The digital transformation of the pharmaceutical and biopharmaceutical industry is proceeding at a rapid pace, in spite of the difficulties in spreading the 4.0 culture, in a homogeneous way, at different company levels. According to a survey published in the Journal of Industrial Information Integration, 64% of multinational companies in the sector are planning to adopt some form of 4.0 principles, first and foremost preventive maintenance and MES (Manufacturing Execution System). However, the degree of knowledge of this topic among employees varies considerably, depending on both the level of seniority and the area in which they operate. Awareness is, for example, very widespread at senior levels (among directors and vice-presidents it is close to 98%), but overall, it stops at 42%.
In addition, there is a 96% probability that those working in Automation and Operations department have a greater awareness of 4.0 principles than operators in Engineering, Quality, Manufacturing, Process Development, Research and Development, Environment, and Health and Safety departments.Meanwhile, the volume of data produced and processed is growing exponentially in Life Sciences, giving companies the opportunity to rapidly integrate digital capabilities into all phases of the production process. This is also because the resulting benefits are significant, as Elvis Graffeo, partner at LifeBee, explains.
What results do your customers achieve in production and logistics through digitization and process overhaul?
From our experience it is clear that, when the digitization of Production and Logistics (more generally Operations) is associated with an overall revision of workflows, it generates a significant improvement in performance, especially in terms of increased productivity (also due to the reduction of timeframes) and compliance. Companies that have undertaken this path with us have seen their performance increase, on average by 20%, fine scheduling timing reduced by 40% and have achieved savings of 20% on Batch Record review. Furthermore, thanks to root cause analysis, they have improved equipment reliability and cut compliance and data integrity costs by 60%.
But there is also a qualitative aspect that should not be overlooked. Having data in digital form makes it possible to manage information in an extremely advanced and effective way compared to traditional paper-based management, which is a given, but above all it makes it possible to simulate different, additional and immediate evaluations in a simple way. Digitalization – in addition to allowing immediate availability of data, its transmission between the various functions, the constant verification of integrity, and the reduction of collection and transfer times – opens the door to Advanced Analytics: from real-time performance evaluation to correlation statistics, up to the use of artificial intelligence for predictive analysis thanks to which it is possible to reduce the failure rate and its associated costs, and increase product quality.
What approaches do you use to achieve these results?
We have been pioneers in designing and supplying Field Integration & Plant Intelligence in Pharma through the LifeBee AIL (Automated Integration Layer) solution. We don't just provide standard solutions for mere digitization; we try to take the opportunity to review the whole production process, we want to create an integrated system, which collects data from the different sectors – in the most automated way possible – and brings them together in a single tool for information management, performance analysis, integrity checks and GMP compliance. The goal is to improve the performance of the entire production system with a digital tool that is secure, controlled, validated and constantly updated.
Can you give us some examples of successful projects?
We have an ongoing project involving two production sites of a medium-large Italian pharmaceutical company: a Pharma preparation site with 16 packaging lines and over 80 pieces of equipment and devices, and an API production site, with five total departments and environmental control systems for a total of over 60 pieces of equipment and devices. This project has two sets of goals. The first strand of intervention focuses on non-GMP aspects and involves the implementation of electronic systems to facilitate data collection and management, in order to improve the overall process, from planning to final settlement. The other branch of the project - more purely GMP - involves implementing a single validated tool for compliance and data integrity. The solution is part of a Digitization Roadmap that has as its ultimate goal the realization of an integrated EBRS (Electronic Batch Recording System) for a completely paperless process starting from a situation, common to many realities, that saw a facility with few integrations, but already equipped with an EBRS system not integrated with the field.
The project was divided into three main phases: the first one concerns the OEE (overall equipment effectiveness) calculation for Pharma packaging lines. Working in collaboration with key users with the LifeBee approach to create a solution that would bring an added value in terms of process improvement (packaging in this case) has allowed to identify and implement a tool for planning, progress and final balance of orders integrated with the field and the ERP system. Over time and always in collaboration with users, this solution has been enriched according to the requests of the users themselves (eg. Balancing resources). The solution developed from OEE calculation has provided significant results in terms of reduction of planning time, detail and control of packaging operations and gave the chance to make comprehensive analysis of the data collected.
The second phase - which is still in progress - concerns the integration of data with GMP relevance for all equipment and devices, for both sites. Here, the approach has been to implement the solution for homogeneous plant areas, and then proceed with roll-outs to other areas or plants. With this approach, the results obtained are gradually accessible by the users; also, the qualification strategy has to consider the project approach and be flexible in relation to that.
The third phase will realize the full paperless EBRS integrated both horizontally with other areas (Laboratories, Quality, Warehouse) and vertically with the various management systems (ERP - Enterprise resource planning, MES - Manufacturing Execution System).
In this project too, the fundamental importance of defining an incremental roadmap emerged, but so did the need for it to be flexible and adapt to changes in the context of the project or in accordance to its findings. Another key to success was the elaboration of partial results for each phase of intervention: having defined measurable and clearly perceptible parameters, the project managed to ensure the necessary involvement of key figures, a fundamental factor for the success of the entire process.
Can you describe the range of your services in this area?
The Automation Integration Layer (AIL) solution, as conceived and designed by LifeBee, aims to fully digitalize the production processes (full paperless) by creating a scalable and integrated data collection and management system that can be integrated both vertically (from the plant to the MES and ERP) and horizontally (between the various Departmental Systems). Thanks to our specific experience in the pharma sector, we have created a solid, validated and absolutely secure system that guarantees full data integrity and total compliance throughout the operating environment. Moreover, AIL can add logics for managing acquired data and/or setting parameters and/or alarm thresholds (e.g., for obsolete and non-validated equipment) in a validated way and therefore with GMP compliant usage. AIL can generate deviations, according to the set parameters, and generate validated exception reports to support the Batch Review process. The collection of large volumes of data on processes, equipment and operator information enables advanced statistical and predictive analysis through the use of artificial intelligence. In this area, LifeBee has also identified innovative solutions based on AI and predictive algorithms.
Why do your customers choose LifeBee to transform their production and logistics systems?
One of the decisive factors is certainly the holistic vision that we can offer, the result of 17 years of experience and over 700 projects in the pharmaceutical sector, one of the most complex and regulated. The quality of the product (drug) has an impact on people's lives, regulations are extremely strict and variable over time and operators must take them into account at every stage of processing; compliance is not an additional parameter of the plant, it must be achieved by design, right from the design of lines and workflows. Knowledge in this field cannot be improvised, as when working on a specific area, it is necessary to take into account all the existing relations with other departments and with all the management systems, especially in the specific context of each company. The entire production process must be reviewed, taking into account the specifics of each situation. The ultimate goal is always reviewing and improving business processes.
Each situation must be evaluated in detail, comparing it with similar experiences, the most suitable best practices must be selected among those available on the market. Together with the stakeholders, we design a sustainable roadmap and solutions suitable for the context. Before implementing solutions, we test their impact on a pilot line, adapting and enriching them according to the partial results. A process that lasts for years, during which we constantly accompany the client.
But doesn't such a customized approach risk being overly expensive?
On the contrary! There are a multitude of solutions available to clients on the market, but choosing the most suitable one is by no means a straightforward process. Generally, a detailed analysis of the client's needs and the specifics of the context will help to identify the most cost-effective solutions and reduce the overall project costs. Sometimes, changing the type or sequence of interventions/projects is enough to achieve savings without sacrificing results. In this context we support software selection processes, with a careful examination of the project requirements, their evolution, and a clear analysis of costs and benefits with possible important economic savings both in selecting, implementing and maintaining the system (TOC).
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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