South African Regional and International Symposium · PDF file · 2015-08-20Hier...

Hier wird Wissen Wirklichkeit

South African Regional and

International Symposium 2014

Medicines eligible for Biowaivers

Prof. Jennifer B. Dressman

Institut für Pharmazeutische Technologie

JWG Universität Frankfurt


Substitution requirements

Therapeutic Equivalence = Pharmaceutical Equivalence

+ Bioequivalence

1) Pharmaceutical Equivalence

2) Bioequivalence

1)PK-Studies: key elements are design, power and evaluation of data

2)BCS based Biowaiver: BCS, dissolution and further criteria

3) IVIVC: more commonly used for MR formulations


What is a “Biowaiver”?

In a “Biowaiver”-based submission the Sponsor tests bioequvalence with in vitro dissolution instead of a pharmacokinetic study

The method can be applied to approval of Generics, approval of products at lower doses and for scale-up and post-approval changes (FDA), also known as Variations (EMA), in the manufacture.


The approach was originated by the FDA

in 1995 and applied to approval of generics

in 2002

„Biowaiver“- based approvals are linked to the

Biopharmaceutics Classification Scheme.


I

Highly permeable

The Biopharmaceutics

Classification System (BCS)

II

Highly

soluble

III IV

Poorly permeable

Poorly

soluble

U.S. Department of Health and Human Services Food and Drug Administration Center for Evaluation and Research (CDER). 2000. Guidances for industry: Waiver of in vivo bioavailability

and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System


Solubility Permeability

BCS Criteria: European Medicines Agency (EMA)

BCS

Dose/ Solubility ratio

≤ 250 ml

in >3 aqueous Media

pH 1.2 – 6.8 (preferably

1.2, 4.5, 6.8 and if

relevant pKa)

37+1°C

Absorption ≥ 85 %

BAabs-, Mass

Balance- Study (human)

Supportive data: well-

performed in vitro

permeability studies

including reference

substances; BE of

aqueous and solid dosage

forms of the API

]/[

][][/

)(max

mlmgSolubility

mgDmlSD

EMLratio


I

Highly permeable

Biowaiver possibilities in the USA (FDA)

II

Highly

soluble

III

IV

Not highly permeable

Not

highly

soluble


Biowaiver- based approval

according to BCS class (EMA)

IV III

II I

Solubility

Perm

eab

ility


I

Highly permeable

Biowaiver possibilities at the WHO

II

Highly

soluble

III

IV

Not highly permeable

Not

highly

soluble


BCS specific solubility data (Shake-flask method) and calculation of

D:S ratio using highest single dose

Dissolution of the pure API and its dosage form, and additionally the

comparator product, over pH range

1.2 – 6.8 under Biowaiver conditions relevant to the permeability

Permeability of the API (BAabs, Mass Balance, e.g. Caco-2, BE

with oral solution)

Consideration of further criteria:

Site-specific absorption, risk of transport protein interactions at absorptive

site, excipient composition and therapeutic risks. NTIs are a „no-go“

Physical characteristics: pKa, aqueous solubility


Initial characterization: pKa, aqueous solubility, API presentation

: NTI or not-NTI?

the aqueous solubility will provide a first estimate of whether the

Biowaiver can be applied. If the D:S is well above 250 ml, a biowaiver

will not in general be possible (Class II APIs) and not at all possible for

Class IV APIs.

Note: the EMA uses the Highest Single Dose in the Prescriber’s

Information as the Dose, whereas the WHO and FDA use the Highest

Dosage Strength .

If the API is an NTI substance, a biowaiver based approval will not be

possible. Both Japan and USA have lists of NTI substances – EU??

