The world economies are increasingly threatened by barriers to trade, while the pharmaceutical sector through the International Council for Harmonization (ICH) has been stepping up the effort to dismantle obstacles to global trade in medicines.
Regulatory Point of View
From 2005 through 2011 ICH published Q8-Q11 guidelines that introduced Quality by Design (QbD) concepts to product development and manufacturing. Industry expected regulatory flexibility and harmonization from these ICH guidelines, but the guidelines did not convey methods for optimal processes and planning. Regulatory filings still contain more information and raise more questions than ever before.
Globally, applicable changes are a logistical challenge due to different timelines and submission requirements for post-approval changes.
Hence, the risk of drug shortages, supply deviations and noncompliance situations are increased. In summary:
- Lack of a harmonized approach on technical and regulatory considerations for lifecycle management
- Several gaps exist that limits full realization of intended benefits of ICH Q8-Q11
- Post-approval “operational flexibility” has not been achieved
- Main emphasis at ICH to date has focused on early stages of the product lifecycle
Hence, to alleviate the gaps, ICH Q12 introduced and issued for comments in December 2017; The draft guidance ICH Q12 entitled “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management,”
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Draft_Guideline_Step2_2017_1116.pdf has been published for comment. It applies for products, including development and manufacture of drug substances (chemical entities and biotechnological/biological entities) - ICH Q11 and drug-device combinations – ICH M3 (R2), Step 4, June 11, 2009.
ICH Q12 explicitly addresses post-approval changes for products already on the market. Following, ICH Q12 most manufacturing and analytical changes (Figure 1) can be managed efficiently under the pharmaceutical quality system (PQS) of a company without regulatory approval prior to implementation. Therefore, cooperation of regulators (assessors and inspectors) is required by ICH Q12.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!
Incompatibility with Established EU Regulatory Framework
During the final framing of drafting ICH Q12 guideline, the European Commission discovered that after a review of the EU rules, parts of the guideline could not be implemented in the EU without changes in legislation. These differences mainly centered on the guideline concept of established conditions (ECs) for manufacturing and control for categorizing quality elements requiring regulatory submission if changed, and product lifecycle management (PLCM) which establishes a repository on details of established conditions.
Both the ECs and PLCM concepts are at the core of Q12 guideline. ECs provide a basis for key objectives behind the guideline of enabling marketing authorization holders (MAH) to commit, with agreement of their regulatory agency to their own lifecycle management protocols for manufacturing and issues related to lifecycle management, particularly to CMC.
Key Aspects of ICH Q12
- ECs - Established Conditions
The concept of ECs, provides a clear understanding between the Marketing Authorization Holder (MAH) and regulatory authorities regarding the necessary elements to assure product quality and identify the elements that require a regulatory submission. - PACMP - Post-Approval Change Management Protocol
For planned changes, the PACMP is a tool that provides predictability regarding the information to support a CMC change and the type (category, which is usually one step lower than without PACMP) of regulatory submission based on prior agreement between the MAH and the responsible competent authority. - PLCM - Product Life Cycle Management
The PLCM document is for proactive management of the product lifecycle.
Regulatory Tools and Enablers - Chapter 1.3
ICH Q12 has the potential to reduce costs and time burdens for regulators and the industry. One of the real benefits could be the potential regulatory commitment among ICH regions related to what is “supportive information” within regulatory submissions. This should also lead to greater application of innovative technologies in manufacturing and control (i.e. analytical methods) in a timely manner.
Categorization of Post Approval CMC Changes - Chapter 2
Categorization of Post-Approval CMC Changes is a framework that encompasses a risk-based categorization for the type of communication expected of the Marketing Authorization Holder (MAH) with the regulatory authority regarding CMC changes.
Harmonizing change management in a more transparent and efficient manner facilitates risk-based regulatory oversight. Harmonized expectations across the ICH regions emphasize control strategy as a key component of the enhanced use of regulatory tools for prospective change management and enabling strategic management of post approval changes.
There are some examples of the CTD Sections that contain ECs (Established Conditions) listed in Appendix I of ICH Q12. The 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.
Established Conditions (ECs) - Chapter 3
- 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.
- All regulatory submissions 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, and to justify the initial selection of ECs and their reporting category.
- ECs in a submission are either implicit or explicit:
- Implicit ECs are elements that are not specifically proposed by the applicant but are derived from and revised according to regional regulation or guidance related to post-approval changes.
- Explicit ECs are specifically identified and proposed by the applicant together with their proposed reporting category as part of a regulatory submission.
Post Approval Change Management Protocol (PACMP) - Chapter 4
- A PACMP provides predictability and transparency in terms of the requirements and studies needed to implement a change.
- An approved PACMP needs to be maintained and assessed routinely:
- ensure that the outcomes of the initial risk assessment are still valid.
- confirm that the control strategy continues to ensure that the product will be produced consistently following implementation of the change(s).
- The use of a PACMP is enabled through an eff ective PQS that incorporates quality risk management principles and an effective change management system.
- Whenever a CMC change is to be introduced under a PACMP regulatory requirements with respect to GMP compliance, an inspection or licensing status should be considered.
Product Lifecycle Management (PLCM) - Chapter 5
- The PLCM document outlines the specific plan for product lifecycle management, and includes key elements:
- Summary of Product Control Strategy
- Proposed ECs for the product
- Reporting category for making changes to approved ECs
- PACMPs to prospectively manage and implement one or more post approval changes
- Post-approval CMC commitments
- Use of a PLCM encourages prospective lifecycle management planning and facilitate regulatory assessment and inspection.
- The PLCM document should be updated throughout the product lifecycle, as needed.
Pharmaceutical Quality System (PQS) and Change Management - Chapter 6
An effective PQS as established in ICH Q10 and in compliance with regional cGMPs is the responsibility of the fi rm. Q12 does not require a specific inspection assessing the state of the PQS before the principles can be used. In the event that the PQS is found not to be compliant, it may result in restrictions on the ability to utilize the flexibility in this guideline.
Consistent with the basic requirements of ICH Q10, an effective change management system is necessary for implementation of this guideline (ICH Q12).
Use of knowledge is the responsibility of the firm and should be described in the PQS (for more detailed information reference is made to ICH Q8, Q9, Q10, Q11, Q/IWG Q&A). As described in ICH Q10, there is no added regulatory requirement for a formal knowledge management system.
Relationship Between Regulatory Assessment and Inspection - Chapter 7
Regulatory assessment and inspection are complementary activities and communication between assessors and inspectors can facilitate regulatory review of a specific product submission.
Post Approval Changes for Marketed Products - Chapter 8
A structured approach to analytical procedure changes, incentivizes structured implementation of equivalent analytical procedures that are fi t for purpose (some complex products and methods would be out of scope). Specific criteria are defined for changes to analytical procedures used to test marketed products is described, if followed, the analytical procedure change can be made with immediate or another post-implementation notification, as appropriate.
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 science-and risk-based approaches that can be used to develop strategies for confirmatory stability studies supporting post-approval changes to enable more timely fi ling, approval, and implementation of the changes.
As a note comparing Figure 1 and Figure 3; we note that there is similarity between selecting ‘Parameter Criticality’ and ‘Established Conditions’. Changes in ‘CPP’ illustrate a requirement for ‘Prior Approval’; changes in ‘KPP’ requires ‘Notifi cation’; and changes in ‘Non-KPP’ is ‘Not-Reported’.
Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management; Annex
The Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management guideline is issued under a separate document to covey ICH Q12 guidance.
https://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM609366.pdf, Endorsed on 16 November 2017, Currently under public consultation.
ICH Q12, Annex Illustrative Examples;
Annex I: ECs –Illustrative Examples
- Annex I A: Chemical Product
- Annex I B: Biological Product
- Annex II: PACMP –Illustrative Examples
- Annex II A: PACMP Example 1
- Annex II B: PACMP Example 2
- Annex III: Product Lifecycle Management Document
Conclusion
As described by ICH Q12, a harmonized approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the biopharmaceutical sector, strengthening quality assurance and improving supply of medicinal products. This guideline provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner. It is also intended to demonstrate how increased product and process knowledge can contribute to a reduction in the number of regulatory submissions. Effective implementation of the tools and enablers described in this guideline should enhance industry’s ability to manage many CMC changes effectively under the firm’s Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight prior to implementation.
References
- ICH Q12, Step 2, Draft, “TECHNICAL AND REGULATORY CONSIDERATIONS FOR PHARMACEUTICAL PRODUCT LIFECYCLE MANAGEMENT,” https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Draft_Guideline_Step2_2017_1116.pdf
- ICH Q12 Annex, Draft, “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management,” https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM609366.pdf, Endorsed on 16 November 2017
- ICH Q8-Q11, 2005-2011
- ICH M3(R2), Step 4, June 11, 2009; “GUIDANCE ON NONCLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRIALS AND MARKETING AUTHORIZATION FOR PHARMACEUTICALS,” https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf