What should you be considering when planning cleanroom cleaning after a renovation? Micronclean’s Business Development Manager David Giles explains

There are many reasons why a cleanroom may require renovation, from replacing floors to ventilation and filtration systems, either way, the cleanroom will need some attention in order to make it fit for operation again.

Due to the disruption to the cleanroom and the inevitable addition of particulate and microbiological contamination, cleaning is a critical aspect of this process.

In a way, the cleaning processes following a renovation will be very similar to that of a new cleanroom build. In both scenarios, there are certain considerations when planning cleanroom cleaning which include:

What is the measure of success?

You first need to decide how ‘clean’ the cleanroom needs to be in order to be fit for operation. Whilst many people will worry about not doing enough cleaning, it can be just as easy to do more than is required. Rather than simply doing ‘what has always been done’ or ‘how it was done at a previous organisation’, time should be taken to assess what needs doing and the level of cleanliness that is required.

Some of the reagents you will need could include Neutral Detergent, WFI, IPA/denatured ethanol, biocide/sporicide

Once an assessment of the required cleanliness has been completed, you need to consider how you will be defining ‘clean’. Depending on the cleanroom classification you are operating in, this might include limits for visible contamination, particulate contamination and microbiological contamination. In addition to clarifying how ‘clean’ will be defined, consideration should be given to how the cleanliness will be measured. There are a number of questions to ask yourself, for example, is physical and/or microbiological environmental monitoring required? If this is the case, do you have an adequate routine in place? You may also consider if a thorough survey is required.

How will the required level of cleanliness be achieved?

Identifying what needs to be cleaned is the best place to start. You will need to consider floors, walls and ceilings, as well as inside and outside equipment, and any high-level cleaning or other specialist cleaning that may be required.

The next step in the process should be to understand what contamination is likely to be present after the renovation. There is likely to be significant physical contamination (e.g. dust and sealants), but you should also consider microbiological contamination such as spores.

Once you have clarity on what needs to be cleaned, you are ready to consider how the cleaning will take place. For example, does the cleaning need to be phased? Dependent on the cleanroom and its renovation, it may be best practice to phase the cleaning process into the following processes:

1. Cleaning of gross contamination prior to HVAC system being turned on
2. Cleaning before equipment is positioned and installed in the cleanroom
3. Fine cleaning once HVAC system is in operation

The method of cleaning is vital in the process in order to ensure compliance when commencing work in the newly renovated cleanroom. You will need to ensure the cleaning methods are GMP compliant and follow best practice recommendations. It is also worth checking if the chosen cleaning processes have been validated or proven to be effective in any way.

The selection of materials and equipment should always refer to the point made earlier in the article about identifying what you are aiming to achieve from the clean. Asking yourself again if the clean needs to follow full GMP best practice methods and then deciding what will be required from there.

Like any project, timelines can slip with little to no notice

Some of the reagents you will need could include Neutral Detergent, WFI, IPA/denatured ethanol, biocide/sporicide, but even once you have made the selection, there are some questions to ask yourself. Have the products been validated for use? Are the reagents compatible with one another and are they compliant? Once you have determined if the products are validated, compatible and compliant, you should ensure stable supply for the required quantity and period. This will require you to know how much stock you need for the cleaning and have an approved supplier for the items.

Reagents play a huge role in getting your cleanroom clean. However, you will also need to consider the equipment you use to clean, apply products and remove residues. Common equipment used for cleaning cleanrooms include vacuums, mops, wipes, sprays and fogging, to name a few. Additional equipment may be required for hard-to-reach areas of the cleanroom, including high level access equipment and safety equipment, etc.

How will the cleaning be completed?

Personnel and resource are two key areas to consider when thinking about how cleaning will be completed after a cleanroom renovation. It is important to ensure the team who will be carrying out the cleaning are suitably trained and experienced, to ensure good practice is adhered to. Whether you clean using your own staff or have a professional cleanroom cleaning partner, the operators should be trained and familiar with all aspects of cleanroom gowning, material transfer, GDP and GMP. This includes GMP cleaning as well as the equipment and materials that they will be using throughout the process.

