API Archives - European Industrial Pharmacists Group (EIPG)

European Council’s conclusions on the European Innovation Agenda and research infrastructures


by Giuliana Miglierini The European socio-economic framework is undergoing a profound transformative moment, as a result of the new vision impressed by the von der Leyen Commission, with its goals in the field of the Digital and Green transitions. The Read more

EMA’s new Quality Innovation Expert Group (QIG)


by Giuliana Miglierini Innovative approaches to the development manufacturing and quality control of medicines are becoming the new paradigm to be faced both from an industrial and regulatory perspective. Not only innovative technologies for delivery, such as mRNA vaccines, many Read more

ICMRA report on best practices against antimicrobial resistance


by Giuliana Miglierini Antimicrobial resistance (AMR) is the consequence of mutations that allow microbes to survive pharmacological treatment. Resistant strains can often be tackled only by a limited number of therapeutic options: according to a systematic analysis published in The Read more

How to approach drug substance supply in new product introduction (NPI) processes

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by Giuliana Miglierini

A key issue to be faced during pharmaceutical development refers to the supply of the active pharmaceutical ingredients and other raw materials to be used for the manufacturing of the first batches of investigational medicinal products, and then up to commercial production once approved.

Changes of specifications can frequently occur during experimentation, thus leading to the need to modify supply requirements for clinical programs. This is more true when dealing with biopharmaceutical investigational products, for which the traditional models for forecasting and demand processes may prove unfitted. The result is a lower robustness and predictability at early stages of the new product introduction (NPI) manufacturing processes. The complexity of the NPI supply chain is also impacting on manufacturing operations, with possible delays in the clinical program and launch schedule.

These issues have been addressed in the document “Guidelines for materials introduction supporting drug substance delivery”, published by the B2B organisation BioPhorum. A summary of its contents has been published in Bioprocess Online.

A good internal communication is fundamental

The ability to produce robust supply forecasts for new product introduction bases on a detailed knowledge of the planning of different activities to be run for a timely launch. Role and responsibilities have to be clear, as well as the information to be collected and timely shared between the manufacturing and commercial departments of biopharmaceutical companies.

The availability of such information is crucial to reduce the variability intrinsic in the NPI process for a biopharmaceutical product, which costs much more compared to a traditional smallmolecule based one. Reducing variability also impacts on the ability to better compete in the often highly dynamic market for biosimilars, or to address the launch of a new biotherapeutic under the correct perspective. Issues may be encountered also with respect to the regulatory approval processes, which may require different time lengths in different geographic areas or countries. This adds another uncertainty factor to estimates of the quantities of product to be manufactured.

Upon this considerations, the BioPhorum document identifies four key issues to be addressed to provide for a timely NPI process, including capacity and lead-time restrictions or oversupply, late change evaluation and implementation, governance issues and network complexity and in-licensed (or non-platform) products.

The availability of a good NPI process may avoid to incur many problems once operations are in place; all the needed master data information to support the use of raw materials should also be present and correct. BioPhorum’s suggestion is to include NPI processes in the creation of master service and supply agreements for the supply of raw materials, as they help to reach clarity on what a supplier can deliver and what it cannot.

A four steps methodology and roadmap

The document by the BioPhorum describes the results of a project aimed to develop a materialsbased methodology and roadmap to support improved NPI processes, on the basis of a collaborative industry approach to identify and implement best practices.

The result is a four steps process referring to the different activities needed to set up materials introduction and supply. The proposed different steps include the establishment of product lifecycle materials requirements, materials evaluation, supplier selection and qualification, and a manufacture and business review. Each of them should be supported by specific tools and checklists to be developed internally by the company. The governance of the process should involve senior supplier/manufacturer nominees to formally approve the package of deliverables at each stage gate.

Establishing product lifecycle material requirements

For each of the four steps of the NPI process, the BioPhorum document offers detailed lists of information to be collected and of expected outcomes.

