Ensuring That Media Components are AOF
Cell culture media manufacturers have three levels of quality control over the raw materials used in their media: basic analysis,
questionnaires, and site audits. These levels are used because generally it is not feasible for media manufacturers to audit
all of their raw material suppliers. Major media suppliers work with hundreds of raw material suppliers to source thousands
of components and because each audit takes an average of two to three days and extensive travel, a team of full-time auditors
would be required if every single supplier had to be audited.
Basic Analysis and Questionnaires
For well defined raw materials that form a very small proportion of the total volume of the media produced for clients, most
cell culture media suppliers carry out a basic analysis. This analysis involves testing each raw material and comparing it
against the Certificate of Analysis (CoA) provided by the raw material supplier. Such testing rarely reveals whether a product
was made using AOF components, but if a product matches its written specifications, the testing can offer a degree of assurance
that the vendor is selling what it says it is. Alternately, if the results do not match the CoA, the test will raise concerns
and prompt the company to investigate.
Cell culture media suppliers typically also ask their raw material manufacturers to fill out a questionnaire. The questionnaire
should include questions such as:
- Is the material derived directly from an animal?
- Does the manufacturing process use any other animal-derived components?
- Does the supplier classify the manufacturing components and process as AOF?
- What enzymes and cell culture media have been used to produce the raw material?
- How is the product analyzed for quality?
- What cleaning and cleaning validation steps have been used to ensure there is no cross contamination of the product with any
product of animal origin?
A questionnaire also can be used when a cell culture media supplier is unhappy with the results of a basic analysis. Having
a raw material manufacturer provide additional documentary evidence that its component is AOF to either a primary or secondary
level provides an additional level of assurance that the component is indeed AOF.
Questionnaires have several disadvantages, however. Questionnaires take time to complete, and there is the potential for inaccuracy.
Also, even if the information provided in response to a questionnaire is accurate, it is only a snapshot in time. Good communication
with a raw material supplier and using a change notification system will serve to keep the information current and robust.
For suppliers of large amounts of critical components of a cell culture medium (e.g., amino acids or insulin), a cell culture
media manufacturer should conduct both a basic analysis and site audits to ensure that the written standard operating procedures
(SOPs) are being followed by technical personnel. Many raw material suppliers follow current good manufacturing practices
(cGMPs) and are ISO 9001:2000 certified; therefore SOP documentation should be readily available for inspection. A site audit
is the best method of determining that a supplier of bulk raw materials really does understand its SOPs and is implementing
them correctly for producing AOF materials. The audit should review batch ingredients and supporting documentation that confirms
the origin of those ingredients.
In addition, a site visit provides the opportunity to ask the technical personnel in-depth questions. A direct interview reveals
more than having staff send in answers to a questionnaire, which can sometimes be completed by a committee or someone other
than the person in charge of process handling. Media manufacturers, just like the FDA, may use the track record of a supplier
to determine the frequency of audits. This allows the media manufacturer to balance its resources against risks.
Biopharmaceutical companies are concerned about the potential for cross contamination between AOF and non-AOF manufacturing
processes carried out in the same facilities. To address this concern, some modify their definition of AOF to require that
AOF products be made in an area where only AOF production is performed. For many cell culture media suppliers, however, such
separation is not always possible to achieve and many AOF products or raw materials are still manufactured alongside those
of animal origin. To overcome this challenge, many media suppliers carry out validated cleaning and process controls to ensure
there is no potential for animal product carryover, and provide information to their customers about these steps.
Country of Origin
Many manufacturers of good quality, cGMP-grade raw materials are now located around the world, including countries with emerging
suppliers of media component raw materials like China and India. Components sourced from those countries are being used more
frequently, especially by companies that are seeking to keep costs down while improving the level of AOF status. Other companies,
however, prefer not to source from such countries. Mandating limitations on the countries from which raw materials can be
imported, or requiring that all raw material suppliers be audited, however, can increase manufacturing costs. Those costs
may have to be passed on in the price of the media and could mean the finished product would become prohibitively expensive.
Maintaining an AOF Media Supply Chain
When choosing a supplier of AOF cell culture media, there are a few important question to ask. For example, does the supplier
have a secondary source of critical components that is equivalent to the primary source? And what steps has this supplier
taken to mitigate AOF risk and the risk for back order? Many cell culture media manufacturers do not maintain large inventories
of raw materials, and instead carry just enough to cover one to two months without any new deliveries of critical components.
This reinforces several important recommendations about maintaining any supply chain:
- Attempt to forecast as accurately as possible, so that suppliers are not surprised by sudden increases in demand.
- Use a mitigating safety stock strategy to assist with sudden, unforecasted increases in demand.
- Avoid including specifics in regulatory filings that will leave suppliers without options to use alternative equipment or
locations to make media. For example, do not indicate the serial number of a piece of equipment used to make media.
- Set specifications for the desired quality and put the burden of compliance on the media supplier (which can be audited as
frequently as requested).
- Work closely with media suppliers to ensure product specifications balance risks with cost and availability.
The lack of industry standards around the definition of when the manufacturing process begins and ends, as well as whether
an adventitious agent can remain through various AOF levels, will continue to affect perceptions of safety and patient risk.
This is why the levels of AOF necessary must be considered when choosing a cell culture media supplier. If most therapeutics
are only primary level AOF, then is the additional burden of evaluating secondary or tertiary level AOF components really
essential? Biopharmaceutical companies that demand cost-effective, guaranteed AOF media and ingredients should determine how
well their cell culture media supplier is assessing their raw material manufacturers before entering into a long term agreement.
In short, biopharmaceutical manufacturers must ensure public trust that they are maintaining the highest levels of safety
for their end products. It is important to weigh actual risk when requiring levels of AOF beyond the primary level. If a critical
or high-cost AOF component such as insulin is going to be used, the biopharmaceutical company is justified in specifying the
assurances it needs to be confident it is getting the safety required. Following the steps a media manufacturer uses to qualify
raw materials and working with the company to agree on the acceptable level of risk versus benefit (for example, willingness
to accept an audited source from India that meets GMP requirements and an AOF definition at the desired level to ensure a
regular supply) should help achieve desired patient safety while ensuring cost-effective availability.
Leslie E. Madigan is the global purchasing manager, Laurel Donahue-Hjelle is the director of cell culture product development, Satyam S. Nampalli is a technical area manager, and Mark J. Stramaglia is a senior product manager, all at Invitrogen, part of Life Technologies Corporation, Grand Island, NY, 716.774.6860, firstname.lastname@example.org
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