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

Felicity Thomas

The formulation development outsourcing market is expected to grow at a compound annual rate of 7.2% between 2021 and 2026 (1). Major factors driving growth in this sector are expected to be increasing innovation of novel drugs due to patent expirations, a focus on developing poorly water-soluble compounds that require bioavailability enhancement, and overcoming the risks associated with development (1).

To learn more about the industry trends, common requests, biggest challenges, and benefits of outsourced formulation services, 

 spoke with a panel of experts. The panel includes Sabine Hauck, senior vice-president of Corporate Development, Leukocare; Alexander Faude, director Process Science, Downstream Processing, and Marvin Kadisch, director Process Science, Upstream Processing, both at Rentschler Biopharma; and Stefan Heindl, business development manager, Coriolis Pharma.

 Could you provide some insight into industry trends that have been impacting the formulation development outsourcing market in recent years?

 Formulation development has gained momentum in recent years. Beyond the stabilization of the drug substance by molecular design, formulation development is a key opportunity in the process of drug product development that offers potential to generate further commercial value. To accommodate this trend, continuous expansion of formulation expertise is recommended so that client requirements for viral vector stabilization, vaccines and advanced therapy medicinal products (ATMPs), higher drug substance concentration, longer storage time at higher temperature, or creation of new intellectual property can be met. For example, Leukocare has successfully managed the development of targeted formulations by applying its database and algorithm-based formulation development approach.

Formulation development itself has developed rapidly, making use of highly sophisticated analytical methods and bioinformatics. This trend supports outsourcing formulation development to a specialized provider, such as Leukocare, that excels with high-end scientific expertise, an analytical toolbox, and bioinformatics excellence. Especially for smaller companies, using an outsourcing partner allows access to best-in-class formulation development.

 The value and benefits of early formulation development have increasingly gained recognition and acceptance across the industry. Hence, companies are looking closely at all aspects of biopharmaceutical production, from start to finish, to identify opportunities for timeline optimization. As a result, it has been the experience of Rentschler Biopharma that the trend of collaborating with external experts in formulation development is picking up.

 Coriolis began specializing in formulation development in 2008 when formulation was often not the highest priority during drug product development. This has changed and the formulation development outsourcing market has been in a sustainable growth phase for several years now. Daily work at Coriolis has demonstrated a clear trend towards more complex products, for example, highly concentrated liquid formulations (HCLFs) with protein concentrations of up to 300 mg/mL or higher, or novel protein formats that require dedicated scientifically driven formulation strategies, rather than standard platform approaches. Also, requests regarding vaccine development, particularly in the context of the ongoing coronavirus pandemic have increased in the past two years; nucleic acid-based therapeutics gain more and more importance. However, the most important trend in my view is the increase in ATMPs, such as viral-vectors, oncolytic viruses, and other genetically modified organisms, that are entering the scene. Many of these products require new and innovative formulation approaches, analytical strategies, as well as special facilities.

 What type of formulation work is more commonly outsourced and has the type of project changed over the years?

 Formulation development services are requested across all stages of development, from early-stage pre-formulation work to late-stage reformulation projects, in-use studies, or trouble-shooting activities. Two different trends have been seen at Coriolis. One trend is an increasing demand for the outsourcing of complete packages, including pre-clinical tox manufacturing and good manufacturing practice (GMP) manufacturing (e.g., for first clinical phases of the developed formulation). To meet this demand, it is important to expand the service portfolio, for example, by expanding tox-batch manufacturing capabilities for liquid and lyophilized formulations. Moreover, it is necessary to seek out and maintain partnerships with other established players in the field to cover GMP manufacturing. These close partnership networks allow for comprehensive outsourcing packages to be offered while keeping the number of interfaces for the client low. The second one is outsourcing of highly challenging and individual formulation tasks that require a scientific background and a very specialized formulation approach. For this trend, it is important that the service provider has the required track record, experience, and scientific background for the task.

 All kinds of formulation development are outsourced, depending on the needs of the sponsors. Early pre-formulation development supports stability already in tox studies and allows de-risking success of a clinical candidate due to stability issues. Fully fledged formulation development is outsourced in all stages of clinical development, depending on the clinical development strategy. Even if the asset is planned for out-licensing after clinical stage, a well-designed formulation will increase the value of the drug product package. In general, time has become more critical over the years, while quality requirements are still increasing. That´s why it is key to outsource formulation development to an expert contract development and manufacturing organization (CDMO) developing high-quality formulations in an accelerated period.

 What are the biggest challenges for outsourcing partners when approaching/working on a formulation project with a sponsor company?

Faude (Rentschler Biopharma): When collaborating with a sponsor company, the success of early formulation development depends heavily on material that has been generated via ‘preliminary’ processes. These processes are themselves undergoing development and optimization. Hence, they are bound to change right until first current GMP production for clinical development. Moreover, the process may undergo further improvement or adaptations for market approval. Therein lies a challenge for the outsourcing partner but also great benefit for the sponsor company’s product. This is because these adaptations can be sequentially incorporated into formulation development to further maximize product potential.

