risk analysis Archives - European Industrial Pharmacists Group (EIPG)

The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

Swissmedic’s technical interpretation of Annex 1

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by Giuliana Miglierini

New insights on the interpretation of the new Annex 1 to Good manufacturing practices (GMPs) comes from the Swiss regulatory authority Swissmedic, that at the end of October 2023 published the first revision of its Q&As document (you can find it on the Swissmedicines Inspectorate webpage)

The technical interpretation refers to the revised Annex 1 to the PIC/S GMP Guide (PE 009), adopted on 9 September 2022 and entered into force on 25 August 2023 (with the exception of point 8.123 on lyophilisation, which will enter into force on 25 August 2024). The Q&As follow the same scheme and chapters of Annex 1.

Scope and Premises

According to Swissmedic, for certain types of advanced medicinal products (e.g. ATMPs or allogenic and autologous cell therapy products) specific considerations are required with respect to the fact they cannot be terminally sterilised or filtered. The unsterile patient material should also be considered. Requirements of Annex 2A, paragraph 5.29(b) should be followed for aseptic processing, that should be maintained from the time of procurement of cells through manufacturing and administration back into the patient.

Exceptions to the application of Annex 1 need to be always justified: the Contamination Control Strategy (CCS) is the appropriate tool to detail all risk analysis performed on the basis of the specific manufacturing processes under consideration.

As for the Premises, segregated unidirectional flow airlocks for material and personnel for grade A and B cleanrooms are expected in the case of new facilities. Temporary separation of the flows in the airlocks is the minimum requirement for existing facilities, together with a detailed risk analysis to assess the need for additional technical or organisational measures.

The transfer of materials in and out of a critical grade A cleanroom should be based on the careful definition of the technical and procedural measures associated with it. For example, prior introduction of materials in an isolator followed by decontamination is considered possible only for small batches and for materials resistant to VHP treatment. In all other cases, materials have to be sterilised before entering the already sterile isolator. The transfer process is also subject to a risk analysis to be included in the CCS, as well as to measures to control the maintenance of the integrity and functionality of the systems (also with respect to aseptic process simulation, APS).

Swissmedic specifies that the cleanroom sequence for the transfer of materials via airlocks or passthrough hatches is expected to be fulfilled for zones A and B. In the case of the passage from grade A to C, qualification is needed to prove adequacy of the established systems and procedures. The corresponding risk analysis has to be included in the CCS.

Updating equipment to reach full compliance with the new Annex 1 may require high investments. According to the Q&As, older barrier technologies should be subject to an in-depth internal evaluation to assess the need for new technical measures. The document underlines that starting from 25 August 2023 all barrier technologies not compliant with the new Annex 1 are considered deficient, thus companies should start projects to evaluate the upgrading of background cleanrooms and to define CAPA plans and interim measures to reduce risks.

The risk assessment should also include the evaluation of all automated functionalities and processes associated with the use of the isolator and the activities taking place in it. To this instance, Swissmedic highlights that robotic systems may help improving the reproducibility of operations and minimising both errors and manual interventions. Automatic processes are also expected for the decontamination of isolators, while for RABS manual processes might be used, provided they are designed to ensure reproducibility and are subject to validation and regular monitoring. The absence of negative effects on the medicinal product associated to the cleaning or biodecontamination substances used should also be validated.

As for barrier technology systems with unidirectional air flow, air velocity must be defined so that uniform airflow conditions prevail at the working positions where high-risk operations take place. Alternative air speed ranges or measurements at different heights in the system have to be scientifically justified in the CCS.

Utilities and Personnel

The section on Utilities offers additional guidance on systems used for water generation, that should be designed to allow for routine sanitisation and/or disinfection. Procedures are needed to define regular preventive maintenance of the reverse osmosis system, including the regular change of membranes. A suitable sampling schedule should be in place to regularly check water quality. More stringent controls are needed for the sampling of water-for-injection distribution systems, including daily microbial and bacterial endotoxin testing. The monitoring of the process gas should be performed as close as possible before the sterilisation filter.

