Questions & Answers

 

 Questions & Answers


Any questions with respect to biowaivers? Post your question here- maybe, another worker in this field posts an answer. Alan Parr, Moderator of the Discussion Forum. Disclaimer: The content of items posted in the Discussion Forum represents the opinion of the submitting author(s). It should not be construed as representing the opinion of either the Special Interest Group or the FIP.

 

“Question”

 
 PMQ wrote:                                                                     February 2017

In Annex 7 of Multisource (generic) pharmaceutical products:
guidelines on registration requirements to establish
interchangeability  it reads:

It is recommended that potency and in vitro dissolution characteristics
of the multisource and the comparator pharmaceutical products be ascertained
prior to the performance of an equivalence study. 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.

Question
May I clarify what is meant by "difference between the label claim of the two products being compared should not be more than +/- 5%"?
Does it mean that the test product must not be less than or more than 5% of the actual label claim of the reference product OR the test and reference products must be within the range of 95% to 105% of the acceptable range?

Replies to this question: 

 
Prof. Dressman wrote:                                                                                   February 2017

I would interpret the text as meaning that:
1. The label claim must be the same for both
2. The actual content (assay) in the comparator must not be more than 5% different from the actual content (assay) of the test product.
For example: if the label claim is 100 mg, then the comparator could have 98 and the test 93 mg, or if the comparator had 98, the test could have 103 mg.
I hope this helps

 

 

“Question”

 
 PMQ wrote:                                                                     October 2016

1. Do we need to conduct analysis (eg. complete monograph testing) for both the test and reference/comparator products?
2.        Do we need to reflect the batch sizes of both the test and reference products in the biowaiver report?
3.        Is the proof of proper storage and shipping (from the source up to the site of dissolution testing) necessary for the reference product?
4.        Is the volume of dissolution media as specified in the WHO guidelines be strictly followed or we may modify it as long as we can justify the use of a particular volume?

Replies to this question: 

 
Prof. Dressman wrote:                                                                                   October 2016

1. Not if already done and you can reference a reliable source. E.g. a biowaiver monograph, but also well-documented permeability or solubility studies and clinical information relevant to therapeutic index may be referenced from separate, reliable sources.

2. I think you would need to comply with the same rules for testing as are applied for pharmacokinetic BE.

3. Again, I would apply the same requirements as for the PK studies

4. It says 900 ml or less, so within that range it is left open to the sponsor. A higher volume would not be possible.   

 

“Question”

Harikiran wrote:                                                                     09-07-2015


Good Afternoon, Is it mandatory to generate multimedia dissolution profile between RLD strength and lower strength if want to get biowaiver for lower strength or is it enough to generate profile comparision between RLD strength and lower strength in OGD media?. Pl reply.

                                              

Alan wrote:                                                                                    01-09-2015


Expectations may vary from one agency (e.g., FDA, EMA, etc.) to another and one reviewer to another. Therefore, if you are looking for approval in the USA then I would recommend that you look at the SUPAC guidelines as well as the FDA website for guidance on specific products to determine the best way forward. If you are looking for approval outside of the USA I would recommend that you look at EMA and WHO guidelines. Ideally, it would be best to discuss with the regulatory agency of interest to ensure you are generating the appropriate data that the given regulatory agency would like to see.

 

 

 

 

“Question”

 
 Raymond Maikokera wrote:                                                      27-07-2015

Does Amlodipine besylate tablets now have bcs biowaiver monograph?\r\nDoes amlodipine besylate 10mg tablets qualify for bcs biowaiver?

Replies to this question: 

 
Alan wrote:                                                                                     01-09-2015

Based on a review of the FIP website a monograph for this compound does not exists at this time. A monograph for this compound is being considered, but there is no date as to when it will be available.

 

“Question”

 
Barbara Roth wrote:                                                        31-07-2015

Dear FIP Team,WHO published a"GUIDANCE ON THE SELECTION OF COMPARATOR PHARMACEUTICAL PRODUCTS FOR EQUIVALENCE ASSESSMENT OF INTERCHANGEABLE MULTISOURCE (GENERIC) PRODUCTS". If there is no identified comparator, which criteria would you recommend to follow to choose between various products on the market? Thanks

Replies to this question: 

 
Alan wrote:                                                                          01-09-2015

While a number of factors could be considered to select a comparator, it would be best to address this question to the appropriate regulatory agency to ensure that the agency will accept any data you generate using the selected comparator.

