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James D. Colandene, PhD, is manager, Biopharmaceutical Product Sciences, GlaxoSmithKline.
Douglas P. Nesta, PhD, is director, Biopharmaceutical Product Sciences, GlaxoSmithKline.
Kashappa Goud Desai, PhD, is investigator, Biopharmaceutical Product Sciences, GlaxoSmithKline, email@example.com
This article provides an overview on important aspects related to bracketing strategies in Japan.
Article submitted: Jan. 15, 2017.
Article accepted: March 2, 2017.
Japan’s pharmaceutical market is one of the top priorities for global pharmaceutical companies. Drug manufacturers are required to fulfill Japan-specific regulatory requirements. One of the requirements is to submit bracketing strategies for critical and non-critical aspects of the manufacturing process in a new drug application. These aspects include process parameters, quality attributes, operating and storage conditions, type and concentration of materials used, and other relevant aspects (also referred to as manufacturers’ proposals for handling post-approval changes). The critical and non-critical aspects of the manufacturing process are typically enclosed in major and minor brackets, respectively. Any post-approval changes to the bracketed aspects require appropriate regulatory action. Each bracketing strategy offers advantages and limitations, and determines whether a manufacturing deviation is allowed or not and whether a pre-approval for implementation of a post-approval change is required or not. Hence, it is important to submit a well-thought-out bracketing strategy. This article provides an overview on important aspects related to bracketing strategies.
Japan represents the second-largest pharmaceutical market in the world, accounting for approximately 10% of the total global pharmaceutical market (1, 2). Driven by new product launches and the healthcare burden of an aging population (1), Japan’s pharmaceutical market value is predicted to grow at a compound annual growth rate (CAGR) of 1.3% from $72.8 billion in 2013 to $79.8 billion by 2020 (3). Hence, entering the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan oversees the regulatory affairs for drugs and medical devices (4-7). It is essential to understand Japan-specific regulatory requirements to achieve successful approval for new drug products there. Accessing Japanese regulatory information, however, is challenging due to differences in language and culture.
The drug approval process in Japan involves a series of activities, including non-clinical and clinical (Phase I, II, and III) studies, bridging studies, submission of a new drug application (NDA) by the manufacturer, and review of NDA by the PMDA (4-9). Application documents for a new drug should be prepared and submitted in the Japan Common Technical Document (Japan CTD) format (4-9). After review and evaluation of an NDA, the PMDA provides a recommendation and forwards the application for approval to the Ministry of Health, Labor, and Welfare (MHLW). The MHLW is the regulatory authority that issues NDA approval or rejection.
Figure 1: Japan Common Technical Document (CTD) triangle (high-level structure of the Japan CTD dossier).
The Japan CTD dossier is organized into five modules (Figure 1). Module 1 is a legally binding document and consists of the application form (AF) (4-9). The content of the AF is considered registered detail and includes several categories of information (some categories are shown in the box on the right of Figure 1), including a description of the manufacturing process (4-9). In the Manufacturing Process section, the manufacturer must propose appropriate bracketing strategies for critical and non-critical aspects of the manufacturing process. These aspects include process parameters, quality attributes, operating and storage conditions, type and concentration of materials used, and other relevant aspects (also referred to as regulatory strategies for post-approval changes) (4-13). Critical and non-critical aspects should be enclosed in major and minor brackets, respectively (4-13). Any post-approval changes to the bracketed aspects in the AF require appropriate regulatory actions (9-13). This requirement is the key difference between Module 1 of the Japan CTD and the United States/Europe CTD. In the United States and Europe, Module 1 is considered an administrative section only (4-9). Module 2 of the Japan NDA should include a quality overall summary, non-clinical and clinical overviews, and non-clinical and clinical summaries. Modules 3, 4, and 5, respectively, contain more extensive information on quality, safety, and efficacy. In the Japan CTD, Modules 1 and 2 must be written in Japanese and are considered review documents. Modules 3, 4, and 5 are considered reference documents and may be written in English (4-13).
Bracketing is a Japan-specific regulatory strategy in which critical and non-critical aspects of the manufacturing process such as process parameters, quality attributes, operating and storage conditions, type and concentration of materials used, and other relevant aspects are enclosed in major (<< >>) or minor (“ ” or ãã) brackets in the written AF (10-13). The type of bracketing strategy proposed determines whether a post-approval change is subject to the partial change application (PCA) approval or minor change notification (MCN). The aspects enclosed in major and minor brackets are referred to as PCA and MCN matters, respectively (10-13). If an aspect is not enclosed in any brackets, it is considered a PCA matter (10-13).
In general, a PCA is submitted for making a major change (change in a critical aspect enclosed in major brackets or submitted without any brackets) or a change that has significant impact on quality, stability, safety, and/or efficacy of the product (8-13). On the other hand, an MCN is submitted for implementing a minor change (change in a non-critical aspect enclosed in minor brackets) or a change that has a negligible impact on quality, stability, safety, and/or efficacy of the product (8-13). Other differences between PCA and MCN are listed in Table I.
Table I: The difference between a partial change application (PCA) and a minor change notification (MCN). PMDA is the Pharmaceuticals and Medical Devices Agency.
Critical aspects (e.g., process parameters, quality attributes, operating and storage conditions, or other aspects that are considered to be critical) of the manufacturing process are expected to be enclosed in << >> or submitted without any brackets and are regarded as PCA matters. For example, the critical process parameters (CPPs) belong to the major bracketing category and are enclosed in << >> or submitted without any brackets (Table II and Table III) (9-13). The major bracketing approach proposed determines whether a manufacturing deviation is allowed or not. For example, a manufacturing deviation is allowed when a set/target value or midpoint of a normal operating range (NOR)/proven acceptable range (PAR) is enclosed in << >> (9-13). In contrast, the manufacturing deviation is not allowed if a process parameter or other aspect is submitted without a bracket (Table II) (9-13).
Table II: Major and minor bracketing strategies, respectively, for critical and non-critical process parameters, and associated deviation acceptability and regulatory actions.
Different major bracketing strategies can also be adopted. For example, not less than <<lower limit of NOR>> or <<NOR>> can be proposed instead of <<target/set value or midpoint of NOR/PAR>>. For <<NOR>> approach, a PAR must have been established and documented in the manufacturing site documents (e.g., manufacturing guide, batch records, and control strategy). If the process parameters are set for parametric release (limited to cases where a release is determined from a sterilization parameter instead of a sterility test), or if the process parameters are shown to have a significant impact on product quality and stability, then the PMDA recommends specifying an allowable range in the AF instead of set/target value (13).
Figure 2 shows standard procedure, timing, and period associated with PCA and MCN matters. To make post-approval changes in the PCA matters, a PCA with essential data must be submitted to the PMDA for review and approval (10-13). Within six months of initial submission, a request for GMP inspection is submitted by the PMDA. The inspection usually takes place within three to nine months of request. It should be noted that the total duration associated with the PCA review, GMP inspection, and PCA approval depends on a number of factors, including the impact of change, data submitted, and outcome of the review and inspection (10-13). It usually takes about 9-12 months to obtain PCA approval provided all requirements are met in a timely manner (10-13). The change can be implemented once PCA approval is received.
Figure 2: Standard procedure and period associated with partial change application (PCA) and minor change notification (MCN) matters.
Non-critical aspects (e.g., process parameters, quality attributes, operating and storage conditions, or other aspects that are considered to be non-critical) of the manufacturing process are expected to be enclosed in minor brackets (“ ” or ã ã) and are regarded as minor bracketing strategies or MCN matters. For example, non-critical process parameters (non-CPPs) belong to the minor bracketing category and are enclosed in minor brackets (Table II and Table III) (10-13). The type of minor bracket and minor bracketing strategy proposed determines whether a manufacturing deviation is allowed or not. For example, the deviation is allowed when the set/target value or the midpoint of NOR/PAR is enclosed in ã ã(Table II) (10-13). Alternatively, not less than ãlower limit of NORã or ãNORãcan be proposed instead of ãtarget/set value or midpoint of NOR/PARã. In the case of ãNORã, a PAR must have been established for this parameter and documented in the manufacturing site documents.
The non-CPPs or other non-critical aspects of the manufacturing process without an established allowable/acceptable range are enclosed in “ ” (10-13). For example, the manufacturing process described in the AF includes a time limit for the bulk drug product hold at room temperature as follows: If sterile filtration of the bulk drug product will not be initiated within 24 hours of preparation, it is stored at 2-8 °C. The 24-hour time limit is enclosed in this bracket (“24 hours”). This approach is also used to bracket concentration of formulation excipients (e.g., “10% w/v”). A key limitation of this bracketing strategy is that an out-of-limit result cannot be treated as a deviation.
