Hi all,
I was hoping you can help me. I have some question about cleaning validation in ointment/creams product. It is a topical product. How can I calculate MACO follow ADI ( acceptance daily intake) ? or I can use 10 ppm to calculate the limit. I have worst case contain betamethasone dipropionate and the next lowest batch size contain dexamethasone acetate.
All product was prodcued through 4 equipment. I validated worst case for each equipment, didn’t right ??
Thanks everyone
Nope. Carryover is now calculated using the molecule’s ADE or PDE (acceptable or permitted daily exposure, a measure of toxicity) not the ADI. This means you will have to review each molecule, perform a ‘risk analysis’, and target the lowest ADE or ‘hardest to clean’ formulation. It is the cleaning procedure that is being evaluated and the cleaning method (based on the toxicity or health based limits) that is the yardstick. Review the Eudralex chapters 3 and 5. Even topicals must meet this ‘new’ criteria!
As I recall Betamethasone dipropionate is a steroidal hormone so it will have a ‘very’ low ADE.
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Also, be sure to use/adapt current APIC calculations (issued in 2014).
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This is a common topic discussed in these forums. A search for keywords: MACO, or cleaning validation, or carryover limit will help answer some of your questions already.
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what shall be calculation formula for PDE in case topicals.
Supppose MACO = PDE X SBS/LRDD, but how LRDD to be find in case of topical,
if it is by A X C X F, as per Long and Finley , than what will be unit of A X C X F ?
if unit will be mg/cm2, than in this case for PDE value unit required mg/cm2 instead mg/day.
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Sandi,
Now we are getting into the weeds! In short, MACO (now called MSC or maximum safe concentration) is based on the PDE, a health based limit. For your entire process train the limit will be in units of mass/swab or mass/rinse volume. The LRDD or ‘largest recommended daily dose’ will be in the same units as the SBS (smallest batch size), usually Kg, so it will divide out. The LRDD for a cream is based on the packaging insert. You should have this for something like a hydrocortozone cream, but you will have to translate it from FTU (finger tip units), where 1 FTU is so many mass units (applications).
For a cream that will make you ‘healthy, wealthy, and wise all instantly’ your approach is wrong. You should determine which cream is ‘hardest to clean’ (therefore Long and Finley are irrelevant) since it is your cleaning procedures that will be eventually evaluated by your analytical method (the yardstick). TOC or conductivity may be your ‘best’ method.
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Sandi,
The approach of the cleaning validation depends on your ‘risk analysis’ to the consumer and whether you have a toxic API (thus health based limits), or ‘hardest to clean’ formulation (cream that makes you healthy, wealthy, beautiful and wise all instantly). In latter case you can use VRL (visual residual limits), but you will have to train your operators to differentiate between a clean versus unclean surface. You can use the FDA’s GRAS (generally regarded as safe) website to reduce the number of PDEs you have to evaluate in your risk analysis.
Bruce (Boomer)
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Thanks Bruce
I have read a guideline
Setting Cleaning Validation Acceptance Limits for Topical Formulations,
follow the equation , base on lowest available strength of Topical formualation A.
MACO = 0.1% x C x BS, in which C is the lowest available strength of the API in the product A (%), BS is the batch size of the product B (mg).
Eg. The topical have 0,05% betamethasone. and the next batch size is 128 kg so MACO = 0.1% x 0.05% x 128 x 10^6 (mg) = 64 mg
Need more information. Is this a shared or dedicated manufacturing facility? Who decided on the 0.1%? Can you justify your decision using this factor based on the toxicity of Betamethazone (what is the ADE/PDE)? Remember it is a steroidal hormone, and may have a low ADE.
This may help you;
This may help those who manufacture Hydrocortisone topical cream.
I presume you have seen this. They have a section on cleaning validation;
I explain detail, I based on information “The dose criterion is based on the principle that an API should not be present in a subsequently produced product at levels higher than 1/1000 (0.1%) of the minimum daily dose of the API in a maximum daily dose of the subsequent product”.
The product A (cream contain 0.05% betamethasone) was used 2 times/day, and the product B (cream) used 2 times/day, about ( 0.5 g cream) so I have a equation.
MACO = (0.1% x 0.05% x 0.5 x 128 x 10^6 )/0.5 =64 mg.
Manufacturer was prepared for only ointment/cream product.
Equation is wrong. It is;
MACO = 0.1% x 0.05% × 128 kg × 10^6 mg/kg = 64 mg
Do not use 0.5. 64 mg is for the whole manufacturing process train. Therefore, to continue;
64 mg x SA/TSA
where SA = surface area of a piece of equipment in direct contact with the cream (cm^2)
TSA = surface area of the whole manufacturing process train in direct contact with the cream (cm^2)
smallest SA/TSA is about 1%. Thus, 1% of 64 mg = 640 ug. Swab area is about 5 x 5 cm^2 so you may only have to inject 10 uL into an HPLC.
Be sure you can defend using this equation based on the toxicity of Betamethasone and that you have no other more toxic APIs!
I’m curious. How many products do you have which share equipment? I ask because there are a few ways to set up the calculations which are worth doing especially if you have a few products. Ways to calculated are: (1) With an overall worst case, and (2) to calculate carryover limit for each product individually.
Doing each product individually (#2 above), is more precise for each product and doesn’t artificially have super tight cleaning limits based on worst-case assumptions (a pain for labs, manufacturing, CAPA’s, etc.). But #2 requires a lot of calculations because you look at product A into B, product B into A, product A into C, product C into A, etc. etc.
At one site I was at, we initially used #1 above, but then invested the time to do #2. When we did this we closed a bunch of old CAPAs and virtually eliminated new CAPAs for cleaning failures. It was an investment to redo the calculations in a precise way, but we recovered the time almost immediately (due to fewer failures). Also, it increased manufacturing time, because we weren’t holding the product/equipment until a cleaning resolution could be made.
It would have been a lot of calculations by hand, but excel made it super easy if you are good with excel.
I create a matrix product include 3 product because my manufacture just have had new facility for cream and ointment. I chose the worst case from active ingredient of 3 product.
If I do cleaning validation for each product --> consume much time for validation each method. So I chose worst case for validation.
Yes! Worst case based on toxicity or hardest to clean formulation. This is the rationale for the worst case (to reduce targets).
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