 

“Question”

 
Nagesh Chopade wrote:                                                      28-05-2015

We are developing Immediate release tablets of one non-potent drug with strengths of 5 mg and 10 mg. Both RLD strengths are lookalike formulation with 150 mg average weight. As per USFDA 10 mg is RLD strength and we want to take waiver for 5 mg based on proportionally similar criteria. For US it is not the problem as changes for lower strength will be within SUPAC level I criteria but for Europe the (I) criteria of percentage of active below 5\% will not work in case of 10 mg strength. Plz suggest whether we can go with lookalike approach for 5 mg strenth or we have go for dose proportional criteria for EU market.

Replies to this question: 

 
Alan wrote:                                                                           16-06-2015

This is a great question, but one that needs be to be asked of the appropriate regulatory agency to ensure that the proper data is generated to support a regulatory filing and subsequent approval.  Please let me know if you have any questions about my response.

 

“Biowaiver for Cyproheptadine HCl”

 
S. Biradar wrote:                                                       24-02-2015

Dear Researcher, Do we have biowaiver monograph for Cyproheptadine HCl Tablets 4mg for US

Replies to this question: 

 
Alan wrote: 

We currently do not have an approved monograph for Cyproheptadine HCl and it is not a monograph that is currently under development. We are always looking for individuals to develop monographs and if you are interested in developing a monograph for this compound we would be happy to work with you in development of this monograph.

 

“Conversion of FIP to mg”

 
Li wrote:                                                       17-02-2015

Hello, I am interested in the conversion of FIP to mg. Specifically bromelain 3000 FIP units = how many mg? Thanks, Li 

Replies to this question: 

 
Alan wrote: 

Unfortunately, this question is not related to biowaivers and therefore we are not in a position to address this question. We would recommend that you consult with various pharmacopoeia organizations to address this question. Additionally, you might want to review a paper on this topic by Scharpe et. al (1997).  

“RLD”

 
Srujan wrote:                                                       10-02-2015

Dear Sir, Our formulation (Injectable Suspension) having 2 strengths.FDA recommended invivo bio equivalence study for higher strength and waiver for lower strength. The dissolution behavior is dose proportional but excipient concentrations are same. we are unable to match f2 of higher and lower strength but matching with RLD. Is it possible to get a waiver by comparing only with RLD not with higher strength?Regards SK

Replies to this question: 

 
Alan wrote: 

Our focus group focuses on BCS and Biowaivers for oral products and not parenteral products. Due to our focus we cannot address this question and recommend that you consult guidance documents related to biowaivers for injection products for the countries in which you would like to obtain approval in.
 

 

“Allopurinol”

 
Desireen wrote:                                                                   27-01-2015

Dear Sir/Madam, kindly advise if Allopurinol can be biowaived based on WHO BCS classification (class I), knowing that FDA classifies the same under class III. Also please share with us the approximate date of when the Allopurinol monograph is likely to be published.Thanks

Replies to this question: 

 
Alan wrote:
 

The monograph for allopurinol is in the final stages of being submitted for publication. Based on the review of the draft monograph, allopurinol will not be recommended for biowaiver status. Please let me know if you have any follow-up questions about this monograph.
 

 

“Biowaiver monograph for Moxifloxacin”

 
Thahera wrote:
04-10-2014

Dear Sir, Good Morning. We would appreciate if you could provide us Biowaiver monograph for Moxifloxacin.Thanks & Kind Regards, Thahera

Replies to this question: 

 
Alan wrote:
 

I am sorry to inform you that the FIP Focus Group "BCS and Biowaivers", does not formulate biowaiver monographs for API's on request. The procedure is as follows: any scientist can participate in the process of developping biowaiver monographs, by making one's interest known to the project leader prof Dressman, and to reserve an API in the Progress Table, which is based on the WHO's List of Essential Medicines, and accessible on the FIP website. In collaboration with the project leader and other members of the Focus Group, the monograph will be drafted and subsequently submitted to the Journal of Pharmaceutical Sciences. Details on guidance to writing such monographs are given on the website too. Please feel free to develop the monograph of Moxifloxacin yourself, in collaboration with the FIP BCS and Biowaiver Focus Group.
 

