Production of culture media was for many years a labour-intensive routine for the microbiological testing lab. Technological advancement then introduced dehydrated media that needed only to be dissolved and sterilised on site to provide a reproducible and reliable product. By the 1970s the advent of automated preparators and plate pourers enabled a well equipped microbiology department to produce several hundred plates a day, with only two or three technicians employed for production and quality control/performance testing.
Ultimately, the demand for guaranteed quality standards in both pharmaceutical and clinical testing, as well as the volume and range of media required, led to the development of the ready-to-use prepared media market. Within the pharma industry, the subsequent increase in the use of cleanrooms for aseptic filling led to a fast growing requirement for culture media for environmental monitoring and sterility testing. Similar pressures on quality and quantity began the move towards outsourcing media production.
The 1970s also saw the introduction of standards for cleanrooms. Demands from regulators for conformance soon raised the level of quality of culture media and service delivered by suppliers. For example, certificates of analysis and sterility are now required. In addition, the sterility of packaging, in part delivered by gamma irradiation of triple wrapped agar plates, is now considered essential to eliminate the risk of extremely costly false positives.
Microbiological culture media is used in a wide range of activities – from checking the purity of cell cultures used in production, through the absence of pathogens and spoilage organisms in raw materials and intermediates, to the assurance of sterility in the finished product. Similar concerns apply in food, beverage, cosmetic and medical device manufacture. In every case the starting point is safety of the consumer and clearly parenteral medicines represent a greater risk to the individual than beer or yoghurt.
Risk to safety can be translated into a financial risk. For example, if confidence in the sterility of a sterile medicine is less than absolute the batch must be discarded or reprocessed. As the use of isolator technology grows in place of staffed cleanrooms for aseptic production, there is a regulatory expectation that the atmosphere and the internal surfaces of the isolator should be demonstrated to be sterile throughout the manufacturing or filling process and consequently the sterility test.
As a result, a false positive in either the sterility test or critical environmental monitoring has the potential for the loss of a batch, plus an expensive and time consuming investigation of the cause and a corrective action programme. This means that confidence in the culture media used in the production and sterility testing areas is critical.
why outsource?
The process of regulatory inspections is intended to drive a constant escalation of best practice. This can lead to a genuine improvement in patient safety, together with the potential for large variations in the amount of testing required. For example, validation of a new process or plant might require a high frequency of environmental monitoring that need not be sustained when it becomes routine. Outsourcing of prepared culture media, therefore, has some clear advantages for the pharmaceutical manufacturer:
- Production and quality of media is not a distraction from the company’s product expertise
- Economy of scale
- Independent growth promotion testing
- Accommodates flexible demands
- Gamma irradiation of packed plates ensures sterility
assessing your needs
Each of the above is sufficient reason for buying culture media ready to use, but how should the appropriate supplier be chosen? A good starting point would be reduction in risk. The various media product requirements should be weighted according to their influence on risk to the whole business of the site. Such requirements should be considered as follows:
What products do I need?
The pharmacopoeia describes suitable media and the set of challenge organisms that should be used to test them. However, local circumstances might dictate specific modifications, for example, if there are any inhibitory substances, such as disinfectants and antibiotics, which must be neutralised by the environmental monitoring and sterility test media. Or will the standard media actually support the growth of the predominant local microflora?
What documentation do I need?
Does the supplier provide the information needed for each batch of media? Needs vary. Most microbiologists would probably demand at least growth promotion results for the pharmacopoeia strains, pH reaction, a unique batch identifier and a use-by date. Traceability of raw materials might not be essential for everyone, although other parameters such as storage requirements might also be helpful.
What packaging do I need?
There are many different ways to pack an agar plate or a bottle of broth. Some manufacturers offer a choice, but it is important that the packaging meets the needs of the user, rather than just those of the supplier. Consequently, there are a number of considerations:
- For environmental monitoring plates – the packaging should maintain sterility until the point of use e.g. by multilayer sterile packaging. The number of layers depends on the process of delivery to the point of use. For example, consider how many times a pack of plates might be transferred from one area to a cleaner one before finally being opened to remove a plate. Also, plates should be protected from mechanical damage in transit. Can the user check for sterility failure before opening the pack? Is it transparent?