 The role of the outsourcing partner as an expert consultant for the sponsor company is also very crucial. It is essential that the outsourcing partner sees the project as an extension of their own operations and advises the client from this point of view. Aspects such as which formulation best suits the molecule in question, subsequent implementation and regular project status updates are central to a successful collaboration.

 Well, every client is different, and each molecule of interest and target product profile require a dedicated strategy. A common aspect is that the timeline is always key. While in early stages, drug substance availability is often a challenge, though mostly manageable, real challenges arise when formulation development is squeezed in between other development activities such as drug substance development and drug product manufacturing. Depending on the drug substance and client, knowledge about the stability profile of the API can be very scarce. Due to all these reasons, an understanding of the specific requirements of each client, a smart, scientifically-sound study design with built-in flexibility and a clear expectation management is important.

 Formulation development is always linked to other aspects of product development, such as process development for upstream processing and downstream processing, pharmaceutical development or fill/finish, logistics, and product administration. It is important to consider interactions and interdependencies.

 How do outsourcing partners overcome these challenges?

 At Coriolis, for example, a lot of investment is made into the upfront discussions with the client to understand the particular needs for the project. In combination with our experience as a formulation specialist, these discussions provide the basis for a tailored and scientifically-sound proposal considering all specific requirements of the client. During an ongoing project, open and transparent discussions on a regular basis (e.g., in weekly or biweekly meetings) help to align development efforts and allow for quick reactions to scope changes or unforeseen issues. Especially during early-stage projects, a high degree of flexibility is often needed, requiring a specific skill set of the team working on the projects to quickly provide a stable formulation backed-up by a suitable analytical toolbox and stability data.

 A very helpful solution to tackle these challenges are access to a large database, as well as experience with different classes of molecules. This includes tools like in-silico modeling and more targeted wet-lab trials. This can significantly accelerate the development of suitable formulations for the sponsor company’s product.

 Requests for faster formulation development should be met with innovative strategies; extending the analytical toolbox can help to save time and material. Moreover, automation in formulation and analytical technology supports parallelization and thus supports higher turn-over. Making use of bioinformatic expertise leads to timesaving as well as quality improvement for projects.

 To overcome these challenges a review of the ‘fit of the formulation to the product’ can be continuously addressed during preclinical and clinical product development. This allows one to quickly identify ‘constellations of fitness’ that can then be focused on to further optimize both formulation and the end product.

 What are the key benefits for outsourcing formulation development?

 Based on the experiences of projects undertaken by Rentschler Biopharma, it is believed that the seamless integration of formulation development into the entire product life cycle and timelines harbors two key benefits: it allows for exceptionally efficient product optimization and ensures that project delays are avoided. Furthermore, the consultation provided by the outsourcing partner is key in defining the best-fit for both client and product.

 Outsourcing partners, such as Rentschler Biopharma, have holistic offerings where the entire process and formulation development is offered in an optimally integrated form. In this manner, clients can greatly benefit from the experience and expertise of the outsourcing partner for an ‘improved’ product within optimal timeframes.

 Essentially, it enables companies to gain access to best-in-class formulation development. For smaller companies with few products, an external formulation development team can be used just for the short period of time needed and avoids the efforts required of recruitment and training. Typically, it is much easier for an outsourcing partner to answer short notice demand on higher required effort. Formulation development can be performed whenever it suits best.

 In the context of the increasing complexity mentioned before, the outsourcing of such projects to specialized and experienced service providers can significantly improve development times and the probability of success. Outsourcing to service providers offering all required analytical capabilities in-house also expedites development as shipment between third-party labs and time-consuming data consolidation can be avoided. Finally, following a first-time right approach with a specialized formulation partner in the long run also saves money, and includes the possibility to generate and protect intellectual property in a collaborative and transparent approach.

The outsourcing of formulation development activities should be seen less like a one-way service and more like a collaboration between two partners. If both parties work together collaboratively and maintain an open and transparent communication, a positive project outcome is almost guaranteed.

Formulation Development Outsourcing Market—Growth, Trends, COVID-19 Impact, and Forecasts (2021–2026)

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 45, No. 8
August 2021
Pages: 52–56

When referring to this article, please cite it as F. Thomas, “Developing the Best Formulation Partnership,” 

Articles

Collaborative partnerships can foster success in formulation development projects.

Developing the Best Formulation Partnership 

In 2015, a global framework was set up to ensure dangerous climate change was avoided through efforts to limit global warming. The Paris Agreement is aimed at achieving climate-neutrality before the end of the century and is a universal, legally binding global agreement (1).

