Thierry Gastineau is Global Head of Quality Advocacy, Culture, & Innovation at Sanofi Vaccines.

Thierry Gastineau

The International Council for Harmonisation’s (ICH’s) Q10, 

, Annex 1 describes potential opportunities to enhance science and risk-based regulatory approaches to post-approval changes (PACs) as follows: when a company can “demonstrate effective PQS and product and process understanding”, this is an opportunity to “optimize science and risk-based PAC processes to maximize benefits from innovation and continual improvement” (1). Current regulatory mechanisms and guidance for PACs do not consider the company’s latest product and process knowledge when determining the type of filing required to implement the change. Further, the application of ICH Q9, 

(2), or the effectiveness of the company’s pharmaceutical quality system (PQS) to manage PACs is not considered during the assessment of individual PACs, or during inspections. Demonstrating a detailed understanding, effective implementation, and compliance with ICH Q10, will allow companies to overcome barriers to continual improvement and innovation. Additionally, it will help mitigate drug shortages in the global pharmaceutical supply chain by allowing faster implementation of PACs and reduce the burden on both industry and regulators.

This article was originally published online on August 19, 2022.

This specific PAC example of changing a lot or extending the shelf-life of a Reference Standard (RS) has demonstrated the application of the principles outlined in ICH Q9, Q10, Q12 (3) irrespective of current national or regional reporting category and concluded that it could be managed in the PQS only, rather than as a prior-approval change submission when meeting pre-determined criteria.

This position paper is part of a series of industry case studies intended to demonstrate the standard application of the principles outlined in “Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)—Through Enhanced Science and Risk-Based Approaches: Industry One-Voice-of-Quality (1VQ) Solutions” (4).

This PAC example and the 1VQ for PAC Initiative are sponsored by the chief quality officers from more than 20 pharmaceutical companies (5).

Current state for a change of lot or the extension of shelf-life of RS

A RS is a material used as a quantitative or qualitative comparator in the release or stability testing of APIs, drug products (pharmaceuticals/ biologicals), or intermediate products. A RS can be a certified reference material (e.g., 

]), a commercially supplied material, or a material prepared in-house. Both chemical and biological standards (termed as primary reference standard or a working standard) can be used as RS.

Regulatory authority prior-approval is required in several countries for changes associated with introduction of a new lot of RS or with shelf-life extensions for the RS even when there are no changes to the product quality, patient safety, or drug product efficacy, or to the manufacture of the RS.

Differences in regulatory requirements between countries are observed and range from no requirement to submit the PAC to regulatory authorities, to major variation as type II in the European Union, or prior-approval passing through annual reportable, notification, and minor variations.

The use of approved qualification protocol to downgrade the level of submission is accepted by some regulatory authorities but not all.

Differences in regulatory requirements between countries is shown below in 

Drug shortage situations, in particular for vaccines, caused by stock-out of a RS lot, either because it reached its expiry date, or it was fully consumed, could in many cases be avoided by extending shelf-life using sound scientific and risk-based assessment principles or introducing a new RS lot in a timely fashion. However, for countries requiring regulatory authority approval prior to implementation of such a change, the approval process usually varies between 18 to 24 months from submission at an international level, until the last national regulatory authority has approved the change. This lengthy approval timeline can lead to drug shortages. Although companies are carefully planning the supply and use of each RS lot, they are not always in full control of the rate of consumption particularly when drug product demand suddenly changes or if regulatory authorities make a sudden increase in their request for RS samples for their own testing.

This PAC example demonstrates how applying a science- and risk-based approach using laboratory control strategies including qualification protocol, comprehensive implementation planning, and bundling of changes, can support a faster implementation of this type of PAC.

This position paper describes how ICH Q9, ICH Q10, and Q12 can provide the basis for regulatory relief for the change of lot or the extension of shelf-life of RS when it presents no additional risk to product quality and/or patient safety and minimal regulatory risk.

