Federico Colombari is Quality Risk Management Specialist at Roche.

Federico Colombari

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, 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

 (4) to a PAC for replacing identity (ID) testing of incoming liquid drug substance (DS) with ID by visual verification.

The conclusion drawn from this case study is that this change presents a low risk and, therefore, can be downgraded from a prior approval to a notification (EU Type 1A/US Annual Reportable/Canada Level III) 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” (3)

 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 a PAC to replace ID testing of incoming liquid DS with ID visual verification demonstrates the application of the principles outlined in ICH Q9, Q10, and Q12 irrespective of current national or regional reporting category and concludes that it could be managed as a minor variation (EU Type 1A/US Annual Reportable/Canada Level III).

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

Description of current state for a change to replace id testing of incoming liquid DS with ID visual verification

Regulatory authority notification or prior-approval with long waiting periods is required in most countries for PACs associated with changing ID testing for incoming liquid DS, even when there are no changes to the product quality and/or patient safety, and the product and laboratory controls remain the same. This PAC is an example of aligning an ID verification strategy of incoming liquid drug substances across several manufacturing sites. Such an approach can be used, for instance, when a company wants to align, harmonize, and simplify testing procedures across their network.

The execution phase for such a PAC can be quite complex and challenging if it impacts several drug substances or drug products that are marketed worldwide. Regulatory relevance and reporting category may typically vary from product to product and country to country. Regulatory relevance ranges from prior-approval submission to annual reportable for each regulatory relevant product. Therefore, the PAC cannot be implemented for all impacted products across all countries at the same time.

The planning phase for such a PAC should include regulatory assessments and a quality risk assessment specifically for the PAC. Based on the quality risk assessment the PAC can be managed as a minor variation (for EU Type 1A/US Annual Reportable/Canada Level III) instead of a prior-approval (refer to section “Standard Risk-Based Approach”).

Due to differences in regulatory relevance of products, implementation of this type of change is performed via a transition phase. This leads to an execution phase of up to minimum 10 months, depending on when the green light is received for each specific regulatory relevant product.

Differences in regulatory relevance between countries is shown below in Table I.

Table I: Regulatory Reporting Category in Different Countries

This position paper describes how ICH Q10 and Q12 can provide the basis for regulatory relief for this specific change from ID testing to ID visual verification for incoming liquid DS, as it presents no additional risk to product quality and/or patient safety and minimal regulatory risk.

The position paper applies science- and risk-based concepts from ICH Q9, Q10, and Q12 such that a change from ID testing to ID visual verification for incoming liquid DS can be implemented proactively using the framework of an effective PQS, and without extensive regulatory burden. The following are in scope for this PAC:

Liquid DS for manufacture of parenteral products, specifically liquid DS, frozen for storage and shipment

All batches intended for human (clinical and commercial) use

Direct shipments within the company as well as shipments via the internal distribution center (central warehouse/hub).

Shipments from third parties (e.g., contract manufacturing organizations)

Batches not intended for human use (e.g., technical batches)

Storage in an external central warehouse/hub, not under the company’s control

Partner products not owned by the company but handled through a partnership

Transfer of containers within the same area/campus (DS and drug product (DP) manufacture on the same site).

Definition and baseline criteria include:

Multi-use containers (tank and bulk cans), as well as single use containers (bottles and bags), are considered primary containers.

Industry 1VQ for PAC position for replacing ID testing of incoming liquid DS with ID visual verification

In companies with several manufacturing sites, the implementation of PQS over time might have led to a misaligned approach on defining certain processes and procedures. Especially, when mergers or acquisitions take place, processes and procedures need to be aligned to ensure application of the same standard across the company. Having an aligned approach allows establishing and maintaining a state of control and supporting continuous improvement across the lifecycle.

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

Applying the principles in ICH Q9, Q10, and Q12, including risk-based implementation planning, appropriate bundling of changes, and proactively engaging with health authorities that are known to require long prior-approval timelines, can enable this low-risk change to be managed through annual reports or notifications without prior regulatory approval, and speed up implementation of the PAC.

