Basic concepts about regulatory affairs
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Regulatory affairs professionals act as the interface between the pharmaceutical industry and drug regulatory authorities. Their main goals are to protect human health, ensure drug safety and quality, and ensure accurate product information. Key roles include liaising with regulatory agencies, preparing regulatory submissions, and advising on regulatory requirements and guidelines. An investigational new drug (IND) application is filed with regulatory agencies to legally test an experimental drug in humans after preclinical testing. A new drug application (NDA) is filed to obtain approval to market a new drug, while an abbreviated new drug application (ANDA) is filed for generic drug approval based on demonstrating bioequivalence to an existing drug. Drug master files and active substance master files provide confidential manufacturing
Basic concepts about regulatory affairs
- 1. BASIC CONCEPTS ABOUT REGULATORY AFFAIRS RAJKUMAR KOLEY EXECUTIVE ā QUALITY ASSURANCE MICRO LABS LTD. rajkoley89@gmail.com
- 2. What is Regulatory Affairs? Regulatory Affairs in a Pharmaceutical industry, is a profession which acts as the interface between the pharmaceutical industry and Drug Regulatory authorities across the world. It is mainly involved in the registration of the drug products in respective countries prior to their marketing. What are the goals of Regulatory Affairs Professionals? ļ¼ Protection of human health ļ¼ Ensuring safety, efficacy and quality of drugs ļ¼ Ensuring appropriateness and accuracy of product information What are the Roles of Regulatory Affairs professionals? ļ¼ Act as a liaison with regulatory agencies ļ¼ Preparation of organized and scientifically valid NDA, ANDA, INDA, MAA, DMF submissions ļ¼ Ensure adherence and compliance with all the applicable cGMP, ICH, GCP, GLP guidelines, regulations and laws ļ¼ Providing expertise and regulatory intelligence in translating regulatory requirements into practical workable plans ļ¼ Advising the companies on regulatory aspects and climate that would affect their proposed activities ļ¼ Apart from the above main roles, there are various other roles which Regulatory Affairs professionals play.
- 3. What is an Investigational New Drug (IND) application? It is an application which is filed with FDA to get approval for legally testing an experimental drug on human subjects after completing preclinical testing. It is not an application for marketing approval. Main components of an IND are: ļ¼ Description of the drug substance ļ¼ Chemistry, manufacturing and control information ļ¼ All known pre-clinical information ļ¼ Any previous human study reports ļ¼ Investigatorās brochure ļ¼ Clinical development plan ļ¼ Protocol and investigate list submission for the phase I clinical trial. The FDA has 30 days to respond to the sponsorās IND. Refer to 21CFR312.23 for specifics regarding the IND format and content. The IND application must contain information in three broad areas: ļ¼ Animal pharmacology and Toxicology studies ļ¼ Manufacturing information ļ¼ Clinical protocols and Investigator information
- 4. What is a New Drug Application (NDA)? The NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational new drug become part of the NDA. In simple words, āIt is an application which is filed with FDA for permission to market a new Pharmaceutical drug product for sale in USAā Fundamentals of NDA submissions: 1. Index 2. Summary 3. Chemistry, manufacturing and control 4. Samples, methods validation package, and Labeling 5. Non-clinical pharmacology and Toxicology 6. Human pharmacokinetics and Bioavailability 7. Microbiology (for anti-microbial drugs only) 8. Clinical data 9. Safety update report (typically submitted 120 days after the NDAās submission) 10.Statistical 11.Case report tabulations 12.Case report forms 13.Patent information 14.Patent certification 15.Other information
- 5. What is an Abbreviated New Drug Application (ANDA)? It is an application filed with FDA, for a U.S. generic drug approval for an existing licensed medication or approved drug. In simple words, āIt is an application for the approval of Generic Drugs ā Generic drug applications are termed āabbreviatedā because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent. Bioequivalent review study information: ļ¼ Formulation comparison for products whose bioavailability is self-evident. ļ¼ Comparative dissolution testing where there is a known correlation between in vitro and in vivo effects. ļ¼ In vivo bioequivalence testing comparing the rate and extent of absorption of the generic to the reference product ļ¼ For non-classically absorbed products, a head to head evaluation of comparative effectiveness based upon clinical endpoints. What is a Generic Drug Product? A generic drug product is the one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. What is a 505 (b)(2) application ? 505 (b) (2) application is a type of NDA for which one or more investigations relied on by applicant for approval were not conducted by/for applicant and for which applicant has not obtained a right of reference. What kind of application can be submitted as a 505(b)(2) application? New chemical entity (NCE)/new molecular entity (NME) Changes to previously approved drugs
- 6. What are the examples of changes to approved drug products for which 505(b)(2) application should be submitted ? ļ¼ Change in dosage form. ļ¼ Change in strength ļ¼ Change in route of administration ļ¼ Substitution of an active ingredient in a formulation product ļ¼ Change in formulation ļ¼ Change in dosing regimen ļ¼ Change in active ingredient ļ¼ New combination Product ļ¼ New indication ļ¼ Change from prescription indication to OTC indication ļ¼ Naturally derived or recombinant active ingredient ļ¼ Bioequivalence