 

“Amlodipine Besylate tablets”

 
Daysi de Miranda wrote:
Wednesday 04-12-2013

Dear Sirs
I will really appreciate if you can share with me the on going biowaver monograph of Amlodipine Besylate tablets

Amlodipine besylate) Fotaki Uni Bath (UK)
Thank you very much for your soon asnwer

Replies to this question: 

 
Alan wrote:
 

I have checked with the author of the amlodipine besylate monograph and they indicated that they plan to submit the monograph by the end of October 2014. 
Thank you 

“Biowaiver for co-amoxiclav tablets”

 
N.ANANDHI wrote:
Thursday 02-08-2012

Is BCS based Bio-waiver applicable for registration of Co-amoxiclav tabs in EU?
( As per WHO, Amoxicill in class I and Potassium clavulanate is Class III drug)

 

Replies to this question: 

 
Alan wrote:
Wednesday 05-09-2012

Section V of appendix III of the EMEA's guidance document entilted "Guideline on the Investigation of Bioequivalence" indicates that "BCS-based biowaiver are applicable for immediate release fixed combinations (FC) products if all active substances in the FC belong to BCS-class I or III and the excipients fulfill the requirements outlined in section IV.2. Otherwise in vivo bioequivalence testing is required". Please refer to section IV.2 of the referred document for specifics around excipient requirements. Therefore, based on this guideline a biowaiver should be possible provided that all API's belong to BCS-Class I or III AND the requirements for excipients are fulfilled. This response is provided by the BCS & Biowaivers Special Interest group (SIG).

“Biowaiver - Misoprostol Category”

 
sunilkumar c jain wrote:
Friday 30-03-2012

Dear Sir,
Is Misoprostol included in BCS Class 1 or in BCS Class 3 ?

 

Replies to this question: 

 
Alan Parr wrote:
Tuesday 17-07-2012

Literature information (WHO guidelines) indicates that misoprostol is most likely a BCS 3 or 4 compound and therefore not eligible for a biowaiver. Response is from the BCS and Biowaivers Special Interest Group.

 

 

 
Mr. Arif wrote:
Wednesday 17-10-2012

Is Misoprostol included in BCS Class 3 or in BCS Class 4 ?

“Biowaiver for the other strengths”

 
Olga wrote:
Sunday 26-02-2012

Please, explain me, if I can use the biowaiver procedure into lower strengths when the highest dose was registered by this procedure. The API corresponded to the Class 1 of BCS. 

 

Replies to this question: 

 
Alan Parr wrote:
Tuesday 17-07-2012

Based on information in the literature, it should be possible to apply for a biowaiver for a lower strength product. It should be noted that regulatory agencies have slightly different guidelines (e.g., requirement that dissolution profile needs to be the same as the higher strength product), therefore you should check the guidance from the appropriate regulatory agency to determine what is required in that jurisdiction and possibly also check with the agency itself to ensure that they agree with this approach for your specific compound/product. Response is from the BCS and Biowaivers Special Interest Group.

“Biowaver for Rosuvastatin”

 
guruprasad wrote:
Wednesday 29-06-2011

Is Biowaver applicable for Rosuvastatin, as this falls under BCS III classification

 

Replies to this question see below: 

 
Alan Parr wrote:
Wednesday 15-02-2012

At this time rousuvastatin is not on the list of compounds for which a monograph will be developed.

 

 

 
dhrumil wrote:
Thursday 08-11-2012

solubility of rosuvastatin is very poor than how it fall under BCS 3 classification

“Use of Surfactants on Biowavers”

 
Juan Eduardo Vargas González wrote:
Friday 10-06-2011

If the API we have under evaluation is not soluble in the three medias recommended for biowaivers, how viable and acceptable is the use of surfactants so that we can keep sink conditions and trust that the comparative dissolutions profiles will not be affected by the poor solubility, and at the same time we can infer that the in vitro behavior will be representative on biological fluids? Is there a guideline regarding the kind and ranges of surfactants that we can use? 

 

Replies to this question: 

 
Alan Parr wrote:
Tuesday 17-07-2012

Since the drug is not soluble in the three different dissolution media then the compound would not be eligible for a biowaiver. The current biowaiver guidelines do not allow for the use of surfactants in dissolution media. 
If for QC applications a surfactant is needed, then the lowest concentration possible should be used. This would be a concentration that enables the release specification to be met, but retains good discrimination between acceptable and not acceptable batches.
If the purpose is to predict in vivo performance, the use of biorelevant media is advised. response is from the BCS and Biowaivers Special interest Group.

