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A new member within EIPG


The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

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Trends for the future of the pharmaceutical manufacturing

April 21, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The technological evolution of pharmaceutical manufacturing towards the full implementation of the Industry 4.0 paradigm is rapidly advancing. Digitalisation of productions is supported by the wide spread of automation, devices connected to the Internet of Things, and machine learning algorithms able to keep entire processes under control. Looking at pharmaceutical development, new types of treatments are emerging, also requiring a retuning of current approaches. Results from a survey among experts and industry insiders (56 respondents from 13 different countries) run by Connect in Pharma show new challenges are to be faced in the incoming years by the pharmaceutical industry in order to maintain its market position.

The combined value of the global pharmaceutical market in 2022 is estimated to be approx $650 billion. The main component reflects pharmaceutical manufacturing (US$ 526 billion in 2022, data Insight Slice), while the global pharmaceutical packaging market value is roughly US$131 billion (data Fact.MR).

Many different factors supporting the transformation of pharmaceutical manufacturing have been identified by Connect in Pharma, ranging from ageing of population to Covid19 and Ukraine crisis, to climate change and pressures on energy costs, up to the shortage of healthcare professionals. The final conclusions and opportunities identified by the report indicate new partnerships and collaborations (mainly with startups, and small and medium-sized companies) will remain fundamental to support competitiveness, together with growing investments in tech-driven innovations. Involvement of patients and healthcare professionals in identifying unmet needs and optimal solutions is another item to be considered in order to increase adherence to therapy, suggests the report.

Digitalisation still waiting to full exploit its potential

Innovation in automation and digitalisation of processes has been introduced in the pharmaceutical sector at a slower pace compared to other industrial sectors, due to its higher regulatory barriers. About one third (28%) of respondents to the survey indicated their companies are developing artificial intelligence (AI) or other digital tools for application in the manufacturing and packaging process. The main drivers towards the implementation of such systems are more efficient data collection, reduction of manufacturing down times and human errors, and the use of machine learning to support continuous manufacturing. Better workflow integration and anticounterfeiting, and the ability to share supply chain data with regulators are also relevant. These are all objectives that would need to provide new specific training to the workforce, e.g. on AI or tools for augmented reality.

One of the main barriers that, according to the report, is still slowing down the full potential of AI and digitalisation in the pharmaceutical industry is represented by the need to comply to regulations, including data integrity and security. The human factor may also prove relevant, as many people (including top management) may be reluctant to accept this change in technology. The availability of data scientists with a deep knowledge of the pharmaceutical sector is another critical point to be addressed.

Advances in drug delivery technologies

Connect in Pharma’s report also shed light on some drug delivery technologies that, despite not being an absolute novelty, are gaining relevance for the development of new products and treatments.

The moving of pharmaceutical pipelines towards a continuously increasing number of new biologic / biosimilar products, including mRNA-based and gene therapies, requires the availability of manufacturing and packaging capacities able to accommodate the specific needs of such often very unstable macromolecules. New drug delivery systems have been developed in recent years to provide answers to this need, among which is inhalation technology.

Dry powder inhalers and nasal delivery devices are the preferred formulations for the 50% of respondents to the survey that indicated actions are ongoing to develop new products using inhalation technologies. According to the report, these devices might prove particularly useful to deliver drugs that need to rapidly pass the blood-brain barrier in order to become effective, as well as for the delivery of vaccines. Fast absorption and higher bioavailability compared to other routes of administration are other elements of interest for inhalation technologies, which is also believed to be able to contribute to the reduction of carbon footprint.

Once again, the regulatory environment resulting from the entry into force of the EU Medical Devices Regulation (especially for drug-device combination products), together with the need to demonstrate patient safety and satisfactory bioavailability of these devices, are among the main barriers to their development, says the report. Inhalation technologies may also give rise to a new generation of delivery devices connected to the Internet of Medical Things (IoMT).

