The fierce and aggressive competition for moving new pharmaceutical products quickly through development and registration to an effective market launch creates high demands for production efficiency, capacity, fast changeover, high performance, and low production costs. A single-use (SU) production platform can be an economical approach to meeting these production demands.
The SU concept was first applied many years ago to plastic bags intended for infusion bags (often called drop bags) and blood bags in hospitals. New applications for SU products soon included holding bags for media and buffers, mixers, single-use bioreactor bags, and related equipment. Today the market is filled with SU products and equipment used for mixing, cell cultivation, and downstream purification, as well as for formulation and filling.
Choosing an SU production strategy will usually provide high flexibility, fast changeover, and eliminate the time required for tedious cleaning validation studies. (On the other hand, SU production does add time and cost for risk-based, extractables-leachables studies.) Such benefits as reduced initial investment, no chance for cross-contamination, reduced time (and thereby increased capacity), lower space requirements, and reduced start-up costs render SU an attractive production scenario.
Deciding to base the production process partially or fully on SU equipment brings new challenges with its benefits. The SU systems become an additional part of the production materials to be delivered from a supplier and thus cannot be easily controlled by the end user. Relevant questions to ask before electing to use an SU strategy are:
- Will there be more than one supplier of the equipment?
- If there will be only one supplier, how robust is the business?
- Will the chosen supplier survive for the expected lifespan of the product?
- What are the back-up plans if the SU product drops out of the market?
- Will changes in film or additives change the profiles for extractables and leachables?
- What if a new film has a negative impact on the yields?
- Will the new film have an impact on cell growth?
- Is an agreement with the supplier in place to ensure a reasonable amount of the old film will be available for the product, while the reasons for the new cell growth patterns in the new batch of SU equipment are addressed?
- Will temperature variations for deliveries have an impact on the cell growth profile due to storage or transport of the SU equipment in extremely hot or cold weather?
- Will transport by air due to sudden expedited delivery needs cause any surprises?
The end user is dependent on the supplier. In the ideal case, the supplier is a trusted collaborator who responsibly and proactively informs and works with the end user. They troubleshoot occasional problems together, just as they share responsibility for creating the registration files.
These considerations apply to all SU-based processes. A special class of biological products raises even more concerns. These products require special consideration and even closer attention before deciding whether an SU-based process is safe and advisable.
Potent, toxic, carcinogenic, mutagenic, genetically modified, and allergenic compounds and vaccines for highly contagious diseases, especially the almost eradicated or emerging diseases, are a very special group of products that have high levels of containment as a common requirement. An exacting risk analysis must be performed to determine whether SU is a strategy to pursue. The consequences of larger spills or even just smaller leaks while working with the systems can suddenly create a risk event that changes the picture of whether SU systems are feasible as a reliable production platform. Suddenly, a spill is not just an economic disappointment, but rather a life-threatening hazard to workers. An unintended release to the environment might also have disastrous consequences, depending on the agent that was released.
The traditional risk assessment methods, such as root cause analysis, HAZOP (Hazard and Operability), HACCP (Hazard Analysis and Critical Control Plan), FEMA (Failure Mode and Effect Analysis), SWIFT (Structured What IF Technique), and numerous other methods that focus on the mechanical and general production risks, must be supplemented by risk assessments addressing the active biological agent itself and the specific characteristics of the agent.
Risk is the likelihood of an event with a hazard that has a certain consequence. In the case described, the hazard is the biological agent. The event could be a bag rupture, and the consequence could be the agent infecting a worker or being released into the environment. Risks when using SU equipment can be categorized into two groups: the construction-related risks and the operator-related risks.
The construction containment risks relate to the plastic material in itself and the weldings and seams and the fact that a fluid needs to be contained in a non-rigid plastic medium. For example, a welding can be unintentionally weak and unable to withstand the physical stress from the process.
Operator-related risks are associated with unintended or unforeseen behavior of the operator. For example, a worker can use sharps when opening the boxes and inadvertently damage the SU equipment. Failure to assemble connectors correctly and failure to inspect the setup for kinking tubes or other conditions that might escalate to create an unanticipated situation during the production time of the batch are all operator-related risks.
The consequences of a spill with a dangerous biological agent could be severe compared with the unfortunate situation of spilling a couple hundred liters of harmless product or buffer on the floor.
When handling biological agents, some of the questions to ask are:
- Where do we keep the agent?
