- [Bapu] Welcome everyone.
I'm Bapu Gaddam Quality Reviewer
from Division of Lifecycle API.
In this presentation I will discuss
a word recommended documentation for API sameness
for synthetic therapeutic polymers,
Specifically cross-couple polymers.
For the approval of gender drugs,
the API sameness is required
to show pharmaceutical equivalency.
It is considered same API as RLD,
if it possess same physical
and chemical characteristics as RLD.
I will be showing a few examples of cross-couple polymers
and discussing the way to approach
to determine the API sameness
of this kind of complex molecules.
This is the title of the poster presentation.
Synthetic Therapeutic Polymers:
Recommended Documentation for APA sameness.
In this slide I'm showing three examples
for a cross-couple polymers.
In cross-couple of polymers,
two or more polymer chains are coupled together
with linked up portions.
Here, the first example,
sevelamer which is derivative of polyallyamine
cross-coupled with epichlorohydrin.
Colesevelam hydrochloride,
they are additional alkylations
in addition to the cross-coupling of polyallylamine
with epichlorohydrin.
There are two types of cross-coupling in Patiromer
additional patiromer and is complex with calcium sorbitex.
I just give a little background.
There were these three molecules.
All of these three examples are FDA approved drugs.
Currently sevelamer and colesevelam
are approved generic equivalents.
Sevelamer is approved as Carbonate salt
and Hydrochloric salt for treating hyperphosphatemia.
Coselevelam Hydrochloride is approved
as cholesterol lowering agent.
Patiromer is scavenger of potassium
and used to lower blood potassium levels.
As discussed in previous slides,
these molecules have complex chemical structures.
There's a molecule show following properties.
Each particle is considered as one molecule.
And molecular weight is depending on the particle size.
So there is no fixed molecular weight for these molecules.
However, the molecular formula can be derived.
The API contains heterogenous complex mixtures
of small molecules
and treat it as a single active ingredient.
In general cross-couple polymers
are not soluble in any solvent.
These drugs are not absorbed.
The activity of these drugs is scavenging.
The intended activity happens in gastrointestinal tract.
Hence characterization using traditional methods
to establish API sameness is difficult.
Each complex molecule possess different properties
and challenges.
Hence the base was to determine API sameness
for each complex API is also a different.
So, hence the totality of evidence approach
is a recommended for API sameness cross-couple of polymers.
In this strategy, the information and fashioning process,
such as selection, starting materials,
control off intermediates,
characterization of intermediates,
is used to establish API sameness.
The orthogonal methods are used to come from the
structure signatures of the final API.
Usually it is dark on multiple lost to show consistency
from batch to batch.
The impurity profile should be assessed
and justify the limits in FDA
as well as any chemicals used in the process.
Such as starting materials and intermediates.
In-vitro biological activities
considered to establish API sameness.
They are required to provide the justification
for analytical methods
used for the characterization of APIs and Intermediate.
To establish the equivalent,
it's recommended to use at least three bases of data
with at least three batches of RLD.
So as I discussed the manufacturing processes,
also one of the parameter in the API sameness,
are discussed [indistinct]
principles to consider manufacturing process.
That equivalent starting material
expected to provide equivalent structural signatures
of the molecule.
The applicant process should contain
same chemicals proposed in the product label
for Sevelamer and Colesevelam.
If other materials are used,
justification should be provided.
Once cross-coupling is done,
the material is not soluble in any of the solvents.
Hence unwanted structural fragments
cannot be identified after cross-coupling.
If they are present,
proper controls for impurity should be established
for the starting materials intermediates
and then used in the process.
So, that unnecessary reactions won't happen.
So, suppose if polyallylamine present some,
react to amine groups which are addition to polyallylamine.
They may react with epichlorohydrin
and can give some impurities which cannot be identified.
The amount of cross-coupling reagent
used into reaction can have effect on
the degree of cross-coupling.
Similarly, the amount of alkylating agents
in proposed reaction conditions
can affect the percentage alkylations.
And some manufacturing conditions like CPP,
should be established with appropriate
amount of cross-coupling reagent and alkylating agents
to get the proposed structure.
Demonstrate the analytical methods are suitable to use
for IPC and CPP and other analysis of KSM and intermediates.
Establish adequate release and stipulated specifications,
including input their profile for API
based on that data obtained for API
extracted from RLD.
Batch data in at least three batches is required
to show consistent process.
manufacturing process should be
in compliance with cGMP regulations.
So, the characterization can be discussed
as characterization of intermediates
and characterization of final API.
In the preparation of Colesevelam,
there are at least two intermediates,
polyallylamine and cross-couple polyallylamine.
Polyallylamineis the backbone for Sevelamer and Colesevelam.
And the final API,
the properties of polyallylamine cannot be determined.
It's appropriate controls for polyallylamine,
such as molecular weight should be established
at intermediate stage on polyallylamine.
Due to complexity of NMR,
The degree of cross-coupling is difficult to establish
on final API.
It is recommended to evaluate the degree of cross-coupling
on cross-coupled polyallylamine intermediate,
using solid state NMR and other analytical methods.
The cross-coupled polyallylamine
is the final API in Sevelamer.
The degree of cross-coupling in Sevelamer
and Colesevelam are different.
Additionally, other characterization methods
such as IR, Elemental analysis,
TGA, DSC,
should be compared for batch to batch consistency
after intermediates.
And these tests also can be used to compare
degree of cross-coupling.
It is recommended to use at least three batches of data
to show consistency of intermediates from batch to batch.
In addition to the optimizer process parameters
and quality of intermediates,
Orthogonal methods are recommended
to compare structural signatures
of API with API in the RLD.
There are methods recommended,
are generally IR elemental analysis,
Solid state NMR,
TGA DSC, Total titrable amines,
swell index and others.
And these tests, also provide the information
on degree of cross-coupling
and degree of alkylation.
Hence these tests can be used during the process
to element also.
Other physical chemical properties,
such as physical form, particle size distribution,
bulk density, tapped density,
swelling ratio, surface morphology, compressibility
and other should be also compared.
Comparable in-vitro bile acid binding study for Colesevelam,
phosphate binding study for Sevelamer,
potassium binding study for patiromer
are to show these molecules
have similar scavenging property as RLD.
Compare data in front at least three batches of API
and three batches of the API in RLD,
to assure the consistency and equivalency.
As discussed to establish the API sameness
for cross-couple polymers,
totality of evidence approach should be used.
Development studies are needed to establish the quality
of basic polymeric chain,
amount cross-coupling reagent.
And amount of alkylating agents and reaction conditions
The API Should be compared with API obtain from RLD
to proposed API, is highly similar to RLD.
Compare In-vitro biological activity to support
the proposed API similar scavenging properties
as are RLD.
provide necessary literature support when needed.
These other references if you would like to refer,
the product specific guidance is from FDA
are available for Sevelamer and Colesevelam.
Thank you for your time.
And if you have any questions or comments,
please send them to the email address on this slide.
Looking forward to see you at the workshop in March.