International governments and parties, such as the European Union and its member states, involved in the Paris Agreement have agreed to work on emissions reductions to meet the ultimate goal of the agreement. Additionally, countries have submitted national climate action plans in contribution to the objectives of the agreement. The EU’s most up-to-date and enhanced national determined contribution was published in December 2020 and specified a target to reduce emissions by at least 55% by 2030 compared to the levels in 1990 (2).

The environmental performance of the chemical industry, which includes pharmaceuticals, of the EU and its member states, that is to say, the reduction in greenhouse gas (GHG) emissions, has improved since 1990, according to the European Chemical Industry Council (Cefic) (3). However, there is still much work to do in order to meet the goal of the Paris Agreement.

A new association, Alliance to Zero, was formed earlier this year (2021) by eight companies representing the pharmaceutical supply chain, with the specific purpose of aiding the pharma sector with compliance to net zero GHG emissions (4). To learn more about this non-profit organization, 

 spoke with Sebastian Gerner, president, Alliance to Zero.

 Could you please provide a brief introduction to the Alliance to Zero association?

 Alliance to Zero is a non-profit membership association for pharma and biotech supply chain companies that aims to facilitate the transition of the pharma sector to compliance with net-zero GHG emissions. As a working group with commonly shared goals, we will engage in collaboration with academia and non-profit organizations as well as sponsors projects. We will involve, connect, and coordinate suppliers, pharmaceutical companies, manufacturers, and service providers along the supply chain of pharma products. While the alliance is registered in Switzerland, the reach and intention of this membership association is global, and each of our founding companies have operations and facilities across the globe.

 Why is it important for members of the pharmaceutical industry to participate in associations, such as Alliance to Zero?

 Climate change is a global challenge that affects all of us. The Alliance to Zero is committed to developing a common standard for GHG emission reduction methodology within the pharmaceutical supply chain. The overarching goal is to collaboratively shape a net-zero emissions product offering, which is certified by a third party. This can only be reached with a powerful working group of individual suppliers co-developing net-zero standards and implementing them within the value chain.

 What sort of work is already underway by the founding members of the association?

 The alliance was founded on 1 June 2021 and is currently establishing working groups to progress on a net zero emission concept for pharmaceutical manufacturing and supply chain products. This foundational work also includes agreements on harmonized language and principles for the assessment and control of the total emissions footprint for the final pharmaceutical products, as well as the company-specific responsibilities.

 How will the work progress? Could you provide a roadmap of what progress is expected to be achieved and the timeframe in which it will be done?

 The alliance targets the commercial launch of net-zero pharmaceutical products in regulated markets by no later than 2030. To reach this date, the alliance founding members commit to developing a collaborative net-zero offering by 2026 to leave time for the pharmaceutical companies to finalize the overall product based on this offering.

Each alliance member has begun programmes to realize substantial GHG emission reduction that relates to their business responsibility and area of influence. The alliance is supporting those programmes via best-practice exchange and providing guidance and inputs on emission reduction or circular economy principles.

 Will the work of the association be transferrable to other contributors/providers within the pharmaceutical sector?

 The alliance started off as a working group of motivated companies, which came together to initiate a change in the industry. The alliance targets are being established to develop standards for the pharmaceutical industry and share a common language. Based on this approach, other companies could profit from and contribute to it.

 Are there plans to expand the alliance in the future?

 Currently the alliance represents the majority of the value chain along pharmaceutical injectable products. Initially, the work is intended for a small group of highly committed companies to set up the basic directions and get things started. Nevertheless, the alliance will accept applications from a few companies with high motivation for active input which would enrich the value chain and fill potential gaps in the near future.

, accessed 26 July 2021.
2. EC and Germany, “Update of the NDC of the European Union and its Member States,” 

, 17 Dec. 2020.
3. Cefic, “2021 Facts and Figures of the European Chemical Industry: Environmental Performance,” 

, February 2021.
4. Alliance to Zero, “Alliance to Zero Founded to Achieve Net Zero Emissions Across the Pharmaceutical Supply Chain,” Press Release, 2 June 2021.


Vol. 33, No. 8
August 2021
Pages: 40–41

When referring to this article, please cite it as F. Thomas, “Working Towards Zero Emissions” 

Pharma and biotech supply chain companies are working together to help facilitate the transition of the pharma industry to net zero emissions compliance.

Working Towards Zero Emissions

Within Europe, drug pricing regulations are in place to ensure affordable access to drugs; however, these regulations do not mean that more expensive drugs are ‘off the table’ for patients or that pharma companies won’t ever increase prices of currently available medicines (1). External reference pricing is one way in which a European country can have an idea of the ‘reasonable’ cost of a drug. This policy allows governments to compare the price of a drug to that charged in other countries to gain a benchmark price.

In 2016, Pfizer and its distributor Flynn Pharma had a record fine imposed upon them for excessive price hikes to the United Kingdom’s National Health Service (NHS) for phenytoin capsules, which were priced much higher than in any other European country at the time, as determined by the UK’s Competition and Markets Authority (CMA). However, this decision was appealed, and in 2020, the Court of Appeal dismissed the attempts by the CMA to reinstate the fines (2).

