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Cleaning Method Validation by TOC Analyser

What would be acceptance criteria for cleaning method validation if I wish to use TOC analyser for evaluation/ analysis.

You have to compare TOC of incoming and outgoing water.Results must be the same.

Arzakan is wrong. The carryover acceptance criteria (MSC or maximum safe concentration) depends on your process and the toxicity of the most toxic molecule. As an example (BIG NOTE!);

MSC in mg = [ADE(mg/Kg) x lot size (Kg)/MDD (Kg) x SA (cm2)/TSA (cm2)]

ADE = ‘acceptable daily exposure’ or a measure of toxicity of the API molecule
MDD = maximum daily dosage of the API molecule
SA = surface area of each individual piece of manufacturing equipment
TSA = total surface area of the entire manufacturing process train

Thus, the MSC could be (depending on the API’s toxicity) in the high ppm not the same as water for injection, which is 500 ppb.

It doesn’t make any sense to have a very ‘strict’ carryover acceptance criteria for a nutritional substance that is non-toxic but promises to make you ‘healthy, wealthy, wise and beautiful instantly’!

BTW. You can obtain the ADE from www.affygility.com It is listed or can be determined in the ‘Clinical Phase II’ by a registered toxicologist if you are manufacturing a generic drug product.

Remember, the world has changed, especially in ‘cleaning validation’!

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I guess we cannot quantify the particular API through TOC analyser. The resultant TOC of the sample could be of API, Excipients, surfactant, water etc. Please detail if we can use the said formula to set acceptance criteria for Cleaning method validation by TOC analyser. I think the formula is very useful if we can quantify the API.

Not really since there are many variants of the formula even ones that include the ‘average body weight (BW)’ of the consumer (MDD can also be unitless). The formula variant is appropriate for a specific method like HPLC. Thus, as part of the 'site cleaning validation master plan (SCVMP) you need a cleaning validation strategy. Remember, it is your cleaning method that is being evaluated for cleaning effectiveness and the analytical method is the ruler.

TOC can be used for nutritional supplements where the API is >100 mg despite the fact that the excipients also react. It catches EVERYTHING thus you may end up chasing a ‘ghost’ like IPA which is non-toxic and is a common sterilization agent.

Therefore, TOC (MSC x mole ratio) is a common screening method but there is a specific method like HPLC when things fail.

MDD can also be replaced by SBS or the ‘smallest batch size (Kg)’ in that manufacturing train since it is the most likely product to be contaminated (worst case). Each shared manufacturing process whether it is a soft-gel, cream, lotion… has its own cleaning procedure and thus cleaning validation study (strategy, equation, protocol, report…). Thus, the SCVMP (site cleaning validation master plan).

Also, in order to be more mind numbing! Cleaning validation applies not just to your drug products, shared manufacturing processes and cleaning methods but;

  1. APIs
  2. Cleaning Agents
  3. Microbes
  4. Bioburden or dead microbes (thus TOC)
  5. Endotoxins (for parenterals)

Each, will have a different equation.

As you can see cleaning validation is a ‘very’ complex subject! It is motivated by the question of ‘How clean is clean’? The answer is your MSC calculation which is based on the toxicity of the target molecule (API).