Annex 11 Archives - European Industrial Pharmacists Group (EIPG)

Home  /  EMA’s 3-year work plan for the Quality domain  /  Annex 11

Insights to the Industrial Pharmacist role for the future


A concept paper from EIPG Advisory Group on Competencies vol.2, 2023 This paper is an update of the previous EIPG paper and intends to raise awareness of the changing requirements of the professional profile of Industrial Pharmacists for Pharmacists at Read more

EMA’s reflection paper on AI in the pharmaceutical lifecycle


by Giuliana Miglierini The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle Read more

The New Pharmaceutical Legislation


by Jane Nicholson To celebrate the 70th Anniversary of the foundation of the Belgian Association of Industrial Pharmacists (UPIP-VAPI) a Seminar on “The New Pharmaceutical Legislation” was held on 8th September in the European Parliament. The meeting was arranged in Read more

•••

EMA’s 3-year work plan for the Quality domain

July 7, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The European Medicines Agency has released the input notes made by the GMDP Inspectors Working Group (IWG) as for the drafting of the 3-year workplan for the Quality domain. The document, which reflects the objectives of the Network Strategy and Regulatory Science Strategy, addresses many aspects which may affect the overall efficiency of the pharmaceutical supply chain, both at the routine and specific level.

The document identifies a number of strategic goals aimed at improving the overall integrity and resilience of the pharmaceutical supply chain and the product quality, and to optimise the im-pact of new technologies. Description of the tactical goals follows, i.e., the projects and actions to be activated in order to reach the above-mentioned strategic objectives.

Improved traceability of the supply chain

Strategical goals include the enhancement of traceability, oversight and security for both the human and veterinary medicine supply chain. Four different actions are planned at the tactical level, starting from a better sharing of information regarding manufacturers, distributors, pro-ducts and their respective compliance. To this instance, actions to improve EudraGMDP records are expected.

Inspections of the repositories system should also be tackled by means of a liaison with the Ex-pert Group in inspectional procedures. The implementation of the new Veterinary Regulation should be addressed paying attention both to GDP for veterinary medicines and active substances. Improvement of the inspection capacity may benefit from the development of a specific training curriculum for GDP inspectors; to this instance, the IWG suggests a possible collaboration with PIC/S, through the EU4Health Joint Action 11 and the associated Work Programme 6.

Enhanced inspector capacity

Another strategic goal set forth by the GMDP IWG aims to improve inspector capacity building at EU and international level. To this regard, suggested actions include the support to the international API programme, comprehensive of the provisions of the new Veterinary Regulation related to API inspections and controls. Veterinary specific GMP guideline annexes 4 and 5 should be harmonised in collaboration with PIC/S. The collaboration should also include ongoing initiatives on inspection reliance, in order to better identify barriers preventing member states from accepting inspection results from other trusted authorities. PIC/S and the International Coalition of Medicines Regulatory Agencies (ICRMA) should also collaborate with the GMDP IWG to reach an agreement on shared definitions, best practices and harmonised approaches for distant assessment and hybrid inspections. The pilot programme for sterile inspections should be also finalised, with participation of all member states. Routine assessor-inspector joint inspections are suggested, as well as a training course specific to the new Annex 1.

The development of a harmonised, EU level guidance on data integrity is the tool identified by the GMDP IWG to reinforce responsibility of marketing authorisation holders (MAHs) for product quality. This goal may be achieved by adapting the current guidance published in the form of Q&As into Chapter 4 and Annex 11 of the GMP Guide, in collaboration with the WHO and PIC/S. A better attention on MAHs responsibilities and to the supervision of API manufacturers should also build upon the recommendations contained in EMA’s lessons learnt report (LLE) on Nitrosamines.

Critical manufacturing sites and new technologies

The review of long-term risks resulting from dependency on limited number of manufacturers and sites should support a better supply chain resilience. The review should be aimed to the identification of sites manufacturing a significant number of products or producing medical pro-ducts for a significant number of markets within the European economical area (EEA). The GMDP IWG also suggests performing cooperative supervision of these sites between member states and other strategic partners.

