Introduction to the Chemistry, Manufacturing, and Controls (CMC) regulatory requirements in low- and middle-income countries (LMICs)

Transcription

1 TOPRA Annual Human Medicines Symposium 2017 Introduction to the Chemistry, Manufacturing, and Controls (CMC) regulatory requirements in low- and middle-income countries (LMICs) Rajneesh Taneja Sr Director, Pharmaceutical Product Dev, Global Alliance for TB Drug Development ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

2 Presentation objectives Rationale for the development and a description of the database of CMC regulatory requirements for low- and middle-income countries (LMICs) Share the key challenges highlighted by the data analysis and their impact on product introduction time and cost 2

3 Diverse CMC requirements in LMICs can be a challenge for product introduction Current State Solutions Heterogeneous group of countries with evolving and diverse regulations Global health products face significant delays and cost overruns Delays the introduction of life-saving medicines to patients in LMICs There are multiple approaches underway to address the challenges: Regulatory alignment Regionalization Facilitated pathways Regulatory intelligence 3

4 Global health drug introduction is often delayed by reg. deficiencies Some of these deficiencies can be addressed through improved planning enabled by upfront visibility into LMIC CMC requirements Mean no. of deficiencies per dossier Deficiencies in generic product dossiers submitted for WHO Prequalification (PQ) Apr 2007-Dec 2010 API spec. & charac. Pharma. development Mfg process & controls Process validation Excipients FFP specification Analytical methods Containers Source: Worku W, Gordon J, Stahl M, Rago L. Deficiencies in generic product dossiers as submitted to the WHO Prequalification of Medicines Programme. Journal or Generic Medicines 9(2) May Stability 4

5 Our pilot knowledge base improves visibility into CMC requirements Example Data GMP inspection requirements Guidance on biostudies and reference product selection Stability study requirements Prior marketing authorization requirements Administrative requirements In-country manufacturing restrictions Excipient restrictions Sample requirements Functionality Country comparison Compare requirements among selected countries Individual country Identify unique requirements for product development and regulatory strategy Single requirement Summarize individual requirements across countries (e.g., Stability study conditions) 5

6 A summary of the regulatory pathways and unique requirements is captured Overview of pathways for clinical and commercial manufacturing National Regulatory Authority (NRA) Standard Process NRA Accelerated Process Stringent Regulatory Authority (SRA) Approved, WHO PQ, and EMA Article 58 Accelerated Processes Overall considerations Noteworthy requirements Procedural & Administrative Core CMC Registration 6

7 The database captures requirements for LMICs and Procurement Agencies 75 Low- and Middle-Income Countries 10 Procurement Agencies Bangladesh China Ethiopia India 7

8 The project revealed specific LMIC requirements that are challenging A global health product is generally introduced in over 30 countries, therefore each requirement can add cumulative cost and delays in product introduction Focus Today Diverse labeling requirements In-country manufacturing Prior NRA marketing authorization Varied stability study requirements In-country QC testing API assessments GMP inspections Excipient restrictions Reference product selection 8

9 Requirements are driven by quality, safety, development and supply chain needs Research and interviews have indicated that most of the unique regulatory requirements driving the pain points have four common objectives: Assuring drug quality Enabling safe and effective use of product Developing the country economies and NRAs capabilities Supporting supply chain and logistics 9

10 We sought to understand the drivers and impact of the CMC challenges 15 generic and multi-national pharmaceutical companies shared the cost and time impact of LMIC requirements on global health product introduction Literature review and interviews provided insights into the rationale behind the requirements The information provides a starting point to understand potential approaches to minimize the impact of the requirements 10

11 Diverse labeling requirements result in up to 70 SKUs for a single product Labeling: Impact associated with addressing the aggregate of unique labeling requirements for each country or procurement organization as well as managing subsequent variations Drivers Enabling safe and effective use of product Assuring drug quality Supporting supply chain and logistics Impact Administrative burden to manage and maintain multiple labels with staggered initial and variation approvals across multiple countries High relative cost for global health products associated with producing PILs (10cents/pack) Data source: Anecdotal information gathered from manufacturer interviews 11

12 Prior Marketing Authorization can delay introduction by an average of 1.5 years Prior NRA Marketing Authorization (PMA): Impact associated with requirement for written evidence of a PMA in the form of a Certificate of Pharmaceutical Product (CoPP) or equivalent from the country of manufacture, and/or with marketing authorization Drivers Assuring drug quality Building NRA capabilities where capacity is scarce by leveraging SRA reports Impact A paper-based CoPP scheme adds administrative burden and delays Requirements for initial product registration which enables subsequent LMIC filings may differ from LMIC requirements: Stability studies Biostudies GMP Inspections Data source: Anecdotal information gathered from manufacturer interviews 12

13 In-country QC testing could cost an average of $240K per product annually In-country Quality Control Testing: Impact associated with product introduction, and release of commercial samples to perform in-country QC testing for initial registration and each import. Drivers Assuring drug quality Building NRA capabilities and operational sustainability Impact Inconsistent application of analytical methods on samples Additional cost to manufacture and supply sample batches with 12 months shelf-life Provision of working/reference standards, and impurities are costly and require temperature-controlled shipping Data source: Anecdotal information gathered from manufacturer interviews 13

14 A global health manufacturing site can have LMIC inspections / year GMP Inspections: Impact associated with having to obtain GMP certificates from multiple LMIC NRAs for facilities, despite the availability of inspection reports from other National Regulatory Agencies (NRAs) Drivers Assuring drug quality NRAs inspect due to political, economic, expertise, and regulatory differences leading to a lack of mutual confidence Impact 100+ countries perform foreign inspections NRA inspections per year at a manufacturing site each requiring an estimated 15 days and resulting in 10-60% loss of productivity during the inspections TB Alliance product site was occupied 158 days for multiple GMP inspections Data source: 1) Anecdotal information gathered from manufacturer interviews, 2) Rönninger S., Meshkovski, A. GMP Inspection practice: a case for global benchmarking, convergence and mutual reliance/recognition. GMP News. 25 April

15 MIC reference product and biostudy requirements costs $400K-700K/study Reference Product Selection: Impact associated with conducting additional bioequivalence studies with a reference product that is registered in the country of registration and/or conducted at NRA certified centers Drivers Enabling safe and effective use of product Assuring drug quality Impact Requirements related to biostudies add additional cost and time to drug introduction: Use local comparator for bioequivalence (BE) studies Conduct studies in-country of registration Conduct of BE studies at NRA-certified centers Data source: Anecdotal information gathered from manufacturer interviews 15

16 We are currently exploring potential approaches to address the challenges We are focusing efforts on three of the requirements: Diverse labeling requirements Prior NRA marketing authorization In-country QC testing Proposed solutions align with seven overarching solution themes to address the pain point drivers although there may be other potential solutions to explore Overarching Solution Themes 1 Capacity building 2 Data sharing 3 Harmonization 4 Regionalization Underpinning Solution Themes 5 Partnerships 6 Education / awareness 7 Workarounds 16

17 Summary A CMC regulatory knowledge base for pharmaceutical development in LMICs is under development and is expected to be commercially available in 2018 The knowledge base provides awareness of the unique requirements to help developers accelerate the introduction of life-saving drugs in LMICs The learnings from the knowledge base and manufacturer interviews have provided further insights on the extent of the impact on product introduction We are currently exploring potential approaches to minimize the impact of the requirements 17

18 Presentation objectives - Recap Rationale for the development and a description of the database of CMC regulatory requirements for low- and middle-income countries (LMICs) Share the key challenges highlighted by the data analysis and their impact on product introduction time and cost 18