PIC/S GMP Guide Archives - European Industrial Pharmacists Group (EIPG)

Lessons learnt to transition from Horizon 2020 to the new FP10


by Giuliana Miglierini The European Commission published the ex post evaluation of Horizon 2020 (H2020), the FP8 framework programme for research and innovation (R&I) run in years 2014-2020. The report identifies several areas of possible improvement, which may be taken into Read more

Approvals and flops in drug development in 2023


by Giuliana Miglierini Approvals and flops in drug development in 2023 The European Medicines Agency published its annual highlights, showing 77 medicines were recommended for marketing authorisation, and just 3 received a negative opinion (withdrawals were 19). In 2023 some highly expected Read more

Webinar: Oral Colon Drug Delivery - Design Strategies


EIPG webinar Next EIPG webinar is to be held on Wednesday 21st of February 2024 at 17.00 CET (16.00 GMT) in conjunction with PIER and University College Cork. Anastasia Foppoli, will discuss on the various approaches and the general aspects Read more

Swissmedic’s technical interpretation of Annex 1

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by Giuliana Miglierini

New insights on the interpretation of the new Annex 1 to Good manufacturing practices (GMPs) comes from the Swiss regulatory authority Swissmedic, that at the end of October 2023 published the first revision of its Q&As document (you can find it on the Swissmedicines Inspectorate webpage)

The technical interpretation refers to the revised Annex 1 to the PIC/S GMP Guide (PE 009), adopted on 9 September 2022 and entered into force on 25 August 2023 (with the exception of point 8.123 on lyophilisation, which will enter into force on 25 August 2024). The Q&As follow the same scheme and chapters of Annex 1.

Scope and Premises

According to Swissmedic, for certain types of advanced medicinal products (e.g. ATMPs or allogenic and autologous cell therapy products) specific considerations are required with respect to the fact they cannot be terminally sterilised or filtered. The unsterile patient material should also be considered. Requirements of Annex 2A, paragraph 5.29(b) should be followed for aseptic processing, that should be maintained from the time of procurement of cells through manufacturing and administration back into the patient.

Exceptions to the application of Annex 1 need to be always justified: the Contamination Control Strategy (CCS) is the appropriate tool to detail all risk analysis performed on the basis of the specific manufacturing processes under consideration.

As for the Premises, segregated unidirectional flow airlocks for material and personnel for grade A and B cleanrooms are expected in the case of new facilities. Temporary separation of the flows in the airlocks is the minimum requirement for existing facilities, together with a detailed risk analysis to assess the need for additional technical or organisational measures.

The transfer of materials in and out of a critical grade A cleanroom should be based on the careful definition of the technical and procedural measures associated with it. For example, prior introduction of materials in an isolator followed by decontamination is considered possible only for small batches and for materials resistant to VHP treatment. In all other cases, materials have to be sterilised before entering the already sterile isolator. The transfer process is also subject to a risk analysis to be included in the CCS, as well as to measures to control the maintenance of the integrity and functionality of the systems (also with respect to aseptic process simulation, APS).

Swissmedic specifies that the cleanroom sequence for the transfer of materials via airlocks or passthrough hatches is expected to be fulfilled for zones A and B. In the case of the passage from grade A to C, qualification is needed to prove adequacy of the established systems and procedures. The corresponding risk analysis has to be included in the CCS.

Updating equipment to reach full compliance with the new Annex 1 may require high investments. According to the Q&As, older barrier technologies should be subject to an in-depth internal evaluation to assess the need for new technical measures. The document underlines that starting from 25 August 2023 all barrier technologies not compliant with the new Annex 1 are considered deficient, thus companies should start projects to evaluate the upgrading of background cleanrooms and to define CAPA plans and interim measures to reduce risks.

The risk assessment should also include the evaluation of all automated functionalities and processes associated with the use of the isolator and the activities taking place in it. To this instance, Swissmedic highlights that robotic systems may help improving the reproducibility of operations and minimising both errors and manual interventions. Automatic processes are also expected for the decontamination of isolators, while for RABS manual processes might be used, provided they are designed to ensure reproducibility and are subject to validation and regular monitoring. The absence of negative effects on the medicinal product associated to the cleaning or biodecontamination substances used should also be validated.

As for barrier technology systems with unidirectional air flow, air velocity must be defined so that uniform airflow conditions prevail at the working positions where high-risk operations take place. Alternative air speed ranges or measurements at different heights in the system have to be scientifically justified in the CCS.