Current ID testing involves thawing of the DS prior to DP manufacture. The DS is thawed and then sampled (unless side samples are provided). Biologics DS are temperature-sensitive with limited stability in unfrozen states. Additionally, allowed number of freeze-thaw cycles are limited for product stability reasons. Testing is a holding step, as confirmed test results are the prerequisite to start with DP manufacture.

Visual ID verification is performed as verification of the documented identity as well as assessment of discrepancies during transport or interim storage. After thawing, the DS can be used immediately for production.

The visual ID verification is aligned with the quality concept to focus on ensuring adequate preventive controls such as correct delivery instead of establishing additional detection controls. A quality risk management approach is leveraged to determine the adequateness of the prevention controls to ensure the correct DS is delivered at the DP site.

The pharmaceutical industry’s position is that a change from ID testing to ID visual verification for incoming liquid DS as described in the Scope section, should not need to be assessed as a prior-approval submission. This will allow faster implementation of this change, and alignment of a company’s network.In addition, it will contribute towards 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 for this PAC.

 (1) describes the risk-based approach for assessment of a PAC to replace ID testing of incoming liquid DS with ID visual verification. Application of this risk-based assessment, based on current product control strategy, should demonstrate that at a minimum 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 the change.

When a PAC to replace ID testing of incoming liquid DS with ID visual verification is proposed and entered into the change management system, the potential quality, safety, and efficacy (QSE) and legal/regulatory impact of the change needs to be considered during the initial high-level impact assessment. This can be assessed by using the following risk questions: What is the potential impact on QSE for implementing this change? What is the potential risk on QSE during the process of 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.

The methodology of ID verification is not clearly defined and aligned among the different GMP regulations (

 Vol. 4, 5.35 and Annex 8 [European Union]; AMWHV §13, I-SMI.TI.10 [Switzerland]; 21 

] 211.84. [United States]; C02.009, C02.010, C02.011 [Canada]; RDC Nº 17, Art. 165. [Brazil]; NOM-059-SSA1-2015 10.1.3 [Mexico]; Korean GMP Annex 6 [Korea]; Pharmaceutical Inspection and Cooperation Scheme [PIC/S] [Singapore; Japan]; Chinese GMP article 110 [China]; Russian GMP III, 3(2) [Russia]).

World Health Organization (WHO) Annex 4 states: “Guidelines acknowledge different procedures justified if the material is homogeneous and that opening of each container is ‘not prudent”’ when it is ‘liable to deteriorate’” (5).

Biologics DS are temperature-sensitive with limited stability in unfrozen states. Additionally, allowed number of freeze-thaw cycles are limited for product stability reasons. Based on the composition, biologics DS are stored and shipped in frozen state. For analytical testing, the DS container needs to be thawed and sampled. Specifically, for DS used for parenteral use, such sampling introduces a potential risk of microbial contamination.

The initial impact assessment indicated a potential QSE risk and a potential legal/regulatory impact. Therefore, a more detailed risk assessment was performed to define the reporting category of the change.

Step 2A: change evaluation—quality risk assessment.

 The initial impact assessment concluded that there might be a potential impact associated with the change, or the potential impact is unclear, therefore, a quality risk assessment should be performed for the PAC. As the risk assessment covers development, commercial manufacturing, quality control (QC) testing and release, subject matter experts (SMEs) from each of these areas should be involved. When assessing potential risks of the change, any potential impact (direct or indirect) on the identity, strength, quality, purity, or potency of the product should be considered, based on current product/process knowledge and the control strategy. Some examples of risk questions that should be considered to assess the potential risks associated with a change to replace ID testing of incoming liquid DS with ID visual verification include

Can this change potentially lead to DP containing the wrong active ingredient or to product mix-ups?

Can this change result in inadequate detection of an issue with the incoming liquid DS?

Can potential product tampering or counterfeit of the incoming liquid DS be detected as part of the process?

Can the change potentially affect conformity of the product to current specifications?

Can the change potentially affect potency of the product (i.e., ability of the product to affect a given result)?

Can the change impact performance of an analytical method?

