1. INTRODUCTION
1.1 Objectives
This guideline provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner. A harmonised approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance and improving supply of medicinal products.
The concepts outlined in prior ICH Quality Guidelines (ICH Q8(R2), Q9, Q10 and Q11) provide opportunities for science- and risk-based approaches for use in drug development and regulatory decisions. These guidelines are valuable in the assessment of Chemistry, Manufacturing and Controls (CMC) changes across the product lifecycle. ICH Q8(R2) and Q11 guidelines focus mostly on early stage aspects of the product lifecycle (i.e., product development, registration and launch).
This guideline addresses the commercial phase of the product lifecycle (as described in ICH Q10); and it both complements and adds to the flexible regulatory approaches to post-approval CMC changes described in ICH Q8(R2) and Q10 Annex 1. This guideline is also intended to demonstrate how increased product and process knowledge can contribute to a more precise and accurate understanding of which post-approval changes require a regulatory submission as well as the definition of the level of reporting categories for such changes (i.e., a better understanding of risk to product quality). Increased knowledge and effective implementation of the tools and enablers described in this guideline should enhance industry’s ability to manage many CMC changes effectively under the company’s Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight prior to implementation. This approach can incentivize continual improvement by providing an opportunity for greater flexibility in making post-approval changes. It could also result in fewer associated post-approval submissions to the Marketing Authorisation Application (MAA), and less associated regulatory burden. The extent of this operational and regulatory flexibility and its adequate implementation is subject to the regulatory framework in place, as well as product and process understanding (ICH Q8(R2) and Q11), application of quality risk management principles (ICH Q9), and an effective pharmaceutical quality system (ICH Q10).
Regulatory Members of ICH are encouraged to provide publicly available information, preferably on their website, about the implementation of ICH Q12 in their region, especially with regard to regulatory considerations.
1.2 Scope
This guideline applies to pharmaceutical drug substances1 and products (both chemical and biological) that require a marketing authorization; and to drug-device combination products that meet the definition of a pharmaceutical or biological product. Changes needed to comply with new or revised pharmacopoeial monographs are not within the scope of this guideline.
1 For drug substance information incorporated by reference (e.g., a Master File) in an MAA, the holder of the referenced information may use Q12 tools where applicable. Use of Q12 tools is not intended to change the responsibilities for the holder of the referenced information, the MAH or the regulatory authority. For example, the holder of the referenced information has a responsibility to report relevant drug substance changes to the MAH referencing their submission, so that the MAH can assess the impact of the change and report any related changes to the approved MAA, as necessary and per regional requirements.
1.3 ICH Q12 Regulatory Tools and Enablers
Use of the following harmonised regulatory tools and enablers with associated guiding principles, as described in this guideline, will enhance the management of post-approval changes, and transparency between industry and regulatory authorities, supporting innovation and continual improvement.
• Categorisation of Post-Approval CMC Changes (Chapter 2)
Categorisation of Post-Approval CMC Changes describes a framework that encompasses a risk-based categorisation for the type of communication expected of the Marketing Authorisation Holder (MAH) with the regulatory authority regarding CMC changes.
• Established Conditions (ECs) (Chapter 3)
The concept of ECs provides a clear understanding between the MAH and regulatory authorities regarding the elements to assure product quality and that involve a regulatory communication, if changed. This guideline describes how ECs are identified as well as what information can be designated as supportive information that would not involve a regulatory communication, if changed. In addition, guidance is included for managing revisions of the ECs.
• Post-Approval Change Management Protocol (PACMP) (Chapter 4)
The PACMP is a regulatory tool that provides predictability regarding the information required to support a CMC change and the type of regulatory submission based on prior agreement between the MAH and regulatory authority. Such a mechanism enables planning and implementation of future changes to ECs in an efficient and predictable manner.
• Product Lifecycle Management (PLCM) Document (Chapter 5)
The PLCM document serves as a central repository for the ECs and the associated reporting category for changes made to ECs. The document also captures how a product will be managed during the commercial phase of the lifecycle including relevant post-approval CMC commitments and PACMPs.
• Pharmaceutical Quality System (PQS) and Change Management (Chapter 6)
An effective PQS as described in ICH Q10 and compliance with regional GMPs are necessary to gain full benefit from this guideline. In particular, management of manufacturing changes across the supply chain is an essential part of an effective change management system. This guideline provides recommendations for robust change management across single or multiple entities involved in the manufacture of a pharmaceutical product
• Relationship Between Regulatory Assessment and Inspection (Chapter 7)
This guideline outlines the complementary roles of regulatory assessment and inspection in the oversight of post-approval changes; and how communication between assessors and inspectors facilitates the use of the tools included herein.
• Structured Approaches for Frequent CMC Post-Approval Changes (Chapter 8)
In addition to the other tools described above, this guideline describes a strategy for a structured approach applicable to frequent CMC changes, and a discussion of data expectations, to enable the use of immediate or other post-implementation notification.
• Stability Data Approaches to Support the Evaluation of CMC Changes (Chapter 9)
This guideline provides additional science- and risk-based approaches that are relevant to strategies for confirmatory stability studies to enable more timely implementation of CMC changes.
Tools and enablers described above are complementary and are intended to link different phases of the product lifecycle. Pharmaceutical development activities result in an appropriate control strategy, elements of which are considered to be Established Conditions. All CMC changes to an approved product are managed through a company’s Pharmaceutical Quality System; changes to ECs must also be reported to the regulatory authority. Where the regulatory system provides for Categorisation of Post-approval CMC Changes for reporting according to risk, the 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 transparently conveys to the regulatory authority how the MAH plans to manage post-approval CMC changes. The tools and enablers in this 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 by regulators. This guideline provides Structured Approaches for Frequent CMC Post-Approval Changes to enable the implementation of certain CMC changes for authorised products without the need for prior regulatory review and approval. Finally, this guideline provides Stability Data Approaches to Support the Evaluation of CMC Changes; i.e., where the stability study is undertaken to confirm previously approved storage conditions and shelf-life.
2. CATEGORIATION OF POST-APPROVAL CMC CHANGES
Regulatory mechanisms that allow the timely and efficient introduction of CMC changes are important for drug quality, safety, and availability. There is a range of potential CMC changes for which communication between a company and the regulatory authority is required. CMC changes vary from low to high potential risk with respect to product quality, safety, and efficacy. A well-characterised, risk-based categorisation of regulatory communication requirements is important to the efficient use of industry and regulatory resources.
In such a regulatory system, the types of CMC changes that occur during the commercial phase of the pharmaceutical product lifecycle that invoke communication with regulatory authorities are classified with regard to the potential to have an adverse effect on product quality of the drug product. The regulatory communication category, supporting information/documentation requirements, and associated time frame for evaluation are commensurate with that potential risk. Based on potential risk, an inspection may be needed.
Regulatory authorities are encouraged to utilise a system that incorporates risk-based regulatory processes for (a) requesting prior approval from the regulatory authority, (b) notifying the regulatory authority, or (c) simply recording CMC changes, with associated information requirements and, where applicable, timeframes for decision. Such a system would include the following categories for regulatory communications with one or more levels in each case:
• Prior approval: Certain changes are considered to have sufficient risk to require regulatory authority review and approval prior to implementation and are requested by the MAH in a suitably detailed regulatory submission.
• Notification: Certain moderate- to low-risk changes are judged to not require prior approval and generally require less information to support the change. These changes are communicated to the regulatory authority as a formal notification that takes place within a defined period of time before or after implementation, according to regional requirements. A mechanism for immediate notification is useful when prior approval is not required, but timely awareness of the change by the regulator is considered necessary.
In addition, the changes that are not required to be reported to regulators are only managed and documented within the PQS, but may be verified during routine or other inspection.
Harmonisation or convergence toward a system of risk-based categorisation of post-approval changes is encouraged as an important step toward achieving the objectives of this guideline. Such a system provides inherent, valuable flexibility in regulatory approach and a framework that can support additional regulatory opportunities such as:
- Facilitating the use of tools and enablers described in this guideline by providing a range of request and notification categories available as a target for a lowering of regulatory submission requirements.
- The use of a lower category for request/notification if certain criteria/conditions are met and the relevant supporting documentation is provided as described in regional regulatory guidance; the need for regulatory inspection associated with the change may preclude the ability to use a lower category.
- Providing options for converging to the same or similar reporting category as that in other jurisdictions.
