufacturing.” 

	Rajabi-Siahboomi suggests that the most commonly used oral solid-dosage controlled-release technology, out of all oral solid dosage types, is hydrophilic matrices, due to the fact that tablets are easy to develop and produce, while also being versatile for a broad range of solubility and dosage strengths. “With matrix tablets, high viscosity hydrophilic polymers such as hypromellose are used as the rate-controlling polymer,” he explains. “Multiparticulate systems are also versatile for achieving different release profiles and dosage design, suitable for capsule forms. Non-ionic, water insoluble ethylcellulose is also commonly used in achieving extended-release formulations, usually multiparticulates for capsule formulation.”

	The other formulation concept, reservoir systems, are represented by coated dosage forms, Karry continues. “Hereby, insoluble or soluble core substrates (e.g., pellets, mini tablets) are film coated with insoluble polymers to obtain a sustained-release functionality,” she states. “Independent of the substrate’s formulation, drug release results from permeation of dissolved API from within the core through the membrane.” 

	“In the field of immediate-release dosage forms, general formulation concepts can be applied to a variety of different drugs. API features, such as solubility kinetics, pH-value, particle size distribution, osmolarity, dose, and many more, merely provide minor challenges during the development,” emphasizes Cech. “In contrast, the understanding of all these characteristics is essential when aiming for controlled drug release. In this case, every drug requires a customized formulation concept to address its unique features.”

	The advantages gained through controlled-release dosage forms, such as convenience of dosing, better therapeutic management of conditions, and lower side effects, can override the potential challenges associated with development and manufacture, asserts Rajabi-Siahboomi. Each approach offers its own set of advantages and challenges, he states; hydrophilic matrices, for example, are the simplest technology to use for controlled-release formulations but in cases of high-dose and high-solubility ingredients can result in an oversized tablet or a fast, initial “burst” release profile, respectively.

	“Matrix excipients that ensure a controlled drug release independent of pH, have a lower ratio of soluble to insoluble pore formers, and have binder properties for strong tablet compacts are highly sought for,” notes Karry. “Matrix systems are advantageous because they employ direct compression processes-the least complex of all platforms-and can be easily scaled-up, transferred, and validated. There is the disadvantage, however, that some amounts of API will be present on the surface of the tablet. These quantities are immediately dissolved after administration.”

	Reservoir systems, which are primarily attained via film coating processes, also offer simplicity for developers, but the coating process is less forgiving than direct compression, continues Karry. “An imperfect tablet coating can lead to fast water uptake and uncontrolled API diffusion out of the defective film,” she says. “Even if the coating process is flawless, elastic recovery of the tablets post-compression or during stability can crack the polymer film and render the system inadequate.” 

	As a disadvantage, reservoir systems can produce a lag phase before the API can be dissolved, which is caused by the fact that the dissolution media needs to permeate the coat to dissolve the drug so that it can diffuse out, Cech adds. “Polymers that can readily meet the latter conditions or require lower concentrations of additional components to reach them are preferred,” he says.

	Cech emphasizes the decisive role process parameters can play in the manufacture of controlled-release dosage forms. “Variations in the compression force during tableting or an alteration of product temperature during coating can result in a distinctive change of the dissolution pattern,” he notes. “When conducting the risk analysis as part of the quality-by-design (QbD) process, the list of potentially critical material attributes and process parameters appears to be endless.”  

	“Furthermore, it’s not only about the reliable manufacturing of a controlled-release dosage form, where each individual tablet provides exactly the same dissolution pattern; the dissolution is also not allowed to change during shelf-life, even if the dosage form is stored at elevated temperature and humidity,” Cech asserts.

	“The advantages of barrier membrane-coated multiparticulate extended-release systems may be related to the flexibility of achieving different release profiles and co-formulating more than one drug or release profile into one dosage formulation,” Rajabi-Siahboomi notes. “The challenge for this technology is fine-tuning drug release and maintaining stable performance over the shelf-life of the product.” 

	However, Rajabi-Siahboomi also stresses the need for consideration of specific critical formulation and processing parameters during development and manufacture of extended-release multiparticulates. “In general, the choice and level of polymer, plasticizer, and pore-former, for example, all impact drug release performance,” he says. “Additionally, coating process conditions, such as spray settings, air humidity, and post-coating processing also affect drug release performance.”

	The use of multiparticulate systems rather than single-dose systems was clearly a milestone in the field of controlled-release dosage forms. “Even though the idea is much older than a decade, there is hardly any other formulation concept that provided so many advantages,” Cech says.

