EIPG Training Course: Annex 1

January 29, 2024

Annex 1, Course, eipg, GMP, manufacturing, ML Making Life, modules, Pharmaceuticals, q&a, Sterile products, training

Dear colleagues,

I am very pleased to announce the GMP/Annex 1 Professional Training Course which will be held as 8 webinars of about 2 hours each from the 3rd of April to the 29th of May (one module per week except 1st of May).

EIPG took care of defining the training plan, which is divided into 8 modules covering the entire contents of GMP/Annex 1, and the identification of the trainers who are all highly qualified professionals with specific experience in sterile medicinal products manufacture and control.

EIPG agreed with all trainers that for each module, the text of a few chapters/paragraphs of Annex 1 be presented, explained and commented focusing on the critical requirements and describing the implementation solutions with examples.

A Q&A section will be open as a chat during the training module and all trainers will ensure the presence of time slots for replying to the questions.

EIPG has found MakingLife Srl, an Italian innovative communication company, as a qualified partner to entrust all organizational, technical and commercial features for making this EIPG training course possible.

Though this training was mainly developed for industrial pharmacists who are members of the associations joining EIPG, it is open to all professionals working in the pharmaceutical area who are interested in manufacturing sterile medicinal products.

As EIPG members, you are entitled to a discount of 25% of the price.

When you apply to buy the full course or single modules, you will have to put in a coupon number.

To get your coupon number you can use the following link to the MakingLife platform where you are requested to specify your name, association and e-mail address, which will be also used for the connection to the webinars:

ANNEX 1 Course: EIPG Coupon

To register yourself to this training courses, follow the below link.

Courses And Webinar

You are invited to disseminate this announcement within your association promoting participation in this training course to your colleagues and also within your contact network with other professionals and non-EIPG members.

Piero Iamartino

President, European Industrial Pharmacists Group (EIPG)

A concept paper on the revision of Annex 11

November 18, 2022

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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.

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment

November 4, 2022

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by Giuliana Miglierini

A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject this possibility, that is considered a significant violation of cGMP.

The letter addresses the lack of process validation for the manufacturing of over-the counter (OTC) drugs and of qualification documentation proving acceptance criteria were met and the process was under control. Deficiencies were reflected in the batch records missing important pieces of information. Aspects pertaining cleaning validation were also found critical.

The requests of the FDA

The Warning Letter asks the company to provide the FDA with a full qualification programme of the equipment and facility. This should include a detailed risk assessment for all medicinal products manufactured using shared equipment. Plans are also needed on how to separate the manufacturing areas for pharmaceutical and non-pharmaceutical productions.

Furthermore, the program for cleaning validation should be reviewed to include at least (but not limited to) drugs with higher toxicities or potencies, drugs of lower solubility in their cleaning solvents and that may result difficult to clean. Maximum holding times before cleaning and swabbing locations for areas that are most difficult to clean should be also provided. A retrospective assessment of the cleaning process has to be included in the required CAPA plan; change management for the introduction of new manufacturing equipment or a new product should be also discussed.

The FDA also addressed many other violations, such as the lack of robust laboratory controls, identity testing of incoming raw materials including active ingredients (APIs), and the inability to demonstrate the respect of minimum USP monograph specifications and appropriate microbial limits for drug manufacturing. Management and controls on data integrity were also found deficient.

The European perspective

In the EU, the possibility to use the same equipment and premises for the manufacturing of both pharmaceutical and non-pharmaceutical products can be referred to the provisions set forth by Chapter 3 (Premises and Equipment) of the EU GMPs.

The document clearly states that the “premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination”.

The application of Quality Risk Management principles is used to assess the specific risk of cross-contamination and the consequent measures to be put in place. Dedicated premises and equipment may be needed in some cases, especially if the risk cannot be adequately controlled by operational and/or technical measures, the product has an unfavourable toxicological profile, or relevant residue limits cannot be satisfactorily determined by a validated analytical method. Attention should also be paid to the positioning of equipment and materials, so to avoid confusion between different medicinal products and their components, and to guarantee the correct execution of process controls. Particular provisions are needed in the case dusty materials are used, also with respect to cleaning validation.

All cleaning procedures should be available in written form, designed to allow for an easy and thorough cleaning (including drains, pipework, light fittings, ventilation points and other services). In the case of exposed materials, the interior surfaces of the premises should be smooth and easy to clean and disinfect.

All documentation needed to support the above mention requirements should be prepared according to Chapter 4 (Documentation) of the European GMPs.

EMA’s Guideline on shared facilities

The European Medicines Agency (EMA) published in 2014 a guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.

Threshold values expressed in terms of Permitted Daily Exposure (PDE) or Threshold of Toxicological Concern (TTC) are the key parameters to be used to run the risk assessment. The so determined threshold levels for APIs can also be used to justify carry over limits used in cleaning validation. EMA’s guideline discusses how to address the determination of the PDE, also with respect to specific types of active substances (e.g. genotoxic, of highly sensitising potential, etc.)

The WHO guidelines

The World Health Organisation released in 2011 its GMP guideline Annex 6 (TRS 961) on the manufacturing of sterile pharmaceutical products. Clean areas are the location of choice for such productions. High-risk operative areas for aseptic manufacturing are classified in Grade A, with Grade B representing their background zones. Grade C and D areas are reserved to less critical steps of the production process.

A frequent and thorough sanitation is important, coupled with disinfection with more than one biocide and/or a sporicidal agent, as appropriate. The effectiveness of the cleaning procedure should be closely monitored to exclude the presence of contaminants, both in the form of vital and not vital particulate.

The guideline specifically mentions the case of preparations containing live microorganisms (such as vaccines), that can be prepared in multiuser facilities only if the manufacturer can demonstrate and validate effective containment and decontamination of the live microorganisms. To transport materials, the conveyor belt should be continuously sterilised as a requirement to pass through a partition between a Grade A/B and a processing area of lower air cleanliness.

