News from EIPG Archives - European Industrial Pharmacists Group (EIPG)

PIC/S Annual Report 2021

by Giuliana Miglierini The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure Read more

Joint implementation plan for the IVDR regulation

by Giuliana Miglierini Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Read more

Key issues in technical due diligences

by Giuliana Miglierini Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due Read more

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.

Academic Research in industrial pharmacy field

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By Anni Svala

Dear Colleague,

As a part of our University of Helsinki Industrial Pharmacy specialization studies we are conducting a research of remote audits.

The purpose of our academic study is to gather information and knowledge about remote audits together with the company practices and remote audit policies. The study consists of an audit survey created with the Webpropol® survey platform.

On our studies, we research both the Auditor and the Auditee experiences and points of view.

The supervisor of the study is Professor Anne Juppo from University of Helsinki, Faculty of Pharmacy (e-mail: [email protected]).

All responses are anonymous and the respondents cannot be recognized by the survey results.

In case you have experience in both Auditor and Auditee perspective, we would highly appreciate it if you could answer the survey twice, once for each point of view.

The survey material is solely collected for the study purposes to which this invitation to response also includes. All study material is archived and kept on our personal computers for 6 months after the study publication, after which the material is destroyed.

Answering the electronic survey will take approximately 15-20 minutes. Link to the survey is at the end of this letter. This survey has been sent as a sampling to Auditors and quality professionals working in pharmaceutical companies and wholesale distribution companies.

Our study will be completed during summer 2022 and it will be published in an academic journal. Our research is also stored in the publication archive of the University of Helsinki, where it is freely readable.

Please fill in your contact information via separate link after answering the survey questions if you wish to receive the publication when available.

The survey is open until 17 April 2022.

If you have any questions regarding our research feel free to contact us by email.

Link to the survey:

Our utmost gratitude for giving a moment of your time to answer to our survey.

Kind regards,

Terhi Liukko & Anni Svala

University of Helsinki, Faculty of Pharmacy

Industrial Pharmacy Specialization students
[email protected], [email protected]

Draft Guideline on the acceptability of names for human medicinal products

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The scope of this guideline is to provide information on the overall procedure for submitting and reviewing the acceptability of proposed (invented) names for human medicinal products processed through the centralised procedure, as well as detailed guidance on the criteria applied by the Name Review Group (NRG) when reviewing the acceptability of names. The main aim is to promote patient safety as an essential principle.

Based on the experience gathered by the NRG since the last revision of the guideline in May 2014, it became apparent that some areas of the guideline would benefit from further clarifications, in particular with regards to the requirements for acceptability of proposed (invented)1 names of medicinal products processed through the centralised procedure.

This 7th update of the guideline further clarifies specific aspects of the criteria applied to address safety and public health concerns, international non-proprietary names issues and product-specific concerns in proposed (invented) names. This update also provides further information on the conditional acceptability of invented names and the process for bilateral negotiations and proposes changes to the duration of the validity of an (invented) name and the review process of the NRG.

Consultation dates: 16/12/2021 to 16/03/2022

Reference number: EMA/CHMP/287710/2014 Rev. 7

Virtual Symposium: The Post-COVID Era and Pharmacy (report)

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by Jane Nicholson

Luigi Martini, Chief Scientist at the Royal Pharmaceutical Society chaired an EIPG Symposium on the lessons learned from the pandemic and how pharmacists can shape the future in a post-COVID era.

To coordinate the development, authorisation and safety monitoring of therapeutics and vaccines intended for the treatment or prevention of COVID -19, a Task Force was established in April 2020 commented the first speaker, Fergus Sweeney, European Medicines Agency. The EMA is providing guidance for medicine developers and pharma companies to help speed up medicine and vaccine development and how regulatory challenges arising from the pandemic should be addressed. In addition, the Agency is acting as the central coordinator to support Member States in preventing and reducing possible disruptions to the supply of medicines during the pandemic. The EMA is a leading member of the International Coalition of Medicines Regulatory Authorities (ICMRA) involving more than 30m countries and WHO. It is holding bi-weekly policy teleconferences, regular working group meetings and workshops. Regulatory agility, work on vaccine confidence, virus variants, inclusion of pregnant and lactating women in trials and pharmacovigilance collaboration are all under discussion as well as digital transformation of GCP and GMP inspections and clinical trials.

The EMA has opened its procedures to non-EU Authorities (OPEN Initiative) and are sharing scientific expertise, tackling common challenges and enhancing transparency on regulatory decisions. A pilot was launched in December 2020 for Covid-19 vaccines and therapeutics. Authorities in Australia, Canada, Japan, Switzerland and the WHO are participating in the assessments of the Committee for Medicinal Products for Human Use (CHMP) with experts keeping full scientific and regulatory independence, existing confidentiality arrangements and with no role in final Committee decisions.

The Good Manufacturing and Distribution Practices Inspectors Working Group (GMDP IWG) have agreed some regulatory flexibility until the end of the COVID-19 restrictions. These are published in Q and A guidance on the ec.europa website and include automatic extension of validity date for GMP certificates, product specific GMP flexibilities for crucial medicines and non- product specific GMP,GDP and PMF ( plasma master file) specificities. Dr Sweeney discussed distant assessment, cooperation between regulators on post authorisation changes and the challenges of rapid building of manufacturing capacity and the global nature of development and manufacturing.
Looking to the future, he considered a, leaner post-approval change management, harmonisation of data standards, descriptive information assessment and inspection and realisation of the benefits foreseen in ICH Q10 and Q 12. However, he considered that extensive future work with all stakeholders will be needed to bring this about.

