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

Thank you. The guidance refers to Class III PMA medical device. What if the device is Class II?

Thank you. Correct me if Im wrong, isnt it refers to Medical Device Class III PMA? What if the medical device is Class II under FDA 510k?

Right - QIII.6 contains this: "Manufacturing changes for Class I and II devices should be in accordance with the quality system regulation, 21 CFR part 820", implying that no regulatory action is required when changing from one (alternate) BET method to another. Since the other Q&A items are silent for other than Class III devices, this quote can be considered generally applicable to the rest of the guidance except for this - quote: "When a manufacturer of medical devices plans to use LAL testing that deviates significantly from this guidance or recognized standard, a premarket notification (510(k)) under section 510(k) of the Federal Food, Drug, and Cosmetic Act (the Act) or a premarket approval application (PMA) supplement under section 515 of the Act should be submitted."

planB said:

Right - QIII.6 contains this: "Manufacturing changes for Class I and II devices should be in accordance with the quality system regulation, 21 CFR part 820", implying that no regulatory action is required when changing from one (alternate) BET method to another. Since the other Q&A items are silent for other than Class III devices, this quote can be considered generally applicable to the rest of the guidance except for this - quote: "When a manufacturer of medical devices plans to use LAL testing that deviates significantly from this guidance or recognized standard, a premarket notification (510(k)) under section 510(k) of the Federal Food, Drug, and Cosmetic Act (the Act) or a premarket approval application (PMA) supplement under section 515 of the Act should be submitted."

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Hi, I'm reviewing a situation similar to what petdressiva had asked about here a few months ago. I have a Class II device for which LAL testing is performed on every lot and the manufacturer is reviewing whether it is permissible to reduce this frequency - perhaps even to the point where testing would only be performed upon major changes to the device (e.g., a change in a critical component).

I am vaguely gathering that that desired frequency would not be sufficient, but I'm not terribly clear from the FDA guidance in question what frequency would be acceptable. Or using the above quote, at what point would the frequency deviate from the guidance significantly enough that PMA would be required for this device?

Thanks!

Thomas88 said:

Hi, I'm reviewing a situation similar to what petdressiva had asked about here a few months ago. I have a Class II device for which LAL testing is performed on every lot and the manufacturer is reviewing whether it is permissible to reduce this frequency - perhaps even to the point where testing would only be performed upon major changes to the device (e.g., a change in a critical component).

I am vaguely gathering that that desired frequency would not be sufficient, but I'm not terribly clear from the FDA guidance in question what frequency would be acceptable. Or using the above quote, at what point would the frequency deviate from the guidance significantly enough that PMA would be required for this device?

Thanks!

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@Thomas88 It might be ideal to purchase the ANSIAAMIST72-2019 as a guide to alternate batch sampling. The standard recommends of possible frequency reduction. Both FDA and and ST72 requires verification and validation and risk analysis for us to deviate from the standards. Another thing is that, Class II medical device under FDA, in my understanding does not need PMA supplement. Either you document it in your quality system or submit another 510(k) if the change is significant.

@Thomas88 it seems your intended change would fall under a change of the sampling plan for which a previous response applies in terms of reportability. In addition to reducing frequency via a risk-based justification as @petdressiva pointed pout, have you already thought about reducing the test sample size of 3% (10 samples max) of the batch size?

planB, petdressiva, thank you for the responses. This is a Class II device. For context, it is implantable/injectable. I have read opinions elsewhere that device type may influence frequency of testing and, specific to implantable devices, testing for each lot may be required.

I will speak aloud here about what I've learned thus far:

I will need to purchase a copy of the 2019 version of ST72 but I do have a 2011 copy handy. I see that it states that it states among its alternatives to batch testing include sample size reduction (as planB has suggested) and a reduction of frequency - "from every batch to every nth batch or...one batch per shift or per day." As the Alternatives to Batch Testing section of ST72 suggests, and as discussed here, a risk assessment and data demonstrating that the modified manufacturing process (i.e., with less frequent testing) meets endotoxin limits. The fact that the standard begins with "every batch" makes it seem as though this is the basic expectation, with alternatives allowed provided that the risk assessment, data, etc. are addressed.

Provided that this remains true with the 2019 version, it would appear that some reduction in testing from every lot to every nth lot would not significantly deviate from a recognized standard (here, ST72), and accordingly, the above quote from the FDA guidance regarding additional 510(k) submission or PMA being required does not apply. Provided that ST72's clause on alternative methods is being followed, documentation in the QMS would be sufficient.

All of this makes assumptions about the standard being followed appropriately, but is my line of thinking correct here?

Thanks again for the insight on this matter.

When purchasing a standard, you might prefer ISO 11737-3:2023, Sterilization of health care products, Microbiological methods, Part 3: Bacterial endotoxin testing, which transposes the US national ST72 standard into an international standard with unchanged requirements.

The fact that the standard begins with "every batch" makes it seem as though this is the basic expectation, with alternatives allowed provided that the risk assessment, data, etc. are addressed.

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correct

Provided that ST72's clause on alternative methods is being followed, documentation in the QMS would be sufficient.

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In case 30-day notices do not apply to your device - correct.