A risk-based categorisation 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 categorisation systems, refer to existing regulations and guidance of ICH members, and WHO guidelines and guidance on changes to authorised products.
3. ESTABLISHED CONDITIONS (ECS)
3.1 Introduction
This guideline establishes a harmonised approach to defining which elements in an application are considered necessary to assure product quality and therefore would require a regulatory submission if changed post-approval. These elements are being defined in this guideline as “Established Conditions for Manufacturing and Control” (referred to as ECs throughout this guideline).
3.2 ECs in the Regulatory Submission
3.2.1 ECs Definition
ECs are legally binding information considered necessary to assure product quality. As a consequence, any change to ECs necessitates a submission to the regulatory authority.
3.2.2 ECs in a Regulatory Dossier
This chapter describes scientific risk-based approaches which can be used when defining ECs and their reporting categories. Regional legal frameworks, supplemented through regulation and guidance, may define ECs with their reporting categories and/or may allow the scientific risk-based approaches described in this chapter to be considered.
All regulatory dossiers contain a combination of ECs and supportive information. Supportive information is not considered to be ECs but is provided to share with regulators the development and manufacturing information at an appropriate level of detail. Knowledge gained throughout the product lifecycle (including pharmaceutical development and characterisation of chemical and biological drug substance and drug product) is the basis for identifying the elements of CMC that are ECs and those elements which are supportive information.
An MAH should clearly identify the elements of CMC which they consider to be an EC and those which they consider to be supportive information. The rationales for the ECs are provided in the appropriate CTD modules.
Similarly, the rationales for the associated reporting categories for changes to the ECs should be provided in the appropriate CTD modules. The regulator assesses the ECs with respect to established scientific guidelines. Where appropriate, regulators approve the EC and associated reporting category in line with the principles outlined in Chapter 2.
See Appendix 1 for more information regarding sections of the dossier that contain ECs and supportive information. Unless otherwise specified by regulatory requirement identifying ECs for a given product is not mandatory.
ECs should not be confused with CMC regulatory commitments (e.g., stability, post-approval CMC commitment and other commitments) made by a MAH to provide data or information to the regulatory agency in a MAA. Such information, in the context of this guideline, is considered supportive information. Changes to CMC regulatory commitments are managed according to existing regional regulations and guidance.
3.2.3 Identification of ECs
This chapter outlines approaches to define ECs for manufacturing processes and analytical procedures. A similar approach can be used to define other types of ECs (e.g., performance of the container closure system, device elements of drug-device combination products) and should be justified by the applicant and approved by the regulatory agency.
The extent of ECs may vary based on the company’s development approach, product and process understanding, and the potential risk to product quality. Appropriate justification should be provided in support of the identification of ECs, the proposed reporting categories for ECs, and those aspects that are not ECs.
3.2.3.1 Identification of ECs for the Manufacturing Processes
A control strategy is designed to ensure that a product of required quality will be produced consistently (ICH Q8(R2)). It is a planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control (ICH Q10).
The ECs for a manufacturing process should be defined, based on product and process understanding, taking into account all the relevant elements of the control strategy. In addition to the unit operation and the sequence of steps, and in considering the overall control strategy, ECs proposed and justified in a manufacturing process description should be those inputs (e.g., process parameters, material attributes) and outputs (that may include in-process controls) that are necessary to assure product quality.
Process parameters that need to be controlled to ensure that a product of required quality will be produced should be considered ECs. These ECs are identified through an initial risk assessment and application of knowledge gained from executed studies, prior knowledge, and a criticality assessment that determines the level of impact that a process parameter could have on product quality. The criticality assessment should account for severity of harm and whether the ranges studied sufficiently account for the expected variability in the EC. CPPs and other process parameters where an impact on product quality cannot be reasonably excluded should be identified as ECs.
Once ECs are identified, an updated assessment of the potential risk to product quality associated with changing the EC, taking into account the overall control strategy informs the reporting category for the EC. The assessment of potential risk is derived from risk management activities as described in ICH Q9. The output of the risk assessment can include changes to manufacturing process ECs that range from high to low risk to product quality. The reporting category should be defined based on level of risk. A justification of the potential risk for changing ECs and corresponding reporting categories should be provided.
A decision tree which illustrates the above step-wise approach to identifying ECs and reporting categories for process parameters is shown in Figure 1. The principles in the decision tree can be applied to identify ECs for other parts of the manufacturing process and control strategy (e.g., relevant elements of input material attributes, equipment, and in-process controls) and associated reporting categories.
Figure 1: Decision Tree for Identification of ECs and Associated Reporting Categories for Manufacturing Process Parameters
The details of ECs and the associated reporting category will depend on the extent to which the company can apply knowledge from product and process understanding (i.e., development and experience accumulated throughout the product lifecycle) to manage the risks to product quality. Different approaches can be used alone, or in combination, to identify ECs for manufacturing processes; these include, but are not limited to the following:
• Parameter-based approaches, including:
A minimal2 approach, with a limited understanding of the relationship between inputs and resulting quality attributes, will include a large number of inputs (e.g., process parameters and material attributes) along with outputs (including in-process tests).
• An enhanced approach with increased understanding of interaction between inputs and product quality attributes together with a corresponding control strategy can lead to identification of ECs that are focused on the most important input parameters along with outputs, as appropriate.
In a performance-based approach, ECs could be primarily focused on control of process outputs (e.g., attributes, measurements, responses) rather than process inputs (e.g., process parameters and material attributes). This is enabled by knowledge gained from an enhanced approach, a data-rich environment, and an enhanced control strategy (e.g., models, Process Analytical Technology (PAT)). For example, a performance-based approach could be considered for manufacturing process steps with in-line monitoring of relevant attributes or with feedback controls or optimisation algorithms to achieve the relevant targets for that process step. When considering this approach, it is important to ensure that all relevant parameters and material attributes that have a potential to impact product quality are monitored and equipment used remains qualified in order to assure a stable process It should be noted that not all elements of the decision tree in Figure 1 apply because the enhanced control strategy used may remove the need for certain process parameters to be ECs.
Use of this guideline should not lead to providing a less detailed manufacturing process description in the MAA. A suitably detailed description of the manufacturing process in Module 3 is expected to provide a clear understanding regardless of the approach used to identify ECs for manufacturing process parameters. Manufacturing process descriptions include supportive information as well as identified ECs. Information regarding product-specific post-approval change activities, such as post-change monitoring, may be provided as supporting information to aid in the determination of ECs and associated reporting categories. Criticality and risk should be periodically reviewed (as expected by ICH Q10) during the lifecycle of the product and the ECs and reporting categories should be updated based on acquired knowledge.
When implementing the change, and consistent with Appendix 2, an MAH should consider the impact of the planned change, whether concurrent changes are planned, and if the originally proposed reporting category should be revised.
This guidance does not impose additional regulatory filing expectations for process ECs due to non-conformance during routine operations. Non-conformance to process-related ECs should be handled in accordance with GMP regulations (i.e., deviation/non-conformance handling process).
3.2.3.2 Identification of ECs for Analytical Procedures
Similar to the principles described for manufacturing process, ECs related to analytical procedures should include elements which assure performance of the procedure. The extent of ECs and their reporting categories could vary based on the degree of the understanding of the relationship between method parameters and method performance, the method complexity, and control strategy. A justification to support the identification of ECs and corresponding reporting categories for changes to ECs based on risk management should be provided.
Different approaches can be used to identify ECs for analytical procedures, for example as analytical technology and development approaches advance; these approaches include, but are not limited to the following:
• When more limited development studies have been conducted this may result in a narrow operating window to ensure method performance. In such cases ECs may be more extensive with fixed and/or tight conditions.
• Enhanced understanding can lead to a wider operating window that ensures method performance, where ECs can be reduced and focused on method performance (e.g., method parameters acceptable ranges rather than set points, performance criteria).
Use of this guideline should not lead to providing a less detailed description of analytical procedures in the MAA. A suitably detailed description of the analytical procedures in Module 3 is expected to provide a clear understanding regardless of the approach used to identify ECs for analytical procedures. Description of analytical procedures includes supportive information as well as identified ECs.
3.2.4 Revision of ECs
It may be necessary to change approved ECs as a result of knowledge gained during the product lifecycle (e.g., manufacturing experience, introduction of new technologies or changes in the control strategy).
