EU Requirements for Biowaiver for different strengths, BCS biowaiver

Ivana Taševská

1 25/10/2015

Content

• Guidelines EU connected to BES, biowaivers

• Questions and answers on some BW points

• Examples, Links

• Conclusion

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Pharmaceutical assessor in Drug Agency – Biowaiver documentation

• Pharmaceutical and Pharmacokinetic assessment are separated

• BCS biowaiver and strengths assessed by two assessors (pharmaceutical and pharmacokinetic)

• Pharmaceutical assessor evaluates composition, physico-chemical characteristics of AS, dissolution method and profiles, manufacturing process …

• PK assessor evaluates influence of AS and some excipients on human body, BES, dissolution profiles …

• Pharmaceutical form waiver and variation mostly by pharmaceutical assessor.

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EU Guidelines

• Guideline on the investigation of Bioequivalence,

CPMP/EWP/QWP/1401/98 Rev.1/Corr*, valid since 2010

• Variation guidelines on EMA pages www.ema.europa.eu

• Note for Guidance on Pharmaceutical Development

(CHMP/ICH/167068/2004) , Guideline on pharmaceutical development of

medicines for pediatric use (CHMP/CHMP/QWP/805880/2012 Rev2)

• Guideline on excipients (EMEA/CHMP/QWP/396951/2006)

• Guideline on quality of oral modified release products

(EMA/CHMP/QWP/428693/2013)

• Dissolution - EMA (draft 2015)

Application of biobatch dissolution results on the finished product

specification

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What are the possibilities for reducing BES

AS Discovery and Development → Agency review, approval → Manufacturing, marketing, post-approval changes

Biowaiver (BW) waiver of clinical bioequivalence study, where dissolution testing is used instead after fulfilling of certain criteria related to the properties of active substance and finished product (including excipients).

It might represent a surrogate for in vivo bioequivalence.

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Biowaiver

1)Pharmaceutical forms – evident biowaiver

2) IR: Class I, class III: BCS based

Class II, IV: BES

3) MR

4) Strength

5) Variations (post-approval changes)

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Waiver for BES – EMA/FDA (2015) IR systemic action, oral form, not NTI

1) AS group I, dissolution NLT 85 % within 15 or 30 minutes for T and R, excipients of R and T qualitatively similar, „active“ excipients quantitatively the same

FDA: no such excipients that affect rate or extent of absorption (polysorbate 80, sorbitol, mannitol)

2) AS group III, dissolution NLT 85 % do 15 minutes, excipients qualitatively very similar for R and T, active excipients the same

FDA: TP must contain the same excipients as the reference product . The excipients within SUPAC IR level 1 and 2 changes in relation to RP.

EU: I and III, WHO: I and III,

US: I and III, Japan: No

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BCS Solubility • The highest strength (US), highest dose per intake

(EU) • pH

– US: 1.0 – 6.8 – EU: 1.0 - 6.8 + pKa (if within the specified pH range)

BCS permeability EU: complete absorption ≥ 85 %, US formally ≥ 85 %

In vitro permeation studies, CaCo2 US: accepted, two internal standards EU: supportive FDA: Attachment A of Waiver guideline with some AS list

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Data to support BCS biowaiver

• Information on chemical structure, molecular weight, nature of AS (acid, base, amphoteric or neutral), dissociation constants (pKa), solubility, permeability (absorption), polymorphism (the most stable/best crystallizing – poorest dis.rate), particle size

• Module 3, specially Information on product

characteristics (composition, function of excipients, dissolution, comparison of composition, dissolution and impurities between tested and comparator products)

• In-vitro validation report

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BW Point 1: f2 calculation

BE guideline, Appendix I: • Minimum of 3 time points (zero excluded) • The time points should be the same for the two formulations • 12 individual values for every time point for each formulation • NMT 1 mean value of > 85% dissolved for any of the

formulations. • The relative standard deviation or coefficient of variation of

any product should be LT 20% for the 1st point and LT 10% from 2nd to last time point.