A better understanding of the possible implications resulting from the introduction of new manufacturing technologies has been also deemed important to regulate the new supply chains. To this instance, the indication of the IWG is to consider if a specific GMP annex would be re-quired in order to support the adoption of new and innovative technologies. As for decentralised manufacturing, this topic should also be evaluated in the GMP Guide to medicinal products other than advanced therapies.

Amendments to current guidelines

The document of the GMDP IWG details the specific guidelines that would need consideration in view of the proposed interventions.

Many actions are planned to achieve their objectives by the end of 2023. More specifically, the IWG expects to provide the EU Commission with the final text of the GMP for novel veterinary medicinal products and for autogenous veterinary vaccines. GMPs should be also revised to include Nitrosamines LLE recommendations to MAHs, so to ensure adequate quality agreements are in place with manufacturers.

The same deadline should apply to the development of specific training material on ICH Q9, addressing risk identification and risk management. This action would support EU members of the Expert Working Group (EWG) and should be coordinated with the dedicated PIC/S expert circle. A similar action is planned with respect to ICH Q12 on lifecycle management and ICH Q7 (GMP for active substances), as well as to other quality guidelines for veterinary medicines. The GMDP IWG is also expected to support the EWG in developing the new ICH Q13 guideline on continuous manufacturing.

Annex 15 on the Qualification and Validation may be revised by Q2 2024 in order to include considerations on new technology in facilities, products and processes, including also the possible extension of LLE recommendations to APIs.

The end of 2024 is the date indicated for the review of GMPs for advanced therapy medicinal products in order to include the new provisions of the revised Annex 1. The same deadline applies to the possible revision of Annex 16 on the certification by a Qualified Person and batch release, in order to provide further guidance on batch traceability according to LLE recommendations. The end of next year may see also the drafting of the final text of Annex 4 on the manufacture of veterinary medicinal products other than the immunological ones, based on comments received on the concept paper and the resulting draft text. A similar action is planned for Annex 5 on the manufacture of immunological veterinary medicinal products.

Chapter 4 (Documentation) and Annex 11 (Computerised systems) of the GMP Guide should be revised to assure data integrity in the context of GMP. The proposed deadline for these actions is Q1 2026.

Support to scientific advice and communication

A specific chapter of the GMDP IWG document is dedicated to actions deemed to support scientific advice activities. In this case too, target dates are provided for the completion of the different actions. These include the provision to the EU Commission of scientific advice on GMP standards to be included in the implementing act on GMP for veterinary medicinal products and active substances.

At the international level, the IWG plans to continue its efforts to reach a better convergence through existing mutual recognition platforms and programmes and to support the EU Commission to establish and maintain mutual recognition agreements. Collaborations with ICRMA, the EDQM, Chinese and Indian regulators should be also continued, as well as the dialogue with interested parties and stakeholders.


A concept paper on the revision of Annex 11

November 18, 2022 , , , , , , , , , , , , , , , , , , , , , , ,

This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to the participating authorities of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The current version was issued in 2011 and does not give sufficient guidance within a number of areas. Since then, there has been extensive progress in the use of new technologies.

Reasons for the revision of Annex 11 include but are not limited to the following (in non-prioritised order):

  • The document should be updated to replace relevant parts of the Q&A on Annex 11 and the Q&A on Data Integrity on the EMA GMP website
  • An update of the document with regulatory expectations to ‘digital transformation’ and similar newer concepts will be considered
  • References should be made to ICH Q9
  • The meaning of the term ‘validation’ (and ‘qualification’), needs to be clarified
  • Guidelines should be included for classification of critical data and critical systems
  • Important expectations to backup processes are missing e.g. to what is covered by a backup, what types of backups are made, how often backups are made, how long backups are, retained, which media is used for backups, or where backups are kept
  • The concept and purpose of audit trail review is inadequately described
  • Guidelines for acceptable frequency of audit trail review should be provided
  • There is an urgent need for regulatory guidance and expectations to the use of artificial intelligence (AI) and machine learning (ML) models in critical GMP applications as industry is already implementing this technology
  • FDA has released a draft guidance on Computer Software Assurance for Production and Quality System Software (CSA). This guidance and any implication will be considered with regards to aspects of potential regulatory relevance for GMP Annex 11

The current Annex 11 does not give sufficient guidance within a number of areas already covered, and other areas, which are becoming increasingly important to GMP, are not covered at all. The revised text will expand the guidance given in the document and embrace the application of new technologies which have gained momentum since the release of the existing version.

