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Method Transfer to the Contract Lab


Hi, I am doing the HPLC API Impurity Method Transfer to the contract lab.

As per method transfer protocol i made six samle preparations from a single lot of API sample, but Impurity xyz % RSD (six impurity preps) failed 17% (spec 15%).

Interesting thing here is only %RSD of impurity xyz failed but imprity xyz is still within the spec 0.2% (spec. is <0.25%) as per Certificae of Analyis (COA).

Should i initiate the oos investigation ?
or Repeat the whole testing by making six preps and if % RSD passes then just mention in the method trasfer report and labnotebook that %RSD WAS NOT ACHIEVED, CAUSES UNKNOWN, SO TESTING REPEATED.

i think impurity sample %RSD Failure is not an OOS investigation. so i should not initiate oss investigation. What do you think???

Dear VJP,

RSD derived from mathematical data evaluation term dispersion data rather than central of tendency, for determination of precision of data,RSD is used that the results are how much closer with each other and for central of tendency i.e mean, mode, median it indicate that result how close to targeted value rather than true value.
In my opinion there is some problem in testing/ analysis, did u perform system suitability? Is method response limit with in threshold detecting limit? Did sample prepare appropriately? Kindly recheck your testing methodology.

Thanks

[quote=vjp]--------------------------------------------------------------------------------

Hi, I am doing the HPLC API Impurity Method Transfer to the contract lab.

As per method transfer protocol i made six samle preparations from a single lot of API sample, but Impurity xyz % RSD (six impurity preps) failed 17% (spec 15%).

Interesting thing here is only %RSD of impurity xyz failed but imprity xyz is still within the spec 0.2% (spec. is <0.25%) as per Certificae of Analyis (COA).

Should i initiate the oos investigation ?
or Repeat the whole testing by making six preps and if % RSD passes then just mention in the method trasfer report and labnotebook that %RSD WAS NOT ACHIEVED, CAUSES UNKNOWN, SO TESTING REPEATED.

i think impurity sample %RSD Failure is not an OOS investigation. so i should not initiate oss investigation. What do you think???[/quote]

[quote=vjp]--------------------------------------------------------------------------------

Hi, I am doing the HPLC API Impurity Method Transfer to the contract lab.

As per method transfer protocol i made six samle preparations from a single lot of API sample, but Impurity xyz % RSD (six impurity preps) failed 17% (spec 15%).

Interesting thing here is only %RSD of impurity xyz failed but imprity xyz is still within the spec 0.2% (spec. is <0.25%) as per Certificae of Analyis (COA).

Should i initiate the oos investigation ?
or Repeat the whole testing by making six preps and if % RSD passes then just mention in the method trasfer report and labnotebook that %RSD WAS NOT ACHIEVED, CAUSES UNKNOWN, SO TESTING REPEATED.

i think impurity sample %RSD Failure is not an OOS investigation. so i should not initiate oss investigation. What do you think???[/quote]

I think %RSD is the one criteria that should meet, and you will have to initiate OOS and LIR (Lab Investigation report), in fact in OOS u will resample, reanalyze and retest the samples.

%RSD is not the best method to determine impurity reproducibility in multiple preparations. Instead of %RSD, I like use aboslute differences and means for impurities, specially low level impurities. You have rounding and other potential errors. For example, imagine an impurity present at approximately 0.1%. A value of 0.132 will round to 0.1 while a value of 0.152 will round to 0.2. The RSD of the original values is already around 10% but do you really think those two levels are that different? The RSd of the rounded value is almost 50%. Also, look at the signal to noise ratio of your impurity, are you close to 10:1? Set up your criteria based on what you think the LOQ of the method may be. For an impurity at that low level, I would use an absolute difference of 0.1% sp 0.1 and 0.2 meet the criteria. Keep in m ind these are impurities you are looking at, not the active. Also, if the results are calculated using a RRF value, that will have variability on its own. You do need to conduct and document a formal investigation. The value is not OOS but the results is non-conforming. You should used your investigation to decide whether it is justified to change the acceptance criteria based on excessive requirements.

Yes there is problem with method or system as u are not geting RSD. It is different that ur product is passing in impurity limit.
For example my impurity limit is 0.2% and i am geting 0.1% and 0.25% with average of 0.18% This results indicate that i have problem with method of anaysis or system.

I think %RSD should be taken at least in three digits after points, so there will be no Q for rounding off. All in all it depends on the proposed limit on the basis of peak response, For an impurity method, results obtained in multiple laboratories will be statistically equivalent or the mean results will be within 10% (relative) of the value obtained by the primary testing lab for impurities, If Impurity limit is from 0.1-1.0 % then criteria would be within 25% and it can be within 50% for impurities limit less than 0.1%.

Hi everybody

I think that LOQ should be retested and limit of %RSD (NMT 15 %), conc. of standard impurities xyz must be NLT LOQ limit, if still you get %RSD MT 15%’'then you have to do OOS investigation to check system suitability, carry over, resample, etc…

Good luck

Mohammed .H Yacout
Asst. Manager R&D
Julphar Pharmaceuticals