harmonisation Archives - European Industrial Pharmacists Group (EIPG)

Patient involvement in the development, regulation and safe use of medicines


by Giuliana Miglierini The Council for International Organizations of Medical Sciences (CIOMS) has published the CIOMS report on “Patient involvement in the development, regulation and safe use of medicines”. The report marks an important step forward towards a harmonised approach to 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

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


ICMRA, two pilot programmes to optimise regulatory assessment and inspections

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by Giuliana Miglierini

New flexible modalities for the management of regulatory procedures are becoming progressively accepted even for routine activities, upon the experience built during the pandemic. Efforts are ongoing at the global level in order to better harmonise the new approaches. To this instance, the International Coalition of Medicines Regulatory Authorities (ICMRA) has launched two pilot programmes focused, respectively, on the collaborative assessments of chemistry, manufacturing and control (CMC) and Post-Approval Change (PAC) submissions and related regulatory actions and on hybrid inspections.

Each programme is expected to last 1-1.5 years and should see the involvement of at least two regulatory regions, each one conducting three assessments or collaborative hybrid inspections. Recommendations resulting from the pilots shall be published in 2023, representing the basis of an initial common framework for collaborative assessment and hybrid inspections. The initiative follows the results of a workshop organised by ICMRA in July 2021, during which emerged the need for more convergence and reliance across regulatory authorities in order to support the timely supply of critical medicines.

ICRMA has invited industrial sponsors to participate to the initiative, with particular reference to those planning to file an application for a new product or for post approval changes of already approved products to more than one regulatory agency. All details and the procedure for application are available at this link.

Therapeutics which may be object of the submission include both small molecules and biological products. The submission may refer to products for the treatment of Covid-19, other medically necessary/critical medicines or products granted for access to fast-track procedures such as the Breakthrough (US), PRIME (EU) or Sakigake (JP) schemes.

Interested sponsors are required to check with the involved facility’s management to ensure readiness for inspection and possibility to host a collaborative hybrid inspection, with a particular attention to the availability of suitable IT infrastructures and interpretation services, and the possibility to coordinate at least two inspectorates across different time-zones.

Applications are open since 15 June 2022 and have to be forwarded using the EudraLink secure file transfer application provided by EMA. After a rolling review of the applications, starting of the first pilot is scheduled for September 2022.

The general objectives

The main goals of the initiative include the definition of best practices and standards in the quality assessment of CMC-related post-approval changes and collaborative hybrid inspections. A single list of questions to the sponsor or manufacturer should also be delivered, and answers be shared with the participating quality assessors and inspectors.

The exercise should lead to the identification of misalignments and potential areas of harmonization across participating regulatory regions. An improved convergence and collaboration among regulators in specific data expectations and assessment approaches for the assessment of manufacturing facilities for Pre-Approval and Pre-License Applications (PAIs & PLIs) and reviewing PACs and PAC Management Protocols may also be supported by the analysis of the data acquired during the two programmes.

Hybrid inspections

Hybrid inspections are based on the collaboration of at least two different National Regulatory Authorities (NRAs), one of which in charge of the on-site inspection activities, the second acting as a remote inspectorate. The respective tasks shall be coordinated and run using virtual technologies, so to enable real-time collaboration in the inspection activities, which should target facilities and products of interest for multiple regulatory agencies (see more details here and here).

The pilot is expected to reduce the need of multiple inspections or facility assessments and to support the identification of the best virtual platforms and information technology (i.e., video) to facilitate concurrent on-site inspection and distant assessment. Focus on the development of a common framework to accommodate time zone differences between the facility location and the distant inspectorates is also expected.

Best practices to prepare and conduct the hybrid inspection are another important outcome, as both the on-site and distant inspectorates needs to obtain from the activities all the information needed to run their respective assessments.

In the critical field of GMP expectations, a possible target of the pilot may be represented by how the inspection is reported and how deficiencies are classified by different regulators. Aligned reports and protocols may also support the sharing of information with other interested ICRMA inspectorates. In any case, each participating authority remains the sole responsible for the evaluation of the outcomes of the inspection and the enforcement of any consequent action, according to its own reference legal framework.

A final protocol describing how to execute a hybrid inspection is a main expected outcome of the fist pilot, to be then applied by the Working Group to evaluate at least 3-5 facilities with at least two regulatory agencies involved in the hybrid assessment.

Collaborative assessment

The second pilot aims to run collaborative quality assessment for a minimum of three different applications and a minimum of three regulatory agencies involved each time. The initial phase of the pilot should see a limited number of regulatory agencies (3-5) participating to the project, on the basis of specific confidentiality agreements.

Sponsors participating to the pilot shall submit a single application for the proposed CMC changes for assessment by multiple regulatory authorities; the initial focus is expected to be on post-approval change management protocols (PACMPs; chapter 4 of ICH Q12) for Covid-19 therapeutics. More in detail, participating regulatory agencies will agree on the procedure to be used for the collaborative assessment. They are expected to share and discuss in advance any information request or comment, prior to the interaction with the applicant. Any participating authority can maintain its independence to issue information requests, but in any case, the so obtained answers shall be shared with other NRAs and assessed on the basis of a common approach, so to avoid the need of multiple independent lists of clarification seeking comments.

The project also aims to achieve a single regulatory decision regarding the joint assessment (see more details here and here).

More specifically, priorities to be addressed should include for example the evaluation of information or data on specifications, stability, and/or PACMP that support site changes or additions.

As for the hybrid inspections, expected outcomes are represented by the identification of the best practices and standards in the quality assessment of post approval changes, including PACMPs, and of potential areas for alignment or harmonisation across regions.

A forum of discussion should be also created in order to facilitate convergence on the basis of such best practices. Each evaluation should lead to the preparation of lessons-learned summaries to share the acquired knowledge; new quality assessment guidance and standards might also be proposed, where appropriate.


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

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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.