EXAMINING MEDICINAL PRODUCTS QUALITY DEFECTS AND RECALLS Pilot Research Project Dr. Nuala Calnan
2016
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“Looking to the future, we must continue to meet patients’ legitimate expectations for access to new and safe therapeutic options. This requires that the medicines authorisation process not only supports the early stages of research and development, but also strives to make the best possible use of real world data throughout a medicine’s lifecycle.” (EMA, 2015d) Professor Guido Rasi, EMA Executive Director 1st October 2015
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TABLE OF CONTENTS EXECUTIVE SUMMARY.........................................................................................................................................................................7 RESEARCH DESIGN AND METHODOLOGY..........................................................................................................................11 DEFECTIVE MEDICINES - THE BACKGROUND.................................................................................................................... 15 PROBLEM IDENTIFICATION.............................................................................................................................................................................. 25 GENERATING KNOWLEDGE FROM DATA – A PARADIGM SHIFT........................................................................ 31 RESEARCH ANALYSIS......................................................................................................................................................................... 41 ENHANCING PATIENT SAFETY THROUGH KNOWLEDGE EXCELLENCE........................................................... 67 CLOSING REMARKS............................................................................................................................................................................ 81 APPENDIX 1.................................................................................................................................................................................................................... 84
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RESEARCH PROJECT OVERVIEW RSI MISSION & RESEARCH VISION Regulatory Science Ireland (RSI) was formed in 2014. It is a network of interested parties from the Pharmaceutical Industry, Medical Devices Industry, Academia, HPRA and Government Agencies, who are committed to the development of an integrated Irish contribution in the fields of research, education/training, and knowledge sharing to enhance the global regulatory science effort. One of RSI’s goals is to conduct innovative, high quality research in the field of regulatory science for medicinal products that has direct relevance to the industry, the regulators (HPRA) and to the patients.
HPRA GOALS & OBJECTIVES The Health Products Regulatory Authority’s (HPRA) role is to protect and enhance public and animal health by regulating medicines, medical devices and other health products including monitoring the safety of cosmetics. The HPRA are a state agency that puts the health of people and animals at the core of everything they do. Using scientific and clinical expertise to review and monitor health products available in Ireland or exported abroad. Their aim is to make sure that the health products they regulate are as safe as possible and do what they are intended to do. Formerly known as Irish Medicines Board (IMB), but renamed to the HPRA in July 2014 to better reflect their broader remit and regulatory functions which include: »» Human medicines »» Veterinary medicines »» Clinical trials »» Medical devices »» Controlled drugs »» Blood and blood components »» Tissues and cells »» Cosmetic products »» The protection of animals used for scientific purposes »» Organs intended for transplantation
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QDR PILOT RESEARCH PROJECT
RSI / HPRA QUALITY DEFECT & RECALL RESEARCH SCOPE The Health Product Regulatory Authority (HPRA), in partnership with the Dublin Institute of Technology (DIT) and the Irish industry association Pharmachemical Ireland (PCI), established this research study to examine reporting of quality defects and product recalls related to medicinal product investigated by the HPRA over a five-year period. The principle aim of this research is to explore strategies that support the reliable supply of high quality medicines for patients and reduce the likelihood of them receiving a defective medicine.
PRINCIPLE ACTIVITIES UNDERTAKEN This research study took place in 2015 and examined a total of 3,999 Quality Defect Reports received from the marketplace by the HPRA over a five-year period January 2010 to December 2014. The study was conducted in three phases: 1. Data Analysis: Overview and analysis of the HPRA QDR database over the 5 year period 2. Case File Review: Detailed review of a selected sample of individual case files 3. Expert Interviews: Insight development with three experts from within the HPRA
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“The ever increasing complexity of health care products requires a data-driven evidencebased approach to their regulation…that’s understood and recognized worldwide.” Pat O’ Mahony Former CEO HPRA RSI Knowledge Management Symposium Dublin, March 2015.
EXECUTIVE SUMMARY THE EU MEDICINES AGENCIES NETWORK STRATEGY TO 2020 IDENTIFIES THE HANDLING OF EMERGING EVENTS SUCH AS, SAFETY CONCERNS OR QUALITY DEFECTS AS A MAJOR CHALLENGE FOR AUTHORISED MEDICINES. INTEGRATION BETWEEN MEMBER STATES ON DEFECT AND PRODUCT RECALL HANDLING IS CRUCIAL IN ADDRESSING THE ‘EMERGING EVENTS’ THAT RELATE TO QUALITY DEFECTS AND IN DRIVING BEHAVIOURS TOWARD PREVENTION RATHER THAN CURE.
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Substandard medicines are a significant problem in Ireland, with a 7-fold increase in critical quality defect incidents reported over the last 10 years. This is in line with rising trends of rapid alerts reported in Europe. Parenteral medicinal products are most likely to be substandard due to failures arising from contamination and sterility assurance. Traditionally, Quality Defect and Recall reporting has been focused on a rate-based annual reporting model with limited, if any, communication of the outcomes to the stakeholders. In some cases a summary of these annual rates are included in the annual report produced by the individual National Competent Authorities, along with a few lines of comparative commentary on trends with the previous years data or noting any major
new contributing causes. In other cases they go unreported. This pilot research project examines the available medicinal product quality defect and recall data at the Irish Health Products Regulatory Authority (HPRA) over the fiveyear period 2010-2015 to explore what is “known� about quality defects and product recalls. The research explores opportunities for incident prevention through enhanced knowledge transfer of the learnings across industry and the regulatory communities. The principle aim of this research is to examine strategies that support the reliable supply of higher quality medicines for patients and reduce the likelihood of them receiving a defective medicine.
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QUALITY DEFECT AND PRODUCT RECALL RESEARCH AT THE HPRA 2015
Goals and Objectives
Benefits and Expected Learnings Inform GMP & GDP Inspectors where to focus their inspection time and resources on:
Establish do certain types of manufacturing processes / product generate more serious defects than others
»» Specific process validation activities »» Quality risk assessment work »» Change management activities »» Corrective action effectiveness Such data could also feed into future risk-based inspection planning. Enable recommendations for Pharmaceutical Assessors, on what parts of Module 3 might benefit from higher levels of assessment, in particular: »» Justifications in critical attribute/ parameter assignment »» Validation plans presented for certain types of manufacturing processes. Such data could also feed into risk-based assessment approaches. This should provide useful information for developing Annual Sampling and Analysis plans at OMCLs and NCAs. Products that are at a higher risk of having a quality defect could be targeted for more surveillance testing. Understanding what percentage of QDR’s are related to:
Identify what kind of issues are actually investigated as quality defects at NCA level
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Underlying quality failure arising at the manufacturing site MA-Non compliance issue involving the failure to implement a variation Stability Out-of –specification (OOS) Distribution or supply chain failure
Inform the Pharmaceutical Industry about areas requiring increased attention, such as:
Identify if there are certain product lifecycle activities that contribute more frequently to failures that result in defects and recalls
Examine current QDR communications methods to identify improved knowledge sharing and transfer mechanisms
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Product and Process Development (e.g. for better process understanding & robustness) Validation (e.g. Process, Cleaning) Qualification (e.g. Equipment, HVAC & other Utilities, Suppliers) Quality Control (e.g. more robust QC methods) Corrective and Preventative Actions (e.g. effectiveness and root cause analysis) Product Quality Review Activities (e.g. use as a Knowledge Management tool) Improved knowledge sharing could assist Regulators and Industry by leading to better prevention strategies, thereby reducing incidents and could also improve the performance of QDR investigations e.g:
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Knowledge of recurring quality defect issues could determine how much regulatory oversight should be devoted when assessing and agreeing CAPAs with companies Knowledge of the historical incidence rate of a certain type of quality defect could inform regulators and industry about the likely extent of a defect in a batch
“Patients require quick access to safe, affordable, effective and good quality medicines.� (European Commission, 2015) Fernand Sauer, European Commission - Directorate for Public Health
DEFECTIVE MEDICINES THE BACKGROUND The expectation for high quality, safe medicine is an intrinsic requirement for patients. The responsibility for assurance of high quality in the manufacture and supply of these medicinal drug products lies largely with the manufacturers and distributors of these products with assessment, oversight and guidance for safety and efficacy provided by the international regulatory community.
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REGULATION OF MEDICINAL PRODUCTS IN THE EU
Typically, NCAs do not conduct inspections in each The European regulatory system for medicines is other’s territories and work together on postbased on a unique model in the global regulatory marketing safety issues; including pharmacoviligance environment (EMA, 2015). The system is comprised activities and rapid alerts relating to suspected of a network of National Competent Authorities quality defects and medicinal product recalls. (NCAs) responsible for medicines regulation from member states in the European Union (EU) and In recent years the degree of integration of European Economic Area (EEA), who the network has increased. Inspection are closely coordinated through activity has become increasingly the European Medicines Agency coordinated and the recently (EMA) and the Heads of Close integration of this published consultation draft Medicines Agencies (HMA). of the EU Medicines Agencies network, bringing together The EMA is responsible Network Strategy to 2020 the necessary expertise for the coordination of indicates that serious the scientific evaluation consideration is being and knowledge, is critical of all medicines that are given to the on-going to ensuring that medicines authorised through the development of integrated centralised procedure. The IT systems that underpin in the region are regulated NCAs work closely with the regulatory work of to the highest scientific the EMA providing scientific the network in order to enhance information exchange expertise in the assessment standards. efficiencies. of centralised products. The EMA is also responsible for the EU wide coordination of safety monitoring for medicines. National Competent Authorities (NCAs) seek to share workloads and scientific competence and do attempt to avoid duplication of efforts.
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The role of integration between member states on defect and product recall handling is crucial in addressing emerging market-based events that relate to quality defects, and to assist in driving behaviours toward prevention rather than cure.
The network serves a population of over 500 million, the world’s third largest population after China and India. Together, this closely integrated network ensures that patients and animals in Europe have access to medicines that are safe, effective and of good quality and that patients, healthcare professionals and citizens are provided with adequate information about medicines.
One of the major challenges relates to the handling of emerging events with respect to authorised medicines. Such events are mainly safety concerns or quality defects, putting into question the positive benefit/risk balance of medicines.
EU Medicines Agencies Network Strategy to
EU Medicines Agencies Network Strategy to
2020 - Working Together to Improve Health
2020 - Working Together to Improve Health
(Consultation draft, March 2015)
(Consultation draft March 2015)
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RELIABLE DRUG QUALITY The subject of reliable drug quality has received increased attention in recent years as a result of some highly publicized public health tragedies and the focus on the manufacturing quality problems underpinning recent drug shortage situations (EMA, 2012; FDA, 2013; ISPE, 2014; Kweder & Dill, 2013). The ICH Q10 Guidance outlines that an effective Pharmaceutical Quality System provides a pathway to ‘...enhance the quality and availability of medicines around the world in the interest of public health’ (ICH, 2008). This statement has universally become known as the desired state for pharmaceutical products. Yet, eight years on from the publications of the guideline, the achievement of this desired state where top-quality medicines are universally available to meet the current health needs of patients remains an on-going challenge.
Despite the potential for serious or critical consequences, quality problems in pharmaceutical manufacturing continue to arise. U.S. Food and Drug Administration (FDA) Centre for Drug Evaluation and Research (CDER) director Janet Woodcock cautions that, “the consequences of quality problems such as subpotency, lack of sterility, or product mix-ups can be so devastating” (Woodcock, 2012). If other manufacturing sectors have successfully adopted quality management techniques such as six-sigma, this should imply that reliable, high quality manufacturing is also attainable in the pharmaceutical sector. Woodcock asks why, in an area where the stakes are so high, is this not being achieved?
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