If possible, the revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications. This is an area where regulatory guidance is highly needed as this is not covered by any existing regulatory guidance in the pharmaceutical industry and as pharma companies are already implementing such algorithms.

The draft concept paper approved by EMA GMP/GDP IWG (October 2022) and by PIC/S (November 2022) and released for a two-months consultation until 16 January 2023.


EMA’s consultation on draft Q&As on remote certification of batches by QP

June 3, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The last two years saw the implementation of a high degree of regulatory flexibility as a mean to respond to the many challenges posed by the travel bans consequent to the pandemic. After this “experimental” phase, regulatory authorities are now considering the possibility to allow the routine implementation of some remote procedures in the field of pharmaceutical production.

It is the case of the remote certification/confirmation of batches by the Qualified Person (QP): after the publication of a draft guideline in the form of Q&As (EMA/INS/169000/2022), the European Medicines Agency (EMA) has launched a short public consultation which will remain open up to 13 June 2022. Comments may be sent by email.

The guideline offers EMA’s point of view on the requirements for the physical attendance at the authorised manufacturing site applying to QPs in order to routinely run the remote certification of batches, outside emergency situations. The document has been drafted by the GMDP Inspectors Working Group; it is composed of four questions and their relative answers and it addresses some considerations arising from the experience gained on the application of the guidelines for human and veterinary medicines issued during the pandemic. These last ones were elaborated in cooperation between the European Commission, the Coordination group for Mutual recognition and Decentralised procedures – human (“CMDh”), the Inspectors Working Group, the Coordination group for Mutual recognition and Decentralised procedures – veterinary (“CMDv”) and EMA.

The Agency also warns that the contents proposed by new Q&As’ guideline may be subject to any other interpretation by the European Court of Justice, which is the ultimate responsible for the interpretation of the EU legislation.

The contents of the Q&As

The routine remote certification or confirmation of batches may in future apply to the activities carried out by the QPs within the EU and European Economic Area (EEA), with reference to manufactured or imported human and veterinary medicinal products and investigational medicinal products.

The first answer clarifies that it could be possible for the QP to routinely run remote batch certification or confirmation only if this type of practice is accepted by the relevant national competent authority (NCA) of the member state where the authorised site is located. To this instance, it should be noted that some NCAs may request some specific requirements to authorise the routine remote certification procedure, for example with reference to the location of the QPs.

Should the remote certification be allowed on a routine basis, specific requirements should be met in order to validate this practice, starting from its full compliance to the EU legislation and EU GMP guidelines.

The answer to question 2 specifies that all activities should take place in an EU/EEA country, and that the time spent by the QP at the authorised site “should be commensurate with the risks related to the processes” hereby taking place. To this instance, it is of paramount importance the ability to demonstrate that the QP acting from remote has maintained full knowledge of the products, manufacturing processes and pharmaceutical quality system (PQS) involved in the remote certification/confirmation of batches. That also means that the QP should be highly reliant on the PQS of the authorised site, and this would be only possible by spending an adequate time on-site to verify the adequacy of the PQS with respect to the processes of interest. The pharmaceutical quality system should also include details of all the procedures used for the routine remote certification/confirmation of batches. The possible use of this type of remote procedure by the QP should be also clearly mentioned in the technical agreement governing the relationship between the authorisation holder and the QP, which should also specify all cases requiring the presence on-site of the QP. A robust IT infrastructure should be in place to guarantee the remote access of the QP to all the relevant documentation in the electronic format needed to achieve bath certification/confirmation, according to the provisions described in Annex 16 to the GMPs (Certification by a Qualified Person and Batch Release). To this instance, presence on-site should be always considered to solve issues that cannot properly be addressed from remote. The demonstration of the presence on-site of the QP falls under the responsibility of the Manufacturing/Importers Authorisation (MIA) holders.

These are also responsible to make available to the QPs all the hardware and software needed to guarantee the remote access to the relevant documentation (e.g. manufacturing executions systems, electronic batch records system, laboratory information systems etc.) as well as batch registers. All IT systems used for remote batch release should comply with the requirements of Annex 11 to the GMP (Computerised Systems).

