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Post-Approval Change Management On A Global Scale: An Inconvenient Complexity For Pharma? Managing the post-approval regulatory change process for pharmaceuticals at the global level is complex, unpredictable and time consuming because of regional differences and frequent changes in procedures, requirements and timelines. More international harmonization of legislation relating to post-approval changes would help to increase regulatory compliance and to support continuous improvement and optimization of manufacturing and control processes, say Julia Radzihovsky, Claus- Dieter Schiller, Ralf Gleixner and Barbara Jentges. In all countries the granting of a marketing authorization is necessary to place a medicinal product on the market. But this is not the end of the story. In order to ensure a constant supply of the product, to support continuous improvement of manufacturing and control processes, and to comply with changing regulatory requirements, the marketing authorization holder (MAH) may need to make postapproval changes to the product in order to meet these conditions. Most post-approval changes must be reported to, or even approved by, the respective regulatory authorities. Often these changes relate to the drug substance (DS) and drug product (DP) manufacturing process and control strategy 1 and are hereinafter referred to as "technical" changes. The rules of most regulatory authorities categorize post-approval changes into minor and major changes, depending on their potential risk to public health. The underlying procedures and timelines that affect the implementation of the change differ among countries. These differences are seen in the requirements for administrative documentation and supporting data needed to show that the proposed change does not negatively impact quality, safety, or efficacy. As a result, the MAH must follow country-specific procedural and administrative requirements for each change. Moreover, some countries do not even have defined procedures for post-approval changes in place. Consequently, pharmaceutical companies are faced with nationally or regionally differing and frequently changing procedures, requirements and timelines. Particularly for globally operating pharmaceutical companies, managing these different provisions in, say, more than 100 countries is a complicated, unpredictable, and very time-consuming process 2. This could make companies reluctant to implement changes that could otherwise result in the modernization of manufacturing and control processes for medicinal products. In this article we present the results of an investigation of the impact of different regulatory requirements on overall approval timelines of post-approval changes made to the manufacturing and control of DSs and DPs, of both synthetic and biotechnological (biologic) origin. The investigation was based on an evaluation of officially available country-specific information and data. Nine representative countries (including the EU, Japan, and the US ie the founding members of the International Council for Harmonisation (formerly the International Conference on Harmonisation) were evaluated. The purpose is to demonstrate the complexity of submitting a single postapproval change to regulatory authorities on a global scale by focusing on different factors that need to be considered to maintain compliance with the varying requirements. We describe the impact of particular influence factors on the overall approval timelines of technical changes that are made to medicinal products marketed in multiple countries. Selection Of Post-Approval Change Types Three of the most frequently used types of post-approval changes were selected for the investigation: change in manufacturing site of DS (a change in manufacturing site can be indicative of the addition of a site or a replacement of a site. For the most part, both scenarios are handled in the same manner in terms of regulatory requirements; as such, data in the current review also applies to both, unless indicated otherwise); change in manufacturing site of DP; and change in analytical test methodology (for either DS or DP testing methods). For each of the change types, a distinction was made between biologic and synthetic entities. Selection Of Countries The countries that were selected for the investigation (see Figure 1) (including the EU), were meant not only to be representative of the major regions (e.g., Europe, Southeast Asia, Latin America, Middle East) but also to illustrate the entire spectrum of required regulatory activities and timeliness of the different post-approval changes. Each country can also be understood as being representative of other countries that have similar regulatory requirements. Selection Of Influence Factors Affecting The Post-Approval Process The following influence factors, which have a significant impact on the approval timelines of the post-approval change management process, were investigated: change reporting category; country-specific regulatory authority approval timelines (determined by the type and reporting category of a specific change); requirement for stability data to support the change in question; and requirement for a certificate of pharmaceutical product (CPP). The effect of each influence factor on the approval timelines of the aforementioned post-approval changes is described in detail. In addition, the combination of several influence factors on the overall approval 2 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015