An end-to-end assessment should be conducted starting with the bulk filtration/filling step into the primary container at the DS site up to the in-bound check of the material identity at the DP manufacturing site. The Table II provides a possible risk assessment template for a change to replace ID testing of incoming liquid DS with ID visual verification. Other risk assessment tools may be used as appropriate.

Table II: Possible Risk Assessment Template

A potential hazard considered in this risk assessment example is 

‘wrong (mixed up) DS is used at a DP manufacturing site’

. Possible failures leading to the hazard and relevant controls are assessed to determine the overall risk level.

Wrong/incorrect delivery documentation, etc.

To manage the risk of this hazard the already established prevention (P) and corresponding detection (D) controls for each process step were considered. The set of controls implemented need to be able to securely prevent the use of a mixed up (wrong) DS for a DP manufacture. Additional controls should be identified as needed, as shown in the example. The risk assessment should be completed for all applicable failures.

Upon completion of the risk assessment, it should be determined if sufficient controls are in place to deem the change as low risk and if the residual potential risk (in this example of contamination and mix up) is acceptable.

Assignment of Regulatory Reporting Category:Consistent with ICH Q12 (6), it is recommended that:

High-risk changes are categorized as prior-approval, and as such require regulatory authority review and approval prior to implementation.

Moderate- to low-risk changes are communicated to the regulatory authority as a formal notification, that takes place within a defined period before or after implementation, according to regional regulatory requirements.

Based on the outcome of the risk assessment (performed in step 2A), a change to replace ID testing of starting material/DS with ID visual verification can be managed as a minor variation (Type 1A), provided there are no high risks for instance, due to inadequate risk controls. Where several sufficient prevention and detection controls are already in place and additional controls, implementation plans, and procedures for these controls were defined to control the identified risk (e.g., mix up), the level of risk can be determined to be low. It can therefore be managed as a notification with immediate effect for implementation through the company’s PQS. It is recommended to share the risk assessment and risk controls with regulatory agencies and discuss a downgrade from a prior-approval to a notification reporting category.

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

 Change implementation, review, and closure should be performed according to the change management process and based on the regulatory assessment outcome. Activities that can be bundled should be considered to increase overall speed of the PAC. Outcomes of the impact assessment and risk assessment should be integrated into the overall 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 effectiveness of the changes.

After change closure, relevant risk assessment tools and documents should be updated post-effectiveness assessments and documented in the PQS. Product quality monitoring and periodic product quality review should be performed post-closure for the ongoing review/monitoring of the risks associated with a change to replace ID testing of incoming liquid DS with ID visual verification.

Demonstrating effective management of a change to replace ID testing of incoming liquid DS with ID visual verification within the PQS

The following risk control elements have been considered and documented within the PQS for ensuring effective management of a change to replace ID testing of incoming liquid DS with ID visual verification:

No other changes in DS or DP release testing

Training and qualification of personnel performing visual verification

No change in approved analytical specifications, or system suitability

Comprehensive implementation planning of change is documented and managed in the PQS as part of the change control process.

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

t (7) 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 to replace ID testing of incoming liquid DS with ID visual verification, 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 (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 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:

Sean McEwen (Abbvie), Jackie Elbonne, (Amgen), Kunihiko Kokubo (Astellas, CQO at time of completion of example), 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), Flemming Dahl (Novo Nordisk, CQO at time of completion of example), Andi Goddard (Roche), Philippe Germanaud (Sanofi), Jerry Greco (Takeda), Edith Koller-Dette (Teva)

The authors wish to acknowledge members of the 

 team who contributed to development of this manuscript.

Articles

A Post Approval Change (PAC) to replace identity (ID) testing of incoming liquid drug substance with ID by visual inspection is considered a low risk provided questioned listed in this example have been answered favorably. In that case the PAC can be downgraded from a prior approval to a notification to health authorities, and managed in the PQS with immediate implementation effect.

Industry 1VQ Solutions: Replace Identity (ID) Testing of Incoming Liquid Drug Substance with ID by Visual Verification 

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).

 (4) to a PAC in thermal shipping solution size used for transport of product.