Options available for the MAH to change approved ECs, and to revise the associated reporting category for approved ECs include:
• Submission of an appropriate post-approval regulatory submission describing and justifying the proposed revision to the approved ECs. Justification may include information such as validation data and batch analyses.
• Submission of a PACMP, in the original MAA or as part of a post-approval submission, describing a revision to ECs or reporting categories, and how the change will be justified and reported.
• Use of an approved post-approval regulatory commitment, as appropriate.
3.3 Roles and Responsibilities
The management of all changes to, and maintenance of, the approved marketing authorisation is the responsibility of the MAH. There is a joint responsibility to share and utilise information between the MAH and any manufacturing organisations to assure the marketing authorisation is maintained, reflects current operations, and that changes are implemented appropriately across relevant sites. Maintenance of the marketing authorisation should follow regional expectations. See Chapter 6 for information related to interactions between an MAH and any manufacturing organisations.
For any referenced submission (e.g., Type II Drug Master File, Active Substance Master File) in an MAA, the holder of the referenced submission has a responsibility to communicate changes to their ECs to the MAH referencing their submission, so that the MAH can assess the impact of the change and report any related change to the ECs found in the approved MAA, as necessary and per regional requirements.
The approval of ECs and subsequent changes to ECs is the responsibility of the regulatory authorities.
4. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL (PACMP)
4.1 Definition of a PACMP
A 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 lifecycle, 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 regulations and guidance, 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 may address one or more changes to be applied to multiple products (see section 4.5). The PACMP may be submitted with the original MAA or subsequently as a standalone submission and can be proposed independent of any prior identification of ECs. The PACMP requires approval by the regulatory authority, and the conditions and acceptance criteria outlined in the protocol must be met and results communicated to the regulatory authority in the manner previously agreed, in order to implement the change(s).
A PACMP should describe changes with a level of detail commensurate with the complexity of the change. Once approved, there is an expectation that the validity of the proposed approach and control strategy is confirmed prior to implementation of the change(s). For example, if new information becomes available following approval of the protocol, the risk assessment provided in the initial PACMP submission should be reviewed by the MAH before implementing the change(s), to ensure that the outcomes of that risk assessment as they pertain to the planned change(s) are still valid. If the review of the initial risk assessment indicates an increased level of risk associated with execution of the change, the previously approved reporting category should no longer be considered appropriate; instead, existing regional regulation or guidance should be followed or the relevant regulatory authority consulted.
The MAH is responsible for ensuring that whenever a CMC change is to be introduced under a PACMP, the facility meets the regulatory requirements of the regulatory jurisdiction where the PACMP was approved with respect to GMP compliance, and inspection or licensing status.
4.2 Application of a PACMP
The application of a PACMP process typically involves the following two steps:
Step 1: Submission of a written protocol that describes the proposed change(s), its rationale(s), risk management activities, proposed studies and acceptance criteria to assess the impact of the change(s), other conditions to be met (e.g., confirmation that there is no change to the approved specification), the proposed reporting category for the change(s), and any other supportive information (see also below). The PACMP document can be located in CTD Module 3.2.R.3 This protocol is reviewed and approved by the regulatory authority in advance of execution of the protocol.
Step 2: 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 categorisation (classification) 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 (see step 1) are not met, the change cannot be implemented using this approach and should instead follow existing regulation or guidance and associated reporting category.
Significant changes to the manufacturing process or controls that were not anticipated in the PACMP step 1 (e.g., change of order of unit operations) 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 related to the intended change and not affecting the technical principles of the protocol are normally considered within scope, if appropriately justified.
No change outlined in a PACMP should introduce any additional risks to patient safety, product quality or efficacy. A CMC change that would require supportive efficacy, safety (clinical or non-clinical), or human PK/PD data to evaluate the effect of the change (e.g., certain formulation changes, clinical or non-clinical studies to evaluate new impurities, assessment of immunogenicity/antigenicity) is not suitable for inclusion in a PACMP.
4.3 Elements of a PACMP
The development of the PACMP is informed by the application of process and product understanding gained from product development and/or manufacturing experience. A PACMP would typically include the following, e.g.:
• A detailed description of the proposed change(s), including a rationale. The differences before and after the proposed change(s) should be clearly highlighted (e.g., in a tabular format).
• Based on an initial risk assessment, a list of specific tests and studies to be performed to evaluate the potential impact of the proposed change(s), such as: characterisation, batch release, stability (as appropriate, see Chapter 9), in-process controls. The PACMP should include an appropriate description of the analytical procedures and proposed acceptance criteria for each test or study.
• Discussion regarding the suitability of the approved control strategy or any changes needed to the control strategy associated with the planned change(s).
• Any other conditions to be met, such as confirmation that certain process qualification steps will be completed before implementation.
• Where applicable, supportive data from previous experience with the same or similar products related to: development, manufacturing, characterisation, batch release, and stability to allow for risk mitigation.
• Proposed reporting category for step 2 of the PACMP.
• Confirmation, as appropriate, that ongoing verification will be performed under the PQS to continue to evaluate and ensure that there is no adverse effect of the change(s) on product quality. In cases where monitoring of the impact on product quality following implementation of the change(s) is required, a summary of the quality risk management activities should be provided to support the proposed PACMP. If multiple changes are to be implemented, these activities should address the potential risk from the cumulative effect of multiple changes and how they are linked.
The MAH should demonstrate in the PACMP suitable scientific knowledge and understanding of aspects impacted by the proposed change in order to conduct an appropriate risk assessment of the proposed change(s). Typically, more complex changes would require enhanced product/process understanding.
4.4 Modification to an Approved PACMP
A modification to an already approved PACMP, such as replacement or revision of a test, study or acceptance criterion, should provide the same or greater capability to assess the effect of the proposed change on the product quality and would normally involve a notification type of communication with the regulatory authority. A modification that more significantly alters the content of the protocol may require either prior approval of a protocol amendment or submission of a new protocol, as agreed upon with the regulatory authority.
4.5 Types of PACMPs
There are different types of PACMPs:
• One or more change(s) associated with a single product – see above and Annexes ID and 1E, for content and implementation. A PACMP can also be designed to be used repeatedly to make a specified type of CMC change over the lifecycle of a product, applying the same principles.
If the protocol describes several changes for a particular product, a justification should be added showing how the changes are related and that inclusion in a single protocol is appropriate.
• Broader protocols – the general principles outlined above apply. The risk of the proposed change(s) should be similar across products; additional considerations should be taken into account depending on the approach, for example:
a. One or more changes to be implemented across multiple products (e.g., change in stopper across multiple products that use the same container closure system): the same risk mitigation strategy should be applicable across all impacted products;
b. One or more changes to be implemented across multiple products and at multiple sites (e.g., change in analytical method across multiple sites, change in manufacturing site(s) across multiple products): the same risk mitigation strategy should be applicable across all impacted products and/or sites (see Annex IE).
5. PRODUCT LIFECYCLE MANAGEMENT (PLCM) DOCUMENT
The PLCM document outlines the specific plan for product lifecycle management that includes the ECs, reporting categories for changes to ECs, PACMPs (if used) and any post-approval CMC commitments. Its purpose is to encourage prospective lifecycle management planning by the MAH and to facilitate regulatory assessment and inspection. The PLCM document should be updated throughout the product lifecycle as needed.
5.1 PLCM Document: Scope
The PLCM document serves as a central repository in the MAA for ECs and reporting categories for making changes to ECs. It includes the key elements described below and references to the related information located elsewhere in the MAA (see Annex IF). Submission of the PLCM document is critical when the MAH proposes ECs in line with the risk-based approaches in Chapter 3.
The elements of the PLCM document are summarised below:
• ECs (refer to Chapter 3): The 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 CTD.
• Reporting category for making changes to approved ECs (refer to Chapter 3): The 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.
• PACMPs (refer to Chapter 4): PACMPs that are submitted to prospectively manage and implement one or more post-approval changes should be listed.
• Post-approval CMC commitments: specified CMC development activities, agreed between the MAH and regulatory authority at the time of approval (e.g., specific process monitoring, additional testing) that will be performed during the commercial phase should be listed in the PLCM document.
5.2 Submitting the PLCM Document
The PLCM document is submitted in the original MAA or in a supplement/variation for marketed products when defining ECs (Chapter 3).
