World Bank Training Program on HIV/AIDS Drugs
Training Module 4
Quality Assurance
Ben K Botwe April 2005
Learning Objectives
Upon completion of this module, you will be able to
Explain the need for a systematic quality assurance process for pharmaceutical products
Describe key elements of the quality assurance process for pharmaceuticals
Discuss the procedures and standards for prequalification of suppliers of pharmaceuticals Apply quality assurance and supplier selection principles to case discussions
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Rationale for this Module
Quality medicines are safe, effective and efficient tools for treatment of HIV/AIDS Poor quality (sub-standard) medicines may not produce desired effects, may cause harm Errors in production can lead to sub-standard medicines Quality Assurance principles can be used to detect errors or problems in production and ensure suppliers conform to standards and expectations Battling HIV/AIDS: A decision makers guide to the procurement of medicines and related supplies provides framework for quality assurance 3
Outline of the Presentation
Introduction, Definitions and Quality Assurance Good Manufacturing Practices Product Selection Suppliers and Manufacturers Selection and Sourcing Procedures for Prequalification of Suppliers Stability and Equivalence Conclusion Case Study
Quality Assurance
A process, not an end-point Must be independent of financial pressures Must ensure that quality policies are followed Must have final authority in product acceptance, rejection and release to public Integral to production, not an add-on Responsible for day-to-day operations and for longer term goal settings Quantitative discipline with specified parameters
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DEFINITIONS
QUALITY
The totality of features and characteristics of a medicinal product and its ability to satisfy stated and/or implied needs
QUALITY ASSURANCE
The sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended 6 use.
DEFINITIONS
GOOD MANUFACTURING PRACTICE (GMP)
That part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use.
QUALITY CONTROL
That part of GMP which is concerned with sampling, specifications and testing.
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Quality relationships
QA GMP
QC
Quality relationships
Quality Management
Quality Assurance
GMP Quality Control
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FACTORS IN DRUG QUALITY ASSURANCE
LEGISLATIVE FRAMEWORK -REGULATIONS IMPORT & EXPORT CONTROL
PACKAGING
HUMAN RESOURCESPROFESSIONALS
LABELLING & PRODUCT INFROMATION
RAW MATERIALSACTIVE & INACTIVE
DRUG PRODUCT QUALITY
QC & ANALYSIS
MANUFACURING PROCESSES & PROCEDURES
STORAGE
TRANSPORT DISTRIBUTION DISPENSING & USE
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Quality Assurance
Primary Functions Quality Control
Analytical testing of products
Active and Non active material control
Sampling, inspecting and testing of incoming raw materials
Packaging and labeling components
Bottles, caps, foils, labels, measures, cartons
Physical inspection of product and operations at critical intermediate stages
In-process controls, HHACCP
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Quality Must Be Designed Into A Product
Quality is not an add-on: it begins with research and development Product quality criteria must be established Detailed specifications provide quantitative parameters for measurement Written procedures document how quality is attained and maintained Continuous monitoring (sampling, testing) to confirm quality is being built-into 12 product
Quality Assurance: Essential At All Stages
Quality Assurance Cycle
Research Development Raw Materials Facilities Documentation Equipment Personnel
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Elements of the Quality Assurance Cycle in Pharmaceutical Manufacturing
Research Development Prototyping Documentation Raw Materials Facilities Equipment Personnel and Supervision Monitoring, Feedback, Follow-up
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Analytical Control Laboratory
Heart of Quality Management in Pharmaceuticals
Academically trained and certified staff
Experienced supervision/management Capable of performing complex analyses Able to report honestly and in a timely manner Equipment and instrumentation must be suitable for performing testing Access to reliable power, water and other stable infrastructure
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Quality Control & Analysis
Qualification
Calibration Validation SOPs
Design, Installation, Process and Operational Daily and periodic Equipment, Method and process Authorized, used and updated
Documentation Quality Manual
Systematic and well kept
Quality manager, staff trained and motivated to comply.
