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

Felicity Thomas

Method development is a critical and continuous process that, if optimized, ensures successful progression of a drug product through its life cycle to commercialization. “Method development consists of three main stages: feasibility—where you determine if the method will work with your sample; development—where you optimize the method; and validation—where the optimized method is validated to the relevant regulatory requirements,” explains Vincent Thibon, technical development lead, RSSL. “Developing a robust method will ensure that routine testing occurs smoothly and limits the amount of testing required.”

“First of all, it is crucial to collect as much background information as possible on the API to understand its characteristics or what development challenges it poses,” says Anders Mörtberg, analytical chemist at Recipharm. “It is also important to check the established literature for analytical methods for compounds with similar profiles.”

In addition to gathering all the relevant data, it is important to define the objective of the method development, asserts Amanda Curson, head of Analytical Development, Tredegar, PCI Pharma Services. “At the beginning, an analytical target profile should be prepared that clearly outlines the requirements of the method, so that all involved understand and know what needs to be achieved with developing that method,” she notes. “The timelines, costs, and client expectations must be defined.”

Curson highlights that some useful questions to ask during these initial phases are as follows: What is the objective? Do you want the method to be suitable for drug substance (DS) initially, but maybe potentially further down the line for drug product (DP)? What is the basic chemistry of the DS? Is there any information on degradation products? Is there any information on chemical, solubility, molecular structure, stability?

For more information on outsourcing method development, read '

Developing a Method for Success through Partnerships

June 2021 issue of Pharmaceutical Technology.

Then after searching pharmacopeial methods for any existing information that can be used for the method development project, the phase of the development of the product, which impacts the amount of work required, should be assessed. Defining the phase of development early on is important, Curson emphasizes.

“In order to develop an accurate, reproducible, and reliable method, there must be an understanding of the final purpose of the method. This purpose should be the driving principle behind the research and development stages,” adds Emma Leishman, manager, Advanced Analytics, Avomeen.

However, Leishman notes that there are some starting considerations for any method development, regardless of the final purpose. “First, there is consideration of the analyte itself, as this can determine suitable instrumentation. Some analytes are inherently more difficult. Platform methods or templates may exist for the analyte or close structural analogues, or it might be that a method needs to be developed from scratch using published literature as a starting point,” she says. “Analytes might also be unknowns belonging to broader categories of chemicals, which require a different approach compared to a targeted method for a known compound.”

The next stage is about minimizing the complexity of the methods to ensure they are user-friendly for routine use, Curson continues. “[A method] will be used by different analysts and may be transferred between different labs,” she says. “When it comes to sample preparation and standardization, you want to ensure you can extract the API, which has a pharmacological effect when it gets into the body, from the sample matrix.”

Analyte matrix considerations can highlight some of the hurdles that need to be overcome, adds Leishman. “More challenging matrixes, like oral syrups or topical formulations, may require some creative sample preparation techniques for partial purification, such as solid-phase extraction, liquid-liquid extraction, and centrifugal filters,” she emphasizes. “Some instrumentation is more prone to matrix effects than other techniques, but standard addition curves can be useful for quantitation when matrix effects are present.”

“Developers need to select an appropriate solvent system for dissolving the sample and they should also choose a suitable separation mode, such as reversed phase chromatography or hydrophilic interaction chromatography (HILIC),” states Mörtberg. “A detection principle should also be chosen—for example, for [ultraviolet] UV or visible light, an appropriate detection wavelength should be selected. UV detection is preferred if the analytes contain a UV chromophore due to the widespread availability of UV detectors in [quality control] QC laboratories.”

Sample preparation is also an essential part of method development, Mörtberg continues. “Early on in the development process, suitable sample preparation conditions ensuring quantitative recovery of the analytes should be tested,” he says. “Sample preparation should provide reproducible and homogeneous sample solutions that are compatible with the mobile phase system. Sample preparation techniques are dependent on the nature of the drug product (solid, semi-solid, liquid etc).”

Finally, the specificity and sensitivity of the method should be considered, continues Leishman. “The analyte may be a primary component of the matrix, or it might be an impurity present at trace levels. Instrumentation and sample preparation approaches may change if trace level sensitivity is required,” she reveals. “Regulatory guidelines and a knowledge of toxicology are especially important for impurity methods, as these often dictate the permissible limits. Given the trend for increasingly tight regulatory limits, such as for nitrosamines, then it might be prudent to develop a method with sensitivity beyond the minimum requirements in case regulatory authorities decide to lower limits in the future and to fully understand the risk to the consumer.”

