dosage forms Archives - European Industrial Pharmacists Group (EIPG)

Real-world evidence for regulatory decision-making


by Giuliana Miglierini Digitalisation is rapidly advancing also in the regulatory field, as a tool to improve the efficiency and accuracy of processes used for the generation and use of data to inform the regulatory decision-making. To this instance, real-world Read more

Webinar: Implementation of Contamination Control Strategy Using the ECA template


The next EIPG webinar will be held in conjunction with PIER and University College Cork on Friday 21st of October 2022 (16.00 CEST), on the implementation of Contamination Control Strategy (CCS) using the ECA* template. This is the second Read more

ACT EU’s Workplan 2022-2026


by Giuliana Miglierini The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Read more

Trends in Drug delivery and Formulation

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

According to the 2021 Global Drug Delivery & Formulation Report, signed by Kurt Sedo, Vice President Operations, PharmaCircle LLC and published in a three-part series on Drug Development & Delivery, the Covid-19 pandemic seems to have had little impact on the regulatory approvals of new dosage forms and formulations. A positive sign from the pharmaceutical ecosystem, considering the difficulty to maintain normal operative conditions, the issues with international supply chains and the many hurdles to regulatory activities posed by the emergency.

According to Kurt Sedo, products newly approved by the FDA and based on new chemical entities have been the less affected, as they reflect a larger benefit for patients. On the other hand, are generics, together with new dosage forms and new formulations. Simple dosage forms continue to represent the great part of new approvals, while biologics prevail in terms of NCEs for injection.

The FDA approved in 2021 a total of 31 new products under the Biologics Licence Application (BLA) procedure, slightly more than in the previous two years. The increase is mainly linked to the higher number of vaccines and cell and gene therapies, while approval of biologic medicines maintained stable.

Approval trends by category of product

A marked decrease characterised Abbreviated New Drug Approvals (ANDA) (627 in 2021, vs 903 in 2020 and 962 in 2019). New Drug Applications (NDA) also slightly decreased. Analysing this category by type of product, the decrement is marked for new molecular entities and new dosage forms, while an opposite trend can be observed for new active ingredients and new formulations/new manufacturers.

As for administration route, the report indicates a marked prevalence of injection in all geographic areas (US 55%, EU 36%, JP 59%); oral drugs also continue to be highly represented. The author warns about the difficulty to reliably interpret the figures for European and Japanese approvals, as “The European Medicines Agency (EMA) approvals relate only to specific classes of pharmaceutical products and don’t capture the full range of products. The Japanese Pharmaceutical Medical and Medical Devices Agency (PMDA) published approvals are hard to access and properly assess”.

Looking more in detail at the injection route of administration, intravenous injectable products remain the leading category (US 39%, EU 38%, JP 38%), followed by subcutaneous injection. Simple solutions with or without a dedicated delivery device were the most commonly approved injectable simple dosage forms in 2021. Tablets and capsules remained the favoured oral dosage forms, while granules and pellets are especially represented in paediatric formulations.

Small molecules are the more represented category of active ingredients (US 64%, EU 74%, JP 52%), followed by antibodies and peptides; this last category of API offer the advantage of a possible formulation as non-injectable dosage form.

A deeper insight on the main approvals

Part 2 of the series debates the main products approved in 2021. The trend hints to a higher interest towards products and technologies targeted to wider patient populations and more diverse applications. According to Sedo, mRNA and gene therapy platforms have decrease their appealing due to need of validation for applications different than vaccines in the first case and safety and durability concerns in the latter.

Skytrofa (Ascendis Pharma) is a pegylated form of the growth hormone lonapegsomatropin-tcgd for injection or subcutaneous administration, using the dedicated rechargeable and reusable auto-injector. The weekly administration is the main advantage, overruling the need of daily injections.

Invega Hafyera (Janssen Pharmaceuticals), containing paliperidone palmitate as the active ingredient, has been approved in the US to treat adult schizophrenia by intramuscular injection every 6 months. Despite the parent molecule has already lost its exclusivity, Kurt Sedo highlights the remarkable lifecycle management of the Invega family of products, which allowed Janssen to maintain significant revenues for almost 20 years.

Tyrvaya (Oyster Point Pharma) is indicated to treat dry eye using the nasal delivery route. The formulation containing varenicline is administered using the Aptar’s CPS Spray Pump, representing the first approval for this type of technology platform. The possibility to overcome issues in treating ocular conditions connected to the difficulty many patients may experience with the administration of classical ocular drops is the main point of innovation.

Acuvue Theravision (Johnson & Johnson Vision Care) are contact lenses firstly approved in Japan and containing ketotifen to treat allergic conjunctivitis. In this case too, the approach may be replicated to administer other types of drugs in the eye. Issues may be represented by the difficulty of patients in using contact lenses and the need to stabilise the active ingredient to prevent leaching.

Cabenuva Kit (ViiV Healthcare) contains the combination cabotegravir – rilpivirine to treat HIV infection. Firstly, approved in Canada, it is administered monthly by intramuscular injection. Long-acting formulations can prove interesting to overcome compliance issues which may result in serious consequences for patients, as already proved in the case of hepatitis.

The monoclonal antibody Susvimo (anibizumab; Genentech) is formulated as a refillable ocular implant to treat wet acute macular degeneration. After implantation, the intravitreal injections using the Port Delivery System (PDS) occur every 6 months.

Other relevant technologies mentioned among new 2021 approvals include the Medicago Virus Like Particles (VLP) technology, which uses tobacco-related plants as bioreactors to produce noninfectious VLP that mimic the target virus, and LICA technology (Ionis), based on Ligand Conjugated Antisense (LICA) to favour the interaction of ligands and their respective receptors.

The Denali Transport Vehicle (TV) platform uses specific antibodies, enzymes, oligonucleotides, or proteins to link to the transferrin receptor of the blood vessel wall in the brain, thus providing a way to pass the blood-brain barrier by endocytosis.

MedRing (Ligalli) is a smart vaginal insert containing a miniaturised liquid formulation drug container with pump, battery, antenna, electronics, and sensors to monitor various biometric parameters (e.g. glucose or ovulation status).

Q-Sphera (Midatech Pharma) provides a bioencapsulation process using a microfluidic device to obtain discrete droplets without use of surfactants, toxic solvents, biphasic mixtures, shear, or heat forces.

Products in the pipelines

Part 3 of the series addresses the expectations for new approvals of products still in the pipelines The trend shows a higher percentage of early-stage products (research and pre-clinical phases), which is attributed to the higher interest of investors towards new companies able to fill the pipelines with early stage projects. The impact of Covid-19 has proved to be more relevant on projects at the clinical stage.

Small molecules still represent the main focus of development (59% in 2021/22), even if a drop has been observed from values recorded in 2015/16 (66%). Biological products may pose issues due to their highly speculative nature, suggests the report, while oligonucleotide and RNA products still represent only the 2% of the total in the pipelines; a more mature technology are antibodies (12%).

Cancer continues to be the leading therapeutic area of development, followed by infectious diseases and drugs to treat the central nervous system. The report indicates a very high attrition rate for anti-infectives under development, while many anti-cancer therapeutics in the pipelines may be me-too products pursuing validated therapeutic mechanisms. As seen above, injectable formulations maintain the leading position also for products under development (52%), followed by oral formulations.


Trends in the development of new dosage forms

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.