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Safety measures
Quality Assurance Throughout the Manufacturing Process
Monitoring environmental conditions under which products are manufactured/stored
Monitoring of air and water systems to prevent contamination Air Handling Units Monitoring of humidity
Monitoring of personnel Feedback and follow-up
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Manufacturing Process and Procedures
Dispensing / Weighing Mixing / Granulation / Preparation Compression / Encapsulation / Filling Equipment, Operational & Process Qualification Validation & calibration Documentation and record keeping 18 Yield Reconciliation
A Guiding Philosophy for Quality Assurance in the Pharmaceutical Industry
Poor Quality Medicines:
Are a health hazard Waste money for governments and consumers May contain toxic substances that have unpredictable, unintended consequences Will not have a desired therapeutic effect Does not save anyone any money in the long term Hurt everyone patients, health care workers, 19 policy makers, regulators, manufacturers
CONSEQUENCES OF QA BREACHES
Poor Treatment outcomes High Health Bills Treatment Failures & Deaths Loss of Confidence in the Health Services Enormous Economic Losses National Security Issue
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What is GMP? (WHO)
Comprehensive system for ensuring products are consistently produced and controlled according to quality standards
Designed to minimize risks involved in any pharmaceutical production that cannot be eliminated through testing of final product alone
Cross-contamination
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Major Risks in Pharmaceutical Production
Contamination of products (microbial, particulate or other)
Incorrect labels on containers
Insufficient active ingredient
Excess active ingredient Poor quality raw materials Poor formulation practices
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Analysis of Substandard Medicines
Correct Ingredient 7% Incorrect Ingredient 16%
Incorrect Amount 17%
No Active Ingredient 60%
Source: (WHO)
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The Breadth of GMP
Covers all aspects of production including
Raw or starting materials Finished products Premises and environment Equipment personnel Training Hygiene
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GMP Principles
Must be built into manufacturing process
Prevents errors that cannot be eliminated through quality control of finished product Ensures all units of a medicine are of the same (within specified parameters) quality Poor medicines leads to loss of credibility for everyone: manufacturers, health care workers and governments
WHO Guidelines for GMP
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WHO Technical Guide to GMP
First prepared in 1967
Updated and revised regularly Quality Management in the Drug Industry outlines general concepts and principle components of GMP Good practices in production and quality control describes implementation
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WHO Technical Guide to GMP
General Consideration
Licensed pharmaceutical products should be manufactured only by licensed manufacturers whose activities are regularly inspected by competent national authorities
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WHO Technical Guide to GMP
Key Concepts
Validation Action of proving (in accordance with principles of GMP) that any procedure, process, equipment, material, activity, or system actually leads to expected results
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WHO Technical Guide to GMP
Key Concepts
Qualification Action of proving that any premises, system, and items of equipment work correctly and actually lead to expected results
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Associated Concepts
Good Laboratory Practice (GLP) Good Clinical Practice (GCP) Clear language use Effective record keeping Design, installation, operational and process qualification (DQ, IQ, OQ and PQ) Self-inspection and self-regulation Good Distribution Practice (GDP)
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Key Elements of GMP (WHO Technical Guide)
Sanitation and hygiene Qualification and validation
Complaints
Product recalls Contract Production and Analysis Self-Inspection and Quality Audits
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Key Elements of GMP (WHO Technical Guide)
Personnel
(Training, Hygiene)
Documentation
Premises
(Equipment)
Materials
(Supplies, Ingredients)
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Product Selection Issues
Unique nature of medicines heightens need for effective quality assurance
All medicines used must be safe, effective, and of consistent quality Failure to select proper products will lead to treatment failure, drug resistance, wasted resources and human suffering
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Product Selection Issues
(Cont.)
Selection of product and goal of treatment may vary depending upon patient group Infected adults
Infected women (who may be/may become pregnant)
Infected children (blood-borne or sexual transmission) Emergency workers Victims of sexual assault
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Demographic Profile of HIV Patients
Age distribution of HIV Patients in India (2003)
6% 8% 4% 10% 5% 0-9 years old 10-19 years old 20-29 years old 30-39 years old 25% 40-49 years old 50-59 years old >60 years old 42%
Source: (Zaheer et al., 2003)
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Demographic Profile of HIV Patients (Cont.)
