Post-approval Change Management Research Articles

Approaches to Design an Efficient, Predictable Global Post-approval Change Management System that Facilitates Continual Improvement and Drug Product Availability.

The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC ManagementSystem to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.

Overview of Drug Approval Process and Post Approval Changes in Europe

The European Medicines Agency (EMA) is facilitate development and access to medicine, evaluating applications for marketing authorization, monitoring the safety of medicines across their lifecycle and providing information to healthcare professionals and patients.
 In order to obtain a marketing authorization in Europe, a medicine must meet a number of criteria before it can be filed with the European Medicines Agency (EMA). This article is looks at the EMA’s Drug approval process and post approval changes. The decentralized regulatory body, or EMA, is in charge of overseeing the safety of food and drug (pharmaceutical products) in Europe. The applications are examined, and member state looks over the safety and effectiveness data before approving the drug. EU establishes 4 different drug approval processes:
 1) National Procedure
 2) Decentralized Procedure
 3) Centralized Procedure
 4) Mutual Recognition Procedure
 The goal of the current study is to clarify the function of post-approval change management in preventing non-compliance. The current study has concentrated on locating the current regulations and practices in this field and comprehending the fundamental ideas for post approval compliance for licenses relevant to marketing permission. Though change management is essential to a pharmaceutical's lifespan that is the study's main finding. However, the expense of compliance has escalated due to a lack of a clearly defined framework and a lack of understanding of the same, which has led to step-motherly treatment being applied to compliance and license maintenance.
 Conclusion
 Europe has the highest thought-due approval rates worldwide. The European Medicines Agency (EMA) aims to guarantee that patients in the EU have access to medicines that are of the highest caliber, are reliable, and are secure. Public regulatory agencies have the responsibility of ensuring that pharmaceutical firms follow the law. In order to ensure patient safety and well-being, laws mandate that pharmaceuticals be created, tested, tracked, and manufactured in compliance with the standards. A guideline, in addition to the European legislation that defines variation types, gives out a harmonized list of anticipated variations with categorization codes. A defined list of variations for European
 A MA has existed since 1998. Legislation has been amended on a regular basis, and the most recent amendment, in August 2013, made implementation mandatory at the national level, and the variation process was totally harmonized across the EU.

Microbiologically Controlled Products: Regulatory Management of Postapproval Changes.

Microbiologically Controlled Products: Regulatory Management of Postapproval Changes.

Path Forward to Optimise Post-approval Change Management and Facilitate Continuous Supply of Medicines and Vaccines of High Quality Worldwide

Post-approval changes (PACs) to the registered information of authorised medicinal products are introduced routinely worldwide to enhance the robustness and efficiency of the manufacturing process, ensure timely supply in case of increased demand, improve quality control techniques, respond to changes in regulatory requirements and upgrade to state-of-the-art facilities. These are critical to prevent supply disruption and continuously improve existing medicines and vaccines. Due to the complexity of current PAC systems across markets, a change can take 3 to 5 years to approval globally (Hoath et al in BioProcess Int, 2016) thus hindering innovation and increasing the risk of shortages. The key messages are as follows: 1. Industry believes that global regulatory convergence of post-approval changes to Marketing Authorisations (MAs) using science- and risk-based approaches will enable a more efficient management of quality and supply improvements and will facilitate patients’ access to innovative medicines and vaccines of the highest quality. 2. National Regulatory Authorities (NRAs) should establish national or regional guidelines in line with international standards (regarding a risk-based classification of changes and standardisation of requirements) (Guidelines on procedures and data requirements for changes to approved biotherapeutic products, in WHO Technical Report Series, 2018, Guidelines on procedures and data requirements for changes to approved vaccines, in WHO Technical Report Series, 2015), have clear procedural guidance including timelines and implement reliance pathways to accelerate the approval of changes. This paper briefly outlines the challenges for PACs and provides solutions for a more flexible and aligned global system.

WHO collaborative registration procedure using stringent regulatory authorities’ medicine evaluation: reliance in action?