	Listing the advantages gained through the use of multiparticulate systems, Cech begins by highlighting the inherent risk of dose dumping that may occur with tablets coated with a sustained-release polymer. “Dose dumping may occur either because of a defect in the coat or because the patient decided to break the tablet before administration,” he comments. “If the dose is split among hundreds of pellets (e.g., filled in a capsule or compressed to a tablet), defects of a small number of single compartments bear no safety risk.”

	Further to the safety benefits, particles below a threshold of approximately 2–3 mm behave as fluids in the stomach, which eliminates the potential effects of diet and food during drug absorption as the particles are able to freely move to the intestine, Cech confirms. “Additionally, developers are not obliged to develop one product that precisely matches the dissolution profile required,” he says. “Combinations of pellets coated with different coating formulations are often seen in these multiparticulate systems. The different dissolution patterns sum up to the required one, if the pellets are mixed in the right ratio.” An added advantage of using a combination of pellets is that if there is a variation in one coating batch, there is only a minor impact on the overall dissolution pattern. Conversely, if there is a variation in coating of a product based on one pellet formulation, the products are instantly out of specification, Cech stresses.

	“Finally, multiple pellet formulations enable oral delivery of combination therapies without the interaction risk, and they reduce first-pass effects for acid-sensitive drugs,” Karry adds. “The formulations can either be swallowed or suspended in water to release the API-loaded pellets. The pellet nucleus can be a placebo bead coated with API and a suitable controlled-release polymer.”

	Although many of the technologies available for controlled-release formulations have been around for a long time, such as matrix tablets and multiparticulate formulations, there have been line extensions and reformulations made to expand the potential applications of the technologies that are enabling developers to achieve different release profiles or formulate challenging drugs, continues Rajabi-Siahboomi. “A good example is the application of a barrier membrane coating to a hydrophilic matrix,” he notes. “By adding this top-coat, formulators have been able to overcome the so-called initial burst release for highly soluble drugs, which is important to maintaining controlled release.”

	Push-pull osmotic pump (PPOP) technology is very robust in providing a zero-order release profile, which is critical for certain drugs with a narrow therapeutic index or those with undesirable side effects related to blood plasma C

, Rajabi-Siahboomi asserts. “The manufacturing technology is multi-step; hence, experience and access to expertise in the different unit operations is very important,” he says. 

	“Furthermore, the use of extended-release technologies for fixed-dose combinations (FDC) has allowed a significant number of new drug applications to be made under the 505(b)2 scheme with the US Food and Drug Administration,” Rajabi-Siahboomi says. “Some of these may be a combination of extended and immediate release in the same dosage form, like bi-layer tablets, or a mix of barrier membrane-coated multiparticulates that are loaded into a capsule. The FDC technology improves patient experience by reducing the pill burden (taking one dose rather than two or more) and enables synergistic treatment of a condition with a single dosage formulation.”

	As is the case with all pharmaceutical products, materials used in the development of controlled-release dosage forms must be safe and ideally have precedence of oral use, asserts Rajabi-Siahboomi. “Regulators look for data to support stability, safety, and efficacy of the dosage form. It’s important that formulators select raw materials from suppliers with high quality standards and who fully understand the science and nuances of rate-controlling polymers to ensure consistency of the materials,” he says.

	Rajabi-Siahboomi adds, “QbD can help to determine if there is any batch-to-batch variability of ingredients and how to manage these during manufacture at commercial scale. Demonstrating stability for any product is a key requirement (i.e., keeping the identity, purity, and performance of the drug and dosage unit consistent over the assigned shelf-life of the product). In addition, formulators must clearly demonstrate safety when drugs are administered orally as the drug load of many of these formulations are higher than their immediate-release dosage forms.”

	“Especially in the field of controlled drug release, QbD-based formulation development can be quite demanding,” continues Karry. “Various process parameters and material attributes do not only have an impact on the resulting drug release, but also provide interactions pronouncing their effect.”

	By way of example, Cech highlights that the film formation during coating is a thermodynamic process. “Consistently, the integrity of the coat depends on the product temperature during the process and process humidity,” he says. “Varying one of these parameters already has some impact on the dissolution, yet varying both at the same time has a major impact on the drug release kinetics.”

	Concurrently, regulatory hurdles can be met when targeting specific patient populations, Karry explains. “Pediatrics and geriatrics are quite challenging to address,” she says. “It is more difficult to conduct clinical studies, and the age-specific metabolism provides additional challenges.”

