Post-approval Changes Research Articles

Modeling and Simulations in Latin-American Generic Markets: Perspectives from Chilean Local Industry, Regulatory Agency, and Academia.

In the last 20 years, modeling and simulations (M&S) have gained increased attention in pharmaceutical sciences. International industry and world-reference agencies have used M&S to make cost-efficient decisions through the model-informed drug development (MIDD) framework. Modeling tools include biopredictive dissolution models, physiologically based pharmacokinetic models (PBPK), biopharmaceutic models (PBBM), and virtual bioequivalence, among many others. Regulatorily, health agencies are becoming more and more open to accept the use of M&S to support regulatory applications, including setting dissolution specifications, quality-by-design (QbD), postapproval changes (SUPAC), etc. Nonetheless, the potential of M&S has been only barely explored in Latin America (Latam) across different actors: industry, regulatory agencies, and even academia. In this manuscript, we discuss the challenges and opportunities for implementing M&S approaches in Latam. Perspectives of regional experts were shared in a workshop. Attendance (professionals from industry, regulator, academia, and clinicians) also shared their views via survey. The rational development of bioequivalent generics was considered the main opportunity for M&S in regional market, particularly the use of PBPK and PBBM. Nonetheless, a critical mass of modeling scientists is needed before Latin American industry and regulators can actually benefit from M&S. Collaborations (e.g., Academia-Industry and Academia-Regulatory) may be a path to develop applied research projects and train the future modelers. Reaching that critical mass, scientists from industry may apply modeling across generic drug development process and life cycle, while regulatory scientists may issue guidelines in local language to support regional industry. Only at that stage could the full potential of MIDD be reached in Latin American generic markets.

Synthetic membrane selection for in vitro release testing (IVRT): A case study of topical mometasone furoate semi-solid dosage forms

In vitro release testing (IVRT) is extensively used to develop the formulation of topical semi-solid products, to evaluate the quality and consistency of the product after scale-up and post-approval changes, and more recently to aid the evaluation of topical generic products’ equivalency. The selection of synthetic membrane is one of the most critical parameters of the method development part of IVRT. It is well known that the membrane features namely its polymer matrices, porosity, pore size, thickness can have a substantial effect on the IVRT data. However, there is no detailed information available in the literature regarding the membrane selection for different types of topical dosage forms. Therefore, we aimed to investigate whether difference topical semi-solid dosage forms of the same drug molecule would cause to variation in the membrane selection. Within this framework, rheological behaviour of commercially available three different types of topical semi-solid dosage forms (ointment, cream, and lotion) of mometasone furoate (0.1%) were primarily characterized. Then, the membrane inertness test was conducted using a series of synthetic hydrophilic membranes (regenerated cellulose, cellulose acetate, cellulose nitrate, mixed cellulose ester membranes) and hydrophobic membranes (polyether sulfone, polypropylene, polytetrafluoroethylene membranes) after identifying of an appropriate receptor medium that ensures sink condition for mometasone furoate. Lastly, IVRT studies from the topical semi-solid products were performed utilizing Franz-type diffusion cells. The membrane inertness and in vitro release data demonstrated that the cellulose acetate membrane showed superior diffusion properties in general while the other synthetic membranes exhibited varying outcomes for different semi-solid dosage forms of mometasone furoate. Overall, the results indicated that the release rate and the cumulative drug released amount of drug after 6 h through the different synthetic membranes might vary depending on the semi-solid dosage form. In order to select the synthetic membrane for IVRT, it should also be considered potential interactions between the polymer matrices and the chemical structure of drug molecule as well as formulation components prior to conducting membrane inertness test and IVRT studies.