A “Comparison of EU GMP Guidelines with WHO Guidelines” was published by the German Federal Ministry for Economic Cooperation and Development (BMZ) to support the understanding of differences between the two approaches, and with a special emphasis to the alleged higher costs of implementation and compliance to EU GMPs.

Analysing the requirements relative to premises and equipment, they aim to guarantee the suitability of rooms to the intended tasks, minimise the risk of failure and cross-contamination and ensure easy cleaning and maintenance. According to the BMZ, EU’s and WHO’s requirements are the same, even if the WHO guideline is more detailed in some aspects (to this instance, the BMZ document was published prior to the release of the new Annex 1 to the GMPs). The theme of equipment is also discussed in other WHO guidelines, i.e. the “WHO good manufacturing practices: starting materials” and the WHO guidelines on transfer of technology in pharmaceutical manufacturing.

Cleaning and sanitation should be addressed according to the provisions set forth by the ISO 14644 family of technical standards. Cleaning validation is also treated in Appendix 3 of the WHO TRS 937 Annex 4. Cleaning validation should be used as the main tool to ensure the removal to pre-established levels of all residues of an API of a product manufactured in any equipment with direct contact to the surface, so that the next product manufactured using the same apparatus would be not cross-contaminated.

According to the BMZ, indications on qualification, process validation and cleaning validation contained in Annex 15 of EU GMPs (paragraph 6) should be integrated with the contents of the ICH Q2 guideline. The only two points of the EU GMPs not covered by the WHO’s guide refer to the allowance that toxic or hazardous substances can be substituted under special conditions for the validation process and the indication that “Test until clean” is not considered an appropriate alternative to cleaning validation.

Current inspection trends and new approaches to the monitoring of post-inspection activities

July 8, 2022

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by Giuliana Miglierini

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published its Annual Regulatory GMP/GDP Inspection Survey 2021, highlighting the more recent trends in inspections and how the pandemic affected this critical verification process of pharmaceutical productions. Meanwhile, UK’s regulatory authority MHRA launched the Compliance Monitor Process pilot, aimed to use eligible consultants as Compliance Monitors to supervise companies in the delivery of actions identified in the Compliance Protocol agreed with the regulatory authority.

Main trends in inspections

The main effect of the lockdowns has been the implementation of new ways to run inspections. The recommendation resulting from EFPIA’s report is now for virtual tools combined with onsite presence; to this instance, data gathered in 2021 show that the two modalities of inspection have a similar duration (2.9 days for on-site inspections vs 2.8 days for virtual ones). The report also indicates there is still a backlog of inspections due in 2020, the critical period of the pandemic; suggestions to manage expiring GMP/GDP/ISO-certificates include a one-year prolongation of current certificates, a dedicated communication process between the industry and regulators in the case of issues with the registration in third countries, and a planning of inspections based on the quality history of the site.

Domestic inspections confirming the trend observed since 2016, are almost double of the number of foreign inspections. These last ones focused in 2021 on only 23 countries, compared to the 44 countries visited by inspectors in 2017. EU’s countries were the most visited ones, with some 350 inspections reported vs the 150 of US, confirming the importance of European pharmaceutical manufacturing. According to the report, 2021 saw an increased attention to GDP inspections, while the percentage of sites with no inspections remains stable for six years.

A new mix of inspection tools

The use of new tools, additional to physical on-site presence, has now become a routine possibility accepted by many regulatory authorities. Many different approaches have been tested during the pandemic, including different inspections tools. Different combinations of tools cannot be considered to be equivalent, according to EFPIA. In general, a mixture of physical presence, document review and virtual presence flanked by the sharing of experience, collaboration and reliance is deemed suitable to confirm compliance and capability while supporting a risk-based efficiency.

Data show that the number of virtual inspections was higher in 2020 compared to 2021; the last year saw an increase of on-site presence vs 2020 and a mixture of virtual and on-site inspections. According to the report, only seven European countries have experience with the implementation of virtual inspection tools (Germany, Denmark, Finland, Ireland, Italy, Poland and Sweden). As a consequence, the impact of mixed virtual and on-site domestic inspections in 2021 was lower in EU member states that, for example, in the US, Brazil, Russia and Singapore.

There is still space for improvement

EFPIA’s survey presents the respective advantages and disadvantages of on-site inspections vs virtual tools. The implementation of the new modalities is far from being accomplished, the process is still on the learning curve, says the document.

While the remote, virtual interaction allows for a greater flexibility of the inspection process, it may result stressful for some people; furthermore, it impacts on the way work is organised, as it needs a flexible schedule and time to prepare for the next day meetings. Also, the style of communication changes to become less natural and more focused. Overall, virtual inspections appear to be more efficient when performed in real-time, as it would be for on-site inspections. While being less costly, due to avoiding extensive travelling, virtual inspections require a careful preparation, including the availability of a suitable IT infrastructure and connectivity. Documents are also often required in advance of the meetings to be shared with regulators.

How to further improve inspections

According to EFPIA, the future of inspections calls for improved collaboration and reliance in order to increase the knowledge shared by the different inspectorates and overcome the limits intrinsic to self-dependency. The expected final outcome of the new approach to inspections is an improvement in the decision-making process. Inspection frequency may be set every 1 to 5 years on the basis of a risk-based evaluation.

Collaboration, reliance and delegation appear to be the new mantras to guide the actions of regulators: the focus suggested by EFPIA is on inspections run by domestic authorities, coupled to the implementation of Mutual Recognition Agreements (MRA) to avoid duplication of efforts. According to the report, it would be needed to harmonise the scope of existing MRAs and to establish new ones between the EU and PIC/S participating authorities (e.g. Argentina, Brazil, South Korea, Turkey and UK). The European legislation should be also updated to include the concept of listed third countries, as already in place for the importation of active substances under the provisions of the Falsified Medicines directive.