	A demonstration of stability for any product is also a key requirement, emphasizes Rajabi-Siahboomi. “In addition, formulators must clearly demonstrate safety when the drug is administered orally, because the drug load of many of these controlled-release formulations are higher than their immediate-release dosages,” he states. “There should not be any ‘dose-dumping’ due to exposure of the dosage form to gastrointestinal tract content, so fed and fasted studies need to be conducted, in addition to studies assessing the effect of alcohol.”

	New technologies, such as three-dimensional (3D) printing, are gaining interest throughout industry. “The interest in 3D printing is because of potentially personalized medicine, but it also offers opportunities in the field of controlled-release dosage forms,” Karry highlights. “By employing 3D printing, rather complex tablet designs are possible. Concepts carrying several compartments with very specific drug-release features have already been tested successfully. Both technology and formulation concepts are still quite young in the pharmaceutical field, and we need to see in which direction we are proceeding. However, new opportunities support innovation that could lead to a paradigm shift.”

	“In addition, there are various efforts in personalized medications leveraging new technologies or less frequent dosing, such as once a week therapy, which enhances patient adherence even further than current once-a-day formulation,” Rajabi-Siahboomi summarizes. Furthermore, he emphasizes the R&D work to achieve oral delivery of large-molecule drugs, which also has the potential to cause a paradigm shift in targeted and controlled-release formulations. 

	1. P.I. Lee and J.X. Li, “Evolution of Oral Controlled Release Dosage Forms,” In 

Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice

, H. Wen and K. Park (John Wiley & Sons, Hoboken, NJ, 23 August 2010) pp. 21–31.
	2. Grand View Research, “Controlled Release Drug Delivery Market Size, Share, and Trends Analysis Report by Technology (Micro Encapsulation, Targeted Delivery), by Release Mechanism, by Application, by Region, and Segment Forecasts, 2020–2027,” 


	Vol. 44, No. 7
	July 2020
	Pages: 26–29

	When referring to this article, please cite it as F. Thomas, “Taking a Controlled Approach,” 

Controlled-release formulations offer numerous advantages for developers and patients, and this market is expected to continue to experience growth in the near future.

Taking a Controlled Approach

	It is well known that vaccine development is usually a costly, complex, and lengthy procedure, with estimates of it lasting between 10 to 15 years (1). Yet, in the current pandemic situation, the speed at which developers have responded and managed to achieve in-human testing has been touted as ‘unprecedented’ (2).

	When developing a vaccine under normal circumstances (i.e., not in a pandemic situation), there are linear steps that developers tend to follow, which include multiple pauses in order to assess data or check on manufacturing processes (3). However, in a pandemic the timeline is shortened, with faster starts and steps being performed simultaneously without prior confirmation of success, which increases the potential financial risk (3).

	At the time of writing, there are 16 candidate vaccines in clinical evaluation, and 125 candidate vaccines in preclinical evaluation for COVID-19 (4). The first to begin Phase III studies, AZD1222-developed by Oxford University and being progressed in partnership with AstraZeneca-already involves 10,000 enrolled participants in the United Kingdom, and trials of the vaccine have also commenced in South Africa (5,6). 

	AZD1222, formerly known as ChAdOx1 nCoV-19, is a non-replicating viral vector vaccine, which essentially works by tricking the human body into thinking it has the virus, triggering the immune response. Oxford had been previously working on a similar style vaccine to prevent Middle East respiratory syndrome, aiding the speed at which the researchers were able to develop a vaccine targeting the virus that causes COVIDâ19. However, the timeline for AZD1222’s development is still very impressive, a fact that is reinforced by the support from a multitude of European countries for the project (7). 

	Other in-human trials are also underway, including Imperial College London’s new self-amplifying RNA vaccine (8). Imperial’s approach represents the first time such technology-self-amplifying RNA-has been tested in humans, and the college’s researchers claim it has the potential to revolutionize vaccine development (8). 

	Vaccine development requires significant funding, which is generally attained both through public and private organizations. In Europe, the European Commission has raised €9.8 billion in the Global Coronavirus Response pledging campaign that will be used to accelerate vaccines and other technologies to combat COVID-19 (9). 

	The UK’s government has committed £84 million (€92 million) in new funding for coronavirus vaccine research (10), and in the United States, ‘Operation Warp Speed’ has been initiated, which is aimed at delivering 300 million doses of a safe and effective COVID-19 vaccine by January 2021 (11).

