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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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Environmental sustainability: the EIPG perspective

March 25, 2024 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

Piero Iamartino

Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the 2000s that specific regulatory interventions have been designed to promote the identification of the different sources of pollution and the determination of possible actions to be taken.

The obligation to submit the result of an environmental risk assessment of a medicinal product at the same time as the application for marketing authorisation was introduced only after the publication of the Environmental Risk Assessment (ERA) guideline issued by EMA in 2006, which sets out the guidelines and describes a series of standard tests to be performed. However, this first piece of legislation immediately highlighted limitations as it was applied only to the marketing of medicines from that moment on, without considering the contribution of medicines with the same active ingredient and neglecting the evaluation of those already authorised and on the market.

Over the following years, the problem of the environmental impact of medicines was tackled more extensively with the launch of several projects promoted by the European Commission in partnership with the EFPIA (IMI: Chem21, iPiE and Premier) which have deepened the characterisation of environmental risks, with the identification of priority criteria to be assigned to interventions and the development of models and tools to measure the sustainability of the processes of manufacture, in particular of active substances.

These important projects in recent years have been added to the initiatives undertaken at the European level with the publication in 2020 of the new European pharmaceutical strategy which defines some specific objectives for the mitigation of the environmental impact of medicines that will be reflected in the upcoming revision of European pharmaceutical legislation and which are part of the broader regulatory acts for the ecological transition envisaged by the Green Deal European.

In light of the above, a gradual transformation of some processes and operating methods carried out by the European pharmaceutical industry is envisaged, starting from the development of a new medicinal product to its distribution and, similarly, adequate regulatory interventions will have to be envisaged on the management of the correct use and disposal of medicinal products since the environmental impact of this last phase of the life cycle of a medicinal product is predominant.

Although these changes involve all professionals working in the pharmaceutical industry, a key role is played by the industrial pharmacist who, due to his professional profile dictated by his university curriculum, has the fundamental knowledge bases to occupy different positions in the industry, covering the entire path of medicine from its conception and manufacture as an active ingredient, its development as a medicinal product and its distribution on the market.

With this in mind, EIPG has started the preparation of a document that analyses the main critical areas of the entire production process of a medicinal product and sets out its position on the interventions considered a priority in a perspective of changes that will lead to the inclusion of new methods alternative material resources and will require new skills.

The first critical area examined is the manufacture of the active ingredient, both for its impact as such on the environment and for the process applied to its manufacture. The problem is particularly relevant for small molecules, while it is substantially insignificant for large molecules and even less so for products based on the use of cellular tissues or biological structures (ATMPs). The fundamental parameters to be considered are the environmental toxicity and the bio-degradability of the product. The problem is how to reconcile these two parameters with the chemical-physical and biopharmaceutical characteristics that an active ingredient must possess to be administered, absorbed and then carry out the desired pharmacological activity. The effort required in the design and screening phase of a new small molecule is the identification of a structural parameter that makes it more eco-friendly without compromising its purpose. Although this criticality does not arise in the case of large molecules and ATMPs, for these active ingredients the environmental impact due to higher energy consumption attributable to the need for low-temperature storage conditions may prevail.

About the production process of small molecules, which today still represent the largest percentage of active ingredients in development and on the market, it is essential to definitively introduce the application of the principles of Green Chemistry, as highlighted by the most recent studies (IMI Premier Project). The prospect is that of a progressive change in the synthesis processes with the use of reagents and less toxic solvents that are entirely recyclable and reusable, as well as the development of a synthesis route that allows the least number of operations, generating the least amount of waste and maintaining the best possible efficiency. It is desirable to increase biocatalysis processes as well as the introduction of more incisive treatments in the management of industrial wastewater to accentuate chemical degradation before their transfer to eternity.

A second large critical area where important changes are expected is the manufacturing processes of the medicine from the active substance to its availability for distribution on the market. Also in this area, interventions can be identified to optimize the use of the resources used, with particular reference to energy consumption and the use of water. These two parameters are already the subject of numerous studies for the development of new energy containment processes with the introduction of innovative plant solutions, and further improvements are expected considering the benefits that derive from them in terms of efficiency and therefore costs.

Among the parameters closely linked to the medicinal product that shows a significant environmental impact, attention must be paid to the packaging materials used in the pharmaceutical industry. A priority intervention must focus on certain widely used plastic materials that are difficult to dispose of and not recyclable, identifying alternative materials with the consequent need to study their compatibility with the medicinal product, especially if used in direct contact, and their impact on the stability profile of the same, as required by the reference standards. Other objectives should be the choice of secondary packaging materials that can be easily recycled by the end user, as well as the reduction of their volume, also favoured by the digitization of the information materials related to them. The implementation of these interventions will require adjustments both to the packaging lines used in the pharmaceutical industry and to the alternative ways of managing products in the transport and distribution phase, with a marked increase in studies for the reuse of packaging materials in line with the principles of the circular economy.

The prospects of the expected changes in the path from the active substance to the medicine will have to be accompanied by an assessment of the possibilities of intervening in the supply chain used by the pharmaceutical industry involving suppliers of active ingredients, materials and medicines. The regulatory guidelines and commitments on actions to improve environmental sustainability will require a progressive review in the management and evaluation of suppliers according to their ability to apply the ecosustainability criteria of their processes, giving preference to those who take this path.

The above analysis, limited to the areas of greatest environmental criticality, highlights the transformations that are expected in the pharmaceutical industry in the coming years with the implementation of the provisions that will be progressively adopted at the European level. We think there should be good coordination between the impositions for environmental sustainability and the need to adhere to pharmaceutical regulatory requirements to facilitate the implementation of changes. This coordination is essential as innovation will be the guiding criterion for the introduction of the required changes to meet the sustainability objectives.