If the API is presented in a form with different properties to that in the

Reference product (e.g. salt vs. ester, type of salt etc.), it may not fulfill

the criterion of pharmaceutical similarity -> no biowaiver


Solubility specifications for BCS

Classification: FDA, EU and WHO

FDA Guidance for

Industry

EMA Guideline

WHO Bioequivalence

of Multisource

Products

Methods

accepted

Shake-flask method

(other methods can be

used with justification)

Shake-flask method

(other methods can be

used with justification)

Not specified

pH range

pH 1 - 7.5 (pH = pka, pH

= pka 1, pH 1, pH 7.5)

pH 1.2 - 6.8 (aqueous

media), preferably 1.2,

4.5 and 6.8, when

appropriate also at pKa

pH 1.2 - 6.8 (aqueous

media)

Temperature

[ C]

37 1

37+1

37 1

Replications

at least 3

At least 2, end pH should

be verified

at least 3

D/S ratio

≤ 250 ml at highest

dosage strength

≤ 250 ml at highest

single dose administered

≤ 250 ml*

*calculated for the highest listed oral strength on WHO EML


If the initial analysis looks promising, the next step is to

carry out the pH/solubility profile according to the

Guideline – e.g. according to EMA…..

The highest single dose administered as immediate

release formulation must dissolve completely in 250 ml

of buffer within the range pH 1-6.8 at 37+1°C.

At least three different buffers (preferably 1.2, 4.5 and

6.8) and in addition at the pKa, if relevant.

Shake-flask or other method; replications

Verification of pH before and after addition of the API

If the API is NOT highly soluble, no biowaiver will be

possible from the EMA or FDA

BCS specific solubility data (Shake-flask method) and calculation of

D:S ratio using highest single dose


Permeability specifications for BCS

Classification: FDA, EU and WHO

FDA Guidance for Industry

EMA Guideline

WHO Bioequivalence

of Multisource Products

Highly permeable

≥ 90 %

≥ 85 %

≥ 85 %

Accepted methods

Mass balance, absolute BA,

intestinal perfusion (in

humans)

Mass balance, absolute BA

(in humans)

Mass balance, absolute BA

(in humans)

Acceptable

alternative methods

In vivo or in situ intestinal

perfusion in a suitable animal

model, in vitro permeability

methods using excised

intestinal tissues or

monolayers of suitable

epithelial cells

none

In vivo intestinal perfusion in

humans, in vitro permeation

using excised human or

animal intestinal tissue (only

in comparison to a

reference product)

Supportive data

Not specified

Bioequivalence of aqueous

and solid formulations; well

performed in vitro

permeability studies

including reference

standards

In vivo or in situ intestinal

perfusion using animal

models or in vitro

permeation across a

monolayer of cultured

epithelial cells


The next step is to determine the permeability, since this will

dictate what dissolution criteria are to be applied (EMA, WHO)

or whether the biowaiver can be applied at all (FDA).

Studies that can be used to support complete (>85% or 90%)

absorption are absolute bioavailability or mass-balance

studies.

Mass-balance: only metabolites formed after absorption may

be taken into account (not those formed in the GI tract) i.e.

parent (urinary) plus Phase I oxidation and Phase 2

conjugation metabolites (urinary and fecal) must together

account for at least 85% of the dose

Additional data that may be supportive: p.o. bioequivalence of

aqueous solution to solid dosage form; well-performed in vitro

permeability including reference standards.

Permeability of the API (BAabs, Mass Balance, e.g. Caco-2, BE

with oral solution)


Consideration of further criteria I:


site, excipient composition and therapeutic risks.

The in vitro permeability experiments may help establish the

mechanism of absorption and thus help answer questions

such as the site-specificity of the absorption (active transport,

paracellular transport) and risk of transport protein

interactions at the absorptive site (active transport).

Such information may be useful in helping forecast excipient

interactions and risks associated with biowaiving


Consideration of further criteria II:



In general, well-established excipients in usual amounts should be

employed. A description of the function of each excipient and a

justification that the amount used is in the usual range is required.

Excipient choices are more limited for Class III APIs than for Class I

APIs (EMA)

Class I: “advisable to use similar amounts of the same excipients

used in the reference product”.

Class III: Excipients have to be qualitatively the same and

quantitatively very similar to exclude different effects on

transporters”.