	With the financial support of various vaccine programmes, it is no surprise that an impact is being seen on the stock market. Companies, including Novavax and Moderna (12), that are in the COVID-19 vaccine ‘race’ have seen impressive stock price increases, mainly related to innovative techniques leading to accelerated development timescales and positive news stories on trial outcomes.

	Although previous disease outbreaks have seen the bio/pharma industry take on huge responsibilities in vaccine development, never before have the efforts been so rapid and so promising. Will the COVID-19 pandemic usher in a new approach to vaccine development? Only time will tell, but there is certainly a reinvigoration of vaccines happening and, as discussed in last month’s editorial (13), public opinion of industry is on the up, which is an added boost.

	Stay alert, stay safe, and stay healthy.

	1. The History of Vaccines, “Vaccine Development, Testing, and Regulation,” 

, Educational Resource, 17 Jan. 2018.
	2. CNBC, “Coronavirus Vaccine is Being Developed at ‘Unprecedented’ Speed, Says Expert,” Interview, 6 April 2020.
	3. N. Lurie, et al., 

, 382 1969–1973 (2020). 
	4. WHO, “Draft Landscape of COVID-19 Candidate Vaccines,” 

 [accessed 24 June 2020].
	5. Oxford University, “Oxford COVID-19 Vaccine to Begin Phase II/III Human Trials,” 

, Press Release, 22 May 2020.
	6. Oxford University, “Trial of Oxford COVID-19 Vaccine in South Africa Begins,” 

, Press Release, 23 June 2020.
	7. AstraZeneca, “AstraZeneca to Supply Europe with Up to 400 Million Doses of Oxford University’s Vaccine at No Profit,” Press Release, 13 June 2020.
	8. Imperial College London, “First Volunteer Receives Imperial COVID-19 Vaccine,” 

, Press Release, 23 June 2020.
	9. EC, “Coronavirus: Commission Unveils EU Vaccines Strategy,” 

, Press Release, 17 June 2020.
	10. UK Government, “Funding and Manufacturing Boost for UK Vaccine Programme,” 

, Press Release, 17 May 2020.
	11. HHS, “Fact Sheet: Explaining Operation Warp Speed,” 

, Press Release, 16 June 2020.
	12. V. Ferreira, “These are the COVID-19 Vaccine and Treatment Plays that are Making Investors a Fortune,” 

, News Release, 9 June 2020.
	13. F. Thomas, “A Little More Respect,” 

	When referring to this article, please cite it as F. Thomas, “Unprecedented Times in Vaccines,” 

COVID-19 vaccines are being developed rapidly, giving rise to a reinvigoration of the sector.

Unprecedented Times in Vaccines

Brexit was formally finalized on 31 January 2020, indicating the departure of the United Kingdom from the European Union. The UK and EU are currently in the transition period of Brexit, set to end on 31 December 2020, during which time negotiations on the future relationship should be taking place.

	However, Brexit talks have stalled, mainly as a result of the COVID-19 pandemic that has swept the world and is still a major cause of disruption for many industries, including the bio/pharma industry. In a recent news story from 

 (1), it was revealed that the UK’s prime minister, Boris Johnson, and the European Commission’s president, Ursula von der Leyen, have agreed to intensify negotiations, so that an outcome, whether that be a deal or no-deal, may be achieved by the end of the 2020.

	During the negotiations, many issues will be discussed, with perhaps the most pertinent to the bio/pharma industry including reduced friction trade, mutual recognition of certificates of good manufacturing practice (GMP), clinical trial cooperation, and access to talent-requiring certain allowances for immigrants. To learn more about how post-Brexit changes to immigration may impact the bio/pharma industry and whether there are any practical tips on how companies might be able to prepare for 1 January 2021, Pharmaceutical Technology Europe spoke with Tom Brett Young, partner, VWV law firm, and Peter Gough, vice-president, Pharmaceutical Services, EMEA, NSF Health Sciences.

 How might changes to the immigration system impact the bio/pharma industry, both in the UK and Europe, post-Brexit?

 The biggest change will undoubtedly be the additional layers of complexity that bio/pharma businesses will need to navigate when employing workers from the other side of the Brexit divide.

	Under free movement rules, European Economic Area (EEA) nationals working in the UK and UK nationals working in the EEA must be treated in the same way as citizens of that country (2). From 1 January 2021 the free movement rules will change.