For international coordination needed to encourage conduct of large, decision-relevant COVID-19 clinical trials, guidance on the management, methodological aspects and GCP renovation has been proposed and a reflection paper is available for comment. This will modernise ICH E8, clinical trial design principles and ICH E6, GCP clinical trial conduct principles. It is about doing things differently and not just adding more to the status quo and should link to and emphasise ICH E8 focus on achieving quality by good design. Change management is the greatest challenge and adjusting behaviours and attitudism away from preconceived ideas and interests and on to a new better way of working is needed. An evolving regulatory landscape, the accelerated use of digital tools and increased dialogue along the development pathway needs reflection and selection of what works concluded Dr Sweeney.

Speaking from Cambridge, Massachusetts, Derek O’Hagan, Global Head of Vaccine Chemistry and Formulation GSK discussed advances in formulation development strategies for vaccines and what is next. He explained that technological advances continue to expand the range of possible vaccine targets from the old empirical approach (diphtheria, rabies and polio ) to glycol-conjugates (Guillain-Barre, pneumococcal) reverse vaccinology (meningitis B , C.difficile) to new technologies with adjuvants and RNA vaccines.

He noted that adjuvants have been used safely for 100 years and can enhance and extend immune response. GSKs adjuvant systems have been formulated for vaccine delivery but they also contain immune potentiators. An example is an AS01 adjuvant vaccine against Herpes Zoster (shingles). Another such adjuvanted vaccine is AS03, H5N1 influenza vaccine which is much more potent than the same vaccine unadjuvanted. AS03 fulfills several criteria required to be an adjuvant of choice for pandemic vaccines as it enhances immune responses, broadens the response, is antigen sparing and has an acceptable safety profile. GSK is collaborating with several companies on Covid and AS03.

An alternative approach is mRNA vaccines which involve chemically modified nucleotides (e.g. Moderna vaccine). An improvement is self-amplifying mRNA (SAM) vaccines. Self -amplifying mRNA makes many copies of itself intracellularly with the advantage that it produces multiple copies of RNA and an enhanced immune response. SAM drives early and persistent antigen expression versus conventional mRNA in vivo. However, SAM represents a unique delivery challenge including protection against degradation in vivo, facilitating uptake into target cells and enabling endosomal escape. RNA vaccines can simplify product development and enable the rapid production of safe and effective vaccines. They eliminate biologicals in production and have no cell lines to cause problems. There is a generic platform approach to manufacturing and they have a rapid response to newly emerging pathogens. Pre-clinical proof of principle has been achieved for many SAM vaccines. The next steps are to establish robust GMP production and test SAM in human clinical trials.

Mahendra Patel, pharmacy and ethnic minority communities research lead and co-investigator, PRINCIPLE trial at the University of Oxford discussed innovation in trial delivery with COVID -19. This UK study can be joined by patients online, at home from anywhere in the country, regardless of the patient’s background or with which surgery they are registered. PRINCIPLE is the largest platform trial in the world testing treatments in the community setting. This is critical as one of the biggest problems with COVID -19 has been its ability to overwhelm health care systems. Treatments that can be used in the community setting to lessen the severity of the illness and reduce hospitalisations are essential. The aim is to find the most promising treatments and to ensure resources are not wasted on ineffective treatments. As it is a platform trial it can constantly evaluate multiple treatments simultaneously. This provides answers and clinical evidence much quicker, allowing clinicians to stay at the forefront of evidence based knowledge. 2642 general practices have recruited at least one patient and approximately 8000 community pharmacists are promoting engagement with PRINCIPLE.

The PRINCIPLE trial confirmed that two commonly used antibiotics, Azithromycin and Doxycycline are not effective treatment for reducing time to recovery or to reduce the risk of hospitalisation and the recommendation was to cease these treatments unless there are additional indications for which their use remains appropriate. The trial has shown that inhaled budesonide is useful for patients during the early stages of the illness so that general practitioners can prescribe. The product has been included in the clinical guidelines of India and Canada.

There have been new ways of working with virtual trial delivery and innovative recruitment routes. PRINCIPLE has a hybrid recruiting model with both general practices and non-general practice sites. Invitations to participate have been sent to patients using social media. There has been direct National Health Service digital feed of positive cases. Online patient consent has been used with web and telephone follow up. There has been central distribution of medications and study materials and ethnic minorities community engagement. There have been action plans for COVID-19 “hot spots”. There has been UK wide collaboration and support involving pharmacy networks, universities and their communities, pharmacy organisations, research groups and media messaging. PRINCIPLE will continue to evaluate promising drugs and new treatment arms will be opened as potential products are discovered, reviewed and approved.

The last speaker Oksana Pyzik from the School of Pharmacy, University of London discussed future preparedness. She showed this week’s WHO graphs and tables of the current new and total cases and deaths from COVID-19 and the percentage change in weekly cases. Today, 20.9% of the world population has received at least one dose of a COVID -19 vaccine but only 0.8% of people in low income countries have received at least one dose. There should be an elevation of leadership for global health, strengthening of the authority and financing of WHO, investment in preparedness and a new global system of surveillance established said Dr Pyzik. There should be effective national coordination, international financing for global public goods and a platform for tools and supplies.

A high-level Global Health Threats Council should be set up and led by heads of state and governments and IMF should routinely include a pandemic preparedness assessment, including an evaluation of economic policy response plan. Strengthening the supply chain resilience is essential to deal with the fake vaccines, fake chloroquine, fake and unauthorised testing kits for COVID-19, fake surgical masks and fake Covid vaccine certificates. Dr Pyzik commented that Cybercrime has increased and suspicious web domains appeared just a month after the availability of vaccines was announced.