Post-approval changes in Labelling regulations in the United States, European Union and Canada

The review “Post-approval changes in Labelling Regulations in the United States, Europe and Canada” goes into the details and consequences of post-approval changes in labeling regulations for pharmaceutical products. It covers the concept of post-approval changes and outlines the key areas of changes, such as various elements of product lifecycle management, market access, innovation, risk control, and legal compliance for manufacturers in the United States, Europe, and Canada. Apart from that, the abstract discusses the similarities and differences in labeling regulations across the regions in authority, structure, and the affected changes. In summary, the abstract outlines the complexities and effects of post-approval-related changes in labeling regulations concerning the pharmaceutical industry in multiple jurisdictions and the challenges encountered in implementing them. More specifically, the issues include differing regulatory frameworks and varying interpretations; operator compliance, safety evaluation and management; consolidation approaches; and the influence of digitalization and automation as a pivotal and minor player.

A Global Industry Survey on Post-Approval Change Management and Use of Reliance.

Post-approval changes (PACs) to the control and manufacturing processes of medicines and vaccines are routinely undertaken and critical to enable both innovation and secure sustained supply. In a world of global supply chains, the existence of divergent national PAC requirements (with additional countries introducing new requirements with potential differences) and other factors including document preparation and response timelines, can lead to long delays in approval (of up to 3-5years) increasing the risk of disruption and shortages.We undertook an Industry survey in 2023 to assess implementation of ICH Q12, PAC procedures (change categorisation and review timelines) and use of reliance mechanisms across different countries (9 selected ICH Members and 19 Observers). Although this survey revealed limited implementation of Q12 in ICH Member countries, when comparing the data collected with those of a previous survey performed in 2020, we observed a broader adoption of risk-based approaches to variation categorisation (in all countries). This, however, was not reflected in improved timelines for approval.With regards to ICH Q12 adoption, the uptake of Post-Approval Change Management Protocols (PACMPs) was unchanged (with only one country reporting in-use) and implementation gaps were evident for Established Conditions (EC) and the Product Life Cycle Management document (PLCM). The survey found greater awareness of ICH Q12 and its tools compared to 2020, potentially illustrating the positive impact of training efforts. This illustrates the challenges being faced to broaden its implementation and use globally.In the same Industry survey, we also assessed PAC processes across different international countries. Long unpredictable timelines were the major concern across the countries surveyed together with limited capacity of the regulators. Four different CMC changes were selected and categorized by the respondents according to current knowledge of national classifications and timelines in the selected countries and compared with a reference classification and timeline from the European Medicines Agency and the World Health Organisation. This highlighted the lack of harmonisation of many countries with EU/WHO requirements, especially within the ICH Observer group.Last, this survey showed that some use of unilateral forms of reliance to Reference Authorities for PACs is starting. This is a mechanism all countries can employ, regardless of convergence of requirements and expertise, to enhance capacity building and reduce duplication of reviews, streamline variations approval, whilst accelerating patient access to innovation and securing supply.

Unleashing the Power of Reliance for Post-Approval Changes: A Journey with 48 National Regulatory Authorities.

Post-approval changes (PACs) to marketed products are routinely introduced to continuously enhance the product lifecycle management. However, bringing a chemistry, manufacturing and control (CMC) change through the global health authorities can be a complex and lengthy process taking up to several years, therefore negatively impacting supply continuity. In order to accelerate the review and approval of regulatory submissions and ensure continuous supply to patients, the World Health Organization (WHO) is strongly supporting the implementation of reliance among National Regulatory Authorities (NRAs). While some promising developments have been made with the use of reliance pathways for initial marketing authorizations, reliance is still not widely used for PACs. With the support of the European Medicines Agency (EMA) and WHO, Roche launched a reliance pilot based on EMA approval to file a supply critical variation for a monoclonal antibody. The variation constitutes major changes to the approved manufacturing process. Sameness of the product is ensured by submitting to all participants the same variation package as in the EU. The objectives of the pilot are to ensure continuous supply of this critical medicine by targeting global approval in 6.5 months, to promote regulatory convergence by waiving country specific requirements, and enhance greater transparency by sharing EMA Committee for Medicinal Products for Human Use (CHMP) final assessment report and Q&As to participating NRAs. Globally 48 NRAs have agreed to join the pilot. This article outlines the process of establishing the pilot project, including a planning phase and an engagement phase with the EMA, WHO and the participating NRAs.

