The first references to the term “dedicated facility” appeared in GMP literature in the early 2010s in response to potential cross contamination risks of manufacturing toxicologically sensitive products in shared facilities. The WHO Technical Report Series, No. 957, 2010 ‘Annex 3 WHO good manufacturing practices for pharmaceutical products containing hazardous substances’ specifies that “production of certain products containing hazardous substances should generally be conducted in separate, dedicated, self-contained facilities”.
Regulators had been battling the pharmaceutical industry over the trend towards contract manufacturing and the use of shared manufacturing facilities, due to the potential cross-contamination risks they may pose to public health. Especially with respect to the manufacture of toxicologically sensitive products. Manufacturers had been increasingly looking at facilities as something akin to Swiss Army Knives – able to process anything from food and Agri-medicine through to sterile injectables – provided one could justify the associated risk. The reality was a glut of aging and/or ill-equipped facilities taking on a suite of products they were never designed to produce.
This ‘one size fits all’ mentality eventually led regulators to put their foot down and pull out the “toxicology card”. They insisted that manufacturers provide scientific evidence from a qualified toxicologist, such that their shared facilities were not considered a danger to public health – with the only alternative being a commitment to strictly dedicated facilities and equipment. This sent a shock wave through the industry that still resonates today.
There are some obvious examples where industry has had no choice but to give ground and establish dedicated facilities – PIC/S uses the example of Beta-lactams due to the allergy risk they pose.
From a regulator’s perspective, the ideal scenario was for each product line to have its own dedicated manufacturing facility and equipment. This would certainly make the pharmaceutical industry easier to regulate, however, the reality is that the industry is ultimately trending towards smaller batches of niche products – with complicated processes and a limited life cycle.
Manufacturers must be able to pivot between product lines in as short amount of time as possible to remain competitive. This speaks to the “idealisation” of the Pharma 4.0® initiative and the concept of “Lot Size One”.
“Lot Size One” can be summarised as the final-destination for custom manufacturing, with each unit being a batch unto itself, tailored to the individual needs of the patient. The pharmaceutical industry has a lot of work to go before this kind of manufacturing can be rolled out as it would require a significant increase in connectivity between stakeholders to be viable. It is worth noting that it is already being explored in less regulated sectors and maybe closer to becoming a reality than you think.
Shared Facilities are Here to Stay
The impact of the dedicated vs shared facilities debate is significant with respect to the decisions made by industry in designing and operating manufacturing sites. All facilities rely heavily on the quality systems, procedures and training that have successfully governed the industry thus far. However, we will be looking at some of the architecture and engineering, as well as some of the specific process requirements that go into building a modern shared facility.
So, what can be done to mitigate the inherent risks posed?
There should be enough space so that product lines can expand, and contract as required in a controlled manner and with minimal interruption to the existing production lines.
The facility should be fundamentally modular, with sections able to be cleaned down and fitted out without interrupting other sections. Each section of the production facility needs to be able to be isolated, the floor layout relocated, cleaned, and brought back into production. This process must be relatively quick and easy to perform and not damage the facility or negatively impact other lines. Using materials that are designed for such an application and that are robust enough to survive the relocation process is a must.
Higher risk product lines should be contained essentially in a mini-dedicated facility with its own air supply, entry/exit, within a section of the facility completely isolated for the purpose. It should always be part of the conversation between relevant stakeholders, whether having such products on-site is worth the risk to the facility as a whole.
Consider the following as more specific design requirements:
Basis of Design (BoD):
A good planning and design philosophy is at the heart of every example of production facility excellence. It is essential to front end the project efforts at the planning and design phase, making as smooth as possible, the transition to construction and then to validation. Nowhere is this more apparent than with the Basis-of-Design (BoD) document. This document details the fundamental specifications of the site and facility before ever a tool is picked up and is pivotal to the success of the project. It is normally included as part of the contractual requirements when the project is put out to tender.
PharmOut has noted several recent examples where the cause of a project’s misfortunes can be traced back directly to the absence of this document or lack of adherence to its principles.
Risk Assessment for Cross Contamination
The cross-contamination risk assessment document is a cornerstone of any shared facility. This document explores each facet of what could go wrong in terms of cross contamination while outlining the mitigation strategies to be implemented.
It should be a “living document”, to be amended as products and conditions change, as they inevitably will in a shared facility.
Product storage and incoming goods:
The ideal warehouse for a shared facility allows each product line to be segregated without the possibility of mix-ups. This means having more storage space than you will ever need and having a robust warehouse management system.
Embracing Just-In-Time manufacturing principles may offer a suitable alternative. This will mean having a robust working relationship with your suppliers and empowering them to do your warehousing for you.
Dispensing and Sampling:
Dispensaries may need to be dedicated to a product line or group of products. This may mean having as many dispensaries as there are lines which are likely impractical (however ideal). An alternative is dedicating dispensaries for bracketed product lines. Perhaps having a single dispensary that is reserved for higher-risk products which undergoes a more thorough clean after each use.
Air filtration and HVAC Cross Contamination Risks:
Services to the production line need to be engineered in such a way that they should not pose a contamination risk to other products. The most important of these is the HVAC system.
The best way of ensuring that the air supply is not a source of contamination is the practice of pressure cascades, using techniques such as ‘sweeping’ to avoiding areas where dust may accumulate, and having a robust HEPA filter maintenance program. It may also be necessary to isolate HVAC with general sections having their own service of filtered air from others within the facility. Particularly for product lines of higher risk.
