Assessment of Interchangeable Multisource Medicines
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Assessment of Interchangeable Multisource Medicines BCS-Biowaivers . Dr. Henrike Potthast ([email protected]). Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009. Basis for BCS-based Biowaiver Applications/Decisions.

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Assessment of Interchangeable Multisource Medicines BCS-Biowaivers

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Regulatory requirements

Assessment of Interchangeable Multisource Medicines

  • BCS-Biowaivers

Dr. Henrike Potthast ([email protected])

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009


Basis for bcs based biowaiver applications decisions

Basis for BCS-based Biowaiver Applications/Decisions

  • WHO – Technical Report Series No. 937, May 2006

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

    Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms

  • FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000)

  • EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1


Definitions

Definitions

BCS-based ‘Biowaiver’.....

.....is defined as

  • in vitro instead of in vivo ‘bioequivalence’ testing

  • comparison of test and reference

    ....is not defined as no equivalence test


Definitions1

Definitions

acc. to the FDA guidance:

”BCS-based biowaivers are intended only for

bioequivalence studies. They do not apply to

food effect bioavailability studies or other

pharmacokinetic studies.”

(e.g., rel. bioavailability)


Definitions2

Definitions

  • Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!)

  • Bioequivalence – equivalent bioavailability within pre-set acceptance ranges

  • Pharmaceutical equivalence Bioequivalence

  • Bioequivalence Therapeutic equivalence


Bcs based biowaiver

BCS-based biowaiver

In vivo bioequivalence testing is generally required

but

” Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.”

  • for oral immediate release dosage forms with systemic action!


Bcs based biowaiver1

BCS-based biowaiver

Evaluation of drug substance and

drug product

Drug substance

  • pharmacodynamic/therapeutic aspects

  • physicochemical aspects

    Drug product

  • in vitro dissolution


Bcs based biowaiver2

BCS-based biowaiver

RISKassessment

(see e.g. WHO guidance; sect. 9.2 and 5.1.(a))

  • “critical use medicines”

  • “narrow therapeutic index drugs”

  • “documented evidence for BA or BE problems

  • “scientific evidence that API polymorphs, excipients or the manufacturing process affects BE”


Bcs based biowaiver3

BCS-based biowaiver

Biowaiver justification

based on

”………criteria derived from the concepts underlying

the Biopharmaceutics Classification System ......”


Bcs based biowaiver4

BCS-based biowaiver

Biopharmaceutics Classification System (BCS)

dissolution

drug product  drug substance in solution

membrane transport

drug substance in the system

simplified mechanistic view of bioavailability


Regulatory requirements

Melting point

Charge

Solubility

Size

Shape

Ionisa-tion

H-bonding

Charge

Distribution

Lipophilicity

Amphiphilicity

Fig.1: Physicochemical properties that affect absorption (after oral administration) [H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3]


Bcs based biowaiver5

BCS-based biowaiver

Pillars of the BCS

SolubilityPermeabilityDissolution


Bcs based biowaiver6

BCS-based biowaiver

High solubility

  • the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C)

  • generate a pH-solubility profile

    cave: possible stability problems have to be considered

  • Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility

  • Definition of low solubility?


Bcs based biowaiver7

BCS-based biowaiver

High permeability

  • EU guidance: ”Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability”

  • FDA guidance: absolute BA >90 %

  • WHO guidance: at least 85 % absorption in humans

  • Human data are preferred;

    in vitro data may be submitted if sufficiently justified and valid

  • Definition of low permeability?


Regulatory requirements

BCS-based biowaiver


Bcs based biowaiver8

BCS-based biowaiver

♦ „….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.“

[Faassen et al. Clin Pharmacokinet 43 (2004)1117]

 what does the product do to the drug substance?


Bcs based biowaiver9

BCS-based biowaiver

  • When are in vitro results sufficient for bioequivalence evaluation?

  • When is in vitro instead of in vivo bioequivalence testing scientifically justified (or even more restrictive)?

  • Minimizing risk by means of ‘worst case’ investigation?

  • Which in vitro investigations may be sufficient?


Bcs based biowaiver10

BCS-based biowaiver

in vitro dissolution objectives

  • quality control

  • justification of minor variations

  • iviv-correlation (e.g. major variations; bridging)

  • additional to BE studies

  • proportionality based biowaiver

  • BCS based biowaiver

  • ….


Bcs based biowaiver11

BCS-based biowaiver

in vitro dissolution prerequisites

  • reasonable, stability-indicating, validated methods

  • discriminative methods

  • reproducible methods

  • biorelevant methods (?)

    ……one fits all?!