	In the UK, EEA nationals will need to hold an appropriate immigration status that enables them to work in the UK. EEA nationals, resident in the UK before 1 January 2021, will be able to apply under the EU Settlement Scheme (3), but those arriving in the UK from that date will need to apply for status that permits them to work. Most people coming to the UK for work will need an employer to sponsor their visa application, although this will only be possible where the role is skilled to level 3 or above on the UK’s Regulated Qualifications Framework (approximately A-Level) (4). This won’t be so much of an issue for EEA nationals coming to fill research, development, technical, and managerial roles in the sector, but for roles which are classified as lower skilled there are likely to be few if any options. UK nationals who want to work in an EEA country will need to satisfy the immigration requirements of that particular country in the same way that someone from outside of the EEA currently does.

	In addition to the administrative hurdles employers and EEA nationals will need to overcome, sponsorship and visa applications come at a cost, with fees for UK immigration applications and employer sponsorship running into thousands of pounds.

	Another issue will be that business trips by EEA nationals coming to the UK and UK nationals travelling to EEA countries will be governed by the respective immigration rules for visitors. In the UK, this means that some business activities that would have been possible for EEA nationals under free movement rules-such as filling a short-term vacancy and direct selling to the public-will now be prohibited. UK nationals travelling to Schengen zone countries will need to ensure that they adhere to the equivalent visitor rules, including the requirement that they do not spend more than 90 days within a 180-day period in the Schengen zone (5).

 Are there any practical tips and/or advice on how companies, both in the UK and Europe, can best prepare for a smooth transition on 1 January 2021?

 I regret to say that at this time we simply do not know what the position will be for medicines moving between the UK and the EU from 1 January 2021, which makes giving specific advice virtually impossible. The trade negotiations between the UK and the EU are on-going and everything depends on the outcome of these talks. Reports are that the sides are still pretty far apart in their positions, so it is hard to know what, if anything, is going to be agreed. The position of Northern Ireland is one of the more contentious issues (i.e., is there going to be virtual border down the North Sea or not?) (6).

	The UK government has said that they will not extend the transition period beyond the end of this year so there must remain the possibility of the UK making a no-deal exit. On the other extreme, harmony could breakout and the UK could secure a comprehensive agreement with the EU, but this does not appear to be likely given the present state of the talks.

	In the event of there being no trade deal at the end of 2020, the EU has consistently stated that the UK would be treated as any other third country and all of the existing legal provisions that pertain to third countries will apply to medicines being imported from the UK (7).

	The UK position on no-deal, as detailed in guidance issued through 2018/2019 (8) was more pragmatic in that it continued to accept testing and qualified person (QP) certification on medicines imported from the EU but would require companies to obtain separate UK marketing authorizations for medicines that were centrally authorized by the EU. This UK guidance was withdrawn after the political deal was concluded and the UK formally left the EU at the end of January 2020. One imagines that the same guidance could simply be re-issued at the end of 2020 in the event of no agreed trade deal. Alternatively, the UK could adopt a ‘tit-for-tat’ approach and mirror the restrictions imposed on medicinal products exported from the UK to the EU. However, this seems unlikely in the short term as it would risk there being shortages of medicines in the UK that the government would not want.

	The other issue we face is that of the ability to physically move goods between the UK and the EU from 1 January 2021. Additional customs checks at the border seem to be inevitable and the risk that ports, like Dover, will simply grind to a halt is still real. 

	Most companies made detailed provisions for coping with a no-deal exit from the EU in time for the original exit date at the end of March 2019 (e.g., re-routing supply chains, moving the holder of EU marketing authorizations, making arrangements for testing and QP certification of medicinal products to locations within the remaining 27 EU countries).

	So, the best advice that I can give companies is to review the contingency plans that they made for the original 29 March 2019 deadline, which have yet to be implemented, to ensure they remain current and ready to be acted upon, if necessary, later this year. For example, the Medicine and Healthcare products Regulatory Agency’s no-deal Brexit guidance introduced a new good distribution practice responsible person for imports (RPi) role (9), so UK distributers need to ensure that they have a suitable person identified for this role should it be needed. As I have said throughout this protracted process; plan for the worst and hope for the best.