The report also suggests a qualitative tool that would fulfil the legal requirements for “inspections” and may prove useful to support inspection planning on the basis of the knowledge of the GMP compliance history of the site, the footprint history of critical and major deficiencies and the type of inspection to be run. These elements lead to the identification of the hazards to be considered, including the intrinsic risk and the compliance-related one. The final output of the tool takes the form of a risk-ranking quality metric, to be used to establish the frequency of inspection for a certain site and the number and level of expertise of the required inspectors, as well as the scope, depth and duration of routine inspections.

All these items may form the basis for the drafting of a GMP inspection “Reliance Assessment Report”, which would also include the statement about the name of the hosting national competent authority and the basis on which country reliance has been established. Such a document may be then used to support regulatory decisions. According to EFPIA, the suggested approach would benefit of a better knowledge of the site inspected by the local NCA, a better insight in the local culture and less barriers to the interaction, with optimisation of resources. A better transparency of the inspection process is also expected, as a non-compliant site may negatively impact on the reputation of local inspectorates. Identified pre-requisites to allow the implementation of such an approach are the availability of high-quality standards at the local level and the evaluation of national regulatory systems by and independent body (e.g. PIC/S or the WHO Global Benchmarking Tool).

UK’s pilot of a Compliance Monitor Process

A new approach that may represent a first example towards the new paradigm of collaboration and reliance has been undertaken in the UK, where the Medicines and Healthcare products Regulatory Agency (MHRA) launched in April 2022 a pilot project focused on the Compliance Monitor (CM) Process (see more here and here). The pilot is part of MHRA’s delivery plan 2021-2023 and will focus on the CM supervision process for appropriate GMP and GDP Inspection Action Group (IAG) cases.

According to the MHRA, the new process would allow companies to concentrate on the delivery of the required improvements without the need to use resources to manage MHRA supervision inspections to assess compliance remediation activities. On the regulatory side, the MHRA should be able to concentrate on the delivery of the routine risk-based inspection programme. The risk-based approach to supervision and monitoring is also expected to limit the number of potential shortages of supply.

The CM process is based on the figure of eligible consultants acting as Compliance Monitors (CM) in charge of working with the company to deliver the remediation actions identified in a Compliance Protocol (CP) agreed with the MHRA. The supervision by the CMs is expected to contribute to lower the need of on-site inspections with respect to the current process managed by the IAG. The CP also includes the transmission to MHRA of high-level updates at fixed intervals of time, which should include only exceptions to the agreed timelines or significant related compliance issues which were identified. Once completed the CP protocol, the CM informs the regulatory authority that the company is ready for inspection, so that the MHRA can verify onsite the possibility of its removal from IAG oversight.

CMs will be selected by the involved company from a dedicated register and accepted as suitable for that case by the MHRA. At least five years’ experience in independent audits of GMP/ GDP companies is needed to be eligible as CM. Furthermore, not having been personally the subject of MHRA regulatory action and/or significant adverse findings in the previous three years, a suitable CV and the completion of a MHRA training as CM. All details on requirements for the CM role and application are available at the dedicated page of the MHRA website.

Suitability criteria to act as a CM for the specific case include as a minimum a sufficient experience of the dosage form manufactured, testing activities being performed, or distribution activity being carried out and a written confirmation of absence of Conflict of Interest. These criteria will be assessed by the company selecting the CM.

BIA’s view of the reliance in the UK medicines regulatory framework

The UK’s BioIndustry Association (BIA) contributed to the debate on the reliance in the UK medicines regulatory framework with a Reflection Paper. According to BIA, the MHRA has a well recognised status and history as a valued contributor to the global regulatory ecosystem and a point of reference for the regulatory decision-making which should be preserved also in the future.

BIA recalls the role played by the MHRA in the development of the concept of regulatory reliance at the EU level, as a way to support the agile management of resources and simultaneously focusing on core and innovative national activities across all stages in the product lifecycle. The central concept sees regulators from one country to rely on the decision and assessments of trusted authorities from another country in order to speed up the timeline of regulatory procedures. At the end of the process, each regulator remains fully responsible and accountable for all its decisions.

BIA also highlights the contribution of reliance to the advancement of good regulatory practices and international networks of regulators, so to better allocate resources potentially taking into account also the respective fields of specialisation. The proposal is for a list of accepted reference regulatory authorities as a way to recognise the evolution of partnerships over time. Examples of recognition pathways already active in the UK are the EC Decision Reliance Procedure (ECDRP) and international work-sharing through the Access Consortium and Project Orbis, through which the MHRA may act as the reference regulatory agency in many procedures.

BIA also warns about the risks of a sudden interruption at the end of 2022 of the reliance pathway, that would have a highly disruptive impact on companies and patients.

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

June 3, 2022

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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

FAT and SAT, a critical step for the introduction of new equipment

March 25, 2022

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by Giuliana Miglierini

There are two key moments to be faced to introduce a new piece of equipment in a pharmaceutical plant: a factory acceptance testing (FAT), usually performed by its manufacturer to verify the new equipment meets its intended purpose, prior to approve it for delivery and once arrived at its final destination and installed, a site acceptance testing (SAT) run by the purchasing company and is part of the commissioning activity.

According to an article published in Outsourced Pharma, the commissioning of a new piece of equipment poses many challenges, and criticalities needs to be considered both from the business and regulatory point of view. Pharmaceutical plants are very complex and often customised upon the specific business needs, and the delivery of a new equipment requires the interaction of many different parties, both internal and external to the purchasing company. FAT, SAT and commissioning activities require a careful planning and detailed responsibilities for all participating parties to be included within the Commissioning and Qualification Plan (CQV plan). A possible responsibility matrix is suggested by the authors to provide clarity and ensures ownership of activities.

FAT, assessing the equipment at the manufacturer site

FAT and SAT testing involve the visual inspection of the equipment and the verification of its static and/or dynamic functioning, in order to assess the actual correspondence to the user requirement specifications (URS). While FATs are usually based on simulations of the equipment’s operating environment, SAT testing occurs at the final site after installation, thus it reflects the real operating conditions and environment in order to support qualification.

There are many different elements to be considered during FAT testing, including for example verification of the existing site drainage, piping, or room dimensions, or the position of the handle for accessibility, as well as software design specification, interface, and device integration.

