Achievwin
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2022-09-07 20:22
(146 d 10:47 ago)

Posting: # 23275
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 T/R potency <5% [Regulatives / Guidelines]

Colleagues:

Somewhere in the Bioequivalence guidance I remembered that when designing the studies we try to keep T/R potency +/-5%. Can someone point out where this kind of condition existed, (latest guidance has no mention of this)

Thanks in advance for your guidance,
Helmut
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2022-09-07 20:55
(146 d 10:14 ago)

@ Achievwin
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 T/R potency <5%

Hi Achievwin,

❝ Somewhere in the Bioequivalence guidance I remembered that when designing the studies we try to keep T/R potency +/-5%. Can someone point out where this kind of condition existed, (latest guidance has no mention of this)

  • AFAIK, it was never stated by the FDA in any guidance.
  • For Health Canada is was mandatory (‼) to present two evaluations: One ‘as is’ and the other corrected for potency (irrespective whether T and R differed more than 5% or not). Was removed in 2018.
  • The EMA recommends that you find batches of T and R which differ ≤5%. Only if this is not possible (nope, »we weren’t successful in the pharmacy next door« is not an acceptable justification), in ‘exceptional cases […] content correction could be accepted. If content correction is to be used, this should be pre-specified in the protocol and justified by inclusion of the results from the assay of the test and reference products in the protocol.’

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Achievwin
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US,
2022-09-07 22:50
(146 d 08:19 ago)

@ Helmut
Posting: # 23277
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 T/R potency <5%

❝ ❝ Somewhere in the Bioequivalence guidance I remembered that when designing the studies we try to keep T/R potency +/-5%. Can someone point out where this kind of condition existed, (latest guidance has no mention of this)


❝ – AFAIK, it was never stated by the FDA in any guidance.


It was there in 2001 guidance as desired requirement-not mandatory... problem is that I can not find that 2001 (first) BE/BA guidance
I can not find that 2001 (first) BE/BA guidance. Also in 2021 guidance lines 807-808
jag009
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NJ,
2022-09-08 21:54
(145 d 09:15 ago)

@ Achievwin
Posting: # 23281
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 T/R potency <5%

❝ It was there in 2001 guidance as desired requirement-not mandatory... problem is that I can not find that 2001 (first) BE/BA guidance

❝ I can not find that 2001 (first) BE/BA guidance. Also in 2021 guidance lines 807-808


Correct the "should be within 5%" does exist in the FDA guidance (not the BE guidance for individual products). I was asked to provide the info last yr in a meeting...

John
dshah
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India/United Kingdom,
2022-09-09 12:48
(144 d 18:21 ago)

@ Achievwin
Posting: # 23282
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 T/R potency <5%

Hi Achievwin!
Unlike Health Canada, there is no provision for potency correction in FDA.
So if the difference is more, there is higher probability to find difference in PK parameters for treatments, which ultimately affects BE outcome.
It's best to have less difference in Assay of Test and Reference for any BE study.
Regards,
Divyen
Helmut
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2022-09-09 14:13
(144 d 16:57 ago)

@ dshah
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 T/R potency <5%

Hi Divyen,

❝ Unlike Health Canada,…


Here you err. A potency correction (additionally to the uncorrected analysis) was mandatory since 1992 (Section 8 e). However, it’s gone since June 2018.

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Achievwin
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US,
2022-09-09 16:56
(144 d 14:14 ago)

@ dshah
Posting: # 23284
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 T/R potency <5%

Hi Divyen!

❝ So if the difference is more, there is higher probability to find difference in PK parameters for treatments, which ultimately affects BE outcome.


It is not about potency correction, it is about controlling errors wherever possible and designing rationale BE study design. BE studies are meant to detect minor formulation differences, therefore it is better to keep T/R <5% (just compare acceptable variabilities we observe in pharmaceutical dosage form analysis and PK parameters) to improve your BE success probability. I believe I heard (in the 2000 BE workshop) rationale for this 5% difference is to accomodate aging differences (time of manufacture to time of dosing) between Test and RLD (usually RLD is older than Test and also assay variabilities (Damn: everyone blames poor analytical chemist :confused::confused:).