“Ibuprofen suspension”

 
Dirk Barends wrote:
Thursday 12-05-2011

Tali Rabiner questioned on 18-11-2009:
I read the ibuprofen biowaiver monograph and wonder if you have reference publication that support the acceptance a biowaiver for an ibuprofen suspension 400mg/ml.
changed Thursday 12-05-2011

 

Replies to this question: 

 
Dirk Barends wrote:
Thursday 12-05-2011

On 18-11-2009, Jenny Dressman replied: 
For jurisdictions that follow the WHO Guidelines, I would assume that as long as the suspension dissolves according to the requirements of the Guideline (> 85% in 30 minutes in the pH 6.8 buffer and similarly to the reference product in the pH 1.2 and 4.5 buffers) and as long as there are no excipients in the formulations which would affect permeability of ibuprofen or motility in the GI tract (e.g. large quantities of mannitol, sorbitol or glycerine), as biowaiver for the ibuprofen suspension should be feasible. However, I have no specific publication to which I can point you regarding this question.
changed Thursday 12-05-2011

“Excipients and BCS I”

 
Rodrigo Cristofoletti wrote:
Tuesday 15-02-2011

Dear all,

What to do if the comparator contains excipients such as sorbitol, sodium laurilsulfate, or propylene glycol, and the test product not? Is it obligatory that the test be qualitatively and quantitatively identical to its comparator regarding this class of excipients?

Best regards

Rodrigo Cristofoletti

 

Replies to this question: 

 
Dirk Barends wrote:
Tuesday 15-03-2011

With respect to: ”What to do if the comparator contains excipients such as sorbitol, sodium laurilsulfate, or propylene glycol, and the test product not?
Reply: For the biowaiver risk analysis, the situation that a test drug product contains a "critical excipient", such as sorbitol, sodium laurilsulfate or propylene glycol, and the comparator not, is not different from the reversed situation: i.e. the comparator contains sorbitol, sodium laurilsulfate or propylene glycol and the test drug product not.”

With respect to: “It is not always obligatory that the test drug product is qualitatively and quantitatively identical to its comparator regarding this class of excipient": 
Reply: Indeed, the EMA guidance 2010 indicates so. The EMA Guidance, is, however, the most stringent regulation, aiming at reducing the risk that a test drug product might be bioinequivalent to an extremely low level. 
The WHO and the SIG BCS & Biowaiver accept a slightly higher risk that a test drug product might be bioinequivalent, taking into account that a biowaiver is never acceptable for narrow therapeutic index (NTI) drugs, and recommend slightly wider acceptance criteria for the excipients: 
“Evidence that each excipient present in the multisource product is well established and does not affect GI motility or other processes affecting absorption, can be documented using the following information:
i) the excipient is present in the comparator product, or the excipient is present in a number of other products which contain the same API as the multisource drug product and which have marketing authorizations in countries participating in the ICH or associated countries; and
ii) the excipient is present in the multisource product in an amount similar to that in the comparator, or the excipient is present in the multisource drug product in an amount typically used for that type of dosage form. (WHO 2006).

This is the general policy, for drug substances reviewed in a Biowaiver Monograph sometimes slightly different criteria were defined, as a result from data available for that particular drug substance. 

“50/75 rpm or 100 rpm”

 
Helen wrote:
Wednesday 19-01-2011

WHO: 'Comparative in vitro dissolution should be performed with 12 units of actual batches in standard buffer media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 50/75 rpm, or the basket apparatus at 100 rpm'

My question is: may I use the paddle apparatus at 100 rpm for biowaiver of immediate release tablets?

Thank you

 

Replies to this question: 

 
Jennifer Dressman wrote:
Tuesday 07-06-2011

Generally speaking, no. The Guidance does not foresee higher rpm than 75 for the paddle method. A possible exception might be if there is documented strong coning at 50 rpm, which is not eliminated by raising the rpm to 75, but this would be an unusual case.

“Diazepam biowaiver monograph”

 
Natalie wrote:
Friday 26-11-2010

Dear FIP, 

Could you give an approximate date of when the Diazepam monograph is likely to be published?

