How do I work out acceptance criteria?

Hello everyone,
I am doing some cleaning validation for the equipment used to manufacture a cytotoxic medicine. I plan to use the minimum daily dose criterion for working out my acceptance level. Is there a particular convention for working this out? Published information has doses for the API that goes down to a 1 month old child! If we use this dose then our acceptance levels are going to be almost undetectable using TOC.
I would be grateful if anyone can offer any advice.

Please chcek the LD 50 of the API, However ypu have to use the most stringent.
In this case you have following options,

  1. decrease the rinse quantity,
  2. Increase the swabbing surface area
  3. Use the instrument requiring lesser sample quantity and more sensitivity ( HPLC,GC etc)
  4. Last option, restrict the batch of the product inmatrix , which requires lesser carryover.

VG

You should base your acceptance criterion on Toxicity using LD-50 is used to calculated the Residual accaptance level (RAL), using the ADI (Acceptable Daily Intake).

Roughly for RAL:
ADI = LD50 x Average Body Weight x Safety Factor (1/10000 for IV)
RAL = ADI x # doses

Otherwhise, if your product is not toxic, you may use the 10 ppm criterion and calculate a MACO (maximum carry-over)

Refer to PDA Technical Report #29 and Destin Lablanc Cleaning Memo for more details.

Good Luck!

[quote=JohnB]Hello everyone,
I am doing some cleaning validation for the equipment used to manufacture a cytotoxic medicine. I plan to use the minimum daily dose criterion for working out my acceptance level. Is there a particular convention for working this out? Published information has doses for the API that goes down to a 1 month old child! If we use this dose then our acceptance levels are going to be almost undetectable using TOC.
I would be grateful if anyone can offer any advice.[/quote]

Dear JohnB,

whether to use the pediatric dose of the API or not, depends on the other products manufactured in that equipment. If any of the other products produced in the equipment are intended for infant use, you should calculate your acceptance level with that criterion in mind.

In our experience, TOC is excellent for routine verification of cleanliness because it is fast and simple, but for cleaning validation, and especially with high potency compounds, the LOQ of the method is rapidly reached. On top, with very stringent acceptance levels for the API it is extremely hard to reach the accepted level, because the carbon contamination from other sources (excipients) will far exceed the API contamination, and you will find contamination levels above the limit, which you know are due to the excipients, but cannot demonstrate it.

Best regards

Alfred

Dear JohnB,

The acceptance criteria for cleaning validation studies may be calculated by various means, some of them include:
a. Dose criterion (which uses minimum daily therapeutic dose).
b. Toxicological Criterion (which uses LD50/No-Observed effect level/Acceptable daily intake values).
c. 10 ppm criterion, etc.
One thing is not at all clear from your question, you want to carry out cleaning validation study for a cytotoxic drug and the product is recommended for that young age (1 month), usually cytotoxic drugs are not advisable for infants due to adverse effect concerns. In order to obtain meaningful dose, please refer to doses of the products (containing the same active) available on the market. In that case use standard daily dose (for an adult), once you have the dose and all other parameters required for the calculation of acceptance criteria use the spreadsheet available at


for estimation of maximum allowable carry over (MACO). If not clear about it, please email me for clarification.