“With optimization, you want to make sure your initial method is compatible with the sample matrix,” confirms Curson. “To meet the industry standard, we subject the product to harsh, acidic or basic conditions, oxidation, temperature, and heat so that we are forcing degradation products to be produced, the method must be capable of showing the degradation products and that they do not interfere with the active product potency.”

Once all the relevant screening of the mobile and stationary phases are completed, which should include the samples from forced degradation, further optimization of the chromatographic system should be performed to determine the most appropriate column temperature, as well as optimal solvent gradient or solvent composition, adds Mörtberg. “To streamline the experimentation phase, a design of experiment setup or a method-development-aiding computer program is highly useful. If planned and documented correctly, the data can be used for a later robustness test included in any later method validation,” he says.

“Prior to formal validation of the analytical test procedure, pre-validation experiments using final method conditions should be conducted,” Mörtberg continues. “This will provide an assessment whether the method is ‘validatable’ and a basis for setting relevant acceptance limits for the validation characteristics.”

Ultimately, the method must be transferable between scientists and equipment, irrespective of any potential slight changes in method conditions that may arise, emphasizes Curson. A transferable method is a robust one that will be applicable for future development requirements.

“Without solid analytical methods, it is impossible to make evidence-based conclusions on the safety and efficacy of a product or process,” concludes Leishman. “Strong analytical methodology provides clarity and focus to any scientific endeavor. Costly delays may arise when methods fail during routine analysis, which can be avoided by devoting more resources and thought into the development stages.”

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Articles

Thought and foresight into method development stages can ensure costly errors and delays are avoided later on.

Outlining the Key Steps to Method Development

Particle engineering plays a vital role in optimizing a drug’s effectiveness. The size of a particle will have an effect on the delivery of a drug, the route of administration—particularly in cases where an inhaled formulation is being developed—and will impact the rate at which a drug is metabolized in the body.

“In formulation and development, both active and excipient particles can be engineered to tailor the performance/efficacy of the drug product,” confirms Jamie Clayton, operations director, Freeman Technology (a Micromeritics company). “A relatively simple example would be controlling the particle size of an active to influence dissolution rate and by extension bioavailability.”

Additionally, particle size, along with other properties, influences bulk powder properties, Clayton continues. “Therefore, particle engineering is equally important for achieving desirable bulk powder properties, properties associated with the consistent manufacture of a drug product of acceptable quality, for example, a tablet with the required hardness,” he says.

“With drug particles or particle assemblies being the crucial component of solid dosage forms, which represent the vast majority of all medicines, it has become clear that ‘drug particles are of the essence’ when designing quality, safe, and efficacious medicines,” agrees Peter York, chief scientist at CrystecPharma.

Critical attributes, such as a drug’s solid state, particle size, and morphology, all impact a drug’s bioavailability, remarks João Henriques, group leader—Drug Product Development, Hovione. As a vast proportion of the development pipeline is now incorporating compounds with low aqueous solubility and permeability, addressing bioavailability is forming a significant part of development approaches.

“Particle engineering plays a pivotal role in addressing bioavailability issues,” says Henriques. “By modulating the solid state, particle size, or morphology, one can increase both the solubility and dissolution rate of a drug. The former is generally required when dealing with solubility-limited compounds and can be achieved by particle engineering techniques, such as spray drying and nano-milling.”

Furthermore, for downstream operations, particle engineering will dictate the processability of a drug, adds Henriques. “Even in the absence of bioavailability challenges, particle engineering can be used to mitigate processing problems, from avoiding segregation to improving flow and compactability,” he reveals. “Particle engineering is therefore an essential tool for formulators to enable successful pharmaceutical development programs of challenging drugs.”

“The importance of particle engineering and particle size analysis take on an even stronger role in the development of therapeutics with more novel routes of delivery, such as inhalation,” York notes. “Here, the particle properties not only dictate the pharmacokinetic performance of the drug, but also the amount of drug that reaches the targeted site of administration.”

A major challenge with particle engineering is access to the information needed to guide the process, Clayton explains. “The goal is to determine robust correlations between manipulable particle properties, process variables, and critical quality attributes of the drug product,” he adds. “Bulk powder properties are often vital in elucidating such correlations, but with a wide range of analytical techniques to choose from, it can be difficult to identify those of most value.”