Kind regards

 

Replies to this question: 

 
Alan Parr wrote:
Wednesday 22-12-2010

I have checked with the intented first author for the diazepam monograph and have determine that they are no longer available to develop this monograph. We are currently looking for a new first author for this monograph and once that individual is selected we will than determine a new delivery date this this monograph. Please let me know if you would be interested in serving as the first author for this monograph, or if you know someone else who might like to serve as first author. 

“Mebeverine HCl biowaiver monograph”

 
shahnaz daoud wrote:
Saturday 07-08-2010

please, is there any information about Mebeverine HCl biowaiver 

Thank You 

 

Replies to this question see below: 

 
Alan Parr wrote:
Wednesday 22-12-2010

Dr Daoud,

We currently do not have an identified first author for a mongraph for Mebeverine HCl therefore we do not have an intended deliver date for this monograph. We are looking for first author for this mongraph and many others so please let me know if you would like to serve as first author on this monograph or another monograph, or if you know of someone that would like to serve as a first author. Please let me know if you have any follow-up questions on this topic.

“Azithromycin Dihydrate usp equivalent to 500mg of Azithromycin”

 
Moinul Hakim wrote:
Wednesday 24-03-2010

Dear Sir/madam,
Hope this mail finds you in good health and cheerful.
We would appreciate if you could provide us 
1.biowaiver monograph for Azithromycin.

2. Boiwaiver approach for BCS class III actives.

thanking you, with kind regards

Moinul 


 

Replies to this question see below: 

 
Alan Parr wrote:
Wednesday 22-12-2010

Thank you for your interest in our work.

Regarding your questions: 

Ad 1)
I am sorry to inform you that the FIP Special Interest Group, BCS and Biowaiver, does not formulate biowaiver monographs for API's on request. The procedure is as follows: any scientist can participate in the process of developping biowaiver monographs, by making one's interest known to the project leader Dr Barends, and to reserve an API in the Progress Table, which is based on the WHO List of Essential Medicines, and accessible on the FIP website. In collaboration with the project leader and other members of the Special Interest Group, the monograph will be drafted and subsequently submitted to the Journal of Pharmaceutical Sciences. Details on guidance to writing such monographs are given on the website too.

Ad 2)

The acceptance of biowaivers for BCS Class III compounds varies between regulatory agencies. 
Presently, the FDA does not allow biowaivers for IR solid oral dosage forms containing BCS class III drug substances, see: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070246.pdf 

Recently, the EMA does allow biowaivers for IR solid oral dosage forms containing BCS Class III drug substances when the test drug product and its comparator (=reference) are both very rapidly dissolving, and the exipients present in the test drug product and its comparator (=reference) are qualitatively the same and quantitatively very similar, and the drug substance is not a narrow therapeutic index dug, see:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf

The WHO is not a regulatory agency, but recommends biowaivers for IR solid oral dosage forms containing BCS Class III drug substances under the same conditions as the EMA, but is not so strict with respect to the excipients as the EMA, see: http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf 


changed Friday 11-02-2011

Biowaiver acceptance in EU”

 
Ron Liedorp wrote:
Friday 05-03-2010

Is there experience with the acceptance of biowaivers for such well known products as (immediate-release tablets) paracetamol, paracetamol+coffeine, combination acetylsalicylic acid_ paracetamol+ coffein, ibuprofen, in countries in the EU like PL, CZ, IT, BE, DE and UK. 
changed Wednesday 21-07-2010

“Class I Drugs Biowaivers”

 
Rahul Jain wrote:
Friday 06-11-2009

A tablet dosage form contains Class I drug (Highly soluble /highly permeable/linear kinetics).
- BE Study is performed on the Highest strength. Dissolution for BE strength is 82-83 % for both test and reference in pH 1.2/4.5/6.8 dissolution medias. 
- Lower strengths dissolve approx. 90% in 10-12 minutes for both test and reference in dissolution medias (pH 1.2/4.5/6.8).
- Since lower strengths for both test and reference are dissolving more than 85 % in 15 minutes in all medias, is it still required to prove dissolution similairty between BE strength & additional strengths of test product as per latest draft Guidelines on Bioequivalence (CPMP/EWP/QWP/1401/98 Rev1) 

“Betamethasone”

 
Nino Jinjolava wrote:
Wednesday 28-10-2009

Dear Sir/Madam,

I would be thankful, if you could help me in determining can be Betamethasone (BCS Class 2) directed as biowaver (according to WHO technical Report Series 937). 