The conclusion drawn from this case study is that this change presents a low risk and, therefore, can be downgraded from a prior-approval to a notification 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”(3)

 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 a PAC in the size of a thermal shipping solution used for transport of productdemonstrates the application of the principles outlined in ICH Q9, Q10, and Q12 irrespective of current national or regional reporting category and concludes that this change could be managed as a notification after implementation instead of a prior-approval submission.

Description of current state for a change in size of thermal shipping solution used for transport of product

Regulatory authority notification or prior-approval is required in several countries for PACs associated with changing the size of the thermal shipping solution for cold chain products to be shipped worldwide, even when there are no changes to the product quality and/or patient safety and the shipping and transportation controls remain the same. Adjusting the size of shipping solutions increases the efficiency and flexibility without increasing any risk to product quality and/or patient safety.

The complexity of the submission level in different countries represents the primary challenge. In many countries, this PAC is not considered regulatory relevant; reporting levels in other countries where it is considered regulatory relevant are listed in Table I.

This position paper describes how ICH Q10 and Q12 can provide the basis for regulatory relief for this specific change in the size of the thermal shipping solution for cold chain products, as it presents no additional risk to product quality and/or patient safety and minimal regulatory risk.

The position paper applies science- and risk-based concepts from ICH Q9, Q10, and Q12 such that a change in the size of the thermal shipping solution for cold chain products can be implemented globally utilizing the framework of an effective PQS, and without extensive regulatory burden. All cold chain products (+2 to +8 °C) that are shipped in small volumes to affiliates and third-party customers worldwide are in scope of this PAC.

 position for change in size of thermal shipping solution used for transport of product

Applying the principles in ICH Q9, Q10, and Q12 and proactively engaging with health authorities that are known to require notification or prior approval can enable this low-risk change to be managed solely in the PQS, and speed up implementation of the PAC.

The pharmaceutical industry’s position is that changing the size of the thermal shipping solution for cold chain products should not need to be assessed as regulatory impacting. Adjusting the size of the thermal shipping solution to the volume of product being shipped increases the efficiency and flexibility for small-volume shipments. In addition to the higher flexibility in delivering small volumes worldwide, it reduces packaging material, transport costs, and CO2 emissions by using the right packaging solution related to the individual order volume while maintaining a state of control. Transport validation should be performed prior to implementation of the PAC.

This change presents no increased risk to product quality and/or patient safety, allowing for faster implementation of the change. In addition, it will contribute towards 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 and transport validation will be documented for a change in the size of the thermal shipping solution.

 (1) describes the risk-based approach for assessment of a PAC to the size of the thermal shipping solution used for transport of product. Application of this risk-based assessment, based on current controls including shipping/transport validation, should demonstrate that at a minimum the change does not increase the risk to product quality and/or patient safety.

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

. When a PAC in the size of the thermal shipping solution used for transport of product is proposed and entered into the change management system, the potential quality, safety, and efficacy (QSE) and legal/regulatory impact of the change needs to be considered during the initial high-level impact assessment. This can be assessed by using the following risk questions: What might go wrong when changing from the current size to the proposed one? Why or how could this happen? This initial impact assessment should consider existing product and process knowledge (including current shipping validation) and current control strategies.

Due to the availability of data and experience, the initial impact assessment indicated that the impact on product quality is low. Transport validation activities will be completed to confirm. An assessment to determine potential regulatory impact needs to be performed.

 A quality risk assessmentis performed when assessing potential risks of the change. Any potential impact (direct or indirect) on the identity, strength, quality, purity or potency of the product should be considered, based on current product/process knowledge and the control strategy. Some examples of risk questions that should be considered to assess the risks associated with a change to size in thermal shipping solution used for transport of product include:

Can the change potentially impact stability of the product?

Existing knowledge was leveraged to determine the risks and controls that need to be tested during shipping qualification. Potential impact on product quality was assessed as low due to the available data and experience.

The qualification was successful and the risk to product quality confirmed to be low. Temperature monitoring is performed according to requirements in the PQS.

Step 2B: assignment of regulatory reporting category: 

In an assignment of regulatory reporting category, consistent with ICH Q12 (4), it is recommended that:

Moderate- to low-risk changes are communicated to the regulatory authority as a formal notification, which takes place within a defined period before or after implementation, according to regional regulatory requirements.