This practical PAC example applies science- and risk-based concepts from ICH Q9, Q10, and Q12 to the change of lot or extension of the shelf-life of a RS used in a test already registered, so that such changes can be implemented timely utilizing the framework of an effective PQS and without extensive regulatory burden. The scope covers RS used in qualitative assays or quantitative assays.

Industry 1VQ for PAC position for change of lot or extension of shelf-life of reference standard. ICH Q12, 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

, provides regulatory flexibility for post-approval changes to the product or its manufacturing process based on latest product and process knowledge, sound scientific and risk-based approaches (3).

The industry 1VQ for PAC position is that the change of a lot or extension of the shelf-life of a RS can be managed in the PQS only, without prior regulatory authority approval, provided pre-registered acceptance criteria are met. It is recommended for each PAC that the company shares its testing and acceptance criteria for introducing a new lot or extending the shelf-life of a RS with regulatory authorities in the form of a qualification protocol/plan. This document would be the basis for changes of lot or extension of shelf-life of a RS without the need to submit documentation for each specific PAC.

The industry 1VQ for PAC position is that information about the lot reference number or expiry date should not be required in the marketing authorization dossiers. If, for historical reasons, the reference standard lot number or expiry date is mentioned in the dossier for those RSs, this information should not be considered as an “Established Condition” (per ICH Q12 definition) but only informative, and the reference number can be removed in the context of any future variation application impacting the concerned Common Technical Document (CTD) sections.

This will allow faster implementation of this type of change and optimize the testing network for timely and efficient testing and disposition of product. In addition, it will contribute toward meeting the ICH Q10 objectives of achieving product realization, establishing and maintaining a state of control, and continual improvement.

As part of a company’s change control process, a science- and risk-based approach with appropriate justification will be documented in the PQS for each change of lot or the extension of shelf-life of RS.

 (4) describes the standard risk-based approach that can be used for assessment of a PAC to change a lot or to extend shelf-life of RS. Application of this risk-based assessment should demonstrate that the change does not increase the risk to product quality and/or patient safety.

The following steps are completed to assess the impact and risks associated with a change of lot or extension of shelf-life of RS as described in the scope section.

 When a PAC to change a lot or to extend shelf-life of RS is proposed, the potential quality, safety, efficacy (QSE), and legal/regulatory impact of the change needs to be considered during the initial high-level impact assessment. This impact can be assessed by using the following risk questions: What might go wrong with the new RS or with the extended shelf-life? Why and how could this happen?

This initial impact assessment should consider an absence of:

RS used for qualitative tests intended to give a pass/fail result, or for all quantitative tests not considered as biological or potency tests, as these RSs do not need an extensive qualification as a RS used for quantitative biological or potency tests. Standards used in quantitative tests not considered as biological or potency tests have a well-defined composition and structure. They are highly characterized and controlled.

RS used for potency or biological assays if the change is performed according to qualification/extension strategy and met the acceptance criteria described in a submitted and approved protocol as established condition (EC). The approach and level of detail given in justifying ECs for qualification/extension of a RS is a company decision, and may depend upon other elements associated with the overall control of the product. The approach must be adapted to ensure the absence of QSE impact.

Legal/regulatory impact in the above-mentioned situations. There is an absence of any legal or regulatory obligations which would require reporting to regulatory authorities. If there is a regulatory impact per local/regional regulation, a more detailed risk assessment should be performed to define the reporting category of the change.

When the initial impact assessment indicates that there is no additional potential QSE risk and no legal/regulatory impact, no additional risk assessments are needed. The change is managed directly in the company’s PQS only.

Steps 3 and 4: change implementation, review, and closure. 

Change implementation, review, and closure should be performed according to the change management process. The outcomes of the impact and risk assessments (if needed) will be integrated into the change implementation plan. After implementation of the change, residual risks should be assessed and managed to acceptable levels prior to change closure; any unintended consequences or risks introduced as a result of the change should be evaluated, documented, and handled adequately through effectiveness verification mechanisms. In case several changes are introduced at the same time or related to each other, the company should assess the cumulative effect of the changes.