On the same basis, it should be possible for NCAs to contemporaneously access for inspection all documentation and batch registers involved in routine remote certification/confirmation at the authorised site of batch release. MIA holders should also guarantee the QP is the only allowed person to access the batch certification/confirmation function and batch register, that the transferred data are complete and unchanged, and that an adequate system for electronic signatures is in place.

Question 3 simply clarifies that some members states may have some specific requirements about the country of residence of the QP, for example it should be the same where the authorised site involved in the remote certification procedure is located.

The last question discusses technical requirements linked to IT-security and data integrity for remote access, a type of procedure presenting a higher intrinsic risk in comparison to the same activities carried on-site. Here again, the main reference is Annex 11; all equipment and software used for remote certification of batches should always reflect the current technological developments.

Among the suggestions made by the Q&A draft guideline is the precise identification of all hardware transferred off-site to the QP, that should be inventoried and kept updated. Hard disks should be encrypted, and ports not required, disabled.

Attention should also be paid to the configuration of any virtual private network (VPN) used by the QP to improve the security of the connection to the IT infrastructure of the authorised site and to prevent unauthorised accesses. Authentication should be based on recognised industry standards (e.g. two-factor or multifactor authentication, with automatic date of expiry). The transfer of data should be secured by strong transport encryption protocols; assignment of individual privileges and technical controls falls under the responsibility of the MIA holder


PIC/S Annual Report 2021

May 20, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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 has been used to manage important decisions. PIC/S also supported the harmonisation of the distant assessment procedures used by the various regulatory authorities to run GMP inspections during the pandemic period.

The non-binding co-operative arrangement between international regulatory authorities aims to implement harmonised GMP standards and quality systems in support to harmonised inspection procedures. PIC/S’ new strategic plan for 2023-2027 will be presented at the PIC/S 50th anniversary in 2022. The PIC/S Committee has elected Paul Gustafson (Canada/ROEB) as the new Chairperson for the period 2022-2023; he takes the place of Anne Hayes (Ireland/HPRA).

New memberships and re-assessments

Last year saw the entry into the PIC/S scheme of the Brasilian Agência Nacional de Vigilância Sanitária (ANVISA), one of the main regulators of South America, representing the largest market for medicinal products for this geographic area. ANVISA is the 54th member of PIC/S.

Five other membership applications continued the process of assessment. These include the application of Armenia’s Scientific Center of Drug and Medical Technologies Expertise (SCDMTE), that was requested to update its documentation; the preliminary report should be issued soon.

The Bulgarian Drug Agency (BDA) will benefit of a partial assessment of its application, due to the fact the agency already went through an audit under the EMA Joint Audit Programme (JAP) whose report was shared with PIC/S. Health Canada will also collaborate to this assessment under a MRA procedure.

The Jordan Food and Drug Administration (JFDA) also filed a membership application, as well as another regulator from Africa, the Saudi Food & Drug Authority (SFDA), whose preliminary report is soon expected.

Particularly complex is the case of the application by several Competent Authorities of the Russian Federation that jointly submitted a complete membership application in December2020. A larger team, consisting of a Rapporteur and several Co-Rapporteurs, shall be nominated to better manage the procedure. The involved Russian authorities are the Ministry of Industry and Trade of the Russian Federation (Minpromtorg Russia), the Federal Service for Surveillance in Healthcare (Roszdravnadzor), including the “Information and Methodological Center for Expertise, Accounting and Analysis of Circulation of Medical Products” (FGBU “IMCEUAOSMP” of Roszdravnadzor),the Federal “State Institute of Drugs and Good Practices” (FSI “SID & GP”), and the Federal “Scientific Center for Examination of Medical Devices” of the Ministry of Health of the Russian Federation (FSBI ”SCEMD”).

Among authorities undergoing the pre-accession procedure is the Chinese regulatory agency National Medical Products Administration (NMPA), whose application will be assessed by Jacques Morenas (France/ANSM) as Rapporteur and Raphael Yeung (Hong Kong SAR, China/PPBHK) as Co-Rapporteur.