Route of HIV Transmission
32% Sexual Contact Blood/Blood Products 54% Not known/specified
14%
Source: (Zaheer et al., 2003)
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Clinical Outcomes
Successful treatment for HIV with quality medicines will:
Improve general health status/well-being Reduce viral load to <20 cells/mL Maintain CD4 within normal range (550-1400 cells/mL) Prevent/reduce drug resistance Manage and minimize drug-related sideeffects Reduce need for medical intervention
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WHO Essential Medicines Categories (for HIV)
NRTIs (Nucleoside reversetranscriptase inhibitors) (e.g. AZT, ddI, 3TC)
NNRTIs (Non-nucleoside reversetranscriptase inhibitors) (e.g. NVP, EFV) PIs (Protease Inhibitors) (e.g. ritonavir, saquinavir) In the future: Fusion Inhibitors, Integrase Inhibitors
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Combination Products
More convenient, improve adherence, reduce pill burden for patient
E.g. Triomune (NRTI-NNRTI triple combination therapy consisting of stavudine, lamivudine, and nevirapine) Product formulations to allow twice daily (or even once daily) dosing
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Use of Medicines in Women Who are Pregnant
Acceptable combination treatments
d4T + 3TC + NVP ZDV + 3TC + NVP
Combination treatments to avoid
d4T + 3TC +EFZ ZDV + 3TC + EFZ
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Suppliers/Manufacturers
Many reliable manufacturers, both innovator and generic companies, can offer quality productsthe aimis sustained, consistent and acceptable quality rather than high or better quality, terms that are impossible to quantify
Battling HIV/AIDS, World Bank 2004
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Sources of Pharmaceutical Products
Multi-source
Well-established products, long history of use, no longer subject to patent protection (e.g. Rifampin)
Single source
Newer products still subject to patent protection in many countries (e.g. Saquinavir)
Limited source
More than single source/supply possible (e.g. AZT); may be difficult to manufacture (e.g. amphotericin); may be unprofitable drug with limited market potential
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Comparison of Sources
Multi-source # of manufacturers Many World-wide Public information Available C ompendia Public experience Long-standing Well-documented Accessible Single/limited source Innovator manufacturer Limited local generic Not available In-house specifications Very limited Not documented Not easily accessible
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Identifying Product Suppliers
Systematic Approach
Pre-qualification of suppliers and products Specifying supplier conditions in contract Monitoring quality of product and processes Continuous evaluation of supplier performance and product performance in clinical practice
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Identifying Product Suppliers
Specify Conditions Evaluate Monitor
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Selecting and Sourcing MultiSource Products
Innovator vs. generic issues Prequalification systems
Specific issues related to interchangeability of products stability, bioavailability, bioequivalence, etc.
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Selecting and Sourcing MultiSource Products
Innovator vs. generic issues Prequalification systems
Specific issues related to interchangeability of products stability, bioavailability, bioequivalence, etc.
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Procedures for Prequalification of Suppliers
Rationale More meaningful, effective, efficient and less expensive to eliminate sub-standard manufacturers and products at the opening of bidding/tendering than during the process
Purpose To ensure that products are manufactured in compliance with GMP and products meet established quality standards
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Procedures for Prequalification of Manufacturers
Local Procurement Committee comprising managerial, technical, and professional staff Manufacturers submit dossiers for review; must be reviewed/re-inspected every 3-5 years to ensure adherence to policies Review/re-inspection also performed if product changes occur that may impact on safety, efficacy, quality, manufacturing method, or location of manufacturing
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Procedures for Prequalification of Manufacturers (Cont.)
Evaluation of Product Dossier Random testing of samples
Verification of compliance with GMP
Verification of compliance with good distribution practices
Role of national drug regulatory organizations (in compliance with WHO standards)
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Prequalification: Evaluation of Product Dossier
Specifications in WHO guidelines Must include details regarding: Regulatory status Pharmaceutically active ingredient(s) Manufacturing processes Finished product specifications (stability, bioavailability, interchangeability etc.) - Packaging/labeling/storage details - Product/patient information
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Prequalification: Evaluation of Product Dossier- Multi-source Products
For products manufactured and registered in countries with a stringent regulatory authority, the product dossier presented may be the same as that presented to the regulatory authority Appropriate documentation/certification provided if product differs in any way from product registered in original country (e.g. packaging, formulation, 52 strength, manufacturing site, etc.)
Prequalification: Evaluation of Product Dossier- Single/Limited Source Products
Include specifications of in-house quality-control and quality management practices in sufficient detail to allow replication by another laboratory Validation of in-house methods must be provided by manufacturer Quality assessment of products to be undertaken by external laboratory
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Prequalification: Random Testing of Samples
Undertaken to verify compliance with standards and references provided in dossier Test samples should be from supplies, not from pre-supply batches
On-going random sampling and quality control analysis post-supply
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Prequalification Verifications
Compliance with GMP
Inspections and certification of facilities or reliance on national regulatory authorities Compliance with good distribution practices Quality assurance methods for selection of raw material suppliers, storage of products, transportation delivery of final product, etc. 55
Summary of Prequalification Processes: WHO Perspective
Issue Guidelines Receive Submissions
Evaluate Submissions Communicate Decision
Perform Inspections
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Summary of Prequalification Processes: Manufacturers Perspective
Submit EOI
Submit Product Dossier
Submit Site Master File Submit Additional Data if needed
Submit Corrective Action Plan if needed
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Options for Prequalification
WHO Prequalification Regional Prequalification International Low-cost Suppliers
Development of international consolidated prequalification system
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Pharmaceutical Stability
GMP state there must be a written testing program designed to assess stability characteristics of drugs. Results of stability testing are used to determine appropriate storage conditions and expiration dating
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Stability Definitions (1)
Capability of a particular formulation of a pharmaceutical in a specified container/closure system to remain within specified physical, chemical, microbiological, therapeutic and toxicological specifications
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Stability Definitions (2)
The time from the date of manufacture and packaging of the formulation until its chemical or biological activity is not less than a predetermined level (generally, 90%) of labeled potency and its physical characteristics have not changed appreciably
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Stability Issues
Time-related harmful events include
a) Deterioration of therapeutic activity below specified threshold
b) Potentiation of therapeutic activity above specified threshold
c) Appearance of toxic substance forming as a degradation by-product
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Factors Affecting Stability of a Pharmaceutical Product
Stability of active ingredient Interaction between active/inactive ingredients Manufacturing process Dosage formulation Container/Liner/Closure System Environment during storage, handling Length of time between manufacturing and usage
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Evaluation of Therapeutic Equivalence of Generic Products
Basic Assumption Drug quality is a function of consistent and optimal release, dissolution, and absorption of active ingredient from a dosage form: this impacts upon chemical equivalence, lot-to-lot uniformity in manufacturing, stability, etc.