Problem – usual only the qualitative composition is disclosed!


Consideration of further criteria III:



Excipients that might affect bioavailability through non-

dissolution mechanisms should be identified e.g. sorbitol,

mannitol, SLS and other surfactants.

These excipients should preferably be qualitatively and

quantitatively the same as in the reference product

Their impact on

GI motility,

susceptibility to interactions with the drug substance,

drug permeability and

interactions with membrane transporters

should be discussed.


Dissolution testing requirements for

in vitro BE testing: FDA, EU und WHO

FDA Guidance for Industry

EMA Guideline

WHO Proposal to Waive in

vivo BE Requirements

Apparatus

1 (basket) or

basket

basket or

2 (paddle)

paddle

paddle

Dissolution media:

0.1 HCl or SGF USP without

enzymes and

Three buffers: pH 1-1.2, 4.5,

6.8

- Ph. Eur. Buffers

recommended

- No surfactants

- Enzymes may be

acceptable for gelatin

capsules and tablets

pH 1.2 IP standard

dissolution buffer (HCl

solution)

pH 4.5 standard buffer and

pH 4.5 IP standard

dissolution buffer (acetate

buffer)

pH 6.8 standard buffer or SIF

USP without enzymes

pH 6.8 IP standard

dissolution buffer (phosphate

buffer)

Temperature [ C]

37 0.5

37 + 1 C

37

Volume [ml]

900 or less

900 ml or less

900 or less

Agitation [rpm]

100 (apparatus 1)

usually 100 (basket) usually

50 (paddle)

100 (basket)

50 (apparatus 2)

75 (paddle)

Release

at least 85 % within 30 min

>85 % within 15 min (VRD)

or > 85% within 30 min (RD)

at least 85 % within 30 min


The dissolution characteristics of the pure API are

always interesting as this will indicate whether there are

any wetting problems with the API and if its particle size

needs to be reduced.

For biowaiver purposes, both the test and reference

product must be subjected to exactly the same battery of

dissolution tests. The range of test conditions that can

be used is very specific to the biowaiver and the

standard QC tests are not relevant to the biowaiver

procedure.

The tests are the same for Class I and III APIs, but the

evaluation criteria are different (EMA, WHO)


reference product, over pH range

1.2 – 6.8 under biowaiver conditions relevant to the permeability I


Test conditions

Apparatus – Paddle or Basket

Volume of medium: 900 ml or less

Temperature of Medium: 37 + 1°C

Agitation: usually 50 rpm (Paddle), usually 100 rpm

(basket).

Sampling: e.g. 10, 15, 20, 30, 45 min

Buffers: 1-1.2 (usually 0.1 N HCl or SGF sans enzymes),

pH 4.5 and pH 6.8 (or SIF sans enzymes). Ph.Eur. Buffers

preferred. NO SURFACTANTS! Enzymes OK if gelatin

capsules or tablets are involved.



1.2 – 6.8 under biowaiver conditions relevant to the permeability II


Data Evaluation

Different criteria apply according to BCS Class of the API

Class I: either very rapid dissolution (>85% in 15 min) of both

the test and reference product

or

Similarly rapid dissolving = both reference and test product

result in >85% dissolution in 30 minutes AND profile similarity

is demonstrated with the f2 or another suitable statistical

comparison.

Class III: very rapid dissolution (>85% in 15 min) of both the

test and reference product is required.

Problem: sometimes the Reference product cannot meet the

dissolution criteria. In this case a biowaiver-based approval is

not possible.