If ECs are not met (strategy and/or acceptance criteria) or if there is no EC registered, the initial impact assessment should consider a potential QSE and legal/regulatory impact for these changes as well as all the other changes related to RS not included in the scope of the document and managed through a prior-approval submission.

Demonstrating effective management of a change of lot or extension of shelf-life of reference standard within the PQS

The following risk control elements have been considered for ensuring effective management of the change of lot or extension of shelf-life of RS within the PQS:

It is not triggered by any out-of-trend results or out-of-specification results.

Statistical analysis (e.g., extrapolation linear regression) shows the RS parameters and/or values of control(s) generated with the RS remain within acceptance range throughout the proposed shelf-life extension.

The completion of qualification activities and the implementation of this change will be documented and tracked within the change management PQS element.

This change should be included in the annual product quality review and reported to concerned regulatory authorities through the annual or periodic regulatory reporting mechanism as appropriate.

The Pharmaceutical Inspection and Co-operation Scheme (PIC/S) Recommendation Paper on How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Management (6) provides a practical checklist tool that can be used by the company to evaluate the effectiveness of its risk-based change management process.

This position paper provides a standard and enhanced risk-based approach within the framework of an effective PQS that can be utilized by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC for a new lot of RS or extension of its shelf-life, without increasing risk to the patient and/or product quality, safety, and efficacy.

The benefits of practical application of the principles of ICH Q9, Q10, and Q12 as described in this document are continual improvement with timely (weeks or months vs. years) implementation of such PACs, enhancing product availability and mitigating potential drug shortages, focusing regulatory resources on PACs that may have a potential to impact product quality as it relates to safety and efficacy, reducing the regulatory review and approval burden for medium and low risk changes, and faster implementation of new knowledge and innovative technologies (if applicable).

Many PACs require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual PACs usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods.

Senior quality leaders (chief quality officers and heads of quality) from more than 20 global pharmaceutical companies are speaking with “One-Voice-Of-Quality” (1VQ) to advocate for an effective management of specific PACs that currently are handled as a prior-approval change in some countries, but where a standard science and risk-based approach concludes that these should be downgraded to a notification or handled only in the PQS. This benefit would be a reduction of the implementation timeline from years to months with no increased risk to patient safety.

The authors would like to thank the following chief quality officers (CQOs) for their endorsement of this example and for their continued sponsorship of the 1VQ for PAC Initiative: Kunihiko Kokubo (Astellas, CQO at time of completion of example), Jackie Elbonne (Amgen), Anthony Mire-Sluis (AstraZeneca), Oliver Brehm (Bayer), Melissa Seymour (Biogen), Lothar Halmer (Boehringer Ingelheim), Kerstin Koenig (Bristol-Myers Squibb), Laura O’Brien (CSL Behring), Valerie Brown (Gilead), Paul Daly (GSK), Anil Sawant (Merck Sharp & Dohme Corp.), Dirk Bissinger (Merck Healthcare KGaA), Maria Soler (Novartis, CQO at time of completion of example), Christine Møller-Jensen (Novo Nordisk), Andi Goddard (Roche), Philippe Germanaud (Sanofi), and Scott Gunther (Catalent). The authors also wish to acknowledge Joanna Baszczuk (Global System Owner Change Control, GSK at the initiation of this document) and members of the 1VQ for PAC team who contributed to the development of this manuscript.

PDA Journal of Pharmaceutical Science and Technology

Recommendation: How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Management

Marie-Claire Beckers is global subject matter expert for QC Materials and Samples Management, and Delphine Collete is global subject matter expert for QC Materials Management; both at GSK Vaccines. Julie Barthuet, is head Regulatory CMC&D Vaccines, and Thierry Gastineau is global head quality innovation, Culture & Engagement; both at Sanofi Vaccines.


