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tablets. The drug product contained 90% of DS. The DS properties are then critical and drive the drug product quality. DS A has involved multiple external partners worldwide since the launch of the medicine and has been supplied using different chemical synthetic pathways. One source in particular led to difﬁculties during the DP process compared to the others. Even though studies demonstrate the equivalence in terms of chemical properties and impurity proﬁle and meet the speciﬁcation, some observations were reported on the physical behavior of the powder. The manufacturing team especially reported difﬁculties to load the mixer (5 hloading time insteadof 1 h30)because of the tendency of the DS to agglomerate. For this reason, a crushing step was added to the process.Then, the compression step required more adjustments (distributor speed, pre-compression force, compression speed) than usual because of a variability of the tablet mass and a nonconforming friability of the tablets. These adjustments depended on the DS batch due to batchto-batch variability.

Studies were performed to better understand the behavior of the DS powder. Many factors can be involved: the synthesis pathway, the packaging quality, the type of shipment (i.e., boat, plane), the time of storage (i.e., at supplier site, during transition, at manufacturing site), and the condition of storage (i.e., temperature and relative humidity). During the investigation, the physical properties – PSD, densities, compressibility proﬁle, and mechanical properties – were assessed to identify the physical characteristics varying between batches and sources. The hardness of the DS powder was identiﬁed as the main difference between DS batches. The hardness was measured on tablets manufactured with the pure DS by using a tablet tester.

Figure 8 illustrates the compressibility proﬁles of 12 DS A batches coming from the same supplier. It was seen that the hardness of the DS can vary from 28 to 65 N in the compression range (i.e., 2500–3100 daN).

Fig. 8 Compressibility proﬁles of several DS A batches from the same supplier colored by DS batch

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As dry granulation precedes the tableting, it mitigates the difference in terms of tabletability and standardizes the ﬁnal blend. However, when the hardness of the DS was too low, signiﬁcant differences in terms of tabletability persisted (tablet hardness and friability typically).

Though the impact of storage conditions is mostly reported for deliquescent drugs [48] or amorphous solid dispersion [49], crystal defects can also induce water sorption of crystalline powders [50] with a direct impact on their physical behavior. To better understand potential causes of the variations between the DS batches, the impact of shipment and storage was then investigated. Storage conditions (temperature and humidity) were found to be highly variable in the warehouse and intermediate storage locations. The variations were even more impacted by the type of shipment (boat or plane). Storage tests were performed by exposing the DS powder in open dish to a variation of temperature and humidity. As expected, variation in storage conditions was found to impact the PSD, particle shape, and hardness. After prolonged storage at 40 increased; the powder particles presented smoother edges and looked transparent. Finally, the hardness decreased after exposure to stress conditions.

This case study highlighted that even if the equivalence between the different sources is demonstrated, the impact of storage conditions on DS physical properties is key for the drug product performance.

◦

C and 75% RH, the particle size had

5.2 Apparition of a New Polymorphic Form

The second example concerns drug substance B, which is also a powder. The drug product was a coated tablet manufactured via direct compression. The drug load was 90%; the DS physical properties were therefore again critical for the DP process. Deviations in tablet thickness and hardness were reported by the manufacturing team leading to out-of-speciﬁcations. An investigation was triggered to understand and resolve the issue and implement preventive actions. In view of the high drug load, DS batches were withdrawn and analyzed for PSD, densities, microscopy, Xray powder diffraction, compressibility behavior, and mechanical properties.

Figure 9 presents the results of optical microscopy for a reference batch (left) and one of the batches under investigation (right).

The optical microscopy allowed to observe a difference in terms of particle opacity. The particles from the reference batch were transparent, whereas a mix of transparent and opaque particles was observed for the batch under investigation.

In addition, another polymorphic form was detected in the batches under investigation, and so not only one form was present but also a mix of two polymorphic forms in the powder. This change of polymorphism means a difference in molecular rearrangements and consequently a modiﬁcation of particulate properties.

The next step was then to study the mechanical properties and especially the consolidation behavior of the DS (Fig. 10).

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Fig. 9 Optical microscopy of a reference batch (left) versus a batch under investigation (right)

Fig. 10 Tabletability of various DS batches. In orange and red: DS batches under investigation. In

green: reference DS batches

Figure 10 represents the tensile strength according to the compression pressure. The DS batches under investigation (in orange/red) presented a higher tensile strength at a given compression pressure compared to the reference batches (in green) and were therefore more cohesive. Moreover, the brittleness of the particles was estimated using Heckel equation [51, 52] showing lower brittleness of the batches under investigation.

As a conclusion, the investigation allowed to highlight a new polymorphic form that impacted the physical properties of the DS and therefore the manufacturability of the DP. Identifying the source of the apparition of this new polymorphic form will be critical to solve the issue on tableting.

6 Conclusions

This chapter addressed the challenges associated with material attributes during drug product process development and life cycle. As seen in the ﬁrst case study,

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material availability and variability are very limited during process development. It is, however, possible to start developing the knowledge around material attributes by applying an enhanced quality-by-design approach. In the second case study, process miniaturization was applied to a roller compaction process, allowing the determination of relevant material attributes for process development and enabling process acceleration and reduction of API consumption. In the third case study, the knowledge acquired about an API variability was utilized to develop a more robust drug product process that is able to cope for this variability. The last case study showed challenges related to life cycle management of a drug product. Batch-tobatch variability indeed evolves by the introduction of new sources that can have a dramatic impact on drug product performance. A targeted material characterization shows to be key to anticipate process adjustments. As seen throughout the chapter, material science should not only be considered at development level but also should play an active role during the entire life of a product to ensure process robustness and therefore an improved product quality and undisturbed supply chains to meet patients’ needs. Good practices should therefore include the following:

• A systematic identiﬁcation of API CMAs, not only in regard to product speciﬁ-

cations but also CMAs relevant for the DP process.

• Harmonized characterization guidance for all raw materials since the start of the

development, allowing the creation of a database per product.

• Targeted studies allowing to understand the interplay between drug substance

properties and drug product process.

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