risk analysis Archives - European Industrial Pharmacists Group (EIPG)

Insights to the Industrial Pharmacist role for the future

A concept paper from EIPG Advisory Group on Competencies vol.2, 2023 This paper is an update of the previous EIPG paper and intends to raise awareness of the changing requirements of the professional profile of Industrial Pharmacists for Pharmacists at Read more

EMA’s reflection paper on AI in the pharmaceutical lifecycle

by Giuliana Miglierini The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle Read more

The New Pharmaceutical Legislation

by Jane Nicholson To celebrate the 70th Anniversary of the foundation of the Belgian Association of Industrial Pharmacists (UPIP-VAPI) a Seminar on “The New Pharmaceutical Legislation” was held on 8th September in the European Parliament. The meeting was arranged in Read more

ECA’s guide to compliant equipment design

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By Giuliana Miglierini

The legislative evolution of the last decades emphasised requirements for equipment used in pharmaceutical productions. This is even more true with the entry into force of the new Annex 1 to the GMPs, characterised by many new requirements impacting on different manufacturing processes (i.e. production of water for injection, sterilisation, Form-Fill-Seal and Blow-Fill-Seal technologies, single use systems, lyophilisation, etc.).

Each pharmaceutical process requires the careful design of the needed equipment in order to provide the expected efficiency and performance. Furthermore, some equipment may be used for different industrial applications (e.g. pharmaceutical, cosmetic or food), thus needing a fine tuning to reflect relevant requirements. In pharmaceutical manufacturing, a further step of complexity may be represented by the need to handle highly potent active pharmaceutical ingredients, requiring isolators to segregate production, etc.

To facilitate the correct design of equipment compliant to GMPs, a new guidance document has been published by the ECA Foundation. The document was initially drafted in German by a task force of experts in pharmaceutical technology and engineering and published by Concept Heidelberg, and it has now been translated in English

Elements relevant to reach compliance

The first part of the document discusses general requirements that should always be part of the design of GMP-compliant equipment. Four different points of attention are listed: the equipment must not adversely affect the product quality, it must be easy to clean, it must comply with applicable technical rules, and it must be fit for its intended use.

As for the first point, “The question is rather what is tolerable without adversely affecting the product quality”, states the guidance. Avoidance of contamination and cross-contamination are the main goals of cleaning activities, both for sterile and non-sterile medicinal products. There are several issues to be taken in mind from this perspective, including the presence of endotoxins, sealing points, the efficiency of cleaning-in-place (CIP) processes, or the presence of unreachable dead leg areas. According to the guidance, the 3D/6D rule for the prevention of dead legs in water systems often used for specification would not always be correctly applied, due to some confusion in terminology. Official GMPs are also deemed “very vague”, as they are not drafted by engineers and apply to an extremely wide range of different equipment and processes. “Consequently, the question is, which technical rules have to be followed or where the actual state of the art can be looked up”, says the document. Many different references are possible, from pharmacopeia monographs and regulatory guidelines, to ISO standards, and other documents published by international professional bodies.

Qualification and calibration of equipment should always be targeted to the specific product, as it is an essential in proving compliance to the intended use. Regulatory compliance of submitted documentation is not less important, and it greatly impacts on change control and implementation of new productive technologies.

Risk analysis (RA) is the tool introduced in 2005 by ICH Q9 to evaluate all items which may impact on the design of productive processes and related equipment. There is no standard methodology to run risk analysis, the choice depends on the process/product under assessment. According to the guidance, RA can be performed both from the perspective of the product and the equipment, the latter being also considered a GMP risk analysis.

Design and choice of materials

Materials (and coating materials where relevant) used to build pharmaceutical equipment should be completely inert. Pharmaceutical equipment must comply with the EC Directive on Machinery 2006/42/EC and DIN EN ISO 14159. The ECA guidance discusses material selection (plastics or stainless steel); hygienic system design is also addressed by many different guidelines, e.g. those published by the European Hygienic Engineering and Design Group (EHEDG). An important item to consider is service life considerations for the materials used (EHEDG Document 32), as well as their chemical-physical characteristics and materials pairing.

Particularly critical are process contact surfaces, as they may impact product quality. Establishment of specific requirements is thus needed. The guidance focuses its attention on austenitic stainless steels (i.e. CrNiMo steels 1.4404 and 1.4435). The main elements to be assessed are the risk of corrosion, the risk of contamination of the product or process medium and the cleanability of the metallic surface. Topography, morphology and energy level are the main characteristics to be used to describe surfaces, addressing respectively the geometric shape, chemical composition and energy required per unit area to increase the size of the surface. The guidance provides a detailed discussion of all different aspects of surface treatment methods, and the hygienic design of open and closed equipment. Other sections discuss the optimal design of pipework and fittings, connections, welding and seam control. Detailed information is also provided on equipment of electrical engineering, measurement and control technology, as well as the process control technology (PCT) measurement and control functions.

A highly critical area within a pharmaceutical facility are cleanrooms, for which the design of the equipment and the choice of materials is even more stringent. Elements to be considered include stability/statics as concerns dynamic loads, smoothness of the floor, tightness of external façades and of enclosing surfaces of cleanrooms. Smooth nonporous surfaces are required, together with avoidance of molecular contamination, resistance to the intended cleaning or disinfection agents and the cleaning procedure, simple and tight integration of various fittings, efficient and rapid implementation of subsequent functional and technical changes. The ECA guidance document goes deeper into relevant requirements for all elements that are part of the design of a compliant cleanroom.

Documentation and automation

User requirement specifications (URS) are the key document to demonstrate equipment is fit for the intended use, as stated by GMP Annex 15 (2015). The ECA guidance suggests translating the URS in a technical version to be submitted to the potential equipment supplier, so to ensure the design would reflect product and quality-relevant requirements, being thus GMP compliant.

The management of documentation along the design life cycle of a new piece of equipment is also taken into consideration, with the different construction phases identified according to Good engineering practices (GEP): conceptual design, basic design/engineering, and detailed design/engineering.

The extensive use of data to monitor and document pharmaceutical manufacturing process represents another area of great attention. Requirements relevant to the design of validated computerised systems, data protection and data integrity must be kept in mind. ECA’s experts highlight the need to carefully delimitate areas subject to validation and their extention, particularly with reference to automated systems. Differences between qualification and validation of automated systems are also addressed, including equipment that might either be defined as “computerised” or “automated” system. Regulatory reference for validation is GAMP 5, while qualification refers to Annex 15.

Automation of aseptic manufacturing

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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.