The FAT exercise is always highly recommended, as it is essential to solve in advance (before shipment to the final destination) any error or malfunctioning of the equipment, that otherwise might occur at the purchasing company’s site. This results in the optimisation of the delivery and commissioning process, with important savings in terms of both time and costs for the purchasing company. To ensure for the transparency of FAT testing, the entire procedure (that requires usually 1-3 days, depending on the complexity of the equipment to be verified) is usually performed in the presence of a third party inspector and customer representative.

A comprehensive set of documentation should be always available to support FAT, including URS, drawings, checklists and procedures, calibrations and certifications, data sheets, references, etc. Raw data acquired during FAT are transmitted to the customer for analysis and validation. FAT should take into consideration all aspects relevant to the evaluation of the safety and functionality of the equipment and its compliance to URS, GMPs and data integrity. To this regard, it is also important for the engineering team called to run the new equipment at its final location to learn and share knowledge with the manufacturer along the entire commissioning process, so to increase the first-hand direct experience. According to the article, this is also critical to authorise the shipment of the equipment to the final destination, a step that should always be performed by an authorised, trained, and approved subject matter expert.

SAT acceptance testing

All criticalities emerged during the FAT exercise are then checked again at the final site, after installation and verification; additional test cases may also be added to the SAT protocol to check for potential failure modes. SAT testing is performed once all connections between the new equipment and other machines/softwares are in place, under the real operating parameters, and may be witnessed by a representative of the equipment’s manufacturer.

Results from SATs may thus differ from those obtained from the FAT previously run by the manufacturer. From the regulatory point of view, SAT testing is a key element to demonstrate the compliance of the equipment to GMP requirements and to support the overall quality and safety of pharmaceutical productions. In this case too, many are the possible elements to be inspected and verified, including interlocks, ventilation, internal box pressure, electrical/hydraulic connections and safety systems, visual checks of components, training of the operators, etc.

A plan for each testing phase

FAT planning begins at the very moment of the purchasing company placing the order for the new equipment, and it has to reflect all URS to be checked for acceptability of the manufactured apparatus. This step in the design is critical and calls for a strict and positive communication between the manufacturer and its customers, a key point to take into consideration all elements that should enter the project.

All identified items and procedures to be challenged during FAT and SAT testing are usually addressed within the CQV plan, that connects the design phase to user requirements specifications and the other elements impacting the commissioning and qualification processes (i.e. system impact assessment, design specification, functional risk assessment, hardware / software specifications, Installation / Operational / Performance Qualification), including deviations and change management. The plan specific to SAT testing should include the scope, test specifications and logs, a test summary, the Commissioning report and the final Certificate of Acceptance.

Transparency and a robust statistical approach should represent main targets along the entire commissioning and validation procedure, that may be run with the assistance of external consultants. All activities that shall enter the regulatory dossiers should always be justified and documented, also under the perspective of data integrity. The Outsourced Pharma’s article also suggests paying a particular attention to controls on data provided by the manufacturer in the case a risk-based leveraging is applied.

The new Annex 21 to GMPs

March 11, 2022

ACAA, Agreement on conformity assessment and acceptance of industrial products, Annex 21, clinical trial authorisation, custom clearance, documentation, EU Guide to Good Manufacturing Practice for Medicinal Products, European Commission, full batch documentation, GMP, GMP requirements, Human medicinal products, import of medicinal products, importation responsibilities, importation testing, imported bulk, imported intermediate products, investigational medicinal products, MAHs, Manufacturing Import Authorisation (MIA), marketing authorisation, marketing authorisation holders, MRA, Mutual Recognition Agreement, ongoing product quality, ongoing stability program, periodic on-site audits, Pharmaceutical Quality System, physical importation, PQR, PQS, Product Quality Reviews, QP certification, QP confirmation, Qualified Person, quality agreement, reconciliation of batches, record retention, reference and retention samples, review of deviations, risk assessment, safety features, sampling, segregated quarantine area, site of physical importation, site of QP certification, site of QP confirmation, testing requirements, transportation, veterinary medicinal products

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.

The main contributions to the consultation on the revision of the pharmaceutical legislation

March 4, 2022

academics, active pharmaceutical ingredients, advanced therapy medicinal products, Affordable Medicines Europe, Alliance of Regenerative Medicines, API manufacturing, ARM, ATMP, bedside manufacturing models, biosimilar medicines, Bolar exemption, centralised EU monitoring system, citizens, civil society organisations, combination products, community pharmacists, cross-border healthcare, Decentralised procedure, EFPIA, electronic Product Information (ePI), EU SPC framework, European Commission, GDP, generic manufacturers, genetically modified organisms, GIRP, GMOs, GMP, healthcare professionals, hospital exemption, hospital pharmacists, incentives, innovator industry, MAH, manufacturing, medicine repurposing, Medicines for Europe, medicines shortages, microbiome science, off-patent industry, parallel distributors, patent linkage, PGEU, pharmaceutical compounding, Pharmaceutical Group of the European Union, pharmaceutical industry, pharmaceutical legislation, post-authorisation activities, pricing and reimbursement, public consultation, public service obligations, radiopharmaceutical legislation, rare diseases, RDP, real-world data, redistribution mechanism, Regulatory Data Protection, regulatory framework, Repeat Use Procedure, repurposing, research institutions, revision, Summary Report, supply chain, Variations Regulation, wholesale distribution

by Giuliana Miglierini

The European Commission has published the summary of the outcomes of the public consultation on the Evaluation and revision of the general pharmaceutical legislation, which closed on 21 December 2021. A total of 478 contributions were received, mostly by companies and business organisations (25.10%), non-governmental organisations (19.67%) and business associations (14.02%). At the geographical level, Germany contributed the 18.2% of feedbacks, followed by Belgium (16.7%), and France (9.2%); 12.8% of contributions came from non-EU countries.

Almost half of the respondents (48.1%) are registered in the EU Transparency Register; one third (33.1%) provided also separate position documents. The Summary Report and single contributions to the consultation are available at the Commission’s dedicated webpage.

