Read the first part here Document and data digitisation: an essential practice for conducting GxP Distant Assessment and Remote Inspection in Pharma.
Two years after the start of the COVID pandemic that disrupted not only our lives, but also our way of working, we have learned to juggle, more or less effectively, a thousand new challenges and opportunities for change.
GMP requirements and common surveillance practices that had been established for decades and with which we had become accustomed to dealing have been strongly impacted, and have forced all players in the Life Science world to change their working methods. The same regulatory authorities have been forced to deal with the critical issues related to the impossibility of travelling and reaching the sites to be inspected, and with the even more pressing need to exercise the fundamental role of surveillance essential to ensure public health.
After two years of remote inspections, ICMRA (International Coalition of Medicines Regulatory Authorities) and its COVID-19 working group (1) analyzed the experience gained with the new remote inspection approach and summarized their considerations in an interesting reflection paper.
The members of the ICMRA group all agree that, although remote inspections have been an important tool to carry out the surveillance necessary to ensure public health in the pandemic period, they cannot be considered as a complete substitute for on-site inspections.
The limits identified by inspectors in the execution of remote inspections refer to aspects linked to the relationship between inspector and inspected (e.g. inability to read non-verbal language that often allows to create the climate of trust necessary for the conduction of an effective inspection), inability to intercept structural anomalies or to verify in a rigorous way parts of machines or rooms with difficult access (technical areas, climatic chambers...) due to the limited visual field of the video cameras. Another obstacle to the effective conduct of remote audits was the extensive presence of paper documentation and the consequent difficulty and slowness in making it available.
The level of availability of relevant documentation was also taken into account as a factor that, along with others (such as complexity of activities, type of production -sterile, non-sterile...-, compliance history), determined the authorities' choice to proceed with a remote inspection rather than applying the traditional on-site approach. Accessibility of electronic systems and access to original documents (e.g., SOPs, validation methods, process validation data, machine qualification data, participant medical records, signed informed consent forms, etc.) were seen as necessary factors for conducting an effective remote inspection.
The ICMRA working group found that the application and availability of the technologies needed to perform virtual facility tours (visual technologies & video streaming glasses) and to create platforms for sharing relevant GMP/GCP documents and information were key elements in the successful execution of remote inspections.
In the document prepared by the working group ((1) par 4.1.3), inspectors indicate how videoconferencing tools can also be used to review Data Integrity approaches through, for example, screen sharing of computer systems (a preferred option), data retrieval using a standalone computer, or review of exported audit trails. All of this can, of course, be applied as long as the entire process of making data available in GxP environments occurs under the supervision of Quality Assurance and that the computer systems remain in a validated state.
However, these types of inspections do not only involve the companies' Quality departments. The inspectors' experience has shown that the involvement of IT representatives from both sides in the early stages of logistics discussions and the execution of dry runs have been extremely beneficial, also in order to remove any obstacles related to the use of non-shared software, applications, transfer protocols that could have negatively affected the outcome of the inspection itself.
Some regulatory agencies are currently considering whether to use remote approaches in the future. There has been interest expressed by some inspectors in supplementing or replacing on-site inspection with remote inspection or hybrid approaches, e.g., to address a specific issue, contribute to an application assessment, or verify corrective/preventive actions that became necessary as a result of on-site inspections.
Therefore, after two years of remote inspections, what emerges from the inspectors' feedback is that, although with some limitations and circumscribing the scope of the inspection, the remote approach can be considered a useful tool to enable regulatory agencies to effectively exercise their oversight role in the future.
(*) The working group was chaired by MHRA and had representatives from US-FDA, EMA, Health Canada, Swissmedic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO, and Saudi-FDA.
(1)International Coalition of Medicines Regulatory Authorities (ICMRA) Covid-19 Working Group: Remote GCP and GMP Regulatory oversight inspections. Reflections on the regulatory experience of remote approaches to GCP and GMP regulatory oversight during the COVID-19 Pandemic
The transformation of procedures from paper to knowledge: this was the theme of the webinar organised by LifeBee last March 3, with the patronage of Assolombarda and the original and innovative contribution of Heike Roeder, authoritative voice at international level as executive expert in Digital Solutions for Quality Assurance in Pharma.