You need to consider how you will be defining ‘clean’

By ensuring you have allocated sufficient time and resource for cleaning after a renovation, you increase your ability to complete the project on time and to the correct level of quality. Like any project, timelines can slip with little to no notice. With this in mind, it may be worth allowing a contingency within the plan or considering if the resource is flexible enough to meet a revised deadline.

Specific PPE and training may be required for all personnel. All safety considerations should be made before commencing the clean and planned into the project schedule.

Once the cleanroom is clean, how will cleanliness be maintained?

Now that the deep clean is completed and you have a newly renovated cleanroom, you have a responsibility to maintain the cleanliness. Many organisations use specialist cleanroom cleaning companies to support the design and fulfilment of effective and efficient cleaning, starting with a deep clean and then leading into routine cleans.

The benefits of using a professional cleanroom cleaning service is their expertise built through specialisation, thorough training and experience. The quality of the clean is always consistent, with full documentation and traceability to support this. A cleanroom cleaning specialist will also take responsibility for cleaning equipment and consumables stock through their established supply chains and can be flexible around clients’ deadlines and time constraints.

Next time you are building a cleanroom or having a renovation done, it will serve you well to start at the beginning and plan cleaning as a critical aspect of the overall programme. Alternatively, you can outsource this service and rely on the work of professionals.

n designing the specific spray dry plant for small scale production (≤ 1 MT/yr) for VitaSquare Wolvega Netherlands, Kropman Contamination Control looked at many design considerations

Image 2

VitaSquare Wolvega produces nutritional premixes. In the Netherlands, the company enriches dry or ‘instant’ food with vitamins, amino acids, minerals, trace elements, and many more components.

For this to work, the nutrients need to be added in powdered form.

For the design of the specific spray dry plant for small scale production (≤ 1 MT/yr), many design considerations are implemented.

First of all process steps are identified and assessed for: product susceptibility, the risk of spilling, the method to clean in place as well as the exterior, including the room. Logistics of materials, product, staff and waste are also planned for.

Dosing and fine ingredients mixing

Logistics are set up to handle most raw material in bulk containers, positioned outside the process rooms, are hooked up to the process lines (Image 1). This all is done in a non-classified but controlled area of basic hygiene level.

Image 1

Spilling is not expected as all raw materials here are in containers or per piping such as feed water. Also, the CIP and waste flows are run as fixed piping. Specific additives are added in the processing room via a tank lid. (Image 2)

The tank itself is at the other side of the wall, with all its pumps, valves, sensors, actuators, wiring and supports. This leaves the processing room quite easy to clean. The various connections for the process and transfer steps can be made by transfer panels. The fine ingredients come to this processing room by an elevator from the ground floor. The elevator acts as an airlock as it is interlocked and flushed by overflow air maintaining the pressure flow cascade.

As shown in images on p55, the logistics are well separated as well as the majority of the process equipment is located in a non-classified hygienic zone. The area of exposure is very limited and in a controlled; ISO Class 9 environment.

The doors have opened for the largest Cleanroom Technology Conference to date! Co-located with Manufacturing Chemist LIVE, this event will welcome over 400 attendees for two days of talks and networking in Birmingham, UK

The doors have officially opened for this year’s Cleanroom Technology Conference at the NCC in Birmingham, and what a lovely sunny day for it!

Over the next two days, more than 400 attendees will walk through the National Conference Centre doors for two days of talks and networking with the best of the best in the cleanroom sector.

Companies such as Ecolab, AstraZeneca, Pfizer and many more, will be represented at the conference. So delegates will have the opportunity to converse with industry powerhouses.

The multi-sector, international event will cover a wide breadth of the industry through case studies and lectures from a panel of global experts, shedding light on the latest industry developments over the past year, as well as future projections for all sectors.

Topics covered include Annex 1, containment, sterility testing, regulations and standards, operation and validation, clothing & PPE, data integrity, HVAC and energy, cleanroom design & build, cleanroom operations, garments & consumables.

Univercells Technologies’ Head of Manufacturing & Supply Chain talks about his approach to building a scalable pharmaceutical manufacturing facility in Belgium. Gareth Crothers from Univercells explains

Belgium is currently positioning itself as a Biotech valley, with a mixture of established “Big Pharma” companies and cutting-edge startups. Given the ready access to highly educated and experienced biotech professionals (including engineering firms) within a relatively small area, it is fertile ground for establishing new biotech activities.