timelines for a more complex change e.g., a change in the manufacturing site is presented. For the purpose of the present investigation, the EU, the US, and Japan are spelled out, whereas the other selected countries are blinded and thus referred to as country A, B, etc. Influence Factor: Change Reporting Category Depending on the classification of a postapproval change (minor or major) by each regulatory authority, country-specific regulatory requirements must be followed that differ in complexity, effort, and consequently in the time period between application for and implementation of the change. The change reporting category indicates the required regulatory effort that correlates with the documentation, data, and time required by local regulatory authorities before a MAH can implement a post-approval change. Based on official guidelines and a survey of the specific requirements for the selected countries, each change type in question was allocated to one of the four change reporting categories. Table 1 and Table 2 show the change reporting categories required for DS and DP in the different countries regarding a change in manufacturing site for medicinal products of biologic and synthetic origin respectively. Table 3 and Table 4 show the change reporting categories for DS and DP for a Table 1: Change reporting categories for a manufacturing site change for biologic drug substances and drug products in the selected countries No Notification Prior approval New registration regulatory activity EU Japan US A B DS DP C DS a DP D DS DP E F Abbreviations: DS = drug substance; DP = drug product. a Changes to DS are not required for submission as long as the composition/finished product specifications/ stability of the DP are not affected. change in analytical test methodology for biologic and synthetic medicinal products respectively. In some countries, changes made to the DS may require no regulatory action (i.e., the change can be implemented immediately), such as in country B or country C, whereas the same change may require formal prior approval in another country, such as country E or F, before it can be implemented. Other countries may simply require the regulatory authority to be notified of the change, and its immediate implementation is often allowed without awaiting formal approval. By contrast, certain change types could trigger a new marketing authorization application as a consequence of the proposed change, for example when a new marketing license is required to account for changes in DP manufacturing sites, such as in the case of country C or country B in Table 1, Table 2). The results demonstrate that the change reporting category varies across countries and that no correlation between change type and change reporting category could be detected. In general, it could be observed that a higher change reporting category is required for post-approval changes made to medicinal products of biologic origin. Influence Factor: Regulatory Authority Approval Timelines For some types of post-approval changes such as a change in analytical test methodology where no stability data or CPP (described in detail in the following sections) is required for submission, the regulatory authority approval timelines are the time-defining steps. For the purpose of the current review, only theoretical regulatory authority approval timelines were considered, without time required for questions and answers (Q&A). They include the time between submission of the change dossier until approval by the corresponding regulatory authority. In practice, the observed approval timelines are often longer, depending on the nature of the product, the complexity of the dossier, and the individual regulatory authority. Figure 2 and Figure 3 show a comparison of the different theoretical regulatory authority approval timelines between DS and DP for a change in analytical test methodology, where Figure 2 relates to biologic products and Figure 3 relates to synthetic products. 3 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015

Table 2: Change reporting categories for a manufacturing site change for synthetic drug substances and drug productsa in the selected countries No Notification Prior approval New registration regulatory activity EU DS,DP b Japan US DP DS A DS DP B DS c DS c DP DS DP Cd D DS DP E F Abbreviations: DS = drug substance; DP = drug product. a For synthetic products, a change of manufacturing site of DP refers to the manufacture of a non-sterile solid dosage form. b For products registered before 2010, no activity is required; for products registered after 2010, prior approval is required. c Changes to DS are not required for submission as long as the composition/finished product specifications/ stability of the DP are not affected. d Prior approval is necessary only when the new manufacturing site requires an inspection. Influence Factor: Requirement of Supporting Stability Data Depending on the type of change, stability data may be required as a part of the submitted change dossier. The generation of such data is a time-consuming process that has a significant impact on submission timelines. For example, as shown in Figure 4 and Figure 5, the US (for synthetic medicinal products only) and E (synthetic and biologic medicinal products) require the generation of stability data not only for the DS (as with most of the other countries) but also for the DP that was manufactured using the "changed" DS (i.e., the resulting DP). In such instances the resulting DP manufacturing time and the subsequent generation of the necessary stability data from this DP must be factored into the overall timelines. Table 3: Change reporting categories for a change in analytical test methodology for biologic drug substances and drug products in the selected countries No Notification Prior Approval New Registration Regulatory Activity EU/ A Japan US B C DS a DP D E F a Changes to DS are not required for submission as long as the composition/finished product specifications/ stability of the DP are not affected. Influence Factor: Requirement of a CPP The CPP is the primary document of the WHO certification scheme for finished pharmaceutical products. The scheme is an administrative instrument that requires a participating member state, upon application by a commercially interested party (e.g., the applicant), to certify/attest that a specific pharmaceutical product is authorized for marketing in the certifying country, or if not, the reason why authorization has not been accorded. The manufacturing facilities and operations must conform