ABSTRACT Introduction The regulatory approval of medical products in countries with limited regulatory resources can be lengthy, which often compromises patients’ timely access to much-needed medicines. To improve the efficiency of regulatory systems, reliance is being used. Reliance allows an authority to leverage the work performed by other authorities, such as scientific evaluations, to decide on medical products approval within their jurisdiction. This reduces duplication of regulatory efforts, resources and time, while maintaining national sovereignty. Areas covered This article analyzes the outcomes and stakeholders’ experience of using medicines assessments performed by Stringent Regulatory Authorities (SRA) in the Collaborative Registration Procedures (CRP). Since its establishment in 2015, 59 approvals were granted to 16 medicines in 23 countries through SRA CRP. Results show that the procedure is delivering on the intended benefits of access and speed, with long-term positive impact for resource-limited countries. The article concludes with recommendations on the need for guidance on management of post-approval changes, wider promotion of the procedure, and increased collaboration between authorities. Expert opinion The SRA CRP provides a mechanism for the use of reliance by strengthening communication and promoting the exchange of information among regulators. This fosters faster regulatory approvals and, consequently, earlier access to medicines.

Multivariate Spectroscopic Method Lifecycle Management as Part of the Quality Management System.

Multivariate model based spectroscopic methods require model maintenance through their lifecycle. A survey conducted by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) in 2019 showed that regulatory reporting categories for the model related changes can be a hurdle for the routine use of these types of methods. This article introduces industry best practices on multivariate method and model lifecycle management within the Pharmaceutical Quality System. Case studies are provided to demonstrate how the Established Conditions and Post-Approval Change Management Protocol concepts may be leveraged to allow regulatory flexibility for change management and to encourage the use of these techniques for the development and commercialization of pharmaceutical products.

Alignment in post-approval changes (PAC) guidelines in emerging countries may increase timely access to vaccines: An illustrative assessment by manufacturers

A comparison of the regulations and guidelines from 33 countries, across different regions, on the requirements and procedures for the management of chemical, manufacturing and control (CMC) changes for vaccines, also known as post- approval changes (PACs), reveals significant variability and lack of predictability of timelines for regulatory review and approval. These shortcomings imply that multiple data packages have to be prepared for submission to different authorities, generating a complex regulatory environment. Moreover, the timelines for approval by individual national regulatory authorities are variable, which results in manufacturers keeping various stocks of vaccines produced in accordance with the various approved specifications and procedures, in the different countries. This can seriously affect timely availability of vaccine in those countries. The World Health Organization (WHO) guidelines on procedures and data requirements for changes to approved vaccines provide a consensual framework for alignment, but are still underused. Reliance on both the review and approval by the regulatory authority in the country of manufacturing, or on the review performed by other national regulatory authorities, recognized by WHO as stringent, or on WHO prequalification dossier, offer alternative ways forward. These and other options to improve the management of post-approval changes during the product lifecycle of vaccines are discussed in this report, and aimed at improving guidelines alignment and regulatory convergence to advance immunization equity and coverage.

Industry One-Voice-of-Quality (1VQ) Solutions: Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)-through Enhanced Science and Risk-Based Approaches.

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. This paper has been sponsored and endorsed by senior quality leaders (Chief Quality Officers/Heads of Quality) from >20 global pharmaceutical companies who have collaborated to speak with "One-Voice-Of-Quality" (1VQ). The paper provides two specific solutions that lay the foundation for an aligned and standardized industry position on the topic of effective management of post-approval changes in the pharmaceutical quality system (PQS). This document represents the 1VQ standard approach for the steps necessary to establish and demonstrate an effective quality system to fully leverage a risk-based approach to post-approval changes as laid out by ICH Q10 Annex 1. Implementation of the solutions presented in this paper can help achieve a transformational shift with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes. The Chief Quality Officers/Heads of Quality are inviting other companies to join the 1VQ (contact either Emma Ramnarine or Anders Vinther) and other stakeholders to join the dialog.

Post-approval Change Submission: ICH Q12 Impact Analysis on India and Japan

The present research provides a discussion on post approval change management of pharmaceuticals, biologics and drug device combinations, which is an important part of life cycle management. The present study focuses on understanding the existing post approval change management system in India and Japan. Comparison is then made with the elements and principles provided in draft ICH Q12 guideline. In November 2017 the draft guidance ICH Q12 entitled Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management has been published for comment. The discussion of this study would bring to light the key requirements, challenges and impact of future implementation of ICH Q12 in India and Japan. The initiative taken by ICH Q12 with this guideline focuses mainly on harmonizing the post approval system throughout the world which has the potential to reduce costs and time burdens for the regulators and industry.