In general, 5-8 samplings within 0-60 min recommended for profiles. f2 50 - 100 suggests that the two dissolution profiles are similar

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f2 calculation, cont.

?? Can I discard points that I do not like: i.e. if I have 5, 10, 15, 20, 30

minutes for sampling can I take 10, 20, 30 because results are better for me ?

Example (IR)

0 0.00 0.00

5 62.2 51.8

10 84.4 75.4

15 95.5 80.9

20 98.8 86.2

30 102.6 92.9

If I take 5, 10, 15 min → f2 = 47% If I take 5, 10, 30 min → f2 = 51%

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BE guideline, Appendix I:

For IR comparison a sample at 15 min is essential to know if complete dissolution is reached before gastric emptying. In case MT 85% is not dissolved at 15, but at 30 minutes, minimum3 points are required:

- before 15 min

- at 15 min

- time when the release is close to 85 %

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Comment on f2 (from statistician)

• If criteria f2 not fulfilled, be vigilant with using of Mahalanobis distance. Calculate, but look if there is not „strange“ difference between profiles at any time.

• If by visual inspection there is such suspicion, better is regressive model (modeling value of dissolution depending on type of product, time, and interaction of time with type of product).

• For ex. Modeling of curve by logistic function or Gompertz trend – more than 3 time points necessary, or linear model with random effect, or GEE model.

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Comparison of in vitro dissolution profiles of IR tablets of oxcarbazepine by different methods (M. E. Ruiz, M. G. Volonté,

Dissolution technologies, 02/2014, 32-43)

Biowaivers - for such situations, model-independent methods are the most suitable for profile comparison. • ANOVA-based statistical methods do not meet the

fundamental hypothesis of independence between observations when applied to percentage dissolved, and therefore the data processing is not appropriate.

• Model-dependent methods are over discriminating and not easy to calculate the most suitable for profile comparison.

Proposal to use combined approach: to report f2 along with the result of the AUC or DE (dissolution efficiency) comparison as quantity indicators.

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BW Point 2: the Q&A on BE EMA/618604/2008 Rev. 11, 01/2015

Question 3. Bioequivalence of gastro-resistant preparations (e.g. omeprazole) Summary: Concluding similarity if dissolution of more than 85% is obtained within 15 minutes is not applicable for gastro-resistant formulations. In case of gastro-resistant formulations the release occurs after gastric emptying (median approx. 13 – 15 min). Therefore, the comparison of dissolution profiles should be performed even if dissolution is more than 85% before 15 min in either products or strengths. Hence, a tight sampling schedule is recommended after the product has been investigated for 2 h in media mimicking the gastric environment (pH 1.2 or 4.5) since profile comparison (e.g. using the f2 calculation) is required.

?? What to do if dissolution is fast in pH 6.8 (after pH 4.5) i.e. for test and ref >90% in 10 minutes to ref and 8 minutes for test… complicate to sample and to have a f2 which would pass.

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f2, 4 times from 122 to 128 minutes = 40 % => dossier rejected

time ref test

0 0 0 pH 1.2

120 3 2 pH 1.2

122 5 5 pH 6.8

124 25 40 pH 6.8

126 50 70 pH 6.8

128 70 90 pH 6.8

130 90 100 pH 6.8

135 100 100 pH 6.8

140 100 100 pH 6.8

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Justification is given in the document to the problem that in case of G-R formulation the time 15 minutes is not the most important parameter for waiving statistical comparison of profiles. Influence of Migrating Myoelectric Complex and inter-digestive cycle on enteric coating is unpredictable. Two dissolution profiles (pH 1.2 + 6.8 and pH 4.5 + 6.8) required.

No comment on it.

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BW Point 3 BCS biowaiver and strengths

Question 16. Acceptability of an “additional strengths biowaiver” when bioequivalence to the reference product has been established with a BCS-based biowaiver • Summary “Biowaiver of additional strength

should be applied only when the test product has shown bioequivalence to the reference product by means of an in vivo bioequivalence study.”