- How robust is the container?
- What volume do we have?
- What concentration do we have?
- What are the possible ways the agent can get out of the contained space?
- What are the routes of transmission for infecting a worker?
- Is it air- or aerosol-borne?
- What is the infectious dose?
- Who can act as a host?
- Are silent carriers (symptomless disease transmitters) a possibility?
- What is the incubation period?
- How stable is the agent at ambient temperature and humidity?
- How resistant is the agent to daylight and ultraviolet light?
- How resistant is the agent to various decontamination agents?
- What should be the soaking time of the decontamination agent?
- How are the SU items decontaminated after use?
- Is an autoclave adequate?
- Are special programs required?
- How easy is it to decontaminate the production room and equipment after a spill?
- Will a spill necessitate a gaseous decontamination of the rooms?
- What is the best-suited decontamination agent?
- Are the building materials in the room resistant toward that specific chemical?
- What can be done during the decontamination downtime?
- Can activities in adjacent rooms or anywhere in the building continue during gaseous decontamination?
This special category of agents also requires further consideration of the rooms where the process will occur. Compared to traditional stainless-steel (SS) systems, SU bags acting as the primary barriers are more likely to leak. Questions to be addressed include:
- Where will the spill go?
- Is the room prepared to contain the spill or is it a retrofit that needs further attention to containment when using SU?
- Are special dams around the production unit needed to minimize the spill area?
- How will the spill be handled?
If infection occurs in a SS batch due to contamination from the surroundings, the whole batch must be discarded. Often the SS systems have automatic SIP (steam in place) and CIP (clean in place) systems that allow the operator to heat the full batch up to 121°C while in the bioreactor. Should any uncertainty linger, the operator can repeat the process several times before discarding the disinfected batch to the sewer system. This raises several questions to be addressed for an infection in an SU system:
- What measures have been planned if a batch of several hundred to a thousand liters needs to be discarded from a SU system?
- How will the contaminated batch be inactivated and discarded safely without exposing the workers to the contagious agent?
- Can the autoclave accommodate the full batch in the bag?
- Is the autoclave even a viable option, as the bag might melt when autoclaved, thereby releasing the contaminated batch?
- Is there a kill system in the facility?
- Is it able to handle the full volume of a tank?
- Is a chemical-based decontamination strategy a possibility?
- How will that be validated?
- How will we be certain there are no lumps or cell aggregates in the bag that will shield some infectious units from being exposed to the chemical?
- Is a filtration step needed?
- Is special equipment required for safe and well-planned disposal of the decontaminated batch?
One of the strongest advantages of using SU systems is the great flexibility they provide. Flexibility can also be a danger to any GMP (good manufacturing process) production process, because it allows operators to be creative. It is just as easy to place the media bag to the left as to the right, but, depending on what happens later in the process, it would be better to have it at the right place from the beginning. Moving the bag around can pose a risk for leaks or accidents. The required training for operators must consider such issues, because humans are creative and with a flexible production system unforeseen situations can and surely will arise. Staff training must be tailored to assure that the flexibility of the SU process does not increase risk. The staff should be trained to envision and foresee what consequences even the smallest deviation can have downstream in the production process. Often there will be no one but the operators to determine whether an adjustment that might save the batch could also have disastrous consequences for themselves or others later in the process.
There can be no doubt that SU equipment is an attractive alternative to old-fashioned SS production technology. But, when choosing the SU systems for agents that can cause harm to either the workers or the environment, thorough risk assessments must be performed, adequate measures must be in place to handle unforeseen events safely and reliably, and personnel must be trained to implement these measures perfectly, if necessary. A very close surveillance system of incidents and near misses is also recommended, as the knowledge that can be gained by collecting this data could be very helpful in adjusting procedures to prevent more severe accidents from occurring.
Author Biography
Vibeke Halkjaer-Knudsen is Principal Member of the Technical Staff in the International Biological Threat Reduction program at Sandia National Laboratories. Her work focuses on the responsible use of biological agents, designing equipment and building facilities with an emphasis on impact- and risk assessment from a product-, GMP-, health and safety-, emergency preparedness-, animal welfare, chemical-, and biological point of view.
This article was printed in the September/October 2011 issue of American Pharmaceutical Review - Volume 14, Issue 6. Copyright rests with the publisher. For more information about American Pharmaceutical Review and to read similar articles, visit www.americanpharmaceuticalreview.com and subscribe for free.