Although there appears to be a clear increase in the use of QbD principles during the drug development process (Fig. 7), defining ECs in regulatory submissions remains limited in the US and EU (Fig. 1). Therefore, we examined the potential reasons for the slow adoption of ECs.

The United States and Europe have had post approval change guidelines in place since 1999 and 2008, respectively and they are still in use today.

ICH Q8/9/10 guidelines reached Step 4 in 2006, followed by a revision for Q8 in 2010 and for Q9 in 2023. There was slow adoption of QbD principles due to a lack of understanding of how best to use this approach, and the amount of work that needs to be done during development when it is unclear as to whether or not the product will be successful. To assist in their use, ICH published a Points to Consider document for Q8/9/10 in 2011 which was revised in 2013.

In Europe, it was reported that only 38% of new drug applications were developed using full QbD between 2014 and 2019. Several products were not developed via full QbD implementation but instead used one or more QbD elements, including design space [11]. The use of QbD development in Japan marketing applications began in 2009 when the description that: it was developed by QbD elements or quality risk assessment” appeared in PMDA new drugs review reports (including biosimilars). As shown in Fig. 7, in 2009, 4% of marketing applications used elements of QbD (including 1 item/26 items, including 2 biosimilars: however, the application was made using the experimental design method), in 2013 it was 31% (12 items/39 items), 60% by 2018 (26/43 items, including biosimilars), and in 2021, when Q12 reached Step 4, it was 71% (37/52 items, including biosimilars), in 2022, it was 79% (30 items/38 items), and in 2023, it was 76% (34 items/45 items). In recent years it has stabilized at more than 70%. Not all new drugs approved in Japan are approved in the EU and the US, still, the data show that the QbD approach is being used more often in the development of products.

The Q12 guideline preparation discussion began in 2014 and reached Step 4 in 2021. “This guideline addresses the commercial phase of the product lifecycle (as described in ICH Q10); and it both complements and adds to flexible regulatory approaches to post-approval CMC changes described in ICH Q8(R2) and Q10 Annex 1.“ [12]. It allows companies that effectively operate the PQS, as indicated in Q10, to use various Q12 tools, including ECs, if they develop products using the methods outlined in Q8 and Q11 and perform appropriate risk assessments according to Q9. Tools and enablers described in Q12 are complementary and are intended to link different phases of the product lifecycle [12].

The number of products approved using the QbD approach has been increasing, so it is believed that many products can set ECs, which is a tool available in Q12. However, as of 2024, ECs are still rarely used in the EU and the US even when QbD principle as are used during development of a product. Note that at the time of the survey, the legal framework for accepting ECs was not in place in the EU and therefore sponsors could not submit applications defining ECs even if they had the supporting data available.

Figure 2 shows that the primary reason for not setting ECs is that companies generally remain reluctant to do so because of the uncertainty it adds with regards to approval of a new drug application. Not receiving approval would have impact beyond manufacturing and testing to patient access and business-related predictions. In fact, only three companies included ECs in new drug applications to the US and EU. As shown in Fig. 3, a significant number of companies are considering EC settings for future applications in EU and the US (28% and 38%, respectively) and seven companies tried to set ECs as part of PACs, suggesting that many companies are contemplating using the comparably shorter review period of a PAC submission to gain experience before deciding on the future use of ECs. As the EU’s Change Variation guidance is revised to allow the use of ECs [20] companies may leverage existing experience from other companies to determine the actual benefits of defining ECs which may also increase the use of QbD principles during drug development.

As discussed previously, before the publication of ICH Q8/9/10, new product submissions to Japan required sponsors to assign symbols or annotations indicating the post-approval change category that would be used for specific parameters. This use of Approved Matters in Japan has been in use since 2005 and is similar to the concept of ECs.

