QbD and risk management through HVP technology

The increasing development of biopharmaceuticals with active properties that would be destroyed by terminal sterilisation means that the requirements for aseptic processing have grown. Traditional manual approaches to sterilisation using detergent sprays are unable to reliably achieve the required reduction in bioburden levels. Hydrogen peroxide vapour (HPV) sterilisation can safely provide a validated 6-log sporicidal reduction in bioburden within a contained environment, be that an isolator, transfer chamber or a room.

Figure 1: A large scale room/zone bio-decontamination solution with HPV technology – the Bioquell Z-2

Quality by Design (QbD) is the latest paradigm shift that pharmaceutical producers must achieve. Richard Lucas, Product Manager, Bioquell UK, argues that HPV technology offers a QbD approach to risk management in cleanrooms.

Quality cannot be tested into products; it should be built in by design. These wise words are used to support a range of manufacturing processes and are echoed in the ICH Guidelines for Pharmaceutical Development,1 where they set out a clear message that for the manufacture of medicinal products – quality can be planned. The principle of the Quality by Design (QbD) approach is that quality can be built into a production process through a clear knowledge of the process requirements, the risks involved and how these can be mitigated.

One of the most important challenges for quality control during pharmaceutical manufacturing is the risk of biological contamination. It is critical that medicinal products are manufactured within a sterile environment, both to ensure patient safety and to maintain production efficiency. Investigating the causes of incidents of biological contamination is a time-consuming and costly process. Root-cause analysis tests need to be carried out, alongside microbiological identification, and corrective and preventative action has to follow. The controlled destruction of contaminated batches of product will also be required.

The careful design and planning of effective decontamination and sterile procedures is an imperative step, therefore, in any pharmaceutical manufacturing process, particularly as changing trends in drug development and regulatory enforcement drive the search for new sterilisation solutions.

Benefits of hydrogen peroxide vapour (HPV) sterilisation: The increasing development of bio-pharmaceuticals, with active properties that would be destroyed by terminal sterilisation means that the requirements for aseptic processing have grown. Pressure from regulators to comply with the microbial levels defined in Annex 1 of the EU GMP Guidelines for Medicinal Products2 and the FDA Guide to Industry on Sterile Drug Products Produced by Aseptic Processing3 has further driven the need for efficient sterilisation technologies.

Traditional manual approaches to sterilisation using detergent sprays are unable to reliably achieve the required reduction in bioburden (biological contaminant) levels to conform to Annex 1 requirements. One solution is to use HPV technology. HPV can safely provide a validated 6-log sporicidal reduction in bioburden within a contained environment, be that an isolator, transfer chamber or a room. The HPV decontamination process (see Figure 2) can be validated with the biological indicator Geobacillus stearothermophilus4 to the level of biological decontamination required, typically 6-log for critical areas/surfaces and 4-log for surrounding environments (i.e. a microbial reduction of 1,000,000 and 10,000 units respectively).

Figure 2a: Overview of the HPV process

The optimised HPV technique combines a proprietary vapour generation system with high velocity gas distribution to ensure a uniform delivery of HPV throughout an enclosure (Figure 1). A layer (2–6µm, invisible to the naked eye) of the active agent on all surfaces provides rapid bio-decontamination. Traditional approaches to decontamination based on the use of manual detergent sprays can leave surfaces ‘wetted’ with disinfectant residue, potentially causing damage to materials in the cleanroom. Conversely, HPV is rapidly removed by catalytic conversion to water vapour and oxygen, as part of the decontamination process, without leaving a residue. HPV has the flexibility to be used with a broad range of materials and can therefore be used in areas containing sensitive electronics or in hard to reach areas.

HPV and the Quality by Design approach: Integrating high efficiency, automated bio-decontamination processes (including in-process critical control point monitoring) into pharmaceutical cleanrooms can provide sterility assurance and justify reduced microbiological monitoring, therefore delivering efficiencies and reducing costs. HPV technology is applicable from commissioning through to running pharmaceutical manufacturing facilities to deliver production efficiencies.

Biodecontamination and cleanroom design: When designing a cleanroom, it can be beneficial to get advice from decontamination experts early on. Although many systems offer the flexibility to be retro- fitted, significant process efficiencies and cost savings can be achieved by considering bio-decontamination requirements and solutions at the design stage.

A significant contamination risk point for consideration is the transfer of materials in and out of the cleanroom environment. Traditionally, steam sterilisers and autoclaves have been used for material transfer, however by nature of the application of heat and humidity, they are limited in the types of materials they can process. This can result in alternative manual methods being used where sensitive electronics or protein-based therapeutics are being transferred, with consequent contamination risks.

HPV ‘gassed’ transfer chambers are a way of meeting the challenge of the wide range of materials now entering cleanrooms and can provide a more thorough, validated and repeatable bio-decontamination process.