Large companies represented the main industrial contributors (39%). Feedback from the pharmaceutical sector accounts for 28.4%, those from patient or consumer organisations 13.8%. A great part of the comments from public authorities (26 respondents in total) came from public authorities at national level (82.6%).

The main themes emerged from the answers

The Summary Report provides an outlook of the received comments from the perspective of the different categories of stakeholders.

Key topics of interest for the Industry included the decline of R&D investment and clinical trials in Europe, paralleled by the need of a more attractive regulatory framework for global investment and a facilitated access to value-added products and over-the-counter switching. Slow response rates of regulatory agencies, high administrative costs, convergence of data requirements of EMA and HTA, digitalisation of regulatory processes and optimisation of regulatory pathways for vaccines are other issues looking for solutions.

The impact of parallel trade on the security of supply, a predictable system of incentives for innovative products and unmet medical needs, a strong framework for intellectual property (IP) protection, and attention to the EU manufacturing of active pharmaceutical ingredients (APIs) were also reported.

Some of these topics were also addressed under the perspective of public authorities and healthcare payers. Comparative safety assessments, coherence with the blood, tissues and cells (BTC) legislation, affordability issues due to high prices/monopoly positions, transparency of medicinal product R&D and market launch costs, and abuse of existing incentives are other issues on the table, together with incentives for APIs manufacturing in the EU and a clear framework for medicine repurposing. On the clinical perspective, regulators ask for the inclusion of up-to-date clinical information in the Summaries of product characteristics, and for patient involvement in the definition of unmet medical needs.

The Summary Report also provides feedback on comments received by academics and research institutions, civil society organisations, citizens, healthcare professionals and other respondents. A total of six different campaigns were identified through the statistical analysis of the received answers, addressing respectively the need to update the radiopharmaceutical legislation, medicines shortages and the role of wholesale distribution, incentives for the innovative pharmaceutical industry and for generic manufacturers, access to treatments for rare diseases from the patient perspective, and the integration of microbiome science in the legislation.

EFPIA’s contribution

EFPIA, representing the innovator industry, highlighted the “significant interdependencies between the R&D policy environment and the manufacturing ecosystem downstream”. At the regulatory level, suggestions include the reinforcement of expertise-driven assessment and a more agile centralised authorisation framework, the improvement of expedited pathways framework supporting innovation, an expanded role of EMA in the assessment of drug-device/diagnostic combination products, and the replacement of the paper patient information leaflets with electronic versions.

The impact of further modifications of the EU SPC framework would need a careful assessment, while a Regulatory Data Protection (RDP) would support a better evaluation of products with lower development times, insufficiency/inadequacy of patent protection and new indications.

EFPIA also provides its vision on the sustainability of the off-patent market, including procurement practices and interchangeability of medicinal products. Actions to prevent and mitigate medicines shortages should be differentiated and coordinated at the European level, on the basis of a harmonised definition of shortage. Harmonisation should also represent a target for quality requirements at the global level, as well as for supply chain and GDPs. Other identified barriers at the manufacturing level include manufacturing site authorisations referring only to the local premises specified, full import testing, Official Medicines Control Laboratory testing for vaccines and biologics, and the revision of the Variations Regulation.

Comments from Medicines for Europe

Medicines for Europe, representing the off-patent industry, asks for a fit-for-purpose, efficient and fully digitalised regulatory framework. Among the priorities at the regulatory level are the optimisation of the Decentralised and Repeat Use Procedures. The regulatory framework should also avoid the unnecessary and unethical repetition of clinical studies, so to encourage generic and biosimilar medicines development. Global access and competition in the field of off-patent medicines should benefit of a single global development framework for multiple jurisdictions.

According to Medicines for Europe, the revision of the pharmaceutical legislation should also address the absence of rewards for manufacturers, in order to find a balance with their obligations of supply. As for IP protection, the association asks for the clarification of the Bolar exemption and the legal ban of patent linkage in all EU member states. The availability of multiple API suppliers should be encouraged through a single and efficient assessment of ASMP (Assembling Surfactants-Mucoadhesive Polymers) and API authorisations, and the separation between the regulatory dossier (regulatory assessment-subject of variations) and GMP (subject of inspection) should be introduced; a broader use of virtual inspections should also be promoted.

Other comments from industrial associations

AESGP, representing the self-care industry, considers the incentive of one added year of data protections not sufficient to reward investment in innovative switches. The burden posed by the Sunset Clause is also critical with regard to un-marketed licences, as well as extending the data exclusivity for a new indication or a switch. Stringent pharmacovigilance and post-approval change requirements are considered by AESGP unjustified or disproportionate, due to the limited gains in patient protection. The suggestion is for a risk-based approach for the submission of Risk Management Plans as a part of Market Access Authorisation, based on existing API safety info and provided there are no great differences in conditions of use. At the regulatory level, the applicant should be free to choose the procedure to authorise the product, and all procedures should perform equally and according to defined timelines. A broader definition of unmet needs would allow for more non-prescription medicines to be accessed; differences in the legal status of this type of medicines in different EU’s countries may also affect their availability to patients.

The European Healthcare Distribution Association (GIRP) addressed mainly issues related to medicines shortages. Among these are the need to strengthen the existing obligations for supply chain actors, and a better framework for the implementation of Article 81, paragraph 2 and 3 of Directive 2001/83 in member states legislation, so to place obligations on both marketing authorisation holders (MAHs) and pharmaceutical full-line wholesalers. The latter should be appropriately and continuously supplied by MAHs with the full range of products. Unjustified supply quotas based on legal and ethical grounds should be abolished.

A legal basis should be established for a EU-wide early warning system for anticipated/potential and verified/confirmed shortages for critical medicines. EU-wide harmonised categories for root causes of shortages should be implemented in the shortages databases managed by member states. GIRP also addressed access to market, suggesting pricing and reimbursement for centrally registered products should be separated from the availability of centrally registered products on national markets.