A subject that is very important for the future, also in light of the current developments in Pharma.
The webinar, "Digital and 4.0 in Life Science: the transformation of procedures from paper to knowledge", targeted the SOP (Standard Operation Procedure) totem in its traditionally documental and paper-based form, and shows the way to move from document to data and information, in the spirit of genuine digital transformation of processes and mindsets in Life Science.
A successful strategy, judging by the numbers of the webinar, which saw more than 200 participants from 90 companies, mainly in pharmaceutical, API and Medical Device sectors, but also nutraceutical, homeopathic, packaging subcontractors, production machinery and CROs. And 4 participants from the Medicines Agency.
Felice Lopane for Assolombarda gave a brief and significant greeting, reminding us of the ambitious and realistic Life Sciences Hub project: to aim for the development of digital solutions in industry and healthcare, both concretely on the ground and in close connection with the global movement, not least through the chairmanship of the Health & Life Science task force in 2021 of the B20, the G20's business counterpart.
Teresa Minero, CEO and Founder of LifeBee, introduced the 4.0 scenario that acts as humus in the digital transformation of Life Science, and is the coherent framework from document management to knowledge management in the case of SOPs.
In the same way, we should not forget why we should adopt the 4.0 approach in its entirety: to have the right information at the right time and in the right place; to support decisions, large and small, always with a perspective of prediction and guidance; to pursue and improve compliance and, ultimately, to provide quality, effective and safe medicines, at the right price, to the patient.
For this reason, Teresa Minero's LifeBee has been advising Life Science organisations to devise and implement their own roadmap for 4.0, focusing on their areas and goals. A roadmap based on the continuous improvement of processes and which, using the best available methodologies, identifies and defines the projects to be implemented, monitoring their evolution, their path, their budget and their benefits.
Regarding the 4.0 evolution of Quality Assurance processes, recent and settled experience shows and demonstrates the value of the applications of new technologies in predictive analysis for quality management, in the definition and use of KPIs (Key Performance Indicators) for the continuous assessment of processes, in on-demand analysis during inspections and audits, in virtual training for sterile areas, in the categorisation and investigation of Quality Records with the aid of artificial intelligence. Just to give a few examples.
The right framework in which to evaluate the new perspective of digital SOPs: information and knowledge, no longer documents, especially not on paper.
Heike Roeder introduced us to the concept, aims, criteria and practice of digital SOP. A simple idea, revolutionary in its own way, with great cultural value and inviting prospects: moving from documents to information. From the centrality of paper to a focus on process. All processes. A simple idea, which is not trivial without a paradigm shift in mentality and approach. In culture, supported by technology.
The SOP of the future is digital, easy to use, accurate and intuitively easy to understand. It is accessible from anywhere and provides the right information at the right time and in the right place in an attractive personalised format, such as text, voice or image and video.
It is not a distant future, nor is it some kind of luxury: let's see it.
As it should be, let's start with the "why", which in turn is quickly stated.
The reason is well represented by the combination of the evolution of Life Science and the situation of SOPs. Life Science is going through a period of turbulent evolution, with economic pressures, urgent demand for new drugs and vaccines, increasing structural complexity, supply chain transformation, reorganisation, generation change and, at the same time, it has embarked on the road to digitalisation and the increasing adoption of new technologies in many directions.
On the other hand, documentation is increasingly at risk of appearing as a bureaucratic frill rather than an effective support to operations, and with digitisation processes too often resembling 'paper on the glass' (which refers to mere digitisation), rather than a real attempt to add digital value.
So, let's look at the "what". That refers to what it means to move from documents to data or, if you prefer, to digitalise SOPs in terms of holistic transformation.
It means forgetting about documents, and focusing instead on processes: what information is needed at what time?