Overview and Lifecycle Management of Generic Pharmaceutical Drugs in Mexico, Guatemala and Brazil

Objective: The generic pharmaceutical markets in Mexico, Guatemala, and Brazil are influenced by distinct regulatory frameworks, production and distribution dynamics, and marketing strategies, which shape lifecycle management. Regulatory policies, market competition, and healthcare initiatives impact accessibility, affordability, and quality, presenting both challenges and opportunities for enhancement in these areas. Summary: This thesis offers an in-depth examination of lifecycle management strategies in the generic pharmaceutical markets of Mexico, Guatemala, and Brazil. Generic drugs are crucial for increasing access to affordable healthcare, especially in emerging economies. Through comparative analysis, this research explores the regulatory frameworks, market dynamics, and key challenges in the development, approval, marketing, and post-marketing surveillance of generic drugs in these three Latin American countries. The study starts with an overview of the regulatory landscape for generic pharmaceuticals in Mexico, Guatemala, and Brazil, highlighting similarities and differences in registration requirements, approval processes, and post-approval obligations. It investigates the roles of regulatory agencies like COFEPRIS, DIGEMID, and ANVISA in ensuring the quality, safety, and efficacy of generic drugs throughout their lifecycle. Additionally, the research delves into the strategies used by pharmaceutical companies for lifecycle management of generic drugs, including variations, biowaivers, and labeling changes. Real-world case studies illustrate post-approval changes and their regulatory implications in each country, providing insights into the complexities of managing generic drug portfolios in different regulatory environments. The thesis also examines the market dynamics affecting the availability, pricing, and accessibility of generic drugs in Mexico, Guatemala, and Brazil. Factors such as patent expirations, competition, healthcare policies, and public procurement practices are analysed to understand their impact on market entry, competition, and the affordability of generic drugs. Furthermore, the study addresses the challenges and opportunities in pharmacovigilance and post-marketing surveillance of generic drugs, emphasizing the need for robust systems to detect and manage adverse drug reactions and ensure patient safety. Conclusion: The key findings highlight regulatory frameworks, market dynamics, and lifecycle management strategies in the generic pharmaceutical markets, identifying challenges and opportunities. The study reflects on implications for stakeholders and suggests areas for future research to enhance accessibility, affordability, and quality.

Conventional vs Mechanistic IVIVC: A Comparative Study in Establishing Dissolution Safe Space for Extended Release Formulations.

The use of in vitro-in vivo correlation (IVIVC) for extended release oral dosage forms is an important technique that can avoid potential clinical studies. IVIVC has been a topic of discussion over the past two decades since the inception of USFDA guidance. It has been routinely used for biowaivers, establishment of dissolution safe space and clinically relevant dissolution specifications, for supporting site transfers, scale-up and post approval changes. Although conventional or mathematical IVIVC is routinely used, other approach such as mechanistic IVIVC can be of attractive choice as it integrates all the physiological aspects. In the present study, we have performed comparative evaluation of mechanistic and conventional IVIVC for establishment of dissolution safe space using divalproex sodium and tofacitinib extended release formulations as case examples. Conventional IVIVC was established using Phoenix and mechanistic IVIVC was set up using Gastroplus physiologically based biopharmaceutics model (PBBM). Virtual dissolution profiles with varying release rates were constructed around target dissolution profile using Weibull function. After internal and external validation, the virtual dissolution profiles were integrated into mechanistic and conventional IVIVC and safe space was established by absolute error and T/R ratio's methods. The results suggest that mechanistic IVIVC yielded wider safe space as compared to conventional IVIVC. The results suggest that a mechanistic approach of establishing IVIVC may be a flexible approach as it integrates physiological aspects. These findings suggest that mechanistic IVIVC has wider potential as compared to conventional IVIVC to gain wider dissolution safe space and thus can avoid potential clinical studies.

Accelerating Process Development and Product Formulation.

