intended use Archives - European Industrial Pharmacists Group (EIPG)

The drug shortage situation - EIPG's point of view

by Maurizio Battistini The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort Read more

EP’s draft position on Unitary SPC and SPC Regulation revision

by Giuliana Miglierini The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to Read more

Reactions to the proposed ban of PFAS

by Giuliana Miglierini A proposal to ban around 10,000 per- and polyfluoroalkyl substances (PFAS) was submitted in January 2023 to the European Chemicals Agency (ECHA) by authorities of Germany, Denmark, the Netherlands, Norway, and Sweden. The proposal was published on Read more

ECA’s guide to compliant equipment design

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.