biopharmaceuticals which is largely due to their sensitivity to vari­ous conditions such as temperature, pH and mechanical stress [22]. Exposure to these factors can easily aect the quality, safety and ecacy of the end product. Therefore, monitoring these conditions is crucial to ensure that these conditions vary within appropriate specified limits. Clearly, significant challenges are encountered in the manufacture of biopharmaceuticals, and it is vital to adopt rel­evant GMP guidelines. According to the PIC/S, GMP ensures that

The increasingly globalized nature of commerce allows manufac­turers to outsource activities such as procurement of raw materi­als overseas, where dierent regulatory requirements may exist. Thus, there is a need to ensure that the GMP guidelines adopted by the RAs and IOs are harmonized and robust. A robust set of GMP guidelines helps to safeguard public health by assuring the quality, safety and ecacy of the bio-pharmaceuticals [26]. To date, review on the biopharmaceutical regulatory framework has been done on western countries such as Canada and the US, as well as some Asian countries, such as Japan and Korea [27, 28]. However, few studies have been done on the regulatory framework for biopharmaceuti­cals in Association of South East Asian Nations (ASEAN), with the exception of Singapore and Malaysia [27, 29].

ASEAN provides numerous incentives to biopharmaceutical man­ufacturers. The low manufacturing cost in some ASEAN Member States (AMS) enables greater cost-savings in the manufacture of bio­similars [30]. In addition, ASEAN is experiencing a general epide­miological shift from communicable to non-communicable chronic

expanded via sequential scaling up using bioreactors of increasing vol­umes, up to the maximum cell density. The cell culture is terminated before the death phase and the culture medium is harvested.

Table 3 shows a comparison of GMP principles and guidance doc­uments adopted by selected RAs and IOs. They are chosen because most of them are key players in regulatory harmonization or bio­pharmaceutical manufacturing [27, 29, 73]. In general, IOs and majority of the RAs adopt similar GMP principles. They emphasize on the implementation of quality risk management (QRM) princi­ples: 1) risk evaluation should be scientifically sound and relevant to protection of patient; and 2) the amount of resources used for risk management should be proportional to the risk level [74]. QRM also facilitates better management of the manufacturing process by identifying and prioritizing the control on critical process param­eters (CPPs) [75], as their variability can impact the CQAs and con­sequently the product quality [76]. Most guidelines acknowledge the inherent variability of biopharmaceutical quality and recom­mend using in-process controls and improving the robustness of manufacturing process to control the variability [1, 37, 77]. Table 3 also shows that most RAs and IOs adopt relatively similar GMP standards for API, suggesting a significant level of harmonization is already in place. However, there are major dierences in the scope of the GMP standards. For instance, PIC/S provides guidance on all types of biopharmaceuticals within Annex 2 of its GMP guide, while the European Medicines Agency (EMA) provides recommen­dations for ATMPs in a dedicated guidance (Eudralex, Volume 4, Part IV) [78]. However, it is noted that PIC/S is currently drafting a dedicated GMP guide for ATMPs which may be implemented in the future [79]. In addition, PIC/S provides further guidance for selected types of biopharmaceuticals in Annex 2 Part B of its GMP guide [1] while WHO does not [37].