The new industrial paradigm of digital integration is yet well established in the pharmaceutical sector, where the Industry 4.0 approach takes on the more specific declination of Pharma 4.0. «With this term, we mean the development of a holistic, systemic control strategy to manage the entire life cycle of a medicinal product, and all the factors contributing to the process», explains Dos & Donts’ CEO, Piercarlo Soana.

Processes compliant to the new Annex 1

The integrated approach is also key to the new Annex 1 to GMPs, those final version is expected to be published shortly. «Quality in a pharmaceutical process must be based on Quality Risk Management (QRM), leading to the adoption of a Contamination Control Strategy (CCS). It involves the definition of the critical elements, to then prove the effectiveness of the controls and monitor the adopted measures. This dynamic process recalls the principles of Galileo’s scientific method, and the Deming cycle (Plan-Do-Check-Act) linked to the Japanese-style “lean production” known as Kaizen», adds Piercarlo Soana. The presence of operators in sterile areas is a critical element to be considered, as it represents the main risk factor for contamination. «The number of people working in sterile rooms must be minimised, on the basis of a specific risk assessment», underlines Dos & Donts’ CEO. The design of the facilities and equipment, the utilities, the environmental monitoring and the preventive maintenance should also be considered.

A qualified staff is important

Personnel must be properly trained and qualified before receiving authorisation to enter cleanrooms. «Training must also extend to the staff responsible for cleaning and maintenance. It has to be repeated at least once a year, for example with regard to the correct dressing methods or the simulation of the aseptic process (media-fill), which represent critical elements subject to periodic evaluation», explains Piercarlo Soana. Furthermore, an additional “aseptic process qualification” is required to access grade A and B areas. Should a risk of cross-contamination be identified, Annex 1 establishes that for a certain period of time the personnel who worked in one production department cannot access a different department. «A qualified operator can become “dis-qualified” for a certain time», underlines Soana.

The importance of access control

Control of accesses to sterile areas can be achieved by use of automatic electronic systems in order to authorise a certain operation only if the operator holds a valid credential. The system tracks the code associated with each person, which also contains all information about his/her qualifications and daily actions performed within the plant. «A control system for access to cleanrooms cannot be compared to the ones used to manage payrolls. Even if the technologies are similar, their purposes are completely different, as well as the equipment used, and the functions and characteristics of the software», underlines Piercarlo Soana. «Dos & Donts access control system has been internally designed and built by our engineers; it is calibrated to reflect  the needs typical of areas subject to control of contamination. Its implementation strictly follows the evolution of the legislation». The most adequate technology to track accesses to cleanrooms – also under a usability perspective – is represented by RFID (Radio Frequency IDentification). It consists of a transponder chip (tag) containing the identification code, an antenna governed by the controller and a reading unit used to read the information, that can write the tag’s memory and transmit the data to the central PC control unit.

A case-study on the implementation of access control

«Implementing an access control system is more complex than a simple supply. Teamwork involving both the user and the supplier is needed from the very early steps. Clarity on roles and objectives is a critical factor of success; it is desirable both teams are coordinated by a project leader able to monitor all phases, and to act as the collector point of information within its group», explains Piercarlo Soana. Dos & Donts has collaborated with Liosintex, an Italian company part of the Recipharm Group, to implement a new access control system specifically dedicated to two departments manufacturing, respectively, penicillins and cephalosporins antibiotics. «The need to overcome the use of paper logbooks to record entries/exits from the production departments (including a daily check at the end of each working day) emerged as the result of a inspection run by the Italian regulatory agency AIFA. The agency considered these methods not enough suited to guarantee a preventive block of access for people who had previously operated in one of the two antibiotics’ departments. We run a small manufacturing site, thus we cannot make use of dedicated staff to operate in the different areas. Therefore, our strategy aimed to implement a strong control system. With this respect, we have found a competent and reliable partner in Dos & Donts», explains Federico Barberis Negra, Plant manager and QP at Liosintex.

Planning the monitoring of entrance/exit gates

The first step in the project saw the definition of the entrance/exit gates of the two  antibiotics’ departments needing for the activation of “anti-pass-through laws”. This is particularly true for the gates giving access to areas where the pharmaceutical product is exposed. «A critical issue, for example, was represented by the bulk, lyophilized powders of beta-lactam antibiotics. We had also to take into consideration the structural and dimensional constraints of the facility», explains Federico Barberis Negra. Access to the aseptic areas has been regulated by mean of a Personal Identification Number (PIN) additional to the badge, so to overcome the problem operators cannot bring any object with them in certain sterile areas. «The reading unit checks the operator did not enter another production department in the previous 11 hours. In the case of an absolute need to access, we have requested the intervention of the QA manager in order to remove the block. This approach allowed us to solve the non-compliance received from AIFA. Access control is important also from the point of view of aseptic manufacturing, as it enables the monitoring of the flows of people entering and exiting the different areas, as well as residence times. These data are then verified vs the maximum number established for each area and manufacturing step, as challenged during the process simulation». For Federico Barberis Negra, the adoption of this access control system has proved essential in order to comply with the requests of the regulatory body, avoiding divergences that could potentially cause the issuance of a non-compliance. Furthermore, the availability of a computerised register of accesses has allowed Liosintex to completely eliminate paper documentation, and to better support the editing and revision of the production documents.


About Dos & Donts

Dos&Donts is operating in the Pharma sector since the beginning of the ’90, when it specialised in the development and production of access control and automation systems dedicated to cleanrooms. Its solutions have been implemented in many pharmaceutical facilities world-wide. Following the adoption of the Industry 4.0 paradigm, since 2015 Dos & Donts is being developing a modular and scalable platform to implement integrated solutions in various fields needing for the control and security of manufacturing facilities.

About Liosintex

Liositex’s manufacturing site is located in Lainate, close to Milan (Italy); it is the Recipharm Group’s sterile facility for the lyophilisation of beta-lactam antibiotics. The manufacturing plant has been inspected and approved by the Italian Regulatory Agency AIFA (EU-GMP) and the Japanese Ministry of Health, Labour and Welfare (MHLW); it exports its productions in many international markets, including Japan.


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