Bcs based biowaiver12

BCS-based biowaiver

in vitro dissolution and BCS concept

  • meet prerequisites

  • ensure risk minimization

  • justify absence of difference

  • biorelevant?!


Bcs based biowaiver13

BCS-based biowaiver

In vitro comparison of immediate release oral

drug products (T and R)

first option: very rapidly dissolving products

  • Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required

  • reasonable, validated experimental conditions/methods are strongly recommended!


Bcs based biowaiver14

BCS-based biowaiver

In vitro comparison of immediate release oral

drug products (T and R)

second option: rapidly dissolving products

  • Not less than 85 % of labeled amount are dissolved within 30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer)

  • reasonable, validated experimental conditions/methods are strongly recommended!


Bcs based biowaiver15

BCS-based biowaiver

Experimental conditions:

  • EU guidance – no specific information yet

  • US-FDA guidance – ‚USP‘-conditions

    • 50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C

  • WHO –

    • 75 rpm (paddle) or 100 rpm (basket); 900 ml or less; USP buffer; 37 °C

  • all: no surfactants!


Bcs based biowaiver16

BCS-based biowaiver

In vitro comparison of immediate release oral

drug products (T and R)

  • Proving similarity of dissolution profiles of T and R

    e.g., using f2-test, unless similarity is obvious

    (see e.g. WHO guidance sect. 9.2 or app. 2 of the current EU guidance; note prerequisites)


Bcs based biowaiver17

BCS-based biowaiver

f2-test

  • acceptance value based on 10 % difference between profiles

  • „identical“ profiles: f2 =100

    „similar“ profiles: f2 between 50 and 100

  • any other reasonable/justified test possible!


Bcs based biowaiver18

BCS-based biowaiver

  • Requirement: either “very rapid” or “similar” in vitro dissolution

    • how similar is ‘similar’?

    • discussion of differences usually not appropriate


Bcs based biowaiver19

BCS-based biowaiver

BCS-based biowaiver in-vitro dissolution

  • no iviv correlation

  • no biorelevant conditions (except pH)

  • concept to justify absence of difference!


Bcs based biowaiver20

BCS-based biowaiver

  • Evaluation of excipients(e.g., large amounts, possible interactions....; e.g. IsoniazidJ Pharm Sci 96 March 2007: “…permeability changes due to excipient interaction cannot be detected in vitro…”)

  • Evaluation of manufacturing processes in relation with critical physicochemical properties


Bcs based biowaiver21

BCS-based biowaiver

BCS-based Biowaiver for immediate release drug products

containing eligible drug substances.

No BCS-based biowaiver for:

  • locally applied, systemically acting products

  • non-oral immediate release forms with systemic action

  • modified release products

  • transdermal products


Bcs based biowaiver22

BCS-based biowaiver

Provided that ......

drug solubility is high,

  • permeability is limited,

  • excipients do not affect kinetics,

  • excipients do not interact ,.....


Bcs based biowaiver23

BCS-based biowaiver

....then very rapid dissolution (at least >85% in 15 min) of test

and reference may ensure similar product characteristics

because...

....absorption process is probably independent from

dissolution and not product related…

 limited absorption kinetics due to poor drug permeability and/or gastric emptying

  • Biowaiver for BCS class III drugs (see WHO guidance)


Bcs class iii

BCS-class III?!

Fig. 1. Mean in vitro dissolution profiles of metformin for 500mg immediate-release tablet of Glucophage® or Glucofit® in 0.1N HCI (○,●) pH 4.6 (□,■) and pH 6.8 (∆,▲) buffer solution.


Bcs class iii1

BCS-class III?!

Fig. 2. Mean in vivo plasma conentration-time profiles of metformin in 12 healthy

Chinese subjects after oral administration of a 500mg immediate-release tablet of

Glucophage (○) or Glucofit (●).

Fig.

Fig. 2


Bcs class iii2

BCS-class III?!

Fig. 1. Comparison of mean cimetidine released-time profiles obtained from dissolution testing of cimetidine

tablets containing methacrylate copolymer and Tagamet® tablets in different media. Each value is the mean of

six observations. Data for the Tagamet® tablet were obtained from dissolution testing in 0.01N hydrovhloric acid

(HCI) and simulated intestinal fluid without pancreatin (SIFsp): (a) 0.01N HCI, pH 2; (b) phosphate buffer, pH

4.5; (c) SIFsp, pH 6.8; and (d) fasted-state simulated intestinal fluid, pH 6.5 pancreatin.

Clin Pharmacokinet. Jantratid et al 2006


Bcs class iii3

BCS-class III?!

Fig. 2.Comparison of mean plasma cimetidine concentration-time profiles obtained after

administration of a singel oral dose of cimetidine tablets containing methacrylyte copolymer or

Tagamet® tablets. Each point represents the mean plasma cimetidine concentration (standard

error) from 12 subjects.

