A game of risk: The challenges faced in aseptic processing
Michael Arthur from Wickham Labs explores the challenges pharma professionals face in aseptic processing.
Although we may not realise it, every single person in the world could be affected by the use of sterile products. This may include the use of needles to inject vaccines, administering lifesaving prescription drugs such as Insulin or Epinephrine or in a hopefully rare, but very real situation for 2020, the insertion of a ventilator tube to enable a patient suffering from Covid-19 to breathe.
Many parenteral or sterile products may be produced in a clean but non-sterile environment, then terminally sterilised, however there are also many other parenteral or sterile products for which terminal sterilisation cannot be performed.
Commonly used sterilising activities may include wet heat (i.e. autoclaving), dry heat (i.e. depyrogenation ovens), using Hydrogen Peroxide Vapour, application of Surface Action Chemicals commonly known as surfactants (e.g. 70% Isopropyl Alcohol [IPA] or Sodium Hypochlorite [Bleach]), or Gamma Irradiation using a Cobalt 60 isotope.
Use of these methods in some cases can potentially cause damage, degradation or inactivation of the final product. The cost of these methodologies will also have a heavy influence upon sterilisation methods chosen as the manufacturer must consider the effect this will have on the cost of the final product. For example, a competitor may be able to undercut the production value of a product and therefore will be able to subsequently sell at a lower price. This is not to say that use of such sterilising techniques must not be in place where aseptic processing is used, but this will bring about new challenges.
The first challenge in aseptic processing is the facility in which the product is to be produced. The facility must be constructed in such a way as to minimise occluded surfaces, be well ventilated using High Efficiency Particulate Air filters (known as HEPA) and be easily cleaned, maintained and decontaminated.
The second challenge is that the equipment used in the room to produce the components, intermediates or final products must also be easily cleaned, maintained and be non-shedding (releasing particles through interactions with items or airflow). In ever improving industries, when innovations are made there will be a cost benefit balance as to whether you should buy the newest equipment or stick with older technologies that have proven efficacy. As equipment ages, it may be prone to damage, breakdowns, leaks of lubricant or shearing of parts (even microscopically), which could cause potential contamination of the facility. This is why it is of vital importance to have a regular maintenance and requalification regime as these issues can be minimised and contained more readily if equipment is installed and maintained correctly.
Further challenges are then produced through the introduction of specific equipment such as tools for maintenance or extraction of materials and also the component materials necessary for the manufacture of the finished product. All of these items must be transferred into the aseptic production environment from an originally open and uncontrolled environment, for example the delivery vehicle, a storage warehouse, or a pre-production facility. To do this the aforementioned decontamination method must be utilised upon the materials prior to packaging for entry into the aseptic processing area and again upon the outer layer of packaging immediately prior to entry.
Again, the method of decontamination may cause damage to the item being passed into the aseptic production facility or may be cost prohibitive. Such examples may include heat sterilisation of active pharmaceutical ingredients, which could denature proteins or molecular bonds rendering the compound inactive. Use of irradiation is vastly expensive, when wet heat sterilisation would be a faster and more cost-effective option for non-porous materials.
Each method must be routinely re-evaluated for effectiveness and robustness in its action, routinely known as re-validation.
The largest challenge of all is that the processing will involve human interaction at some stage. This may be minimised through the use of barriers such as glove ports or by the use of mechanisation, but even if there is intended to be complete isolation of the process, any errors or faults will require the intervention of humans.
Humans routinely carry vast amounts of bacteria on their bodies, with the average human reportedly composed of 1-3% bacteria. In fact, the number of bacteria outnumber the number of human cells by a ratio of around 10 to 1.1
Due to the ubiquitous nature of bacteria on the human body, it is not possible to purge them entirely. The body also sheds skin continually when moving, through abrasion and also passage of air currents. This can amount to around 35kg over the course of a lifetime.2
All shed skin and bacteria pose a large threat of contamination during aseptic processing and must be controlled by minimising interaction with the process as far as practically possible, maximising shielding through the use of barriers and non-shedding clothing. The human body itself is by far the weakest factor in the chain of control of contamination. As such it is necessary to impose restrictions on the number of people involved in aseptic activities and also to monitor environmental trends seen in microbial contamination in the production areas. Alongside effective cleaning and disinfecting procedures this helps to maintain a relatively low level of bioburden in the aseptic processing area and allows for early intervention if any “spikes” in contaminants arise.
In conclusion, as far as practicable, there are many possible actions that can be made to reduce the risk of contamination entering the aseptic processes. These actions range from controlling and monitoring the environment, maintaining the facilities and machinery used, sanitising input materials and having precise instructions for the process flow. There are many other controls including use of pressure differentials to move air, particulates and bacteria away from the production process areas, which have not been mentioned here but the interaction of humans will cause the biggest concern for a breakdown in contamination control. Therefore, regardless of what processes are put in place, continual monitoring will always be required, along with a continual review of the controls in use to ensure that critically ill patients will continue to have access to a safe, regulated supply chain of aseptically manufactured products.