Volume 46, Number 9
September 2022
Pages: 44–47

When referring to this article, please cite it as M.C. Beckers et al., "Industry 1VQ Solutions: Change of Lot or Extension of Shelf-life of Reference Standard," 

Articles

Change of lot or extension of reference standard shelf-life is considered low
risk and should be downgraded from prior-approval to being managed in the Pharmaceutical Quality System (PQS) only based on a science and risk-based approach.

Industry 1VQ Solutions: Change of Lot or  Extension of Shelf-life of Reference Standard

Post-approval changes (PACs) are inevitable and necessary throughout the lifecycle of pharmaceutical products—to implement new knowledge, maintain a state of control, and drive continual improvement.

This One-Voice-Of-Quality (1VQ) for Post-Approval Changes (PAC) position paper is part of a series of industry case studies intended to demonstrate the standard application of the principles outlined in the publication “Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)–Through Enhanced Science and Risk-Based Approaches: Industry One-Voice-of-Quality (1VQ) Solutions” (1)

Furthermore, this 1VQ for PAC position paper provides a practical application of the concepts described in International Council for Harmonisation (ICH) Q9 (2), 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management 

(4) to PACs that bring an additional restriction on the product compared to registered conditions.

The conclusion drawn from this case study is that those changes present a very low risk, and therefore, can be downgraded from a prior-approval to a notification after implementation and managed in the PQS with immediate implementation effect.

, Annex 1 describes potential opportunities to enhance science and risk-based regulatory approaches to PACs as follows: When a company can “demonstrate effective PQS and product and process understanding” this is an opportunity to 

optimize science and risk-based PAC processes to maximize benefits from innovation and continual improvement

 Current regulatory mechanisms and guidance for PACs do not consider the company’s latest product and process knowledge when determining the type of filing required to implement the change. Further, the application of ICH Q9, 

 or the effectiveness of the company’s PQS to manage PACs is not considered during the assessment of individual PACs, or during inspections. Demonstrating a detailed understanding, effective implementation, and compliance with ICH Q10, will allow companies to overcome barriers to continual improvement and innovation. Additionally, it will help mitigate drug shortages in the global pharmaceutical supply chain by allowing faster implementation of PACs and reduce the burden on both industry and regulators.

This specific example of PACs that bring an additional restriction on the product compared to registered conditions,has demonstrated the application of the principles outlined in ICH Q9, Q10, and Q12 irrespective of current national or regional reporting category and concluded that it could be managed as a notification after implementation.

This PAC example and the 1VQ for PAC Initiative is sponsored by the Chief Quality Officer’s from more than 20 pharmaceutical companies (5).

Description of current state for changes that bring an additional restriction on the product compared to registered conditions

Putting additional restriction(s) on the drug product or vaccine compared to registered conditions does not affect compliance to the license as it is produced and controlled under more stringent conditions than the ones registered in the approved Marketing Authorization Application (MAA, NDA [new drug application], BLA [biologics license application], or similar, depending on country/region of approval). As a company generates new product and process knowledge during commercial manufacturing and testing, it may decide to tighten or add certain operational parameters to reduce process variation and/or tighten manufacturing and testing controls. Such continual improvement activities should be encouraged.

Specific examples of PACs that add restriction(s) on the product compared to registered conditions are:

 of acceptance criteria on manufacturing process ranges or test methods performed on the product, materials, or excipients

 of a test method performed on the product, materials, or excipients as long as it is not necessitated by a change in a critical process parameter (CPP)

 of a validity criterion for an analytical method

 of a CPP in the master batch record of the product, without any change in the manufacturing process.

For any such change mentioned above, the company should provide rationale for the change and supporting documentation in their PQS. These changes do not have a negative impact on the critical quality attributes (CQAs) of the product, and consequently on quality and safety. However, in certain countries, these changes require prior-approval by the regulatory authority.