Clin Pharmacokinet. Jantratid et al 2006


Bcs based biowaiver24

BCS-based biowaiver

♦biopharmaceutics assessment (with necessary underlying PK background!!) ≠ pure PK assessment

♦ differentiation between solubility (API) and dissolution (product performance)

♦ volume of dissolution medium (900 vs 500 ml) not relevant (no concerns regarding hydrodynamics; recent findings); sink conditions!

♦ in-vitro/in-vivo relationship rather than correlation!!

♦ slow absorption…intestinal transit about 3hs!!


Bcs based biowaiver25

BCS-based biowaiver

For drugs showing ....

  • ‘very’ high permeability

  • pH-dependent solubility within the physiologically relevant pH range

    .....an ‘intermediate solubility’ class is suggested

    [Polli et al. J Pharm Sci 93 (2004) 1375; see WHO guidance]


Bcs based biowaiver26

BCS-based biowaiver

“pH-dependent soluble, highly permeable, weak

acidic, ionizable drug compounds may be handled

like BCS class I drugs”(e.g. chpt 8 in: Drug Bioavailability, van de Waterbeemd, Lennernäs, Artursson (edts) 2003 Wiley-VCH)

  • in vitro dissolution requirements acc. to WHO guidance

    • at least 85% within 30 min at pH 6.8 and

      f2 testing for pH 1.2 and 4.5 profiles

  • but no biowaiver for weak basic drugs


Bcs based biowaiver27

BCS-based biowaiver

  • meaningful literature data may be used for drug substance characteristics(and excipients)

  • product related data must always be actually generated for the particular product


Bcs based biowaiver28

BCS-based biowaiver

  • BCS-based biowaiver are not just in-vitro dissolution, but in-vitro dissolution is meant to be an important part of BCS-based biowaiver applications


Bcs based biowaiver29

BCS-based biowaiver

  • Current recommendation for TB drugs

  • no BCS-based biowaiver for RMP

  • ‘regular’ BCS-based biowaiver possible for levofloxacin and ofloxacin (“rapid dissolution”)

  • currently a BCS-based biowaiver is possible for isoniazid (cave: excipients!), ethambutol and pyrazinamide if the same “very rapid” dissolution (T and R) is demonstrated

  • see specific, currently published WHO guidance documents at: http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_studies.htm


Bcs based biowaiver ex pyrazinamide dressman et al 2008 unpubl

BCS-based biowaiverex.: Pyrazinamide [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex pyrazinamide dressman et al 2008 unpubl1

BCS-based biowaiverex.: Pyrazinamide [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex pyrazinamide dressman et al 2008 unpubl2

BCS-based biowaiverex.:Pyrazinamide [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex isoniazid dressman et al 2008 unpubl

BCS-based biowaiverex.: Isoniazid [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex isoniazid dressman et al 2008 unpubl1

BCS-based biowaiverex.: Isoniazid [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex isoniazid dressman et al 2008 unpubl2

BCS-based biowaiverex.: Isoniazid [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex ethambutol dressman et al 2008 unpubl

BCS-based biowaiverex.: Ethambutol [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex ethambutol dressman et al 2008 unpubl1

BCS-based biowaiverex.: Ethambutol [Dressman et al., 2008, unpubl.]


Bcs based biowaiver ex ethambutol dressman et al 2008 unpubl2

BCS-based biowaiverex.: Ethambutol [Dressman et al., 2008, unpubl.]


Bcs based biowaiver30

BCS-based biowaiver

  • Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide; J Pharm Sci. 2008 Feb 12; [Epub ahead of print]

  • Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride; J Pharm Sci. 2008 Apr;97(4):1350-60.

  • Vogt M, Derendorf H, Krämer J, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: prednisone; J Pharm Sci. 2007 Jun;96(6):1480-9.

  • Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM; International Pharmaceutical Federation, Groupe BCS: Biowaiver monographs for immediate release solid oral dosage forms: isoniazid; J Pharm Sci. 2007 Mar;96(3):522-31.

  • Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, Shah VP, Stavchansky SA, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol); J Pharm Sci. 2006 Jan;95(1):4-14.

  • Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, Shah VP, Vogelpoel H, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen; J Pharm Sci. 2005 Oct;94(10):2121-31.

  • Kortejärvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride; J Pharm Sci. 2005 Aug;94(8):1617-25.

  • Verbeeck RK, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride; J Pharm Sci. 2005 Jul;94(7):1389-95.

    ……….


Bcs based biowaiver31

BCS-based biowaiver

THANK YOU FOR YOUR ATTENTION!


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