Another level of consideration is the concept of pressurisation profiles where different areas are dedicated to a particular type of product requirements. No fixed pressurisation regime is necessarily suitable for every product to be manufactured. These cascades profiles can generally be categorised as “Liquid”, “Powder”, “Bubble” and “Sink”.
The need for different cascade profiles should be considered at the design stage and if necessary, the design can accommodate different modes of operation for the HVAC.
Top-down cleanrooms construction
A recent strategy of building cleanrooms from the ceiling down has allowed certain facilities to move around walls with ease.
By suspending the ceiling first and attaching the walls underneath, the ceiling load is placed onto the suspension instead of the walls.
The significance of this is that there is very little resistance when it comes time to rearrange space and the workload is significantly reduced.
Another recent innovation is prefabricated “pod” cleanrooms. This “Podular” design turns each manufacturing suite into a self-contained cell.
The pods have advantages in flexibility and adaptability over traditional stick-built cleanrooms as well as helping to combat the long-standing mould contamination issues inherent in older designs.
This essentially treats cleanroom facility design and construction as though it were another piece of manufacturing equipment.
Another feature is the mobility of individual pods in that they can be easily relocated around the facility, or even between facilities, with minimal interruption.
Pressurised Rooms and Interlocking doors:
Modern interlocks are entirely automated, utilising card scanners and magnetic locks to ensure that only one (interlocked) door is open at a time. Personalised cards have made it easier to control who can go where in the facility, based on their role and training status. Some manufacturers still prefer mechanical interlock due to it being effective during a power outage and one must consider the connection of these controls to the UPS (allowing exit in the event of a power failure). Stop / Go signals show personnel when a door is in use and when it is ok to pass.
BMS systems measure the relative pressure between rooms in real-time and alarm when they drop below a defined threshold.
In a genuinely shared facility, it may become necessary to bite the bullet and bring a dedicated toxicological role on site – this person would have similar input to the quality system as a senior chemist or microbiologist, for which the early engagement can be incredibly valuable.
One of the primary responsibilities of the toxicologist would be to perform the complicated and ongoing process of determining the Health-Based Exposure Levels (HBEL) of the relevant medicines on-site, which include No Observed (Adverse) Effect Levels (NOEL or NOAEL) and Permitted Daily Exposure (PDE) levels. Whether or not they are employed full time or on a contract basis, this is an activity that should only be assigned to a qualified toxicologist.
The role would be heavily involved in the process of bringing new product lines into the facility, wherein the facility they belong and determining risk factors such as Maximum Allowable Carry Over (MAC or MACO).
Product contact surfaces pose the greatest risk of cross contamination and are where most of the effort should be expended in proving that your manufacturing processes are safe. Where possible, equipment should be dedicated to a process, however, if this is not practical then a robust automated cleaning program is recommended (in some cases essential). If you can reliably demonstrate (and evidence) that target residues are below an established safe level, there should not be an issue with using shared equipment.
This is also where an effective equipment bracketing system comes into its own. Product lines are separated by various risk factors with each set of product brackets having their own equipment train. You may end up with only two or three brackets depending on your product risk profile.
The way that you go about implementing bracketing should ultimately fall back on your cross-contamination risk assessment. As new products are proposed for introduction into the facility, they must be cross-examined with this risk assessment to determine which of the current brackets (if any) they belong to.
Cleaning policy and validation
A shared facility cannot effectively operate without a robust cleaning program.
Key policy and validation documents should include a justification of product grouping for shared equipment use and justification for the methodology for cleaning.
Cleaning should be automated as much as possible. Cleaning validation should be an extension of the process validation effort, not just an afterthought.
Disposable wall/equipment surfaces:
Like the disposable sticky mats that are normally in the entry to key doorways, a removable film may reduce the need for extensive validation of cleaning processes. Processing each batch in a disposable plastic bag so to speak would significantly reduce the risk of cross contamination – recent technological advances are enabling manufacturers to move towards the adoption of disposable and single-use sterile items – and away from equipment that must be sterilised or consumables that are recycled or pose a risk with their transfer into cleanrooms. Of course, this would have legacy implications with respect to increasing the amount of plastic waste (in an already largely wasteful industry) – the counter-argument to this would be that reducing the need for massive amounts of wasted water would be a net positive for the environment.
Continuous manufacturing seemed to be the darling concept of regulators due to its improved reliability over traditional batch manufacturing. However, its core process parameters inevitably require committing to a single product line, 24hrs a day, for an extended period. This would appear antithetical to the need for shared facilities to remain flexible.
The idea may be worth considering even for a shared facility if there are one or two tent-pole products that the manufacturer is confident can be relied upon.
If this is the case then continuous manufacturing can be applied to a section of the facility that would be semi-permanent, allowing the manufacturer to streamline production and release for their most dependable, high-volume lines.
There is much that is up for discussion, and this topic continues to provide a great deal of interest within the industry.
The shared manufacturing facility will continue to evolve to fit the needs of the market and that technological developments have so far been able to keep pace.
Shared facilities are here to stay.
PharmOut provides highly professional architecture and engineering services for a wide variety of GMP project streams – we can oversee projects from site master planning, facility design and equipment selection right through to implementation. If you would like to continue the discussion, please do not hesitate to contact one of our consultants today.