In July 2021, however, several cases were raised against pharma companies regarding price hikes. Most recently, the CMA issued a fine of more than £100 million (€117 million/$139 million) to Advanz and its former private equity owners after an investigation demonstrated ‘excessive and unfair prices’ were being charged for liothyronine tablets (3). A little earlier in the month, the CMA had also imposed fines worth £260 million (€306 million/$361 million) on a number of drug companies for price increases on a steroid treatment by more than 10,000% (4). Additionally, the Dutch authority—Netherlands Authority for Consumers and Markets (ACM)—has issued a fine worth €19.5 million ($23 million) on the Italian pharmaceutical company Leadiant Biosciences for excessive pricing of a drug to treat cerebrotendinous xanthomatosis, which the company had raised by 1800% (5).

Whether or not these fines are appealed against or are upheld, it is apparent that authorities are closely examining pricing strategies and are sending a clear message to the industry that infringements of the Competition Act 1998 will not be tolerated.

WHO Guideline on Pharmaceutical Pricing Policies, Guideline

, 1 Jan. 2015.
2. Simmons and Simmons, “Appeal Court Dismisses CMA Attempt to Reimpose Fines on Pfizer/Flynn,” Insight Article, 10 March 2020.
3. BBC, “Drug Firm Fined for Huge Price Rise that Hit NHS,” Press Release, 29 July 2021.
4. K. Beioley, “Pharma Companies Fined After 10,000% Price Rise for Life‑Saving Drug,” 

, 15 July 2021.
5. B. Nijhof, “Dutch Competition Authority ACM Fines Pharmaceutical Manufacturer €19.5 Million Over Price Increases of More than 1800%,” 

When referring to this article, please cite it as F. Thomas, “Pricing Scrutiny Increases” 

Excessive drug pricing is being scrutinized across Europe, as hefty fines are set to send out a clear message of intolerance to anti-competition conduct.

Drug Pricing Scrutiny Increases in Europe

Insights into underlying mechanisms of ASDs

Researchers from the University of Basel in Switzerland and The Peoples’ Friendship University of Russia (RUDN University), investigated the underlying drug absorption mechanisms of amorphous solid dispersions (ASDs), proving the effectiveness of a novel, particle-forming ASD drug-delivery system for poorly soluble compounds (1).

 employed a model ASD formulation of efavirenz, which is an antiretroviral medication that is classified on the biopharmaceutics classification system as a class II drug—one with poor solubility but high permeability. The model formulation comprised hydroxypropyl methylcellulose phthalate (HPMCP) as a polymer with sucrose palmitate and polysorbate 80 as surfactants in a hot-melt extrusion process.

Sixteen healthy male patients were included in the study and were randomized to receive efavirenz in three different ways: intervention 1 was ASD of efavirenz (50 mg) as a capsule with 500 mL buffer solution; intervention 2 was dissolved ASD of efavirenz (50 mg) in 500 mL of buffer solution, forming drug-rich particles; and intervention 3 was efavirenz (3 mg) solution in a 500 mL buffer solution. The study participants were randomly selected to receive the interventions in different orders (either 1-2-3, 2-3-1, or 3-2-1) and a washout period of 14 to 21 days was performed between interventions.

Blood samples were obtained pre-dose and at multiple time points post-dose so that the plasma concentration of efavirenz could be determined through bioanalysis techniques. The pharmacokinetic profiles of efavirenz plasma concentrations compared to time were used as the primary study endpoints, with further pharmacokinetic analysis and modeling used as secondary endpoints. Furthermore, study results were compared with existing pharmacokinetic data available for a marketed formulation of efavirenz (Stocrin).

Based on the study results, it was found that the dissolved ASD of 50 mg of efavirenz (intervention 2) pharmacokinetically behaved nearly identically to the solution of efavirenz 3 mg (intervention 3). Therefore, intervention 2, which comprised a supersaturated aqueous solution containing drug-rich particles, behaved as a solution, and assuming passive absorption, the researchers deduced that the dissolved drug concentration in the intestine of intervention 3 was higher by a factor of 16.7 than intervention 2.

As a result of the drug concentration exceeding that of the aqueous solubility of efavirenz, it was concluded that drug-rich particles from ASDs are efficient oral drug delivery systems and drug absorption was fast and complete in humans. Additionally, the findings of the study confirmed the conceptual models of how drug molecules are released from ASDs and how they are subsequently absorbed into the intestinal tract.

Non-classical nucleation theory and application on ASD design

A group of international researchers (from Northern Ireland, China, Switzerland, and the United States) have recently reviewed the potential theory behind the formation of drug-rich phases of ASDs with a focus on non-classical nucleation (2). In the study, Kaijie Qian 

 specifically assessed the associated thermodynamics and kinetics of the formation of drug-rich phases from the dissolution of an ASD, as well as the in-vitro permeability enhancement and 

 bioavailability enhancement of the ASD formulation, among other aspects associated with drug-rich phases.