- 7. What is a DMF? A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. Important facts regarding DMFs ļ¼ It is submitted to FDA to provide confidential information ļ¼ Its submission is not required by law or regulations ļ¼ It is neither approved nor disapproved ļ¼ It is filed with FDA to support NDA, IND, ANDA another DMF or amendments and supplements to any of these. ļ¼ It is provided for in the 21 CFR (Code of Federal Regulations) 314. 420 ļ¼ It is not required when applicant references its own information What are the types of DMFās? Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (No longer accepted by FDA) Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type III: Packaging Material Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Type V: FDAAccepted Reference Information (FDA discourages its use)
- 8. What is a Marketing Authorization Application (MAA)? It is an application filed with the relevant authority in the Europe (typically, the UK's MHRA or the EMAās Committee for Medicinal Products for Human Use (CHMP)) to market a drug or medicine. As per UKās MHRAApplications for new active substances are described as 'full applications'. Applications for medicines containing existing active substances are described as 'abbreviatedā or āabridged applicationsā. What is an ASMF? Active substance master file (ASMF) is a submission which is made to EMA, MHRA or any other Drug Regulatory Authority in Europe to provide confidential intellectual property or 'knowhow' of the manufacturer of the active substance. In simple words, āIt is a submission made to European Drug regulatory agencies on the confidential information of Active Substance or Active pharmaceutical Ingredient (API)ā. What are the types of active substances for which ASMFs are submitted? ļ¼ New active substances ļ¼ Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State ļ¼ Pharmacopeias active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member State What is the difference between DMF and ASMF (with respect to submission)? ASMF is submitted as Applicantās Part (Open Part) and Restricted Part (Closed Part). There isnāt any differentiation of DMFās into parts.
- 9. What is ICH? International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): is a project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of pharmaceutical product registration. What is CTD? The Common Technical Document (CTD) is a set of specification for application dossier, for the registration of Medicines and designed to be used across Europe, Japan and the United States. Quality, Safety and Efficacy information is assembled in a common format through CTD .The CTD is maintained by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). CTD format for submission of drug registration applications/dossiers is widely accepted by regulatory authorities of other countries too like Canada, Australia etc. What are the ICH guidelines to be referred for preparation of registration dossiers/applications of medicines (With respect to format and contents in each module)? M4-Guideline, M4Q-Guideline, M4S-Guideline, M4E-Guideline What are the modules in CTD? The Common Technical Document is divided into five modules: Module 1. Administrative information and prescribing information Module 2. Common Technical Document summaries (Overview and summary of modules 3 to 5) Module 3. Quality Module 4. Nonclinical Study Reports (toxicology studies) Module 5. Clinical Study Reports (clinical studies)
- 10. What is Orange Book? It is the commonly used name for the book āApproved Drug Products with therapeutic Equivalence Evaluationsā, which is published by USFDA. It contains the list of drug products, approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. What is Hatch Waxman act? It is the popular name for Drug Price Competition and Patent Term Restoration Act, 1984. It is considered as the landmark legislation which established the modern system of generic drugs in USA. Hatch Waxman amendment of the federal food, drug and cosmetics act established the process by which, would be marketers of generic drugs can file Abbreviated New Drug Application (ANDA) to seek FDA approval of generic drugs. Paragraph IV of the act, allows 180 day exclusivity to companies that are the "first-to-file" an ANDA against holders of patents for branded counterparts. In simple words āHatch Waxman act is the amendment to Federal, Food, Drug and Cosmetics act which established the modern system of approval of genericsā What are the patent certifications under Hatch Waxman act? As per the Hatch and Waxman act, generic drug and 505 (b) (2) applicants should include certifications in their applications for each patent listed in the āOrange Bookā for the innovator drug. This certification must state one of the following: (I) that the required patent information relating to such patent has not been filed (Para I certification) (II) That such patent has expired (Para II certification) (III) That the patent will expire on a particular date (Para III certification), or (IV) That such patent is invalid or will not be infringed by the drug, for which approval is being sought (Para IV certification). A certification under paragraph I or II permits the ANDA to be approved immediately, if it is otherwise eligible. A certification under paragraph III indicates that the ANDA may be approved when the patent expires.
