All of these questions can affect the optimal formulation of a drug. For example, an early formulation question is whether
the product will be lyophilized (freeze-dried) or sold as a liquid. The advantages of a liquid include time savings, lower
cost, and ease-of-use for patients and clinicians, all of which are good sales points. But stability questions often make
freeze-drying necessary for protein and peptide pharmaceuticals. Freeze-dried drugs have a longer shelf life and better stability
for shipping and storage, even if they cost more and take longer to make.
For these reasons, the formulation team must communicate with other teams within the company right from the start: protein
biochemists, purification scientists, quality control and regulatory affairs personnel, clinical investigators, manufacturing
technicians, marketing specialists, and managers. There is a tendency on the part of upper management to rush a formulation
along into initial clinical studies with little or no stability data. This can be a costly move; FDA will stop any clinical
study where the formulation has lost or is losing its potency.
The seemingly endless variation of polypeptides makes them interesting as potential therapeutics, but it also makes them a
challenge to develop into products. Each protein is unique, and just as variation from protein to protein affects biologic
production and purification, so it is central to the formulation development process. Methods developed for one biopharmaceutical
are not always directly applicable to others. Similarly, it is quite likely that a formulation developed for one biopharmaceutical
may not provide the same level of stability for a different biopharmaceutical.
While there are numerous ways for a protein to lose its stability, the three most commonly encountered modes of denaturation
and degradation are aggregation, oxidation, and deamidation. The commonly accepted strategy for rational formulation development
relies on identifying mechanisms of denaturation and degradation in order to develop effective countermeasures. Once the specifics
of any particular degradation pathway are understood, a more informed choice regarding excipients and formulation can be made,
accelerating product development.
Using the scanning electron microscope
Characterization. Information gathering begins as soon as a molecule is chosen for development. Internal data sources include the research,
discovery, and analytical groups, along with the company's history with any similar molecules in development or on the market.
Formulators need to know the composition (amino acid sequence and molecular weight) and other characteristics of the protein
with which they'll be working, so they want to start with as much information as possible. External data sources include published
literature and other products already on the market. Talking to other formulators at industry meetings and conferences can
be a great help. One of the characteristics the formulator is trying to generate is the stability profile.
No matter where the process ends, preformulation begins with a study of the drug's pharmacokinetics and physicochemistry.
If the active molecule is not stable on its own, formulators can usually make it so by adding buffers or other excipients.
It's wise to choose a buffer that is familiar to regulatory authorities, easy to get from vendors and suppliers, and compatible
with relevant characteristics of the active molecule (such as pH range). Formulators may also choose other excipients to protect
the protein and enhance its stability — and these excipients also must be compatible with the necessary conditions, the buffer,
and each other.
Product concerns. As early as possible, formulators want to know the drug's indication, which is based on the drug's pharmacokinetic profile.
Early research should indicate where the drug travels in the body, what it will treat, and its site and method of delivery.
Formulators also need to know early on whether the product will be sold as a single dose or in multidose vials. Single-dose
formulations are easier to protect against contamination. Multidose vials, which are entered several times over several weeks,
can become contaminated, so preservatives must be chosen and tested for stability and compatibility with the protein.
International disagreement over preservatives in food and drugs may present a problem at this stage. US, EU, and Japanese
compendial standards differ regarding the timing of antimicrobial tests and which preservatives and excipients are allowed.
Japan, for example, does not accept phenol, a preservative used commonly in the US. So at this early stage, companies must
decide if and where their products will be distributed outside the US. The EU is known to have the toughest acceptance criteria
for preservatives. The International Conference on Harmonization is working toward a common standard, but many formulators
have criticized its slow progress.