Revision of the PIC/S GMP Guide: Annex 13 and Annex 16

April 1, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The entry into force of EU Regulation 536/2014 “Clinical trials”, at the end of January, resulted in the parallel updating of some international guidelines. In particular, a new version of the GMP Guide PE016 was published by PIC/S (Pharmaceutical Inspection Co-operation Scheme) on 1st February 2022. The revision included Annex 13 on the manufacturing of Investigational Medicinal Products (IMPs), and the new Annex 16 on the certification and batch release to be performed by Authorised Persons (AP) (click here to access all PIC/S guidance related to GMP). The revision of PIC/s guidelines is aimed to reflect the last changes occurred in the corresponding EMA documents, so to maintain the alignment between the two regulatory references (as established by the cooperation agreement between EMA and PIC/S). PIC/S has invited all non- EEA Participating Authorities and applicants to transpose the new Annexes 13 and 16 into their own GMP Guides.

The new Annex 16

Annex 16 represents a completely new addition to the PIC/S GMP guide; the EU Annex 16 (part of the EU GMP Guide) was initially considered to be too EU-specific and difficult to transpose for PIC/S purposes. Following a consultation in 2017, PIC/S Participating Authorities agreed to make an attempt to transpose EU Annex 16, as the adaptation may support a better harmonisation of GMP standards at the international level.

Annex 16 refers to both human and veterinary medicinal products which are subject to the PIC/S Participating Authority or are made for export. Furthermore, the Annex applies to investigational medicinal products for human use, “subject to any difference in the legal provisions and more specific guidance published by PIC/S Participating Authorities under national law”. With reference to imported medicinal products, each PIC/S Participating Authority may independently and voluntary decide whether to adopt the guidance as a legally-binding standard.

Certain types of medicinal products (e.g. blood and immunological products) are not addressed by the Annex, as they are regulated by national laws and fall under the competences of National authorities; to this instance, Annex 16 applies to the certification process performed by the AP and to the subsequent release of the batches.

The marketing authorisation holder (MAH) remains the sole responsible for the safety, quality and efficacy of the marketed products. Authorised Persons are required to check each single batch to verify compliance to national and GMP requirements, as well as to those detailed within the marketing authorisation (MA). After certification by the AP, batches of finished products can be transferred to saleable stock and/or export. Specific and documented agreements are needed should this require transfer to a site different from the certification’s one. Authorised Persons should be clearly identifiable, with reference to any quality defect leading to investigation or batch recall. APs certifying the release of the finished product are responsible for verifying the conditions of storage and transport for the batch and the sample, if sent separately, and of all testing required upon importation (including sampling, where needed).

A formal Quality Risk Management (QRM) process is required when sampling is performed at a manufacturing site located in another jurisdiction; Annex 16 provides detailed guidance on the elements to be considered in this exercise. Documentation of the continuous training received by the AP in charge of certification and batch release should be always available, with specific reference to the product type, production processes, technical advances and changes to GMP.

Annex 16 provides detailed guidance on how to conduct the process of certification of each batch of finished product, independently of the number of sites involved. With reference to specific manufacturing or control steps performed at different sites, their respective AP has to provide confirmation of the performed activities, sharing responsibilities with the AP in charge of the final batch release.

The certification process should take into consideration the entire supply chain of both the active substance and the finished product, including manufacturing sites of the starting and packaging materials. The AP responsible for certification should be able to access results of the audits performed at the sites involved, in order to check the consistency of all activities with those described in the MA and within GMPs. Audits run by third parties should reflect requirements set forth in Chapter 7 of the PIC/S GMP Guide.

In particular, suppliers of active substances should comply with GMP and GDP requirements relating to the supply of the active ingredient used to the finished product manufacturing. Excipients should also fulfil GMP requirements, and be possibly manufactured and supplied in accordance with the PI 045-1 guideline. Specific guidance may also apply for other types of products, i.e. biological active substances and medicinal products for human use or radiopharmaceuticals. Annex 16 provides templates for the confirmation letters to be used for the partial manufacturing of a medicinal product and for the content of Batch Certificates.

The revision of Annex 13

Annex 13 has been revised in order to reflect the contents of the new EU Regulation n. 536/2014 on clinical trials, which will replace EU Annex 13. PIC/S Annex 13 discusses the manufacturing of Investigational Medicinal Products (IMP), apart from the reconstitution phase, which is not considered to be part of the process. Provisions set forth by Annex 13 should be taken into consideration with reference to the re-labelling or re-packaging of IMPs and to the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products, occurring in hospitals, health centres or clinics and performed by pharmacists or other persons legally authorised in the country concerned.

All activities should refer to an appropriate Pharmaceutical Quality System to be in place, according to requirements set forth in Chapter 1 of Part 1 of the PIC/S GMP Guide.

 The characteristics of IMPs may intrinsically evolve along the development process, as new data become available that may require changes to, for example, the formulation or the dosage form. This has to be reflected into the respective product specifications and manufacturing instructions, that should also evolve in parallel and be fully traceable and documented. Annex 13 indicates that all deviations should be registered and investigated, and preventive and corrective actions put in place. The new Annex provides detailed guidance on the different items to be considered within the product specification file, as well as for the proper management of personnel, premises and equipment.

All the documentation generated during the clinical development phases should fulfil requirements specified by the PIC/S GMP Guide, Part I, Chapter 4. To this instance, relevant documentation includes specifications and instructions, orders, manufacturing formulae and processing instructions, packaging instructions and batch records. Detailed guidance is provided also for production, including packaging materials and manufacturing operations, the modification of comparator products, blinding operations, and the packaging and labelling of the IMP. Annex 13 also offers guidance on how to perform quality control and batch release, and how to address outsourced operations, complaints and recalls and or the destruction of batches of IMP products.