1.2 – 6.8 under biowaiver conditions relevant to the permeability IV


16 Point-Text: Level Biowaiver

Criteria

16

16 Point-

Biowaiver

BCS Classification

Therapeutic

Index, interactions

Of excipients with

GI physiology and

transporters

BE Studies

Aq. Solution vs.

solid dosage form

API presentation, dosage form

similarity, interactions with

excipients in the dosage form


BCS Class (II, IV)

NTI

slow or incomplete dissolution

Interacations with excipients

lack of bioequivalence of solid

dosage form with aqueous solution

excipients that might cause

effects in GI tract

Biowaiver

BCS Class I or III

wide therapeutic index

rapid or very rapid dissolution

no interaction with excipients

No critical excipients

BE of solid dosage form with

aqueous solution

Weighing the data


The Essential Medicines WHO

Model List (EML)

This list comprises the most important drugs which should be available in

every health care system

There are ~ 250 drug products in the “Core List” and ~ 80 in the

“Complementary List”

The products are chosen on the basis of safety, efficacy and price

The dosage form and strength is listed for each product and there are

currently about 150 IR solid oral products in total i.e. products to which in

principle the biowaiver process could be applied

http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf


Examples of APIs on the EML

Antituberkulotics

Rifampicin

Isoniazid

Ethambutol

Pyrazinamide

Antimalarials

Quinine

Primaquine

Proguanil

Mefloquine

Sulfadoxine/ Pyrimethamine

Artemeter/ Lumefantrin

Atovaquone

Doxycycline


Results for Antituberculotics

API Solubility Permeability BCS Biowaiver Justification or

limitations

Test

Rifampicin borderline High II/I No Instability, poor

wettability,

Polymorphism

In vivo

Pyrazinamide High borderline III/I Under

certain

conditions

Liver toxicity ->

adequate medical

support needed

In vitro

(in vivo)

Isoniazid High borderline III/I yes Reducing sugars

should be

excluded as

excipients

In vitro

(in vivo)

Ethambutol

• 2 HCl

High low III Under

certain

conditions

Visual toxicity->

adequate medical

support needed

In vitro

(in vivo)


Results for Antimalarials

API Löslichkeit Permeabilität BCS Biowaiver Justification or

limitations

Test-

Verfahren

Quinine

hydrochloride

High borderline III/I No NTI, does not

dissolve fast

enough

In vivo

Primaquine

diphosphate

High High I Yes

-

In vitro

Proguanil

hydrochloride

High ? III/I Yes ≥ 85 % dissolution

in 15min: test and

reference product

In vitro

Mefloquine

hydrochloride

low

?

IV/II No Low solubility In vivo

Doxycycline

hyclate

High High I Yes - In vitro


Doxycycline hyclate

Physicochemical Properties

• MW: 512.94 g/mol

• Melting point: 201°C

• Solubility: ~ 50mg/mL

• pKa (20°C): 3,5; 7,7 and 9,5

• log P: ~ -1,90

• Tetracycline antibiotic

Structure of Doxycyclinhyclat


Dissolution Profiles of

German Doxycycline Tablet products


Biowaivers for the German products?

All three of the generic products were approved in Germany via

pharmacokinetic bioequivalence testing (Antadox being the innovator

product).

Doxycyclin AL dissolves 85% in 15 minutes, as does the innovator. So

it would have passed the biowaiver criteria.

Doxy- Wolff dissolves 85% in 30 minutes, and similarly to the

innovator, so it too would likely have passed the biowaiver criteria.

Doxy- Stada dissolves too slowly to meet the biowaiver criteria, so

could not have been approved through the biowaiver procedure.

These results illustrate that the biowaiver procedure is sometimes

tougher than a pharmacokinetic proof of bioequivalence!!


Future Directions for Biowaiving……

………some ideas

Resolve the Dose to be used for Dose:Solubility calculations

Harmonize the Permeability (Suggestion – to 85% absorption)

Use BDDCS as supporting evidence for the BCS classification

* * *

Consider solubility in more biorelevant media (simple buffers are

„worst case“) but also adopt more biorelevant media volumes

Harmonize definitions of NTI on a global basis

Investigate excipient interactions that are NOT detectable with

dissolution testing more thoroughly


Many thanks for your attention!

The Biowaiver Monographs can be accessed

at www.fip.org/bcs

South African Regional and International Symposium · PDF file · 2015-08-20Hier...

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