Isolation technology and new Annex 1: an interview with Tim Sandle

A fundamental consideration in Annex 1 is the risk posed by people and the necessity to exclude people from Grade A environments. Any personnel interaction with Grade A poses a risk. The primary means to address this is trough the use of separative devices – isolators and forms of RABS.

Once again, we spoke to Tim Sandle, microbiologist, author and science journalist, known as one of the leading experts in the field, to discuss in the most appropriate way what challenges the pharmaceutical industry is facing in adapting the use of separative devices to the Annex 1 requirements.

Risk-based approach and choice of technology

Already in the “Principles” section, the new Annex 1 clearly expresses the need for the use of appropriate containment technologies:

“The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid microbial testing and continuous monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and the product.”

Not only that, but the new Annex also explicitly calls for justification for their non-use. There use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified. This last step represents a major difference from past versions.

A fundamental consideration in Annex 1 is the risk posed by people and the necessity to exclude people from Grade A environments. Any personnel interaction with Grade A poses a risk. The primary means to address this is trough the use of separative devices – isolators and forms of RABS.

The choice between RABS and isolators has to be made accordingly to a risk based process with a wide meaning of “risk”, embracing technical, economic and environmental considerations.

Isolators are devices that provide for total separation between one environment and another. An isolator does not directly exchange air with the surrounding environment and all air must enter through a HEPA filtration system. All transfer of material into the isolator must be accomplished while maintaining complete environmental separation. The interior of the isolator, and all equipment contained therein, must be able to be subject to a decontamination process in a highly reproducible manner. An alternative to an isolator or to a conventional cleanroom is a Rapid Access Barrier System (RABS). The debate between isolators and RABS is driven by several factors: patient needs, personnel capabilities, finance. The major technical factor in favour of the isolator is, of course, the total segregation of the operator from the process. This separation serves to protect the product during aseptic production: the environment / operator in containment applications, and the patient, product, operator and environment when used for sterile or cytotoxic products. With aseptic filling there is a far greater chance of achieving a zero growth with the media filling trial on a repeated basis that there is within a conventional cleanroom or with a RABS.

As RABS become more sophisticated and in some cases look very similar to isolators there is a risk that they are considered to be the same, or that a RABS is a lower grade of isolator. RABS are an advancement on the Grade A zone with Grade B surrounding cleanroom concept whereas isolators are designed to totally isolate the aseptic process and therefore do not need to be located in a Grade B zone. Misunderstanding the fundamental differences in operating principles has led to requests for isolators to be located in Grade B areas and RABS gloves to be tested in the same way as isolator gloves.

Design according to CCS

Key considerations when performing the risk assessment for the CCS of an isolator should include (but are not limited to); the bio-decontamination programme, the extent of automation, the impact of glove manipulations that may potentially compromise ‘first air’ protection of critical process points, the impact of potential loss of barrier/glove integrity, transfer mechanisms used and activities such as set-up or maintenance that may require the doors to be opened prior to the final bio-decontamination of the isolator. Where additional process risks are identified, a higher grade of background should be considered unless appropriately justified in the CCS. Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress.

The processes of compliance with the new Annex 1 and especially the Contamination Control Strategy, which is a pillar of it, seem to involve automation in an extremely important way. The ultimate goal seems to be to eliminate the human factor in Grade A.

These are important points and central to the CCS. It is very important to focus on the design of the isolator or RABS and to build in as much quality as possible at this stage. When designing an isolator for a particular process, the following should be considered:

– Knowledge of the process steps
– Choosing between positive and negative pressure type isolators
– Choosing between open (continuous process) or closed (batch process) isolators
– Deciding upon whether unidirectional or turbulent flow is required
– Selecting the appropriate continuous or batch transfer systems for the ingress and/or egress of components
– Fabrication of a essentially identical mock-up of the finished isolator
– Simulating the process with full consideration of fatigue factors
– Identifying the materials of construction
– Preparation of a detailed functional description include detailed drawings

An important additional aspect is the selection of realistic leak tightness criteria for the isolator, consistent with process requirements and fabrication capability. Isolators rely on the integrity of the physical barrier to protect the aseptic process and so frequent integrity testing is required.

