These are the exact types of questions that a pre-formulation screening
study is designed to answer. While protein chemistry may be able to predict
which elements should have a greater or lesser effect on the stability of a
protein product, you must conduct the study for verification and
quantitation of stability of your actual product. There are three main
elements in product formulation development: 1) evaluating the product's
degradation pathways, and identifying degradants, via forced degradation
studies, 2) verification of selected analytical methods to detect and
quantitate the degradants that may form from your product (via forced
degradation study and method validation), and 3) preformulation screening to
assess the utility of excipients, containers/closures, lyophilization
profiling, etc... using the stability-indicating methods from #2. Typical
preformulation screening protocols for protein products involve a
matrix-designed set of experiments that look at dozens of combinations of
excipients and storage conditions using 3-5 orthogonal stability-indicating
methods (e.g. RP-HPLC, SEC-HPLC, IEF, SDS-PAGE, peptide mapping).
Generally, this kind of study takes 3 - 6 months and is conducted before
Phase III trials.
Incidentally, there is an article on forced degradation of proteins in this
month's BioPharm. I haven't read it yet, but it looks like it might be a
good overview of the strategies and issues involved in stability assessment
for proteins. Also, there have been some conferences lately (and more are
coming in 2001) specifically addressing selection of excipients for
formulation of protein products. Finally, there is a good book on protein
formulation edited by John Bontempo (Development of Biopharmaceutical
Parenteral Dosage Forms, Marcel Dekker, 1997).
Actually, one of the conferences in 2001 (hosted by IBC; www.ibcusa.com)
will be chaired by John Bontempo and John McEntire, and will specifically
address protein formulation development and stability-indicating
biomolecular methods. As you might expect, protein-based pharmaceuticals
have significantly different needs versus traditional small molecule drugs
in the formulation matrices required to keep them happy and stable.
Bontempo and McEntire between them have experience with almost every
licensed biological product on the market, and many currently in
development, so this should be a good presentation of the issues. Both are
now independent consultants (not surprisingly!).
Nadine Ritter
BioReliance
> -----Original Message-----
> From: PAOLO BARTOLINI [SMTP:pbartoli@baitaca.ipen.br]
> Sent: Monday, November 27, 2000 11:38 AM
> To: Recipients of ABRF List
> Subject: stability of lyophilized proteins
>
> Does anybody have an idea on what is more critical for the stability of
> lyophilized proteins for human injection? We have products that last a
> little more than one year, being slowly degraded or altered, possibly
> with the formation of dimeric, deamidated or sulphoxidated forms. But we
> need 2-3 years stability. What is more critical? Type of excipient
> (glycine, mannitol, lactose, etc.), residual moisture, type of vial or
> stoppering, lyophilization conditions ?
> Thank you.
> Paolo Bartolini
> Biotechnology Department
> IPEN-CNEN/S“o Paulo-Brasil
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