Reviewing of the pre-accession application is also ongoing for the Analytical Expertise Center (AEC) of the Ministry of Health of Azerbaijan, the Bangladesh’s Directorate General of Drug Administration (DGDA, this 2-year timeframe for the pre-accession expired in February 2021, and a new application was required) and the Drug Regulatory Authority of Pakistan (DRAP), that was invited to apply for membership subject to the implementation of the PIC/S GMP Guide.

PIC/S also run a Joint Reassessment Programme (JRP) in parallel with the EU’s JAP to re-evaluate its members for equivalence on a regular basis. In 2021 the JRP included the reassessment of regulatory authorities from Indonesia (NADFC), New Zealand (Medsafe), and South Africa (SAHPRA).

PIC/S also established new contacts in 2021 with other non-member authorities, including Cameroon’s Laboratoire National de Contrôle de Qualité des Médicaments et d’ Expertise, China’s Institute of Veterinary Drug Control, Cuba’s Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Médicos (CECMED), and Montenegro’s Institute for Medicines and Medical Devices.

New guidances and revisions of existing ones

Among the new guidances adopted in 2021 are the Annex 2A for the Manufacture of ATMP for Human Use and Annex 2B for the Manufacture of Biological Medicinal Substances and Products for Human Use, that entered into force on 1 May 2021 (PE 009-15). The documents were finalised by the PIC/S Working Group on the revision of Annex 2 of the PIC/S GMP Guide.

The Working Group on Data Integrity issued two other guidance documents that entered into force on 1 July 2021, the Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1) and a restricted Aide Memoire on inspection of data management and integrity (PI 049).

PIC/S also issued the Good Practice Guidelines for Blood Establishments and Hospital Blood Banks (PE 005) and the related Aide Memoire to Inspections of Blood Establishments and Plasma Warehouses (PI 008), that entered into force on 1 June 2021. The dedicated Working Group will now address the revision of PI 019 (PIC/S Site Master File for Source Plasma Establishments) and PI 020 (PIC/S Site Master File for Plasma Warehouses).

PIC/S and EMA’s joint Working Group on Annex 1 reviewed the comments received to the second public consultation and drafted the final version of the Annex.

The Working Group on Harmonisation of the Classification of Deficiencies is finalising the revision of the PIC/S SOP on Inspection Report Format (PI 013-3) in order to align it with the abovementioned PI 040-1. The Working Group on Controlling Cross-Contamination in Shared Facilities is as well finalising the revision of its Guidance on Cross-Contamination in Shared Facilities (PI 043-1).

PIC/S is also working to harmonise its GMP Guide and Annexes to the rules established by the European Union, in collaboration with EMA through the PIC/S-EMA Joint Consultation Procedure. Many chapters and annexes of the PIC/S-EU GMP Guide were considered during 2021, including Chapter 1 (Pharmaceutical Quality System), Chapter 4 (Documentation) and Annex 11 (Computerised Systems), Annexes 4 and 5 (Veterinary Medicinal Products), Annex 13 (Investigational Medicinal Products), Annex 16 (Certification by an Authorised Person & Batch Release), and Annex21 (GMP Obligations for Importation to the EU).

Virtual training in the pandemic period

Four virtual training events were organised in 2021, among which a PIC/S webinar for inspectors on ICH Q12 (Pharmaceutical Product Lifecycle Management) that was attended by around350 participants from 50 agencies and 44 different jurisdictions.

The webinar on Distant assessment/Remote Virtual Inspection co-organised with the EU Commission Expert Sub-Group on Inspections in the Blood, Tissues and Cells Sectors (IES) was attended by around 325 participants.

The 2021 PIC/S annual seminar was hosted by the Ministry Food and Drug Safety (MFDS) of the Republic of Korea, and saw the participation of 315 inspectors from 54 authorities.

The 2nd meeting of the PIC/S Expert Circle on Controlling Cross-Contamination in Shared Facilities (CCCISF) was virtually hosted and was attended by 375 participants.

Last year saw also the provision of new harmonised and standardised GMP training activities for inspectors under the PIC/S Inspectorates’ Academy (PIA) initiative, a web-based educational centre also involved in setting up a standardised qualification process of inspectors.