safety Archives - European Industrial Pharmacists Group (EIPG)

PIC/S Annual Report 2021


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

Joint implementation plan for the IVDR regulation


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

Key issues in technical due diligences


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

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

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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 guideline on combination products between medicines and medical devices

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by Giuliana Miglierini

The new “Guideline on quality documentation for medicinal products when used with a medical device” (EMA/CHMP/QWP/BWP/259165/2019), adopted by the European Medicines Agency in July 2021, will come into force starting 1st January 2022.

The first draft of the guideline was presented in May 2019; according to EMA, the document aims to solve the often observed issues of inconsistent and/or incomplete data submitted to competent authorities. It also considers the amendment to Annex I of Directive 2001/83/EC introduced by Article 117 of the new Medical Devices Regulation ((EU)2017/745, MDR).

A Questions and Answers document to support in the implementation of the MDR and In Vitro Diagnostic Medical Devices Regulations ((EU) 2017/746) was also published by EMA in June 2021.

Three different combinations with medical devices

The guideline applies to the product-specific quality aspects of a medical device/device part, that may have an impact on the quality, safety and/or efficacy of the associated medicinal product, as defined by a specific risk assessment. The submitted documentation is part of the Quality part of a marketing authorisation dossier. Makers has also to prove the conformity of the device/device part to MDR’s requirements by mean of a EU Declaration of Conformity or CE certification released by the Notified Body that assessed the device.

The products covered by the new guideline include integral products made up of an integral and not reusable combination of the medical device/device part and the medicinal product (where the action of the medicinal product is principal), medical devices placed on the market co-packaged with a medicinal product, and referenced medicinal products to be used in conjunction with a specific medical device described in the product information (SmPC and/or package leaflet) and obtained separately by the user. The classification in one of the above mentioned categories of medicine/device combination impacts the information that should be submitted to competent authorities.

The guideline applies also to medicinal products intended to be used with a Class I medical devices, with electromechanical devices (including active implantable devices), electronic add-ons and digital elements of devices (if expected to impact the benefit-risk assessment of the medicinal product from a quality perspective). Combined advanced therapy products defined under Article 2(1)(d) of the ATMP Regulation fall out of the scope of Article 117, as well as veterinary products, in-vitro diagnostic devices (including companion diagnostics), system and procedure packs regulated under Article 22 of the MDR.

Examples of integral products include medicinal products with an embedded sensor performing an ancillary action, single-use prefilled syringes, pens or injectors, drug-releasing intrauterine devices or pre-assembled, non-reusable applicators for vaginal tablets, dry powder inhalers and preassembled, ready-to-use pressurised metered dose inhalers, implants containing medicinal products whose primary purpose is to release the medicinal product. For this type of products, the safety and performance of the device/device part has to reflect the relevant General Safety and Performance Requirements (GSPRs) described in Annex I of the MDR.

Examples of co-packaged or specifically referenced medical devices include spoons and syringes used for oral administration, injectors needles, refillable or reusable pens/injectors, dry powder inhalers and metered dose inhalers, nebulisers and vaporisers and single use or reusable pumps for medicinal product delivery. These two categories of products should comply with the requirements of the applicable medical device legal framework.

The approach to the overall product quality

The discussion of the quality of the device/device part on the Quality Target Product Profile (QTPP), Critical Quality Attributes (CQA) and overall control strategy of the medicinal product has to be included in the regulatory dossier.

More specifically, for integral products the EU Declaration of Conformity or the relevant EU certificate issued by a Notified Body for the device/device part has to be produced. Should this not be possible, the applicant has to provide an opinion (NBO) on the conformity of the device/device part with the relevant GSPRs, issued by a Notified Body enlisted in the NANDO website.

The information provided with the authorisation dossier shall be assessed by the competent authority to determine the overall benefit/risk ratio of the medicinal product. All information relevant to the device/device part has to be submitted using the usual eCTD format. Data on preexisting combination of the device/device part with an already approved medicinal product can be provided on a case-by-case basis and needs to be adequately justified. Early scientific and/or regulatory advice can be activated in the case of particularly innovative and emerging technologies.

The guideline provides a detailed description of the information to be submitted to competent authorities in relation to each of the different types of device/medicinal products combinations.

Reference is made to Module 1 (Product Information), Module 3.2.P (Drug Product), Module 3.2.A.2 (Adventitious Agents Safety Evaluation) and Module 3.2.R (Regional Information, Medical Device). This last section includes the Notified Body Opinion for integral medicinal products in the form of a summary technical report. Usability studies should be also available in the case supporting information is not included in the dossier, and the device/device part has not been used in the intended user population before, or where other aspects of the intended use, including changes to the clinical setting or use environment, are new or different from the intended use as confirmed by the EU certificate issued by a Notified Body or NBO.

The guideline also highlights the need the device/device part should be as advanced as possible in the development process (e.g. meets relevant GSPRs) by the time pivotal clinical trials commence. Any change to the device occurred during the trials has to be described, evaluated and justified with respect to the potential impact on the quality, safety and/or efficacy of the medicinal product. The guideline also provides information on how to manage the life cycle of the integral, co-packaged or referenced medicinal products.