Worst Case and MAC calculation - Multi Active

GOOD VALIDATION PRACTICE (cGVP) CLEANING VALIDATION
1

Hi

Can some explain how to calculate MAC for multiple active products eg. Paracetamol (400 mg), Codeine Phosphate (8 mg) and Caffiene(30 mg).
What do are use as the target compound? Paracetamol is the least soluble and Codeine is the most soluble.
Do I include the most potent component (codeine) in the MAC calculation?

Paracetamol - least soluble, highest dose, most potentially contaminating.
Codeine - Most potent, least contaminating.

Water is use to wash.

Jay

2

Dear Mr. Jay,

If you are using method based on “Toxicological Criterion” as one of the approach for determination of MACO, then you need to consider the most potent active. The active with the lowest “LD50 or No Observed Effect Level (NOEL)” value is used for setting CV limit for the product containing multiple ingredients (in your case Codeine). The MACO you get will be applicable to all the actives (i.e. for example, Paracetamol, Codeine and Caffeine will have a single MACO limit, one calculated based on LD50 value of Codeine).

For determining acceptance limit based on other criteria (i.e. Dose and 10 ppm criteria), I will suggest you to estimate the MACO for individual actives. This will depend on your analytical method, I hope you must be having a single analytical method for the determination of all the three compounds. Having a single method for the estimation of all the actives will make your job much easier (need not to perform three separate recovery studies, need not to take three different samples from each location, need not to analyze actives using three separate runs).

Ovais

3

Ovais

I am using dose and 10 ppm to determine acceptance criteria. If I intepret you correctly, you mean if I use determine the MAC using different actives, establish the one with the lowest MAC, in my case it will be codeine. eg if the MAC determined was 5 ppm using codeine, then I intepolate that to the level of paracetamol. If the ratio of codeine : Paracetamol is 5 : 400, then the accepatance criteria can be 400 ppm paracetamol.

Currently I am using paracetamol as my worst case due to lower solubility and high dose. My acceptance criteria is 14 ppm for paracetamol determined in a matrix of products (minimum of dose and 10 ppm). I would think this is more stringent. What do you think?

Am I on the right track?

See attachment.
Jay

PYNMED ABFLEX CLEANING VALIDATION MATRICES 28 April 2009 .pdf (22.9 KB)

4

Ovais

See full attachment

CLEANING VALIDATION MATRICES April 2009 .pdf (10.5 KB)

CLEANING VALIDATION MATRICES 1 April 2009 .pdf (9.3 KB)

CLEANING VALIDATION MATRICES 3 April 2009 .pdf (10.6 KB)

CLEANING VALIDATION MATRICES 4 April 2009 .pdf (10.6 KB)

5

Dear Mr Jay,

I think you got me wrong. What I meant was that if you are using “toxicological criterion (i.e. the criterion in which LD50 value of the active is used)” for the determination of MACO then you have to consider the most potent active (i.e. the one with lowest LD50 value) as your worst case. Since you are not using this criterion, this approach won’t be applicable.

You are using only “dose” and “10 ppm” criteria for the estimation of MACO. In this case, I suggested you to determine MACO for the individual actives (i.e. different MACO for Paracetamol, Codeine, Caffeine etc.) rather than using a worst case active only. To be more clear, I meant that you test your swabs for the presence of all the actives (present in worst case product) and then compare the result obtained with their individual MACOs.

Usually I am not in the favor of setting limits based on worst case active. If you have selected a worst case product containing multiple ingredients, you have to test for all the active ingredients in the cleaning validation samples. Thats why I said, it would be easier for you if you have a single analytical method for testing all the actives (i.e. all the actives being analyzed in a single run).

