James Drinkwater is Process and Compliance Director at Bioquell UK and independent Chairman of the Pharmaceutical and Healthcare Sciences Society - PHSS. James Drinkwater is also a member of the PHSS freeze dryerâlyophilisation special interest group.

James Drinkwater

James Drinkwater is Process and Compliance Director at Bioquell UK and independent Chairman of the Pharmaceutical and Healthcare Sciences Society - PHSS. James Drinkwater is also a member of the PHSS freeze dryerâlyophilisation special interest group. The increase in aseptic processing driven by the growing number of biologically-derived products has led to an increase in freeze-drying applications in this area at both research and production scales. Sterilisation by steam (or moist heat) is the accepted and, to date, preferred option for the biological decontamination of a lyophiliser. This traditional method has a number of advantages: 

a proven and regulatory accepted technology

validation methodologies are well developed and accepted

no potential for chemical impact on biological products

limited impact from process residual water.

However, the process is not without its problems. The process generates residual heat and requires cool-down time ahead of the freeze-drying process—cool down times can be long because of material thermal mass. The pressure and thermal cycling also stresses the freeze dryer such that significant and robust (and often expensive) engineering is required, in addition to robust seals that have to operate in two contra directions. Pressure vessel codes require more significant design input, as well as qualification and certification, which increases project execution times, complexity and costs. And developments or alterations require significant requalification because these pressure code ratings may change. Finally, such a sterilisation process (and the clean steam generation plant and delivery system required) may be impossible to retrofit to existing lyophilisers built without a decontamination facility; product and process development today require such upgrades to have a validated biological decontamination process. Because of these challenges, there has been considerable interest in alternative decontamination methods.

One alternative decontamination method is to use hydrogen peroxide (H202 ). Although not yet widely used, H202  is a long-established method for surface biological decontamination. Validation methodologies are also well established, although the process is under more regulatory scrutiny than well-accepted, traditional steam sterilisation. Using the H202  method, it is possible to validate surface sterilisation with a sporicidal log reduction (SLR) of 6-log with Geobacillus stearothermophilus biological indicators (1). 

H202 vapour  also offers several other advantages:

The process uses ambient temperature process, so there is no residual heat impact to freeze-drying.

Stressing is significantly reduced. Vacuum design is the main design requirement and there is no need for pressure vessel coding.

Sealing integrity is not as challenging as with steam sterilisation.

Vapour phase H202  generators are significantly lower cost and feature less complex engineering compared with clean steam generators.

If an isolator or restricted access barrier systems (RABS) offload barrier is decontaminated with H202 vapour , there is no timing issue between when the barrier and lyophiliser are decontaminated because they can be done at the same time. With steam sterilisation, the hot door prevents simultaneous decontamination of the offload barrier.

Vapour phase H202  surface treatment is usually applied to indirect product contact parts. Surface sterilisation is achieved by a gassing-in-place (GIP) process. In aseptic filling operations, separating potentially contaminating operators from sterilised parts is a significant risk mitigation issue. Using GIP for indirect product contact parts (e.g., cap/stopper feeder bowls that have an indirect route of bio-contamination transfer to products) enables operator separation to be maintained once the surface has been sterilised (2). 

When it comes to lyophiliser sterilisation, H202  offers several benefits. However as there is significant air turbulence during the lyophilisation process, as well as open, exposed product the lyophiliser surfaces may be considered indirect product contact. Such critical surfaces must be validated for surface sterilisation but also if chemical agents are used then verification that the decontamination process is residue free to prevent potential of transfer to sensitive products is important. The regulatory acceptance for GIP, using vapour phase H202 , as a surface sterilisation, residue free process could translate to lyophilisers, and has recently received international regulatory approval. 

Additionally, because H202 vapour  uses ambient pressures, it eliminates any issues relating to the design of pressure vessel codes. It also significantly lessens the difficulties relating to integrity via pressure and thermal cycling. However, it should be noted that for full lyophiliser surface biological decontamination, H202 vapour  requires a vacuum transfer method to assure decontamination of connection dead legs. Using this method, together with buffer systems, standard H202 vapour generators can be used, which optimises design, integration and cost. Lyophilisation cycle times can also be optimised because there are no undesirable thermal loads (from a previous sterilisation process) at the start of the freeze-drying processes.

Steam sterilisation is a well-established and GMP-compliant process suitable for sterilising porous loads, and will remain the preferred method over other alternatives until new processes are fully developed. H202 vapour , as with any new process, has several drawbacks, such as:

Until widespread acceptance, the process will be under more regulatory scrutiny

Clean-in-place heat residuals can impact on H202  vapour decontamination. This issue requires further study, and greater monitoring and control

End point study for gas residuals needs to be controlled to ensure that biological products are not exposed to oxidising agent residuals

Vapour is poor at passive diffusion. Vacuum transfer methods are required to decontaminate dead leg connections (typically up to six pipe work diameters).

As a chemical-oxidising, free-radical attack-kill process, hydrogen peroxide bio-decontamination requires process compatibility studies to assure both effective 6-log SLR bio-decontamination and prevention of chemical impact on products (particularly biological based). 

Extra study is also required for cycle optimisation, biological efficacy assurance and product compatibility in the following areas: 

heat residuals from any clean-in-place process ahead of the H202 process

chemical compounding of cleaning agent residuals with H202  and possible chemical transfer to product (not an issue with the water-for-injection cleaning step)

water residuals in the lyophiliser chamber and condenser that potentially compound with H202  and impact efficacy. 

end-point residuals of H202  that may impact via oxidisation on biological products. Additionally, until the implementation of Quality Risk Management (QRM), the automated gaseous vapour phase H202  bio-decontamination process was not developed for GIP of indirect product contact parts and under specified conditions accepted by regulators to achieve surface sterilisation. Also, without closure of the research issues on water residuals in the Condenser and verification that H2O2 will not contaminate products, it is not enough to just prove biological decontamination efficacy.

Ongoing research and work is taking place to further develop and improve H202  decontamination processes, however, and it is becoming a viable option. H202 , under specified conditions, is very capable of achieving surface sterilisation conditions. Compared with steam sterilisation, the daily costs are also lower, which is an important consideration given the increasing need to reduce manufacturing costs. 

Research-scale lyophilisers using vapour phase H202  could pave the way for integrated hydrogen peroxide generators or retrofitted systems that do not require steam generators. Once proven, the application can be scaled up to production size units. Because the H2O2 process is based on vacuum backfill of the decontamination vapour whatever the size of lyophiliser it is just the back fill rate that is variable hence fully scalable. Applying the same process at research and production scale reduces any possible issues during process scale-up transfer.

Biological Indicators for Gas and Vapor-Phase Decontamination Processes: Specification, Manufacture, Control and Use

 (PDA Technical Report 51, November 2010)

2. Restricted Access Barrier Systems — RABS (Pharmaceutical and Healthcare Sciences Society, November 2010)

Articles

The increase in aseptic processing driven by the growing number of biologically-derived products has led to an increase in freeze-drying applications in this area at both research and production scales.