Recently published collaborative studies have demonstrated the drive for industry to refine analytical strategies (1–3), Clayton continues. “These [studies] focus on the potential of material property databases to accelerate the identification of critical material attributes, support process optimization, and improve supply chain management. Such work is equally helpful for those learning how to efficiently gather information to support particle engineering,” he confirms.

“A particle engineering technology should ideally be built upon an understanding of the mechanical, physical, and/or chemical events taking place during particle formation,” adds York. “For drug substances, the requirements of good manufacturing practice (GMP) and regulatory specifications must be embedded into the engineering and operation of the process.”

Traditionally, particle size reduction methods are approached in a ‘top-down’ way, so, reducing the size of larger crystalline drug particles uses high-energy impact mills, York explains. “This method continues to be widely used as a ‘first approach’ in solving the dissolution challenge; however, the high energy applied, and uncontrolled fracture and breakage of particles frequently imparts negative features to the milled drug particles such as changes in the solid state and causing highly charged, static particles, which are difficult to process downstream,” he says. “These factors, as well as the need for particle engineering tools that address not only the issue of low drug dissolution, but also potential physicochemical and biopharmaceutical challenges, have provided the basis for innovation in drug particle engineering and new concepts and approaches in drug particle design and delivery.”

To ensure the desired characteristics have been achieved through particle engineering, it is necessary to employ analytical tools, highlights York. “Whilst particle size and size distributions are a key property to be measured, the wide range of effects of particle size reduction methods on drug substance structural chemistry necessitates additional analytics to determine whether the process has led to any detrimental changes in solid state, physicochemical properties and, in the case of biotechnology substances, the biochemical and potency characteristics,” he states.

Other common challenges encountered with particle engineering and size analysis are related to process scale-up, asserts Mafalda Paiva, group leader—Analytical Development, Hovione. “Particle size methods are product and size specific, and method development should be performed with lead process candidates,” she says. “A change in process scale is often accompanied by an increase in size that can translate to challenges in measuring the desirable primary particles. Attention is required when analyzing this data, for instance, employing an orthogonal technique such as scanning electron microscopy (SEM) to ensure the employed method is still fit for purpose.”

Further challenges can arise with particle engineering as a result of solid-state changes, emphasizes Paiva. “The use of particle engineering can often lead to changes in the solid form,” she reveals. “These [changes] may be as simple as residual amorphization upon high energy milling operations and the emergence of different polymorphs after spray drying.”

The hurdles associated with new drug candidates are numerous and varied, particularly when accommodating different routes of delivery, York continues. “By far the major current challenge is the low aqueous solubility of drugs, which constrains the dissolution and thereby subsequent bioabsorption of drug particles when administered to patients,” he notes. “Incorporating micron sized drug particles in the medicine provides a high surface area and drives up the rate of solution of the drug, which in some cases is sufficient to provide an efficacious product.”

Henriques concurs that low aqueous solubility of new chemical entities represents the most common challenge facing formulators that requires the use of particle engineering. “The increasing number of BCS [biopharmaceutical classification system] class II compounds means that the interest and demand for such technologies is also increasing,” he says.

BCS class IV actives, which have both low solubility and low permeability, represent one of the toughest formulation challenges, remarks Clayton. “Gastroretentive (GR) oral solid dosage forms can be the answer, with floating, sustained release tablets the most common approach,” he adds. “Engineering such tablets is a complex task and calls for an array of analytical insight, with particle morphology, blend flowability, and porosity information all of proven value (4).”

Another trend of note, highlights York, is the increasing prevalence of biotherapeutics entering the development pipeline. These compounds are typically more sensitive to high energy processing techniques that are used in conventional particle engineering, he explains.

“Emerging technologies enable particle engineering to be conducted in low temperature and chemically benign environments, providing opportunities to engineer particles of biological substances with high levels of retained biological activity and targeted particle properties to enable specific target product profiles to be achieved,” York stresses.

There are many established particle engineering techniques that are being used for commercial supply of API programs, Henriques specifies. Techniques such as spray drying, hot-melt extrusion, and co-precipitation are commonly encountered, but there are also new methodologies emerging within academic and industrial initiatives, he comments.

“One [such technique] is the use of mesoporous silica for the impregnation of APIs,” says Henriques. “[This technique is providing formulators with the opportunity to overcome] some of the limitations of amorphous solid dispersions and is providing opportunities for the formulation of challenging compounds.”