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Bioavailability
Measurement of both the rate of drug absorption and total amount (extent) of drug that reaches the general systemic circulation from an administered dosage form
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Equivalence
More general, relative term indicating a comparison of one drug with another along a set of established standards/criteria Bio-equivalence
Clinical equivalence
Therapeutic equivalence
Pharmaceutical equivalence
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Therapeutic Equivalence
Two different brands of a drug product are expected to yield the same clinical result For therapeutic equivalence Pharmaceutical, chemical and bioequivalence must be demonstrated Product must be appropriately labeled Product must be manufactured in compliance with GMP
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Factors Affecting Equivalences
Properties of the Drug Properties of the Dosage Form Properties of Inactive Ingredients (e.g. binders, fillers, disintegrants, lubricants)
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Bio-Equivalence
Indicates that a drug in two or more similar dosage forms reaches the general circulation at the same relative rate and the same relative extent
Does not necessarily demonstrate clinical or therapeutic equivalence (but does not necessarily rule it out either!)
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Evaluation of Equivalence
Products frequently tested in small samples, not whole populations Individual variations may emerge Must adhere to GMP Appropriate and accurate labeling (e.g. generic or brand-name product)
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Conclusions
GMP as a quality management system
Ensure appropriate infrastructure encompassing organizational structure, procedures, processes, and resources Ensure systematic actions necessary to provide adequate confidence that product will meet quality standards and expectations
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Conclusions
Good Manufacturing Practices are
Pivotal to quality assurance Everyones responsibility (manufacturers, purchasers, distributors, consumers) Clear, transparent, documented, readily observable On-going, consistent, reproducible
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Conclusions
GMP are aimed at reducing risks inherent in pharmaceutical production
Qualification and validation provides confidence in manufacturers processes Prequalification provides greatest assurance regarding quality of pharmaceutical products, based on GMP and product dossier
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Case Study
In your small groups, review the case study which you have already read. As a group, identify critical issues raised by this case study. Use the guided discovery questions to prompt discussion.
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Case Discussion Question
How should the government of Fatakia prioritize elements of Good Manufacturing Practices, given the unique situation it faces in procurement, storage, and distribution of antiretrovirals? What if Fatakia does not have the capacity to pre-qualify suppliers?
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Case Discussion Question
Given the unique factors of the drug distribution system in Fatakia, what particular issues related to stability must be considered? How can the drug distribution be modified to optimize pharmaceutical stability?
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Case Discussion Question
In evaluating claims and documents made by different manufacturers of the same drug, what principles must be weighed to ensure optimal health outcomes?
How would you advise the government of Fatakia to develop an evaluation scheme for multiple, competing providers of the same medicine?
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Case Study Summary
Key Issues Health System Infrastructure (e.g. laboratory testing facilities, medics, etc.)
Drug Distribution System (e.g. transport/storage logistics, deterioration in quality of products, drug diversion issues) Financial Pressures (e.g. use of generic products) 78
Case Study Summary
Prequalification of suppliers In accordance with GMP Provision of dossier Random testing of samples (not presupply) Changes/variances must be qualified/validated Demonstrated on-going commitment to standards Options in case there is insufficient capacity to pre-qualify suppliers 79
Case Study Summary
WHO Certification Scheme on the Quality of Pharmaceutical Products Moving In International Commerce
Manufacturing authorizations Marketing authorizations
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Case Study Summary
Equivalency Decisions
Linked directly to GMP Additional burden of proof based on pharmacopeial/compendial standards Differentiate bio-equivalence, therapeutic equivalence, and clinical equivalence
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Case Study Summary
Stability Issues
Drug specific issues Drug-formulation specific issues Container issues Storage/handling/transportation issues Drug Distribution System considerations Health Care System considerations
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