Speciality Chemicals Magazine MAR / APR 2024 | Page 30

PHARMACEUTICALS

surfaces . A validated analytical method with suitable sensitivity must be developed for each compound .

With these tools in place , a sampling protocol must be established that will collectively define the state of cleanliness for the entire isolator . The safety limit for each potent species was determined on the basis of the OEL , volume and surface areas of the isolators , and applying correction factors , to link the amount present on the surface and the OEL data . 3

For our particular design , more than 30 critical sampling points were defined for each isolator , with procedure defined for the different surfaces ( stainless steel , gloves and glass ). With these procedures and analytical methods , it is possible to assess the residual potent compounds on the specific swabbed areas and then these data can be extrapolated to the entire isolator . Once it is confirmed that the isolators are cleaned to values below the defined safety limit , the isolators can be opened .

Case study : Olaparib

Recently , Cambrex selected Olaparib ( Figure 2 ) to be included in its generic APIs portfolio . Olaparib is a PARP inhibitor that was approved in 2014 for the treatment of some forms of breast , ovarian , and prostate cancers . 3 Literature data were used to assign an OEL of 1-10 µ g / m 3 .

After the selection of the target API , an extensive analysis was performed , to define the preferred manufacturing strategy . The analysis included an assessment of the IP landscape , the various published synthetic routes , and the availability of potential building blocks at commercial scale . On this basis , the final route of synthesis ( RoS ) was selected for development ( Figure 2 ).

Next , we analysed which intermediate in the selected RoS should be considered as the first highly potent species , thus requiring high-containment isolators . Biological activity and toxicity were available for the API and for the last intermediate C , but few or no data were available for earlier intermediates . Based on our tox assessment , we elected to treat intermediates A , B and C as highly potent and thus conducted the entire project under high potency protocols .

The process was then developed with acid A being condensed with a protected piperazine to obtain intermediate B . The use of high quality piperazine derivative was crucial in this phase , as the presence of traces of free piperazine could lead to the formation of the bis-acylated impurity ( Figure 3 ). The bis-acylated impurity was difficult to purge in the downstream process , requiring several purification operations to be

removed , which had significant impact on costs and process sustainability .

B was de-protected to give C , which was then reacted with D , an activated ester of cyclopropane carboxylic acid , to obtain Olaparib . Attempts to acylate C with acid chloride derivative of cyclopropane carboxylic acid or with in situ activation resulted in formation of several impurities , presumably due to the competitive acylation on the phthalazinone .

The synthetic route was developed and demonstrated in Cambrex ’ s HPAPI development facility . Upon completion of the project , both isolators were subjected to cleaning procedure following the approach described in the previous section . A previously reported selective acylation using acylimidoyl-derivative of the cyclopropane was unavailable due to IP constraints . A final purification step afforded Olaparib with purity of ≥ 99.9 %.

The experimental data confirmed that the procedure was efficient and that isolators could be opened for programmed maintenance . The optimised process was subsequently validated with three manufacturing campaigns producing 6 kg each , confirming the results of the development work . ●

30 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981