No less, no more. This is why processes must be designed, their logical and physical steps must be implemented, and each step must be provided with the necessary information in the most appropriate manner: process principles for the supervisor, work instructions for the analyst, technical diagrams for the maintainer (here the most user-friendly interface technologies may finally be useful). In other words, it is necessary to design a process architecture, to define a flow of information that corresponds to it, and to identify appropriate digital solutions: that manage flows and processes, and information as objects, also in integration with other digital systems, such as MES and LIMS.
It is an important transformation, and we have to observe what values are at stake, also by measuring them: performance, organisation, compliance, flexibility. Values such as culture itself, which is both cause and effect of this transformation.
And it is important "how" to implement the transformation, perhaps the most difficult part.
It is a structured path, defining the architecture and structure of the approach, going through standardisation, integrated process coverage, organisation of information modules. In successive steps from the design of the intervention, to the application in well-defined areas, to incremental roll-outs until the whole organisation is covered.
And should we talk about the company's attitude, and the implementation team itself? Yes, we should. But time is short: we'll talk more about this in future webinars.
A quote from Heike Roeder deserves the final space: “Excellent webinar with an impressive large number of experts in the audience. Inspiring to see that digitalization is has reached the industry, the use of innovative digital technologies is progressing. Digitalization offers a new dimension of mastering information in the meaning of “the right information at the right time at the right place”. Especially our SOP Management will benefit from the new digital capabilities to increase compliance, effectiveness and efficiency, and user-friendliness. It was a pleasure for me to share my perspective about the “SOP of the future” and path of transformation towards a data-driven process-oriented information management system.”
The Covid-19 health emergency has confirmed that a digital company is also a resilient company, capable of adapting quickly in the wake of unforeseen events and guaranteeing effectiveness and continuity of its core business processes. In the pharmaceutical industry, this means ensuring that drugs and medical devices - which must meet stringent quality and safety requirements - continue to reach patients in a timely manner.
A LifeBee survey on Laboratories conducted in November 2020 confirmed the role of digitalisation during the Covid-19 pandemic. Responses collected from lab managers and analysts, IT managers and process efficiency managers in more than 30 pharmaceutical companies revealed that:
In fact, those who were ready were able to respond quickly to the emergency and also took full advantage of the opportunities that were created.
For example, a Nomisma survey on generic drugs showed that in March 2020 orders for many products related to the management of the Sars-Cov-2 virus grew - in just one month - between 128% and 782% compared to the previous year. However, only the most innovative companies - which had already implemented many digital tools - were able to react quickly. According to the survey, only 40% of manufacturing companies managed to seize this opportunity, while more than half achieved only ‘partial success' and 7% did not meet the surplus demand at all.
In addition, 60% of respondents cited the availability of a system for complete supply chain traceability and the use of predictive models as essential factors for rapid response in times of emergencies.
The importance of having digital systems already in place in the pharmaceutical industry is also confirmed by the experience of Matteo Santi, compliance and quality director of the Helsinn Group, a Swiss company with a broad portfolio of innovative therapies for cancer and rare diseases, with worldwide distribution.
«In the Lugano office – he explains in his interview – remote working was nothing new, but until then only 20% of employees were using it. In a fortnight, the IT team succeeded in the impossible mission of extending this possibility to 100% of the office staff».
This was possible because Helsinn has invested in digital transformation over the years and many of its processes are now fully electronic and paperless. These include: the lifecycle of GxP documents, (around 3,000 policies, procedures and forms), main processes in Corporate quality management system(change control, deviation, CAPA, Oos), laboratory LIMS systems, batch release, contract review, and ethics and compliance assessment of third parties (about 2,000 collaborations).
Having demonstrated the benefits of a structured digital system, the pandemic has also forced a further acceleration of planned digital transformation programmes. Projects in the pipeline have taken on a new priority and, in pharma companies, a process has begun that is strongly sponsored by top management to complete the digital transformation, building on the lessons learned during the pandemic. The aim is to extend the overhaul process to the majority of operational workflows to make them more agile, streamlined and effective by also initiating the more advanced - or complementary - phases of the programmes.
