A shutdown is a well-known concept within many production facilities of various kinds. In principle, every company is affected by a temporary shutdown of production, and there is virtually no possibility of carrying out a planned shutdown without an economic consequence. After all, employees are not able to work normally, so there is no output, and the activities that are carried out usually cost a lot of money. Let us not confuse the planned shutdown with an incident leading to a lockdown of part or all of production. Possibly, we will issue a separate White Paper on this in the future.

A recurring shutdown is seen in many industries in order to carry out preventive maintenance and, where appropriate, smaller corrective projects in the facility. However, if we focus on our area of expertise “Controlled Environment” (CE), the objective and content of a shutdown is clearly more complex compared to most general industrial sectors. In contrast to general industry, the shutdown within the CE market is also often an annual operation.

In a CE facility, it is primarily about the concept of contamination. This contamination can consist of dust or fibres, airborne micro-organisms, fine dust, or chemical vapours. We try to create an environment in which contamination to the product process or to the research that takes place in that environment can be limited, or if possible, excluded. In addition, there is often a controlled climate (temperature and RH) in such areas in order to be able to carry out the specifically planned activities.

For the sake of convenience, let us use the umbrella term ‘clean room’ when we talk about these spaces. Of course, an OR in the hospital, or high-care area in the food industry, is also a facility in which the exclusion of contamination plays an important role, yet you do not say that you will be transported to the ‘clean room’ if your tonsils need to be removed. In the following paragraphs, we will try, among other things, to clarify why a shutdown in a production facility with clean rooms differs from other industries.

In the case of a shutdown of a somewhat larger production company, of a general nature, a specialised facility manager or maintenance manager will usually make the start-up by putting together an experienced shutdown project team. This project team should first of all freeze the time plan of the shutdown period. Starting time and expected duration are important for all other stakeholders within the organisation. Needless to say, clients are not allowed to notice anything or little of this necessary evil. Sales and logistics, among other things, must be and remain well informed about the shutdown organisation and its progress. If external communication to customers is necessary, the sales management will need good and up-to-date input!

The shutdown team will then prepare, plan, and coordinate the entire implementation process and record all related information in a comprehensive Shutdown Management Plan (SMP). Obviously, the team will also be responsible for monitoring and evaluating the entire process during and after the shutdown.

They start by determining whether all planned work actually requires a shutdown. If this is not the case, an activity that is not necessary is scheduled for normal maintenance during the operational functioning of the site. They will then usually consult the evaluation of the previous shutdown and learn from experience. This is followed by the collection and study of up-to-date information about the site, normally documented in an updated Site Master File with all attachments that may be relevant in relation to legislation and regulations as well as the possible risk assessment carried out. The Master Validation Plan and the Calibration Plan may of course not be omitted during the preparation.

Ideally, all the files mentioned are included in a Document Management System (DMS software), and the maintenance planning is implemented in the CMMS (Computerized Maintenance Management System) on the basis of an LTMP (Long-term Maintenance Plan). If such software systems are not available, it will have to be manually traced and clearly registered in order to be able to follow the planning flexibly and adjust it where necessary during the execution of all activities.

Possible internal optimisation programmes such as an Overall Equipment Effectiveness (OEE) programme as an important part of a Total Productive Maintenance (TPM) care system can also play a role in the preparation of the SMP.

When talking about a general factory, the shutdown maintenance programme usually concentrates on the following activities:

• The planned maintenance of the equipment;
• The systematic maintenance of the structural interior (floors, doors, etc.);
• Planned maintenance of general HVAC equipment (filters, etc.);
• Systematic periodic work on the infrastructure of the building;
• Planned calibration of equipment, measuring and monitoring equipment, etc.

Of course, the work mentioned above, which is carried out during a shutdown, has been evaluated, and it has been established that it is impossible to carry out this maintenance during normal operational functioning of the plant. That should be clear. Never forget that every day without production costs an enormous amount of money!

In addition to maintenance, minor modifications or renovation work will be carried out, which can only be carried out when production has been completely (or partially) halted. It is useful to establish at the start of the plan who will be responsible for the internal communication of notifications to staff and communication to other external stakeholders.

The CE market can primarily be divided into the High-tech (related) segment on the one hand and the Pharmaceuticals and Life-Science segments on the other hand. In addition to this rough two-part division, the Food sector should be mentioned as the third segment for the time being. Within this sector, there are many developments around the theme of food safety and many changes in legislation and guidelines at a global level. More and more, one can speak of a CE facility within this market segment.