Market access has been addressed also by Affordable Medicines Europe, representing parallel distributors. The suggestion is for the Commission to develop a guidance on the launch of centrally approved products by parallel distributors in markets where the MAHs have not launched. An obligation for MAHs to supply entities launching in markets not covered by MAHs is also envisaged. To better manage withdrawals, Art 123 (2) of Directive 2001/83 should be amended, and a notification by MAHs should be made no less than 12 months before the withdrawal for commercial reasons. MAHs should also compulsory supply entities continuing marketing in markets undergoing commercial withdrawal; in this instance, guidance to member states should be provided on how to delegate pharmacovigilance tasks to another member state where pharmacovigilance data are available, so to limit technical measures aiming to reduce availability and ensure that products can still enter the market.

The Alliance of Regenerative Medicines (ARM), representing producers of advanced therapy medicinal products (ATMP), highlights the risk for Europe of loose positions in the competitive scenarios due to policy and regulatory barriers. According to ARM, all medicines falling under the ATMP definition should undergo the same regulatory requirements. A mandatory centralized procedure of authorisation should be maintained, in order to provide the level of expertise needed for the assessment of these complex products. GMP and pharmacovigilance aspects should be also coordinated at EU level. Bedside manufacturing models or other schemes should be avoided in order to prevent a two-tiered regulatory framework for ATMPs, leading to different quality and safety standards. Hospital Exemption (HE) should also be strictly regulated and harmonised across member states, with application only to individual patients on a case-by-case basis. Accelerated market approval procedures are expected to maintain rigorous regulatory requirements and high-quality standards for ATMPs. A pan-EU infrastructure and standards for collecting, storing and using ATMP-related real-world data, also for regulatory decision-making, is supported. The association asks for changes to the regulatory requirements for medicines containing genetically modified organisms (GMOs). Implementation of the EU cross-border healthcare legislation would support the administration of ATMPs to patients; HTA should be also coordinated at the EU-level.

Obligations accompanying any novel incentives should carefully take into considerations differences compared to traditional pharmaceuticals, as well as withdrawals due to market failures. A new business model is also recommended by ARM to address the shift in cost from chronic to one-time treatment. No modification of the current definition of ATMP to differentiate with respect to BTC products would be needed.

The position of community pharmacists

The Pharmaceutical Group of the European Union (PGEU) also contributed to the consultation with a position paper, providing the perspective of community pharmacists. The document suggests that issues of medicine shortages and patients’ access would require a “bold, ambitious, and coordinated actions at all policy levels”. According to PGEU, the revision of the pharmaceutical legislation should take the form of a new Directive, so to better respect the existing social, cultural and economic differences between European countries, which are reflected in the organisation of their healthcare systems.

An expanded role for EMA in the prevention and management of shortages, in coordination with the HMA, and the availability of a centralised EU monitoring system for (anticipated) shortages of all medicines in the EU would support the improved availability and access for patients. PGEU also asks for a better transparency and timely communication on shortages to affected stakeholders, as community pharmacists are deeply impacted; clarification of European and national laws related to the public service obligations of supply chain actors would also help to improve compliance.

A more effective redistribution mechanism for medicines available on the European market, irrespective of the country of residence of the patient, would help to face health crises and other special circumstances (i.e. the Brexit and its impact on medicines supply in Malta, Ireland and Cyprus). PGEU also suggests that pharmaceutical companies asking for a centralised marketing authorisation for their products should then commercialise them in all member states. Unmet needs of small patient populations may find an answer in pharmaceutical compounding by community and hospital pharmacists; this practice may also help to face shortages in cases where no suitable alternatives are available.

On their regulatory perspective, PGEU suggests that electronic Product Information (ePI) should complement, and not completely replace, printed leaflets. Digitalisation is deemed important also with respect to the exploitation of real-world data for regulatory decision making and Health Technology Assessment. To this instance, the association suggests to consider a rewarding for evidence generation in community pharmacies at the national level, so to better intercept data useful to evaluate the effectiveness, safety, off-label use and therapeutic added value of medicines in practice. According to PGEU, pharmacy organisations should also be better involved in integrated medicines development and post-authorisation activities, in coordination with other actors.

Repurposing of off-patent medicines should be targeted to areas where important public health benefits are likely to be achieved, but attention should be paid not to limit patients access to these medicines for the currently authorised indications. The association of community pharmacists also supports the reshoring of pharmaceutical manufacturing in the EU (e.g. active ingredients, excipients and basic chemical compounds particularly critical in terms of supply), a goal to improve European competitiveness and reduce the direct dependence from extra-EU countries. An improved diversification of the medicines supply chain is also envisaged.

Environmental issues should be tackled by the availability of innovative incentive and business models for the development of new antimicrobials and antibiotics, and a full compliance with environmental quality standards for pharmaceuticals. A coordinated approach among member states to the evaluation of cost-effectiveness and added therapeutic value of new therapies, including HTA, would support the affordability and fiscal sustainability of medicines. According to PGEU, pricing decisions in one country should not negatively impact on patient access in other countries. Cost-effective pharmaceutical care services at national level should be promoted as a mean to support the rational use of medicines through the adequate remuneration.

ICMRA published a Reflection paper on remote inspections

January 21, 2022

aseptic manufacturing, collaborative inspections, CROs, deficiencies, digital technologies, distant assessment, GCP, GMP, health emergencies, hybrid inspections, ICRMA, inspections, inspectors, investigator sites, manufacturing site, on-site inspections, potent active ingredients, quality risk managemet, read-only access, real-time translation services, Reflection paper, regulatory authorities, regulatory compliance, remote assessment, remote inspections, virtual tours

by Giuliana Miglierini

Remote inspections have become a widely used approach since the last two years to ensure the oversight of the compliance of pharmaceutical productions to regulatory requirements, as the prolonged lockdown periods determined by the pandemic made very difficult the maintenance of the regular schedule for on-site inspections.