Other questions include: Is the identity on all the appropriate components (box, bag, plate, etc)? Is the pack size appropriate for my needs to minimise waste of packaging and plates? Is there a risk of using the wrong plate at the point of use? For example, if more than one type is in use, can the user easily check by colour, label or shape? Does it protect the plates from any transient processes in use such as H2O2 gassing or alcohol spray?
- For liquid media – In addition to considerations on type of container, such as ampoule, injection vial, infusion bag, DIN bottle, etc. and its size and fill volume, as well as closure and seal type, other questions include: Is the label adequate – sufficient information without obscuring the contents? Will the tray support the weight of bottles? Is it an appropriate size?
What batch size do I need?
For many licensed aseptic manufacturing sites every batch of externally supplied media must be tested on receipt to meet regulatory requirements. Consequently, to minimise the amount of in-house testing required, it is well worth establishing the smallest number of batch changes necessary to maintain constant availability of in-date, tested product.
What are the storage conditions?
Ambient storage is cheaper and more flexible as long as it doesn’t compromise product quality or shelf life. It is important that agar settle plates and contact plates have no free water on the surface because that might cause the spread of growth rather than discrete colonies. It is equally important that the gel is still sufficiently moist after exposure and incubation to satisfy the growth promotion test.
Once the key requirements have been decided upon, look for the best supplier to service these. It is probable that the basic requirements for a media supplier can be met by any of the several reputable companies in the industry. These will include acceptable QC testing and documentation, as well as presentation and performance. However, there will be differences in the specific solutions to the questions of meeting local requirements.
Logistics – Delivery on time is important to everyone. The difference between suppliers is more likely to be the management of last-minute changes to your requirements and recovery from accidental loss. You should therefore establish what the actual lead time for the products you need is and subsequently how quickly a supplier can respond to any unexpected incidents.
Shelf life – All manufacturers can tell you the shelf life from when a product is made or packed, but how much of this shelf life is actually remaining by the time of delivery? A safe margin should be ensured to avoid waste of expired product if usage changes.
Flexibility – Can one supplier meet all your requirements? For example, they might deliver 10,000 TSA settle plates, but can they also supply just a few vials of broth with neutralisers, or make a trial batch of a new bespoke medium for a trial.
Another key question to consider when selecting a supplier is whether the supplier truly understands your individual needs. Industry knowledge and understanding is therefore another crucial requirement to ensure that critical environments are monitored effectively and in strict compliance with regulations. For example, if a change to the formulation of a medium is required, can you access a trial batch and then three or more further small batches for validation on site before you commit?
If you have different areas or processes that need similar testing, how can you avoid the risk of operators selecting the wrong plate and invalidating the test? Options to overcome this issue maybe by over-specifying to meet the most demanding (expensive) requirement, or colour coding to reduce errors.
Does the supplier’s quality management system control the processes that are critical for your business?
One final consideration should be if the supplier can offer the help, experience and expertise necessary to assist with any new challenges as and when they occur. Such challenges might include a new process, or simply a changed expectation in the level of quality assurance required for your media.
For example, currently there is a growing expectation that pharmaceutical companies now undertake a justification, validation or qualification that includes some local testing for all growth media supplied. This is regardless of the amount of work the supplier puts into testing and certifying every batch of prepared media, and however much care has been taken in selecting the best supplier. This situation is not likely to change in licensed manufacturing.
Consequently, the resultant cost of this new approach serves only to increase the value of high quality prepared media with its quality documentation, as the user of any outsourced product or service does not want to have to reject batches after quarantine and testing. Failure after media has been used is even worse. As a result, the cost of failure – risk of a false negative due to sub quality growth media – is rapidly becoming similar to the cost of a false positive.