Independently of the market segment in which one is active, the general shutdown activities mentioned in paragraph 2 will also apply as a basis for production facilities in which cleanroom spaces are built. The definition of activities will often be regulated on the basis of an existing ISO 9001 quality management system.

In addition to this basic task, there is clearly more being demanded from the shutdown team as a result of the more extensive legislation and regulations within the CE sector.

These more extensive requirements in relation to maintenance, cleaning, and annual validation are often based on the specific ISO 14644 standard as well as sector-specific (VCCN) guidelines. Of course, there are also requirements for the applied cleanroom related to the URS (User Requirements Specification). (VCCN: Dutch national member organization of the ICCCS (International Confederation of Contamination Control Societies)).

The requirements for the design, construction, and start-up of a dust- and germ-free room are described in the ISO 14644-4 standard, but this part of the standard also clearly describes what is required for maintenance activities, performance monitoring, as well as documenting the whole of the equipment, the construction facility, and the complete technical installation, in the broadest sense of the word.

The 14644-3 standard describes the tests that are important for the initial qualification of the cleanroom. However, the standard also requires that, during the use phase, proof is provided that the room continues to meet the initial process qualification as established upon commissioning.

Attention: The standards mentioned often describe what needs to be done, but not how! It is up to the entire management team of an organisation and the EHSQ team (Environment, Health, Safety, and Quality) to determine how all internal (policy) matters and tasks as well as Standard Operating Procedures (SOP) are carried out in order to demonstrate that everything that is required is indeed met.

In the high-tech (related) market, there is normally a check on compliance with agreements made and compliance with agreed standard standards by means of internal or customer audits. The government primarily pays attention to municipal or provincial legislation and regulations (Environmental permits or licences, etc.).

For ISO 14644 standardized cleanrooms within the high-tech (related) cleanrooms, the following repetition cycles apply during the usage period.

In the Netherlands, the Health Care and Youth Inspectorate (IGJ = Inspectie Gezondheidszorgen Jeugd) issues a GMP certificate to the manufacturer if it complies with the GMP guidelines. The IGJ carries out periodic inspections of manufacturers in the Netherlands to verify whether they comply with the GMP regulations. If the GMP rules are not met, the GMP certification is withdrawn and the company loses its production licence. The IGJ also inspects manufacturers in and outside Europe on behalf of the European Medicines Agency (EMA) and the Medicines Evaluation Board (MEB).

In addition to the above validation measurements, the GMP standard also refers to a continuous monitoring process to determine that the effective operation of all technical and structural components is adequate. An LTMP is required and the monitoring of the performance should be documented, as well as the documentation of the entire equipment, the structural facility, and the complete technical installation, in the broadest sense of the word.

Not only during a shutdown period, but also after the implementation of any change or maintenance activity of a significant nature in the composition of the equipment, the HVAC installation, or the structural cleanroom, a full validation of the above requirements, as listed in Table 2, should be carried out.

Risk assessments are performed during cleanroom development and maintenance to identify, assess, reduce/eliminate (where applicable), and control contamination risks. It is clear that the planning and timing of a shutdown in cleanrooms with GMP quality assurance clearly differs from that in general production facilities or cleanrooms within the high-tech sector.

1. PHASE 9 > Checks and measurement procedures (validation).A cleaning regime must be drawn up based on the various processes, the required classification, and the particular market segment in which the cleanroom is to be used. This can be divided into regular cleaning, usually performed by in-house personnel. In addition to this regular cleaning process, periodic cleaning is required in certain cycles in a classified area. Which activities and with which intervals this must take place is described in guideline 4, drawn up by the VCCN. (Vereniging Contaminatie Controle Nederland).

*It should be noted that the periodic cleaning and in particular the disinfection process is often carried out by specialised companies. This is not only because of the qualifications of the trained cleaning staff, but also because of the material and equipment needed to carry out all the work correctly and safely.

Disinfection can be performed manually, using varying disinfectants during the disinfection cycles. However, if there is equipment in the cleanroom and the cleanroom is often visited by external technicians during a shutdown, a risk assessment will often show that a VHP (Vaporized Hydrogen Peroxide) sterilisation might be the best solution to obtain complete certainty that all microbiological contamination (also in seams and cracks of the equipment) will be decontaminated.