Another major trend identified by Connect in Pharma refers to the development of new drug delivery systems for injectable medicines (50% of respondents). This area is greatly impacted by the entry into force of the revised Annex 1 to GMPs, on 25 August 2023, that will increase the requirements for aseptic manufacturing. According to the report, main areas of innovation in this field may include new devices for injectable drug delivery, namely targeted to diabetes (the leading area of innovation), intravitreal ocular injection, autoimmune diseases, oncology, respiratory therapy, and pain management.

Connected devices

Diabetes is a highly relevant field of innovation also with respect to the implementation of connected devices, those embedded sensors and electronics allow for the real-time collection of data on self-administration of the therapy by patients, and their forwarding to health professionals. AI algorithms further enhance the potential of connected devices delivering diabetes treatments, as they support the real-time monitoring of insulin concentration in blood, and the consequent level of insulin delivered by the device. According to Connect in Pharma, other positive characteristics arising from the use of connected devices refer to the possible increase of patient adherence and compliance to treatment, resulting in improved patient outcomes and more personalised treatment.

Regulatory barriers are once again a main burden to the wider spread of connected devices, says the report, due for instance to the ultimate control over the sharing of data, and the choice if to implement single-use or reusable devices. Manufacturing costs, cybersecurity, and patient hesitancy are other hurdles identified by respondents to the survey.

The challenges for sustainability

The green policies put in place especially in the EU are calling industry to revise its processes and products to decrease their environmental impact, improve sustainability of manufacturing and packaging processes, so to eventually meet the climate targets fixed for 2050. According to the report, the global healthcare sector would be responsible for 4.4% of global net emissions. Connect in Pharma’s survey indicates 66% of involved companies are working to implement more sustainable practices. These may include for example the use of recycled materials in secondary packaging, the implementation of energy efficient technologies, and the development of more ecofriendly drug delivery systems. Costs have been identified as the main barrier to transition, together with the lack of common definitions. According to some of the experts, a wider use of data to monitor manufacturing systems and processes may help in improving the overall efficiency and in lowering the carbon footprint. Transport, for example, has a great impact on the sustainability of packaging.


Draft ICH M13A guideline on bioequivalence open for consultation

March 17, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The draft ICH M13A harmonised guideline “Bioequivalence for immediate-release solid oral dosage forms” was endorsed by the International Council for Harmonisation on 20 December 2022 and is now open for consultation. Comments can be forwarded until 26 May 2023; publication of the final document is expected by May 2024.

The new guideline will then be implemented as a European guideline, replacing the current EMA guideline on the investigation of bioequivalence (BE) for oral dosage forms. The ICH M13A is the first of a planned series intended to address scientific and technical aspects of study design and data analysis, so to better support BE assessment both during development and post approval. The guideline covers immediate-release (IR) solid oral dosage forms delivering drugs to the systemic circulation (i.e. tablets, capsules, and granules/powders for oral suspension). Different approaches from those suggested in the guideline are possible, provided they are scientifically justified; applicants are thus encouraged to seek the advice of the relevant regulators in order to share a common approach to development.

Key concepts of the M13 series

The determination of bioequivalence to the originator is a fundamental step in the development of generic and biosimilar medicines. BE plays also an important role for some innovator products, as well as for post-approval changes of formulation and/or manufacturing process. BE is determined in terms of bioavailability of the products under comparison after administration, within predefined limits to ensure safety and efficacy. In vivo BE studies for certain orally administered IR solid oral dosage forms can be waived according to the ICH M9 guideline on Biopharmaceutics classification system (BCS)-based biowaiver, which has already superseded Appendix III of the EMA guideline.

The M13A guideline addresses study design containing multiple comparator products or test products, but not the acceptance of comparator products across different regulatory regions, as this greatly varies according to local legislations. The process of regulatory decision making based on BE is also excluded from the guideline.

The planned M13 series should also include the ICH M13B guideline, focused on biowaiver considerations for additional strengths not investigated in BE studies, and ICH M13C discussing data analysis and BE assessment for highly variable drugs, drugs with narrow therapeutic index, and complex BE study design. It should also address data analysis considerations, for example in the case of adaptive BE study design.