Currently, the lengthy time needed to bring new drugs to market or to implement postapproval changes causes multiple problems, such as delaying patients access to new lifesaving or life-enhancing medications and slowing the response to emergencies that require new treatments. However, new technologies are available that can help solve these problems. The January 2023 NIPTE pathfinding workshop on accelerating drug product development and approval included a session in which participants considered the current state of product formulation and process development, barriers to acceleration of the development timeline, and opportunities for overcoming these barriers using new technologies. The authors participated in this workshop, and in this article have shared their perspective of some of the ways forward, including advanced manufacturing techniques and adaptive development. In addition, there is a need for paradigm shifts in regulatory processes, increased pre-competitive collaboration, and a shared strategy among regulators, industry, and academia.

Overview of Post-approval Submissions Management in US, Europe and Canada

In today’s business era & competition in pharmaceutical industries, post-approval evaluation & cGMP compliance plays an important role. Regulatory approval is a critical milestone in the lifecycle of pharmaceuticals and medical devices, ensuring their safety, efficacy, and quality before entering the market. A regulatory affair is a bridge between pharma industry and health authorities.
 Post-Approval function in Regulatory Affairs department plays a major role in supporting continuous commercialization and facilitating for its implementation. This function are responsible to provide strategic regulatory inputs to plant team on their proposals and to facilitate smooth submission followed by acceptance/ approval. In the USA, the Food and Drug Administration (FDA) governs the regulatory process, employing a thorough and well-defined approach to submission evaluation. Europe, with the European Medicines Agency (EMA) at its helm, utilizes a centralized procedure for marketing authorization, harmonizing regulations across member states. Meanwhile, Health Canada oversees regulatory activities in Canada, emphasizing a risk-based approach to ensure public safety.
 Post-approval submission management is equally vital in maintaining compliance and ensuring ongoing product safety. This paper delves into the strategies and best practices for handling post-approval changes, variations, and renewals. It examines the role of regulatory intelligence, life cycle management, and effective communication with regulatory agencies to navigate the evolving regulatory landscape.
 By comparing and contrasting the regulatory processes in the USA, Europe and Canada, this overview aims to provide valuable insights for pharmaceutical and medical device companies seeking global market access. Understanding the intricacies of regulatory submission and post-approval submission management across these regions is essential for successful product development, commercialisation and long-term regulatory compliance.

Science- and Risk-Based Stability Strategies to Support Product Lifecycle Changes.

ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management. This paper provides ways to leverage science- and risk-based stability strategies as part of the post-approval change-management risk-mitigation strategy, which may enable a reduced stability data commitment and/or a reduced reporting category for change implementation.

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.

Impact Assessment of Divergence on Post-Approval Changes Classifications of Latin America Region With Europe and the United States, and Propositions to Harmonize Classification Based on Risk as a Path to Build the Trust Between National Regulatory Agencies

The lack of harmonization in the post-approval changes (PACs) classifications for pharmaceutical products may have an impact on the efficient implementation of PACs and in the supply of medicine, jeopardizing the continuity of therapies, especially in the case of chronic diseases. The percentage of similarity between the PACs classifications existing between countries of Latin America (Mexico, Brazil, Colombia, Venezuela, Argentina, Chile, Ecuador, Peru, and Central America) versus Europe and the United States (US) has been calculated, focused on the PACs for chemical products and on the minor and moderate variations as defined in the European Union (EU)1,2 and US3 regulations. Even though Mexico, Colombia, Brazil, and Argentina implemented a risk-based PACs classification, a wide diversity is observed, with a high percentage of variations classified as major or high risk for these countries and the rest of the Latin American countries, except for Venezuela (which previously adopted and recognized the EU classification). In addition, we identified a group/subset of PACs that are not categorized in the regulations of Mexico, Brazil, Chile, and Central America countries. Considering that Mexico, Brazil, and Argentina are members or observers of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use4 and the Pharmaceutical Inspection Co-operation Scheme,5 these countries could further align their PACs classification with the EU and US regulations. This could also be an opportunity for other countries of the Latin America region to recognize and adopt PACs classifications aligned to the EU or United States, which would also support the inclusion of reliance processes in their regulation for already considered/recognized reference countries. This would guarantee more health authority efficiency and optimization as well as more uniform implementation of PACs globally.

