It will probably never happen, but…


A breach in sterility within a classified facility can cause delays and lost product batches. Chris Langley, Bioquell UK, looks at how establishing a Contamination Event Recovery Plan can minimise what could otherwise be costly delays

To receive an operating licence, Containment Level 3 laboratories require an approved decontamination protocol in case of a spillage. Such areas are generally much smaller and less complex than a typical aseptic facility, so why not develop a similar plan for a pharmaceutical production plant?

A contamination event in a classified area typically brings a halt to all production activities, resulting in spiralling lost opportunity costs. In such a high pressure and emotional environment, clear strategic thinking can sometimes be compromised, leading to further delays in situation recovery. Formulation of a robust recovery plan in advance of such an event can help restore the facility to operation with minimal delay and cost.

Bioquell offers consultancy services to help prepare Contamination Event Recovery Plans (CERPs) as part of wider business continuity planning strategy. The CERP collates all pertinent information to allow the contamination to be contained, identified and ultimately eradicated, quickly and efficiently.

Detection: Only a small minority of contamination events are immediately obvious (e.g. flood, gross PPE failure, malicious activity etc.) First indication of an issue will typically come via routine environmental monitoring (EM) or product sterility testing; therefore a robust procedure for eradication of false positives is critical.

A robust environmental monitoring policy is essential to avoid costly downtime and investigation

Use of a dedicated sterility test system (such as the Bioquell Qube) goes a long way to eradicate false positives within the finished product, but a robust EM policy is essential to avoid costly downtime and investigation. Bioquell was recently deployed to a client following an ongoing contamination issue, the source of which was eventually traced to an issue in the contract lab analysing the EM swabs!

In the midst of positive sample results, be it environmental or from product testing, the planning for the remediation typically continues alongside the root cause investigation – at this stage having a predefined remediation plan can save precious time.

The site visit: To formulate the site-specific CERP, a Bioquell Project Manager visits the site and tours the facility and meets with all relevant stakeholders – Production Manager, QA/QC, Engineering, HVAC and Microbiology. A brief presentation is given to all convened stakeholders covering all aspects of the hydrogen peroxide vapour (HPV) bio-decontamination process including a number of industry-specific case studies and a list of the outcomes for the visit. Following a Q&A session on HPV technology, process efficacy and verification, there follows a discussion of the general steps that should be taken to optimise the bio-decontamination process. These steps typically include:

  • Removal of gross contamination
  • Temperature stabilisation (coldrooms/incubators)
  • Establishing what equipment should remain running/be switched off
  • Management of consumables
  • General housekeeping to maximise airflow and distribution.

Before embarking on the facility tour it is advantageous to meet with HVAC and engineering personnel to gain a global perspective of the facility. This provides an understanding of the process flow through the facility, and a discussion of the practical considerations involved with performing a large scale bio-decontamination within the building looking at the following factors:

  • HVAC configuration
  • Pressure regimes
  • Available utilities
  • Access restrictions – e.g. vaccination requirements, access restrictions between adjacent areas (i.e. for areas making cephalosporins etc.), any specialist training required (working at heights, confined spaces, etc.)
  • Logistical considerations (shipping of equipment and consumables, visa requirements).

The Bioquell representative then undertakes the facility tour following the entire production process from raw materials receipt, through to finished product packaging. To maximise flexibility the CERP will, in effect, be made up of a number of smaller plans that can be implemented, depending on the scale and scope of the contamination.

At each stage within the production process (e.g. weighing, formulation, filling, lyophilisation etc.) the decontamination representative should meet with the appropriate unit manager and experts to tour the area. The precise discussion will, of course, vary with the area function but generally the following points will be considered.

Containing any potential contamination before it can spread to other areas of the facility can save huge effort and expense later

Possibilities for containment: Containing any potential contamination before it can spread to other areas of the facility can save huge effort and expense later. This can be achieved in both a proactive and reactive fashion by reviewing the biosecurity of the zone and implementing a containment strategy respectively.

Depending on the topology of the area, it may be possible to implement a few simple procedures (e.g. using additional gowning/PPE when working in particular areas or performing a certain task; assigning dedicated cleaning personnel/equipment to specific areas) to increase the biosecurity in high risk areas. This may include additional precautions to protect the product itself, or steps to increase compartmentalisation of adjacent areas thus isolating any potential contamination, e.g. an additional change procedure.