Pharmacokinetics (PK) bioequivalence studies and comparative in vitro dissolution studies are the main tools for BE determination for IR solid oral dosage forms with systemic action. These principles can be also applied to other non-orally administered drug products with immediate action (e.g., certain rectal, inhalation, and nasal drug products), provided BE may be derived from measures of systemic exposure.

The ICH E6 guideline on Good Clinical Practice should also be considered while conducting BE studies, in order to ensure the data integrity of all data generated in the trials.

The main contents of the ICH M13A

Chapter 2 of the ICH M13A guideline discusses the general principles to be used for the establishment of bioequivalence. These include the selection of the study population and the choice of the pharmacokinetic endpoint to be used in the BE studies. Healthy subjects should be the preferred choice, unless there are ethical concerns linked to the safety of the pharmaceutical products under assessment. In any case, inclusion and exclusion criteria should always be clearly reported in the study protocol. The main target of BE studies should be the detection of differences in the in vivo release characteristics between the products. Elements to be considered to select the study population are discussed in the draft guideline.

As for the study design, the recommended suggestion is for randomised, single-dose, two-period, two-sequence crossover studies comparing two formulations, as single-dose studies may better detect differences in the rate and extent of absorption. Multiple-dose studies may be conducted in patients should the single-dose design be not affordable for safety/tolerability or ethical reasons. A parallel design may be indicated for drugs with long elimination half-lives, requiring a prolonged washout period. Alternatives are also acceptable upon scientific justification.

The choice of the test product should be also discussed and justified, and it should be representative of the product to be marketed. As for the comparator, the selection of the batches to be used for BE studies should be based on assay content. The strength of the product to be used in the BE study depends on the dose proportionality in PK and solubility of the analyte.

The draft also indicates standardised fasting conditions should be the preferred choice to run BE studies, as they support a better discrimination between the PK profiles of the product and the comparator. Both fasting and fed BE studies should be conducted for high-risk products, due to their complex formulation design or manufacturing process that may impact differently on their in vivo performance, due to different gastrointestinal (GI) conditions. This is the case, for example, of low solubility drug substances formulated in the form of solid dispersions, microemulsions, lipid-based formulations, nanotechnologies, or other specialised technologies.

Analysis of the parent drug should be the preferred choice to demonstrated bioequivalence. Primary metabolites are considered acceptable in the case of pro-drugs which are rapidly eliminated. Stereoselective assays measuring individual enantiomers should be also considered while assessing chiral drugs.

Specific paragraphs address the setting up of sampling, the need to avoid occurrence of Cmax at the first post-dose sampling time point, the possibility to use truncated AUC for drugs with long half-life and considerations on early exposure.

How to analyse and present data

Specific sections of the guideline discuss how to present and report data obtained from BE studies. The study documentation should include the complete evidence of the protocol, conduct, and evaluation, and it should be written according to the ICH E3 guideline “Structure and content of clinical study reports”.

Unadjusted, measured drug concentrations in a suitable biological fluid should be always provided for both the product and the originator, for each subject participating in the study. Any deviations should be clearly identified. A suggested list of PK’s parameters to be tabulated for each subject-formulation combination is provided, together with summary statistics to be reported. Not less important is the statistical analysis performed on raw data. To this instance, the model of choice for the analysis should be pre-specified in the study protocol. Cmax and AUC(0-t) should be the preferred PK parameters to establish BE.

Chapter 3 discusses specific topics that may impact on the determination of BE. Among these is the presence of endogenous compounds identical to the drug under evaluation, thus requiring the determination of their baseline concentration in the biological fluids of interest. The draft guideline also specifies that both orally disintegrating tablets (ODTs) and chewable tablets should be administered in BE studies according to the comparator product labelling with regard to intake of water. The comparator product labelling should also represent the main reference for BE studies involving tablets, granules, and powders labelled as being only intended to be dispersed in a liquid before administration as an oral suspension. Considerations are also provided for fixed-dose combination products and the dependance of the drug solubility on pH.


Trends in the development of new dosage forms

April 16, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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

February 11, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.