Based on the outcome of the risk assessment (performed in step 2A), a change in size of the thermal shipping solution used for transport of product can be managed either as low risk or as prior-approval depending on the country. In many countries, such a change is considered as ‘not regulatory relevant’ provided there are no high risks for instance, due to inadequate risk controls. It is recommended to share the risk assessment with the regulatory agency and discuss the reporting category.

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

. Change implementation, review, and closure should be performed according to the change management process. Outcomes of the impact assessment and risk assessment should be integrated into the overall 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 effectiveness of the changes.

After change closure, relevant risk assessment tools and documents should be updated post-effectiveness assessments and documented in the PQS. Product quality monitoring and periodic product quality review should be performed post-closure for the ongoing review/monitoring of the risks associated with a change in size of the thermal shipping solution used for transport of product.

Demonstrating effective management of a change to size in thermal shipping solution used for transport of product within the PQS

The following risk control elements have been considered and documented within the PQS for ensuring effective management a change in size of the thermal shipping solution for transport of product:

Potential impact on product quality has been assessed as low based on the available data and experience

The qualification was successful and the risk to product quality confirmed to be low

Temperature monitoring is performed according to PQS requirements.

The Pharmaceutical Inspection and Cooperation 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 1VQ for PAC position paper provides a standard and enhanced risk-based approach within the framework of an effective PQS that can be used by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC in the size of the thermal shipping solution used for transport of product, without increasing risk to the patient and/or product quality, safety, and efficacy.

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

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

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. The 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 

The authors wish to acknowledge members of the 1VQ for PAC team who contributed to the 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,” 

PDA Journal of Pharmaceutical Science and Technology

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.

Manuela Gottschall is Head of Risk and Project Management, Global Quality at Roche. 

Marie Schommer is Quality Manager at Roche.

A Post Approval Change (PAC) in size of thermal shipping solution used for transport of product is considered a low risk provided it has been qualified and temperature monitored, and therefore can be downgraded from a prior approval to a notification to health authorities, and managed in the PQS with immediate implementation effect.

Industry 1VQ Solutions:  Change in Size of Thermal Shipping Solution Used for Transport of Product 

 (4), to a PAC for adding a testing lab to an existing testing site.

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

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

 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 burdenon both industry and regulators.

This specific example of a PAC to add a testing lab to an existing testing sitehas 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 with fast-track approvals for countries that require prior approval.

Description of current state for a change to add a testing lab to an existing testing site

Regulatory authority notification or prior approval is required in several countries, with long waiting periods, up to 21 months, for addition of a testing lab, even when the testing and laboratory controls remain unchanged and there are no additional risks to product quality and/or patient safety. This PAC is an example of how applying a risk-based approach using current product and laboratory control strategies, comprehensive implementation planning, and bundling of changes can support a faster implementation of PACs.

As an example, Table I is an assessment for addition of an adventitious agent testing lab for several biologics products in scope of this change.

This position paper describes how ICH Q10 and Q12 can provide the basis for regulatory relief for the addition of a testing lab to an existing testing site when the testing and laboratory controls remain unchanged, it presents no additional risk to product quality and/or patient safety, and carries minimal regulatory risk.

The position paper applies science- and risk-based concepts from ICH Q9, Q10, and Q12 to a PAC for the addition of a testing lab to an existing testing site, so that such changes can be implemented proactively utilizing the framework of an effective PQS, and without extensive regulatory burden.

The scope of this PAC is the addition of a new testing lab to an existing site, which is already approved for specific testing activities and/or for the same testing activities for other products.

The evaluation of existing controls, such as availability of trained personnel, procedures, existing controls for the monitoring of procedure performance, equipment as well as products already tested at the site, is the basis for the determination of the risks associated with the change.

Industry 1CQ for PAC position for addition of a testing lab to an existing testing site

Applying the principles in ICH Q9, Q10, and Q12, including risk-based implementation planning, bundling of several changes, and proactively engaging with health authorities that are known to require long prior-approval timelines, can enable this low-risk change to be managed through annual reports or notifications without prior regulatory approval and speed up implementation of the PAC.

