National Agency of Drug and Food ControlREGULATORY FRAMEWORK IN RELATION TO NANOTECHNOLOGY BASED MEDICINAL PRODUCTS Dra. Lucky S. Slamet MSc. BADAN POM Nanotechnology State of The Art in Health Care and Pharmaceuticals Jakarta, 23 Agustus 2007 National Agency of Drug and Food Control 2 BACKGROUND (1) Nanotechnology is considered to be one of the emerging fields in science with great potential in a wide range of applications including drug delivery, diagnostics, theranostics and regenerative medicines National Agency of Drug and Food Control 3 Nanotechnology as an emerging technology promise for the development of new drug, new performance of drug, new dosage form Challenges when basic knowledge or technology are increasing the gap between regulation and practice As in EU and US, in Indonesia Nanomedicine will be implemented under the existing regulatory frameworks NANOMEDICINE (contain materials at nanometer scale) BACKGROUND (2) National Agency of Drug and Food Control 4 BACKGROUND (3) The use of Nanotechnology for NADFC- Regulated Products General Drugs (novel NMEs or delivery system) Biotechnology products Vaccines Cosmetics National Agency of Drug and Food Control Specific: Possible opportunities for Nanotechnology in drug delivery Enhanced drug properties such as : Solubility HIGHER ABSORBTION Rate of dissolution Oral bioavailability Targeting ability Enhanced dosing requirements: Lower dosed administered Better side effect profile More convenient dosage forms BACKGROUND (4) National Agency of Drug and Food Control The main mission: to promote and protect public health by among other • Ensuring safety, efficacy and quality of medicine according to the national and international standard • Facilitating easy access to affordable medicine regarded having public health importance without compromising safety, efficacy and quality Regulatory Framework of NADFC, Republic of Indonesia National Agency of Drug and Food Control 7 Drug Regulatory Framework in Indonesia BEFORE MARKET AFTER MARKET Pre market control Post market control Ensure efficacy, safety, quality of marketed drug and objective Product Information National Agency of Drug and Food Control 8 Regulatory framework on Ensuring S,E,Q Assured Medicine Q,S,E Documentation, monitoring and evaluation Regulatory elements (full spectrum/com- prehensive functions incl, inspection, recall, central & provincial lab ) Technical elements (quality specifications, Basic tests, GMP, GLP, GPP, GDP, GSP, GCP) Pre-marketing assessment (marketing authorization/ licensing and registration) Post-marketing authorization surveillance (for quality and adverse events, and product information/pro- motion) Adequate legislation and law enforcement Medicine Quality Assurance Structural Components National Agency of Drug and Food Control 9 Law enforcement with heavy sanction Investigation and justice Good Laboratory Practices (GLP) Good Clinical Practices (GCP) Implementation Of GRP In Indonesia GRP Comprehensive Audit Specification and quality of pharm raw materials, finished product, packaging (Pharmacopoeia and non-compendial) Good Manufacturing Practices (GMP) Good Distribution Practices (GDP) Good Sampling Practices (GSmP) Good Laboratory (GLP) Inspection Good Manufacturing Practices (GMP) Good review practices 3 MAIN PILLARS ON MEDICINE CONTROL : SCIENTIFIC BASED ACTIVITIES & LAW ENFORCEMENT National Agency of Drug and Food Control 1971 1980, 1990, 1993 1984 2000 2001 2003 2008 (indonesian timeline) Licensing for pharmaceuticals and biological product Improvement of criteria for the licensing Implementation of GMP regulation based on WHO GL Imprverment: global harmanization trend, accelerate reg. process w/o compromising Q,S,E Establishment of Indonesian GCP and regulatory framework for clinical trial Updated Indonesian Technical Dossier as ASEAN harmanization (content); GCP Inspection ACTD implementation (full acceptance of dossier format) Pre Market Control (1) Regulatory System on Marketing Authorization National Agency of Drug and Food Control 11 Evaluation and registration to ensure efficacy, safety, and quality Compliance on cGMP Standard production process Evaluation on labeling and advertisement to conform with approved indication and the criteria of objectivity and completeness Pre Market Control (2) National Agency of Drug and Food Control 12 • Pre-clinical trials • Clinical trials (phase I, II and III) CRITERIA FOR DRUG EVALUATION • GMP Standard • Production Process • Product Specification • Complete & objective information that ensures correct, rational and safe use of the drug Efficacy and Safety Labeling Q u a l i t y According to the actual need of the population Risk assessment NationalCommittee on Drug Evaluation Registration system in other countries EVALUATOR Registration system in other countries FDA - Psychotropic: superior E & S over registered drug - Health Program: Clinical Trial Pre Market Control (3) National Agency of Drug and Food Control 