NONPARENTERAL DRUG PRODUCTS
Although currently a relatively small percentage, more biopharmaceuticals are being developed for indications such as wound
healing or certain allergies that would require topical or local administration. A growing number of monoclonal antibody (MAb)
derived molecules also are being developed. This is a trend that is expected to increase. Although MAbs have many benefits
as therapeutic agents, the development of full-sized MAbs is not without significant challenges and disadvantages, from the
high cost of goods, to the limited options for delivery to patients. The development of smaller MAb fragments offers the possibility
of alternative routes of administration, which, in turn, require the development of suitable formulations.
Manufacturing a nonparenteral dosage form requires the consideration of other factors that would not arise with the manufacture
of parenteral drug products. These factors include the required form of the drug substance (solid or liquid), differences
in the approach to formulation development, revalidation of analytical methods, and manufacture.
Requirements of the Drug Substance
For parenteral preparations, the drug substance will be provided in a liquid form, which may need to be reformulated for the
drug product. With other more conventional dosage forms, the drug substance may have to be supplied as a solid for use in
manufacture. This raises two questions for the innovator organization.
First, the solid form for the drug substance must be considered. Is it best to supply the drug substance as bulk lyophilized
or spray-dried material? Is the drug substance sufficiently stable so that it can be processed into the required solid form?
It may be that the importance of selecting the most appropriate solid form of the drug substance for a given program must
to be established on a case-by-case basis, taking into account both the ability to formulate and manufacture the drug substance
into the solid and the compatibility of the bulk solid form with the formulation and manufacture of the required dosage form.
This is an area that is relatively uncharted and could therefore pose unknown challenges.
The second question is whether the biopharmaceutical drug substance manufacturer has the capabilities to produce the required
(intermediate) form of the material in the quantities required for clinical trials supply and beyond.
Requirements for Formulation Development
These formulations are likely to be more complex than the relatively simple buffer systems typically developed for parenteral
products. It is very unlikely that a drug substance manufacturer will have the expertise and the capabilities to formulate
a wider range of dosage forms. In this situation, the formulation development and subsequent activities, including re-validation
of the analytical methods, would be best placed with a CMO which has the required specialist capabilities.
Analytical methods for nonparenteral dosage forms will almost certainly need to be redeveloped and revalidated. In all likelihood,
the formulation will not be readily compatible with the methods commonly used for protein analysis. There is a strong possibility
of matrix components interfering with the analysis. The development of a suitable method of extraction of the drug substance
from the matrix also may be required. The innovator organization may be faced with a choice in relation to where the method
(re-)development and (re-)validation activities for drug product are now best carried out.
If the initial method development and validation for drug substance have already been carried out by an analytical contractor
laboratory or a drug substance CMO (models 1 and 2 in Table 2, respectively), then the cost and time taken for methods transfer
to a drug product CMO (model 3 in Table 2) must be assessed against the potential benefit of bringing together all of the
drug product development and manufacturing activities under one roof.
Currently, it is unlikely that a drug substance CMO also will have the capabilities to manufacture drug product for clinical
trials in the potentially wide range of formulations or presentations that may be required for nonparenteral dosage forms.
For parenteral products, the final step of drug substance manufacture would involve concentration and exchange into a suitable
buffer. Typically, the drug substance solution can then be filled directly into vials, requiring dilution with the formulation
buffer beforehand. The additional manufacturing capabilities required for the production of nonparenteral dosage forms are
likely to be beyond those that are to be found with drug substance CMOs.