More than a decade after the birth of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) at a meeting in Brussels hosted by the European Federation of Pharmaceutical Industries and Associations in 2003, ICH has developed a quality vision to develop a harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science.² Since its inception, ICH has developed many guidelines covering various aspects of the pharmaceutical industry. Among those, ICH Q8, Q9, Q10 and Q11 were specifically developed to provide guidance on some of the fundamental aspects to ensure quality during the development and commercialization of products. One of the arguments that motivated ICH to look beyond Q8-Q11 is that the main emphasis of these guidelines has been on the pharmaceutical development stage.³ Since maintenance of quality during commercial manufacturing is as important as building a product with it, ICH decided to focus on the rest of the product lifecycle.

The Final Concept Paper for Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, endorsed by the ICH Steering Committee on September 9, 2014, contended that while the concepts in ICH Q8, Q9, Q10 and Q11 provide opportunities for a more science and risk-based approach for assessing changes across the lifecycle, a similar focus was needed for the commercial manufacturing phase in order to fill the gaps in the implementation and fully realize the opportunities promised by ICH Q8 to Q11.⁴

After working on the concept for the next few years, in November 2017, the Members of the ICH Assembly under Step 2 endorsed and released a draft guideline for public consultation titled “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management – Q12” (the “Guideline”).⁵ The newly proposed guidance would allow regulators to better understand, and have greater confidence and trust in change management and facilitate applicants’ proposals for operational flexibility based on enhanced product and process understanding and the Pharmaceutical Quality Systems (PQS). For the industry, this lifecycle management guidance will provide clear expectations for change management, among other things, that will encourage manufacturers to adopt prospective approaches for continual improvement and innovation, such as leveraging opportunities to improve the product control strategy and analytical procedures, and use of change management protocols/comparability protocols.

Regulatory tools and enablers
The tools and enablers described in the Guideline are complementary and are intended to link different phases of the product lifecycle. The Guideline connects the established conditions, pharmaceutical quality systems, post-approval CMC change management protocols and Product Lifecycle Management as part of this lifecycle management approach.

Pharmaceutical development activities result in an appropriate control strategy, elements of which are considered to be Established Conditions (ECs). All changes to an approved product are managed through a firm’s Pharmaceutical Quality System; changes to ECs must also be reported to the regulatory authority. Where the regulatory system provides for Categorizations of Post-approval CMC Changes for reporting according to risk, the Marketing Authorization Holder (MAH) may propose reporting categories for changes to ECs based on risk and knowledge gained through enhanced pharmaceutical development. A system with risk-based reporting categories also facilitates the use of Post-Approval Change Management Protocols, which provide predictability regarding planning for future changes to ECs. The Product Lifecycle Management document is a summary that conveys to the regulatory authority how the MAH plans to manage post-approval CMC changes. The tools and enablers in the Guideline do not change the Relationship Between Regulatory Assessment and Inspection; however, collaboration and communication between assessors and inspectors are necessary for the implementation of this guideline. Finally, the Guideline proposes approaches to facilitate Post-Approval Changes to Marketed Products without the need for regulatory review and approval prior to implementation of certain CMC changes.

Post-approval CMC changes
Legislators and regulators have always strived to provide mechanisms that allow timely and efficient introduction of CMC changes that are important to maintain drug quality safety and ensure availability. A well-characterized, risk-based categorization of regulatory communication requirements is important to the efficient use of industry and regulatory resources. The types of changes that require communication with regulatory authorities have also been classified with regard to the potential to have an adverse effect on product quality of the drug product. It appears that the Guideline proposes a slightly different terminology which is more consistent with the practice in the European authorities. In addition, regulatory authorities are encouraged to utilize a system that incorporates risk-based regulatory processes for requesting approval from the regulatory authority, notifying the regulatory authority, or simply recording CMC changes, with associated information requirements and, where applicable, timeframes for decision. For the US, the concept of managing and documenting within the PQS and not reporting to regulators the lowest risk changes is new and will be beneficial.

The Guideline encourages harmonization toward a system of risk-based categorization of post-approval changes as an important step toward achieving the objectives of the Guideline. Such a system provides inherent, valuable flexibility in regulatory approach and a framework that can facilitate the use of tools and enablers described in the Guideline by providing a range of request and notification categories available as a target for a lowering of regulatory submission requirements, use of a lower category for request/notification if certain criteria/conditions are met, possibility of regulatory convergence regarding the association of a certain type of change with a particular category when reasons for being different from other regulatory authorities are not clearly established.

One of the most ambitious suggestions is that a risk-based categorization system may be accomplished by having the principles captured in regulations with further details in guidance, which can provide additional flexibility to modify expectations as science and technology evolve. For examples of risk-based categorization systems, the Guideline refers to existing regulations and guidance of ICH members, and WHO guidelines and guidance on changes to approved products, without being specific.

Established conditions in a regulatory submission
The concept of established conditions is not a new one. FDA defined “established conditions” in the 2015 draft guidance Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products as the description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy, as defined in an application, that assure process performance and quality of an approved product. As indicated in the draft guidance, changes to the established conditions must be reported to FDA.

The Guideline describes ECs in a submission as either implicit or explicit. Implicit ECs are elements that are not specifically proposed by the MAH but are derived from and revised according to regional regulation or guidance related to post-approval changes. Whereas, Explicit ECs are specifically identified and proposed by the MAH together with their proposed reporting category as part of a regulatory submission. The Guideline provides the opportunity to identify explicit ECs and associated reporting categories. However, unless otherwise specified by regional requirement, identifying explicit ECs for a given product is not mandatory. The guidance suggests that the approval and subsequent changes to ECs is the responsibility of regulatory authorities.

