Fixing of specifcations for related substances/impurity limits in Drug product

Dear All,

1. please advise me on how to fix impurity limits (known impurity, unknown impurity) for drug product, if drug product is a non - Pharmacopeial .

2. If API is published in Ph. Eur, we can establish the API limits as per EP. How can we fix the limits for Drug product of the same API. can we fix the limits as  double the API specifcation limits ?? or can we go for same limits as that of API (which is more stringent)






Edited Wed, May 22, 2013 5:19 PM

Replies to this Topic

if monograph is Pharmacopeial then you have to take reference Ph. but if not then u may go ICH guide lines for impurity limit. We observed that If API impurity limit 0.5% then in product 1.0% , But cases no reference  .

Thank you Mr. Azad,

As per ICH Q3, can we consider Identification  threshold or reporting thershold while fixing the specifcation limits.

Can we apply mean+3 sigma in all the cases of fixing the limits for impurities (known)




Dear all ,

In any API unknown impurity people are saying that it is Less than 0.1%, where it is mentioned?? Can  any body suggests me??


Thanking you with regards,


Dear Mr.Prahlad, ICH guidelines will help you understand about setting the specifications for drug substances (Q3A)and drug products(Q3B). For a drug substances / products, the limits would be set based on the Maximum daily  intake/dose. In most of the cases (for API)the daily intake would be less than 2g/day and hence the limit would be 0.1%(As per ICH guide lines , if daily intake is less than 2g/day then the limit would be 0.10% or 1mg/day which ever is lower and if intake is more than 2g/day the limit would be 0.15% or 1.0 mg which  ever is low)



Neelu Bharadwaj

Thanks Ms. Neelu Bharadwaj,

please suggest, can we apply the same for drug product specification.




Dear Ms.Rama,

1. Setting a specification depends up on two things.The first one would be Pharmacopoeial reference and the otherway would be based on ICH guidelines.

For a non pharmacopoeial product, the reference would be purely based on ICH guidelines (Q3B)and based on the data available at your end.the limits would be set with reference to maximum daily dose .

2. For a product, as discussed, the ICH guidelines(Q3B)/ data available  should be considered in  fixing the limits . Doubling API should never be done.


Neelu bharadwaj



Dear Ms.Rama,

This holds good for both Drug substances and drug products.

 For Drug substances-----------ICH Q3A(or pharmacopoia , if official)to be referred

 For Drug products-------------ICH Q3B (or pharmacopia, if official)to be referred

In the European pharmacopia , since there would not be any reference of drug product, ICH guide lines and also the British pharmacopia (as the MHRA agency generally recommends to go with British pharmacopia) should be referred.


Neelu Bharadwaj


Dear Ms.Rama,

The same thing is applicable for drug product too. But as per ICH for a product the classification of the daily doses referred is different w.r.t API. Pls find the same below.

For unknown impurity :

< 1 mg :
1.0% or 5 μg TDI, whichever is lower

1 mg - 10 mg:
0.5% or 20 μg TDI, whichever is lower

>10 mg - 2 g
0.2% or 2 mg TDI, whichever is lower

> 2 g

For known impurities, a different classification of daily doses is referred.


Neelu Bharadwaj

Thank you Ms. Neelu Bharadwaj,

1. If X drug  Max. daily dose of drug product is 62mg,

Limit for maximum unknown impurity as per ICH Q3A is 0.1%, since it is less than 2grams/day.

As per ICH Q3B, if we go with identification threshold, the limit would be 0.2%, since maximum daily dose fall between 10mg - 2 grams criteria. It is double the API limit.

Can we fix 0.1% or 0.2% limit for maximum unknown impurity.

2. Can we write the name of unspecified impurity (as per EP) as 'single maximum unknown impurity' in drug product specification, which will be going to submit in ANDA.




Dear  Ms: Neelu Bharadwaj,

Thank you verymuch for your excellency and guidance to me, I request  everymember to  share their knowledge  to dedicate the  global pharma industries to serve better.

I also sincrely thankful to you PHDG  site for Pharma professionals. 


Thank you with warm regards,


Dear Ms Rama,

If the ICH guideline has such a relaxed limit(0.2%), it is always better to go with it rather than the  stringent limit of 0.1%.  If you fix the stringent limit, If in case  the level of any unknown impurity raises to more than 0.1% or more or to 0.2%, then as per your specification , the drug fails to meet the criteria thus becoming out of specification but as per ICH it would definitely pass. Hence it is always better to follow the allowed relaxed limit . It can be made stringent further in the future based on the data available (3/6 months depending on tha agency) at the time of submission which helps you avoid getting deficiencies,

A stringent limit  in any case can be fixed only if you are more confident about your drug.

Unspecified impurity refers to the unknown impurity,Here all the unknown impurities would come in to the picture.. but maximum unknown impurity is the highest level of the unknown impurity to be reported.

European agency is very particular about the terminology.It is better to refer as ''any unspecified individual impurity'' to avoid any query further.

Dear All

i would like to know about the impurities

1. Known impurity

2. identified but not quantified

3.unknown impurity impurities


All are above imputies we are getting in every Drug sbstance or in Drug product


so pl briefly explain about the above impurities categeory and definitions



Dear all,

               how we specification desire for related substance/Degradation product during stability studies.

Dear All,

The discussion is going on very well. I would request you all to go through the ICH Q3 guidelines thoroughly. I can say you should read in between words. The guideline has lot of information about the impurities in Drug Substance and Drug Product.

It covers all the impurities ie Known, Unknown, Degradation, Organic, Inorganic, Residual solvents etc.

Piyush for your question pls see ICH Q3 B (R2) attachment 3 Decision tree for Identification and Quantification of Degradation product.

Best Regards


If we have tested non pharmacopoeial API and still the impruty levels are beyond our expectations eventhough tested as per ICH, Can we fix the higher limits after proving that we have done enough toxicity studies and we have enough data to prove the harmless nature of impurity in particular API or product?

Dear all, i newly joined in this group.After join in this group first i saw Mr .Raghava profile.He has a very good knowledge about pharma industry.Please sir share ur knowledge to upcommers like me.



Siva prasada rao

Dear Jitendra patel,

For the products which are non Pharmacopeial I would suggest you to compare your product with innovator product and see how it behaves. Also please do some literature search to get more information. 

Toxicity studies mostly conducted for the New Chemical Entities. For generic molecules either you should meet the ICH guidelines or else ensure that your impurity is identified and levels are reduced to the ICH threshold. If you need further more clarification please let me know.



Profile Image for V M V M

Hello Everyone

Can anybody tell me

1) what is the corelation between Reporting/Identification/Qualification Thresholds ?



Dear Raghava,

I have some question please!!!

We want to introduce a new vendor,  from that vendor we are purchasing our key RM for our process validation  of our API whether 3 consignments from vendor are mandaory?? or from a single supply we can manufacture 3 batches. of same batch size??  Also the recent changes of process validation no where it is mentioned 3 batches ?? In this case how can we proceed can you pl. suggest us??

Thanking you with regards,





I have this drug with 3 APIs. There is no monograph forit.

Each individual API has a monograph in EP. The question is: how do I set the limits for the impurities in the finished product ?


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