 

Replies to this question see below: 

 
Dirk Barends wrote:
Thursday 29-10-2009

For a positive biowaiver decision, there need to be sufficient data to make an assessment possible. If there are insufficient data, a negative biowaiver recommendation need to be given. With respect to Betamethasone, there is yet no Biowaiver Monograph available, hence, at present, a negative biowaiver recommendation need to be given.
changed Tuesday 03-11-2009

 

 

 
James Polli wrote:
Tuesday 22-12-2009

I recall the WHO report allows for waivers of class 2 acids, with limitations. I have not studied betamethasone, but it appears that betamethasone is not an acid, so it would not be fall under that description/benefit of the WHO report.

“Biowaivers based on dose-proportionality”

 
Rahul Jain wrote:
Wednesday 14-10-2009

There is a BCS class I molecule and the dissolution for all the lower strengths is more than 85% for both test and reference products i.e. rapidly dissolving. 

For higher strength , BE study had been conducted. Tablets for Test and reference are dissolving more than 85 % in 20 minutes. 

Our F2 between Higher and lower strengths are not matching. 

Can we take Biowaiver in Europe? 

changed Tuesday 03-11-2009

 

Replies to this question see below: 

 
Dirk Barends wrote:
Tuesday 03-11-2009

The question considers only dissolution similarity between the strengths of the same drug product. However, similarity of in vitro dissolution should not only be demonstrated within the product series, i.e. between additional strengths and the strength(s) used for bioequivalence testing, but also between the additional strength(s) of the applied product and corresponding strengths of the reference product. At all conditions, similarity of in vitro dissolution should be demonstrated. In cases where more than 85% of the drug is dissolved within 15 minutes, f2 criteria can be waived. 
However, the lower strengths are said to be rapidly dissolving. i.e. not less than 85% in 30 min, so, here, f2 criteria cannot be waived.
There is an exemption: at pH values where sink conditions may not be achievable for all strengths, f2 criteria can be waived, however, the comparison with the reference medicinal product should then confirm that this finding is drug substance rather than formulation related. In addition, dissolution profiles of the same dose (e.g. two tablets of 5 mg versus one tablet of 10 mg) should meet the f2 criteria.

Reference: EMEA Draft guideline on the investigation of bioequivalence, http://www.emea.europa.eu/pdfs/human/qwp/140198enrev1.pdf.

“Need the pharmacokinetic linearity of a drug to be considered for a biowaiver based on the BCS?”

 
Djellouli Salim wrote:
Wednesday 23-09-2009

I am an young Algerian pharmacologist and I am preparing a thesis about the in vitro testing approach in bioequivalence based on the biopharmaceutics classification system. I wich that you could help me to know if the linearity of a drug pharmacokinetic is needed to be considered for a biowaiver based on the BCS.

 

Replies to this question see below: 

 
fried faassen wrote:
Sunday 27-09-2009

As far as I am aware of only in the European guidelines linearity is a requirement. In the following publication an overview is given on the global criteria applied for biowaivers: Eur J Pharm Sci 29(2006) 315 and you may whish to check this. Also the websites of the EMEA and FDA will give the latest versions of the guidelines. 
Dose linearity reflects that changes in neither solubility not permeability are critical in the dose range dose range tested. However, it is assumed that the formulation is similar or the same, and that the dissolution profile is not changed. The need for dissolution testing is similar to the guidelines from the FDA and the EU, and dose linearity can only be used as surrogate parameters for in vivo solubility and permeability. More information on dose linearity can be found in Clin pharmacokinet 43 (2004) 1117. In this publication solubility, permeability, and Pgp transport are discussed in term of dose linearity and consequences for biowaivers. 

 

 

 
Jan Welink wrote:
Wednesday 14-10-2009

The EU guideline indicates linear and complete absorption as a requirement for a biowaiver. It does not state linear pharmacokinetics, however in practise this is translated into linear pharmacokinetics, which may be questioned. As can be observed in the new EU draft guideline on bioequivalence, complete absorption for Class I drugs is now listed as the main criteria, next to high solubility. Additional linearity is mentioned, but it is not restricted anymore to linear pharmacokinetics. It is only included to ensure that complete absorption has been assessed at the rigth dose. However, as indicated this is a draft version; the final guideline is expected to be available early next year. 

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