What are the currently preferred methods of purification for synthetic APIs and API bioprocessing?
Peter Koklitis
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In processes that use a series of chemical reaction steps to synthesise the API, the removal of reaction by-products, including
colour bodies and metals, is critical to produce high quality pharmaceuticals. The preferred methods for removing residual
metal catalysts are distillation, crystallisation and precipitation. A distillation collects the pure API as a distillate,
leaving the non-volatile compounds in the residue, while crystallisation and precipitation steps both generate solid material
that can be physically removed by selecting a filtration step. In addition, both chromatography and activated carbon powder
treatments are used to exploit charge and adsorptive technologies for impurity removal.
In bioprocessing, whereby APIs are isolated and purified following clarification steps of mammalian or bacterial cell harvests,
a combination of affinity and ion-exchange chromatography are used in conjunction with filtration steps. Protein A coupled
to an agarose matrix is now widely used as an effective affinity column for the purification of monoclonal antibodies, while
anion-exchange chromatography is used for host cell impurity removal.
What are the latest significant innovations in API purification?
In synthetic API manufacture, the use of metal catalysts, such as Palladium, has increased from using convergent reaction
processes to prepare chemical fragments in parallel, which are coupled together to form the API. In these processes, there
is a choice to use either homogeneous (non-immobilised and dissolved) or heterogeneous (immobilised) metal catalyst systems.
For example, many reactions use Palladium bound to carbon (Pd/C), as these offer high surface area supports which are relatively
easily and inexpensively prepared.
Several companies have specialised in providing heterogeneous catalysts, such as using highly cross-linked microporous matrices,
which retain catalytic activity and enable the metal to be reclaimed and reused, but there are other examples where specific
functional groups on a polymer backbone or alumina have been used to attach the metal catalyst. Heterogeneous metal catalysts
bound to supports are easily separated by filtration after the reaction (e.g., Suzuki, Heck and Sonogashu), although leaching
of the metal may occur. The removal of metal residuals has resulted in the need to develop rapid screening devices to identify
suitable adsorbents. There are a wide range of adsorbents to consider for metal removal, e.g. activated carbon, functionalised
polymer resins, silica, diatomaceous earth, alumina and clay—the choice is dependent on the degree of selectively required
and cost of ownership.
In API bioprocess applications, there have been several recent innovations to provide single-use systems that enable modularisation.
For example, large-depth filter systems used in cell harvest clarification are now being considered as single use because
of developments in encapsulation technology. The desire to engineer modular processing units also exists for API synthetic
processes; a modular platform approach provides faster and easier scale up for new processes, with clear visibility of capital
and variable costs. These innovations also provide operational flexibility, while reducing equipment-cleaning issues at the
same time.