Figure 2b

Many companies are considering not just their efficiency, but also their environmental impact; steam sterilisation uses a lot of energy and is therefore costly on both counts. Alternative technology, such as HPV, offers rapid cost effective sterilisation cycles (as short as 20 minutes) that are highly energy efficient. HPV technology can be linked to existing autoclaves, however facilities with walk-in transfer chambers incorporating HPV offer greater versatility.

While some large transfer chambers are difficult to fit once a facility is up and running (requiring pits to be dug or the roof to be removed), modular walk-in chambers, available from companies such as Bioquell, are designed for easy installation. The chambers have led to higher efficiency, due to a significant reduction of investigations into contamination ingress, and cross-contamination, as a result of compromised in-process transfers. Easy to use integrated ‘plug and play’ systems with a single control panel are also an important consideration. This obviates the need for complex training of operators.

Commissioning a new facility: Ensuring that there is a zero bioburden baseline prior to commencing production in a new facility is essential. Performing a facility bio-decontamination using HPV following validation activities and award of regulatory approvals provides documented peace of mind before production or R&D activities begin. A scalable solution applicable to individual requirements can be achieved by utilising multiple HPV generators. Rapid decontamination of all the surfaces in a room can be achieved, with volumes in excess of 10,000m3 treated as single, discrete enclosures.

Routine sterilization

Planning and implementing pro-active scheduled bio-decontamination once a facility is up and running is an equally important principle of QbD. Routine HPV bio-decontamination can treat product filling lines in place, including indirect product contact parts such as feeder bowls. This technique results in significant efficiency savings and risk reduction5 when compared with traditional autoclaving ‘out-of-place’, followed by aseptic transfer and assembly.

The speed of the HPV process also leads to a reduced downtime. The slowest part of the treatment process using HPV is removal of the residual vapour. Cutting-edge patented technology using catalytic filters and air exchange, quickly and efficiently converts HPV to water vapour and oxygen, leaving a HPV residue-free surface and an environment safe to re-enter. Self-sterilising units also minimise the risk of any location-to-location transfer of viable micro-organisms.

Sterility testing prior to batch release is an essential requirement to ensure product quality. By integrating sterility testing systems into the production process, the risks of erroneous test results can be reduced. Closed barrier workstations are available that incorporate automated HPV bio-decontamination technology into a modular isolator system (Figure 3). By ensuring a controlled aseptic test environment, such systems help to minimise the risk of unnecessary, and costly, batch rejection due to false positive sterility test results.

Figure 3: A closed barrier workstation incorporating automated HPV bio-decontamination technology into a modular isolator system – the Bioquell QUBE

Bio-decontamination after shutdown: The closure of a pharmaceutical facility as a result of a scheduled maintenance shutdown or as a result of microbial contamination is an extremely costly affair due to interruptions in production activities and lost or spoiled batches. A bio-decontamination strategy must therefore ensure that the deployment runs smoothly and minimises the impact on the facility. This may simply involve performing the bio-decontamination cycle ‘out-of-hours’, or by fully integrating the bio-decontamination process into the production cycle. Performing facility bio-decontamination upon completion of a scheduled shutdown is an ideal opportunity to ‘reset’ the bioburden levels within the facility to zero. Companies such as Bioquell offer fully outsourced room bio-decontamination services to enable a speedy return of a facility to its production activities.

There is an ever greater need to improve pharmaceutical manufacturing efficiency to meet the challenges of globalisation, competitiveness and the increasing diversity of products. Bio-contamination is a key risk factor both for product quality and production efficiency. New decontamination technologies, alongside best practice approaches, provide the opportunity to design sterility assurance into production and monitoring processes with consequent, significant efficiency savings.

The sterilisation and decontamination needs of a cleanroom can vary dramatically, however HPV technology has proven to be an all-round successful solution. Working alongside a manufacturer who can offer a range of flexible bio-decontamination technologies and the experience of a wide variety of projects, means that solutions can be tailored to individual requirements and maximum efficiencies can be gained.

References

1. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (2009). ICH Harmonised Tripartite Guideline. Pharmaceutical Development Q8 (R2). Current Step 4 version dated August 2009. Switzerland, Geneva: ICH.

2. European Commission Enterprise and Industry Directorate-General (2008) EudraLex. The Rules Governing Medicinal Products in the European Union Volume 4. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products (corrected version).

3. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory Affairs (ORA) (2004). Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. Rockville, MD, USA: U.S. Department of Health and Human Services Food and Drug Administration.

4. Parenteral Drug Association (PDA) (2010) Technical Report No.51. Biological Indicators for Gas and Vapor-Phase Decontamination Processes: Specification, Manufacture, Control and Use. Bethesda, MD, USA: Parenteral Drug Association (PDA).

5. Drinkwater, J. (2010) Impact of QRM on RABS. Cleanroom Technology. Available online at http://www.cleanroom-technology.co.uk/technical/article_page/The_impact_of_QRM_on_RABS/57866 [Accessed 16 September 2012].

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