5.3 Maintenance of the PLCM Document
An updated PLCM document should be included in post-approval submissions for CMC changes. The updated PLCM document will capture the change in ECs and other associated elements (reporting category, commitments, PACMP). The MAH should follow regional expectations for maintaining a revision history for the PLCM document.
5.4 Format and Location of PLCM Document
A tabular format is recommended to capture certain elements of PLCM described in section 5.1, but other appropriate formats can be used. See Annex IF for an example PLCM table.
The PLCM document can be located in CTD Module 3.2.R.4
4 In some regions, the PLCM may be included in Module 1.
6. PHARMACEUTICAL QUALITY SYSTEM (PQS) AND CHANGE MANAGEMENT
6.1 PQS General Considerations
An effective PQS as described in ICH Q10 and in compliance with regional GMP requirements where the application is filed, is necessary across the entire supply chain and product lifecycle to support use of the tools described in this guideline. It includes appropriate change management, enabled by knowledge management, and management review. The principles are further elaborated in Appendix 2. The relationship between knowledge management, change management, and the regulatory process for ECs are illustrated in Figure 2.
Figure 2: Connection Between Knowledge Management and Change Management Process
Maintaining an effective PQS is the responsibility of a company (manufacturing sites and MAH where relevant). It is not the intent of this guideline to require a specific inspection assessing the state of the PQS before the company can use the principles in this guideline. The conduct of inspections in connection with submitted MAAs and surveillance will nevertheless continue as foreseen by regional regulatory requirements.
It is understood that a manufacturing site can be considered to be in general GMP compliance while resolving deficiencies that do not require regulatory action. In the event that such deficiencies have an impact on the effectiveness of change management in the PQS, it may result in restrictions on the ability to utilise flexibility in this guideline.
6.2 Change Management Across the Supply Chain and Product Lifecycle
Supply chains involve multiple stakeholders (e.g., MAHs, R&D organisations, manufacturers, Contract Manufacturing Organisations, suppliers). It is important that these stakeholders interact to effectively utilise knowledge and manage changes during the product lifecycle.
A company has to manage communication of information and interactions of PQSs across multiple entities (internal and external). Therefore, the implementation of robust change management across multiple sites (outsourced or not) is necessary. In conjunction with change control principles in Appendix 2, the following change management activities should be considered to support the approaches defined in this guideline:
• Changes to ECs should be communicated in a timely fashion between the MAH and the regulators, and between the MAH and the manufacturing chain (and vice versa).
• The timeliness of communication is driven by the impact of any change related to ECs and should be targeted to those entities in the chain that need to be aware of or to implement the change over the lifecycle of the product.
• Process knowledge and continual improvement are drivers for change. For example, a CMO may be in a position to propose process improvements which significantly improve control and product consistency. These data can be utilised to revise the ECs and associated PLCM document. The organisation responsible for batch release should be aware of all relevant changes and where applicable, be involved in the decision making.
• The communication mechanisms regarding MAA changes and GMP issues should be defined in relevant documentation, including contracts with CMOs.
• A critical failure in a PQS anywhere in the supply chain may impact the ability to use the tools in this guideline; therefore, the company should communicate such failures to affected regulatory authorities.
7. RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND INSPECTION
Regulatory assessment and inspection are complementary activities and their fundamental roles remain unchanged by this guideline. Nevertheless, effective communication between assessors and inspectors can facilitate regulatory oversight of product lifecycle management.
Appropriate mechanisms to share knowledge and information obtained through inspection or assessment activities can facilitate access to necessary information and mitigate increased submission burden on the MAH. For example, the conclusions from inspections should be available to assessors to support ongoing oversight of product lifecycle management and the most recent PLCM document, when applicable, should be available to inspectors so they are aware of the currently approved status of the PLCM elements.
Communication is encouraged between regulators across regions, in accordance with appropriate bilateral/multilateral arrangements; for example, to communicate about critical failures in aspects of a company’s PQS that may impact the use of tools described in this guideline.
8. STRUCTURED APPROACHES FOR FREQEUENT CMC POST-APPROVAL CHANGES
In addition to the other tools described in this guideline, a simplified approach to accomplish certain CMC changes is needed for products whose marketing authorization did not involve identification of ECs with associated reporting categories. This chapter describes a strategy for a structured approach for frequent CMC changes and includes a discussion of the data requirements for CMC changes (e.g., stability).
The strategy described for structured approaches to frequent CMC changes is exemplified with a description of an approach for analytical procedure changes in Annex II. Similar structured approaches could be developed and applied for other frequent CMC changes such as scale, packaging, etc. These approaches may be applied when the following conditions exist:
• The company’s PQS change management process is effective and in compliance as described in Chapter 6 and incorporates an appropriate risk management system.
• A structured approach can be found in Annex II and describes the scope and the steps to be followed, including, where appropriate, data to be generated and criteria to be met. Compliance with the requirements of relevant internationally-agreed Standards and/or regulatory guidelines may be specified as part of the structured approach.
If the approach is followed and all criteria are met, the change can be made with immediate or other post-implementation notification, as appropriate, to the relevant regulatory authorities. The flexibility provided in Annex II may not be available in all regions and in all situations; some specific changes may require prior approval as defined in regional guidance.
9. STABILITY DATA APPROACHES TO SUPPORT THE EVALUATION OF CMC CHANGES
The data needed for submission to the regulatory authority in support of a post-approval change is established by regional regulations and guidance. This guideline provides additional science- and risk-based approaches that can be used to develop strategies for confirmatory stability studies supporting post-approval changes to enable more timely filing, approval, and implementation of the changes. Such approaches could be included in a PACMP (see Annexes ID and IE).
Unlike the formal stability studies recommended in ICH Q1A(R2), whose objective is to establish a useful shelf-life and storage conditions for a new, yet-to-be-marketed drug substance/drug product, the purpose of stability studies, if needed, to support a post-approval CMC change is to confirm the previously approved shelf-life and storage conditions. The scope and design of such stability studies are informed by the knowledge and experience of the drug product and drug substance acquired since authorisation. Approaches to the design of such studies should be appropriately justified and may include:
• Identifying the stability-related quality attributes and shelf-life-limiting attributes relative to the intended CMC changes, based on risk assessments and previously generated data
• Use of appropriate tools to evaluate the impact of the intended change. These may include:
- Drug substance and/or drug product accelerated and/or stress studies on representative material (which may be pilot or laboratory scale rather than full scale)
- Pre-and post-change comparability studies on representative material
- Statistical evaluation of relevant data including existing stability studies
- Predictive degradation and other empirical or first-principles kinetic models
- Utilisation of prior knowledge including relevant company knowledge and the scientific literature
• Use of confirmatory stability studies post-change instead of submission of data as part of a regulatory change submission
Where applicable, a commitment to initiate or complete ongoing, long-term stability testing on post-change batches can assure that the approved shelf life and storage conditions continue to be applicable after implementing the CMC change.
10. GLOSSARY
CAPA
Corrective Action and Preventive Action – System that focuses on investigating, understanding, and correcting discrepancies while attempting to prevent their occurrence
CMO
Contract Manufacturing Organisation
CPP
Critical Process Parameter – process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to assure the process produces the desired product quality. (Q8(R2))
CQA
Critical Quality Attribute – a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to assure the desired product quality. (Q8(R2))
CTD
Common Technical Document
Company
Manufacturing sites and MAH where relevant
EC
Established Condition
MAA
Marketing Authorisation Application
MAH
Marketing Authorisation Holder
Notification
A change to an approved established condition that does not require approval prior to implementation.
PACMP
Post-Approval Change Management Protocol
PLCM
Product Lifecycle Management
Post-approval CMC commitment
Commitment by the MAH to undertake specific CMC activities to be implemented during the commercial phase.
Prior approval
Change to an approved established condition that requires regulatory review and approval prior to implementation
PQR
Product Quality Review – regular periodic review of API or drug products with the objective to verify process consistency, to highlight any trends and to identify product and process improvements
PQS
Pharmaceutical Quality System
QRM
Quality Risk Management
Submission
Communication to a regulatory authority regarding a change to an established condition that could be prior approval or notification.
11. REFERENCES
ICH M4: The CTD -- Quality
ICH Q1A(R2) Stability Testing of New Drug Substances and Products
ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology
ICH Q8, Q9, and Q10 Questions and Answers
ICH Q8, Q9, & Q10 Questions and Answers -- Appendix: Q&As from Training Sessions (Q8, Q9, & Q10 Points to Consider)
APPENDIX 1: CTD SECTIONS THAT CONTAIN ECS
Notes:
• This table does not contain a complete list of ECs for a product. The intention of the table is to provide general guidance about the elements of manufacture and control that constitute ECs and their location within the CTD structure.
• White rows indicate CTD sections where ECs are generally located. Grey rows indicate CTD sections where supportive information is generally located.
• CTD sections containing ECs may also contain elements of supportive information.
• For information related to the drug delivery system for a drug-device combination product, the location or the relevant content within the CTD structure may vary depending on the design of the particular product and region.
3.2.S.1.2
Structure
For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations, reference is made to Chapter 3, section 3.2.3.1 - Identification of ECs for the Manufacturing processes
Raw material/reagent/solvent critical controls
Source of materials (e.g., cell and seed source, raw materials) and control of critical materials of biological origin
Generation and control of Master - Working Cell Bank / Master - Working Seed Lot, etc. (Applicable to biotechnological/biological products)
3.2.S.3.2
For each Quality Attribute on the specification
• Test Method
• Acceptance Criteria
3.2.P.2.2
3.2.P.2.3
3.2.P.2.4
3.2.P.2.5
3.2.P.2.6
Drug product
Manufacturing process developement
Container closure system
Microbiological attributes
Compatibility
For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations, reference is made to Chapter 3, section 3.2.3.1
For each Quality Attribute on the specification
• Test Method
• Acceptance Criteria
Or, if applcable,
Reference to pharmacopoeial monograph
Novel Excipient Specifiction
For each Quality Attribute on the specification
• Test Method
• Acceptance Criteria
For each Quality Attribute on the specification
• Test Method
• Acceptance Criteria
3.2.P.5.5
3.2.P.5.6
Characterisation of impurities
Justification of specifications(s)
Where applicable, supplier/manufacturer of primary container closure system
APPENDIX 2: PRINCIPLES OF CHANGE MANAGEMENT
Consistent with the basic requirements of ICH Q10, an effective change management system supports the principles of this guideline and is described below:
1. Captures stimuli for change, including those that can improve product performance or process robustness;
2. Ensures full understanding of the scope of the change and its implications for all aspects of the process and control strategy including the impact on ECs and aspects that are not ECs in affected marketing authorisations;
3. Leverages existing process performance and product quality knowledge;
4. Requires science-based risk management and risk categorisation of the intended change; considers the potential impact if the intended change is not implemented;
5. Determines data (existing and/or to be newly generated) needed to support the change and accordingly develops study protocols describing the methods, prospective acceptance criteria as well as additional post-implementation process performance and/or product quality monitoring as necessary;
6. Ensures that an appropriate regulatory submission is filed when required;
7. Uses a defined change control process to approve or reject the intended change and involve appropriate stakeholders, including but not restricted to Manufacturing, Quality, and Regulatory Affairs personnel;
8. Ensures implementation of the change is based on:
a. Review that the change as implemented remains aligned with the relevant study protocols, PLCM document, or PACMP;
b. Assessment of data generated to demonstrate that the change objective and acceptance criteria were met;
9. Ensures that risk-mitigating steps are developed in the case of deviations from acceptance criteria, or identification of unanticipated risks;
10. Verifies, post-implementation, that relevant changes have been effective in achieving the desired outcome with no unintended consequences for product quality;
If deviations associated with post-approval changes are detected, ensures that the issue is managed via the company’s deviation management process and appropriate corrective and/or preventive actions are identified and undertaken via the company’s corrective and preventive action (CAPA) system;
11. Post-implementation:
a. Captures new product/process knowledge gained during implementation of the change;
b. Where applicable, ensures that regulatory filings are updated, and an assessment is made as to whether updates to the PLCM document are needed;
c. Where applicable, ensures that the change is included and assessed as part of the Product Quality Review (PQR);
12. The change management system should be available for review during audit/inspection.
Use of Knowledge in Change Management
An effective change management system includes active knowledge management, in which information from multiple sources is integrated to identify stimuli for changes needed to improve product and/or process robustness. The connection between knowledge management and change management is illustrated in Figure 2. These sources can include, but are not limited to, developmental studies, process understanding documents, product or process trending, and product-specific CAPA outcomes. Provisions should be made for sharing knowledge (e.g., in quality agreements and/or contracts) that relates to product and process robustness or otherwise informs changes between the MAH and relevant manufacturing stakeholders (research and development organisations, manufacturers, CMOs, suppliers, etc.).
In addition to individual sources of information, there should be a mechanism to provide a holistic view of quality performance for a specific product or product family on a regular basis, as captured in the product quality review (PQR) and shown in Figure 2. This should include steps taken to identify and manage sources of variability, which allows for the identification of further need for change not apparent when the data are viewed in isolation. As described in ICH Quality Implementation Working Group on Q8, Q9, and Q10 Questions & Answers, there is no added regulatory requirement for a formal knowledge management system.
Management Review
In addition to the guidance provided in ICH Q10 regarding an effective change management system, the following should be considered in the Management Review:
• Monitoring the timeliness of the change management system to assure that changes are implemented in a timely manner commensurate with the criticality/urgency identified for the change. When implementation is delayed, an assessment and mitigation of any risks associated with the delay should be made;
• Monitoring the performance of the change management system, such as assessing the frequency of intended changes that are not approved for implementation by the quality unit;
• Ensuring that post-implementation verification occurs and reviewing the results of that verification as a measure of change management effectiveness (e.g., to identify improvements to the change management system).
ANNEX I: ILLUSTRATIVE EXAMPLES
The examples provided in Annex IA through IF are mock examples provided for illustrative purposes. They only suggest how the tools described in chapters 3, 4, and 5 could be applied, and should not be used as a template or the sole basis for a regulatory submission. In addition, the reporting categories, as described in Chapter 2, may differ across regions depending on regional legislation, the nature of the product, and the MAH’s demonstrated understanding of the product, process, and analytical procedure.
Terminology used in examples:
Annex 1A and 1B: Identification of Established Conditions for the Manufacturing Process
The examples in 1A and 1B illustrate how the development approaches described in Chapter 3, section 3.2.3.1 of the ICH Q12 Guideline could be applied. The examples describe different development approaches and resulting control strategies to illustrate how they influence the identification of ECs and reporting categories. MAAs could consist of a combination of these approaches.
These examples demonstrate that increased knowledge and understanding gained from progressively more extensive development approaches lead to reduction of uncertainty and improved management of risk. As a result, ECs could become less extensive and reporting categories more flexible.
For example:
- Enhanced knowledge may lead to a reduction in uncertainty, demonstrating that a material attribute or process parameter initially considered potentially critical in a minimal approach is not actually critical, i.e., does not have an impact on product quality and, therefore, is not an EC.
- Risk management activities could lead to different reporting categories e.g., a change from prior approval to a notification for a change to a CPP. Where the performance-based approach is used, some process parameters may not be classified as ECs due to assurance of quality being provided by online monitoring. In this circumstance, the typical operating conditions for process parameters are provided as supportive information. During manufacture, the process parameters may be adjusted to deliver the expected outcome. The risks related to the in-line PAT (Process Analytical Technology) tests, e.g., NIR, should be appropriately managed throughout the lifecycle. In-line PAT tests used for quality control are considered ECs.
A holistic view of the manufacturing process and overall control strategy is necessary when considering ECs since the output of one unit operation is the input for a subsequent operation.
Annex 1A Identification of Established Conditions for the Manufacturing Process - Chemical Medicinal Product
Powder Blending Unit Operation
Comments / Justification
For this example, discussion and justification for selected parameters are provided to illustrate concepts in chapter 3.2.3.1. “EC” refers to the identification of ECs; “reporting” refers to the assessment of appropriate reporting category.
Excipient specifications are ECs and managed in line with the Pharmacopoeia. Equipment operating principle is an EC in all cases.
Minimal Parameter-Based Approach
• API PSD:
- EC: The impact of particle size distribution (PSD) of API on blend homogeneity and dissolution could not be excluded during development. PSD was not studied outside the range of 20-50 um; this range is an EC.
- Reporting: The impact of a change outside this range on blend homogeneity and dissolution is unknown, and the risk to product quality is potentially high. As a result, any future change outside the range would be reported as PA, supported by appropriate studies and data. Changes to tighten the EC range based on knowledge gained during the commercial phase (e.g., better process control observed at tighter ranges) are considered low risk and reported as NL.