	1. Andrew Woodcock, “UK and EU Agree to Intensify Trade Talks as Prospect of No-Deal Brexit Looms,” 

Directive 2004/38/EC of the European Parliament and of the Council

 (Brussels, 29 April 2004).
	3. UK Government, “Apply to the EU Settlement Scheme (Settled and PreâSettled Status),” 

, Guidance [accessed online 22 June 2020].
	4. UK Government, “The UK’s PointsâBased Immigration System: Policy Statement,” 

, Policy Paper, 19 Feb. 2020.
	5. EC, “Visa Free Travel After Brexit: Council and European Parliament Reach Agreement,” 

, Press Release, 3 April 2019.
	6. UK Government, “The UK’s Approach to the Northern Ireland Protocol,” 

Withdrawal of the United Kingdom and EU Rules for Medicinal Products for Human Use and Veterinary Medicinal Products

 (Brussels, 13 March 2020). 
	8. MHRA, “Further Guidance Note on the Regulation of Medicines, Medical Devices, and Clinical Trials if There’s No Brexit Deal,” 

, Guidance, 3 Jan. 2019.
	9. MHRA, “Acting as a Responsible Person (Import) After Brexit,” 

, Guidance, 9 Oct. 2019 (withdrawn 13 March 2020).


	Vol. 32, No. 7
	July 2020
	Pages: 33–34

	When referring to this article, please cite it as F. Thomas, “No Business, Like Brexit Business,” 

As Brexit talks intensify, bio/pharma companies from both the UK and EU need to consider and aim to prepare for all scenarios.

No Business, Like Brexit Business

Stability testing of medicines is a vital component of bringing a drug to market. While there are universal standards and guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), each drug product requires a bespoke program-particularly as new chemical entities (NCEs) are becoming increasingly complex. 

Contract development and manufacturing organizations (CDMOs) have an important role to play in drug product testing. Not only can CDMO partners provide expertise capabilities and capacity to perform the potentially numerous tests required for product commercialization, but an end-to-end partner can offer accelerated assessment programs to help predict long-term stability and planning for late-stage programs. To discuss the significance and best practices of stability testing, as well as the key role of an outsourcing partner, 

spoke with Zhen Liu, executive director of analytical services at WuXi STA.

How important is stability testing during the various drug development steps?

Stability testing, as a mandatory requirement for the filing of investigational new drug (IND) applications and new drug applications (NDA), is naturally a critical component of any drug development program. Tests are required throughout all phases of development from the preclinical stage to post-product launch. (

Early stage testing focuses on the stability of the drug molecules. For example, the initial stages can use studies with severe conditions to get an initial idea of degradation products (impurities) that need to be monitored in subsequent studies. Initial studies can also provide data to help develop the formulation, packaging, and storage conditions required at late phases.  

List of tests required at each phase of development. 

(Table is courtesy of Zhen Liu, executive director of analytical services at WuXi STA.)

Can you explain stability testing for drug product versus drug substance?

In the case of drug product, the use of stability testing determines the re-test date of the clinical trial materials and shelf-life of the commercial product. The finished drug product requires multiple tests to verify its safety and efficacy. A variety of different techniques are used to establish the stability of each drug product based on its dosage form. These can span from simple techniques such as appearance, disintegration, and pH determination to more complex testing requiring chromatography coupled with mass spectrometry.

For example, in the case of oral solid drugs, appearance, assay, degradants, dissolution properties, water content, and microbial testing are usually performed. Whereas for injectable products, additional tests are required for pH, insoluble particulate matter, and sterility.

Unlike drug products (which are dependent upon formulation, the dosage form etc.), the tests for drug substances are relatively standard-including appearance, assay, impurities, water, and physical characterizations.  

What are the regulatory expectations for stability testing?

Globally, the regulatory standards are quite similar as most authorities are using the ICH guidelines, which provides in-depth recommendations for stability testing (1). The ICH pharmaceutical stability guidelines have been implemented by many regulatory agencies such as the US Food and Drug Administration, the European Medicines Agency (EMA), and the Chinese National Medical Products Administration (NMPA). Additionally, recommendations about different testing protocols per climate condition are also in place, with countries grouped into different climatic zones to best determine the type of testing needed. 

There are some slight differences in the ICH guidelines for small and large molecules. Although both follow ICH Q1 guidelines, biologics also follow an additional guideline for stability testing-ICH Q5C. This additional ‘layer’ includes information on the properties of biologics, storage conditions, and testing frequencies. 

Which approach to stability testing is considered the best?

As previously mentioned, stability testing programs are well defined and there are standardized protocols to follow according to the ICH requirements. But several factors may shape the program, including the properties, dosage form, and packaging of the product. 

The importance of capability and capacity of a CDMO partner to deliver drug substance and product testing should never be underestimated, considering the increasing complexity of compounds in development.