Dissolution Profiles Comparison Using Conventional and Bias Corrected and Accelerated f2 Bootstrap Approaches with Different Software's: Impact of Variability, Sample Size and Number of Bootstraps.

Dissolution profiles comparison is an important element in order to support biowaivers, scale-up and post approval changes and site transfers. Highly variable dissolution can possess significant challenges for comparison and f2 bootstrap approach can be utilized in such cases. However, availability of different types of f2 and confidence intervals (CI) methods indicates necessity to understand each type of calculation thoroughly. Among all approaches, bias corrected and accelerated (BCa) can be an attractive choice as it corrects the bias and skewness of the distribution. In this manuscript, we have performed comparison of highly variable dissolution data using various software's by adopting percentile and BCa CI approaches. Diverse data with different variability's, number of samples and bootstraps were evaluated with JMP, DDSolver, R-software, SAS and PhEq. While all software's yielded similar observed f2 values, differences in lower percentile CI was observed. BCa with R-software and JMP provided superior lower percentile as compared to other computations. Expected f2 recommended by EMA has resulted as stringent criteria as compared to estimated f2. No impact of number of bootstraps on similarity analysis was observed whereas number of samples increased chance of acceptance. Variability has impacted similarity outcome with estimated f2 but chance of acceptance enhanced with BCa approach. Further, freely available R-software can be of attractive choice due to computation of various types of f2, percentile and BCa intervals. Overall, this work can enable regulatory submissions to enhance probability of similarity through appropriate selection of number of samples, technique based on variability of dissolution data.

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.

Worldwide Regulatory Reliance: Launching a Pilot on a Chemistry, Manufacturing, and Control Post Approval Change for a Vaccine.

When an initial marketing authorization of a pharmaceutical product is granted, a substantial number of chemistry, manufacturing, and control (CMC) post approval changes (PACs) have to be managed by the manufacturers. Despite efforts undertaken over the years by multiple regulatory jurisdictions, there is still heterogeneity in terms of regulatory requirements and timelines across national regulatory authorities (NRAs). This creates complexity in managing global CMC PACs, putting the supply of medical products at risk. Regulators have developed regulatory mechanisms that aim at accelerating the reviews and approvals of PACs by NRAs. The World Health Organization (WHO) is supporting the concept of "reliance" among NRAs, which are encouraged to rely on the assessment completed by a "highly performing authority". The objective is to accelerate the overall process for PACs, ultimately fostering more equitable and timely access to medical products for populations who need them. With the support of Health Canada, WHO, Pan American Health Organization, and the Paul-Ehrlich-Institut, Sanofi has launched a pilot using the principles of reliance for a CMC PAC for a vaccine, with 21 NRAs who accepted to participate in the pilot. The objective of this pilot was to apply these principles to reduce the approval timeline to a maximum of 6 months in all countries after an initial approval is granted by a reference authority. We discuss the opportunities and challenges of implementing reliance principles for CMC PACs. We also describe the pilot experience by sharing initial lessons learned from the Step 1 of this pilot, which consisted of engaging the reference authority and the NRAs.

A Review on Dissolution Method Development for Drug Products: Current Regulations and Prospects