to good manufacturing practices (GMP) as recommended by the WHO 3. A CPP is only required for those changes that are addressed in the WHO model certificate 4. In this respect, a change in analytical test methodology does not require a CPP in any country. For a change in the manufacturing site of a DP, a CPP is only requested by certain countries. In such cases, local regulatory authorities usually request a CPP from the country of origin (i.e., where the DP is manufactured) together with the submitted dossier; however, some regulatory authorities may only accept a CPP issued by the marketing license-holding country (e.g., country A, EU, or US). In some instances, the CPP must be presented at the time of submission; in other cases it is required only prior to approval. When a specific country requires the submission of a CPP as a part of its postapproval change dossier, consideration must be given to the additional time required to obtain the CPP. As an example, the regulatory authority of country F only accepts a CPP issued by country A, the country where the MAH resides. Taking the change in the manufacturing site for a biologic DP as an example, the following steps must be considered. In the first step, the planned change must be approved by the regulatory authority of country A where an approval time of six to 12 months has to be considered. Subsequently to approval of the change by country A, the MAH needs to request a CPP from country A, which takes another three months. Only thereafter can the MAH submit the complete change dossier (including the CPP) to the regulatory authority of country F. Before implementation of the planned change, approval in country F is required, which takes another four months (see Figure 6). In summary, the entire process of change approval by the regulatory authority of country F could theoretically take at least 19 months. 4 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015

Table 4: Change reporting categories for a change in analytical test methodology for synthetic drug substances and drug products in the selected countries No Notification Prior approval New registration regulatory activity EU A Japan US B C a DS DP D E DS DP F Abbreviations: DS = drug substance; DP = drug product. a Changes to DS are not required for submission as long as the composition/finished product specifications/ stability of the DP are not affected. The original intent of a CPP was to expedite the approval process by relying on the approval of the CPP-certifying country with no need for an additional review. However, now countries requiring a CPP perform their own review in addition. Without this requirement, the approval time in country F could be reduced by 15 months to 10 months (assuming that six months of stability data would be required anyway). Overall Approval Timelines For More Complex Changes For more complex changes such as a change in the manufacturing site of DS or DP several influence factors as described above must be considered for the overall approval timelines. Depending on whether the change is related to a DS or DP and whether a synthetic or biologic DS or DP is affected the significance of specific influence factors on the overall approval time differs, as presented in Figure 4, Figure 5, Figure 6 and Figure 7. As an example, for the change of a manufacturing site for DS, the regulatory authority of country E additionally requests stability data of the DP that was produced from DS manufactured at the new site (six months for synthetics, 12 months for biologics). In such cases, additional time needs to be factored into the overall 5 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015

approval timelines in order to account for the manufacture of the DP and the subsequent generation of DP stability data. However, since the generation of the DS stability data can be performed in parallel to the manufacture of the DP, only the time until the start of DP manufacture needs to be taken into consideration, provided the required long-term stability data timelines are equal for DS and DP. For the purpose of the present investigation, a period of six months was assumed before the DP manufacture can start with the "changed" DS resulting from the time required for transport from DS to DP site and a waiting period for a manufacturing slot in the DP site. In some cases, countries do not require the submission of actual stability data in support of a change, but only ask the MAH to perform a stability study with the changed material. This results in earlier submission of the change, faster approval, and consequently quicker implementation of the change. As shown in Figure 5, the overall approval timelines for a change in a biologic DS manufacturing site vary considerably among the different countries. Variation is already apparent in the first influence factor the required DS stability data which fluctuates from zero up to 12 months, with an average of six months, for most countries. A similar observation can be made for the regulatory authority review and approval timelines, which range from zero to 24 months. A comparison of the overall approval timelines across the nine countries for a change in a biologic and synthetic DP manufacturing site, as shown in Figure 6 and Figure 7, illustrates the high degree of variability of overall approval times on a global scale. For this type of change, the issuing of a CPP, as well as the generation of stability data and regulatory authority review time, need to be considered when estimating the overall approval time. The CPP acquisition can have a significant impact on the overall timelines, depending on which country it is required from. Furthermore, it must be considered that some countries require the DP from the new manufacturing site to be manufactured using all registered DS sources, which complicates post-approval submissions even more. Conclusion The evaluated data illustrate the complexity of the regulatory authority change approval processes and associated timelines. In this context it should be emphasized that