Just based on discussion you have in this thread, I got a question and like to ask you. if we use only water like D.I / RO water for cleaning in this case how to calculate the remaining residual of active on the equipment, the other things for V-blender how to consider the worst location and how many samples we need to get by swabbing, for 1500 lit. V-blender can we say the surface area is the total surface area , for this machine the total surface area is 67000 cm2 , and how to calculate the limit and criteria.
I would appreciate you in advanced.
[quote=ovais]Dear Mr. T Arun,
To start with, for the determination of Maximum Allowable Carry-Over (MACO) for detergent/cleaning agent residues two methods are considered (a) Method based on toxicity of the contaminant (the one which you are using i.e. one based on ADI value) and (b) 10 ppm method (which allows only 10 ppm of the residue to be carried over to the subsequently manufactured product). In order to use both the methods for the estimation of MACO effectively, we need to understand the difference between Product A and Product B.
Product A refers to the product being cleaned, in case of pharmaceutical products identifying “Product A” is usually straightforward and represents the worst case product selected for cleaning validation (CV) studies.
Product B refers to the product which is manufactured subsequently (to Product A) on the same equipment/manufacturing train. It is the product where the residue can end up and is also selected based on worst case approach (like the product with largest daily dose and/or minimum batch size etc.).
Hence, in your case Product A is the cleaning agent (doesn’t require worst case approach for its selection) as it is the product which is being cleaned, Product B, as mentioned earlier, can be selected based on worst case approach.
Coming to your question regarding “surface area of the equipment”, assuming that Product A shall never come in contact with the other equipment(s) of the manufacturing train, in that case you just need to include the surface area (for the calculation of MACO) which is in come between Product A and Product B i.e. shared surface area. For the purpose of explanation I consider two cases (based on the matrix provided by you):
a) Case I: If we assume that the cleaning agent residue(s) is limited to the equipment concerned for example the residue is limited to EPD_001 of Mfg Train/Line_A. The shared surface area between cleaning agent (Product A) and Product B then would be equal to the surface area of equipment EPD_001. In this case, acceptance criteria should be calculated using the surface area of EPD_001 only since other equipments never come in contact with the cleaning agent.
b) Case II: If we assume that the cleaning agent residue(s) moves from one equipment to another of the same manufacturing train for example the cleaning agent residues from EPD_001 of Mfg Train/Line_A is transferred to other equipments following any unsuccessful cleaning and tends to accumulate over time. This (accumulation of residues) may be due to the fact that the cleaning procedures for subsequent equipments are not designed in a manner to remove the residues of the concerned cleaning agent i.e. the cleaning procedures for equipments EPD_002, EPD_003, EPD_004, EPD_005 and EPD_006 are designed to remove pharmaceutical product residues (manufactured on Mfg Train/Line_A) only and not cleaning agent (which is used for cleaning EPD_001) residues. In this case acceptance criteria should be calculated using the surface areas of all the equipments of the upstream process (i.e. the surface area of the equipment concerned and the following equipments in the train). For example, if the Mfg Train/Line_B is considered for cleaning validation, acceptance limit for cleaning agent shall be calculated using surface area of EPD_002, EPD_003, EPD_004, EPD_005 and EPD_006 only (please bear in mind the surface area of EPD_001 is not included).
Comparing the values obtained from both the cases, it would be observed that Case II shall give lower value (hence, shall be used as MACO). However, I would prefer using Case I for the estimation of MACO based on the assumption that the cleaning agents are far easier to clean (which is expected from cleaning agents) as compared to active pharmaceutical ingredients (APIs). If a cleaning method can successfully clean less water soluble APIs, why can’t it remove the cleaning agent residues.
For your reference:
“As with product residues . . . . . manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected” (FDA’s Guide to Inspections of Validation of Cleaning Processes).
It might be observed that the MACO value obtained using “Case I” would come out to be large. For initial studies it would be ok to consider this value, however, for subsequent use I would recommend you to assign the limit based on process capability.
I wouldn’t select any of the options (Option_1/Option_2) as the answer to your question.
Your feedback shall be highly appreciated.[/quote]