Let us say the ratio is 110% you are already at the top of the limit+ combined with variability associated with Bioanalytical, between subjects and other factors you are shooting for failure (unless luck is on your side).

This is my side of the story :-D
Helmut
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2022-09-09 19:08
(144 d 12:01 ago)

@ Achievwin
Posting: # 23286
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 T/R potency <5%

Hi Achievwin,

❝ It is not about potency correction, it is about controlling errors wherever possible …


Agree.

❝ I believe I heard (in the 2000 BE workshop) rationale for this 5% difference is to accomodate aging differences (time of manufacture to time of dosing) between Test and RLD (usually RLD is older than Test …


Which workshop? Let’s compile what we have:
  • FDA ANDA Draft, Appendix A (2013)
    We recommend that the assayed drug content of the test product batch not differ from the reference product by more than ± 5 percent.
  • EMA BE GL (2010)
    Section 4.1.2 Reference product
    The selection of the reference product used in a bioequivalence study should be based on assay content and dissolution data and is the responsibility of the Applicant. Unless otherwise justified, the assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product determined with the test procedure proposed for routine quality testing of the test product. The Applicant should document how a representative batch of the reference product with regards to dissolution and assay content has been selected. It is advisable to investigate more than one single batch of the reference product when selecting reference product batch for the bioequivalence study.
    Section 4.1.8 Evaluation
    In bioequivalence studies, the pharmacokinetic parameters should in general not be adjusted for differences in assayed content of the test and reference batch. However, in exceptional cases where a reference batch with an assay content differing less than 5% from test product cannot be found (see section 4.1.2) content correction could be accepted. If content correction is to be used, this should be pre-specified in the protocol and justified by inclusion of the results from the assay of the test and reference products in the protocol.
  • WHO Section 7.3.2 Choice of comparator product (2017)
    Content of the API(s) of the comparator product should be close to the label claim and the difference between two products being compared should not be more than ± 5%. If, because of the lack of availability of different batches of the comparator product, it is not possible to study batches with potencies within ± 5%, potency correction may be required on the statistical results from the bioequivalence study.

❝ … and also assay variabilities (Damn: everyone blames poor analytical chemist :confused::confused:).


That’s the point. What are the batch release spec’s? Generally ±10% and for NTIDs ±5%. Of course, you don’t get a CoA from the originator. Analyzing the reference with the method validated for the test is not a problem for IR. Little bit more tricky for MR. A nightmare for creams and ointments with their fantastic emulsifiers. You never can’t be sure. Yes, analytical (in)accuracy and (im)precision hits … Say, you have a great routine method with 2% and you measure a potency 100% for T and R. What are the true values? Can be <100% for T and >100% for R. That’s why in sample size estimation one should never (ever!) assume a T/R-ratio of 1.

In [image]:

set.seed(20220909)
T <- rnorm(n = 1e7, mean = 1, sd = 0.02)
R <- rnorm(n = 1e7, mean = 1, sd = 0.02)
round(quantile(T / R, probs = c(0.025, 0.5, 0.975)), 4)
 2.5%   50% 97.5%
0.946 1.000 1.057

That’s why in most sample size functions of PowerTOST 0.95 is the default.

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dshah
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India/United Kingdom,
2022-09-09 19:42
(144 d 11:27 ago)

@ Achievwin
Posting: # 23287
Views: 1,030
 

 T/R potency <5%

Hi Achievwin!

Just trying to be simple, lets assume a T/R ratio of 90-111.1%. Based on your spec, assay limit can be +/- 10%.
The assay of test for assumption is 95% and Ref is 105%. With such scenario, it can be assumed that your T/R ratio can be on lower side and vice versa.
But if assay of test is 98% and ref is 102% (difference is LT 5%), the 90% CI limit can have higher probability be tighter than the previous case.
The ageing impact can vary with drug product, and thus it should be considered on case by case basis.
The overages (for e.g. Vitamins) can also be a challenge in such scenario.
Meeting your target for exact assay can be challenging in manufacturing where loss is observed resulting in to lower assay.

Thank you Helmut for the point in Health Canada.

Regards,
Divyen
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