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Melkor ☆ Greece, 2014-01-20 14:59 (4543 d 20:49 ago) Posting: # 12203 Views: 6,319 |
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Dear all, According to EMA's Bioequivalence Guideline (General Biowaiver Criteria), a BE study for a certain strength can be waived in the case (3rd requirement of the Guideline) i and ii or i and iii are fulfilled. Criteria i reads: "i. The amount of the active substance is less than 5% of the tablet core weight." My question is whether this is referred to the active substance in the base form or in a salt form. According to definitions, an active substance is the one that has the therapeutic effect (usually the base or an active metabolite) which most probably answers my question. Any advice on this?  Thank you. |
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Helmut ★★★   Vienna, Austria, 2014-01-20 15:24 (4543 d 20:23 ago) @ Melkor Posting: # 12204 Views: 5,531 |
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Hi Melkor, ❝ My question is whether this is referred to the active substance in the base form or in a salt form. According to definitions, an active substance is the one that has the therapeutic effect (usually the base or an active metabolite) which most probably answers my question. Very good point! Throughout the GL “active substance” refers to the active core molecule (base, acid); that’s what we find in the systemic circulation. Section 1.2 states: The different salts, esters, ethers*, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. (my emphasis)So when it comes to in vivo the case is clear. Not sure about salts, derivatives in the formulation… See this post of Jean-Michel.
— 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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Melkor ☆ Greece, 2014-01-20 16:28 (4543 d 19:20 ago) @ Helmut Posting: # 12207 Views: 5,532 |
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Hi Helmut, Thanks a lot for the prompt response. That was exactly what i was thinking about this issue. Nevertheless, something that is still unclear to this part of the biowaiver: Both formulations: bio-strength and waiver-strength have to have less than 5% of the active substance? Thanks again  |
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Ohlbe ★★★ France, 2014-01-20 17:21 (4543 d 18:27 ago) @ Melkor Posting: # 12208 Views: 5,387 |
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Dear Melkor, I think the guideline is quite clear on this aspect: If there is some deviation from quantitatively proportional composition, condition c is still considered fulfilled if condition i) and ii) or i) and iii) below apply to the strength used in the bioequivalence study and the strength(s) for which a waiver is considered i. the amount of the active substance(s) is less than 5 % of the tablet core weight, the weight of the capsule content My understanding is that both the formulation used in the BE trial and the formulation you want to waive should contain less than 5 % of "active substance", whatever that may be. — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2014-01-20 18:04 (4543 d 17:44 ago) @ Ohlbe Posting: # 12209 Views: 5,393 |
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Hi Ohlbe, ❝ … to the strength used in the bioequivalence study and the strength(s) for which a waiver is considered So, how is the strength defined? AFAIK, it’s the core molecule, not the salt. ❝ … less than 5 % of "active substance", whatever that may be. Hey, that’s the crucial point. I would follow the argument in Jean-Michel’s extreme example. Therefore, IMHO the 5% should be based on the API seen from a galenic perspective (e.g., the salt), not the PK perspective (“active moiety”). — 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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Ohlbe ★★★ France, 2014-01-20 18:32 (4543 d 17:15 ago) @ Helmut Posting: # 12210 Views: 5,375 |
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Dear Helmut, ❝ I would follow the argument in Jean-Michel’s extreme example. Therefore, IMHO the 5% should be based on the API seen from a galenic perspective (e.g., the salt), not the PK perspective (“active moiety”). I'm not a specialist - but I would agree. This is the most conservative approach, the most protective from the patients' point of view. — Regards Ohlbe |
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Melkor ☆ Greece, 2014-01-22 13:34 (4541 d 22:13 ago) @ Ohlbe Posting: # 12226 Views: 5,354 |
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Thank you both for your help and advice. Concerning the strengths that should follow the rule of 5%, indeed imo bio-strength must comply also with the rule. The main issue is salt of base but i agree that one should better follow the more conservative option. Thank you again. |
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Helmut ★★★ Vienna, Austria, 2014-01-23 01:54 (4541 d 09:53 ago) @ Ohlbe Posting: # 12234 Views: 5,417 |
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Hi Ohlbe, ❝ I'm not a specialist… … nor am I. I found an interesting draft from the FDA: “Naming of Drug Products Containing Salt Drug Substances” Active moiety - The molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester,* salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule responsible for the physiological or pharmacological action of the drug substance.
— 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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kumarnaidu ★ Mumbai, India, 2014-06-27 12:54 (4385 d 23:53 ago) @ Helmut Posting: # 13154 Views: 4,844 |
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Hi all, I have one passed BE study. After that if I change the source of API do we need to conduct a repeat BE study or earlier passed BE study will suffice. — Kumar Naidu |
Ing. Helmut Schütz