SCIENTIFIC DISCUSSION
Product Name: Genta Equine 10% Solution for Injection
MA Holder: Franklin Pharmaceuticals Ltd
I.
INTRODUCTION
Genta Equine 10% Solution for Injection produced by Franklin Pharmaceuticals contains 100mg
of gentamicin (as gentamicin sulphate) per ml. The product has been designed for use in
horses to control severe bacterial infections sensitive to gentamicin, including Pseudomonas
aeruginosa, Rhodococcus equi and Salmonella spp. The dose for adult horses is 6.6mg per kg
bodyweight (3.3ml/50kg bodyweight), introduced by slow intravenous or intramuscular injection.
In foals, Genta Equine is to be used at 7mg per kg bodyweight, (3.5ml per 50kg bodyweight),
introduced as described for adult horses. Dosing may be repeated at twenty-four hour intervals,
and higher or lower dosing may be used based on the results of therapeutic drug monitoring.
To ensure correct dosage, bodyweight should be calculated as accurately as possible.
Susceptibility testing of the target organism should be performed. If this is not possible, therapy
should be based on local, (regional, farm level), epidemiological information with regard to the
susceptibility of target bacteria. The product is not to be used in horses intended for human
consumption, and horses must be declared as not intended for human consumption.
This application for a National Marketing Authorisation, was made with reference to a generic
product, Gentaject 10% Solution for Injection, also produced by Franklin Pharmaceuticals. The
application was made with regard to Article 13 (1) of Directive 2001/82/EC, as amended by
Directive 2004/28/EC. Gentaject 10% Solution for Injection has been authorised in Ireland for
more than 10 years. Exemption from bioequivalence studies was claimed under exemption
article 4.c of the Guidelines for the Conduct of Bioequivalence Studies for Veterinary Medicinal
Products, EMEA/CVMP/016/-corr-FINAL. Identical quantitative and qualitative
composition was claimed, in addition to identical formulation and manufacturing processes.
II.
QUALITY ASPECTS
Product Development and Composition
The product is bioequivalent to the reference product, Gentaject 10% Solution for Injection,
therefore the manufacturing process is the same and is GMP compliant.
A test was performed to check the sterility of the product which entailed filling the glass vials
used to hold the product with tryptone soya broth, known to encourage the growth of a variety of
bacteria. The broth was placed in a pre-sterilised holding vessel for fifteen hours, and then
poured into the glass vials and kept at approximately 30oC for two weeks. No bacterial growth
was seen in the vials, and this was considered a satisfactory validation test.
Three production scale batches of 500 litres of product were produced and satisfactorily tested
with regard to stability and effectiveness of filtration. The product was observed for bioburden
prior to filtration, and for levels of the active ingredient and excipients at the beginning and end
of the manufacturing process. pH levels, fill volume, product stability and environmental
monitoring were all satisfactory. There are no intermediate products.
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SCIENTIFIC DISCUSSION
Product Name: Genta Equine 10% Solution for Injection
MA Holder: Franklin Pharmaceuticals Ltd
Active Substance
The active substance in Genta Equine 10% Solution for Injection is gentamicin (as gentamicin
sulphate). This active substance is monographed in the European Pharmacopoeia (Ph. Eur)
and is commonly employed for veterinary use. Gentamicin sulphate is bactericidal in its effect,
acting on the bacterial ribosome, where protein synthesis is inhibited and translation of the
genetic code is depleted. Transport of gentamicin appears to be linked to electron transport,
oxidative phosphorylation and respiratory quinones in the cell membrane. Antibacterial activity
is directed primarily against Gram-negative bacteria.
Other Substances
Excipients used in Genta Equine 10% Solution for Injection are sodium methyl
parahydroxybenzoate and sodium propyl parahydroxybenzoate (preservatives), sodium
metabisulphate (antioxidant), trisodium citrate (pH regulator), EDTA (chelating agent), citric acid
monohydrate (pH regulator), and water for injection. All excipients are monographed in the Ph.
Eur, and all are commonly used in veterinary medicines.
No class 1 residual solvents are present in any excipients. Where class 2 or class 3 solvents
are present, these comply with the International Cooperation on Harmonisation of Technical
Requirements for Registration of Veterinary Medicinal Products (VICH) limits.
Packaging Materials
Genta Equine 10% Solution for Injection is presented in 100ml volume, clear type II glass vials,
sealed with a bromobutyl rubber bung and an aluminium overseal. The glass vials and bungs
components comply with the Ph. Eur, and the aluminium seals are satisfactory.
The vials are sterilised by dry heat at approximately 280oC for seven minutes, and the rubber
bungs and aluminium seals are sterilised by gamma irradiation at a minimum of 25 KiloGray
(kGy). All procedures are considered satisfactory.
Manufacture of the Finished Product
Water for injection is placed in a mixing container, to which all excipients apart from citric acid
are added. The ingredients are then mixed until a homogeneous solution is achieved. The
active ingredient, gentamicin sulphate, is added to the mixing container, and the product is
again mixed to homogeneity. The pH of the solution is tested, and adjustment made if
necessary with citric acid. Remaining water for injection is added to bring the quantity of
product up to the specified level, and a sample is then sent for analysis prior to being then filter
sterilised and packaged. The final batch quantity is 500 litres.1
Finished Product Quality Control
The finished product is analysed for appearance, pH, relative density, fill volume, sterility and
amounts of active substance and excipients. Where applicable, all analyses follow the
requirements of the Ph. Eur. Data on batch analysis for four production scale batches were
provided, these showed compliance with the proposed release specification. There was no
requirement to test for endotoxins. Satisfactory data for the sterility method used were received.