A Reflection paper on the so gathered experience has been recently published by the International Coalition of Medicines Regulatory Authorities (ICMRA); the document addresses from the point of view of regulatory authorities the many issues encountered to establish appropriate modalities to interact at distance with the industrial counterparts by mean of digital technologies and suggests the best practices for the future. The analysis focused especially on remote GCP and GMP inspections.

The Reflection paper was drafted by a working group chaired by the UK MHRA and inclusive of representatives from the US FDA, EMA, Health Canada, Swiss-medic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO and Saudi FDA.

The lack of a uniform definitions and approaches

Each national competent authority adopted during the pandemic its own approach to remote inspections, evaluating this type of opportunity on a case-by-case basis, making use of established quality risk management principles and tools to reach their decision (par. 3 of the Reflection paper enlists the more widely used parameters for risk assessment and management).Among the factors entering this preliminary evaluation are the regulatory compliance history of the inspectee, the scope of the inspection (pre-approval, routine or for cause), and the inherent risk associated with the activities conducted by the site, the types of products and the need for the product.

The term used to identify the at distance interaction with the company to be inspected also assumed a quite wide variability; “distant assessment”, “remote evaluation”, “desktop assessment” or “remote assessment” are other frequent declinations used to define oversight procedures run by using digital technologies, both at the national and international level.

The choice of the specific term to identify this sort of practice depends upon many different factors, including the type of inspection and of the involved facilities, and the local national legal frameworks governing inspections as well as protection of personal data. The specific areas or sites to be included in the official review of activities, documents, facilities, records, etc. have proved also highly variable, as they may include not only the manufacturing site, but also investigator sites of a clinical trial, the sponsor’s and/or contract research organisation’s (CRO’s) facilities, or any other establishments deemed appropriate by the regulatory authority running the inspection.

Should the preliminary risk assessment had discouraged the possibility to conduct a remote inspection, the on-site inspections were usually postponed until the termination of lockdown measures in the interested countries. Hybrid or collaborative inspections represent another opportunity used to handle critical cases: the first ones involve the assessment or inspection to be conducted using a mix of remote and on-site activities, the second see two or more regulatory authorities collaborating to perform a conjunct inspection of a specific site.

According to the Reflection paper, it thus appears highly unlikely that a unique and fully harmonized approach to remote inspections in all scenarios might be developed for the future. “While the ICMRA group have found remote inspections an enabling tool to maintain at least a minimal regulatory oversight during the pandemic, it is not the view of the group that remote inspections would fully replace an on-site inspection programme”, states the document.

The main issues encountered

The possibility to conduct inspections, evaluations or assessments at a distance/virtually is based on the implicit availability of a robust IT and communication infrastructure; this has proved a fundamental requirement to smoothly share and review all the relevant documentation and ensure access from remote to systems and plants. Virtual tours of the manufacturing facilities are a typical example, for which the availability of solid “hardware and software that can provide an appropriate field of vision, clarity and stabilisation of the picture, while simultaneously facilitating conversation between the inspector and tour host” is essential to enable the real-time transmission of images and sounds captured by the in charge on-site staff by mean of smart devices or more advanced systems as smart-glasses.

In international inspections, the difference in time-zone and the availability of real-time, online translation services have also proved critical in many instances, especially if parallel sessions of discussion were needed. The possibility for inspectors to access on-line the relevant documentation requires the availability of the inspected company to provide credentials to enter in a read-only mode its proprietary document management systems and repositories. To this instance, confidentiality issues often led many companies to provide access to IT systems by mean of a specifically appointed member of the staff, in charge of accessing in real-time the systems and made available all the documentation as indicated by the inspectors.

The main areas of attention

The Reflection paper identifies four different areas for which remote assessment/inspection proved to be particularly useful during the pandemic period.

In the case of virtual tours, the indication coming from ICRMA experts is to limit the use of prerecorded video tours only in exceptional circumstances, and never for inspection of high-risk activities, as the inspector may not be in the right conditions to effectively verify all details needed to evaluate the suitability of the facility.

“Direct access to documentation by inspectors is an expectation, electronically or otherwise, whether the inspection is on-site or remote”, states the Reflection paper. The alternative intervention of site staff may be acceptable, but it should not negatively impact the results of the assessment. Furthermore, this modality may also prove quite time consuming for both the inspector and the inspected company. ICRMA also supports the possibility for regulators to access documentation after the closure meeting, and upon the formal closure of the inspection, in order to facilitate the drafting of the report or to clarify a deficiency already raised.

GCP and GMP inspections

Specific issues for both GCP and GMP inspections are addressed in two dedicated chapters of ICRMA’s Reflection paper.

“It should be noted that within the EU remote inspections at investigator sites are not considered to be feasible”, writes ICRMA. The motivation has to be found mainly in the need to avoid any further impact on the clinical sites during an health emergency like the pandemic, andin the issues posed by local frameworks for data protection. The Reflections paper provides a list of clinical areas not suitable for remote inspection.

As for GMP inspections, not all regulatory authorities adopted the same approach during the pandemic; in general terms, this sort of practice has been judged acceptable by ICRMA to handle emergency situations with restrictions to travels in place, but it cannot fully substitute onsite inspections of manufacturing sites. More specifically, the experience of the past two years shows that remote inspection proved unfeasible for sites requiring detailed observation, as those performing aseptic manufacturing or handling potent active ingredients with low Permitted Daily Exposure.

Automation of aseptic manufacturing

October 29, 2021

ADMA Biologics, advanced therapies, Annex 1, Artificial Intelligence, aseptic manufacturing, aseptic processing, automatic weighing stations, automation, batch size, brushless servomotors, CCS, CIP, cleaning, Cleaning In Place, cleanrooms, CMC dossier, Contamination Control Strategy, defect detection, disposable materials, FDA, fill/finish operations, FMECA, gloveless isolators, GMP, haptic devices, hospital pharmacy, human operators, Jennifer Markarian, microbial monitoring, optimisation, particle sampling, particles reduction, PAT tools, Pharm. Technol. in Hospital Pharmacy, PharmTech, pre-sterilised materials, production “on-demand”, qualification, regulatory risk, reproducibility, risk analysis, risk of contamination, robotic systems, Simulation, single-use materials, SIP, sterilisation, Sterilisation In Place, tailor-made preparations, validation, warehouse management

by Giliana Miglierini

The pharmaceutical industry is often the last industrial sector to implement many new manufacturing and methodological procedures. One typical example is Lean production, those concepts were developed in the automotive industry well before their adoption in the pharmaceutical field. The same may also apply to automation: it appears time is now mature to see an increasing role of automated operations in the critical field of aseptic manufacturing, suggests an article by Jennifer Markarian on PharmTech.com.