- 11. What is meant by 180 day exclusivity? The Hatch Waxman Amendments provide an incentive of 180 days of market exclusivity to the āfirstā generic applicant who challenges a listed patent by filing a paragraph IV certification and thereby runs the risk of having to defend a patent infringement suit. 180 Day Exclusivity could be granted to more than one applicant. The recent example is180 day exclusivity was granted to Ranbaxy and Watson Laboratories for marketing generic version of Lipitor (Atorvastatin calcium). What are the procedures for Approval of Drug in EU? 1. Centralized Procedure (CP) 2. Decentralized Procedure (DCP) 3. Mutual Recognition Procedure (MRP) 4. National Procedure (NP) What is the Full form of abbreviation, CEP? Certificate of Suitability to the monographs of the European Pharmacopoeia (or) Certificate of suitability of monographs of the European Pharmacopoeia (or) Certification of suitability of European Pharmacopoeia monographs. It is also informally referred to as Certificate of Suitability (COS). It is the certificate which is issued by Certification of Substances Division of European Directorate for the Quality of Medicines (EDQM), when the manufacturer of a substance provides proof that the quality of the substance is suitably controlled by the relevant monographs of the European Pharmacopoeia.
- 12. What are the chemical classification codes for NDA? NUMBER MEANING 1 New molecular entity (NME) 2 New ester, new salt, or other noncovalent derivative 3 New formulation 4 New combination of two or more drugs 5 New manufacturer( marketed Drug product ā Duplication) 6 New indication for already marketed drug 7 Drug already marketed, but without an approved NDA 8 OTC (over-the-counter) switch What are the differences between NDA and 505 (b) (2) application? Sl no. NDA 505 (b) (2) 1 All investigations are relied by applicant for approval were conducted by/for applicant and for which applicant has right of reference One or more investigations are relied by applicant for approval were not conducted by/for applicant and for which applicant has not obtained right of reference 2 Generally, filed for newly invented pharmaceuticals Generally, filed for new dosage form, new route of administration, new indication etc. for all already approved pharmaceutical.
- 13. What are the difference between Not-approvable letter, Approvable letter, and Approval letter? Not-approvable letter: lists the deficiencies in the application and explains why the application canāt be approved. Approvable letter: signals that ultimately, the drug can be approved. Lists minor deficiencies that can be corrected. Approval letter: states that the drug is approved. It may follow an approvable letter, but can also be issued directly. What are the essential shipment documents for the import of Clinical trials material? 1. Master airway Bill (MAB) - document issued by airline certifying transport of material at the required destination 2. Certificate of Analysis (COA) ā detailed test analysis report performed on clinical trial material by the manufacturer 3. Certificate of Origin (COO) ā document issued by local chamber of commerce of the shipper certifying that goods being shipped are of particular country of Origin 4. Packing list, document prepared by shipper showing details of the packing e.g. number of boxes, quantities contained in each box etc. 5. Performa invoice, document which specifies price of the material to be imported. Note: an application of import-export of clinical trial drugs and No objection certificate (NOC) is filled with permission from Drugs controller General of India (DCGI). Duration of approval: both of import and export basis within one year.
- 14. Well known Drug Regulatory Agencies across the world United States Of America United States Food And Drug Administration (USFDA) United Kingdom Medicines And Healthcare Products Regulatory Agency (MHRA) European Union European Medicines Agency(EMA) European Union European Directorate For The Quality Of Medicines (EDQM) Australia Therapeutic Goods Administration (TGA) Canada Therapeutic Products Directorate (TPD), Health Product And Food Branch (HPFB) Of Health Canada Japan Pharmaceutical And Medical Devices Agency(PMDA) France French Agency For The Safety Of Health Products (AFSSAPS) Germany Federal Institute For Drugs And Medical Devices (Bfarm) Brazil The National Health Surveillance Agency (ANVISA) Switzerland Swiss Agency For Therapeutic Products (SWISSMEDIC) Singapore Health Sciences Authority (HSA) New Zealand New Zealand Medicines And Medical Devices Safety Authority (MEDSAFE) India Drugs Controller General Of India (DCGI), Central Drugs Standard Control Organization (CDSCO)
- 15. Full forms of some of the Abbreviations related to Regulatory Affairs NDA New Drug Application ANDA Abbreviated New Drug Application IND Investigational New Drug Application DMF Drug Master File ASMF Active Substance Master File MAA Marketing Authorization Application CEP Certificate Of Suitability To The Monographs Of The European Pharmacopoeia ICH International Conference On Harmonization CTD Common Technical Document AP Applicantās Part RP Restricted Part OP Open Part CP Closed Part NME New Molecular Entity NCE New Chemical Entity SmPC Summary Of Product Characteristics PL Packaging Leaflet RMS Reference Member State CMS Concerned Member State CHMP Committee For Medicinal Products For Human Use CPMP Committee For Proprietary Medicinal Products CVMP Committee For Medicinal Products For Veterinary Use SUPAC Scale Up And Post Approval Changes BAPAC Bulk Active Chemicals Post Approval Changes cGMP Current Good Manufacturing Practice GCP Good Clinical Practice GLP Good Laboratory Practice