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sireen ☆ Jordan, 2013-12-14 13:27 (4569 d 15:24 ago) Posting: # 12059 Views: 12,607 |
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Dear members, Probably this is an old issue for most of you... The EMEA guideline on the investigation of BE states that "Similarity of in vitro dissolution should be demonstrated at all conditions within the applied product series, i.e. between additional strengths and the strength(s) (i.e. batch(es)) used for bioequivalence testing."... What about the QC dissolution method.... what I mean to ask is: would an in-vitro dissolution in SGF media, reflect bioequivalency if the three different buffers (pH 1.2, 4.5 and 6.8) demonstrated otherwise. Also, some lectures state to conduct in-vitro dissolution profiles under similar conditions... does that mean within a certain period of time... can't I compare my current data against results from 2 years ago... Would that raise questions by regulatory authorities. Apologies if such questions are depressingly not challenging for you, nevertheless, thank you for your comments... Sireen |
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Dr_Dan ★★ Germany, 2013-12-16 13:58 (4567 d 14:53 ago) @ sireen Posting: # 12061 Views: 10,880 |
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Dear Sireen Test and reference should show similar in vitro dissolution under physiologically relevant experimental pH conditions, i.e. in vitro dissolution should be investigated within the range of pH 1 – 6.8 (at least pH 1.2, 4.5, and 6.8). The QC dissolution method in SGF media alone (=low pH level) will not help you since you miss the information of the other two media. The results of in vitro dissolution tests at three different buffers and the media intended for drug product release (QC media) can serve as bioequivalence surrogate inference to demonstrate in certain cases similarity between different formulations of an active substance and the reference medicinal product and to investigate batch to batch consistency. 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. As long as you obtain your in-vitro dissolution profiles under the same conditions (same lab, same method, same instruments etc.) you can compare your current data with previous results. I hope this helps Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★   Vienna, Austria, 2013-12-16 15:50 (4567 d 13:01 ago) @ Dr_Dan Posting: # 12062 Views: 10,729 |
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Dear Dan, ❝ Test and reference should show similar in vitro dissolution under physiologically relevant experimental pH conditions Should? OK, it has to be done (Appendix I.i – Testing on product quality), but the similarity testing (I.ii) is only relevant if a biowaiver is intended. ❝ 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. Exactly. ❝ However, possible reasons for the discrepancy should be addressed and justified. Addressed? Maybe – though I don’t see its necessity according to the GL. IMHO, reporting is sufficient. Why justified? The dissolution media might not be biorelevant, or dissolution is simply not the driving force for absorption at all (BCS classes II and IV). — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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mittyri ★★ Russia, 2014-01-22 20:39 (4530 d 08:12 ago) @ Helmut Posting: # 12230 Views: 10,595 |
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Hi Sireen, Dr_Dan and Helmut! I would continue this discussion. According to the chapter 4.2.2 "Similarity of in vitro dissolution should be demonstrated at all conditions within the applied product series, i.e. between additional strengths and the strength(s) (i.e. batch(es)) used for bioequivalence testing." Do I understand correct the order:
(Our preceding GL states that we could use 6 units only. Now we use EMA GL.) Is there no need for additional dissolution tests of different strengths of reference product (no need to compare other Reference Batches to the Test Batches)? What could we do if information is published (not from Originator) about instability of the active substance in one of ph media? Should we check it or refer to the source only? — Kind regards, Mittyri |
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Dr_Dan ★★ Germany, 2014-01-23 12:50 (4529 d 16:01 ago) @ mittyri Posting: # 12240 Views: 10,485 |
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Dear mittyri Yes, you are right, you need to perform dissolution tests at three different buffers for the BEQ batches of test and reference and to perform dissolution tests at three different buffers for BEQ batch (test) and all additional strengths of test product if linearity of PK is proven and if the different strengths are qualitative and quantitative proportional (otherwise you would need additional BE studies). 12 units of the Test and the Reference product respectively are needed for each experiment to enable statistical evaluation. According to the EMA guideline similarity of in vitro dissolution should be demonstrated at all conditions within the applied product series, i.e. between additional strengths and the strength(s) (i.e. batch(es)) used for bioequivalence. You do not need to compare your strengths with the respective originator strengths. Instability of the active substance in one of ph media is a substance specific property and will occur for the Test formulation in the same way as for the Reference formulation (there should be no formulation effect). In consequence the dissolution profiles should not differ and you have to demonstrate this. I hope this helps. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Erkin ☆ Turkey, 2015-09-16 13:24 (3928 d 16:27 ago) @ mittyri Posting: # 15404 Views: 9,304 |