• API Moisture:
- EC: The impact of API moisture content on blend flowability, which impacts content uniformity, could not be reasonably excluded during development and has not been further studied in detail. The set point value is based on a limited amount of development and manufacturing data. API moisture content is therefore considered an EC.
- Reporting: A change in this EC is considered moderate risk since downstream processing involves a power-assisted feeder in the tablet press which mitigates the risk of content uniformity failure. The change is reported as NM.
• Blend Equipment:
- EC: Only one type of blending equipment (V-blender) was considered in development. Due to the limited knowledge, blender type is considered an EC.
- Reporting: A change in this EC is considered moderate risk and therefore is reported as NM.
• Blend speed and time:
- EC: Blend speeds and times utilised have not been studied in detail beyond the set points described. The set point values are based on a limited amount of development and manufacturing data. Therefore, the set points and the homogeneity specification are considered ECs.
- Reporting: When assessing the risk of changing set points for these parameters, it was demonstrated that detection mechanisms are sufficient to capture disturbances in homogeneity. Therefore, changes in these process parameters and specification are reported as NM.
Enhanced Parameter-Based Approach
• API PSD:
• EC: The impact of PSD of API on blend homogeneity and dissolution was well understood. DoE studied PSD within 5-200 um. API PSD was confirmed as having no impact on dissolution. The proposed control range for PSD of 5-200 um maintained adequate homogeneity. Compared to the minimal approach, a wider PSD range is the EC.
• Reporting: Enhanced knowledge gained from studying a wider range led to a reduction in uncertainty regarding the impact of changing the EC and a better understanding of the risk related to homogeneity. A change to increase the range beyond that studied is considered a moderate risk and reported as NM. Changes to tighten the EC range based on knowledge gained during the commercial phase (e.g., better process control observed at tighter ranges) are considered low risk and reported as NL.
• API Moisture:
• EC: API Moisture has been studied in detail and demonstrated to have no impact on flowability and content uniformity within the ranges explored. API moisture content is not an EC.
• Blending equipment:
• EC: The impact of different equipment types within the same operating principle on blend quality was studied and no significant impact was observed. Due to this enhanced knowledge, the EC is focused on blending principle, rather than specific type of equipment.
• Reporting: Enhanced understanding regarding the impact of different blending equipment reduced uncertainty regarding the impact of changing blender type on blend homogeneity. A change is considered low risk and is reported as NL.
• Blend speed and time:
• EC: Enhanced understanding of blending parameter variability on homogeneity allows ranges for blend speed and blend time (i.e., design space established across these two parameters) that maintain adequate product quality and offer more operational flexibility than setpoints. The ranges studied for both parameters are considered to be ECs. The EC for blend homogeneity testing seen in the minimal approach is not an EC in this approach as a result of enhanced knowledge about the risk of blend segregation gained through homogeneity assessment and stratified sampling during development.
• Reporting: Changes outside of the design space established for blend speed and time are considered moderate risk and reported as NM.
Performance Based Approach
It is assumed that a performance-based approach is developed on the basis of an enhanced approach. The same relationships between material attributes, equipment, process parameters, and product quality as outlined above for the enhanced parameter-based approach apply. However, some of the ECs are different as a result of a performance-based control strategy.
Using a performance-based approach (online NIR analyser) in the control strategy allows homogeneity confirmation in real-time. Use of the NIR analyser with feedback to blending operating parameters minimizes the need to rely on blend speed and time to ensure blend homogeneity. Therefore, these CPPs are not ECs. The NIR method and blend homogeneity specification are ECs. Enhanced understanding of blending and output measurement allows for a wider range of manufacturing scale. Typical operating conditions for blend speed and time described in Module 3.2 is supportive information and monitored to assure performance.
Annex 1B: Identification of Established Conditions for the Manufacturing Process Biological Medicinal Product
The following monoclonal antibody example illustrates how ECs and reporting categories could be defined differently depending on the related risk and development approaches used.
This example will focus on 2 steps: production culture and anion-exchange chromatography.
Production Culture (XXX L)
Minimal Parameter-Based Approach:
• EC:
• Process development is minimal. Due to the lack of supporting justification, most parameters are considered ECs and ranges are narrow.
• The bioburden test is considered an EC as the production culture step presents a known risk of microbial growth if contaminated.
• Reporting:
• A change of inoculum cell density is medium risk taking into account that control of viability and titre takes place for this step. The change is reported as NM.
• Considering that the impact of temperature and Input Y was not studied, and that literature suggests potential impact of these parameters on CQA, changes to these parameters are considered high risk. These changes are reported as PA.
• A change in the bioburden test or results is considered high risk considering the severity of microbial contamination at that stage. The change is reported as PA.
Enhanced Parameter-Based Approach:
• EC:
CQAs have been identified and DoE studies for selected CQAs show that:
• Temperature and Input Y can impact the CQA G0-F at different magnitude (high impact for Input Y and low to moderate impact for temperature); these are considered ECs.
• Inoculum cell density does not impact CQAs and is not considered an EC.
• Linkage studies demonstrate the lack of impact of viability at harvest on CQAs when reduced to 50%. Process characterisation studies demonstrate that viability at harvest is maintained above 70% when the CPPs (temperature and Input Y) are maintained within the proposed ranges. Viability at harvest is not considered an EC.
• Titre is predicted through a process model. With this knowledge, cell viability at harvest and titre are not considered ECs.
• Bioburden test is considered an EC as the production culture step presents a known risk of microbial growth if contaminated.
• Reporting:
Risk management activities have been performed and concluded that:
• A change to Input Y is considered high risk because Input Y has been shown to have a high impact on G0-F. The change is reported as PA.
• A change in temperature is considered moderate risk given the low to moderate impact on G0-F. The change is reported as NM.
• A change in bioburden test or limit is considered high risk given the severity of microbial contamination at that stage. The change is reported as PA.
Performance-Based Approach:
• EC:
• In-line tests are used to control outputs in real time. In-line tests are considered to be ECs.
• Relevant inputs are monitored through Multivariate Statistical Process Control (MSPC) defining a process signature that is not considered an EC.
• Inputs are adjusted in real time based on a model accounting for the in-line measurements of outputs. Inputs are not considered ECs as the outputs of the step (titre and G0-F level) are assured by in-line testing.
• The bioburden test is considered an EC as the production culture step presents a known risk of microbial growth if contaminated.
• Reporting:
• Changes of viability and titre tests are assessed as moderate risk since CQAs are not directly impacted. These changes are reported as NM.
• A change to G0-F test or ranges is assessed as high risk because this attribute is not tested in the drug substance specification. The change is reported as PA.
• A change in the bioburden test or results is considered high risk given the severity of microbial contamination at that stage. The change is reported as PA.
Anion Exchange Chromatography
Minimal Parameter-Based Approach:
• EC:
• Process development is minimal. The impact of inputs on CQAs has not been studied. Due to the lack of knowledge, all inputs are considered to be ECs as they can potentially have impact on CQAs.
• Output (i.e., bioburden and endotoxin) are considered ECs as they have potential impact on product quality.
• HCP and CQA X are part of DS specifications, and are not tested at this stage. HCP and CQA X are not considered ECs for this step.
• Reporting:
• Considering the lack of understanding of the impact of inputs (feedstock conductivity and pH, resin age, and Input Z) on CQAs, changes to these inputs are considered high risk. These changes are reported as PA.
• Changes to bioburden and endotoxin limits are considered low risk as these are further tested in subsequent steps. These changes are reported as NL.
Enhanced Parameter-Based Approach:
• EC:
• Studies on scale-down models demonstrate that feedstock conductivity and pH, and Input Z can impact CQAs (HCP and CQA X) and are considered CPPs.
• Resin age has been studied up to 100 cycles and up to 3 years, and did not show any impact on CQAs. Impact on CQAs cannot be excluded when the range is further extended. Resin age is considered an EC.
• HCP and CQA X are not considered ECs as multivariate studies demonstrated that they remain within their acceptance criteria when feedstock conductivity and pH, and Input Z are maintained within the studied ranges.
• Bioburden and endotoxin are not considered ECs for this step, taking into consideration testing of the attributes in several of the following process steps, but are monitored.
• Reporting:
Risk management activities have been performed and concluded that:
• Extension of resin age is considered low risk taking into account the ongoing validation protocol which includes time points beyond the claim of 100 cycles/3 years. This change is reported as NL.
