Log in
Register|
Dr_Dan ★★ Germany, 2015-03-17 17:28 (3686 d 15:19 ago) Posting: # 14572 Views: 11,243 |
|
|
Dear all How can I show similarity for a formulation of a BCS class IV substance if dissolution testing shows that at pH x and pH y only 5 to 10% is dissolved from a formulation within 45 min.? The BE-Guideline does not describe this situation and f2 value calculation is not possible. Any idea? Looking forward to your replies. Kind regards Dr_Dan — Kind regards and have a nice day Dr_Dan |
|
nobody nothing 2015-03-17 17:37 (3686 d 15:09 ago) @ Dr_Dan Posting: # 14573 Views: 9,631 |
|
|
Hi Dan! Had a look at pharmacopoeial dissolution methods? FDA? As you do not go for a biowaiver, soap is an option  But the problem might be after all a certain degree of variability that may persist. Worst case: higher than allowed by Guidance for calculation of reliable f2-values. Live is pain... — Kindest regards, nobody |
|
luvblooms ★★ India, 2015-03-19 10:42 (3684 d 22:04 ago) @ Dr_Dan Posting: # 14574 Views: 9,570 |
|
|
Hi Dr_Dan ❝ How can I show similarity for a formulation of a BCS class IV substance if dissolution testing shows that at pH x and pH y only 5 to 10% is dissolved from a formulation within 45 min.? Not only Class IV but same holds true for class II drugs as well (typical example is Phenytoin, insoluble between pH 2-8) and EMA wants f2 calculations (for lower strengths) at Ph 1.2, 4/5 and 6.8. ❝ The BE-Guideline does not describe this situation and f2 value calculation is not possible. Any idea? Condition 1. If you are looking for Biowaiver of lower strengths: for example: BE strength is 400 mg and lowest strength is 100, you can use multiple tablets of 100 mg (4) to show similarity (to show that differences are due to the solubility of the API not formulation related) Condition 2: If BE strength is a single strength and you want to show the similarity in dissolution profile. a) Present whatever release data is with you 5 to 10% is dissolved from a formulation within 45 min (We have tried this with couple of product and later in day 70 query on EMA asked as to use the minimum amount of surfactant to get >80% release and then show the similarity. We had all the data generated at our end and we submitted along with complete solubility studies (done using various surfactants at various concentrations) and with minor suggestions related to the Q point, Products got approved. b) Use minimum amount of surfactant up front and provide a proper dissolution method selection report. c) Even if the F2 is not matching, submit the data and justify the reason behind the same. Guidance clearly says that “In the event that the results of comparative in vitro dissolution of the biobatches do not reflect bioequivalence as demonstrated in vivo the latter prevails. However, possible reasons for the discrepancy should be addressed and justified.” Dear Nobody If higher variability is a constrain you can always use Weibull method or MSD. EMA accept that. — ~A happy Soul~ |
|
ElMaestro ★★★ Denmark, 2015-03-19 11:07 (3684 d 21:40 ago) @ luvblooms Posting: # 14575 Views: 9,522 |
|
|
Hi luvblooms, ❝ If higher variability is a constrain you can always use Weibull method or MSD. EMA accept that. (my coloring) Perhaps, I think those are slightly dangerous statements. Wouldn't you rather say that some assessors may accept the use of a Weibull or MSD model if you are in a sittuation where the basic discussion in 1401/98 does not pave the way forward? Technically I guess EMA won't accept anything as assessment is done at the national agencies and there is as far as I know no guidance in place which forces any national assessor to have any specific opinion about any named dissolution model other than the moderate discussion available in 1401/98. — Pass or fail! ElMaestro |
|
luvblooms ★★ India, 2015-03-20 05:26 (3684 d 03:21 ago) @ ElMaestro Posting: # 14582 Views: 9,499 |
|
|
Hi ElMaestro ❝ ❝ If higher variability is a constrain you can always use Weibull method or MSD. EMA accept that. ❝ ❝ (my coloring) ❝ Perhaps, I think those are slightly dangerous statements. Wouldn't you rather say that some assessors may accept the use of a Weibull or MSD model if you are in a sittuation where the basic discussion in 1401/98 does not pave the way forward? Technically As per EMA BE guidance page 21 of 27, it is very clearly written that When the ƒ2 statistic is not suitable, then the similarity may be compared using model-dependent or model-independent methods e.g. by statistical multivariate comparison of the parameters of the Weibull function or the percentage dissolved at different time points. Alternative methods to the ƒ2 statistic to demonstrate dissolution similarity are considered acceptable, if statistically valid and satisfactorily justified. ❝ I guess EMA won't accept anything as assessment is done at the national agencies and there is as far as I know no guidance in place which forces any national assessor to have any specific opinion about any named dissolution model other than the moderate discussion available in 1401/98.  Will slightly disagree on that. We have submitted the similarity calculation using MSD and Weibull to some national agencies (Netherlands, Germany,UK etc) and got approvals as well. Once Netherlands authority has upfront ask as as to use other methods to show similarity as the RSDs were higher upto 20 min (product having DT of 10 min). Only trick was deciding the MSD (based on reference data) and you are good to go.— ~A happy Soul~ |
|
nobody nothing 2015-03-19 12:00 (3684 d 20:46 ago) @ Dr_Dan Posting: # 14577 Views: 9,500 |
|
|
Hi! This here looks quite experimental: http://www.ncbi.nlm.nih.gov/pubmed/23058042 Any experience on regulatory acceptance for this approach yet? — Kindest regards, nobody |
|
luvblooms ★★ India, 2015-03-20 05:34 (3684 d 03:13 ago) @ nobody Posting: # 14583 Views: 9,542 |
|
|
Hi Nobody ❝ This here looks quite experimental: http://www.ncbi.nlm.nih.gov/pubmed/23058042 ❝ ❝ Any experience on regulatory acceptance for this approach yet? as per "Guidance for Industry Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations" page 8 of 27 "In general, nonaqueous and hydroalcoholic systems (apart from alcohal dose dumping) are discouraged unless all attempts with aqueous media are unsuccessful. Appropriate review staff in CDER should be consulted before using any other media" so we never tried them for submission purpose but yes, have used this extensively for discrimination of CR products. do check — ~A happy Soul~ |
|
Dr_Dan ★★ Germany, 2015-03-23 10:14 (3680 d 22:33 ago) @ luvblooms Posting: # 14591 Views: 9,238 |
|
|
Dear all Thank you very much for your advise. Kind regards Dr_Dan — Kind regards and have a nice day Dr_Dan |
Ing. Helmut Schütz