A lot of interest over the past 20 years has been given to alternative approaches to ‘top down’ particle formation technologies, such as hot-melt extrusion and nano-milling, emphasizes York. “However, the converse strategy of ‘bottom-up’ particle formation techniques has proved a particularly fruitful area for particle engineering. In this approach, a solution of drug substance is subjected to a drying or solvent extraction process to yield drug particles, ideally in a single step operation,” he notes. “Manipulation of targeted particle characteristics, such as particle size, by means of varying process conditions delivers the ambition of particle engineering.”

An example of an innovative approach that is finding success in terms of drug particle engineering includes supercritical fluid (SCF) based technologies, which are available through specialist service providers, such as CrystecPharma, York states. “In supercritical anti-solvent (SAS) configurations, where the supercritical fluid (typically carbon dioxide due to its low critical point) acts as a powerful antisolvent, the solvent from a feed of drug solution is rapidly extracted in a pressure vessel, and dry drug particles precipitate almost instantaneously,” he notes. “The versatility of this technology is impressive in terms of excellent intra- and inter-batch reproducibility, as well as the ability to ‘tune’ the characteristics of the engineered drug particles, for example size, solid state and surface properties. Also, the low processing temperatures possible using supercritical carbon dioxide enable particles of delicate biotech drugs, from peptides to monoclonal antibodies, to be produced.”

Additionally, SCF is being used for wider process and formulation simplification, beyond ‘pure’ drug particle engineering, York continues. “Composite dry particles containing a second drug and/or functional additives can readily be manufactured in a single step—a feature termed in-particle design. Here, solution feed lines containing drug and/or excipients, in addition to the primary drug solution, feed into the pressure vessel to form dry composite particles upon contact with the SCF,” he explains. “Each particle contains a final composition equivalent to that of the sum of the solutes in the feed solutions. The scope and options provided by this feature are vast, and excipient inclusions can be diverse with tunable composition ratios. Added excipients could, for example, be for aiding drug stability, dissolution, absorption, or for modulating drug release profiles.”

The quantification of particle morphology—both particle size and shape—provides more in-depth information than just measuring size alone, a fact that is highlighted when developing a GR tablet, asserts Clayton. “Flowability data adds value here because the agents used to impart buoyancy tend to compromise flow properties,” he says. “Dynamic flow properties measured with a powder rheometer were helpful in identifying optimal formulations. This application also highlights the value of mercury porosimetry, which provides detailed information about pore size, pore size distributions, pore volume, and other metrics, thereby elucidating buoyancy behavior (4).”

“In modern pharmaceutical product development, particle engineering has moved beyond the simple concept of particle size control. Innovative technologies and approaches to particle design and engineering allow molecules to meet their full therapeutic potential, while streamlining development processes, simplifying formulations, and building novelty into products,” York concludes. “In addition to providing opportunities for enhanced intellectual property, cost of goods savings and added process efficiencies, a thoughtful approach to particle engineering can enable the development of therapeutics that better serve the needs of patients and healthcare providers.”

., 549 (1–2) 415–435 (2018).
2. M.S. Escotet-Espinoza, et al., 

., 339, 659–676 (November 2018).
3. F. Tahir, et al., 

., 364, 1025–1038 (March 2020).
4. T.T. Nguyen, et al., 

When referring to this article, please cite it as F. Thomas, “Moving Beyond Particle Size Control,” 

Particle engineering is a vital tool in overcoming many formulation challenges, and technological advances are enabling developers to achieve the full potential of pipeline molecules.

Moving Beyond Particle Size Control

The market for outsourced pharmaceutical and biotechnology services is expected to experience healthy growth and is forecast to reach $91.4 billion by 2028 (1). Factors influencing this market swell include rising pressure on drug prices, increasing drug development costs, higher rates of failure, regulatory hurdles, and deficient internal capabilities of sponsor companies, all leading to an increased demand for outsourced solutions (1).

Method development is an evident area where pharma companies can gain an economic benefit from outsourced services, particularly when there are limited to no capabilities for these services in-house. As an integral facet of drug development, optimization and selection of the most appropriate methods can help save on costs and reduce development times.

“The importance of method development cannot be understated,” says Emma Leishman, manager, Advanced Analytics, Avomeen. “Methods are the backbone of being able to answer scientific questions. Advancements in technology, as well as tighter regulatory needs, are driving methods that are more targeted, efficient, and sensitive. Spending time on method development upfront will build a solid foundation for validation and subsequent sample testing.”

“Method development and evolution of a drug product are continuous processes that progress in parallel with one another,” explains Alex Wheeler, senior technician at Wickham Laboratories. “It can be assumed that as the life cycle of a drug product progresses, overall knowledge of the drug product increases as should the robustness of the analytical tests that are being performed.”