9. In a small pharmaceutical plant, nevertheless, there are easily 50 people who have at least 15 to 20 different tasks and/or disciplines! Make sure that they are well supervised and avoid time wasted waiting for support, advice, or otherwise. Prevent the technical people from your own organisation from being busy with work themselves, but involve them earlier in the supervision and control of the correct implementation of the work by third parties.
10. After 90% completion, have the shutdown plan assessed by an expert with a fresh and independent view. The cost of having an outside specialist do this is often easily regained through prevention of mistakes or smart advice on how to optimise the process.
11. Also consider the implementation of a pre-shutdown and a post-shutdown schedule! There are often many things to be prepared in production prior to the shutdown to ensure that operations run smoothly during the shutdown. Also, there are often tasks to do after the shutdown to get the entire site up and running again correctly. Plan these actions as well and ensure correct implementation and control.
12. Implement in the SMP a contingency plan for unexpected activities and emergencies. After a machine has been dismantled, it may turn out that a problem which was not planned for must be solved immediately. Make sure there is a procedure for this and that a panic reaction is prevented. Those involved need to know what to do to keep the process going and to anticipate the right way in the event of an unexpected situation.
13. Ensure in good time that the external parties involved have a (possibly technical) workplace available and can safely store their administration as well as technical parts and tools.
14. Have the supervisory and coordinating team prepare a daily report and try to evaluate all activities on a daily basis as well. Try to implement the continuous learning process as much as possible, during and of course after completion of the work. Include all data in the evaluation report.
15. It goes without saying that we want to make use of every hour of the shutdown. Therefore, try to set up a work schedule that allows for working in 2 or 3 shifts, also from a supervisory point of view. Ensure supervision and safety at all times when people are working on the plant.
16. Make sure that all people involved, working for third parties, also have the necessary experience of working in a heavily GMP regulated facility and understand what the codes of conduct are in, for example, a sterile working environment.
17. Ensure proper handover of applied procedures, timeline disclosure, as well as other responsibilities. Also, give clear instructions for handover at each stage (Commissioning Cx).
18. Supervise the correct garment regime also during the shutdown period and only allow materials that have been cleaned into the cleanroom. If possible, arrange for access control. Obviously, we do not want people walking around in our cleanroom or other facilities who have no business there!
19. Do not only think about the final cleaning for the validation, but also plan ‘daily cleaning’ in order to prevent contamination as much as possible. It may be possible to deploy part of the in-house staff for this purpose, working under the guidance of a cleaning expert who can supervise.
20. It may be superfluous to mention this, but develop a good evaluation report during all phases of the SMP. Distribute this evaluation report to the stakeholders upon completion of the SMP.

9. Finally, it is worth mentioning that nowadays new sites are designed with modern insights and methods. The building and technical installations are designed in a REVIT Model / BIM environment. Equipment is developed using Industry 4.0 technological capabilities. Digitalisation of production processes and the possibility of connecting and communicating between different systems are therefore new aspects of the current monitoring process.In addition to these developments, there is increasing interest in the ISIO 55001 care system around Asset Management. This means that when starting a purchase or development of a new physical asset, the Total Cost of Ownership (life cycle) or the total cost of acquiring and owning the asset, including maintenance, energy costs, circularity, etc., is carefully examined. We will gain a much better understanding of the technical condition of our assets and our machinery in particular. The improved predictability of the production lines will certainly help in the implementation of risk analyses. All in all, these developments will reduce the need for long shutdown periods.Remember the title of this white paper and the words “necessary evil”! So those new developments are most welcome.

• Various documentation and sites on the subject of maintenance and shutdown operations
• FDA.org website for miscellaneous GMP data
• Understanding GMP in the food industry
• Website eur-lex.europa.eu
• ICT Portal: Documentbeheer farmaceutische industrie (Document management pharmaceutical industry)
• ICT Portal: Overall Equipment Effectiveness (OEE)
• ICT Portal: Total Productive Maintenance (TPM)
• ICT Portal: Een DSM systeem verbetert de documentenstromen (A DSM system improves document flows).
• Bachelor assignment Technical Business Administration written by J.A. ter Harmsel
• Title: Verminderen van productiestop (Reducing production stoppage)