Compendial Methods Need To Be Qualified
September 12th, 2011 by Peter CalcottDuring a recent class I taught at University of California, Berkeley in their Quality and Compliance postgraduate certificate program, a question came up from one of the attendees that mirrored very closely observations I have made in audits over the years. And that question was “do we have to validate compendial methods we use in testing our commercial products?”
That question is, on the surface, very simple. And the answer is no. Neither the FDA nor the EMA requires us to validate compendial tests that we use with our products. But the answer actually has another layer to it which people do not venture too often to address.
While we do not have to validate a compendial method we use with our products, we must demonstrate that it works for the application with our product. ICH Q7 describes in section 12.80, this point clearly.
Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented
Thus it is clear that while formal validation is not required, we must demonstrate that it works for our product for the intended purpose. This is very clearly shown in the original form 483 issued to Chiron Corporation for their flu vaccine product plant in UK in October 2004 that resulted in issuance of a warning letter in December 2004. They were cited for a lack of data to support the use of the USP sterility test for their product. Their response was clearly adequate since it was not cited in the warning letter. This action took them off the market in the 2004 flu season for their flu vaccine product
Many times on audit I have reviewed specifications and seen that compendial methods are used for a variety of tests including sterility, endotoxin, particulates and others. My first question is usually to ask for the data to support use of the method for their product. At least 9 out of 10 times, I get blank stares followed by the statement, “we don’t have to validate compendial methods!” I agree with them but follow on with the statement, “I know, but where is the data to support usage of the method?” They often look puzzled still but cannot provide any data. Too often, I believe, the first sentence of the ICH Q7 document is read but the second missed.
What do you have to do the “qualify” it? I recommend a simple qualification plan – rather like a validation protocol – with a testing plan to check the key parameters of the assay such as accuracy, precision, specificity and ruggedness, including interferences. That sounds like a validation and it is: but an abbreviated one touching only on the parameters of issues that make your product unique or challenging.
Good Afternoon Peter,
Recently at our biotechnology plant we started working with Bioburden methods qualification and have been having issues trying to filter cell culture samples specially Harvest Samples, method proposed was membrane filtration but any feedbacks/recommendations that will help us identify a better method?,
Thanks,
I.Rodriguez
You posed an interest challenge. Firstly, I am assuming that you are dealing with a mammalian cell culture sample. This conditioned medium sample does pose challenges to filtration. There are many ways to approach this including:
1.) Try to pre-filter the sample through a 10 micron filter, followed by 0.2 micron filtration to trap bacteria which are then placed with the filter on top of a nutrient medium eg. nutrient agar (NA). To qualify this you will have to prove that the pre-filter does not remove bacteria. You are probably safe with this.
2.) Use a detergent to solubilise the debris and lyse the mammalian cells. Pre-filter and then 0.2 micron filter to get count. Again you will have to assure that the sample preparation and filtering do not interfere with bacterial recovery.
Both of these are really using the basis for the sterility test to count bacteria. But there is an alternative approach. The sensitivity is less but remember that bacteria once in a cell culture do grow very fast and much more so than mammalian cells.
You can actually use a direct plating technique. Take a sample of culture fluid – say 0.2mL and spread plate it on NA. The mammalian cells will not grow – at least within the 2-5 days you need to incubate the sample to get bacterial colonies. That translates to being able to deterct <5 bugs/mL.
Using the agar pour method, take 2.5 mL of culture fluid and dilute with same volume of double strength NA to yield 5mL of normal NA. Pour onto a shallow plate of NA. In this case you can improve sensitivity about 1 log to 0.4 bugs/mL
These methods have been used in plants I have worked at and accepted by agency people.
In both cases you need to qualify recovery of bugs especially EM samples that might be contaminants as well as a few more. Write out the method and qualification and present to agency. No requirement I am aware of says you must use filtration method with its sensitivity. After all you are looking for gross contamination and we know if a bug gets in it will grow like wild fire.
Good luck and hope this has been helpful
We are working on glucagon bioidentity test. This is a recent revision of glucagon bioassay method, USP 35.
We are planing for verification of the test method USP glucagon bioidentity test. As this method is a indirect method to measure the relative potency of glucagon and the experiment having two measure part one is hepatocytes preparation and second is analysis of samples for glucose estimation by glucose analyzer.
To verify the method suitability in our laboratory condition first we validate the instrument i.e. accuracy, precision, specificity,linearity and range.
The acceptance criteria for hepatocytes preparation is already mentioned in the USP.
Is this required to verify the acceptance limits in verification experiments?
Which factor should be considered for verification of bioassay method.
Anticipating your reply
Regards and thanks
Durgesh
In general, this is how I would do it.
1.) Equiment validation. DQ, IQ OQ and appropriate PQ for the instrument – all components. This includes the software to calculate any data.
2.) Now to method. Examine the method as per USP and determine if it is appropriate for your product through research – ie no GMP conditions
3.) When you are con]mfortable that the mteethod works for you, either as is or with some adjustments, you are ready for qualification
4.) Consider what parameters are importnatn to confirm and incorporate into a protocol. It need not be as detailed as a full validation. It might include accuracy, precision, specificity and ruggedness but it does not have to include all. perform work and see how it turns out. Write up and Voila, there it is.
Hope this helped.
I have found people tend to either go overboard or ignore any qualification. Just define what you will do and why in the protocol.