Table I lists countries requiring prior-approval for PACs to drug product. These additional examples of restriction(s) compared to the registered conditions according to regulations or experience, are based on Sanofi Vaccines experience.

Companies are confronted with the following dilemma: implement continual improvements with no negative impact to patients as soon as possible after gaining new knowledge vs. wait for approval by regulatory authorities requiring prior-approval even though the PAC provides more stringent conditions than those in the approved Marketing Authorization.

By definition, more stringent conditions fall within the registered parameters and thus, comply with the Marketing Authorization.

As part of the company’s change control process, a science and risk-based approach with appropriate justification and documentation must be documented in the PQS when evaluating the changes mentioned in this document.

This document applies to PACs that bring an additional restriction on the product compared to registered conditions for commercial drug substances and products (chemical and biological/biotechnological products including vaccines).The principles and quality risk management approach described in this document are intended to apply globally to all regulatory authorities.

This risk-based approach applies to PACs which fulfill the following conditions:

The change brings an additional restriction on the product compared to registered conditions.

The change does not have any impact on the CQAs of the product, and consequently on product quality and safety.

Industry 1VQ for PAC position for a change that brings an additional restriction on the product compared to registered conditions

echnical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

 provides regulatory flexibility for PACs to the product, or its manufacturing process, based on latest product and process knowledge, sound scientific and risk-based approaches (4).

A PACwhich brings an additional restriction on the product compared to registered conditions with the appropriate supporting data (e.g., validation of the analytical method for an additional test, process validation for an additional monitored CPP) can be managed within the PQS, leveraging the principles outlined in ICH Q9, Q10, and Q12. This type of change may only be managed under the PQS and/or be reported to the regulatory authorities within ICH, Pharmaceutical Inspection Co-operation Scheme (PIC/S) and World Health Organization (WHO) member countries through annual reports or notification after implementation.It should not require prior-approval from the regulatory authorities. This will facilitate use of new knowledge and continual improvement efforts to increase the level of control of products in a timely fashion, including the potential to reduce process variability by implementing additional restriction on the product compared to initial registered conditions.

Figure 1 describes the risk-based approach for assessment of a PAC which brings an additional restriction on the product compared to registered conditions. Such PACs do not increase risks beyond current levels. 

Figure 1: Risk-based assessment of PACs and determination of regulatory reporting category

When a PAC that brings an additional restriction on the product compared to registered conditionsis proposed and entered into the change management system, the potential quality, safety, efficacy (QSE) and legal/regulatory impact of the change needs to be considered during the initial high-level impact assessment. This impact can be assessed by using the following risk questions: What might go wrong when changing from the current situation to the proposed one? Why or how could this happen? This initial impact assessment should consider existing product and process knowledge (including process performance and variability) and current control strategies, as follows:

 There is no potential QSE risk associated with a PAC that brings an additional restriction on the product compared to registered conditions given that the product is manufactured and controlled according to restricted specifications, and providing that data supporting the change are assessed and readily available.

 If there is a regulatory impact per local/regional regulation, a more detailed risk assessment needs to be performed to define the reporting category of the change. In this example, some countries require prior-approval of the PAC despite there being no potential QSE risk.

The initial impact assessment concluded that there is no potential QSE risk associated with this change of additional restrictions on the product compared to registered conditions. In the case, when the change was triggered by recurring events or negative trends arising during manufacture and testing, the assessment should ensure that the relevant PQS requirements have been appropriately followed for managing this change (e.g., appropriate corrective and preventive actions [CAPA], deviation management).

Therefore, no additional risk assessment is required for this low-risk PAC, and the change can be managed within the company’s PQS and implemented immediately without the need for a regulatory prior approval.

Steps 3 and 4: Change implementation, review, and closure. 

