APIs Archives - European Industrial Pharmacists Group (EIPG)

Some perspectives on green pharmaceuticals


by Giuliana Miglierini The central role the green agenda plays within the EU Commission’s transformative policies impacts also on the development and availability of pharmaceutical products characterised by a improved sustainability. The concept of “Pharmaceuticals in the environment” (PiE) is Read more

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

Comments to the draft ICH guidelines Q2(R2) and ICH Q14

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by Giuliana Miglierini

The public consultation on the two draft guidelines ICH Q2(R2) on the validation of analytical procedures and ICH Q14 on analytical procedure development closed at the end of July 2022.The European Medicines Agency published in August two documents summarising comments received (ICH Q2(R2) and ICH Q14).

Many industrial organisations contributed to the consultation with their point of view on the two draft guidelines. In the next phase of the procedure (step 3 of the ICH process), comments will be reviewed by the ICH Q2(R2)/ICH Q14 Expert Working Group (EWG). We summarise for readers some of the main comments received from industrial stakeholders. A webinar organised byEIPG on the implications and opportunities of the revision of ICHQ2 and the ICHQ14 was presented by Dr Phil Borman, Senior Fellow & Director Product Quality at GSK on 15thJune 2022 (recording and slides are available at the webinars page of EIPG’s website).

Key principles from the EIPG’s webinar

During the webinar, Dr Borman gave a comprehensive picture of the process of Analytical Quality by Design (QbD). The systematic approach to method development starts with the identification of the predefined objectives (Analytical Target Profile, ATP). The understanding and control of the analytical procedure are at the core of the process, and they should be pursued according to principles of ICH Q8. Analytical QbD covers both the drug product (ICH Q8) and the active ingredient (Q11). This means that a similar framework to ICH Q8 and Q11 can be applied also for analytical procedures. The ATP is made up of the sum of performance characteristics, precision, range (including sensitivity), and bias/accuracy.

According to ICH Q2(R1), published in 1994, the objective of validation of an analytical procedure is to demonstrate its suitability for the intended scope. Revision of both guidelines started in 2019, based on a Concept paper published in 2018. ICH Q2(R2) covers the validation of the analytical protocols and reports, while ICH Q14 refers to the development of the analytical procedure and its lifecycle management.

Key features of the new drafts include the fact that no additional expectations / mandated requirements for pharmaceutical analytical scientists are present, the possible use of “enhanced approaches” and the clear link between performance characteristics and their related criteria and the validation study. The Q2(R2) guideline shall apply to both small molecules and biologics and includes the possibility to use prior knowledge (e.g., from development or previous validation) as a part of the validation exercise. Assay for the determination of robustness can be conducted, for example, during development. Other key features highlighted by Dr Borman include the possible use of Platform analytical procedures to reduce the number of validation tests and the possibility to use any type of calibration model (including multivariate calibration).

The expected benefits refer to the possibility to reduce the existing burden associated with post-approval changes to analytical procedures and the use of Established Conditions.

As Dr Borman explained, the ATP could form the basis of a Post Approval Change Management Protocol (PACMP), thus favouring the reporting of changes between technologies at a lower reporting category. A more performance driven and flexible approach to validation is expected following the entry into force of the new ICH Q2(R2) guideline. The selection of validation tests shall be based on the concrete objective of the analytical procedure.

Comments to ICH Q2(R2)

The overview of comments relative to the draft ICH Q2(R2) published by EMA consists of a 72-page document, divided into a first section containing general comments and a second focused on specific comments.

APIC, representing manufacturers of active ingredients and API intermediates, focused on the fact that “uncertainty is not part of the validation whereas it has a reality in practice and part of the discussion between laboratories”. The measurement of uncertainty is also considered linked to the Total analytical error (TAE), a concept that would not be adequately addressed in the guideline.

EFPIA, on behalf of the biopharmaceutical industry, asked for a better connection between the two guidelines ICH Q2 and Q14, starting from the alignment of the respective titles. Improved consistency in the use of some terms was also suggested (e.g. ‘performance criteria’). Improved clarity and greater flexibility should be applied to the concept of working and reportable ranges. The association also asked to provide more examples for multivariate analytical procedures using different models to facilitate the understanding of their validation and lifecycle management.

Medicines for Europe, representing manufacturers of generic and biosimilars, asked to provide a more specific methodology for reportable range validation. The association requested some clarification about the possibility of using the minimal requirements of the performance characteristics for the addendum method validation strategy.

The European Association of Nuclear Medicine (EANM) focused its intervention of radiopharmaceuticals, a class of substances that should be considered a special case and therefore be excluded from the scope of the guidance. The request assumes that other approaches different that those discussed may be applicable and “acceptable with appropriate science-based justification”. The same request also applies to the draft ICH Q14 guideline. The EANM contribution also highlighted aspects specific to radiopharmaceuticals that should be considered, including the strength of the radioactivity content, the unavailability of radioactive standards of the active substance, and the need of specific techniques for radioactivity determination. The suggestion is to refer to the specific guideline on the validation of analytical methods for radiopharmaceuticals jointly developed by the EANM and the EDQM.

According to the International Society for Pharmaceutical Engineering (ISPE), there are many sections of the draft Q2(R2) guideline that may pose challenges due to lack of alignment and fragmentation of contents. A revision of the structure is thus suggested, together with the harmonisation of terms with those listed in the Glossary. ISPE also highlighted the opportunity to better clarify the distinction between validation elements and recommended data applicable to multivariate analytical procedures vs traditional analytical methods.

The ECA Foundation/European QP Association reported a very critical position on the two draft guidelines, clearly stating that ICH Q2 and Q14 should integrate with one another. According to ECA, the corresponding US guideline “USP <1220> is far superior”. Many of the points reported above with respect to the general section of the overview are discussed in more deep detail within the part of the document listing specific comments.

Comments to ICH Q14

The same structure of the document also applies to the 54-page overview summarising the results of the consultation on ICH Q14 guideline.

According to the Plasma Protein Therapeutics Association (PPTA), representing manufacturers of plasma-derived and recombinant analog therapies, the draft would be too focused on chemical methods, with just a residual attention to biological methods.

APIC asked for improved discussion of the capability (and uncertainty) of the method of analysis, a fundamental parameter to assess its appropriateness for the intended use within the defined specification range. According to the association, more specific reference should be made in relation to development data that can be/cannot be used as validation data.

ISPE suggested adopting a more detailed title for the guideline; something similar has also been suggested by EFPIA. ISPE also addressed the issue of reproducibility, that may be influenced by external factors across multiple laboratories. Multivariate analysis is also discussed, suggesting adopting additional requirements for the multivariate elements while maintaining the same approach to other analytical procedures.

EFPIA would prefer to avoid the use of the term “minimal” in favour of other expressions denoted by a less negative connotation (e.g., traditional, suitable/historic, classical, fit for purpose) with reference to the validation approach. The availability of training case studies is considered important to support the alignment between industry and regulatory agencies on expectations for regulatory change management, especially with reference to multivariate models. EFPIA asked that the paragraph discussing the relationship between ICH Q2 and Q14 should not address what should be submitted to regulatory agencies. Discussion of OMICS methods used in quality control of complex biological products should be included in the annexes.

ISPE asked to avoid reference to geographic regions, as the final goal is to reach harmonisation. A clearer statement of the scope would be advisable (a possible example is provided), as well as a better linkage to the ICH Q12 guideline on pharmaceutical product lifecycle management.

Specific comments include the suggestion of the PPTA to define all acronyms at first use in text and to include them in the Glossary. According to Medicines for Europe, it would be advisable to add characterisational assays (other than release/stability) for biosimilars. Furthermore, the scope of the guideline should focus on the risk assessment and availability of the analytical knowledge needed to select the most appropriate method for a specific application. Activities deemed to the submission of the regulatory CTD dossier should remain confined to the complementaryQ2 guideline.


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.