5.3. The benefits during development and marketing authorisation

This systematic approach had demonstrated to combine patient’s needs with extensive investigations of all potential impacts on these attributes that are going to impact the product’ performance for and in the patient.

The investments in resources and materials for this approach were quite substantial in order to determine and define first of all the voice of the customer, then assessing the Critical Attributes and how these might be impacted. During the development this number of investigations to determine all material attributes, critical parameters and their interactions in such a systematic way to define the Design Space was significantly adding to the resources needed during this development.

However, while the costs for materials (mainly the drug compound) needed for all experimental trials and the additional pilot bioequivalence study were significant, the time for the overall development of the dosage form was not longer than it had been for the conventional development approaches before. The most time intensive steps ended up to be the definition of a meaningful Target Project Profile and a joint risk assessment of the potential risks in the development team, thus integrating the contribution from all areas such as marketing, clinical and production.

The biggest advantage however, was really that this systematic and holistic approach did get it „right first time“ and this for a project which solely depended on the CMC activities as the safety and efficacy of the drug compound itself are already pre-established for a generic product. Thereby, the CMC activities in generic projects really do determine overall project success and thereby provide a direct evaluation of the benefits of a QbD driven development approach.

Two prior attempts to develop bioequivalent, taste masked pellets for this compound had failed when inadequate taste masking had been achieved or when the pellets did not meet bioequivalence criteria despite fast in vitro dissolution rates.

The QbD approach enabled the development of a drug product meeting all criteria in vitro and in vivo at the first attempt and achieving to do so reproducibly from batch to batch by a robust manufacturing process.

Due to the established Design Space process parameters could be adjusted safely to compensate for the variability of environmental conditions or material attributes without ever failing to meet the test criteria, which had been directly linked to the product’s in-vivo performance to ensure consistent customer satisfaction.

In a post marketing study the superior excellence of the drug product and the higher customer satisfaction could be quantified demonstrating children’s preference for ClaroSip ® due to its improved taste masking and easier handling. The taste of ClaroSip ® was clearly superior to the syrup as depicted in Figure 10, with 60% of the children evaluating the taste as very good even at the end of treatment, while less than 40% of children rated the syrup to taste very good at this time.

marketing study, treatment duration: 7 – 10 days regime: Clarithromycin / Siptechnology bid vs. Klacid ® forte bid." class="wp-image-10032 size-full" height="314" src="https://sgbs.ch/wp-content/uploads/Figure-10-Multicenter-post-marketing-study-treatment-duration-7-–-10-days-regime-Clarithromycin-Siptechnology-bid-vs.-Klacid-®-forte-bid..png" width="476"> Figure 10: Multicenter post marketing study, treatment duration: 7 – 10 days regime: Clarithromycin / Siptechnology bid vs. Klacid ® forte bid.⁶⁴

In the dossier for submission to the authorities no claim for QbD was made but the pharmaceutical development report in module 3 explained the targeted product profile and the product’s critical attributes, summarised the employed DOEs to define a knowledge space, and provided sound justifications for the proposed controls and specifications. All assumptions, conclusions and derived actions were supported by detailed risk assessments and scientifically justified in the development report, which was structured in line with the ICH Q8 requirements for pharmaceutical development.

During the marketing authorisation procedure for the drug product, which was finalised successfully in 14 European countries, Mexico, and Chile, no major questions were raised as to the pharmaceutical development or manufacturing even though this product was a completely novel form of administration as an oral dosage form and innovative manufacturing technologies were employed for the filling of the pellets into the drinking straw system.

Other benefits during MAA included reduced requirement for analytical testing, wide specification ranges for raw materials and wide ranges for process parameters during manufacturing as these had been demonstrated effectively during development not to impact the product’s performance.

The reduced number of analytical assays and test points during release testing reduced the analytical costs for batch release and thereby improved the contribution margin for ClaroSip ® . High yields of drug product complying with all specifications had been achieved at lab scale, pilot scale and production scale manufacturing, thereby reducing waste and further improving the product’s contribution margin.

Summarising the benefits for ClaroSip ® , the new approach had achieved a higher success rate at an improved timeline, a higher value proposition for the product by its excellence and quality and the opportunity to improve the contribution margin for an innovative branded generic.

⁶⁴ Source: Ziegler; Dose Sipping Technology; 2007; slide 7