Elaborating on the mechanistic understanding of ASDs solubility, dissolution, and potential phase separation process during dissolution and storage, the researchers found that if amorphous drug particles are suspended in solution, the drug concentration can temporarily reach beyond the drug crystalline solubility threshold, as a result of their higher Gibbs free energy, and achieve a higher solubility than their crystalline counterparts. The resultant high supersaturation of drug solution leads to phase separation, which the researchers noted will typically happen via a classical nucleation and growth process.

However, as a result of the imperfect miscibility of drug and excipients, there is the possibility for an amorphous-amorphous phase separation (AAPS) phenomenon to occur during manufacture or storage of ASDs. The researchers revealed that several models have been described on the drug-polymer-water interactions, in relation to moisture/solvent presence. Using the same concept, the researchers found that when dissolving the ASD in water the presence of excipients played an important role in the drug’s phase separation. Furthermore, it was found that certain excipients can kinetically stabilize the drug-rich metastable phases of ASDs for a considerable period of time, which may promote oral absorption of the drug due to high concentration levels in solution. Additionally, it was highlighted that the properties of polymeric excipients were important to drug permeability enhancement of ASDs.

Based on their work, the researchers suggested that the enhanced oral bioavailability achieved with supersaturated ASD solutions is aided by the excipient-assisted formation and stabilization of drug-rich metastable phases, which follow a non-classical nucleation pathway. ASD formulations that are designed to enable synergistic effects of a variety of different mechanisms could provide benefits for drug oral absorption and, as such, future medicine development, the researchers concluded.

, 13 (3) 401 (2021).
2. K. Qian, et al., 

Recent research has highlighted the underlying mechanisms of amorphous solid dispersions and theory behind the formation of drug-rich phases.

Recent Research on Amorphous Solid Dispersions

Outsourcing time-consuming and costly services is becoming increasingly popular within the bio/pharma industry. The right contract development and manufacturing organization (CDMO) can not only provide the best equipment for certain tasks but can also provide a wealth of expertise to provide the best possible chance of success.

To learn more about best practices for selecting an outsourcing partner and the questions that should be posed to a sponsor company when approaching a method development project, 

 spoke with a panel of experts. The panel included Emma Leishman, manager, Advanced Analytics, Avomeen; Alex Wheeler, senior technician, and Louise Rigden, technical documentation officer, both from Wickham Laboratories; Rebecca Coutts, general manager, and Amanda Curson, head of Analytical Development, both at PCI Pharma Services; Vincent Thibon, technical development lead, RSSL; Jerry Mizell, senior director, Analytical Services, Metrics Contract Services; and Anders Mörtberg, analytical chemist, Recipharm.

 Could you provide some best practices for selecting the optimal outsourcing partner for method development?

 Finding an outsourcing partner can be tough—nobody wants to be left hanging on a critical project due to outsourcing delays. A good outsourcing partner will understand this and will do their best to meet your needs. Communication is key. You should be able to talk directly to the scientists and technical directors who will be overseeing the project. That way, the project can get started correctly with everyone on the same page.

When selecting an outsourcing partner, the experience, expertise, and equipment capabilities of the outsourcing lab should be assessed. If the method is for filing with a regulatory authority, then quality systems should be part of the initial assessment. It is especially promising when a partner has prior experience with similar methodology or even recommendations from previous clients.

 Before contacting a contract research organization (CRO), the company should establish exactly what aspects of the method development can be done in-house and what needs outsourcing. Once it has been established what testing is required, the relevant stakeholders internally should familiarize themselves with the regulatory guidelines of these tests to provide at least a basic understanding of the testing requirements. By having this knowledge, it will make communicating the company’s needs easier and ensure the chosen CRO can offer the best-suited and most robust testing.

When first reaching out to potential partners, important questions to ask are what they can offer you, which tests they have validated and have experience with conducting regularly, and what regulatory certificates they have. For a good manufacturing practice (GMP) product to successfully go to market, it is imperative to ensure that the testing is performed by a GMP accredited CRO.

Also, and possibly most importantly, expectations around timelines should always be discussed before engaging in testing as just because a company can offer the testing does not always mean their availability will match the required timeframes for any given project. A good recommendation is to establish expectations early, communicate clearly, and ensure there is contingency built into your project timeline to deal with any issues that may arise.

 Moreover, the experts in a CRO can advise on regulatory requirements and therefore assist in advising on the testing required as it can sometimes be difficult to interpret the guidelines. Consultancy services can be invaluable to a smaller drug development organization, or to clients such as student researchers who may not have experience of the industry.

 Best practices for selecting the best outsourcing partner for method development include picking a partner who has the following: previous practical experience in developing methods for particular dosage forms; a number of successful validations as a result of initial method development over the past five years; available equipment with multiple models, capacity, and resources that will be allocated; the ability to deliver within required timelines; the ability to provide summary development reports or copies of data required to support regulatory submissions; a good history with the regulatory authorities; and lastly, the ability to safely handle certain compounds, for example, potent molecules.