Utilities and Personnel

The section on Utilities offers additional guidance on systems used for water generation, that should be designed to allow for routine sanitisation and/or disinfection. Procedures are needed to define regular preventive maintenance of the reverse osmosis system, including the regular change of membranes. A suitable sampling schedule should be in place to regularly check water quality. More stringent controls are needed for the sampling of water-for-injection distribution systems, including daily microbial and bacterial endotoxin testing. The monitoring of the process gas should be performed as close as possible before the sterilisation filter.

Adequate training and qualification of all people working in grade A and B areas, including aseptic gowning and aseptic behaviors, is essential. According to Annex 1, this should include an annual successful APS. Swissmedic adds that, even if not explicitly required, practical process simulations, including manual interventions, should be carried out under the supervision of qualified trainers/QA; the company can choose if to integrate these process simulations into the APS.

Production and specific technologies

As for lyophilisation, initial loading patterns must be always validated, and revalidated annually. The Q&As specify cases where revalidation can be skipped, adding that a theoretical reference load is not acceptable. Revalidation has also to include temperature mapping for moist heat sterilisation systems.

Should a closed system be opened, this should be followed by cleaning (if required) and a validated sterilisation process. Alternatively, the system can be opened in a decontaminated isolator; a class A cleanroom with a class B background might be considered only for exceptional cases.

Non-aseptic connections can be carried out for coupling closed systems, provided a validated sterilisation cycle (SIP) occurs prior to use. Sterile aseptic connectors can be used if the supplier was checked and validated; data from the supplier can be used to file the relevant documentation, but handling of these parts has to be included in the APS.

Swissmedic also underlines that piercing a septum with a needle is to be regarded as a breach of the sterile barrier, and thus avoided for ascetic steps. Should this not be possible, temporary measures should be undertaken to prevent contamination.

Tube welding has also to be qualified and validated, and included in the APS if it is part of the aseptic filling process. The advice is to use more reliable systems, to avoid risks of undetected integrity deficiencies.

Critical single use systems (SUS) should always be tested for integrity by the end user on site before they are used in production. In case of difficult to test, small single use systems, the decision not to test their integrity must be justified in the CCS, as well as the decision to make use of test results provided by suppliers. To this instance, Swissmedic underlines that the comprehensive assessment (including quality system, etc.) should cover the SUS manufacturer/ s, as well as any subcontractors involved in critical services or processes.

Furthermore, the intended use of a SUS in the specific manufacturing process represents the basis for setting the respective acceptance criteria. The Q&As also detail the modalities for the visual inspection of SUSs and the possible acceptance of validation data provided by their suppliers.

As for extractables, the end user is expected to assess the data provided by the suppliers in order to define the need for additional evaluation or leachable studies. A redundant filtration step through a sterile sterilising grade filter, to be included as close to the point of fill as possible, is also encouraged, and its absence has to be justified. A risk analysis is required to justify the choice not to include pre-use/post-sterilisation integrity testing (PUPSIT) of sterilising grade filters used in aseptically processes.

Environmental and process monitoring

According to ICH Q9 (R1), the frequency of the risk review should be based on the level of risk determined for the specific process under consideration, as well as on the level of uncertainty of previous assessments. The recommendation of Swissmedic for new plants is to review the risk assessment after the first year of operations, so to take into due consideration the acquired experience. The document also suggests cases where more stringent action limits may be needed, and the type of statistics to be used to establish alert levels.

The use of rapid microbiological methods (RMM) requires validation and demonstration of equivalence with more traditional approaches. Details on the frequency of the interventions and their inclusion in the APS are also discussed, as well as the container/closure configuration and the distinction between liquid filling and lyophilisation.

The APS of campaign manufacturing represents a complex case for Swissmedic, for which the start-of-campaign (including aseptic assemblies if the case) and end-of-campaign studies should be both conducted. The Q&As also confirm that any contaminated unit with a contamination > 0 CFU results in a failed APS and requires the activation of the consequent actions. Production should resume only after completion of a successful revalidation.

Quality control

A university degree or an equivalent diploma in the field of microbiology (or other natural sciences, or medicine) together with a good understanding of the manufacturing processes under consideration are required for the person in charge of supporting the design of manufacturing activities and environmental monitoring.

As for raw materials, the need for microbiological testing should be evaluated taking into consideration their nature and respective use in the process. All specifications should be discussed and justified in the CCS.

Swissmedic also confirms that the bioburden has to be tested on each batch of raw material as incoming control as well as on the compounding solution in which it is formulated before sterile filtration. In the case of products with short shelf life, should an out-of-specification (OOS) event appear after release of the batch, a procedure is needed to inform doctors, patients, and health authorities, and to assess the connected risks and define remediation actions.


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.


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.