«The pandemic, in my opinion, was a booster – said Toni Valente, director of Pierrel's Capua plant – and a catalyst for a process that many companies, organisations and civil society itself were planning, but much more gradually. From one day to the next, we found ourselves overturning attitudes, behaviours and organisations that had been consolidated, for better or worse, for years».
To maintain business continuity, Pierrel adopted leaner procedures, which required a different mental and operational approach, and new ways of dealing with its responsibilities. Despite the fact that the plant operates 24 hours a day, seven days a week, more than 30% of the staff in the support structures now work in smart working mode.
Here, too, the information solutions already included in the automation, integration and digital transformation plan have been an indispensable support and for this reason expanded and consolidated.
«I believe that we must evaluate this working scenario by stripping it of the emergency need and replicating its positive aspects, so we can turn what has been achieved into a systematic and fluid process».
Toni Valente, manager of Pierrel's Capua plant
The digital transformation in Pharma companies, however, should not be an extemporaneous response to an emergency, but the result of a precise strategic planning. As Davide Smaldone, Corporate IT Demand Manager at Menarini, explains, in the pharmaceutical industry the goal of digital transformation is not the mere transfer of physical processes to digital media, but the complete overhaul of work processes and their integration into a new, more complete, rapid and effective flow.
«Companies that want to take advantage of this circumstance to change the way they work – says Smaldone – will have to continue this journey by rethinking their processes so that they are natively digital. This is the only way we will be able to implement a solid and lasting change that is equally efficient for employees and companies».
In 2018, the World Health Organization (WHO) had set the goal of creating a guideline that would define a harmonized procedure for the execution of desk assessments by the Authorities, in its WHO Technical Report Series, No. 1010, 2018 (Guidance on good practices for desk assessment of compliance with good manufacturing practices, good laboratory practices and good clinical practices for medical products regulatory decisions). The WHO defines a desk assessment as a process of evaluation, not necessarily On-site, of the level of compliance with GMP, GCP and GLP of organisations involved in the main activities of the Life Science world.
This document makes clear that sharing information about the state of compliance with good manufacturing practices, about quality control and about conduct of clinical trials is essential to allow the authorities to maintain a good level of control over all actors who are called to respect the GxP. Actors are manufacturers of medicines and API (including biologicals and vaccines manufacturers, importers, repackaged or relabelled), but also producers of IMP (investigational medical product), service providers of QCLs, CROs and sites of conduct of clinical trials. The definition of Information sharing reported in the document is interesting: an exchange of data between individuals or entities outside the traditional organisational boundaries, to achieve a common goal in terms of better policies and to deliver better services.This may mean that one party is disclosing information while the other is collecting the information or both parties are mutually disclosing and collecting information.The documentrefers to a common goal, to improve mutual relations both on the part of the authorities and of any other entity involved.
In 2018, desk assessment was an option to encourage better optimisation of inspection resources; today, in the COVID era, the discussion is about remote audit, distant assessment and virtual inspection, which are now a necessity.
Therefore, a transparent, rapid and effective sharing of information and documents between organisations involved in inspection processes is even more important. Today, authorities, business partners and customers are called upon to exercise their role as guarantors and compliance monitors remotely, without being able to see in person the site to be authorised or monitored. Hence, it is essential that they have a true and accurate picture of the compliance status of the company to be inspected.
In paragraph 5.4 of the document, we read those words - which are familiar to those who work in the Life Science world: "...Mechanisms and controls should be established to ensure that the information provided by the applicant is authentic, legible, current and accurate." Only when companies have defined real and solid Data Integrity policies, when they have applied ALCOA (+PLUS) rules for all critical data and information, will it be possible for the Authorities or auditors to effectively and safely exercise their control, even remotely.
The Authority itself shows the way forward: Validated electronic assessment tools (software applications) may be used to perform the desk assessments. Although paper-based systems may also be used, electronic tools are preferred (par. 5.5).
It is therefore advisable to equip oneself with robust digital solutions, well-designed on the specific business processes and therefore able to provide readable, truthful and accurate documents and information, in order to give the right confidence to those who have to monitor us (be it a national or international authority, be it a business partner) that a real environment of Reliance can be built, as desired by the guideline, “PIC/S GMP Inspection Reliance Initiative”.