the timelines presented do not take into account the internal company time needed to generate the necessary documentation, including any country-specific documents, the time required by local affiliates to prepare the dossiers for their local regulatory authorities, and the necessity of pre-approval inspections, for example where a manufacturing site is added. The handling of different data requirements and subsequent dossier versions adds a further level of complexity to the overall process. The evaluation of the selected influence factors on approval timelines in a small number of countries can only offer a preview of what implementing a global change affecting 100 or more countries would entail in practice. For complex changes where stability data and CPPs are required the different timelines must be taken into account so that, for example, the need for bridging stocks can be ascertained. Additionally, an effective tracking system of the actual registration status is essential in order to maintain the release of compliant drug products into the market. The observed complexity will increase in some cases, particularly where an 6 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015

organization may have numerous postapproval changes running in parallel, per product per year. Consequently, the handling of technical changes on a global scale is challenging and very time-consuming, and can jeopardize the availability of suitable supply. It is important to keep in mind that such technical changes are triggered in order to respond to increasing supply demands, to ensure an uninterrupted supply of drugs to patients, to support continual improvement and optimization of manufacturing and control processes, and to fulfill changing regulatory requirements. The question arises whether it is really necessary to have differing and countryspecific requirements for any or all of the aforementioned factors. Would it not make more sense to have harmonized change classification concepts with the same timelines, data, and documentation requirements? This would facilitate postapproval lifecycle management and subsequent supply to the patient at the same time all around the world. Mutual recognition of decisions, which has been a common practice in the EU for several decades, could also be a viable option in regions that have a strong economic relationship, such as the Association of Southeast Asian Nations countries, and would be the desirable pathway for more global post-approval change management. In conclusion, more harmonized legislation on post-approval changes across countries would help the industry to implement post-approval changes faster and more predictably, while at the same time fostering compliance and ensuring continuous supply of state-of-the-art medicines. The post-approval guidelines developed by the ICH (ICH Q12) 5 and the ASEAN variation guideline promise to be a step in this direction. Acknowledgment This work was carried out in the context of the master thesis of Julia Radzihovsky, with a specialization in Pharmaceutical Technology at the School of Life Sciences, FHNW. We thank Professor Georgios Imanidis for the arrangement of the project in his role as responsible faculty member. References 1. Lit R. CMC Changes to Biotechnology Products: A Global Perspective from Industry, PowerPoint presentation, 2013 2. Ibid 3. WHO Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce: Questions And Answers (Q & A), May 2010, www.who.int/ medicines/areas/quality_safety/regulation_ legislation/certification/qas_certif_ scheme_2011.pdf 4. WHO Certificate of Pharmaceutical Product; Model Certificate of a Pharmaceutical Product, website accessed Nov. 6, 2015, www.who.int/ medicines/areas/quality_safety/regulation_ legislation/certification/modelcertificate/en/ 5. ICH, Final Concept Paper, ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, July 28, 2014, www.ich.org/ fileadmin/public_web_site/ich_products/ Guidelines/Quality/Q12/Q12_Final_ Concept_Paper_July_2014.pdf 7 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015

Background As part of this investigation, an internal global survey was conducted by F Hoffmann-La Roche AG to collect the information on the country requirements for post-approval changes. The following guidelines were used for providing detailed country- and region-specific information for the current review: ANVISA (2011) Resolution RDC No. 49: Sets forth Provisions for Variations (Postmarketing Changes), Suspension/Restarting of Manufacturing Activities and Withdrawals of Biological Products. ANVISA (2009) Resolution RDC 48: On Post-Registration Changes Concerning Medicinal Products and Other Provisions. ASEAN (2013) ASEAN Variation Guideline for Pharmaceutical Products. European Commission Regulation (EC) No 1234/2008 (2013) concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products. Drug approval and licensing procedures in Japan (2010) Tokyo: Jiho, Inc. US Food and Drug Administration, Center for Drug Evaluation and Research, 2004 Guidance for Industry: Changes to an Approved NDA or ANDA. Gulf Cooperation Council, The GCC Guidelines for Variation Requirements. Version 3.2 (2014). Swissmedic Administrative Ordinance/Instructions (2014): Variations related to Quality Changes Requiring Approval (ZL302). WHO (2010) Guideline on the implementation of the WHO certification scheme on the quality of pharmaceutical products moving in international commerce: Q&A; Working Document QAS/10.374. WHO Model Certificate of a Pharmaceutical Product. Julia Radzihovsky, Claus-Dieter Schiller and Ralf Gleixner work in the Pharma Global Technical Registration division at F Hoffmann-La Roche AG, Basel, Switzerland. Radzihovsky is also a master's student at the University of Applied Sciences and Arts Northwestern Switzerland (FHNW), School of Life Sciences, Institute of Pharmaceutical Technology, Muttenz/Basel, Switzerland, and Barbara Jentges is lecturer at the same organization. Email: claus-dieter.schiller@roche.com. 8 November 2015 www.scripregulatoryaffairs.com Informa UK Ltd 2015