Any analytical tests that are due to be performed must relate to the type of drug being developed and are required to comply to any regulatory requirements, continues Wheeler. “During method development, full transparency of the procedure performed is imperative so that when the information is presented to the relevant market authority, it is clear, accurate, and concisely conveys what has been done,” he says. “Investing in robust analytical tests to be established during the method development process will help to ensure that costs are kept down during the further stages of the drug development program.”

Factors for consideration in method development are dependent upon the molecules being developed, agrees Vincent Thibon, technical development lead, RSSL. “For developing methods for small molecules, the analytical method should be developed by looking into the factors such as pH, ionic strength, mobile phase composition, sample preparation, column technology, type of detection, [liquid chromatography–mass spectrometry] LC–MS compatibility, robustness, speed of [quality control] QC, length of time required for stability indication, cost effectiveness, and whether the method is easy to run,” he states. “For developing methods for large, protein-based molecules, the method should be developed by looking into factors such as sample preparation, sensitivity of technique, time to achieve results, complexity of method, and so on.”

A structured method development procedure is vital to ensure the intended methods are fit for the phase of drug product development, they provide the data required for product development support, and they can be validated to the correct product phase following industry guidelines, such as those from the International Council for Harmonisation (ICH), for the release of the product to clinic or market, asserts Amanda Curson, head of Analytical Development, Tredegar, PCI Pharma Services. “The method should be well developed at the start with the view of having a long lifecycle without major changes,” she says. “Redevelopment later can be time consuming and have an impact on regulatory submissions.”

For Jerry Mizell, senior director, Analytical Services, Metrics Contract Services, developing a ‘QC ready’ method is the most critical aspect in the method development process. “Having a method QC ready implies that it is very robust, [and the] rigorous challenging of the method will also establish a stability indication to ensure the quality of API or drug product over time,” he comments.

“Throughout development, methodologies are challenged with stressed and design-of-experiment samples to demonstrate performance. Design space creation is also used to determine the range of chromatographic performance and cover multiple formulation compositions for the product,” Mizell continues. “This approach sets a project up for success if there are future changes to the drug product as the developed method will be suitable for use.”

“Outsourcing method development can give a drug developer access to a more experienced or advanced skill base with minimal delay than it is able to access internally,” highlights Anders Mörtberg, analytical chemist at Recipharm. “As a dedicated specialist in method development, the outsourcing partner can provide dedicated expertise to deliver a much higher quality service than a developer may be able to achieve alone.”

It is fundamental that an outsourcing partner has solid insight into regulatory guidelines and expectations, in addition to being able to provide access to industry-standard separation equipment, Mörtberg notes. “Access to structure elucidation techniques for impurity identification is also advisable in an outsourced partner, as this is often necessary in method development,” he states. “Resources to provide computer-aided method development is desirable, as this can help the partner provide guidance on reducing labor and laboratory costs for method development.”

The three ‘E’s’—equipment, experience, and expertise—are important aspects for consideration when seeking an outsourcing partner for method development services, confirms Leishman. “Equipment should be up-to-date and able to meet dynamic regulatory needs. A wide range of equipment is a plus, since the most suitable instrumentation can be applied, and many methods can be developed at the same time,” she says. “Experience of the company and their scientists is a strong indicator of future success. Ideally, the company has experience with similar analytes and matrixes. Aside from the scientific experience, having regulatory experience with method development and validation minimizes risk.”

Choosing an outsourcing partner with a broad range of expertise, which is somewhat dependent on experience, and scientists on staff who are subject matter experts is advisable, Leishman continues. “Method development sometimes requires a creative approach, [therefore] adequate expertise can ensure that even the most challenging methods are successfully developed in a timely manner,” she emphasizes.

A desirable outsourcing partner should be able to offer a range of modern, but widely available equipment and should have an experienced technical team with vast method development experience and knowledge, concurs

Rebecca Coutts, general manager, Tredegar, PCI Pharma Services. “A company can benefit by working with an outsourced services team that has in-depth knowledge and experience with a range of dosage forms, particularly with dosage forms that can sometimes prove to be more troublesome for method development, such as ointments, creams, suspensions, or very low-dose potent products,” she says. “Using an outsourcing lab that has previous experience on method development, validation, and quality assurance specialist support will ensure the client is guided through the process required to ensure the method is ready for use to release clinical product, and for stability testing.”