The importance of building mutual trust before, after and during the conduct of a Distant Assessment necessarily relies on the adequacy of the Document Sharing process. It is no coincidence, in fact, that the first trigger that prevents the possibility of remote monitoring by the Authority is the inability of the site to be inspected to share the requested documentation: "Failure of the site to supply the requested information"(par. 5.3.3 PIC-PI_048_1_Guidance_on_GMP_Inspection_Reliance). This gives us a clear measure of the importance of having clear, accurate, easily shareable and therefore digital information, data and documents.
Only a well-designed and validated digital solution can provide data, information and documents quickly and securely, and where necessary, also in different languages, so as to facilitate the process of understanding by all (operators working on the site and international authorities or customers). Paragraph 5.3.4 of the PIC guideline assigns the Authority the task of carrying out the translation of the documents needed to perform the desk assessment, but also gives the Authority the possibility of requesting this task from the manufacturer.
So, what information and documents should an establishment always have available when it is about to receive a Remote GMP Assessment? Of course, there is no single answer to this question, or rather the answer is: all information and data that together give evidence of a robust and stable compliance system.
Some examples are provided by EFPIA in the document Alternative GMP/GDP Inspection Practices in a Pandemic Situation (COVID-19) and Beyond, where the Site Master File and the Quality Manual with the main system procedures are mentioned to provide a holistic overview of the company's Quality System and of the Annual Product Reviews that include complaints, recalls, variations, validation status and quality defects in order to allow adequate knowledge of the product.
Other indications can be found in the above-mentioned PIC guideline, in which paragraph 5.3.1 indicates as necessary information: Corrective and Preventive Actions related to previous inspections and relevant GMP changes (key people, products, medicinal products...).
However, anyone who has undergone or carried out a GMP inspection knows very well that trust is built duringthe inspection, by making available all the evidence necessary to demonstrate that what is being described is real and demonstrable. To do this, you may need a batch record of a specific batch to show that critical process parameters are kept under control; you may need a training record to show that that specific operator is trained to run that machine; you may need a Change form to give assurance that that new excipient has been fully evaluated by everyone. Also, you may need a chromatogram to show that the titre of an API has been correctly determined, and you may need a non-conformity or out-of-specification recording and management form to give assurance that that particular anomaly has been thoroughly investigated, the cause identified and the problem solved. All this is to enable those who are inspecting us to build up a proper idea of our way of working and our knowledge of good working practices, even more so if they cannot see our facilities, our equipment and our people in person.
Making this enormous amount of information, data and documents available without adequate digital solutions is the equivalent of emptying the sea with a spoon: a huge effort to achieve a result that will never be satisfactory.
EFPIA in its "Reflection paper on optimisation of paper-based inspections"of 26 June 2019 reported that some of its member companies used a full-time resource for 5 days and another 10 experts just to prepare the pre-inspection documentation to prepare a paper-based inspection of the Japanese Authority. This shows us how enormous the effort can be to make relevant GMP data and information available to actors outside our organisation when it is not already in a digital format, which makes it easier to produce and share configurable reports.
Only when we are able to provide all the necessary information in an easy, fast and secure way, we can truly aspire to an effective Remote GMP Audit by the Authorities and by all our professional partners.
An important step in this direction will be to identify one's own 4.0 and digitalisation strategy that leads not only to the introduction of more suitable technologies, but also to the development of new technologies.
An important step in this direction will be to identify one's own 4.0 and digitisation strategy that will not only lead to the introduction of more suitable technologies to securely digitalise processes, data and documentation, but also support the adoption of innovative tools for sharing and communicating between all the different actors involved in remote audits and inspections. These tools (including: Internet of Things, Collaborative Platform, Virtual & Augmented Reality) should be chosen and adopted in a way that provides adequate guarantees of robustness and compliance: all this in order to create the right climate of trust to be able to successfully conduct audits and remote inspections.
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