?? So I have done a BCS based biowaiver on the higher strength. Do I have to redo a second on the lower strength or can I do something else?

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• Unfortunatelly, you have to do the same thing for another strength as well. BW for strengths relates only to reference to strength tested in vivo, not in vitro.

It means, by comparing every strength with reference product of appropriate strength in at least three pH media without surfactants and fulfilling conditions of BCS biowaiver (sol/perm of AS, excipients, rapid or very rapid dissolution).

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BW Point 4 BW for strength, later application

• I have a BES for the highest strength (40 mg)

• I make a biowaiver of strength on the lower existing strengths on the market (20 and 10 mg)

• I want in a third step to add a new strength lower (5 mg, to avoid to cut the 10 mg in 2 halves) than the lowest strength on the market (10 mg), the PK is linear, proportionality of composition (homothetic formulation, etc…)

?? Can I do it? Or is that an hybrid application?

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Line extension of lower strength Aspects: • Reference product of 5 mg on the market,

comparison • When BES has been provided? • To which strength is 5 mg related? BW for strengths: a)manufacture same b)qualitatively the same c)quantitatively proportional or i+ii or i+iii: i. amount AS LT 5% ii. amount of core excipients the same iii. amount of filler changed for amount of AS

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DCP: 5-10-20-40 mg strenghts, BES for 20 and 40 mg. Biowaiver for 5 and 10 mg related to 20 mg strength. a)Manufacture OK, b)qualitatively the same, d)Dissolution profiles OK. C) quantitatively not proportional.

AS 5 mg 10 mg 20 mg 40 mg

Rosuvastatin 5.00 mg 10.00 mg 20.00 mg 40.00 mg

Filler 98.5 mg 93.3 mg 186.6 mg 181.05 mg

Core weight 150.0 mg 150.0 mg 300.0 mg 300.0 mg

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Comment from assessor: • Concerning the requested biowaiver for the lower strengths the approach

to calculate the ratio between the amounts of active substance is considered not acceptable.

• The biowaiver could be acceptable for the 10 mg strength only, based on quantitatively proportional criteria between 10 mg and 20 mg strengths.

• Regarding the 5 mg formulation the deviation from the quantitative proportional composition is not justified as the claimed condition c) i) and iii) is not fulfilled: the amount of the active substance(s) is less than 5 % of the tablet core weight only for the 5 mg strength and not for both strengths: 5 mg (3.47%) and 20 mg strength (6.93%) . This condition should apply to the strength used in the bioequivalence study and the strength(s) for which a waiver is considered. Therefore, the biowaiver for the lowest strength 5 mg is not acceptable and the Applicant should submit a new BE study with the lowest strength of rosuvastatine.

Conclusion: 5 mg strength was withdrawn from the Application at Day 180 of procedure.

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Ex: BCS biowaiver, XY 50 mg, IR tablets

• Generic application

• Based on a BCS biowaiver (BES not acceptable due to GLP)

• Highest dose (100 mg XY) is soluble in 10 ml of 0.1N HCl, distilled water, acetate buffer pH 4.5, and phosphate buffer pH 6.8

• Dissolution in 0.1 N HCl, acetate buffer pH 4.5 and purified water all > 85% within 15 minutes similar to reference product

• The absolute bioavailability after oral administration is 14%. The absorption is incomplete.

• XY does not have a narrow therapeutic window

Is BCS waiver acceptable?

If not, what additional information (kinetic and quality) is required?

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XY 50 mg

Is BCS waiver acceptable?

If not, what additional information (kinetic and quality) is required?

• The use of buffers is required to ensure consistent pH

• The qualitative composition should be the same for a BCS class 3 product

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XY 50 mg

Is BCS biowaiver acceptable?

