On April 15, 2022, FDA published a Manual of Policy and Procedures (MaPP) that outlines the FDA thinking on what constitutes a complex drug product for purposes of classification. A MaPP, as you know, is not an industry tool, but rather an instruction to FDA staff as to the policy and procedure that they utilize in addressing a particular issue, a how to guide so to speak. MaPP 5240.10 (here) does just that.
While much of the information in the MaPP has been disseminated at various FDA meetings, webinars, and presentations, this 13-page document has a treasure trove of information about how the agency views complex products and gives the reader a window into how the products are handled within the Office of Generic Drugs and the Office of Product Quality.
It provides FDA’s definition of a complex active pharmaceutical ingredient (API) as follows:
“A complex API is often a mixture of different components and can contain a distribution of molecular weight. Any product whose labeling indicates that it is a mixture of active components or whose chemical structure formula includes repeating structure units or a range of molecular weights is considered complex. A naturally derived product containing a mixture of components is also often classified as a complex API.”
and provides some examples:
APIs that are mixtures of different components (from both semi-synthetic and natural sources) with different chemical formulas, such as:
– Conjugated estrogens, heparin, and low-molecular-weight heparin (e.g., dalteparin sodium and enoxaparin sodium)
– Botanic drug products (e.g., crofelemer)
– Complex oils and oil-derived products (e.g., omega-3 acid ethyl esters and ethiodized oil)
APIs that have a distribution of molecular weight or structures, such as:
– Synthetic polymers (e.g., colesevelam hydrochloride, patiromer sorbitex
calcium, icodextrin, pentosan polysulfate sodium, sevelamer carbonate, and
– Metal complex drugs (e.g., ferumoxytol)
Peptides with no greater than 40 amino acids (AAs) having complex higher-order
structure and/or potential immunogenicity concerns are also considered as
complex APIs (e.g., liraglutide, calcitonin).
– Oligonucleotides (e.g., eteplirsen, nusinersen)
The MaPP discusses what a complex route of delivery is and contains an appendix that identifies the routes that are going to place the drug into the “complex” category. It also defines and provides examples, complex dosage forms and formulations as well as drug-device complex products.
FDA suggests early engagement if a sponsor wants to pursue any of the complex products especially if the sponsor does not have familiarity filing a complex product of a similar type in the past.
Don’t let this MaPP slip by as it gives you the direction you will need to travel to keep yourself on a steady course.