Limulus Amebocyte Lysate (LAL) Testing: A necessity on every lot?

mimic · Aug 6, 2009

Hi everyone,

This is my first post on this forum and I would like to thank everyone in advance for all their comments, questions and suggestions.

I coordinate sterilization and packaging at a medical device company. We manufacture sterile products mostly to EU and North America.

As part of the ISO 10993 requirement of non-pyrogenicity, we perform LAL testing for endotoxin presence. As per the FDA requirements ( i do not know the actual guideline), we perform LAL testing on every lot released.
2 samples for lots 1-30
3 samples for lots 30 above
3% for over 100

Over the years, we have never had a LAL failure and we have collected trend data to show that our manufacuring process is stable.

Is it necessary for us to continue to perform LAL testing on every single lot that is released?
Would a rationale based on history and trend data allow the frequency of LAL testing to be dropped and allow us to do it on a quaterly basis(per year)

Any1 have any experience with this situation.

The reason we would like to reduce our LAL testing is reduce the costs of scrapped products to LAL testing.
Example: There is one product where we make the product in lots of 100. This requires us to perform LAL testing on 3 samples.

We would like to reduce our Lot sizes to 50 for efficiency purposes. However, in this situation, we will have to do 3 samples per 50 causing us to waste 6 units for a 100 pieces.

Thank you and I apologize for the excessive info.

Jimmy the Brit · Aug 7, 2009

Hi Mimic, welcome to the cove.

Indeed, there is a way out of batch testing for bacterial endotoxin, as long as your process is in control and you clearly understand the nature of bacterial endotoxin (where it comes from, how to eliminate it and how to predict failure modes).

ANSI/AAMI ST72: 2002 "Bacterial endotoxins - Test methodologies, routine monitoring, and alternatives to batch testing" > Section 10 is all about alternatives to batch testing, including what steps you must take to qualify your manufacturing processes - all based on a history of control, which it sounds as if you already have to hand. This standard has been recognised by the FDA (Recognition List Number: 020 Effective Date: 09/09/2008).

Be sure to justify your choice of in-process sampling frequencies based on the data, rather than on what suits your operation - the FDA tend to be very hot on that. Also we specifically added a line to our change control forms asking whether possible effect on process endotoxin yield had been considered, to ensure that we never lost sight of the criticality.

I hope this helps,

Jimmy

mimic · Aug 8, 2009

Hi Marc,

Thank you very much for your informative reply. I will soon be browsing through the referenced paper.

Thanks.

Ajit Basrur · Aug 9, 2009

mimic said:
Hi everyone,

This is my first post on this forum and I would like to thank everyone in advance for all their comments, questions and suggestions.

I coordinate sterilization and packaging at a medical device company. We manufacture sterile products mostly to EU and North America.

As part of the ISO 10993 requirement of non-pyrogenicity, we perform LAL testing for endotoxin presence. As per the FDA requirements ( i do not know the actual guideline), we perform LAL testing on every lot released.
2 samples for lots 1-30
3 samples for lots 30 above
3% for over 100

Over the years, we have never had a LAL failure and we have collected trend data to show that our manufacuring process is stable.

Is it necessary for us to continue to perform LAL testing on every single lot that is released?
Would a rationale based on history and trend data allow the frequency of LAL testing to be dropped and allow us to do it on a quaterly basis(per year)

Any1 have any experience with this situation.

The reason we would like to reduce our LAL testing is reduce the costs of scrapped products to LAL testing.
Example: There is one product where we make the product in lots of 100. This requires us to perform LAL testing on 3 samples.

We would like to reduce our Lot sizes to 50 for efficiency purposes. However, in this situation, we will have to do 3 samples per 50 causing us to waste 6 units for a 100 pieces.

Thank you and I apologize for the excessive info.

Hi mimic,

Welcome to the Cove :bigwave:

Your question is very much valid and you could employ the Risk Management approach for elimination of the LAL testing.

rick76 · Oct 28, 2009

I'm currently in the process of reducing the LAL sampling for raw materials, i was wondering if you can share a report or how you justified how to reduced LAL. Our product is very expensive to scrap therefore i would like to maybe go away from testing raw materials on frequent basis, but instead just verify on quaterly basis LAL on finsihed product. Please help!

somashekar · Oct 28, 2009

mimic said:
Hi Marc,

Thank you very much for your informative reply. I will soon be browsing through the referenced paper.

Thanks.

Good thought .., most likely your device may be falling under <20eu/device USP classification. On your sample picks, do you conduct pooled test or each sample is tested and decision is based on pass of all samples ?
For a product release of such a catagory this test pass report is of vital importance.
Where does the endotoxin come to the device during your process ? Most likely it is water which may be used any stage. Correct me if wrong.
Do you have a good pure water system which pass the endotoxin test before use daily, like for example pass a 0.25 eu/ml test ?
If so and if you have a good trend of this water test, the probability of the device passing your LAL test is high. You may perhaps take these test data as a base to a suitable reduced sampling to avoid your device loss.
FDA, I am sure will look for a product release procedure of such a catagory which has within it the LAL test result. The effect on a patient due to use of device considerd pyrogenic is much high compared to your device cost

rick76 · Oct 28, 2009

This definetly help me on starting with a report justifying the change, just wondering if you have a sample of report laying some where with similiar information. To answer your questions all material is extremely below the 20eu and the water endtotoxin are also below the 0.25/ml, therefore we would like to go away from routinely testing samples on a frequent basis.

My only concern that i have now is that if my report does not reference certain ISO/AAMI requirements, clearly explain the reason for the change, and address the risks that are avoided based on my proposal.

mogluk · Nov 3, 2009

yeah, the reduction of testing really depends on your internal QC checks. doing LAL analysis on tools and equipment used ( I have seen weekly tests on industrial washers and daily checks for drain of sterilizers).

If you are manufacturing a disposable injectable, I would say you have to show some control. And especially if its by lots, doing individual lots provides for less recall in the event of a contamination (due to device or operator error). if you start jumping lots for testing recall procedures would have to encompass more product increasing your risk.

petdressiva · Oct 12, 2023

Hi I know this is an old thread. I want to know if we will change the sampling plan based on this post, what are the regulatory actions that we need to do for FDA?

planB · Oct 12, 2023

FDA Guidance for Industry: Pyrogen and Endotoxins Testing: Questions and Answers, Q III.1 may hold the response to your question - quote: "For devices, a 30-day notice may be appropriate for in-process changes to the sampling plan."

HTH,

Limulus Amebocyte Lysate (LAL) Testing: A necessity on every lot?

mimic

Jimmy the Brit

mimic

Ajit Basrur

rick76

somashekar

rick76

mogluk

petdressiva

Starting to get Involved

planB

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