XY 50 mg tablet Reference XY 50 mg tablet

XY 50.0 mg

Lactose monohydrate 70.0 mg

Lactose anhydrate 140.0 mg

Crosscarmellose sodium 3.0 mg

Microcrystalline cellulose 15.5 mg

Magnesium stearate 1.5 mg

Film-coating: hypromellose, titan dioxide, triacetin and red iron oxide

XY 50.0 mg

Mannitol 61.1 mg

Crosscarmellose sodium 12.0 mg

Hypromellose 2.40 mg

Microcrystalline cellulose 10.0 mg

Magnesium stearate 2.5 mg

Film-coating:shellac, carnauba wax and white beeswax

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Composition of the proposed and the reference product

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XY 50 mg

• Is BCS waiver acceptable?

• For a BCS class 3 product, the qualitative composition of the excipients should be the same.

• How critical is this difference in this case?

• Would a difference in composition coating also be a reason for refusal BCS waiver?

• Effect of mannitol 60 mg compared to about 210 mg lactose will not be relevant. Is it possible to defend this assessment in court?

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Biowaiver for strength, CC capsules

• Generic application for CC soft capsules 25 mg / 50 mg / 100 mg.

• The products are soft capsules filled with a liquid mixture, containing 25 mg, 50 mg or 100 mg of CC.

• BES performed with 100 mg capsule.

• A waiver is requested for the 25 mg and 50 mg capsules

• Capsule fillings are dose proportional

What information (kinetic, quality) will be required?

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CC capsules

Quality:

• Manufactured according same process and at same site?

• Comparison of disintegration results at pH 1.2, 4.5 and 6.8

Kinetic:

• Linear kinetics need to be demonstrated.

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CC capsules Additional information:

• The three strengths are all manufactured with the same capsule filling and at the same site. Only the size of the capsules and the amount of filling differ.

• The dissolution method used, 1000 ml 0.1 N HCl containing 0.5% sodium lauryl sulfate, the apparatus 2 (paddles) at a rotation speed of 75 rpm at 37°C, is based on the USP method for CC tablets.

• All three strengths > 80% dissolved in 10 minutes, similar to reference product.

• Disintegration (or rupture time) is NMT 15 minutes for all three strengths.

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CC capsules

Is the waiver for strengths acceptable from chemical-pharmaceutical point of view?

• Waiver is acceptable from chemical pharmaceutical point of view if shown that dissolution conditions are discriminatory (1000 ml, surfactant)

• Linear kinetics need to be demonstrated.

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Biowaiver challenges – links

http://www.fip.org/www/index.php?page=bcs_monographs Biowaiver Public Forum

Biowaiver monographs (supported by WHO), mostly class I and III substances, 43 monographs. Although the monographs have no formal regulatory status, they represent scientific opinion currently available.

Handbook of pharmaceutical excipients, 7th Edition, 2012

FDA Inactive Ingredient List (name, dosage form, maximum potency)

Dissolution Methods Database is available to the public at the OGD website at http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm

BCS: http://c0cre295.caspio.com/dp.asp?AppKey=80cd3000fb78473ae2454974ba6c

Biopharmaceutics Applications in Drug Development, Krishna, You, 2008, Springer

Investigating the Discriminatory Power of BCS-Biowaiver in Vitro Methodology to Detect Bioavailability Differences between Immediate Release Products Containing a Class I Drug. Colón-Useche S, González-Álvarez I, Mangas-Sanjuan V, González-Álvarez M, Pastoriza P, Molina-Martínez I, Bermejo M, García-Arieta A. Mol Pharm. 2015 Sep 8;12(9):3167-74.

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Conclusion

• BCS framework more than 20 years ago • Up to now not so many new registrations with

BCS bio-waiver, but it is increasing (Levetiracetam, Pregabaline)

• Biowaiver for strengths and variations are often used

• Need to read not only guidelines, but also Q&A to these guidelines

• Influence of excipients on product performance is not negligible

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Thank you for your attention

Questions?

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