 In addition to the outsourcing partner complying with regulatory standards (e.g., company standards, GMP approvals, quality compliance procedures, and auditing systems), we think that the correct outsourcing partner would ensure that there is good, clear communication and collaboration, and good planning to meet agreed timelines. With these practices, a strong relationship can be built as trust is key.

Key questions to consider when selecting a potential outsourcing partner include: Are the labs approved by the relevant regulatory body (e.g., FDA or Medicines and Healthcare products Regulatory Agency)? What technical knowledge and instrument capabilities are available at the CRO? Can they assist developing all the methods that are required? Can they develop the methods within the required deadlines?

 A company should ask for examples of previous development projects and what led to success. Detail should be given regarding the types of samples in which methodology was developed. For example, asking whether a company specializes in method development for inhalation, ointments, creams, liquids, or solid oral dosage formulations is an essential first question. Detail should also be given describing development experience with challenging molecules or formulations and how those challenges were overcome. For the initial meeting with the prospective CDMO, sponsors should interview chemists and ask for the strategies that would be employed when developing methodologies. This could include asking what strategy they use to develop a tablet dissolution procedure where the API is practically water insoluble.

 There are a few key questions that a drug developer should ask of a potential partner before entering a working relationship with them. These questions include do you have experience in similar projects to mine? Do you know what to do, and will your solutions work effectively? What is your track record in successful method development in my particular field or category, such as small molecules, or biopharma? What are your team’s qualifications? How many members of your team have in-depth expertise in my field? Do you have the necessary instrumentation and infrastructure to support me and my project? Do you have a GMP-certified laboratory? When can the work be finished? It is often the case that developers ask when the work can be started, but delivery is the key issue to consider. Are you a reliable and well-established partner that will still be around to be able to deliver the project? How will the method development work be documented? It is important to understand how and why specific method parameter choices were made by a partner. When the new International Council for Harmonisation guideline Q14 on method development will become effective, it is important the outsourcing partner is well versed with its implications for method development practices.

 August 2021 print issue: “F. Thomas, “Picking the Perfect Method Development Partner,” 

 Are there specific questions the outsourcing partner should ask too, before undertaking a potential method development project?

 Before undertaking a potential method development project, outsourcing partners may want to ask what data [are] available for review on the physical and chemical properties of the drug substance, also whether there is information on potential dosage form, strength, formulation information, and the phase of drug development. Additionally, they may want to ask if there is any previous analytical information or methodology available. For example, a client may require a method developed for the drug product and may already have developed drug substance methods that can be shared to help inform the drug product method development approach.

 First, the potential partner should ask is there a technical package for the API or drug product that describes the chemical and physical properties of both? Properties such as morphology, solubility (organic, aqueous, and pH range solvents), stability, and any forced degradation data should be requested along with methodology, and any associated validation reports. Having a solid technical package available when beginning development typically accelerates the development process.

 Questions we try to ask before undertaking potential method development projects include: What are the purposes of the method? How many formulations and are there any plans to extend formulations? When the method is used routinely, will it be used for quality control testing or investigation only? When is the method needed by and have other alternative techniques been considered? Is the method development project to improve an existing method or develop something from scratch?

 There are several questions that a drug developer can expect to hear from a potential partner. Answering these questions as comprehensively as possible is key to help the partner provide a realistic timeframe for delivery and deliver the best possible service. The key questions a drug developer should answer include what is the ‘pre-history’ of the project? Could you provide any background information and context to help understanding of the project’s needs? How do you intend to use the method once it is developed? Any method development project needs to address the actual use of the method to be successful. When does the project need to be delivered in full? Answering ‘as soon as possible’ should be avoided as it will necessarily lead to higher costs. What deliverables do you want to specify? What protocols, reports, or method descriptions do you want to receive on completion of the project?

 Potential partners should establish the intended use of the product. Knowing this can not only help the potential partner establish testing but could also help deliver valuable insight regarding how the product should be tested, specific quantities to test, and any regulatory specifications. If the CRO has tested similar products before, they may also be aware of additional requirements which had not already been considered, and capturing these issues early on could save time later.

The CRO should be asking questions specifically relating to the product. For instance, if the testing required is microbial limits testing, then it should be established if the product contains properties or constituents which might inhibit microbial growth during the product’s validation.

A timeframe should also be established early on, with the CRO confirming they have the capacity to perform exactly what the client has requested. If those targets cannot be met, it should be considered whether there is room to compromise on the timeline or alternatively, whether new methods or systems could be considered for validation to facilitate the project.

It is also critical that confidentiality and technical agreements are in place to provide guidelines for the relationship between the parties before any testing commences as this protects the customer and the CRO by establishing responsibilities and ensuring they are meeting regulatory and legal requirements.

