In taking a look at the shared surface area (SSA) between two products, there are several options that are typically used for limits calculation purposes. As a reminder, the SSA is in the denominator of the typical carryover calculation; therefore, the larger the SSA between the two products, the lower the limit. There are several options for choosing the SSA to use for a calculation. The most “accurate” is to use the actual SSA. That is, I exclude the equipment that might be used for one product but is not used for the other product. Note, however, that just because the area of one equipment item is excluded for the calculation in going from Product A to Product B, it might not be excluded from a calculation in going from Product A to Product C.
A second option is to determine the total equipment surface area of each equipments train for each product, and for calculation purposes use the lower of the two values. This approach will give either a value identical to the actual shared area or a value higher than the actual shared area, and therefore is a worst-case approach for the limit calculation.
A third option is to only use the actual total surface area of the equipment used for the cleaned product. Like option 2, this approach will give either a value identical to the actual shared area or a value higher than the actual shared area, and therefore is a worstcase approach for the limit calculation.
Note that if the two products are always made on the same equipment train (with no equipment excluded), the three options will give the same equipment surface area values. It is only if one or more equipment items are excluded (or added) that higher surface area values are possible with Options 2 and 3 as compared to Option 1.
However, there are some situations where these approaches do not work. The specific situation that is the topic of this Cleaning Memo involves the situation where in the processing of either (or both) products, there are multiple identical equipment items that may be used and where the number of a certain equipment item used varies between the two products. I will try to explain this with an example. Suppose I have two products (A and B), where each product is made on an equipment train. But, I have multiple specific equipment items to choose from as I manufacture each product. The key difference to highlight for this example is that Product A uses only one of each equipment type, but that Product B uses two of that same equipment type.
Let me elaborate. Let’s say that in the train there are three equipment types, which I will call “P”, “Q” and “R”. And for each equipment type there are two possible identical equipment items I can select for the train on a given batch of a product. That is, for “P” I can use either “P-1” or the identical (by IQ/OQ) “P-2”. For “Q” I can use either “Q-1” or the identical “Q-2”. And for “R” I can use either “R-1” or the identical “R-2”. Now for the key issue: for Product A I use only one of “P”, one of “Q” and one of “R”, but for Product B Use only one of “P”, two of “Q”, and only one of “R”.
When I do cleaning validation for Product A, what then is my shared area when I calculate the limit for the active in Product A being carried over to the next batch of Product B? If I establish my shared area as only the sum of the areas of one “P”, one “Q” and one “R”, is that adequate? And the answer is “no”, because the next product (Product B) will utilize two items of “Q”, thus increasing the possible carryover amount of the active of Product A into Product B.
In other words, I have to consider the possibility that in one batch of Product A equipment item “Q-1” is used, and then in another batch of Product A (perhaps in a campaign mode), equipment item “Q-2” is used. Then when I get around to making Product B, I would have to use both “Q-1” and “Q-2” for the manufacturing train. Therefore, for the limit of the active in Product A (in the cleaning of Product A), at least one option would use as my shared surface area the sum of the areas of one of “P”, two of “Q” and one of “R”. The net result is that my surface area limit (what I call L3) for the cleaning of Product A would be lower because of the increased “shared” surface area. For this example, the net result is that I would use the larger SSA of the two products as being the most appropriate SSA to use (and in this case, the larger SSA would not be a “worst case”, but would result in possible accurate calculation.
For clarification, in the example I give is NOT a situation where I am using the same identical equipment twice in a sequence; that is, I am not using “Q-1” once, and “Q-1” again for Product B (that is a different situation). In the example given, I am using “Q-1” once and also using “Q-2” once for the manufacture of Product B.
Also, for clarification in the example given for the cleaning validation of Product A, I conceivably could not set my limits the same for all equipment items, but could calculate the total carryover amount (L2), and then allocate that (based on surface area) to each equipment item in the equipment train for Product A. Then I could divide that allocated amount to whatever “Q” equipment was being used for Product A. The net result in this case would be that the L3 limit for “Q” would be half that of the L3 limit for “P” and “R”. While this is possible, most companies avoid this because they prefer to have the same L3 for each equipment type.
Finally, in the example given, let’s see what happens to the limits when cleaning is done for Product B. In this case, the limit for the active in Product B will be determined only if it is carried over to Product A. For this example, what is happening is that for Product B, I am using one of “P”, both “Q-1” and “Q-2”, and one of “R”. What is shared with Product A is one of “P”, one of “Q” (either “Q-1” or “Q-2”), and one of “R”; this, the conventional way of establishing shared surface area applies in this case of cleaning for Product B. This sounds complicated, and it requires careful implementation, particularly when it involves not just Product A and Product B, but also Product C, Product D, and so on. If it is not possible to apply this precisely, certainly one “worst case” option is to always choose the larger of the two surface areas of the two products involved. That option will result in lower limits, but it has the advantage of simplicity. Another caution is that in the examples, I focused on limits for the actives of each product, and did not consider the case of limits of Product B followed by Product B (assuming the equipment will be visually clean, any carryover of the non-degraded active to another batch of the same product is probably not significant). If this discussion were applied to limits for cleaning agents, then in the example given for Product B, the case of “Product B to Product B” should clearly be considered (carryover of cleaning agent from the cleaning of one batch of a product to another batch of the same product is significant).
As a final reminder, this situation of defining the SSA only applies in situations where in the processing of either (or both) products, there are multiple identical equipment items that may be used and where the number of a certain equipment item used varies between the two products.