FDA BE Guidance – Injectables

To facilitate generic drug product availability and assist generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating evidence needed to support ANDA approval, FDA publishes product-specific recommendations describing expectations on how to develop generic drug products therapeutically equivalent to specific reference-listed drugs. After more than a decade in action, this tool has been tremendously helping the generic industry by providing clear guidances on designing clinical or in vitro BE studies.

Generally, the recommended studies are one or combination of the following categories: pharmacokinetic, pharmacodynamics, clinical end point, and in vitro studies. If a bio-waiver is possible, the recommendation will provide the requirement for submission of bio-waver. The list of BE guidance is constantly updated with new recommendations and revisions.

In this article, I selected injectable products listed on the FDA website as of July 2017.

Active Ingredient Dosage Form;

Route

Recommended Studies
Amphotericin B Liposome injection; intravenous in vivo PK

in vitro Liposome size distribution

Aripiprazole Extended-release injectable suspension; intramuscular in vivo PK
Azacitidine Injectable/Intravenous; Subcutaneous in vitro Physico-chemical Characteristics, Particle Morphology, Particle Diameter
Betamethasone Acetate; Betamethasone Sodium Phosphate Injectable Suspension/Injection in vivo PK
Dalteparin Sodium Injectable/Subcutaneous 1. Equivalence of physicochemical properties

2. Equivalence of heparin source material and mode of depolymerization

3. Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species

4. Equivalence in biological and biochemical assays

5. Equivalence of in vivo PD profile

Daunorubicin citrate Liposome injection/Intravenous in vivo PK

in vitro Liposome size distribution

Doxorubicin hydrochloride Liposome injection; intravenous in vivo PK

in vitro Liposome size distribution

Enoxaparin Sodium Injectable/Subcutaneous 1. Equivalence of physicochemical properties

2. Equivalence of heparin source material and mode of depolymerization

3. Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species

4. Equivalence in biological and biochemical assays

5. Equivalence of in vivo pharmacodynamic (PD) profile

Ferric carboxymaltose Injectable; intravenous in vivo PK

in vitro Particle size distribution

Ferumoxytol Injectable; Injection in vivo PK

in vitro Particle size distribution

Fulvestrant Solution; Intramuscular Q1/Q2 bio-waiver
Glatiramer acetate Injection; Subcutaneous 1. Equivalence of fundamental reaction scheme;

2. Equivalence of physicochemical properties including compositions;

3. Equivalence of structural signatures for polymerization and depolymerization; and

4. Equivalence of biological assay results.

Goserelin Acetate Implant/Subcutaneous in vivo PK
Iron dextran Injectable; injection in vivo PK

in vitro Particle size distribution

Iron Sucrose Injectable; Intravenous in vivo PK

in vitro Particle size distribution

Lanreotide Acetate Injectable; Subcutaneous Option 1: Q1/Q2 biowaiver

Option 2: in vivo PK

Leuprolide Acetate Injectable in vivo PK
Leuprolide Acetate Injectable Depot in vivo PK
Medroxyprogesterone Acetate Suspension/Intramuscular in vivo PK
Methylprednisolone acetate Suspension; injection in vivo PK
Naltrexone Extended-release suspension; intramuscular in vivo PK

Dissolution test

Octreotide Acetate Injectable/Injection in vivo PK
Olanzapine pamoate Extended Release Suspension; intramuscular in vivo PK
Paclitaxel Suspension/Injectable in vivo PK

in vitro Particle size distribution

Paliperidone palmitate Extended Release Suspension; Intramuscular in vivo PK
Phytonadione Injectable/Injection in vivo PK
Propofol Injectable; injection Option 1: in vitro option

i) Q1/Q2

ii) comparative physicochemical characterization

iii) comparative in vitro drug release rate tests

Option 2: in vivo PK

Risperidone Injectable; intramuscular in vitro drug release

in vivo PK

Sodium Ferric Gluconate Complex Injectable; Injection in vivo PK

in vitro Particle size distribution

Triamcinolone Acetonide Suspension/Injectable Q1/Q2 and in vitro dissolution
Triptorelin Pamoate Injectable/Intramuscular in vivo PK
Verteporfin Liposome injection/Intravenous Option 1: in vitro option

i) Q1/Q2; ii) equivalent liposome characteristics

Option 2: in vivo PK

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