For Mizell, development experience represents the most critical capability of a potential outsourcing partner. “Development chemists are not created overnight as it is a learning process that takes time—and there’s no substitute for that,” he asserts. “Knowledge is built upon with every successful development project, especially where technical challenges must be overcome.”

In terms of instrumentation capabilities, Mizell agrees that an outsourcing partner with multiple means of detections in-house, such as diode array, ultraviolet–visible, charged aerosol detection, and LC–MS, are beneficial. “Environmental chambers are also great to have for stressed studies,” he adds.

“Some outsourcing partners can also provide training programs to assist in clients’ learning of regulatory requirements, which would be particularly useful to smaller start-up companies,” confirms Thibon.

Oftentimes, contract research organizations (CROs) are employed for method development due to the wealth of knowledge they can offer in specific aspects of analytical tests relevant to the drug development and approval process, comments Wheeler. “An established CRO will operate facilities that are purpose built for analytical testing, maintained to a high standard, often utilize the most cutting-edge technologies, and already have validated and compliant in-house procedures,” he says.

Whether a single provider or multiple providers of outsourced services are used is dependent on the project and its specific requirements, specifies Curson. “For example, it may be possible for most of the method development to be carried out by one provider; however, there may be individual specialized analysis required, such as X-Ray powder diffraction, particle size analysis or Franz cell analysis, which is more unique and may require a specialized provider to perform method development for one aspect of the analysis,” she explains.

It is beneficial to choose a main provider of services—one that can perform the majority of the method development and validation and outsource any specialized aspects of the analysis to a partner laboratory when required—adds Curson. “The main provider would have overall responsibility for the project requirements with one or two outsourced specialized aspects undertaken by a lab with more specific specialized technical experience or available equipment required for the individual analysis,” she says.

According to Thibon, a clear advantage of using a single provider is the fact that all communication between the client and provider can be streamlined, which can mean that a good relationship can be built. “If using multiple providers, then the key thing is that all providers communicate clearly and on time and are willing to collaborate to achieve the goal,” he notes. “Regulations ensure that methods are consistent across providers, but using a single provider for all method development requirements could introduce efficiencies and reduce costs overall.”

“Using multiple providers will add complexity and may result in reduced efficiency due to coordination losses,” stresses Mörtberg, who highly recommends opting for a single supplier that is capable of providing all required resources for a project, wherever possible.

A single point of contact is undoubtedly advantageous, as it can allow for easier access to the specific project manager at the CRO, timelines are generally clearer and more consistent, and all the information is presented in the same style, concurs Wheeler. “However, there are some risks as well such as the potential for a greater impact on the stages/phases of testing if an issue should arise,” he says.

“By using multiple providers, it could be possible for multiple aspects and stages of testing to be performed concurrently if working with strict timelines, but this would generally require more internal coordination on the part of the client in such cases,” states Wheeler.

“A different approach is to use one provider to coordinate a multi-site study, therefore coordinating all testing, tracking of timelines, and compilation of results,” continues Louise Rigden, technical documentation officer at Wickham Laboratories. “This [approach] means the client still only deals with one point of contact for any information required and results can be reported in a consistent fashion.”

If a single provider has all the necessary equipment and expertise, then that approach can be ideal for a client, comments Leishman. There are time and cost efficiencies that can be gained through the use of a single provider, such as employing one sample preparation technique for multiple methods or employing a singular outsourcing lab to do an entire stability program, and in some instances, volume discounts for work can be applied, she adds.

“By reducing the number of outsourcing partners, a stronger relationship can be established with the single provider,” Leishman says. “However, a niche application or a method that needs a state-of-the-art instrument may benefit from a specialist provider.”

Mizell believes that selecting a single contract development and manufacturing organization (CDMO) that can provide all the required development needs provides a multitude of benefits. Not only does it ensure effective communication between the client and provider but can also lead to reduced meeting frequency and eliminates the need to ship API and/or drug product from site to site for different development activities, he asserts.

“When working with a single CDMO that a sponsor has established a working partnership with, they can have greater confidence that the development being performed will meet all project requirements and timelines,” Mizell summarizes.

Biotechnology and Pharmaceutical Services Outsourcing Market Size, Share, and Trends Analysis Report by Service (Consulting, Regulatory Affairs), by End-Use (Pharma, Biotech), and Segment Forecasts, 2021–2028

, Market Research Report (February 2021).

When referring to this article, please cite it as F. Thomas, “Developing a Method for Success through Partnerships,” 

Outsourcing method development offers multiple benefits to companies, including access to experience and expertise, streamlined costs, and development time efficiencies.