1
Due to a Variation Procedure to add a manufacturing site, the batch size increased to 2000 litres.
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SCIENTIFIC DISCUSSION
Product Name: Genta Equine 10% Solution for Injection
MA Holder: Franklin Pharmaceuticals Ltd
Stability of the Product
Active substance
Stability data for gentamicin were provided in accordance with VICH guidelines. Three batches
of the active ingredient were stored for up to four years at 25oC/60% RH, and a further three
batches were stored at 40oC/75% RH for three months. The batches stored were of production
scale (500 litres), and the packaging was a smaller version of the packs to be marketed. In real
time conditions, it was demonstrated that the active substance was generally stable, with a
small increase in water content. However, under accelerated conditions, water content
increased significantly.
A retest period of four years, and storage below 25oC was
recommended.
Finished Product
Stability studies were performed on three production level batches, (stored in the packaging to
be marketed), for up to twenty-four months at 25oC/60% RH. An additional study observed the
same product parameters for up to six months at 40oC/75% RH. Description of methodology
and subsequent validation were satisfactory.
In-Use
The pH of Genta Equine 10% Solution is maintained at between 3.0 and 4.5, conferring good
stability on the product. Unopened, the product has a designated shelf life of two years and the
in-use shelf life of the broached vial is 28 days. The product is to be protected from light.
CONCLUSIONS ON QUALITY
A declaration was made by the Marketing Authorisation Holder that no materials used in the
manufacture of the product come under the scope of the transmissible spongiform
encephalopathies (TSE) guidelines.
Descriptions of the manufacturing process and in-process controls were considered to be
satisfactory. Process validation is generally satisfactory and covers the process parameters,
aseptic manufacture and filter compatibility.
Information provided on the supplier of gentamicin is satisfactory and the active is supplied
against a current certificate of suitability. Batch analysis data were all satisfactory, and all
excipients are commonly used in veterinary products and have Ph. Eur monographs. Data
provided for each excipient was satisfactory, as was all information provided concerning
packaging materials.
III.
SAFETY ASPECTS
Introduction
This Marketing Authorisation was granted in accordance with Article 13.1 of Directive
2001/82/EC, by demonstrating that Genta Equine is chemically equivalent to Gentaject 10%
Solution for Injection, registered in Ireland under VPA 10976/2/1. The formulation and
Page 3 of 5
SCIENTIFIC DISCUSSION
Product Name: Genta Equine 10% Solution for Injection
MA Holder: Franklin Pharmaceuticals Ltd
manufacturing process of the product is identical to the reference product, therefore, no
pharmacological or toxicological data were required for bioequivalence tests.
The product is not to be used in pregnant horses, or in animals intended for human
consumption. Genta Equine is not to be used in cases of known hypersensitivity to the active
substance, or in cases of known renal impairment. The product should not be used for more
than five days without biochemical confirmation of normal renal function, and is not to be used
with other amino glycoside antibiotics. It should be noted that repeat injections may cause
reactions at the site of injection.
Pharmacology
The application is in accordance with Article 13.1 of Directive 2001/82?ec as amended by
Directive 2004/28/EC and therefore the applicant is not required to submit results of
pharmacological and toxicological studies and clinical trials.
Toxicology
The application is in accordance with Article 13.1 of Directive 2001/82?ec as amended by
Directive 2004/28/EC and therefore the applicant is not required to submit results of
pharmacological and toxicological studies and clinical trials.
Residues
The product is only for use in horses not intended for human consumption, therefore no
residues data was required.
Environmental Safety
A satisfactory Phase 1 Risk Assessment was provided. There will be minimal exposure of the
environment to the product, (via slurry or manure), from only a small number of animals. This
qualification falls under question 5 of the Phase 1 Guideline, (CVMP/VICH/592/98-final). Any
unused product or waste material should be disposed of in accordance with national
requirements.
CONCLUSIONS ON SAFETY AND RESIDUES
Conclusions on User Safety
There are no special precautions for user safety.
Conclusions on Consumer Safety
Not applicable.
Conclusions on Environmental Safety
Environmental safety is satisfactory.
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SCIENTIFIC DISCUSSION
Product Name: Genta Equine 10% Solution for Injection
MA Holder: Franklin Pharmaceuticals Ltd
IV.
CLINICAL ASPECTS
Introduction
Bioequivalence is claimed with Gentaject 10% Solution for Injection, the product is therefore
exempt with regard to the provision of data for pre-clinical and clinical trials.
Clinical Pharmacology
Pharmacodynamics
A basic description of the pharmacodynamics of gentamicin was provided. Refer to ‘Active
Substance’ in this document.
Pharmacokinetics
A brief description of the action of gentamicin was provided which explained that the active
substance is poorly absorbed from the gut, and so must be delivered parenterally for effective
systemic action. Gentamicin is readily absorbed from intramuscular injection, reaching peak
plasma concentrations at 0.5-2.0 hours after administration. Elimination is primarily by
glomerular filtration, thus the product is rapidly excreted in the urine.
Tolerance in the Target Species
Resistance
Bioequivalence is claimed with Gentaject 10% Solution for Injection, therefore the claimed
exemption from the need to provide resistance data was acceptable.
Clinical Efficacy
Bioequivalence is claimed with Gentaject 10% Solution for Injection, therefore the claimed
exemption from the need to provide clinical data was acceptable.
CONCLUSIONS ON CLINICAL ASPECTS
PART V.
OVERALL CONCLUSION ON THE PRODUCT
The data submitted in the dossier demonstrate that when the product is used in accordance
with the Summary of Product Characteristics, the benefit risk profile for the target species is
favourable and the quality and safety of the product for humans and the environment is
acceptable.
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