Stage gate 1 addresses the establishment of product lifecycle material requirements, usually corresponding to the activation of first time in human studies (FTIH). Data to be collected include specifications of raw materials (e.g. order of magnitude, grade, supply options, environmental-health-safety (EHS) or geographic issues, etc.) as well as master data such as recipe information, plant diagram, list of equipment and process information. At the clinical level, information on the demand sensitivities on indication and clinical milestones and decision points should support the first estimates of the supply and demand plan, to be then expanded to agree on lifecycle forecasts.

The output may take the form of a ‘Product Lifecycle Demand and Supply Strategy’, a document discussing the long-term supply, demand and manufacturing of the product. Starting from the initial planning, the strategy should evolve through the creation of a data store specific for biopharmaceuticals, and the execution of gap analysis for in-licensed products. The strategy should also include a rough capacity modelling and description of ownership and the definition of a RACI matrix (responsible, accountable, consult, inform) to clarify roles and responsibilities with respect to each task, deliverable, or action. Information should be also available on high level technology requirements (both at the internal and external level). Strategic suppliers should be involved in early activities and materials risk analysis should be initiated.

Materials evaluation

Stage gate 2 refers to the information to be gathered from suppliers on the basis of requests for information (RFI) on materials. This should include all the different aspects relevant to the selection of the supplier, including capacity and costs, contacts, technical specifications and audit history, availability of samples, EHS aspects and business systems (e.g. availability of an appropriate ERP system).

This information should facilitate the identification of supplier that might be able to support the predicted or proposed growth of the product over its lifecycle. Stage gate 2 is also part of the risk management process to be run to validate the activation of full production.

Outputs include the sharing of forecasts and sensitivities with suppliers as needed, the establishment of a standard industrial master data set for biopharmaceuticals, as well as of business acceptance criteria.

Supplier selection and qualification

Stage gate 3 addresses the qualification process to finally select the most suitable suppliers and close the corresponding material supply agreements. The RFI and other information gathered in the previous step represent the basis of this exercise, aimed to develop a supply chain resilience strategic approach. The signature of the initial contracts is the final mark of formal selection, and should be supported by an agreement with the supplier on forecast and schedule for the supply, as well as of the business acceptance criteria.

Manufacture and business review

Stage gate 4 refers to the assessment of the operational performance of the supply chain for raw materials, a key activity in order to ensure continuity of supply and to promptly intercept any emerging issue on the basis of trends analysis.

Tools needed to this instance include the definition of appropriate metrics to monitor supplies (e.g. adherence to schedule, “On time in full”-OTIF, “Cost of poor quality”-COPQ). Information on the innovation potential of the supplier and the provision of a feedback on its performance is also deemed important. Any issue should be timely discussed between the supplier and the biopharmaceutical company, and confirmation of the production schedule agreed upon.


Investing in formulation as success’ factor

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by Giuliana Miglierini

Formulation is a critical step in the development of new medicinal products, as it directly influences the bioavailability, release profile and stability of the active ingredient, overall impacting on both the efficacy and safety of the medicine.

While in the traditional approach the definition of the final formulation was a quite late step along the development process, new models of R&D greatly focus on early formulation as a way to optimise both time and costs of drug development. It is thus important to identify the optimal formulation strategy as early as possible: a quite challenging goal in many instances, especially in the case of last generation complex biopharmaceuticals which may prove difficult to formulate. An article by Felicity Thomas, published in Pharmaceutical Technology discusses how to address early formulation strategies to maximise the chance of success.

Limits and challenges of formulation

The main objective of the drug development process remains the same, reducing as much as possible the time-to-market so to fully exploit the marketing exclusivity period granted by the patents protecting an innovative medicine.

To this instance, some key aspects should be considered in order to rapidly establish the most appropriate formulation, with a special attention to achieving an early access to first-in-human assessment and proof-of-concept studies.

Scaling-up of the formulation process is another critical issue, as it requires a careful consideration of all the steps needed to establish the final manufacturing process at the commercial scale. This exercise is fundamental in order establish the critical quality attributes and process parameters, thus reducing the risk of a change of the initial formulation to make it suitable to the final manufacturing process.