Another important consideration is with the air and airflow. First air must not be interrupted and there should be no turbulence created which could prevent the effective removal of any particles generated by the intervention or which could entrain extraneous particles and carry them towards the process. This is usually carried out by airflow visualization studies – (smoke studies).

Requirements vary between different applications such as small scale sterility test and pharmacy isolators, negative pressure isolators used to contain hazardous materials, and larger scale complex systems for pharmaceutical manufacturing processes. The test pressures and limits used for initial set up and those used for routine monitoring may also vary to account for variations in temperature between tests.

Ideal background of isolator processes

Let us deepen the processes in isolator. The unwrapping, assembly and preparation of sterilised equipment, components and ancillary items with direct or indirect product contact should be treated as an aseptic process and performed in a grade A with a grade B background. The filling line set-up and filling of the sterile product should be treated as an aseptic process and performed in a grade A with a grade B background. Where an isolator is used, the background should be in accordance with paragraph 4.20

What is the ideal background for a process in isolator? And what must a proper risk analysis cover to avoid contamination risks?

Whilst the interior of the isolator is required to meet Grade A requirements, there is no requirement for the isolator be located in a Grade B area. EU Annex 1 specifies at least a Grade D background although many companies use Grade C. This also means that operators are not gowned to Grade A/B standards.

The isolator is therefore not fully protected by the classical cleanroom continuum of Grade D to Grade A zones and so there are a number of additional requirements which are key to successful operation.

During set up isolators may be open to the environment (Grade D or Grade C) and so a validated bio-decontamination of all surfaces is required. This must include the surfaces of the isolator itself and also of any materials and equipment placed into the isolator before closing up the system.  Bio-decontamination is usually carried out by a gaseous bio-decontamination process such as with hydrogen peroxide vapour. A 6 log reduction in a spore challenge is considered to demonstrate effective bio-decontamination.

Packaging for isolator processes

Materials in and out of isolators. Preparing material for its insertion into isolator is a lengthy and extremely delicate process. Many pharmaceutical companies outsource the process, requiring proper packaging in appropriately packaged BetaBags.

What are the indispensable elements that determine the quality of a packaging service provider?

Transfer of materials into and out of the isolator is a major risk area.  In order to meet the requirements that:

– all materials entering the Grade A zone are sterilized and
– the isolator remains physically closed during operation

For small batch operations it might be possible to wrap and sterilize all the items required. These can then be loaded into the isolator before close up and bio-decontamination.  For larger volume processes materials are required to be sterilized and transferred across the isolator’s physical barrier, maintaining the sterility of the items and the integrity of the isolator. This is generally achieved by the use of transfer isolators or rapid transfer ports (RTPs).

Transfer isolators are fixed to the processing isolator. Sterilized wrapped materials are loaded into the transfer isolator and surface decontaminated as described above. Following bio-decontamination the connection between the transfer isolator and the processing isolator can be opened.

RTP’s utilise alpha-beta connections which ensure that when docked together the contaminated sides of the RTP and the isolator doors seal together ensuring a contamination free connection. RTPs can be designed so that materials such as stoppers can be sterilized in the RTP.

A similar concept is with -sterilization bags with docking system. Items such as vial stoppers are sterilized in flexible bags which have an alpha beta port which allows the bag to be docked directly to the wall of an isolator or RABS. The alpha beta system is designed in such a way that the outer nonsterile surfaces of both units lock together and then open to provide a sterile pathway for the discharge of the stoppers.

Conclusions

The Contamination Control Strategy underlying the new Annex 1 finds its backbone in Quality Risk Management: assessing risks on a scientific basis and offering a commensurate response to them is the real key to adapting to the new requirements. And like a domino effect, risk analysis has triggered the development of new supporting technologies that are crucial for classified environments.

Dr. Tim Sandle is a pharmaceutical microbiologist, science writer and journalist. He is a chartered biologist and holds a first class honours degree in Applied Biology; a Masters degree in education; and has a doctorate from Keele University.