The ICH Q12 guideline has been effective in Japan since 2021 and states that “(2) The “Establishment Conditions (ECs)” is an element that is considered necessary to ensure product quality, and if a change is made, regulatory procedures are required. Since it is an approved matter, it should be stated in the manufacturing and marketing approval application as before. Additionally, changes reported as minor change notification still need to comply with the Enforcement Regulations of the Pharmaceuticals and Medical Devices Act (hereinafter referred to as the “Regulations”). Article 47, “Guidelines for Matters to be Stated in Applications for Manufacturing and Marketing Approval of Pharmaceuticals, etc. Based on the Amended Pharmaceutical Affairs Law” (Notice of the Director of the Examination and Management Division of the Pharmaceuticals and Food Bureau of the Ministry of Health, Labour and Welfare No. 0210001 dated February 10, 2005), “Entries related to the specifications and test method columns of the application for approval of pharmaceuticals, etc., and their changes” (Issued by the Pharmaceutical and Herbal Drugs Trial on July 30, 2021) No. 6, Notice of the Director of the Pharmaceutical Evaluation and Management Division, Pharmaceuticals and Public Health Bureau, Ministry of Health, Labour and Welfare). (3) The “Product Lifecycle Management (PLCM) Document” in Q12 consists of information on the EC and related change categories, the relevant post-approval CMC commitments, and the post-approval change management implementation plan (hereinafter referred to as the “PACMP”). Information on the EC and related change categories should be included in the application for approval as before.“ [14] and it is clearly stated that the manufacturing process description in the Japanese regulatory commitment is the same as ECs in Q12. As explained before, in Japan, new drug applications based on QbD development have become more common in recent years. However, many products were developed without applying QbD principles and must continue to use the process of symbols and annotations as was done before ECs were an option.

Comparing to EU and the US, Japan requires more conservative regulatory reporting for the same post approval change [21] in spite of the Notification No. 0210001 [14] which states: “The example described in this application for approval is only an example, and in the actual application for approval, the contents of the application for approval shall be in accordance with Paragraph 2.1, and the determination of the classification of changes and notable matters shall be in accordance with Paragraphs 2.2 and 2.3, and should be described on a case-by-case basis according to the characteristics of each drug.“ [14].

If a company’s PQS is robust, it is likely that there would be no difference between the change reporting category based on the traditional risk assessment approach and ECs if they had been set. In fact, this was suggested in responses from respondents in EU and the US who well-understood the concept of ECs (Fig. 7).

The post approval change process based on the change guidelines [16,17,18,19] that have been implemented in EU and the US before Q8 became effective can be applied to products developed according to the “minimal approach” defined in Q8. This method of change assessment needs resources at the time the change is planned yet can lead to an appropriate submission and review process nonetheless. This approach may be better to support post-approval changes for products not developed by a QbD approach. To avoid misreporting, regulatory authorities confirm that the reporting category is correct. In Japan, however, this approach is not possible and instead the annotation system must be applied at the time of the initial application.

Submissions to countries that do not have a fully staffed review agency often experienced long and/or unpredictable review timelines [22]establishment of ECs can make it easier to estimate workload as the regulatory reporting category is already known. Even though the change type is pre-defined, it is still necessary to provide information about the risk assessment and to generate data for implementation of the changes to facilitate appropriate PQS lifecycle management. Data requirements are not reduced when using ECs.

And as shown in Fig. 5, it is preferable for EU and the US to evaluate the risk of the changes when a change is planned instead of defining and referring to ECs even though having the ECs in place may make is easier to define a post-approval change category. The continued use of existing GMP and post-approval change guidelines remains in place and is used regularly [16,17,18,19].

In Japan, even before the use of Q12 tools such as ECs were defined, companies were required to use annotations explaining future change reporting categories. These categories set after PMDA’s review were more conservative compared to the change categories in the EU and US guidelines. FDA explains challenges and opportunities for applying Q12 to existing products based on their Established Conditions Pilot experience that ECs were not a consideration at the time of process development and regulatory approval. However, developing and evaluating EC proposals for products developed pre–ICH Q8 (i.e. without formal criticality assessments for process parameters) may be achieved by capturing and leveraging extensive manufacturing experience [23].

As discussed before, the use of ECs in EU and the US has not yet become widespread. The application of Q12 ECs varies by region, even among Japan, EU and the US. It is anticipated that achieving a common understanding globally will take considerable time.

Taking these factors into account, it is considered effective to address the discrepancies in procedures across the three regions by introducing and implementing a post-approval change guideline in Japan similar to those in place in the EU and the US in addition to the traditional method of setting and operating symbols/annotations for future change categories.