Change implementation, review, and closure should be performed according to the change management process. The outcomes of the impact and risk assessments (if needed) will be integrated into the change implementation plan. After implementation of the change, residual risks should be assessed and managed to acceptable levels prior to change closure; any unintended consequences or risks introduced as a result of the change should be evaluated, documented, and handled adequately through effectiveness verification mechanisms. In case several changes are introduced at the same time or related to each other, the company should assess cumulative effect of the changes.

Demonstrating effective management of a change that brings an additional restriction on the product compared to registered conditions within the PQS

The following risk control elements have been considered for ensuring effective management of such PACs within the PQS:

No impact on the CQAs of the product, and consequently on quality and safety

No change to in-place analytical methods or system suitability

Validation is adequately performed and documented.

This change should be included in the Annual Product Quality Review and reported to concerned regulatory authorities through the annual or periodic regulatory reporting mechanism as appropriate or through notification after implementation.

How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Managemen

t (6) provides a practical checklist tool that can be used by the company to evaluate the effectiveness of its risk-based change management process.

This 1VQ for PAC position paper provides a standard and enhanced risk-based approach within the framework of an effective PQS that can be utilized by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC that brings an additional restriction on the product compared to registered conditions, without increasing risk to the patient and/or product quality, safety, and efficacy.

The benefits of practical application of the principles of ICH Q9, Q10, and Q12 as described in this document are:

Continual improvement with timely (weeks or months vs. years) implementation of such PACs

Enhancing product availability and mitigating potential drug shortages

Focusing regulatory resources on PACs that may have a potential to impact product quality as it relates to safety and efficacy

Reducing the regulatory approval burden for medium and low-risk changes

Faster implementation of new knowledge and innovative technologies (e.g., new test).

Senior Quality leaders (chief quality officers and heads of quality) from more than 20 global pharmaceutical companies are speaking with “One-Voice-Of-Quality” (1VQ) to advocate for an effective management of specific PACs that currently are handled as a prior-approval change in some countries, but where a standard science and risk-based approach concludes that these should be downgraded to a notification or handled only in the PQS. This benefit would be a reduction of the implementation timeline from years to months with no increased risk to product quality or patient safety.

Thank you to the following Chief Quality Officers (CQOs) for their endorsement of this example and for their continued sponsorship of the 1VQ for PAC Initiative:

Kunihiko Kokubo (Astellas, CQO at time of completion of example), Jackie Elbonne (Amgen), Anthony Mire-Sluis (AstraZeneca), Oliver Brehm (Bayer), Melissa Seymour (Biogen), Lothar Halmer (Boehringer Ingelheim), Kerstin Koenig (Bristol-Myers Squibb), Laura O’Brien (CSL Behring), Valerie Brown (Gilead), Paul Daly (GSK), Anil Sawant (Merck Sharp & Dohme Corp.), Dirk Bissinger (Merck Healthcare KGaA), Maria Soler (Novartis, CQO at time of completion of example), Christine Møller-Jensen (Novo Nordisk), Andi Goddard (Roche), Philippe Germanaud (Sanofi), Scott Gunther (Catalent)

The authors wish to acknowledge Mic McGoldrick (Merck & Co, Inc), Leader of IFPMA VSRWG (Vaccines Scientific and Regulatory Working Group) and members of the 

 team who contributed to development of this manuscript.

E. Ramnarine et. al., "Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS) – Through Enhanced Science and Risk-Based Approaches. Industry One-Voice-of-Quality (1VQ) Solutions,”

E. Ramnarine and A. Vinther, “Solving the Global Continual Improvement and Innovation Challenge: How an Effective Pharmaceutical Quality System Can Transform Post-Approval Change Management; One-Voice-of-Quality Concept Paper,” 

 How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Management

, 2021. Available at: https://picscheme.org/docview/4294

The authors declare no conflict of interest related to the content of the article.

A case study discussing why post-approval changes present a very low risk, and therefore can be downgraded from a prior-approval to a notification after implementation and managed in the PQS with immediate implementation effect. 