If the manufacturer would like to make post-approval changes in non-critical aspects enclosed in minor brackets, change(s) can be implemented immediately (10-13). However, an MCN must be submitted within 30 days of implementation of the change (implementation may refer to a process change or product release for Japanese market). The PMDA reviews the MCN during periodic site inspection or as part of manufacturer’s future PCA approval, whichever is earlier (Figure 2) (10-13).
Part of PMDA’s regulatory responsibility is to monitor post-approval changes in the manufacturing process (8-13). Bracketing in the AF not only distinguishes critical and non-critical aspects of the manufacturing process, but it also represents manufacturers’ proposals and commitment to handling post-approval changes in those aspects. The manufacturer should carefully consider the advantages and limitations of brackets (major or minor brackets) and bracketing approaches (set point, lower limit of NOR/PAR, or range) when making a selection.
The content of the AF is an approved matter in Japan (8-13). Any post-approval changes in approved matter require appropriate regulatory actions (8-13), for example, a PCA approval to implement changes in critical aspects and an MCN to inform PMDA regarding changes made in non-critical aspects. The bracketing strategy also defines whether a manufacturing deviation is allowed or not. A bracketing strategy that allows for deviations to be handled internally by the manufacturer gives flexibility to manufacturers and minimizes the regulatory burden. For example, bracketing of the set point/target value/midpoint of NOR or PAR using << >> or ã ãbrackets allows manufacturing deviations, which can be handled via internal deviation control (9-13). The aspects enclosed in “ ” or without any brackets does not allow for deviations.
The manufacturer is required to maintain consistency between approved matters and routine manufacturing practices. For example, if it is discovered during the GMP inspection that an MCN had been submitted concerning changes in the manufacturing process that should have been addressed as a PCA, the MCN becomes invalid, and there may be a possibility that the manufacturer may be accused of violating the Pharmaceutical Affairs Law (4-13).
The level of information included in the AF on the manufacturing process should be a balanced approach. For example, too little information may lead to delay in approval and too much information may increase lifecycle management/regulatory burden. Typically, important aspects that ensure product quality and stability, safety, and efficacy are included in the AF. Note that no regulatory action is required for changes in aspects that are not included in the AF but described in Module 3.
Submission of a well-thought-out Japan-specific regulatory strategy for handling post-approval manufacturing changes is essential. The important aspects of the manufacturing process (e.g., process parameters, quality attributes, operating and storage conditions, type and concentration of materials used, and other relevant aspects) enclosed in major or minor brackets are considered approved matters in Japan, and any post-approval changes in these matters require appropriate regulatory actions. Whether a manufacturing deviation is allowed or not is governed by the bracketing strategy. The manufacturer should carefully consider the advantages and limitations of bracketing strategies when making a selection. Because the number of aspects bracketed in the AF may affect timely approval and lifecycle management/regulatory burden, a balanced approach (inclusion of those aspects that ensure product quality and stability, safety, and efficacy) should be adopted.
A number of factors play key roles in achieving this goal. Product and process understanding, design space around each process parameter (e.g., NOR and PAR), residual risk level, and control strategy are crucial to make appropriate selection(s). It is also noteworthy to consider prior feedback from PMDA on bracketing strategies. Finally, the bracketing strategy proposed in the AF is subject to negotiation with the PMDA and may be different from the final approved approach.
The authors thank Akihiro Okuda, Department of Regulatory Affairs, GlaxoSmithKline, Japan, for his review and feedback.
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Kashappa Goud Desai*, PhD, is investigator, firstname.lastname@example.org; James D. Colandene, PhD, is manager; and Douglas P. Nesta, PhD, is director, all in the Biopharmaceutical Product Sciences department of GlaxoSmithKline.
*To whom all correspondence should be addressed.
This article reflects the views of the authors and should not be construed to represent PMDA’s views or policies.
Volume 30, Number 5
When referring to this article, please cite it as K. Desai, J. Colandene and D. Nesta, "Japan Common Technical Document: Bracketing Strategies for the Manufacturing Process," BioPharm International 30 (5) 2017.