• Change to feedstock conductivity is considered high risk because it can impact HCP and CQA X. This change is reported as PA.
• Change to feedstock pH is considered high risk when increased beyond 5.5, and is reported as PA. This change is considered moderate risk below 4.5, and is reported as NM.
• A change in Input Z has a moderate impact on HCP and CQA X. This change is reported as NM.
Performance-Based Approach:
• EC:
In-line tests are used to control outputs (i.e., HCP and CQA X) in real time. Inputs are adjusted in real time based on a model accounting for the in-line measurements of outputs. In-line tests are considered ECs.
• Reporting:
The control strategy relies on the in-line tests to ensure that HCP and CQA X remain within acceptable ranges. Changes to these in-line tests or ranges are assessed as high risk and are reported as PA.
Annex 1C: Identification of Established Conditions for Analytical Procedures
The following is an example to illustrate how ECs could be presented for an analytical procedure, acceptance criteria, and testing facility, along with their suggested reporting categories. This example considers an analytical procedure (capillary electrophoresis) for a biological drug substance (non-glycosylated recombinant protein) referred to as Illustropin, using a minimal development approach validated in accordance to ICH Q2. To better illustrate the example, the change categories, conditions, and data requirements are according to the WHO Guidelines on procedures for changes to approved biotherapeutic products. The actual reporting categories and data requirements may differ for a particular product and by region.
The information summarized in the table below provides guidance on:
• The conditions to be fulfilled for a given change to be classified as moderate or minor (if any of the conditions outlined for a given change are not fulfilled, the change is assessed and if appropriate the next higher reporting category may be used– for example, if any conditions recommended for a low quality change are not fulfilled, the change is may be considered to be a moderate quality change);
• Adequate scientific data and justification should be provided to support a given change.
2. The method of analysis is the same and is based on the same analytical technique or principle (for example, change in column length or temperature, but not a different type of column or method) and no new impurities are detected
3. The modified analytical procedure maintains or improves performance parameters of the method
4. The change does not concern potency-testing
5. No changes made to the test method
6. The transfer is within a facility approved in the current marketing authorization for performance of other tests
7. The change does not result from unexpected events arising during manufacture (for example, new unqualified impurity, change in total impurity limits)
2. Copies or summaries of analytical procedures if new analytical procedures are used.
3. Validation/qualification results if new analytical procedures are used.
4. Comparative results demonstrating that the approved and proposed analytical procedures are equivalent.
5. Justification for the proposed drug substance specification (for example, tests, acceptance criteria or analytical procedures).
6. Documented evidence that consistency of quality is maintained.
7. Information demonstrating technology transfer qualification for the non pharmacopoeial assay or verification for the pharmacopoeial assay.
8. Evidence that the new company/facility is GMP-compliant.
Annex 1D and 1E: PACMP Examples
The examples provided below are intended to illustrate the range of PACMPs that are possible for a given type of change. They are not intended to serve as a binding template and other approaches may also be acceptable. The first example below outlines a protocol for a single change (a manufacturing site change) to a single product. The second example outlines a protocol for multiple changes (multiple manufacturing site changes) that could be implemented for multiple products. These examples are not intended to suggest that the only type of change appropriate for inclusion in a PACMP is a manufacturing site change. As described in ICH Q12 Guideline Chapter 4, in order to meet expectations regarding continual improvement of the product and process, many other quality-related changes may be suitable for inclusion in a PACMP.
Annex 1D: PACMP Example 1
Alternative manufacturing site for a small molecule drug substance
Outline for Step 1 Submission
1. Introduction and Scope
This PACMP is intended to allow for the addition of an alternative manufacturing site for the manufacture, testing, and release of the drug substance for a small molecule solid oral drug product.
Based on the risk management activities described below, the implementation of this change in Step 2 is proposed to be reported in a submission type that is a lower category than currently provided for in existing regulations or guidance, or a submission type eligible for accelerated review timelines, depending on regional requirements.
2. Quality Risk Management (QRM) Activities
QRM is conducted for the proposed alternative site and includes:
• Identification and assessment of the potential risks associated with the proposed change, as well as the activities proposed to mitigate each risk;
• Accounting for known elements of the process, such as robustness, existing controls, and potential impact on product quality; and
• Incorporating prior knowledge gained from development and commercial manufacturing experience.
3. Acceptance criteria
Based on the risk assessment, the following acceptance criteria should be met:
• In a comparative batch analysis, three consecutive batches of drug substance manufactured at the alternative manufacturing site should meet approved specification to demonstrate equivalence to batches manufactured at the currently approved site.
Other conditions to be met prior to implementation:
• Stability studies will be initiated immediately on a suitable number of commercial scale batches of drug substance manufactured at the alternate manufacturing site and drug product manufactured with drug substance produced at the alternate manufacturing site.
Stability studies will be initiated immediately on a suitable number of commercial scale batches of drug substance manufactured at the alternate manufacturing site and drug product manufactured with drug substance produced at the alternate manufacturing site.
• Alternative manufacturing site to have acceptable compliance status for small moleculedrug substance manufacturing; depending on the region, this may be indicated by the lastGMP inspection with acceptable outcome, through a valid GMP certificate, or otherappropriate documentation (e.g., Qualified Person declaration)
• Alternative manufacturing site to use similar manufacturing equipment or equipment withthe same type of material of construction
• Technology transfer and process qualification to be completed
• No change to synthetic route, control strategy, impurity profile, or physicochemicalproperties
• No change to any specification or analytical method for starting material or intermediates
• No change in analytical methods or specification for release and stability testing for drugsubstance manufactured at the alternative site
• Any additional regional requirements.
Summary of Step 1 and Step 2 Submissions
Annex IE: PACMP Example 2
Manufacturing Site Transfers of Biotechnological Drug Substances Proposed
Outline for Step 1 Submission
1. Introduction and Scope
The primary objective of this expanded PACMP is to support the mobility across drug substance manufacturing sites, i.e., the transfer of one or multiple products from one donor site to one or more recipient site(s) including CMOs (sites already licensed with appropriate inspection record) thereby reducing the number of regulatory submissions of similar content and driving consistency. The expanded PACMP effectively leverages concepts of Quality Risk Management and ICH Q9. Typical process adaptations linked to scale and equipment differences at the donor and recipient site(s) are in scope of the protocol (e.g., change in raw material sourcing) whereas the scope excludes opportunistic significant process changes (e.g., changes to increase productivity/yield).
2. Quality Risk Management (QRM)
QRM is performed for each individual site transfer, and includes:
• Identification, scoring, and documentation of the potential hazard and harm associated with each manufacturing unit operation and process change, as well as the prevention and detection controls
• Accounting for known elements of the process, such as robustness, existing controls, and potential impact on product quality
3. Comparability/ Acceptance Criteria
The overall comparability plan in line with ICH Q5E comprises the following elements:
• The drug substance meets all release and in-process specifications, as well as comparability acceptance criteria (e.g., tolerance intervals [TI, 95/99]) derived from the entire manufacturing history
• Analytical profiles from selected characterisation tests of post-change material are consistent with pre-change material in side-by-side comparison
• Process performance attributes, e.g., cell culture performance, purification process yields, and impurities levels are comparable between donor and recipient site
• Planned process validation at the recipient site
• Drug Substance degradation studies consistent with pre-change material
4. Site specific Considerations
a) Site Risk
A risk assessment for the receiving site will be conducted by the MAH at the time of implementation. The risk assessment includes the GMP compliance status and should also include factors such as facility experience, process knowledge, and any additional regional assessments (e.g., QP declaration). The outcome of the risk assessment will indicate to the MAH whether a site inspection by the competent regulatory authority may be needed and whether additional data to support the change should be generated (e.g., site-specific stability data).
b) Process Validation
An overview of the process validation project plan and validation master plan for the site transfer in accordance to the current PQS system should be provided (at step 1). A summary of validation studies performed to support the site transfers, e.g., studies adopted from the donor site and new studies at the recipient site are part of the step 2 implementation submission.
The number of proposed validation batches should be based on the variability of the process, the complexity of the process/product, process knowledge gained during development, supportive data at commercial scale during the technology transfer and the overall experience of the MAH.
c) Stability
Stability studies are traditionally rate-limiting to site transfer timelines; following successful demonstration of comparability by analytical characterisation methods, including accelerated and/ or stress stability studies (see ICH Q12 Guideline Chapter 9) can leverage tiered regulatory submission reporting categories and commitments.