Adequate training and qualification of all people working in grade A and B areas, including aseptic gowning and aseptic behaviors, is essential. According to Annex 1, this should include an annual successful APS. Swissmedic adds that, even if not explicitly required, practical process simulations, including manual interventions, should be carried out under the supervision of qualified trainers/QA; the company can choose if to integrate these process simulations into the APS.

Production and specific technologies

As for lyophilisation, initial loading patterns must be always validated, and revalidated annually. The Q&As specify cases where revalidation can be skipped, adding that a theoretical reference load is not acceptable. Revalidation has also to include temperature mapping for moist heat sterilisation systems.

Should a closed system be opened, this should be followed by cleaning (if required) and a validated sterilisation process. Alternatively, the system can be opened in a decontaminated isolator; a class A cleanroom with a class B background might be considered only for exceptional cases.

Non-aseptic connections can be carried out for coupling closed systems, provided a validated sterilisation cycle (SIP) occurs prior to use. Sterile aseptic connectors can be used if the supplier was checked and validated; data from the supplier can be used to file the relevant documentation, but handling of these parts has to be included in the APS.

Swissmedic also underlines that piercing a septum with a needle is to be regarded as a breach of the sterile barrier, and thus avoided for ascetic steps. Should this not be possible, temporary measures should be undertaken to prevent contamination.

Tube welding has also to be qualified and validated, and included in the APS if it is part of the aseptic filling process. The advice is to use more reliable systems, to avoid risks of undetected integrity deficiencies.

Critical single use systems (SUS) should always be tested for integrity by the end user on site before they are used in production. In case of difficult to test, small single use systems, the decision not to test their integrity must be justified in the CCS, as well as the decision to make use of test results provided by suppliers. To this instance, Swissmedic underlines that the comprehensive assessment (including quality system, etc.) should cover the SUS manufacturer/ s, as well as any subcontractors involved in critical services or processes.

Furthermore, the intended use of a SUS in the specific manufacturing process represents the basis for setting the respective acceptance criteria. The Q&As also detail the modalities for the visual inspection of SUSs and the possible acceptance of validation data provided by their suppliers.

As for extractables, the end user is expected to assess the data provided by the suppliers in order to define the need for additional evaluation or leachable studies. A redundant filtration step through a sterile sterilising grade filter, to be included as close to the point of fill as possible, is also encouraged, and its absence has to be justified. A risk analysis is required to justify the choice not to include pre-use/post-sterilisation integrity testing (PUPSIT) of sterilising grade filters used in aseptically processes.

Environmental and process monitoring

According to ICH Q9 (R1), the frequency of the risk review should be based on the level of risk determined for the specific process under consideration, as well as on the level of uncertainty of previous assessments. The recommendation of Swissmedic for new plants is to review the risk assessment after the first year of operations, so to take into due consideration the acquired experience. The document also suggests cases where more stringent action limits may be needed, and the type of statistics to be used to establish alert levels.

The use of rapid microbiological methods (RMM) requires validation and demonstration of equivalence with more traditional approaches. Details on the frequency of the interventions and their inclusion in the APS are also discussed, as well as the container/closure configuration and the distinction between liquid filling and lyophilisation.

The APS of campaign manufacturing represents a complex case for Swissmedic, for which the start-of-campaign (including aseptic assemblies if the case) and end-of-campaign studies should be both conducted. The Q&As also confirm that any contaminated unit with a contamination > 0 CFU results in a failed APS and requires the activation of the consequent actions. Production should resume only after completion of a successful revalidation.

Quality control

A university degree or an equivalent diploma in the field of microbiology (or other natural sciences, or medicine) together with a good understanding of the manufacturing processes under consideration are required for the person in charge of supporting the design of manufacturing activities and environmental monitoring.

As for raw materials, the need for microbiological testing should be evaluated taking into consideration their nature and respective use in the process. All specifications should be discussed and justified in the CCS.

Swissmedic also confirms that the bioburden has to be tested on each batch of raw material as incoming control as well as on the compounding solution in which it is formulated before sterile filtration. In the case of products with short shelf life, should an out-of-specification (OOS) event appear after release of the batch, a procedure is needed to inform doctors, patients, and health authorities, and to assess the connected risks and define remediation actions.


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.