Developing a containment strategy also serves to isolate confirmed contamination. It may be possible to score a few ‘easy wins’ by taking a few simple steps to immediately isolate the contamination and limit the possibilities for further spread. Such steps may include:

  • Reducing HVAC flow rates so adjacent areas are held at a higher pressure with respect to the contaminated zone
  • Restricting foot traffic in/out of the area
  • Implementing a heightened cleaning regime in adjacent ‘at risk’ areas

Optimising the area for bio-decontamination: The Bioquell representative will have a detailed look around the production cell and offer recommendations as to how the area can be optimised for bio-decontamination. This will involve specific advice on how individual items of equipment should be configured (e.g. isolators running), identification of any high risk or process critical areas, and any equipment where a gaseous approach isn’t the best option, e.g. large fermentation tanks may be better treated with a CIP process.

Example of a site plan showing where decontamination equipment would be located

Example of a site plan showing where decontamination equipment would be located

The specific practical aspects of the bio-decontamination will also be considered, e.g. availability and rating of power sources; how to transfer the equipment into the area (pre-decontamination cycle) and out of the area (post-cycle); where the vapour generators will be located; and any equipment that may have an impact on the cycle parameters, e.g. BSCs, isolators, IVC cages.

Target area scope: Based on the configuration of the facility, the scope of the bio-decontamination envelope will be specified for each area. This will be determined based on the configuration of the HVAC systems and the topology of the facility including any ancillary/support areas – e.g. wash rooms/change rooms.

In situations where support services/areas are shared with other production functions, the most robust approach would be to treat both areas concurrently even if contamination hasn’t yet been identified in the other area. This may not always be possible in production schedules and thus, the options to either include or exclude the other area will be incorporated into the plan. This allows the second area to be treated during a subsequent break in production – e.g. a scheduled maintenance shutdown.

The consumables conundrum…: Large stocks of single-use PPE represent a significant bio-security risk due to the high degree of occluded surfaces in between items. Holding large volumes of consumables within the classified areas presents a significant surface area that won’t be subject to routine cleaning procedures. All gaseous bio-decontamination processes are surface-based technologies and as such, occluded surfaces prevent areas being exposed to the decontaminant and can thus harbour viable micro-organisms.

Large stocks of single-use PPE represent a significant bio-security risk due to the high degree of occluded surfaces in between items

Bioquell recommends all consumables are removed from the target area prior to undergoing bio-decontamination. While this seems wasteful, the risk posed by leaving the items, and potential contamination, within the area is unacceptable and would not stand up to cost-risk analysis. Implementation of a robust Consumables Management Policy will ensure that excessive stocks of consumables are not kept within classified areas, therefore minimising the risk of occluded surfaces along with the potential wastage in the event of a contamination.

Non-classified areas: There may also be other areas on site that, although not cleanroom environments in the classical sense, are also at risk from biological contamination. Such areas include QA/QC labs or R&D facilities where contaminated samples may well have been handled. The recovery plan should encompass these areas as well as the cleanrooms with the considerations listed above remaining valid for labs as well as production areas.

The plan: After the facility tour, Bioquell will formulate a complete bio-decontamination protocol for each of the areas visited. The plan will list all recommendations and suggestions discussed during the visit along with the calculated cycle parameters; locations of the bio-decontamination equipment; specific risk assessments and method statements; all areas that will be sealed/ subject to access restrictions; and an outline deployment time schedule. The recovery plan can then be ratified by the appropriate unit managers and QA/QC.

The CERP plans can be implemented individually for an isolated event, or in the case of a larger contamination issue multiple plans are actioned, concurrently or consecutively depending on production schedules and area availability.

For international sites, a detailed logistics plan will be established covering shipping options for both equipment and consumables

For international sites, a detailed logistics plan will be established covering shipping options for both equipment and consumables. To minimise response times some clients have opted to have a cache of Bioquell Room Bio-Decontamination Service (RBDS) equipment stored onsite along with a supply of consumables allowing a ‘next day’ response. The equipment is used for the routine bio-decontamination intervention that re-commissions the facility after each six-monthly maintenance shutdown, and is stored permanently onsite… just in case!

In terms of business continuity a robust and regularly reviewed CERP is a low-cost, easily introduced measure that can potentially save a significant amount of time during an enforced production shutdown. Selecting a method of bio-decontamination, asking the necessary questions and collating all pertinent information before an event allows the planning to be performed in a structured, considered manner without the clock ticking and lost opportunity costs spiralling.

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