Cleaning Validation Limits for Encapsulator

How does one calculate the maximum allowable carryover limit for an encapsulator? For example, if we utilize a 10 ppm limit and want to prepare 5mg, 25mg, and 100mg, and placebo doses, does this include all API/Excipient/Capsule that is processed by the encapsulator from one API to another, or should the placebo, 5mg, 25 mg, and 100 mg doses be treated separately (i.e. 10 ppm of the API used in the 5mg dose batch, 10 ppm of the API used in the 25 mg dose batch…), etc? If the placebo is treated separately, then how do you base 10 ppm off of a 0mg dose? Or in the placebo case, would you use the 1/1000 therapeutic limit? It seems most reasonable to calculate the MACO based on either the 10 ppm or 1/1000 therapeutic dose, whatever is more conservative, and extrapolate to the entire amount of API and excipient that is processed during one API campaign until another different API campaign, but please let me know what your thoughts are. I’d really appreciate your input!

Dear friend…
I went through the above situation.

  1. All excipients are eatables and their LD50 value is very high (may be in grams). So, I have not considered excipients / placebo preparation in my validation

  2. The capsule shell is generally made up of hard gelatin. It is same for previous product and next product. So I have not considered capsule (shell) in my validation

  3. Finally, API is the only contaminant between two different products. So, I have prepared 20% to 200% (to the MACO value) solutions and studied the recovery.

I hope the above aswer may be useful for you


Sorry for any confusion. When I was talking about what to base my 10 ppm calculation off of, I was referring to whether we should calculate 10 ppm of just the incoming API, or of the incoming API and excipient, or 10 ppm of the incoming API, excipient, and capsule, not whether the excipient or capsule should be treated as active residue. For example, if the encapsulation for drug product ‘A’ has been finished, and the encapsulator will only be used for making placebo with a non-active fill from here on out, then would we base the MACO, or the amount of allowable API ‘A’, using 10 ppm of the non-active fill that will be processed into capsules by the encapsulator (i.e. 10^-5 * amount of non-active fill)? Also, how would one assess the total amount of non-active fill if the encapsulator will theoretically be used only for non-active fill for the rest of its life time. For example, if 1 kg of non-active fill will be encapsulated per week, would we calculate the amount of allowable API ‘A’ in the placebo as 10 mg (10^-5 * 1kg). If the placebo operation was planned to continue for a month, then would we calculate the MACO as 40 mg. Or would we calculate the 10 ppm based on the maximum load capacity of the encapsulator? For example, if the maximum load is, hypothetically, 0.5 kg, so that we have to load the encapulator twice a week to process 1kg per week, then would the MACO be 5 mg? Thanks for you input so far in helping me tackle this issue!

Sorry for confusion. I misunderstand your situation.
I feel now i’m clear.

In above case, better you should consider “0.1% (1/1000th) of minimum single dose of the previous product” as MACO. So, there is no question of next product (either it contains API or not). If the minimum single dose of your previous product is 20 mg, then MACO = 20 ppm.