As explained by Jessica Mueller-Albers, strategic marketing director Oral Drug Delivery Solutions, Evonik, the increased pressure to speed up formulation is also connected to the fact “many new drugs target small therapeutic areas, where it is essential for pharma companies to be first in the market from an economic perspective.”

The availability of enabling technologies is fundamental to early formulate niche medicinal products, moving away from the classical mass production. The trend initiated with the development of mRNA Covid-19 vaccines may represent a change of paradigm in drug development, suggests Jessica Mueller-Albers. Lipid nanoparticles (LNPs) are an example of enabling technology that has been widely employed to formulate the mRNAs used in Covid-19 vaccines. LNPs may take many different forms, i.e. liposomes, lipoplexes, solid lipid nanoparticles, nanostructured lipid nanoparticles, microemulsions, and nanoemulsions (see more in Drug Development and Delivery).

Other types of emerging technologies are also widely investigated, such as proteolysis-targeting chimeras (PROTACS). These are heterobifunctional nanomolecules, containing one moiety recognised by the E3 ligase and chemically linked to a ligand (small molecule or protein) able to bond to the target protein. The final outcome is the formation of a trimeric complex, through which it becomes possible to transfer ubiquitin molecules to the target protein. The mechanism represents an alternative approach to “knock down”, as it enables the degradation of the target protein, offering many advantages compared to the use of classical inhibitors.

Another challenge to be faced during formulation development is the need of a broad and specialised expertise in the different domain of drug development, including also material characterisation, drug metabolism and pharmacokinetics. According to Stephen Tindal, director, Science & Technology, Europe, Catalent, this is particularly true for small companies, which are often the focus of early development activities before acquisition of the projects by larger multinationals. As explained in the Pharmaceutical Technology’s article, a possible approach is to use small teams of experts to manage the preclinical phases of development.

The many challenges of early formulation

The solubility of the active pharmaceutical ingredient (API) in aqueous media is often one of the main challenges to be faced in formulation studies, impacting also on the final bioavailability of the drug in the target body compartments and/or fluids. Estimates indicates that at least 70% of new APIs are poorly soluble.

Other challenging points to be taken into consideration include the possible presence of different polymorphic forms, each characterised by its own stability and properties, and potentially giving rise to conversion from one another during the formulation and/or manufacturing process (see more in the article by A. Siew, Pharmaceutical Technology). The often limited amount of API in the early phases of development and the difficulty to evaluate the dose range on the basis of the available data are other critical point to be considered.

The development of an appropriate bioavailable formulation is often based on preclinical data obtained from animal pharmacokinetic and GLP toxicity studies, followed by pre-formulation studies to assess API’s properties (e.g. solubility, stability, permeability, etc.) in commonly used solvents and bio-relevant media. Drug delivery systems might be used to solve solubility issues, to then scale the identified formulation on the selected technology platform to be used for manufacturing (see more in Drug Development and Delivery).

The principles of the Developability Classification System (DCS) may be also considered to better assess the physicochemical and biopharmaceutical characteristics of a new API that may impact of the formulation process.

Some possible approaches to early formulation

The experts interviewed by Felicity Thomas have indicated some possible approaches useful to addresses formulation issues. For systemic oral small-molecule drugs, for example, the use of a solution as the delivery vehicle may allow to reduce the needed amount of API, thus supporting lower costs to reach Phase I proof of concept in healthy volunteers. Various techniques are also available to favour solubilisation and bioavailability of the active ingredient, i.e. hot-melt extrusion, spray drying, coated beads, size reduction, lipid-based approaches, etc. The optimisation of particle size by mean, for example, of micronisation and nanomilling techniques is another option. Co-administration with lipids can enhance the lymphatic transport of lipophilic drugs, as it favours its incorporation into chylomicrons at the intestinal level, and the subsequent delivery to the lymphatic system in the form of chylomicron–drug complexes.

Many algorithm-based platforms and predictive models are also available to support formulators in the selection of excipients and solubilisation methods, avoiding the need of extensive testing. The implementation of real-time adaptive manufacturing is another possible tool, useful to optimise the formulation on the basis of emerging clinical data.