Assigning MAR/MACO value for a cleaning agent

Dear All,
This is a query regarding assigning a MAR/MACO value for a formulated cleaning agent. [Extran MA 02 Neutral]. As usual we’d arrived following formula for calculating
MAR = ADI /SA *B /LDD,
where, ADI- is the Acceptable Daily intake of most potent ingredient in the Formulated cleaning agent .
B- Smallest batch size in kg , manufactured in same equipment.
LDD- Largest daily dosage of a drug product manufactured in the same manufacturing train.
SA- Equipment surface area (in cm2).
My query, for Surface area of equipment
Option_1: Whether we need to consider only the product contact surface(s) of the worst case product [or]
Option_2: Whether we need to consider total surface area of all equipments in the facility.
Refer the attached file for better understanding

Please address this query, as soon as possible, since we are in process of assigning MAR value for the above mentioned cleaning agent


Mfg train.pdf (74.6 KB)

Dear Mr. T Arun,

Before I reply to your query I would need some clarification.

  1. What do you mean by worst case product? Is it the product being cleaned (i.e. Product A) or the subsequently manufactured product (i.e. Product B)?

  2. Are all the equipments in a manufacturing train being cleaned by the same cleaning agent or different?

1.Worst case in the above mentioned scenario, is the Product with lowest batch size [which will be possibly having more amount of detergent /gm of Blend, when considered against other product manufactured in same train.
In my reffered case, Worst case is the product being cleaned [Product A]
2.Only equipments which are having contact with product A is cleaned with the detergent. other equipments are untouched/ isolated.

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.

Dear Ovais,

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.

Best Regards,
bluesky

[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]

Dear Ovais,
As per our VMP, due to variation in structural geometry ,we have customized cleaning procedures for individual equipments.Basically these cleaning procedures for equipments are designed during, based on process capability to individual equipments. Efficiency of these cleaning procedures are verified OQ & PQ stages of equipments. What I mean to say is, I cannot use cleaning procedure (In particular the jet speed, position & etc )followed for FBD 1000 to FBD 100 or to HSMG 100. So, there will be no chances of unsuccessful cleaning procedures for individual equipments and there of No carryover of Detergent residues from One equipment to other equipment in same train. We are having situations, batch size [in Kg] will be lower than the Minimum process capability of the equipment(s). For (ex) Assume EPD002 in manufacturing train ‘A’ shall be HSMG600, having minimum process capability of 30kg and Batch size of product ‘A’ shall be 15Kg. In such cases we choose a HSMG150 with minimum process capability of 7.5kg in manufacturing train ‘B’ . Propagating further assume, only one equipment in each manufacturing trains is involved for manufacturing product’A" and final drug product is from equipment EPD006 in manufacturing train’F’. As shown in attached file, only the diagonal row is in contact with product’A’
If the practical situation(s) is same as described above, during calculation of MAR/MACO value, which of the following option , I need to consider Option_1:Only the equipment surface area [Diagonal row], which has been in contact with product ‘A’ should be considered
orOption_2:To include surface area of all equipments concerned in the following manufacturing train’ Ato F’


Mfg train.pdf (74.6 KB)

Dear Mr. T. Arun,

I am sorry to say that you got it all wrong or may be I wasn’t clear enough.

What do I mean by “No carryover of detergent residues from one equipment to other equipment in same train following any unsuccessful cleaning”? I didn’t mean to say that residue is being transferred from one equipment to another due to the cleaning procedure itself. Well, let me clarify it with an example, suppose you have 5 products manufactured on the same train, lets say Mfg Train/Line_A. The train contains six equipments (i.e. all the equipments are used for manufacturing any of the 5 products) and only one equipment (e.g. EPD_001) is cleaned with the detergent (rest others are not). After the cleaning of EPD_001, Product B was manufactured on this equipment. Assuming that the cleaning for EPD_001 wasn’t successful (meaning that the detergent residues weren’t completely removed from the equipment) due to which some amount of detergent residue is being carried over to Product B. This Product B will then move to next equipment in line (i.e. EPD_002) along with the detergent residues from the previous equipment. While processing at EPD_002 some of the detergent residues which came along with the product/powder (from previous equipment) might be left over the equipment and rest shall be carried along the powder to subsequent stages. Now, there are chances that if the cleaning procedure for EPD_002 or any of the subsequent equipments in the train is not efficient enough, the detergent residues shall not be removed and continue to stay on the equipment. As the process is repeated again and again detergent residues shall continue to accumulate/build-up within the equipment.

I already haven’t taken this case (which is Case II) into consideration as I assume that since detergents are highly water soluble there are least likely chances that its residues shall not be removed from the equipment by subsequent cleaning procedures (which are designed to remove least water soluble active ingredients).

By “Process Capability” I didn’t mean the capacity of the equipment. The investigation of a process and its capability to meet its intended purpose is called as Process Capability. Process Capability is a part of statistical process control which is used for assigning specification limits for processes. It is used for setting (control) limits to the cleaning process. I would recommend using this method for monitoring of cleaning procedures once cleaning validation has been completed successfully.

For cleaning validation purpose estimate MACO (as suggested earlier) based on Option_1 i.e. consider only surface area of the equipment which comes in contact with both Product A and Product B.

Dear Ovais,
Thanks for your kind reply.
Even though higher values of MACO are obtained, after several discussions, since the formulated detergent [EXTRAN MA-02 Neutral] only contains higher proportions of phosphates, We plan to consider case I for arriving MACO value,(ie. only the shared surface area which is in contact with Product A & Product B).

With Regards,

Hey 724218502032125,
What does Ur reply mean?
Whether it has any information?