I have just written the cleaning Validation for an API suite and set an absolute limit of 100ppm relative to subsequent batch size. Does anyone have any opinion on this?:
Dear Sonya,
How did you arrive to this (100ppm) limit? Which criteria are you using to establish CV acceptance limits? Please remember a limit may be considered arbitrary if it is not scientifically justifiable. From my point of view “100ppm” limit is more than the default limit of “10ppm” and hence cannot be used as a CV acceptance limit.
Thanks.
as a industry practice you should fixed minimum 10ppm as a limit.
100ppm is to high amount of product A in to product B.
please once again go through the calculations.
Dear Sonya,
although 100 ppm is a commonly used acceptance criterion for cleaning validation in API, (it stems from the 10 ppm default limit for solid dosage forms and the assumption that the active ingredient is 10% of the formula, hence contributing 10% to the total contamination and thus admitting 10 times more contamination), it is only acceptable as a default limit and not as the solely used acceptance criterion. The limit calculated through the product dosage should be compared with 100 ppm and taken the lower limit among both.
Best regards
Alfred
I Read a document from
www.gmp-compliance.org/eca_news_928.html
which gives justification for setting a 100ppm limit
Alfred how would I calculate the limit through the product dosage?
[quote=Sonya McQuaid]I Read a document from
www.gmp-compliance.org/eca_news_928.html
which gives justification for setting a 100ppm limit[/quote]
Dear Sonya,
read the document through and it says :
“When neither dose nor toxicological data are available for the previous product, the limit is set at 100 ppm.”
and then:
“Consequently, for the equipment in toto either the 1/100th dose criterion, safety factor 10 for calculation with toxicological data, or the absolute criterion of 100 ppm are used.”
In the light of both these paragraphs, if you use only the 100 ppm-criterion, you will have to prove that there are no toxicological or dose data available, which may be true for some by-product or intermediate, but never for the finished API. So, in the best case, you will have two different criteria used at your site, and a strong need to justify the use of less stringent limits.
Best regards
Alfred
Dear Sonya,
for the calculation you need basically four figures:
- The minimum active therapeutic dosage (matd) (in [mg/day])
- The maximum daily intake (MDI) (in [mg/day])
- The batch size (BS) (in [kg/batch])
- The surface of the equipment train (S) (in [cm²]). This applies only to equipment shared between contaminant and contaminated API after the last purification/recristallization step because previous contamination is supposed to be eliminated in this step. This has to be verified.
The first two figures you can get from the leaflet of the formulated products in the market, which contain each API. Be sure to include peediatric dosages. For the maximum daily intake you may use the toxicity as a worst case. The MDI, the batch size and the equipment train surface you should have already used for the calculation of the limit in [ppm], and have the worst case contaminant determined. The usual safety factor for API is 1/100.
Lets call the contaminant A and the contaminated product B. The maximum of A a patient can take per day is 1/100 of the matd: matd/100. This is the quantity of A allowed to be present in the maximum of B taken per day.
That means that in the MDI of B, matd/100 mg of A may be present. So, in one batch of B, (BSmatd1000000/(100MDI)) mg of A may be present. (1000000 is the conversion of the batch size in kg to mg). As one batch of B is in contact with the whole equipment train surface, assuming even distribution the contamination per cm² is (BSmatd1000000/(100MDI*S)), in [mgA/cm²].
Among all the “contaminated” products manufactured, the worst case B ist the one that minimizes the factor (BS/(MDI*S)) because for the worst case contaminant it renders the lowest accepted limit.
Of course this is only one way to calculate the limit, there may be others based on different considerations regarding process, product mix, using toxicity figures, including by-products, intermediates, etc…
Best regards
Alfred
Thanks, for your help. This criterial applies to APIs for vet use as well?
n e one pls suggest me how to calculate the surface area of the equipment