Summary Expanded PACMP Step 1 submission and proposed outline for Step 2 submission
Annex IF: Product Lifecycle Management Document - Illustrative Example
The following example for drug product illustrates how MAH can present the elements of ICH Q12 Chapter 5 in an initial PLCM document. Other approaches and formats can be used as appropriate.
This example follows the ‘enhanced parameter-based approach’ from Annex IA; example for identifying Established Conditions for a Solid Dosage Form Tablet X (small molecule).
ECs defined in the Annex IA example are presented in the table below with additional illustrative ECs, a PACMP and a post-approval CMC Commitment. This table should not be seen as an exhaustive list of ECs. It is recognised that other CTD sections containing ECs, or ECs within a CTD section, as outlined in Appendix 1, may be included in a PLCM document. Additional unit operations (roller compaction, tabletting, and film-coating) are listed for illustrative purposes but their ECs and reporting categories are not described. Similarly, while only the PSD attribute is included in this table, the entire drug substance specification would be provided in an application.
In this example, where the MAH proposes to follow regional regulations and guidance for a change to a particular EC, the reporting category has been left blank.
(Note that identification and justification of EC is presented in the relevant section of CTD)
Widen (NM)
for testing, primary and secondary packaging, device assembly for drug product-device combination products
1. Powder blending
2. Roller compaction
3. Tablet compression
4. Film-coating
The active substance an three excipients are mixed together. The following process parameter are defined as established conditions.
Blend speed: 10-20 rpm
Blend time: 15-25 minutes
Blend speed: 10-20 rpm
Blend time: 15-25 minutes
(Pharmacopoeial)
(Pharmacopoeial)
(Pharmacopoeial)
ANNEX II: STRUCTURED APPROACH TO ANALYTICAL PROCEDURE CHANGES
Principles for Analytical Procedure Changes
MAHs are expected to maintain existing analytical procedures for authorised products and ensure that these are kept up to date. These analytical procedures can relate to the drug substance(s) and drug product. The intent of this approach is to incentivise structured implementation of at least equivalent analytical procedures that are fit for purpose. An approach wherein specific criteria are defined for changes to analytical procedures used to test marketed products is described below. If this approach is followed and all criteria are met, the analytical procedure change can be made with immediate or other post-implementation notification, as appropriate, to the relevant regulatory authorities.
This approach does not apply in the following situations:
• Procedures where the acceptance criteria do not adequately reflect the complex information provided by the method. In particular, procedures for which only a subset of the characteristics are identified and specified (e.g., test for identity by peptide map, assay for complex drug substances), or where the specified acceptance criteria include a general comparison to a reference standard beyond specified characteristics (e.g., “comparable to reference standard” such as for naturally derived products, biotechnology products).
• Change(s) to a test method based on a biological/immunological/immunochemical principle or a method using a biological reagent (e.g., bioassay, binding assay, ELISA, testing for viral adventitious agents).
• Changes to models and multivariate methods; model maintenance for multivariate models is not considered to be a change.
• Changes to analytical procedures (methods) described in pharmacopoeial monographs.
It is important to note that with the exception of the above exclusion criteria, all other methods are in scope including those used for biotechnological/biological products.
In order for this approach to be used, the following should be met:
• The physicochemical basis and the high-level description of the current method and the intended method should be the same (e.g., reversed-phase chromatography with UV spectroscopic detection)
• The acceptance criteria of the validation protocol of the current method can be applied to the proposed method as well.
• Validation results should demonstrate that the intended method is equivalent to or better than the current method
• Test results obtained using the current method and intended method should be equivalent to each other. This should be assessed in two ways: First, the intended method should give an equivalent outcome, i.e., the same conclusion will be made regardless of whether the data was obtained by the current or the intended method. Second, the validation protocol should contain explicit criteria that compare results obtained using the current and proposed method. See step 2 below for further details.
• System suitability requirements should be established for the revised method to ensure the same effectiveness and day-to-day performance of the revised method compared to the current method.
• Acceptance criteria changes (e.g., total impurities, potency) should not be introduced using this mechanism unless tighter/more restrictive acceptance criteria are introduced, or they are allowed by existing regional regulations.
• Toxicological or clinical data are not required as a result of the method change.
If these criteria are met, the methods are equivalent, and changes can be made with immediate or
other post-implementation notification, as appropriate, to regulatory authorities.
Structured Approach for Analytical Procedure Changes
• Step 1: Evaluate the physicochemical basis of the method (the mode) and the method description. When two or more techniques are used together (e.g., HPLC with UV and MS detection), each technique should be included in the method description. The current and intended method (and its mode(s)) should have the same scientific basis and principles. Changes between different modes (e.g. reversed phase to normal phase liquid chromatography) are not in the scope of this guideline.
By way of examples, the following changes could be acceptable:
• A change to a liquid column chromatography method where the mode of separation remains the same e.g. reversed phase to reversed phase, size exclusion to size exclusion etc.
• A change to an electrophoretic method where the mode of separation and method description remains the same e.g. reduced to reduced, non-reduced to non-reduced, etc.
• A change to a pure spectroscopic or chemical/physical property method where principle remains the same e.g., UV to UV, Refractive Index to Refractive Index, DSC to DSC.
This approach can be applied to other methods, as appropriate.
• Step 2: A prospective analytical validation protocol should be prepared and approved internally by the company. It should be based on a comparison of the current and intended method, knowledge of the original validation protocol, and regulatory expectations. The validation should assure that the intended method will be fit for its intended purpose and should contain at least the following:
• The principles of ICH Q2 should be followed to validate the intended method. All validation characteristics relevant to the type of method being validated should be executed as described in ICH Q2.
• The validation protocol should include, at minimum, the tests used to validate the current method and all other relevant tests in ICH Q2, or as required for the analytical method type. For example, if specificity, linearity, precision and accuracy were assessed during validation of the current method, then specificity, linearity, precision and accuracy should also be included in the validation of the intended method. The protocol acceptance criteria should reflect current expectations for method performance, be justified scientifically, and not be less stringent than those used for the validation of the current method.
• The validation should demonstrate that the intended method is at least equivalent to the current method using parallel testing of an adequate number of samples of appropriate concentration based on the intended use of the method. The assessment of equivalency should include the requirement that the new method does not lose any meaningful information provided by the current method. In addition, the same conclusion should result when assessing data from the same samples tested using the current and intended methods.
• If there is a switch from manual to automated methods, the validation should also assess the impact of any related changes in critical reagents, reference standards or software.
• The protocol should also contain the detailed operating conditions of both the current method and the intended method to assure the changes being made are clear.
• Step 3: Consider the system suitability criteria that exist in the current method, if any, and determine, based on method development data and any additional knowledge gained from commercial production, the system suitability criteria aspects that should be part of the intended method. System suitability in this context includes all criteria used to evaluate the day-to-day performance of the method when used for routine testing.
• Step 4: Execute the validation protocol and compare the results to the predetermined acceptance criteria. If all criteria are met, the method is considered acceptable for its intended use. If any criterion is not met, the change in method is outside of the scope of this approach and should not be implemented.
• Step 5: Consider new product information, if any, identified as a result of a change in the context of the current regulatory filing. If new or revised acceptance criteria (e.g., total impurities, potency) are required based on results obtained during method validation, this structured approach may not be used unless allowed by existing regional regulations. In addition, this approach may not be used if toxicological or clinical data are required as a result of the method change. Thus, the method change should have no impact on safety, efficacy, purity, strength, identity, or potency of the product.
• Step 6: Prepare a written summary report documenting the outcome of the validation versus the protocol criteria.
• Step 7: Follow the internal change process as defined within the company’s PQS to implement the change.
• Step 8: Unless new information is identified as a result of this process (see step 5), provide a post-implementation notification of the method change to the regulatory authority after the change is implemented as per regional reporting requirements. This may include the updated method description, the protocol, and the summary report of the validation.
• Step 9: Complete post-change monitoring. The company’s change control system (refer to Appendix 2) should explicitly identify and document a mechanism to assure the change was effective with no unintended consequences. The outcome of the assessment should be documented with a conclusion indicating the acceptability of the change.
• Step 10: All information related to the method change should be available for verification during regulatory inspection.