Recent news of GlaxoSmithKline’s (GSK’s) sale of its entire stake in Innoviva (1), its respiratory drug partner, indicates the company’s momentum to split into two by 2022 is on track. This type of divestiture is certainly not uncommon in the bio/pharma world—with recent news including Takeda and Tejin Pharma’s transaction for diabetes products (2), and Lonza’s divestiture of its specialty ingredients business (3)—as streamlining operations allows companies to focus on strategic priorities in a fast-moving industry.

Yet, concerns are being raised around GSK’s future, as the company has struggled in the COVID-19 pandemic landscape and has seen its revenues dip in the first quarter of 2021. Additionally, a floundering pipeline and the arrival of activist investor, Elliott Management, taking a major stake in the company are placing more fuel on the fire that the company is under the cosh.

The news isn’t all bad, however, as the European Medicines Agency concluded that sotrovimab—a monoclonal antibody being developed by GSK and Vir Biotechnology—can be used as a treatment for patients with COVID-19 (4). Furthermore, positive clinical trial results have been reported for GSK and Sanofi’s COVID-19 vaccine (5), as well as for Medicago’s COVID-19 vaccine candidate, which has been tested in combination with GSK’s pandemic adjuvant (6). So, a potential Europe-wide use of sotrovimab and COVID-19 vaccine developments further down the line will surely boost the company’s reputation and stock price.

1. GSK, “GSK Announces Sale of Stake in Innoviva Inc.,” Press Release, 20 May 2021.
2. Takeda, “Takeda to Divest Four Diabetes Products in Japan to Teijin Pharma Limited,” Press Release, 26 Feb. 2021.
3. Lonza, “Lonza Signs Agreement to Divest Specialty Ingredients Business to Bain Capital and Cinven,” Press Release, 8 Feb. 2021.
4. EMA, “EMA Issues Advice on Use of Sotrovimab (VIR-7831) for Treating COVID-19,” Press Release, 21 May 2021.
5. GSK, “Sanofi and GSK COVID-19 Vaccine Candidate Demonstrates Strong Immune Responses Across All Adult Age Groups in Phase II Trial,” Press Release, 17 May 2021.
6. GSK, “Medicago and GSK Announce Positive Interim Phase II Results of Adjuvanted COVID-19 Vaccine Candidate,” Press Release, 18 May 2021.

When referring to this article, please cite it as F. Thomas, “Divest and Conquer?” 

GSK’s position is raising concerns as it continues working towards its separation of businesses.

Divest and Conquer? GSK's Future is in Question

Sterile fill/finish manufacturing is expected to experience significant growth over the coming years, with some market research analysts predicting the field to be worth $12.1 billion by 2025 (1). Expanded drug development pipelines, incorporating more complex, large-molecule products and therapies that require sterile production, form part of the driving force for this rising demand for fill/finish services.

Ophthalmic therapeutics, in particular, require heightened expertise due to the fact that they are administered to the eyes, which are extremely sensitive and important organs. To learn more about the intricacies of sterile fill/finish manufacturing, specifically pertaining to ophthalmics, 

 spoke with Daniel Kehl, chief executive officer at swissfillon—a fill/finish specialist based in Switzerland.

Pharmaceutical Technology's Biologics and Sterile Drug Manufacturing


eBook: Biologics and Sterile Drug Manufacturing, May 2021
May 2021
Pages: 49–53

When referring to this article, please cite it as F. Thomas, “Eyeing Up Success in Fill/Finish,” 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook

Certain therapeutics, such as ophthalmics, must be provided as a sterile dosage form but can pose fill/finish challenges due to the small batch sizes required and the fact that the products used are difficult to fill and of high value.

Eyeing Up Success in Fill/Finish

The importance and criticality of dissolution testing throughout the pharmaceutical drug development lifecycle is well-known and has been well-documented in literature. “Dissolution testing measures the extent and rate of solution formation from a dosage form, such as a tablet, capsule, or ointment,” says Sool Yeon Cho, department scientist, Nelson Laboratories. “The dissolution of a drug is important for its bioavailability and therapeutic effectiveness.”

Dissolution rate specifications vary depending on the design of the dosage form. In 2018, FDA updated its guidance on recommendations for dissolution testing and specification criteria for immediate-release dosage forms that contain highly soluble compounds (1). However, not all drug products are covered by this guidance, which is applicable only to solid orally administered immediate-release drugs that are intended to be swallowed. Generally, when measuring the dissolution rate for an immediate-release dosage form, a single-time point specification is used—exceptions may occur when evaluating slow-dissolving drugs where two time points can be used—with samples taken between 30 and 45 minutes, and when approximately 75–80% of the active ingredient is dissolved (2).