Coming back to your issue, after seeing the CV matrix I realized that it is possible to select a worst case active as you are sharing the equipment train for manufacturing only two products containing similar type of actives. Both the products differ with each other in two ways: (1) the quantity of actives (i.e. Paracetamol, Codeine Phosphate and Caffeine), and (2) Presence/absence of Meprobamate/Doxylamine Succinate (with Pynmed containing Doxylamine Succinate and Abflex 4 containing Meprobamate). If you ask me to select a worst case product then I would select Abflex 4 (as previous product or Product A). Reason for this is very simple (1) the product is containing three low soluble actives Meprobamate (for your information Meprobamate is Slightly soluble in water not soluble in water, as depicted in your matrix, for which you may check BP 2007), Paracetamol (Sparingly soluble) and Caffeine (Sparingly soluble), (2) the product is containing highest concentration of paracetamol (450 mg in 650 mg). Now, if we look at the worst case product (and its ingredients) and ask which ingredient should be selected as the worst case active for CV studies. Then, the answer would be, the active which has the potential to affect the safety, efficacy and quality of the subsequently manufactured product (or Product B also known as Next Product). If I assume, due to ineffective cleaning, the ingredients/actives of Abflex 4 are being carried over to Pynmed. Then, only the residues of Meprobamate have the potential to affect the safety, efficacy and quality of Pynmed as all other actives (i.e. paracetamol, codeine, caffeine) are already present in Pynmed (except Meprobamate). The other reasons for selecting Meprobamate would be that (1) it is the least soluble active of all (even less soluble than paracetamol and has a solubility of 4.7 mg/mL) and (2) it is a potent active (used as an anxiolytic).

Another approach for determining worst-case active, is by identifying the active which has the potential to degrade/react (with cleaning agent ingredients etc.) to form more toxic components (this could be studied by stressing the actives under worst case processing conditions, for example, subjecting the active to high temperature etc.) This type of study is usually not conducted by scientists involved in development and validation of cleaning processes, although FDA require manufacturers to consider this aspect also.

Remember: If justified in a proper manner, you could easily select a worst case active ingredient for cleaning validation.

Hope you got your answer.

6

Dear Ovais.

I am new to this cleaning validation and i got little knowledge
my quiery is regarding the caluclation steps and how to go further if we are having 20 to 25 products in the facility. [b]

whether we have to validate each product and for each strength[/b]
can we consider worst case same product with different strength (we are following now)??? if not pls guide me how to go further???

pls find attched file and kindly let me know how to caluculate the for my poducts as per your format (modified file earlier by you ) and also elobrate the caluculations steps in simplified manner.

thanks in advance.
BRavi

FORMAT FOR CLEANING VALIDATION.doc (46.5 KB)

7

Dear Mr Ravi,

I am sorry for late reply, hope you understand. Coming to your question regarding how to deal with (or validate) cleaning method(s) involving 20 – 25 products. Well, we can always select worst-case product(s) for CV studies and need not to validate each product for cleaning effectiveness. Now, the question arises how to select a worst-case product (out of so many products)? The answer is probably not so simple and a detailed description might be too lengthy for this forum. For better understanding of the worst-case selection process (and other issues concerning CV), you may refer to following guidelines:
[LIST=1]

  • CEFIC - Active Pharmaceutical Ingredients Committee (APIC), Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants, (CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf (provides various approaches for selection of worst-case product).
  • “Points to Consider for Cleaning Validation–Technical Report No. 29,” PDA J. Pharm. Sci. Technol. 52 (6), 1–23 (1998).

    Over-all worst-case selection process could be outlined in the following steps:

    [LIST=1]

  • [b]Prepare a product-equipment matrix [/b](include all the minor and major equipments ranging from, for example, blister packaging machine, tabletting machine, granulating machine, powder mixer to seives, scoop, scrapper, spoon etc.) This matrix helps in determining the equipments involved in the whole manufacturing train for a particular product. The surface area of the complete manufacturing train could then be used for calculation of acceptance limit i.e. MACO.
  • [b]Identify the equipment [/b]for which you need to validate the cleaning method.
  • [b]Product Grouping[/b]: For the equipment, divide the products (manufactured using the same equipment) into groups. Products are usually divided based on cleaning methods, processing (wet granulation, dry granulation) etc. used. If you are using different cleaning methods (for the same equipment) for different product types then divide the products into separate groups based on cleaning methods. In that case, each of the cleaning method shall be validated. If you are using single cleaning method for all the products then move to next step.
  • [b]Selection of worst-case[/b]: Out of all the products cleaned using the given cleaning method, a worst-case could be selected for CV studies (need not to validate every product). You can use various scientific rationales for the selection of worst-case such as:

    [indent]a) Solubility of product/active ingredient in cleaning solution/solvent.
    b) Operator’s experience, for this you need to ask the personnel involved in cleaning to identify product that is most difficult to clean.
    c) Toxicity of the active ingredient(s).
    d) Concentration of active in the final powder mix or formulation. Higher the amount of active (if its an insoluble active) more difficult to clean.
    e) MACO for the active, etc[/indent]

    One issue, which I observed after going through the file attached by you, is that you are trying to calculate limit for each product using all the possible combinations. Easiest way to obtain MACO for each product is to apply a worst-case approach, for each group you have to select worst-case Product B1 (product with smallest NDU/MNDU or K/J ratio, see attached file for calculation) and Product B2 (Product with smallest batch size in kgs). Once established, worst-case products (& the values) could be used for setting limits for all the products in a group.

    For an example of Product-Equipment Matrix and MACO calculation for more than one product please refer to the attachment.

    Thanks

    CV Matrix Example.zip (11.1 KB)

    • 8

    Thanks Ravi

    Questions :

  • For Multiply active products, do you consider each API?
  • From your example which is the worst case product in this matrix that you would select if you are using dose and 10 ppm approach? Is it Product G with an acceptance criteria of 3,2 ppm?

    Is there anything wrong with my approach where I use the solubility and smallest batch size ?

    Jay

    • 9

    Dear Mr Jay,

    Yes, we have to consider each API for multiple active products. The file which I attached in the earlier post is not meant to give an approach for the selection of worst-case. It is for Mr Ravi, who wanted to know how to calculate limits for 20-25 products. I can select a worst-case from a list, but I don’t think the information is sufficient enough for the same. If a product has the lowest limit (e.g. Product G), it doesn’t mean that it can be selected as a worst-case (it might be easily cleaned compared to other products). Solubility and batch size are only few of the rationales which are used for selection of worst-cases. I would again advice you to go through this guideline to know more about worst case selection process.
    CEFIC - Active Pharmaceutical Ingredients Committee (APIC), Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants, (CEFIC, Brussels, December 2000), available at
    http://apic.cefic.org/pub/pub-cleaning-validation.pdf
    .
    The approach given in the guideline is sufficient for people who are new to the area of CV. Use that as the basis to develop your own approach (but it should be scientific) for the selection of worst-cases.

    Thanks

    10

    hi there. im currently working in pharma industry. can i ask you some questions regarding cleaning validation? They are as below::
    In cleaning validation, how do we calculate MACO for multiproduct facility? (since the factors like worst case scenario and the minimum batch size may be different for different product). For example, let’s say there are 4 equipments in a production line namely 1, 2 ,3, 4 whereby 1, 2 and 3 is used in production of A and B product except 4 is used in the production of B product only. in this case, how to calculate for the MACO limit? is there any formula for calculating MACO for multiproduct facility?
    thank you.

    11

    Dear Ovais,
    hi there. im currently working in pharma industry. can i ask you some questions regarding cleaning validation? They are as below::
    In cleaning validation, how do we calculate MACO for multiproduct facility? (since the factors like worst case scenario and the minimum batch size may be different for different product). For example, let’s say there are 4 equipments in a production line namely 1, 2 ,3, 4 whereby 1, 2 and 3 is used in production of A and B product except 4 is used in the production of B product only. in this case, how to calculate for the MACO limit? is there any formula for calculating MACO for multiproduct facility?

    p/s:your fast reply is appreciated.thank you.

    from: toh tang