The pharmaceutical industry’s position is that addition of a testing lab to an existing testing site as described in this paper’s Scope section should not need to be assessed as regulatory impacting, especially if this is only to update the dossier to include a new testing lab. The new lab can be added in future significant filing updates to the dossier. This will allow faster implementation of this change and optimize the testing network for timely and efficient testing and release of products.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 for the addition of a new testing laboratory to an existing approved testing site.

Figure 1 describes the risk-based approach for assessment of a PAC to add a testing lab to an existing approved testing site (1). Application of this risk-based assessment, based on current laboratory controls, should demonstrate that at a minimum, the addition of a new lab does not increase the risk to product quality and/or patient safety.

Figure 1: Risk-based assessment of post-approval changes (PACs) and determination of regulatory reporting category (1).

The following steps are completed to assess the impact and risks associated with addition of a new testing lab to an existing testing site.

When a PAC to add a testing lab to an existing testing site is 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 can be assessed by using the following risk questions: What might go wrong when adding a new lab? Why and how could this happen? This initial impact assessment should consider existing product control strategies and laboratory controls, including the review of whether the testing to be conducted in the new laboratory is comparable to the current testing for factors such as complexity, experience with same or comparable testing, or equipment.

The initial impact assessment indicated that there is no additional potential QSE risk. This is because the site is already approved for performing various testing activities for certain products with adequate laboratory controls such as trained personnel, qualified equipment, approved testing procedures, existing controls for the monitoring of procedures, performance, etc. Furthermore, the availability of fully trained personnel, established testing procedures, as well as known qualified testing equipment supports the initial assessment. There is a potential regulatory impact due to the divergent local, national, and regional requirements from regulatory authorities for the reporting category of the change. Therefore, the focus is on smart planning of change activities, early engagement, and transparent communications with the countries that require long prior-approval timelines.

 As the initial impact assessment indicated that there is no additional potential QSE risk, no additional risk assessments are needed.

Due to the potential regulatory impact, the focus is on smart planning of change activities, early engagement, and transparent communications with the countries that require long prior-approval timelines.

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

Change implementation, review, and closure should be performed per the change management process. Outcomes of the impact and any risk assessments (if needed) should be integrated into the overall 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 effectiveness of the changes.

Demonstrating effective management of a change to addition of a testing lab to an existing testing site within the PQS

The following risk-control elements have been considered and documented within the PQS to ensure effective management of a PAC to add a new testing lab to an existing approved testing site:

No change to testing procedures, specifications, or system suitability (same as used in other approved labs)

Same equipment as used in other approved labs; Installation Qualification / Operational Qualification / Performance Qualification adequately performed and documented

Site already approved for various testing activities for certain products.

The Pharmaceutical Inspection Cooperation Scheme (PIC/S) recommendation paper on 

This 1VQ for PAC position paper provides a standard and enhanced risk-based approach within the framework of an effective PQS that can be used by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC for addition of a testing lab to an existing testing site, without increasing risk to the patient and/or product quality, safety, and efficacy.

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

Reducing the regulatory approval burden for medium and low risk changes

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.

Sean McEwen (Abbvie), Jackie Elbonne (Amgen), Kunihiko Kokubo (Astellas, CQO at time of completion of example), Anthony Mire-Sluis (Astra Zeneca), 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), Flemming Dahl (Novo Nordisk, CQO at time of completion of example), Andi Goddard (Roche), Philippe Germanaud (Sanofi), Jerry Greco (Takeda), Edith Koller-Dette (Teva).

The authors wish to acknowledge members of the 1VQ for PAC 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," 

Manuela Gottschall is Head of Risk and Project Management, Global Quality at Roche. Federico Colombari is Quality Risk Management Specialist, also at Roche.

Addition of a testing lab to an existing testing site as a Post Approval Change (PAC) is considered low risk when there is no change to testing procedure, specifications, equipment, and the additional lab is already approved by health authorities for other testing activities. Such PACs should be managed in the Pharmaceutical Quality System (PQS) only rather than requiring prior approval.