 The purpose of the method must be established to guide the work. A method development scientist will ask questions to figure out the purpose. For example, who will be using this method? What sort of conclusions will be made based on data obtained from the method? Where is the method going to be used? At a single lab or transferred between sites? When will this method need to be implemented? Why is this method required? How has this testing been performed in the past? Does the method need updating to keep up with current standards?

The regulatory requirements and the timeline should be established to scope the work. Timelines to reach the end goal of the method need to be realistic—it is not possible to develop a method from scratch and validate it within a week. Obtaining detailed information on the analyte, the matrix, and the final purpose of the method assists with devising a customized and purpose-driven scope of work.


Supplement: Outsourcing Resources 2021
August 2021
Pages: 26–29

When referring to this article, please cite it as F. Thomas, “Picking the Perfect Method Development Partner,” Outsourcing Resources 2021 (August 2021).

There are some key questions that should be asked by both the sponsor company and the outsourcing partner before undertaking a method development project.

Picking the Perfect Method Development Partner

The oral administration of drugs has persistently been the preferred route of drug delivery for many years, mainly due to patient convenience and manufacturability of the dosage form. “Tablets are the most stable and used oral sold dosage (OSD) form on the market that allows for drug price reductions while also guaranteeing good production yields combined with patient compliance,” asserts Federica Giatti, compression technologist at IMA Group.

However, conventional immediate-release tablets are designed to release an active ingredient shortly after oral administration, which generally means a rapid absorption of drug occurs without any specific targeting of therapeutic action. Various methods have been employed to be able to manipulate the release of APIs in the body, in order to control the therapeutic efficacy of treatments, improve patient compliance, and reduce dose frequency.

Bi-layer tablets have been employed as a means of administering more than one API in a single dosage form to achieve controlled drug delivery. Although these dosage forms can offer key advantages, there are also specific complications and challenges that must be overcome to ensure success.

In the modern era, continuous scientific research into disease areas and multi-targeted approaches is opening a wide range of possibilities in pharmaceutical development and manufacturing, Giatti confirms. “The possibility to use bi-layer tablets offers some advantages that must be taken into consideration when developing a combination of two or more APIs in a single pharmaceutical form,” she says.

Some advantages of bi-layer tablets include the option of fine-tuning the availability of each API with the possibility of differentiating their release-times, being able to separate incompatible APIs, prolonging the medicine effect after administration, and reducing the dose frequency, Giatti highlights. For example, she continues, in elderly patients, the high number of tablets or medicines that may be required each day can impact quality of life or can lead to medication errors, so bi-layer tablets can be particularly beneficial for this patient population.

“Bi-layer or multi-layer can provide the delivery of more than one drug in one dose thereby adding convenience,” concurs Anthony Carpanzano, director of R&D at JRS Pharma. “Delivery in separate layers can avoid incompatibilities between the compounds that otherwise could not be prevented in a single monolithic structure. Multiple layers also allow for delivery of the components at different rates and visually, multi-layer tablets provide brand recognition.”

Formulating a bi-layer tablet is more complex than for a conventional monolayer tablet as two (or more) suitable granulations must be developed. “Generally, to have a blend suitable for compression, the powder should be free-flowing and uniform in terms of particle size distribution; it should be characterized by particles cohesive enough to lock and hold together but not too much so they can adhere to metal surfaces,” notes Giatti.

“Blend characteristics, such as compactability, flow, homogeneity, and low dustiness—to minimize ‘cross-contamination’ between layers—are important,” agrees Carpanzano. “Flow is especially important for layers two and beyond.”

By guaranteeing the blend characteristics, the final tablet should be uniform and defect-free, Giatti continues. “Compatibility is another crucial characteristic to be considered. If the APIs inserted in the formulation are incompatible, they must be separated in different layers and formulated with dedicated release,” she says. “Last but not least, the sufficient bonding between the two layers must be guaranteed even immediately after tableting and during storage, packaging, and shipping.”

To ensure a stable tablet process, when developing and manufacturing a bi-layer tablet, manufacturers must choose the correct tamping and pre- and main-compression forces, and formulation scientists need to select an excipient that is suitable for direct compression, which will allow for easy flowability, compression, and tableting of the blend, Giatti explains. “The tableting should be performed without any contamination between the two layers,” she adds. “[Formulators can improve the chances of being contamination-free] by choosing powder with a coarser particle size that can reduce blend volatility around the machine, and manufacturers assist with dedicated aspiration.”

Most of the challenges to overcome when developing a bi-layer tablet pertain to process or equipment issues, emphasizes Carpanzano, but other significant considerations include layer adhesion and layer thickness versus tooling shape—in particular, cut depth.

A greater amount of attention should be focused on the bonding between the two layers, asserts Giatti. “From a manufacturer point of view, this [bonding issue] can be solved by applying a slight tamping force in the first layer, whereas for formulators the inner features of all the excipient and APIs present (crystalline habitus, real density, particle size distribution) should be taken into consideration from the beginning,” she says.