13 Essentially the same as that for other products that do not contain nanomaterials for safety, efficacy and quality Special consideration : effectiveness and safety Review Process for Nanotechnology Drugs National Agency of Drug and Food Control 14 Special Consideration: Effectiveness Quality Assessment Important consideration : Characterization of Active substance Formulation Method for identification and assay of drug Stability BA/BE study In conformity with the Compendia, Guideline National Agency of Drug and Food Control 15 Characterization: What are the particles forms? Soluble or insoluble particles Organic or inorganic molecules Nanoemulsions, nanocrystal colloid dispersions Liposomes Nanoparticles that are combination product (drug- device, drug-biologics, drug-device-biologic) How do physical characteristics impact product quality and performance? Special Consideration: Effectiveness Continue….. National Agency of Drug and Food Control 16 What are the standard instruments used for characterization of nanoparticles properties? What are the critical physical and chemical properties, including residual solvents, processing variables, impurities and excipients? What are the critical steps in the scale-up and manufacturing process for nanotechnology products? How are characterization and manufacturing procedures assessed? Continue….. National Agency of Drug and Food Control 17 Formulation: How do nanoparticle formulation enhance performance of dosage forms, such as higher solubility, rapid dispersion, rapid dissolution ? Continue….. National Agency of Drug and Food Control 18 Method for identification and assay: Analytical method for identification and assay should sensitive, accurate, high precise? What are validated assays to detect and quantify nanoparticles in drug product and in tissue? Reference standard ? Continue….. National Agency of Drug and Food Control 19 Stability: How to ensure the particle of active ingredient still nanoscale on storage condition, beside other critical specification? How do determine long and short-term stability of nanomaterials (in various environments)? Continue….. National Agency of Drug and Food Control 20 Bioavailability Study Nanoparticles Maximum absorption molecule of drug in the body Greater therapeutic effectiveness More of cost effective ratio Lower dose National Agency of Drug and Food Control 21 As smaller particle size, there may be size specific effects on activity, such as: Special Consideration: Safety Will nanoparticles gain access to tissues and cells Once nanoparticles enter tissues, how long do they remain there? How are they cleared from tissues and blood? If nanoparticles enter cells, what effects do they have on cellular and tissue functions (transient and/or permanent)? Might there be different effects in different cells ypes? Pre-clinical Trial National Agency of Drug and Food Control 22 (Continue....) Absorption, distribution, metabolism, excretion (ADME) for NME – What are the different in the ADME profile, for nanoparticles versus larger particles of the same drug? – Are current methods used for measuring drug levels in blood and tissues adequate for assessing levels of nanoparticles (appropriateness of method, limits of detection)? – How accurate are mass balance studies, especially if level of drug administered are very low; i.e. can 100% of the amount of drug administered be accounted for? Special Consideration: Safety National Agency of Drug and Food Control 23 Post Market Control Pharmacovigilance Quality aspect: – GDP – Standardization of quality of raw materials, finished products – Licensing of drug establishment – Periodic GMP Inspection – Sampling and Analysis of drugs Regulatory System on Post Marketing Authorization National Agency of Drug and Food Control Maximizing Regulatory Framework for Dialogue PRE-IND AND IND STEPS or FORMULATION R & D - Manufacturing process development - Clinical development Dossier submission Manufacturers Regulatory consultation GMP Phase 1 - Safety - Efficacy/ Immuno genicity Phase 2 - Efficacy/ Immuno genicity - Safety - Dose ranging Phase 3 - Efficacy/i mmunog enicity - Safety - Inspection - Phase 4 study - Monitoring safety, quality PRE-MARKET EVALUATION PRODUCTION GMP III. POST-MARKET CONTROL I. PRE SUBMISSION II. MA APPLICATION & PRODUCTION National Agency of Drug and Food Control 25 FUTURE CHALLENGES Currently approved nanoparticle – containing products as nanomedicine are generic products may be expanded to new drug delivery of Life Saving drugs. Nanotechnology as a new technology has unknown risk/safety and limited scientific data available to address public health concerns may need new approach to review risk-benefit of Novel nanotechnology prior and after marketing. Regulatory oversight for products impacted by nanotechnology, i.e. Tissue engineering products, combination products (multiple constituent drug- device; drug-biological). National Agency of Drug and Food Control 26