However, for modified-release dosage forms, multiple time points are specified for characterization of the 

 dissolution rate—for delayed-release forms two time points are required and for extended-release at least three time points are required (3). For modified/extended-release dosage forms, dissolution testing should show the rate a solution is formed with the release of active ingredients over specified time intervals, explains Cho. Relevant guidance has been published to address the challenges of dissolution of modified or extended-release dosage forms (4,5).

When testing dissolution rates of solid-oral dosage form drug products, immediate-release and modified-release, standardized apparatus as described in the 

 General chapter <711> Dissolution includes four standardized apparatus: basket, paddle, reciprocating cylinder, and flow-through cell,” Cho notes. “Where specified in a monograph, 

 dissolution tests are legal requirements.”

Yet, these standardized approaches are not without limitations, as have been previously reported in the literature (7–9). Issues relating to not only the equipment used in standardized approaches but also the analysts performing the tests can lead to dissolution profile variability.

Furthermore, for some dosage forms there are limited test methods described in the literature. As Speer 

 reported in 2019, for oromucosal film preparations with a modified release profile, despite there being a regulatory requirement to provide dissolution test data for this dosage form, there are no suitable recommendations of methods or established specifications available to follow (10). Therefore, when the test article may not respond to the standardized approaches and regulatory recommended methods, it may be necessary to employ new techniques or devices, Cho asserts.

“The most noticeable analytical method or technological advancement in recent years to aid with dissolution testing is automation,” confirms Cho. Although automated dissolution has been explored for some time, more

recent advancements have been seen in the use of computerized software that aids with the regulatory audit trail required, he adds. For Cho, full dissolution automation—sampling station and analysis—and a paperless dissolution workstation will be important trends in the near future.

 described an automatic method for dissolution testing with high-temporal resolution using high-speed capillary electrophoresis (HSCE) (11). In their work, the researchers’ proposed a system comprised of three components—a flow-through-cell for tablet dissolution, an automatic sequential injection with high-temporal resolution, and on-line separation/detection using HSCE. Validation of the methodology was performed according to FDA guidelines. Immediate and fixed-dose products were assessed by Chi 

 who found that with their fully integrated on-line automatic system it was possible to monitor dissolution with high-temporal resolution in real-time, which is promising particularly for fixed-dose combination drug products.

 in 2019, an artificial neural network (ANN) model was built to predict the dissolution profile of extended-release tablets (12). Using data collected by near-infrared and Raman spectroscopy, as well as the compression force measured by the tablet press as input data for the ANN model, the researchers were able to predict the in-vitro dissolution profile of extended-release tablets. The predictions of dissolution profiles were within the acceptance limit of the similarity factor, f2, and the authors concluded that with more work it could be possible to build models that consider more process parameters, allowing for a deeper understanding of product quality.

“Real-time release testing (RTRT) and how a multivariate model could create a surrogate for dissolution testing is certainly a trend for the industry,” Cho adds. “Since dissolution testing is not favored by industry—it is time consuming and does not always correspond to 

 dissolution—RTRT measurements, as a part of continuous manufacturing platforms are emerging to replace the traditional dissolution tests.”

Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances

 (August 2018).
2. M. Powell, “Specifications for Small-Molecule Drug Products,” PTI Webinar (Nov. 22, 2016).
3. F.R. Lourenço, et al., 

Extended Release Oral Dosage Forms: Development, Evaluation, and Application of 

Guideline on Quality of Oral Modified Release Products

 (London, UK, March 2014).
6. USP, General Chapter <711>, “Dissolution” 

 (Rockville, MD, 2011).
7. S.A. Quershi and I.J. McGilveray, 

, 7 (3) 249–258 (1999).
8. J.L. Baxter, J. Kukura, and F.J. Muzzio, 

, 292 (1–2) 17–28 (2005).
9. Z. Gao, et al., 

, 96 (7) 1794–1801 (2007).
10. I. Speer, M. Preis, and J. Breitkreutz, 

., 9 (Nov.) 17114 (2019).
12. D.L. Galata, et al., 

When referring to this article, please cite it as F. Thomas, “Limitations and Advances in Dissolution Testing,” 

Despite its importance in drug development, dissolution testing still has some limitations, but advances in automation and real-time monitoring are producing promising results.