micronisation Archives - European Industrial Pharmacists Group (EIPG)

PIC/S Annual Report 2021

by Giuliana Miglierini The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure Read more

Joint implementation plan for the IVDR regulation

by Giuliana Miglierini Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Read more

Key issues in technical due diligences

by Giuliana Miglierini Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due Read more

Trends in the development of new dosage forms

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by Giuliana Miglierini

Oral solid dosage (OSD) forms (i.e. capsules and tablets) historically represent the most easy and convenient way for the administration of medicines. Recent years saw an increasing role of new approaches to treatment based on the extensive use of biotechnology to prepare advanced therapies (i.e. cellular, gene and tissue-based medicinal products). These are usually administered by i.v. injections or infusions, and may pose many challenges to develop a suitable dosage form, as acknowledged for example by the use of new lipid nanoparticles for the formulation of the mRNA Covid-19 vaccines.

The most recent trends in the development of new dosage forms have been addressed by Felicity Thomas from the column of Pharmaceutical Technology.

The increasing complexity of formulations is due to the need to accommodate the peculiar characteristics of biological macro-molecules and cellular therapies, which are very different from traditional small-molecules. Bioavailability and solubility issues are very typical, for example, and ask for the identification of new strategies for the setting up of a suitable formulation. The sensitivity of many new generation active pharmaceutical ingredients (APIs) to environmental conditions (i.e. temperature, oxygen concentration, humidity, etc.) also poses many challenges. Another important target is represented by the need to improve the compliance to treatment, to be pursued through the ability of patients to self-administer also injectable medicines using, for example, specifically designed devices. The parenteral administration of medicines has become more acceptable to many patients, especially in the case of serious indications and when auto-injectors are available, indicates another PharmTech’s article.

According to the experts interviewed by Felicity Thomas, there is also room for the development of new oral solid dosage forms for the delivery of biological medicines, as well as for OSD forms specifically designed to address the needs of paediatric and geriatric patients.

Some examples of technological advancements

Productive plants based on the implementation of high containment measures (i.e. isolators and RABS) are widely available to enable the entire manufacturing process to occur under “sea led” conditions, thus allowing for the safer manipulation of high potency APIs and the prevention of cross-contamination. Process analytical technologies (PAT), digital systems and artificial intelligence (AI) can be used to improve the overall efficiency of the formulation process. This may also prove true for previously “undruggable” proteins, that thanks to the AI can now become “druggable” targets denoted by a very high potency (and a low stability, thus asking for specific formulation strategies).

Advances in material sciences and the availability of new nanotechnology can support the development of oral formulations characterised by improved efficacy and bioavailability. To this instance, the article mentions the example of new softgel capsules able to provide inherent enteric protection and extended-release formulation. Functional coating, non-glass alternatives for injectables, and new excipients may also play an important role in the development of new formulations, such as controlled-release products, multi-particulates, orally disintegrating tablets, intranasal dosage forms, fixed-dose combinations.

 The ability to establish a robust interaction with the suppliers enables the development of “tailor-made” specifications for excipients, aimed to better reflect the critical material attributes of the drug substance. The ability to formulate personalised dosage forms may prove relevant from the perspective of the increasingly important paradigm of personalised medicine, as they may better respond to the genetic and/or epigenetic profile of each patient, especially in therapeutic areas such as oncology.

Not less important, advancements of processing techniques used to prepare the biological APIs (for example, the type of adeno-viral vectors used in gene therapy) are also critical; to this regard, current trends indicate the increasing relevance of continuous manufacturing processes for both the API and the dosage form.

 Injectable medicines may benefit from advancements in the understanding of the role played by some excipients, such as polysorbates, and of the interactions between the process, the formulation and the packaging components. Traditional techniques such as spray drying and lyophilisation are also experiencing some advancements, leading to the formulation of a wider range of biomolecules at the solid or liquid states into capsules or tablets.

New models for manufacturing

API solubility often represents a main challenge for formulators, that can be faced using micronization or nano-milling techniques, or by playing with the differential solubility profile of the amorphous vs crystalline forms of the active ingredient (that often also impact on its efficacy and stability profile).

As for the manufacturing of OSD forms, 3D printing allows the development of new products comprehensive of several active ingredients characterised by different release/dissolution profiles. This technology is currently represented, mostly in the nutraceutical field, and may prove important to develop personalised dosage forms to be rapidly delivered to single patients. 3D printing also benefits from advancements in the field of extrusion technologies, directly impacting on the properties of the materials used to print the capsules and tablets.

Artificial intelligence is today of paramount importance in drug discovery, as it allows the rapid identification of the more promising candidate molecules. Smart medical products, such as digital pills embedding an ingestible sensor or printed with special coating inks, enable the real-time tracking of the patient’s compliance as well as the monitoring “from the inside” of many physiological parameters. This sort of technology may also be used to authenticate the medicinal product with high precision, as it may incorporate a bar code or a spectral image directly on the dosage form. Dosage flexibility may benefit from the use of mini-tablets, that can be used by children as well as by aged patients experiencing swallowing issues.

The peculiarities of the OTC sector

Over-the-counter (OTC) medicines present some distinctive peculiarities compared to prescription drugs. According to an article on PharmTech, since the mid-‘80s the OTC segment followed the dynamics characteristic of other fast-moving consumer packaged goods (FMCG) industries (e.g., foods, beverages, and personal care products), thus leading to a greater attention towards the form and sensory attributes of the dosage form.

The following switch of many prescription medicines to OTC, in the ‘90s, reduced the difference in dosage forms between the two categories of medicinal products. Today, the competition is often played on the ability to provide patients with enhanced delivery characteristics, for example in the form of chewable gels, effervescent tablets for hot and cold drinks, orally disintegrating tablets and confectionery-derived forms. The availability of rapid or sustained-released dosage forms and long-acting formulations, enabling the quick action or the daily uptake of the medicine, is another important element of choice. Taste-masking of API’s particles is a relevant characteristic, for example, to make more acceptable an OSD form to children; this is also true for chewable tablets and gels, a “confectionery pharmaceutical form” often used to formulate vitamins and supplements.

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.