# Change over

Dear everyone,
Do we need to perform change over for the products with same active ingredients but different strengths for eg: considering two product having same active ingredient

1. PQR with active A -10 mg (low dose)and
2. XYZ with active A -20 mg (high dose)
So, now i need to manufacture PQR after completion of XYZ. Can we proceed manufacturing PQR without change over?

Anyone please clarify me on it.

SUNITA

We need to consider few things here to determine whether we need to perform CV in between two different strenghths of same product

1. Is the formula for the both the batches are same?
2. Is it worst-case marker selected for cleaning validation?, if yes, then whether lower strenghth was considered during MACO calculations?
3. Does any of this strenghts poses cleaning challenges?
4. is there any Microbial issue?

However, based on the fact that the there is no issue of carry over here, I dont think we need to perform any cleaniing validation activities e.g.- after manufacturing and cleaning high dose, the residue remain on the equipment is of same active
e.g.: considering the 100 microgram/4 inch square is residue left on the equipment surface- Visual clean limit. and total the surafce area equipment is 2000 squre CM
Than carry over of high dose to low dose :
100 microgram/4 inch squareX 2000 squre CM = 200000 Microgram = 200 mg

In this case total carry over of high dose to low dose is 200mg which is neglizable. Therefore, unless it is for very high potent product we dont need CV.

Dear sunita,

the point is what you call change over. If the question is whether you can produce PQR after XYZ without cleaning, my answer is no. You cannot apply the calculation for the MACO because there is no cleaning performed, so you cannot assure that the potentially carried over residue of the higher strength is not overdosing the lower strength (e.g. lumps of granulate of XYX that go into compresion of PQR). So at least a minor cleaning (e.g. vacuuming) is necessary between these products. Another issue are the excipients: if XYZ is coloured, a mayor cleaning should be performed between products, and, even without colour issues, if the excipients are not the same it is not advisable to change products without cleaning.

Best regards

Alfred

Yes it is manadatory to wash the equipment for same active but differ strength. SANJAY GARG 9997186777 [quote=sunita]Dear everyone,
Do we need to perform change over for the products with same active ingredients but different strengths for eg: considering two product having same active ingredient

1. PQR with active A -10 mg (low dose)and
2. XYZ with active A -20 mg (high dose)
So, now i need to manufacture PQR after completion of XYZ. Can we proceed manufacturing PQR without change over?

Anyone please clarify me on it.

SUNITA[/quote]

Thanku everyone,
Dear Alfred,

In our system, the term change over is also the thorough cleaning process and it is used if product A…> B differs. & cleaning is used if batches of same product differs A1 …>A2…A3 etc… Also we have the same excipient in both product XYZ and PQR. colors are also same.
In the same way can we proceed manufacturing From low dose to high dose product following cleaning procedure… if not what are the consequences?

Dear Sunita,

To begin with we need to understand what does “changeover” stands for. As per “Points to Consider for Cleaning Validation–Technical Report No. 29,” PDA J. Pharm. Sci. Technol. 52 (6), 1–23 (1998), changeover is defined as “actions required for switching multi-product equipment and facilities from one product to another.” Now, coming back to your question, Do we need to perform change over for the products with same active ingredients but different strengths? My answer will be “Yes” we have to perform changeover (even weighing the raw materials for the product is a part of changeover). Performing cleaning is a part of “changeover” cycle. To what extent we need to clean in a changeover cycle depends on the type (characteristics) of the product being manufactured. If the following product (to be manufactured) is totally different (i.e. different active ingredients) from the one already manufactured then as per PIC/S Guidelines, one has to perform fully validated cleaning. However, the guideline also states that “in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.” For batch-to-batch production two approaches are generally used: (a) some minor cleaning (vacuuming or rinsing with purified water) is performed between batches, and (b) no cleaning is performed between batches. Probably you are following the same thing in your company. Only thing which is not clear here is the fact that you are performing cleaning between different batches of the same product (As per your query: “In our system, the term change over is also the thorough cleaning process and it is used if product A…> B differs. & cleaning is used if batches of same product differs A1 …>A2…A3 etc.”) but you want to proceed ahead without any cleaning when changing from PQR to XYZ or vice versa. Cleaning (major or minor) is more important when switching from one strength to another than changing from one batch to another. I agree with the argument made by Alfred, one cannot switch from high strength (XYZ) to low strength (PQR) product without performing any cleaning. However, changing from Low strength (PQR) to High Strength (XYZ) with or without any cleaning can be justified provided a thorough risk analysis is performed to evaluate potential risks involved such as impact of processing parameters (on the active and excipients), possible degradation, impact on final cleaning etc. To know more about risk analysis, you may visit this post

Thanks.

Ovais

Dear All,

Do we need to conduct a seperate cleaning validation for steriod and highly potent drugs (Ex. 0.125 mg of active in a tablet) apart from other products?

Dear Mr Sureshmpharm,

A request :), please don’t post questions which are not relevant to the topic being discussed in the thread. You may create a new post if you want.
In its guide “Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation”, PIC/S (under section 7.11 Establishment of Limits) states that “For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.”

If the product you are referring to falls under any of the given categories (e.g. potent steroid) then you need to have a dedicated facility for the manufacturing of such product. For performing CV you need to comply with two requirements: (a) it has to be proven that the analytical method (chosen for the testing of active ingredient/contaminant residue) is the best available method for detecting the said residue, by best available method I mean that the analytical method should be sensitive enough to detect minimum possible amount of residue i.e. the method should have lowest possible “limit of detection (LOD)”, and (b) the residue which is detected should be lower than this LOD.

However, if the products don’t fall under any of the given categories, you need to perform CV as usual. For selection of worst-case product take into consideration the potency and pharmacological effects/category (apart from the commonly used parameters such as solubility, toxicity etc.) of the products. I will suggest you to include the criterion based on toxicological data (i.e. LD50, NOEL etc.) for the calculation of MACO and the acceptance limit for CV studies.