Sterile Injectable Diagnostic Agent
This project spanned a 1 year period and
we managed every aspect of the the CMC activities included
preparing the final Module 3 for the IND filing. The
client came to us with an FDA clinical hold letter due to
insufficient characterization data to progress to Phase 1b
studies. The goal was to get this compound back into
the clinical and progress to Phase 2-3 for a partner
buy-out. Additionally, while the Technetium-complexed
ligand (active drug ingredient) was stable in water, the
active ingredient ligand had only a 30 minute half life in
water. Additionally ligand (API) storage conditions must
be at -78 oC to maintain stability of API.
Identified Synthesis CRO and
developed a route to active ligand to make sufficient
material and suitably characterized the ligand which
was a complex mixture of 4 equilibrating isomers
Identified and liaisoned with an
academic expert in technetium 99m development to
obtain LC-MS on the putative active Tc99m complex
claimed in the patent thus proving unambiguouslty
structure of active ingredient for FDA.
Managed both API and Drug Product
activities; initiated RFPs, managed CROs to ensure
analytical and manufacturing controls were sufficient
to support a Phase 3 clinical trial.
Wrote entire drug substance and
product Module 3 summarizing the activities of the last
year and provided the CMC amendment along with the
proposed clinical Phase 2-3 protocol
A compound that had been on clinical
hold for 3 years and through multiple CROs who were
unsuccessful was finally brought under control and turned
into a well-characterized, well-understood,
commerciallizable drug substance and drug product (sterile
vial kits) in the span of 1 year. The CMC filig
submitted along with the Phase 2-03 clinical protocol and
the FDA removed
the clinical hold and the compound has now completed a
successful Phase 3 trial and no more CMC
activities are currently required. The company is
currently negotiating large pharma deal.
Capsule Formulation Development
Client was developing 'powder in
capsule" and capsules failed stability after 8
months. Capsules were falling apart.
Identified source of capsule
failure. After developing an investigative
strategy, and performing the suggested experiments, it was discovered that API lot associated
with failed capsules was amorphous and
hygroscopic. Water was leached from gelatin capsules
leading to cracking and failure.
API was re-crystallized to obtain
crystalline material to match previous batches (less
Specifications were put in place to
control physical form
New capsules were identified that are
hydroxycellulose based and more resistant to
CMC amendment filed
New capsules are successfully being used
and new API specs and capsules ensure reproducible and
stable capsule batches.
Pre-Formulation Salt Selection (Pre-IND)
A pre-IND lead compound was identified
and was found to be superior in all respects to other
leads yet remained
undevelopable as it presented itself as an oil. The client did not want to develop as an oral gelatin
solution formulation and wanted to explore salt formation
to generate a stable solid API that could be tabletted. A Fortune 20 API CRO
worked to obtain a solid salt form unsuccessfully and
eventually gave up on this task stating it to be not
possible. The client came to us with the
A lead compound that was previously
abandoned due to physical property issues was brought
back into life. A patent is pending on this compound
on the process developed by TRIPHASE principals and
the result is now a druggable lead has been identified.
This success was 100% attributable to TRIPHASE
identifying the appropriate solvents to achieve success
where CROs had failed.
Clinical Hold (Genotoxic Agent
Client came to us
on clinical hold. The following reasons were cited
in the letter from the FDA:
Synthesis reagent was alkylating
agent and potential genotoxic agent. Either this
reagent must be removed or suitable analytical
tecnigue must be
developed and levels must be shown to below allowable
Drug product showed stability issues
and 2 impurities at 0.2% indicated potential
"structure alert' as genotoxics.
Developed and validated a suitable
compliant analytical method to test for levels of
genotoxic agent reagent AND levels were shown to be within
allowable limits for a 1 month clinical trial (120 ppm).
It was observed that the HCl portion
of the molecule reacted with the molecule which led to
the potential genotoxic agents which were also
"uncontrolled". A "free-base' form of
drug was therefore developed to avoid stability issues associated with
The potential genotoxic degradants
were Isolated and tested in AMES test and confirmed not
An amended CMC was submitted for drug substance
and drug product including new methods and data. The
compound removed from clinical hold and studies are
HERE TO READ OUR WHITE PAPER ON GENOTOXIC AGENTS...
Sterile Injectable Drug (ANDA/DMF)
Patent expiration was pending on a marketed diagnostic
product. Active ingredient supply chain was
dominated by several large players. The goal was to
develop a process and manufacture the active ingredient and
drug product vials and obtain an approvable ANDA.
A new synthesis was developed in the
lab and demonstrated on a multi gram scale. RFPs
were preapred and small-scale API manufacture was identified
and registration stability batches were manufactured
Drug product kits were designed based
on marketed cardiolite kits and 3 registration
stability batches were produced.
Wrote DMF Type II and the ANDA was
The ANDA was approved for the product.