Contract manufacturing of a corticosteroid API

1.The Project Scope
PharmaZell Groups Steroid specialists from Farmabios were approached by a EU-based originator with regards to transfer & scale up of an existing Route of Synthesis (RoS). The customers goal was to manufacture the resulting Corticosteroid, used to treat muscle disorders, on commercial scale without changing the process.

2.The Challenge
During the assessment of the customers RoS, the R&D specialist identified several points of concern and potential improvement. Therefore a presumably more scalable, robust and economic route was proposed. The customer insisted in following the existing RoS, which then was transferred to industrial scale. This resulted in several process related issues, including the generation of a critical corticosteroid impurity not predicted by the customer, but by Farmabios experts.

3.Our Solution
The cross-functional Farmabios project team worked closely with the customer on the given RoS, to sort out all the issues and to complete the implementation on scale. At this stage the customer was convinced to prove Farmabios proposed RoS. After an extensive resource re-allocation and intense two month in R&D, the engineering batch was completed successfully on scale, directly followed by four successful registration batches. By trusting in our expertise the customer received a validated and superior RoS:

1.The Project Scope
A scalable and economic process towards a high-volume and low-priced API was requested. Existing processes applied a raw material only available with complex impurity profiles. Furthermore, late stage catalytic reduction resulted in palladium related disadvantages. The main targets were to reduce production costs, to increase product purity and to apply easier chemistry.

2.The Challenge
The patent landscape was unfavorable and many reactions would not have accomplished the targets. After this extensive screening of existing routes, an electrochemical reduction step was suggested to avoid expensive, catalyzed high pressure reactions. At that time, only few electro-organic syntheses for API production ran on commercial large scale. The challenge therefore was to introduce and scale-up this technology in a full GMP environment.

3.Our Solution
The PharmaZell team accepted the challenge and, in collaboration with external experts, the electrochemical key step was developed and transferred to production scale. The resulting process requires only two isolation steps, runs entirely in water and the electrochemical reduction can be driven using renewable energies. The annual capacity was progressively increased to +1000 metric tons, while API quality is unsurpassed high due to the mild reaction conditions. Thanks to this superior process, PharmaZell is the leading manufacturer for this API, serving 3 of the 4 biggest players and +35% of the worlds market.

1.The Project Scope
A complex manufacturing process applying multi-step synthesis, protective groups and various organic solvents should be investigated comprehensively to identify areas of improvement. The targets were to reduce production costs,  number of synthetic steps and to optimize resource, energy & time utilization. Also protective group chemistry should be omitted and the application of organic solvents should be minimized.

2.The Challenge
Based on literature research our team of specialists proposed the transition to a chemo-enzymatic process to achieve the targets. The practical challenge was to identify the required enzymes, to make these enzymes available in large amounts and last but not least to introduce these biocatalysts into commercial large scale production.

3.Our Solution
Overcoming the challenges linked to the use of enzymes, the number of steps was significantly reduced and large parts of the synthesis can now be carried out under aqueous conditions at room temperature. Protective groups are not required anymore, all predefined targets were addressed and could finally be improved substantially.

US expansion of an innovative commercialized drug

1.The Project Scope
PharmaZell Groups specialists were approached by a small European originator company marketing an innovative drug.  At this time the corresponding API was supplied by an Asian manufacturer and solely for the EU market. Based on former successful collaborations, the originators US expansion should be facilitated by PharmaZells process assessment.

2.The Challenge
The customer was initially prevented to launch the product in the US, because the API supply of the Asian API manufacturer was categorized as insecure.

3.Our Solution
The cross-functional custom synthesis team thoroughly assessed the API synthesis, the control strategy and investigated the supply shortage. Root causes for recurring quality issues were identified, many related to process robustness and impurity controls. After a comprehensive overhaul of the synthesis and the analytical methods, the customer received validated analytical methods and an optimized synthesis route, what still ensures the requested high API quality. The more robust process lead to a stable supply chain and finally the originator was in a position to prepare are successful and smooth market launch in the US.