Post-approval change management
A Post-Approval Change Management Protocol (PACMP) is a regulatory tool that provides predictability and transparency in terms of the requirements and studies needed to implement a change as the approved protocol provides an agreement between the MAH and the regulatory authority. A protocol describes the CMC change an MAH intends to implement during the commercial phase of a product, how the change would be prepared and verified, including assessment of the impact of the proposed change, and the suggested reporting category in line with regional requirements, i.e., a lower reporting category and/or shortened review period as compared to similar change procedure without an approved PACMP. The PACMP also identifies specific conditions and acceptance criteria to be met. A PACMP can address one or more changes for a single product, or changes to be applied to multiple products. The PACMP may be submitted with the original marketing authorization application (MAA) or subsequently as a stand-alone submission. The PACMP requires approval by the regulatory authority, and the conditions and acceptance criteria outlined in the protocol must be met in order to implement the change(s). If this sounds familiar, then you must be remembering the 2003 draft guidance (issued by FDA Comparability Protocols: Chemistry, Manufacturing, and Controls Information) that provided recommendations to applicants on preparing and using comparability protocols for post approval changes in chemistry, manufacturing, and controls. That guidance discussed comparability protocols that would be submitted in NDAs, ANDAs, NADAs, ANADAs, or supplements to these applications.

A PACMP typically would involve submission of a written protocol that describes the proposed change(s), its rationale, risk management activities, proposed studies and acceptance criteria to assess the impact of the change(s), other conditions to be met, the proposed reporting category for the change(s), and any other supportive information. This protocol is reviewed and approved by the regulatory authority in advance of execution of the protocol. The tests and studies outlined in the protocol are performed. If the results/data generated meet the acceptance criteria in the protocol and any other conditions are met, the MAH submits this information to the regulatory authority according to the categorization in the approved protocol for review by the regulatory authority as appropriate. Depending on the reporting category, approval by the regulatory authority may or may not be required prior to implementation of the change. If the acceptance criteria and/or other conditions in the protocol are not met, the change cannot be implemented using this approach and should follow existing regulation or guidance instead.

Significant changes to the manufacturing process or controls that were not anticipated in the PACMP step 1 cannot be implemented as part of step 2 and should be the subject of a regulatory submission as governed by regional regulation or guidance. However, minor unanticipated modifications of the process or controls not affecting the technical principles of the protocol are normally considered within scope.

Product lifecycle management
Finally, the Product Lifecycle Management (PLCM) document outlines the specific plan for product lifecycle management that is proposed by the MAH, includes key elements of the control strategy, the ECs, proposed reporting categories for changes to ECs, PACMPs and any post approval CMC commitments. This will encourage prospective lifecycle management planning by the MAH and facilitate regulatory assessment and inspection. The PLCM document should be updated throughout the product lifecycle as needed.
The PLCM serves as a central repository in the MAA for ECs and reporting categories for making changes to ECs. A high-level summary of the product control strategy should be included in the PLCM document to clarify and highlight which elements of the control strategy should be considered ECs. The proposed ECs for the product should be listed in the PLCM document. The identification and justification of ECs are located in the relevant sections of the Common Technical Document (CTD). The proposed reporting categories when making a change to an EC should be listed in the PLCM document. The detailed justification of the reporting categories is located in the relevant sections of the CTD. The reporting category may be based on regional regulations or guidance, or MAH justification. PACMPs that are submitted to prospectively manage and implement one or more post-approval changes should be listed along with the corresponding ECs to be changed. The approval date of the PACMP should be noted in subsequent submissions. If the PACMP is submitted and approved after approval of the original MAA, an updated PLCM document should accompany the PACMP. CMC commitments that will be implemented during the commercial phase should be listed in the PLCM document. Submission of the PLCM document is encouraged; however, the document is expected when the MAH proposes explicit ECs.

Looking ahead
Members of ICH have laid out an impressive document in ICH Q12 covering the lifecycle of a product to provide clear expectations for change management, encourage manufacturers to adopt prospective approaches for continual improvement and innovation using some of the various concepts and documents. The Guideline serves to connect the pieces together and helps put the things in perspective. Although the Guideline provides an excellent overview of these concepts, there appears to be a redundancy in requiring a whole new set of documents that are more or less already covered in other areas of the CTD. One thing that’s not clear is what other concepts were discussed during the expert working group deliberations and if some of the existing documents or sections of the CTD that could have served the purpose with modifications were considered. According to the ICH Q12 EWG Work Plan, the Guideline is now with the regional regulators for public distribution and comment. FDA is expected to publish the guidance as a draft shortly. It will be interesting to see how the rest of the industry embraces or reacts to it. 

(Note: All original content of ICH reproduced herein is the exclusive property and copyright of ICH).

References

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), November 2017, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Q12, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_DraftGuideline_Step2_2017_1116.pdf.  
2. ICH Final Concept Paper, Q10: Pharmaceutical Quality Systems, 9 September 2005, Endorsed by the ICH SC on 10 November 2005, https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Concept_papers/Q10_Concept_Paper.pdf.
3. ICH Final Concept Paper, Q12: Technical  and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, 28 July 2014, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf.
4. Ibid.
5. Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Q12, November 2017, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_DraftGuideline_Step2_2017_1116.pdf

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Sharif Ahmed
Lachman Consultants

Sharif Ahmed is a Principal Consultant in the Regulatory Practice at Lachman Consultants with nearly 30 years of progressive responsibilities in the pharmaceutical industry who is knowledgeable of the product approval processes of U.S. FDA and Health Canada.