Product and Challenge:

The product was an Anticancer drug (NCE) and the challenge was to find a suitable vehicle for oral gavage study in beagle dogs.

Solution:

• Identified challenges with respect to the properties of the test compound (NCE), especially considering that dog was the test animal.
• The compound had unique properties which created a challenge in dose preparation.
• Dog is an animal which tends to vomit, when it finds the medicine unacceptable, especially considering their strong sense of smell.
• Based on the properties of the NCE we developed a unique formulation which was acceptable to the dog. A day of dosing was undertaken in multiple dogs to ensure that the formulation was well received.

This ensured smooth conduct of the study with no challenge, with respect to the development of formulation or emesis in the dogs.

Study:

Repeat Dose through intravenous route of administration  for a product for prevention and treatment of secondary hyperparathyroidism

Challenge:

Preliminary test indicated formation of erythema and swelling at the site of injection followed by necrosis.

Solution:

• The preliminary test on the animals was undertaken under the guidance of an animal welfare officer
• The problem, along with a possible solution based on our past experience, was discussed with the sponsor. We explained that the effect could be attributed to a certain co-formulant and advised them about the options.
• The sponsor modified the formulation as advised by us. The improved formulation did not show any symptoms of erythema and swelling.
• The 28 days study was successfully conducted following EMA as well as USFDA guidelines. This study was well received by the regulators.

Study:

Repeat dose toxicity study of an impurity formed during storage for an anti-cancer compound

Challenge:

Dose calculation

Solution:

• Literature Search for the reference drug and the impurity
• Characterisation of the degraded impurity
• Considering the body weight as well as surface area for the animal as well as the maximum level of impurity exposure
• An algorithm was set for calculation of the dosage to be delivered to the individual animals based on their body weight.

The algorithm worked very well during the course of the study and the purpose of the experiment (arrive at NOAEL) was successfully achieved. The study was well received.

Challenges:

• The test item posed a problem for this particular study due to its being a low melting solid.
• Preparing the test substance with an appropriate dosage delivery for the inhalation study was found to be challenging on account of this property

Solution:

• A unique process was used to ensure generation of aerosol of appropriate particle size consistently during the exposure.
• This was validated by running a “dry” test, i.e., without animals for 5 days.
• Once this was validated actual animal exposure study was undertaken.

The study was successfully completed with uniform particle size at desirable concentration maintained at all dose levels in the individual exposure chambers. This was successfully achieved for the duration of the study. The purpose of the experiment (arrive at NOAEL) was successfully achieved.

Challenges:

• The reported LC50 in an acute study was in micro gram per litre.
• The formulation was a dry powder not amenable to generate aerosol using dust generators
• This necessitated development of unique process for generating aerosols of a certain particle size as well as achieving a substantially low LC50 as compared to the literature value

Solution:

• Several conventional approaches were explored to generate the aerosols with almost no success.
• We considered the physico-chemical characteristics including surface properties of the test compound to find a solution to this problem.
• We identified an equipment which was routinely used for a completely different application.
• The test item was suspended in the appropriate vehicle and the same was fed into the above equipment to ensure uniform generation of aerosols.
• Several trials were undertaken to optimize the parameters under which we could generate uniform aerosols at the challenging concentration.
• This process was GLP validated by undertaking 7 day “dry” runs after establishing the achievement of the concentration of the desirable particle size.
• GLP exposure with rats was undertaken for 28 days establishing the particle size and concentration on each day of exposure.

This study was successfully conducted and well received by the sponsor as well as regulators. The sponsor went on to provide us with the testimonial that they had approached several CROs who refused to continue with the study due to the challenges faced.