Within this context, Univercells Technologies was founded in May 2020 as a spin-off of the company Univercells. Its mission is to focus on the commercialisation of its novel biomanufacturing technologies product portfolio – the scale-X (trademarked) bioreactor range and the NevoLine (trademarked) Upstream platform. Located in Nivelles, the manufacturing activities for the scale-X (trademarked) bioreactor range and associated Single Use Technology (SUT) such as manifolds, require the use of a cleanroom environment in order to control particulate levels.

Considerations for cleanroom design, construction, and operation

The first consideration for building a cleanroom is which level you need to attain and maintain for your operations. There are well established international standards for this, including ISO 14644-11 (particle count limits only) and EU GMP grades (particle and microbiological). The standard that you target should always be based on the products that you manufacture, as well as your customers.

Final drug products destined for injection into patients require more stringent conditions in terms of both particles and microbiological levels than SUT that will be irradiated before use in upstream processes. Licensed drug products are subject to regulatory requirements whereas biotechnology equipment must meet customer expectations.

Choosing the cleanroom level is important as targeting a more stringent grade than strictly necessary “because it is better” will engender significant incremental cost increase in terms of room construction, qualification, energy consumption, cleaning, gowning, and routine environmental monitoring. On the other hand, targeting too low will engender significant re-engineering costs and potential business disruption if the classification does not meet product, regulatory, or customer needs.

At Univercells Technologies, our product range and customer expectations led us to target an ISO Class 8 classification.

Targeting a more stringent grade than strictly necessary ‘because it is better’ will engender significant incremental cost increase

The second consideration is the surface area you need for your operations. Here again, there is a balance to be found. A cleanroom that is under-dimensioned will restrict capacity and could cause operator discomfort; it could even become an EHS problem in terms of personnel/material flows or workstation human-factor design. Also, an over-dimensioned cleanroom will again engender significant incremental cost increase in terms of room construction, qualification, energy consumption, cleaning, and routine environmental monitoring. In a small but rapidly growing company, it is possible to have a modular approach where the basic personnel and material airlocks are in place, and additional cleanroom space can be added in extension as needed.

This is the approach that was adopted at Univercells Technologies: the cleanroom capacity initially installed in 2019 (before the spin-off) was doubled to 1830 sqm in 2022 as product volumes and product range complexity increased. The additional surface area was added in a cost-effective way by leveraging the original infrastructure, positioning Univercells Technologies for the next few years of growth (product range and volumes) without having to move to costly shift operations

It has also given the company a greater flexibility in the organisation of the cleanrooms, an important enabler for creating leaner manufacturing processes.

As a third consideration, the choice of engineering partner for the cleanroom design and construction is important. For smaller companies with a lower level of cleanroom needs, such as Univercells Technologies, a cost-effective approach can be to work with smaller local engineering companies as opposed to larger international groups.

The trade-off here is that larger international groups are more likely to have experience of working in a regulated pharmaceutical environment with the associated documentation requirements; where smaller local companies can sometimes struggle with providing the needed level of documentation in a timely manner without multiple iterations.

Finally, a company also needs to consider the operating parameters for the cleanroom at the targeted classification. These include gowning, cleaning practices, and HVAC optimisation. Each of these parameters require a balance to be struck: too little and the classification will not be maintained; more than necessary, and costs can rapidly rise.

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A good example of this is cleaning: monthly cleaning of all surfaces on an ISO-8 area with a sporicidal agent is arguably over-kill, especially since such an agent requires neutralisation if corrosion of metallic components is to be avoided. Setting this at the right level before initial qualification is important as reducing the cleaning, gowning, or HVAC regimes after this will certainly require requalification (with the associated costs).

There are several ways to sensibly target the parameters for a given classification; these include use of engineering guides (such as the ISPE) and benchmarking with companies having similar product lines. Nevertheless, periodic review of actual operating conditions as the business evolves is essential e.g. given the significant increase in energy costs throughout 2022, the business case for creating a reduced HVAC regime for non-manufacturing periods such as nights and weekends has become much stronger.