The main added value of automation is represented by the possibility to greatly reduce the risk of contamination associated to the presence of human operators in cleanrooms. A goal of high significance for the production of biotech, advanced therapies, which are typically parenterally administered. Automation is already taking place in many downstream processes, for example for fill/finish operations, packaging or warehouse management.

The advantages of the automation of aseptic processes

“The biggest challenges engineers face when designing isolated fill lines are fitting the design into a small, enclosed space; achieving good operator ergonomics; and ensuring all systems and penetrations are leak-tight and properly designed for cleanability and [hydrogen peroxide] sterilization,” said Joe Hoff, CEO of robotics manufacturer AST, interviewed by Jennifer Markarian.

The great attention to the development of the Contamination Control Strategy (CCS) – which represents the core of sterile manufacturing, as indicated by the new Annex 1 to GMPs – may benefit from the insertion of robots and other automation technologies within gloveless isolators and other types of closed systems. This passage aims to completely exclude the human presence from the cleanroom and is key to achieve a completely segregated manufacturing environment, thus maximising the reduction of potential risks of contamination.

The new approach supports the pharmaceutical industry also in overcoming the often observed reluctance to innovate manufacturing processes: automation is now widely and positively perceived by regulators, thus contributing to lowering the regulatory risks linked to the submission of variations to the CMC part of the authorisation dossiers. High costs for the transitions to automated manufacturing – that might include the re-design of the facilities and the need to revalidate the processes – still represent significant barriers to the diffusion of these innovative methodologies for pharmaceutical production.

The elimination of human intervention in aseptic process was also a requirement of FDA’s 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing and of the related report on Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach. According to Morningstar, for example, the FDA has recently granted approval for ADMA Biologics’ in-house aseptic fill-finish machine, an investment aimed to improve gross margins, consistency of supply, cycle times from inventory to production, and control of batch release.

Another advantage recalled by the PharmTech’s article is the availability of highly standardized robotics systems, thus enabling a great reduction of the time needed for setting up the new processes. The qualification of gloves’ use and cleaning procedures, for example, is no longer needed, impacting on another often highly critical step of manufacturing.

Easier training and higher reproducibility of operative tasks are other advantages offered by robots: machines do not need repeated training and testing for verification of the adherence to procedures, for example, thus greatly simplifying the qualification and validation steps required by GMPs. Nevertheless, training of human operators remains critical with respect to the availability of adequate knowledge to operate and control the automated systems, both from the mechanical and electronic point of view.

Possible examples of automation in sterile manufacturing

Robots are today able to perform a great number of complex, repetitive procedures with great precision, for example in the handling of different formats of vials and syringes. Automatic weighing stations are usually present within the isolator, so to weight empty and full vials in order to automatically adjust the filling process.

This may turn useful, for example, with respect to the production of small batches of advanced therapy medicinal products to be used in the field of precision medicine. Robots can also be automatically cleaned and decontaminated along with other contents of the isolator, simplifying the procedures that have to be run between different batches of production and according to the “Cleaning In Place” (CIP) and “Sterilisation In Place” (SIP) methodologies.

The design and mechanical characteristics of the robots (e.g. the use of brushless servomotors) make the process more smooth and reproducible, as mechanical movements are giving rise to a reduced number of particles.

Examples of gloveless fully sealed isolators inclusive of a robotic, GMP compliant arm were already presented in 2015 for the modular small-scale manufacturing of personalised, cytotoxic materials used for clinical trials.

Maintenance of the closed system may be also, at least partly, automated, for example by mean of haptic devices operated by remote to run the procedure the robotic arm needs to perform. Implementation of PAT tools and artificial intelligence algorithms offers opportunities for the continuous monitoring of the machinery, thus preventing malfunctioning and potential failures. The so gathered data may also prove very useful to run simulations of the process and optimization of the operative parameters. Artificial intelligence may be in place to run the automated monitoring and to detect defective finished products.

Automated filling machines allow for a high flexibility of batch’s size, from few hundreds of vials per hour up to some thousands. The transfer of containers along the different stations of the process is also automated. The implementation of this type of processes is usually associated with the use of pre-sterilised, single-use materials automatically inserted within the isolator (e.g. primary containers and closures, beta bags and disposal waste bags).

Automation may also refer to microbial monitoring and particle sampling operations to be run into cleanrooms, in line with the final goal to eliminate the need of human intervention.

Comparison of risks vs manual processes

A comparison of risks relative to various types of aseptic preparation processes typically run within a hospital pharmacy and performed, respectively, using a robot plus peristaltic pump or a manual process was published in 2019 in Pharm. Technol. in Hospital Pharmacy.

Production “on demand” of tailor-made preparations has been identified by authors as the more critical process, for which no significant difference in productivity is present between the manual and automated process. The robotic process proved to be superior for standardised preparations either from ready to use solutions or mixed cycles. A risk analysis run using the Failure Modes Effects and Criticality Analysis (FMECA) showed a lower level of associated risk.

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GMP Archives - European Industrial Pharmacists Group (EIPG)

EIPG Training Course: Annex 1

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment

Current inspection trends and new approaches to the monitoring of post-inspection activities

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

FAT and SAT, a critical step for the introduction of new equipment

The new Annex 21 to GMPs

The main contributions to the consultation on the revision of the pharmaceutical legislation

ICMRA published a Reflection paper on remote inspections

Automation of aseptic manufacturing

News from EIPG