Annex 21 Archives - European Industrial Pharmacists Group (EIPG)

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

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

ACT EU’s Workplan 2022-2026

by Giuliana Miglierini The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Read more

PIC/S Annual Report 2021

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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.

The new Annex 21 to GMPs

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by Giuliana Miglierini

The new Annex 21 to GMPs (C(2022) 843 final) that EIPG gave a significant contribution in reviewing the original draft and thoroughly presented it within a webinar to its members on August 2020, was published by the European Commission on 16 February 2022; the document provides a guideline on the import of medicinal products from extra-EU countries. The new annex will entry into force six months after its publication, on 21 August 2022. Its contents should be read in parallel with the EU Guide to Good Manufacturing Practice for Medicinal Products and its other annexes, those requirements continue to apply as appropriate.

Annex 21 details the GMP requirements referred to human, investigational and/or veterinary medicinal products imported in the European Union and European Economic Area (EEA) by holders of a Manufacturing Import Authorisation (MIA). The new Annex does not apply to medicinal products entering the EU/EEA for export only, as they do not undergo any process or release aimed to place them on the internal market. Fiscal transactions are also not considered as a part of the new annex.

The main principles

According to Annex 21, once a batch of a medicinal product has been physically imported in a EU/EEA country, including clearance by the custom authority of the entrance territory, it is subject to the Qualified Person (QP) certification or confirmation. Manufacturing operations in accordance with the marketing authorisation or clinical trial authorisation can be run on imported bulk and intermediate products prior to the QP certification/confirmation. To this regard, all importation responsibilities for both medicinal products and bulks/intermediates must be carried out at specific sites authorised under a MIA. These include the site of physical importation and the site of QP certification (for imported medicinal products) or QP confirmation (for bulk or intermediate products undergoing further processing).

Marketing authorisation holders (MAHs) for imported products authorised in the EU remain in any case the sole responsible for placing the products in the European/EEA market. Annex 21 requires sites responsible for QP certification to verify an ongoing stability program is in place at the third country site where manufacturing is performed. This last one has to transmit to the QP all the information needed to verify the ongoing product quality, and relevant documentation (i.e. protocols, results and reports) should be available for inspection at the site responsible for QP certification. QP’s responsibilities also extend to the verification that reference and retention samples are available in accordance to Annex 19 of the GMPs, and that safety features are placed on the packaging, if required.

Importation sites should be adequately organised and equipped to ensure the proper performance of activities on imported products. More specifically, a segregated quarantine area should be available to store the incoming products until the occurrence of release for further processing or QP certification/confirmation.

European GMP rules or equivalent standards shall be followed for the manufacturing of medicinal products in third countries due to be imported in the EU. The manufacturing process has to comply to the one described in the Marketing Authorisation (MA), the clinical trial authorization (CTA) and the relevant quality agreement in place between the MAH and the manufacturer. The respect of EU GMP rules or equivalent standards should be documented through regular monitoring and periodic on-site audits of the third country manufacturing sites, to be implemented by the site responsible for QP certification or by a third party on its behalf.

The QP of the importation site is also responsible for the verification of testing requirements, in order to confirm the compliance of the imported products to the authorised specifications detailed in the MA. The verification of testing requirements can be avoided only in the case a Mutual Recognition Agreement (MRA) or an Agreement on conformity assessment and acceptance of industrial products (ACAA) is in place between the European Union and the third country where the production of the medicinal product is located.

All agreements between the different entities involved in the manufacturing and importation process, including the MAH and/or sponsor, should be in the written form, as indicated by Chapter 7 of the EU GMP Guide.

The Pharmaceutical Quality System of the importing site

According to the European legislation (Chapter 1 of the EU GMP Guide), all activities performed in the EU with reference to the manufacturing and distribution of pharmaceutical products should fall under to umbrella of the company’s Pharmaceutical Quality System (PQS). This is also true for sites involved with importation activities, those PQS should reflect the scope of the activities carried out. A specific procedure should be established to manage complaints, quality defects and product recalls.

More in detail, the new Annex 21 establishes that sites responsible for QP certification of imported products (including the case of further processing before export with the exception of investigational medicinal products) have to run periodic Product Quality Reviews (PQR). In this case too, the respective responsibilities of the parties involved in compiling the Reviews should be specified by written agreements. Should the sampling of the imported product be conducted in a third country (in accordance with Annex 16 of the GMPs), the the PQR should also include an assessment of the basis for continued reliance on the sampling practice. A review of deviations encountered during transportation up to the point of batch certification should be also available, and a comparison should be run to assess the correspondence of analytical results from importation testing with those listed by the Certificate of Analysis generated by the third country manufacturer.

Full documentation available at MIA sites

The QP’s certification/confirmation step for an imported batch has to be paralleled by the availability of the full batch documentation at the corresponding MIA holder’s site; in case of need, this site may also have access to documents supporting batch certification, according to Annex 16. Other MIA holders involved in the process may access batch documentation for their respective needs and responsibilities, as detailed in the written agreements. A risk assessment is needed to justify the frequency for the review of the full batch documentation at the site responsible for QP certification/confirmation; the so established periodicity should be included in the PQS.

Annex 21 also lists the type of documents that should be available at the importation sites, including the details of transportation and receipt of the product, and relevant ordering and delivery documentation. This last one should specify the site of origin of the product, the one of physical importation and shipping details (including transportation route, temperature monitoring records, and customs documentation). Appropriate documentation should be also available to confirm reconciliation of the quantities of batches which underwent subdivision and were imported separately.

Requirements set forth in Chapter 4 of the GMPs apply to the retention of the documentation; the availability at the third country manufacturing site of an adequate record retention policy equivalent to EU requirements shall be assessed by the site responsible for QP certification. Should it be appropriate, translations of original documents and certificates should be provided to improve understanding.