Analytical procedure development: Concept to application for chemometry based ultrafast LC estimation of pimavanserin in pharmaceuticals

Analytical techniques with sound scientific understanding and assured regulatory flexibilities for post-approval change management are the need of the current pharma scenario. In the present study, the recent concept of analytical procedure development is utilized along with quality management concepts to address the above issue. A new chromatographic method was developed for quantifying a novel antipsychotic agent pimavanserin tartarate in its dosage form. Critical method variables were identified and were investigated for their possible effect on critical analytical attributes viz. analyte retention, plate count and peak tailing. Methanol%, flow rate, and pH of mobile phase were the sorted critical method variables and were optimized using systematic Box-Behnken experimentation. The optimized chromatography used C18 column (150 × 4.6 mm, 5 µm) and methanol: phosphate buffer (pH 3.5) (80:20, v/v) as the mobile phase with a flow of 1 mL/min. Pimavanserin was separated from tartaric acid (resolution >7.5). Diode array detection at 226 nm presented accurate and precise quantification of pimavanserin. Linear responses were obtained over 0.5–100 µg/mL of pimavanserin. Further, the procedure performance capability index was measured by using Monte-Carlo simulation. In a nutshell, the present studies reveal the aptness of hyphenating chemometry with this novel concept for robust quantification of pimavanserin.

Post-approval Variations to Dossiers for Vaccines: Analysis of Regulatory and Methodological Approaches Used in the Russian Federation and Abroad

The management of post-approval changes to registration dossiers for medicinal products is one of the most important factors for ensuring sustainable quality, safety and efficacy of medicines. Competent authorities that use the module format of the registration dossier, i.e. the regulatory authorities of the European Union, USA and other members of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and the Eurasian Economic Union (EEU), issue guidelines on changes to registration dossiers for pharmaceuticals and biologicals (immunological products). Vaccines (finished dosage forms) and vaccine antigens (active ingredients) are a specific group of immunobiological products which have great prophylactic importance for healthcare, and which are associated with challenging development and specific methods of manufacturing and quality control. The procedure of introducing post-approval variations to dossiers for immunobiological medicinal products is poorly reflected in the current Russian and EEU regulations. The World Health Organization (WHO) established a procedure described in the «Guidelines on procedures and data requirements for changes to approved vaccines». The purpose of the present study was to compare current Russian and international legislation in terms of regulatory requirements for post-approval сhanges to dossiers for immunobiological products. The Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of the Russian Federation is drafting Guideline on introducing post-approval changes into dossiers for immunobiological medicines. The draft includes a detailed review of various categories of changes based on their importance, and a list of conditions and required documents for specific groups of medicines. This article summarises scientific and methodological approaches to evaluation of changes introduced in registration dossiers for vaccines in order to further improve the regulatory framework of the Russian Federation and the EEU.

Solving the Global Continual Improvement and Innovation Challenge: How an Effective Pharmaceutical Quality System Can Transform Post-Approval Change Management.

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many of these post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. Quality leaders speaking globally with "One Voice of Quality" are essential for solving this difficult problem. This concept paper has been developed under the sponsorship of a group of Chief Quality Officers (Heads of Quality) from >25 global pharmaceutical companies and has been endorsed by the Parenteral Drug Association. The intent of this concept paper is to develop and implement aligned, standard solutions within the industry, leveraging the core foundation of the pharmaceutical quality system, such that a transformational shift can be achieved with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes.LAY ABSTRACT: Pharmaceutical manufacturers must make changes to their products and manufacturing processes over time as they incorporate new technology and new information. Because drug products are highly regulated in every country, the manufacturer must often contact national drug regulators before making these changes, even if the manufacturer is confident, based on testing and process controls, that the change will not have a negative impact on product quality or patient safety. For a product that is globally marketed, the manufacturer may have to contact dozens of regulators before making a change. This paper suggests that industry work together to identify ways to demonstrate to regulators that product and process knowledge as well as pharmaceutical quality systems are strong enough that the manufacturers should be allowed to manage some post-approval changes themselves.