But, for Giatti, the most significant challenge to overcome is in relation to incompatibilities of the ingredients. “Different release profiles and physical separation of the APIs should be ensured by choosing the relevant type and percentage of excipient(s) or manufacturing technology to use,” she states.

Additionally, the development of technologies designed for the compression of multilayer tablets has matured with systems now at the point of simply needing ‘fine-tuning’, reveals Carpanzano. “More development of compression coating or ‘tablet-in-tablet’ is ongoing,” he adds.

Software is available that can help developers in choosing the correct formulation, such as IMAGO (IMA Group), highlights Giatti. “This software consists of an instrument that acquires the data of the cells mounted in the machine, such as pre-main compression and ejection force, as well as tablet characteristics (weight, thickness, diameter, and tablet strength) to consider powder behavior,” she explains.

Other software exists that guide the choice of ratio and type of excipient, such as ZoomLab by BASF, Giatti continues. “The combination between these aids and the experience of the supplier and manufacturer, can improve and facilitate the choices of the formulators,” she says.

“Excipient selection for bi-layer tablets is as important as it is for single-component tablets, and there are instances when it is most important,” Gernot Warnke, global head of R&D at JRS Pharma stresses. “For example, when running a high-speed tablet press, the filling of the die with the blend to be compressed occurs when the die passes below the feed frame and the lower punch is drawn downward. This downward motion happens quickly and creates a degree of suction which aids in filling the die. This suction helps to compensate for materials with less than optimal flow in achieving uniform die filling and ultimately consistent tablet weight uniformity.”

However, Warnke warns, for multi-layer tablets, the benefits of the downward motion of the punch are only achieved for the first or lower layer of the tablet. “Any subsequent layers must rely solely on blend flow to fill the die cavity. It is therefore imperative to select excipients that impart the best flow characteristics to provide adequate flow characteristics to subsequent layers,” he says.

Selecting the optimal excipient for the first layer is also important to ensure the surface, after tamping, has a rough enough porosity to allow for adequate adhesion of the second layer, continues Warnke. “It has been shown that if the first layer is too smooth (due to makeup or excessive tamping) the second or subsequent layer will not adhere well and layers may separate with minimal agitation (i.e., during ejection, discharge, packaging, or over the shelf-life of the product),” he says.

“Due to the fact that the first layer [in a multi-layer tablet] is generally subjected to low compression forces, the formulation should be able to cope with further compression in the second phases of tableting without leading to a fragile tablet,” adds Giatti. Furthermore, selecting an excipient with good compressibility can improve the overall tableting output and help to overcome the potential problem of later separation and delamination and capping, she notes.

“To conclude,” continues Giatti, “the flowability of the formulation of the first and second layer should be good enough to not generate any issues during the feeding of the tablet press that could cause a reduction of output or [overall equipment effectiveness] of the manufacturing equipment.”

Widely encompassing regulatory factors are to be considered when approaching bi-layer tablets: following the correct good manufacturing practice approach to ensure a high-quality tablet is produced that complies with the standard customer specifications and pharmacopeial requirements, specifies Giatti. “At the same time, tablets must be defect-free, capping and separation of the two individual layers should be prevented, and the final tablet hardness has to be sufficient to cope with downstream processes or handling,” she adds.

A deep analysis of any incompatibility between the API and excipient is critical, and the cross-contamination among the layers should be avoided, asserts Giatti. “Finally, the two layers should be clearly separated to ensure the correct API release, to avoid undesired contamination, and for aesthetic reasons,” she says.

“Bi-layer (and multi-layer) products fall into the category of combination products, and thus must have a therapeutic ‘reason for being’,” states Carpanzano. “Clinical studies to support the combination must therefore be established and approved.” The analysis, method development, validation, and quality control of bi-layer tablets is more complex than for monolayer products and, as a result, can be a more time-consuming process, he notes.

Ongoing research into various disease areas that demand a multi-targeted approach is broadening the potential utility of bi-layer tablets for developers, asserts Giatti. “[Bi-layer tablets offer developers] a real chance to reduce the number of medicines being taken by a patient, increasing medication compliance on one hand, and reducing the potential for administration error on the other, which in turn increases the therapeutic effect of medicines being prescribed,” she says.

“In my opinion, multi-layer tablets are still under-utilized and can offer cost-effective alternatives to much more complex drug delivery options, both in immediate-release as well as in modified-release formats,” summarizes Warnke. “Even with the advent of 3D printing of tablets, multi-layer tableting remains a much cheaper option, especially in the case of high production volumes.”


Vol. 45, No. 7
July 2021
Pages: 32–34, 46

When referring to this article, please cite it as F. Thomas, “Formulating Tablets Layer by Layer,” 

Bi-layer tablets are an under-utilized option that can be employed to help reduce treatment burden, but their formulation is more complex than for conventional monolayer products.