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Overview of BE approaches for different

.dosage forms

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 Pharmaceutical Equivalents
Pharmaceutically equivalent FPPs may differ

Differences in formulation:
excipients, drug particle size,
mechanism of release
Differences in manufacture:
equipment, process, site

May result in differences in e.g., disintegration and

dissolution, and impact product performance
 Products that require studies to
determine equivalence …

 Solid oral FPPs

– immediate- and modified-release FPPs
 Complex topical formulations
– emulsions, suspension, ointments, pastes, foams,
gels, sprays, and medical adhesive systems
 Complex parenteral formulations
– depot injections, nasal/inhalational suspension etc.
 Establishing Equivalence
 Comparative pharmacokinetic studies
– In vivo comparative bioavailability studies
– Comparison of performance of FPPs based rate and
extent of absorption of API from each formulation
• Area under the concentration-time curve AUC)
• Maximal concentration (Cmax)
• Time to maximal concentration (tmax)
 Comparative pharmacodynamic studies
 Comparative clinical trials
 Comparative in vitro methods
– Biopharmaceutics Classification System (BCS)-
based biowaivers
– Additional strengths biowaivers
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 Essentials of BE
Design, conduct and evaluation of
bioequivalence studies
The formulation and the characteristics of the active
substance are factors which can affect the requirements for
bioequivalence studies.
physicochemical characteristics

pharmacokinetics

proportionality in composition
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:Golden standard study design

single dose, two-period,

crossover

healthy volunteers

Reference (comparator)/
Test (generic)

90% CI AUC and Cmax:

80 – 125%

Applicability
MR formulations?
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Different dosage forms:

Intravenous solution:

same concentration

no special excipients who can influence distribution

no BE study needed: waiver acceptable

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Different dosage forms:

Intravenous solution with addition of a solubiliser:

low solubility drugs: still possible to administer by i.v.

route

solubiliser should be the same or has no effect on

release or distribution

no BE study needed: waiver acceptable

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Different dosage forms:
Intravenous solution with solubiliser; example:
- Vfend: low solubility drug
- i.v. solution contains sulfobutylether beta
cyclodextrin sodium (SBECD)
- if similar solubiliser used in same concentration -> no
BE study needed: waiver acceptable.
- however, SBECD patented; alternative solubiliser
used: hydroxypropylbetadex (HPBCD)
- may be acceptable: proof that release is not
influenced: dissociation constant!

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Different dosage forms:

Intravenous solution with micelles:

low solubility drugs: still possible to administer by i.v.

route

Micelles should be the same or have no effect on release

or distribution: see before solubilisers.

no BE study needed: waiver acceptable

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Different dosage forms:
Intravenous liposomal formulation:

influences distribution kinetics of the drug (uptake cells)

elaborate evaluation/assessment of quality aspects

preclinical studies: distribution

BE study needed: next to total drug concentration, free

drug and bound fraction should be evaluated

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Different dosage forms:
Intravenous biosimilar formulation:

active substance not identical between innovator and generic

elaborate evaluation/assessment of quality aspects: confirm

to which extent similar
preclinical studies: PD and distribution

BE study needed, with possible clinical study!

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Different dosage forms:
Depot injections:

after i.m. or s.c. injection, active substance released from site of

injection

release solubility controlled or matrix controlled

release can be controlled over months (example Depo Provera

(every 3 month injection))

BE study needed

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Different dosage forms:
BE evaluation depot injection:

- single dose study (Cmax, AUC0-t, AUC0-inf)

- multiple dose study (Cmax, AUC0-tau, Ctau)

- waived, if AUC0-tau = 90% AUC0-inf, tested at highest strength (+
partial AUCs)

- If More that 1 strength: Should be chosen based on PK linearity and safety

- Proportionality of formulations and bracketing approach
- safety: multiple dose study patients only

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Different dosage forms:
Transdermal Drug Delivery Systems (TDDS):

A generic TDDS is defined by having the same amount of active substance released per unit time as compared to the reference TDDS!

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Different dosage forms:
BE evaluation TDDS:
- single dose study (Cmax, AUC0-t, AUC0-inf)

- multiple dose study (Cmax, AUC0-tau, Ctau)

- waived, if AUC0-tau = 90% AUC0-inf, tested at highest strength (+ partial AUCs)

- strength: highest/most sensitive (proportionality in dosage form)

- safety: lower strength acceptable for size proportional formulations
- Take into account: local irritation, phototoxicity, sensitization, and similar
or better adhesiveness!

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Different dosage forms:
Creams/gels:

If systemically acting (e.g. testosterone gel):

- single dose study: AUC0-t and Cmax
- application site and area.

If locally acting:
- if possible, PK (safety)
- for safety: clinical study should be submitted (placebo
controlled?!)
- biowaiver: unlikely

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Different dosage forms:
Nasal spray:

solution:
- quality assessment/waiver
- justification difference excipients

suspension:
- quality data/ if waiver can be applied?! -> particle size, other
pivotal variables for comparison?
- bioequivalence study if feasible (with and
without charcoal)
- clinical study with sufficient assay sensitivity

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Different dosage forms:
Orally inhaled products (OIP):

solution:
- quality assessment/waiver
- difference excipients justified

aerosol suspension:
- quality/waiver?! -> particle size, other pivotal variables?
- bioequivalence study with or without charcoal -> no
charcoal in case of negligible oral absorption
- bioequivalence study with suitable spacer

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Different dosage forms:
Orally inhaled products (OIP):

dry powder:
- quality/waiver?! -> particle size, other pivotal variables?
- bioequivalence study with or without charcoal
- + in vitro comparable flow dependency fine particle dose
-> extrapolation healthy volunteers to patients (other
inhalation flow); possible in vivo evaluation

nebuliser:
- quality/waiver -> important type nebuliser

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