Misunderstanding Design Space: a Robust Drug Product Control Strategy Is the Key to Quality Assurance

ICH guidelines Q8/11, Q9, and Q10 introduced risk-based approaches and enhanced scientific understanding as an opportunity to encourage continuous process improvement for pharmaceutical manufacturing. Conceptually, Quality by Design (QbD) promised to improve confidence in quality through the lifecycle of pharmaceutical products. A primary incentive for industry is the prospect of global regulatory concordance for new applications and post approval changes. Unfortunately, during the last decade, the industry has experienced regulatory divergence regarding the interpretation of ICH guidelines across geographic regions. Rather than truly harmonized regulatory expectations, localized interpretations of ICH guidance have resulted in different technical requirements posing significant challenges for a global industry. As a result, the increased complexity of manufacturing supply chains and the regulatory burden associated with maintaining compliance with these diverse regulatory expectations serves as a barrier to continual improvement and innovation. The QbD paradigm has effectively demonstrated a risk-based link between a product’s control strategy and patient needs that has prompted meaningful improvement in the industry’s approach to product quality assurance. Divergent interpretations of the concepts and definitions used in the modern QbD approach to product development and manufacturing, however, has led to challenges in achieving a common implementation of design space, control strategy, prior knowledge, proven acceptable range, and normal operating range. While the concept of design space remains an appealing focal point for demonstrating process understanding, the authors suggest that Control Strategy is the most important QbD concept, and one that assures product quality for patients. A focus by both regulators and manufacturers on the significance of Control Strategy could facilitate management of post approval changes to improve manufacturing processes and enhance product quality while also engendering regulatory harmonization.

CHANGE MANAGEMENT OF DRUG PRODUCTS REGISTRATION CONDITIONS: NEW ICH Q12 GUIDELINE

Introduction of amendments to the registration dossier is the responsibility of the marketing application holder (MAH). Increased knowledge on pharmaceuticals, its manufacturing and control processes can reduce the number of documents submitted to the regulatory authorities. The existing requirements establishing the procedure for the introduction of amendments differ in terms of change classification, period of notification of regulatory authorities, ways of conformity validation of pharmaceutical properties, etc. ICH proposed draft guideline Q12 «Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management» which covers the problem of harmonization of regulatory approaches to the changes provided in the «Quality» section of CTD during the commercial phase of drug life cycle. The new guideline can be considered as the continuation and elaboration of previous ICH documents. The article provides explanations on the main provisions and regulatory mechanisms introduced by the draft guideline ICH Q12: categorization of post-approval changes, established conditions, post-approval change management protocol, and drug product lifecycle management.

Demonstrating Pharmaceutical Quality System Effectiveness and Driving Continual Improvement: Evidence-Based Risk Reduction.

Product knowledge grows and evolves during the life of a product. In order to maintain a state of control and deliver product with consistent quality throughout its commercial life, continuous improvement and product lifecycle management become essential. The practical link between product and process knowledge, risk-based control strategies, and continual improvement and innovation can be made stronger through evidence-based risk reduction. This paper introduces the concept of evidence-based risk reduction within the continual improvement framework. It presents how regulatory relief and flexibility in post-approval change management and overall product lifecycle management can likely only be achieved via (1) effective application of science and risk-based concepts and (2) demonstrated effectiveness of the pharmaceutical quality system in assuring a state of control.

Product Lifecycle Approach to Cascade Impaction Measurements

Over the lifecycle of an orally inhaled product (OIP), multi-stage cascade impactor (CI) measurements are used for different purposes and to address different questions. Full-resolution CIs can provide important information during product development and are widely used but are time- and resource-intensive, highly variable, and suboptimal for OIP quality control (QC) testing. By contrast, Efficient Data Analysis (EDA) combined with Abbreviated Impactor Measurement (AIM) systems pertinent either for QC and-possibly-for adult Human Respiratory Tract (pHRT) has been introduced for OIP performance assessment during and post-development. This article summarizes available evidence and discusses a strategy for using either abbreviated or full-resolution CI systems depending on the purpose of the measurement, such that adequate, accurate, and efficient testing of aerodynamic particle size distribution (APSD) of OIPs can be achieved throughout the lifecycle of a product. Under these proposals, a comprehensive testing program should initially be conducted by full-resolution CI in OIP development to ascertain the product's APSD. Subsequently, correlations should be established from the selected AIM CIs to the corresponding full-resolution system, ideally developing specifications common to both techniques. In the commercial phase, it should be possible to release product using AIM/EDA, keeping the full-resolution CI for investigations, change control, and trouble-shooting, thus optimizing resources for APSD characterization throughout the product lifecycle. If an in vitro-in vivo relationship is established and clinically relevant sizes are known, an AIM-pHRT could serve as a quick indicator that clinically relevant fractions have not changed and also, in the management of post-approval changes.