Dissolution (in vitro release) testing has been the subject of intense scientific and regulatory interest over the past several decades. As an analytical methodology, in vitro dissolution testing measures drug release into the dissolution media. The U. S. Food and Drug Administration (USFDA) Dissolution Database was reviewed and screened regarding the type of dosage forms, apparatus type, agitation speed, media volume, and recommended time points for the dissolution profile. The dissolution method requires special laboratory equipment, following a well-defined protocol. Basic information is available in the United States Pharmacopeia general chapters<711> Dissolution, <724> Drug Release, and <1092> The Dissolution Procedure – Development and Validation and these chapters were used as a starting point for this revision. The article describes current regulatory expectations for establishing a suitable dissolution method for implementing quality control tools, a way to maintain lot quality and consistency between development batches and post-approval commercial batches. Dissolution methods draw offers some advantages as a possible surrogate for extensive clinical studies in certain cases required after scale-up and post-approval changes in the product's life cycle and serves as an essential tool for establishing waivers for filing of lower strengths of the drug product. The step-by-step dissolution method development plan as per current regulatory perspectives and the factors to be considered are explained with examples. Scientist requires detailed insights on the selection of media and volumes, physicochemical properties of active substance, sink condition, type of enzymes, selection of apparatus, deaeration, sinkers, agitation speed, and time point’s measures. The advanced dissolution method is evaluated against its discriminatory power by intentionally varying formulation and process variables

A Spike-Control Approach that Evaluates High Resolution Mass Spectrometry-Based Sequence Variant Analytical Method Performance for Therapeutic Proteins.

An amino acid sequence variant (SV) is defined as an unintended amino acid substitution in protein drug products. SVs contribute to product heterogeneity and can potentially impact product quality, safety, immunogenicity, and efficacy. The analysis of biotherapeutics for SVs is important throughout the product life cycle including clone selection, development of nutrient feed strategies, commercial manufacturing process, and post-approval changes to monitor product quality. The proposed analytical procedure for SVs consists of both qualitative (identification of SVs) and quantitative (quantitation of identified SVs) components. The complexities of SV analysis and the variety of current procedures highlight the need for a systematic approach for assessing the capability of these methodologies to reliably identify and quantitate SVs in biotherapeutics. We described here a "spike-control" approach for evaluating SV analytical procedure. The concept was adopted from quality control samples routinely used in analytical procedure validation. One FDA approved monoclonal antibody (mAb) was spiked with accurate amounts of highly homologous mAb to create mAb samples containing low yet accurate levels of "artificial" SVs. Spike-control samples were denatured, reduced, alkylated, digested and then analyzed by high resolution Orbitrap mass spectrometry. In silico analysis revealed four single amino acid differences between the two mAbs that could be used to represent SVs in the spike-control samples. All four "artificial" SVs were reliably identified by the current workflow. Analytical range (0.01% to 2%), accuracy and precision of identified SVs have also been evaluated. Overall, spike-control sample(s) helped to demonstrate that the SV analytical procedure (i.e., sample preparation, LC separation, mass spectrometry determinations and bioinformatic software) was fit for purpose and suitable for the identification and quantitation of SVs at a pre-determined threshold.

Dissolution Profile Similarity Assessment—Best Practices, Decision Trees and Global Harmonization

During the write-up of the meeting summary reports from the 2019 dissolution similarity workshop held at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), several coauthors continued their discussions to develop a "best-practice" document defining the steps required to assess dissolution profiles in support of certain biowaivers and postapproval changes. In previous reports, current challenges related to dissolution profile studies were discussed such that the steps outlined in the two flow charts ("decision trees") presented here can be applied. These decision trees include both recommendations for the use of equivalence procedures between reference and test products as well as application of the dissolution safe space concept. Common approaches towards establishing dissolution safe spaces are described. This paper encourages the preparation of protocols clearly describing why and how testing is performed along with the expected pass/fail criteria prior to generating data on the materials to be evaluated. The target audience of this manuscript includes CMC regulatory scientists, laboratory analysts, as well as statisticians from industry and regulatory health agencies involved in the assessment of product quality via in vitro dissolution testing. Building upon previous publications, this manuscript provides a solution to the current ambiguity related to dissolution profile comparison. The principles outlined in this and previous manuscripts provide a basis for global regulatory alignment in the application of dissolution profile assessment to support manufacturing changes and biowaiver requests.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Microbiologically Controlled Products: Regulatory Management of Postapproval Changes.

Microbiologically Controlled Products: Regulatory Management of Postapproval Changes.