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Hi All, According to 3-period bioequivalence study with Test-1, Test-2 and Reference, all products have been found as BE. But in dissolution tests in three different buffers, 60-70% of the test products and 95% of the Reference product are dissolved at first 15 min. And also ƒ2 has been found below 50. According to the EMA guideline on the investigation of BE, 2010 CPMP/EWP/QWP/1401/98 on Appendix I: "In case more than 85% is not dissolved at 15 minutes but within 30 minutes, at least three time points are required: the first time point before 15 minutes, the second one at 15 minutes and the third time point when the release is close to 85%." ... "An ƒ2 value between 50 and 100 suggests that the two dissolution profiles are similar. 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." Therefore, choosing 10 min as first point, 15 min as second and 25 min (close to 85% dissolved) as third point and calculating ƒ2 values at these time points at three different buffers are acceptable and adequate for authorities. Thanks in advance. Erkin Alkan |
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Helmut ★★★ Vienna, Austria, 2015-09-16 17:37 (3928 d 12:14 ago) @ Erkin Posting: # 15408 Views: 9,307 |
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Merhaba Erkin, I don’t understand your concerns. In vivo BE always has precedence over in vitro similarity (only a suitable surrogate of BE under certain conditions). See Dan’s and my posts above. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Erkin ☆ Turkey, 2015-09-17 10:39 (3927 d 19:12 ago) @ Helmut Posting: # 15414 Views: 9,202 |
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Hallo Helmut, Of course, not any in-vitro test simulates as best as the in-vivo does. But I don't understand is: we made a bioequivalence study and we found the products as bioequivalent. After that why we bother about f2 unless sponsor wants to improve their product (and they need to do a new BE study afterall.) "An ƒ2 value between 50 and 100 suggests that the two dissolution profiles are similar. 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." I think the key word is "MAY BE COMPARED". Thank you very much Helmut  .Erkin Alkan |
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Helmut ★★★ Vienna, Austria, 2015-09-17 14:41 (3927 d 15:10 ago) @ Erkin Posting: # 15417 Views: 9,129 |
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Merhaba Erkin, ❝ But I don't understand is: we made a bioequivalence study and we found the products as bioequivalent. Fine. End of story. ❝ After that why we bother about ƒ2 unless sponsor wants to improve their product (and they need to do a new BE study afterall.) I never bothered. IMHO, Appendix I 1.i is the most important part. It is highly unlikely that you ever find a discriminatory method for BCS classes II and IV (by definition). Even if you succeed, I would think that’s just a coincidence. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Shuanghe ★★ Spain, 2015-09-18 12:11 (3926 d 17:40 ago) @ Helmut Posting: # 15427 Views: 9,026 |
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Hi Erkin and Helmut, ❝ ❝ But I don't understand is: we made a bioequivalence study and we found the products as bioequivalent. ❝ ❝ Fine. End of story. From BE standpoint, I couldn't agree more. But if you are the one developing the product then ... ❝ ❝ After that why we bother about ƒ2 unless sponsor wants to improve their product (and they need to do a new BE study afterall.) Not all change of formulation require additional BE. For major changes, obviously yes; but for some small modification post approval some times you only need to demonstrate similarity by in vitro dissolution profiles. However, if the profiles are not similar for bio-batch, you might end up with doing BE for those changes that normally do not require in vivo study. This is the request from one EU regulatory agency: Bioequivalence between the formulation applied for and the brand leader product has been demonstrated in-vivo; however, similarity of dissolution profiles could not be demonstrated in vitro. Therefore, the dissolution method is considered to be over-discriminating; as a consequence if any future changes in the formulation are proposed the comparison of dissolution profiles cannot be used as similarity of formulations and new bioequivalence studies have to be carried out. Since I'm working directly with formulation / manufacturing team, my experience is that the possibility of the change of formulation is quite high; actually much higher than you would expect. So it might pay later if you can develop a better in vitro method. Of course, if you are working in a BE CRO then you shouldn't worry it at all. BE passed, in vivo result prevail. sponsor has a dossier to present. End of story. If they change anything later, more BE business for you.  — All the best, Shuanghe |
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Helmut ★★★ Vienna, Austria, 2015-09-18 14:25 (3926 d 15:26 ago) @ Shuanghe Posting: # 15429 Views: 8,971 |
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Hi Shuanghe & all, of course you are perfectly right. One should always try to develop a suitable in vitro method. However, I have some doubts whether matching profiles (ƒ2, Mahalanobis distance, whatsoever) for BCS classes II, IV (and III except weak acids; qualitatively/quantitatively identical excipients) could ever be of any relevance for the in vivo performance. I wonder whether someone got a response from an agency like this: Bioequivalence between the formulation applied for and the brand leader product has been demonstrated in vivo and similarity of dissolution profiles could be demonstrated in vitro. However, the drug does not belong to BCS Class I; as a consequence if any future changes in the formulation are proposed the comparison of dissolution profiles cannot be used as similarity of formulations and new bioequivalence studies have to be carried out. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz