Quality Management for Clinical Pharmacy Practice PDF

CLIN PHARM 171: Quality Management for Clinical Pharmacy Practice Overview of Regulations for Drugs and Biologics Professor Professor Czarina Dominique R. Delos Santos, RPh, M Eng | Reviewed: Aug 11, 2024 | Last Edited: o...

CLIN PHARM 171: Quality Management for Clinical Pharmacy Practice Overview of Regulations for Drugs and Biologics Professor Professor Czarina Dominique R. Delos Santos, RPh, M Eng | Reviewed: Aug 11, 2024 | Last Edited: or official National Formulary; articles intended for use in the diagnosis, cure, mitigation, treatment, OUTLINE or prevention of diseases; or articles intended to affect the structure of any function of the body Biologics THE ELIXIR SULFANILAMIDE INCIDENT ○ A virus, therapeutic serum, toxin, antitoxin, vaccine, DEFINITION OF TERMS blood component or derivative thereof, applicable to ROLE OF REGULATORY AUTHORITIES the prevention, treatment or cure of a disease or REGULATORY AUTHORITIES condition of human beings. US FDA TYPES OF APPLICATIONS UNDER US FDA ROLE OF REGULATORY AUTHORITIES PERTINENT FDA PROCESSES AND Perform a watchdog role to ensure: CONTROL ○ In each stage, the studies are GxP compliant EU REGULATIONS FOR DRUGS AND ○ Animal studies to test for toxicology comply with BIOLOGICS Good Laboratory Practice (GLP) EU REGULATION PROCEDURES GLP in this context is pertaining to the preclinical REGULATION OF DRUGS AND BIOLOGICS IN THE development practices during animal studies PHILIPPINES which involves determining the safety of the drug REGULATORY FRAMEWORK ELEMENTS ○ Clinical trials to determine safety and efficacy are performed in accordance with Good Clinical Practice NON-REGULATORY AUTHORITIES (GCP) INTERNATIONAL ORGANIZATION FOR ○ Drugs are manufactured to the required quality under STANDARDIZATION (ISO) current Good Manufacturing Practice (cGMP) INTERNATIONAL CONFERENCE ON conditions HARMONIZATION (ICH) Examples: FDA, CFDA, Health Canada, European ICH QUALITY GUIDELINES Medicines Agency, etc. WORLD HEALTH ORGANIZATION (WHO) Carry out surveillance to ensure that labels and PIC/S advertising materials are accurate and in accordance with PIC/S GMP approved claims. APPENDIX REGULATORY AUTHORITIES US Food and Drug Administration European Medicines Agency Pharmaceutics and Medical Devices Agency LEGEND China Food and Drug Administration Health Canada black = powerpoint notes Food and Drug Administration of the Philippines red = notes from professor green = additional information from different source Australian Government: Department of Health and Ageing Therapeutic Goods Administration India: Central Drugs Standard Control Organization THE ELIXIR SULFANILAMIDE INCIDENT U.S. FDA Manufactured by S.E. Massengil Co. (1937) Elixir Sulfanilamide (an antibiotic): Our regulations were initially ○ Sulfanilamide dissolved in diethylene glycol, patterned with US FDA’s but more raspberry-flavored recently we have been aiming to The product was tested only for its appearance, harmonize with the ASEAN fragrance, and palatability before its nationwide regulations. distribution Center for Drug Evaluation and Result: >100 US Citizens in 15 states (mostly children) Research (CDER) died after consuming the elixir Center for Biologics Evaluation and Research (CBER) The solvent (diethylene glycol) developed toxicity Center for Veterinary Medicine (CVM) Triggered more safety acts and testing for Center for Food Safety and Applied Nutrition regulating drug products Center for Devices & Radiological Health (CDRH) DEFINITION OF TERMS Drugs ○ Articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia, ARCANGEL, AREL, BARBARONA, CHUA, NARBONETA 1 bit.ly/TransDatabase  Examines evidences: ○ The scientific basis for the drug ○ Compliance to GLP for non-clinical studies ○ Acceptable toxicological studies ○ Manufacture of the drug in accordance to cGMP ○ Adherence of the conduct of CT (Clinical Trials) to GCP ○ Scientific data and Clinical results (at the conclusion of Phase III) for marketing application ○ Health risk and benefit evaluation of the drug TYPES OF APPLICATIONS UNDER U.S. FDA INDA ○ Investigational New Drug Application EU REGULATIONS FOR DRUGS AND BIOLOGICS ○ Applied in order to start human CT (based on 2 regulatory steps a drug must go through prior to preclinical data) approval for marketing in EU (28 member states): ○ “Exemption” to import drugs for CT to different study ○ Clinical Trial Application (approved at Member state) sites (states) INDA in US NDA ○ Marketing authorization application (approved at both ○ New Drug Application Member state & at Centralized levels) ○ Proposal to FDA to approve a new pharmaceutical for Committee for Medicinal Product for Human Use sale and marketing in the US (CHMP)-committee under EMA that approves applications ○ New drug is confirmed to be safe and effective; no unreasonable risk to Px EU REGULATION PROCEDURES ANDA ○ Abbreviated New Drug Application Centralized ○ Contains data which provides for the review and ○ Results in single authorization valid in EU, Norway, ultimate approval of a generic drug product (aim is Iceland, and Liechtenstein to prove the drug is bioequivalent to the innovator ○ Compulsory for biotech derived products, drugs for drug) CA, HIV/AIDS, DM, neurodegenerative disorders, Pharmacokinetics parameters (AUC, Cmax) autoimmune or immune dysfunction and orphan Generic products have the same API but drugs different excipients – excipients affect the release Mutual Recognition of the drug which then affects absorption. Hence, ○ Allows applicants to obtain marketing authorization the need to test and apply for an ANDA. (MA) in concerned member states (CMS) ○ There are some drugs that can have exemptions for ○ Applicant submits dossier to all EU member states in bioequivalence studies = biowaiver which they want MA Dependent on BCS parameters: intestinal ○ Usually used by the Generic Industry permeability and solubility Has previous MA in at least one EU country Class I and III: Can be exempted due to high Decentralized absorption rate, might only need to submit ○ Simultaneous application in more than 1 EU country in-vitro studies relative to rate of distribution not previously authorized in any EU country and do ○ If applying for a different indication, you cannot use not fall within centralized procedure’s drug list ANDA. Nationalized BLA ○ Allows applicants to obtain MA in 1 member state ○ Biological License Application only (submitted to the competent authority of the ○ Approved under the provisions of Public Health member state) Services Act ○ For new active substances which are not mandatory under Centralized procedure PERTINENT FDA PROCESSES AND CONTROL REGULATION OF DRUGS AND BIOLOGICS IN THE Food, Drug, and Cosmetic Act (FDCA) of 1938 for drugs PHILIPPINES ○ Created after the Elixir Sulfanilamide Incident Public Health Service Act (PHSA) of 1944 and the FDCA for biologics US Code of Federal Regulations (CFR) for drug clinical RA 3720 RA 6675 RA 7277 RA 7394 RA 8203 research, manufacturing, and marketing Compliance is ensured through inspections (labs, clinical RA 9165 RA 9711 RA 9994 RA 10354 RA 10532 trial centers, manufacturing facilities) RA 10747 RA 10767 RA 10918 RA 3720- Food, Drug, and Cosmetic Act RA 6775- Generics Act of 1988 RA 7277- Magna Carta for Disabled Persons RA 7394- Consumer Act ARCANGEL, AREL, BARBARONA, CHUA, NARBONETA 2 bit.ly/TransDatabase RA 8203- Special Law on Counterfeit Drugs Registration Requirements: RA 9165- Comprehensive Dangerous Drugs Act of 2002 RA 9711- Food and Drug Administration (FDA) Act of 2009 Administrative Quality Data Non-clinical Clinical data RA 9994- Expanded Senior Citizens Act of 2010 requirements data RA 10354- The Responsible Parenthood and Reproductive Health Act of 2012 RA 10532- Philippine National Health Research System Act of 2013 RA 10747- Rare Diseases Act of the Philippines GMP From API to Safety data Safety and RA 10767- Comprehensive Tuberculosis Elimination Plan Act Site master FP efficacy RA 10918- Philippine Pharmacy Act file MAnufacurin data Certificate of g process PK pharmaceutic and controls PD FDA Philippines al product Process Biopharma Labeling validation ceutics ○ Under the Department of Health (DOH) materials Pharmaceuti Toxicology ○ Mandate: To ensure Safety, Efficacy, and Quality of cal development health products (food, drugs, cosmetics, devices, stability biologicals, vaccines, in-vitro diagnostic reagents, studies and household/urban hazardous substances and/or a Site Master File- Document containing details or combination of and/or derivative thereof Information regarding a company Center for Drug Regulation and Research *INSERT REGISTRATION REQUIREMENTS SLIDE* Center for Food Regulation and Research *Insert Mam Czar notes* (CFRR) Center for Device Regulation Radiation Health Post-Market Surveillance and Research (CDRRHR) ○ AO 2011-0009 (National Policy and Program on Center for Cosmetics and Household Urban and Pharmacovigilance) Hazardous Substances Regulation and ○ Monitoring, collecting, sampling, and testing of drugs Research (CCHUHSRR) ○ Audits/inspections of manufacturers/distributors/retail outlets REGULATORY FRAMEWORK ELEMENTS ○ Monitoring of advertisements and claims ○ Product recall/labeling revision/restriction on use ○ Administrative sanctions Communication, Coordination, and Collaboration ○ International Collaborations (WHO, USP, EU, APEC, ICH, other regulatory authorities) ○ Alignment with other government offices (DOH offices - Pharmaceutical Division, Philippine Institute of Traditional and Alternative Health Care (PITAHC), PDEA, PRC) Licensing and Inspection of Establishments ○ Partnerships with professional and private ○ GxPs institutions (PPhA, PMA, Ad Standards Council) ○ AO 2014-0034 (Rules and Regulations of licensing establishments engaged in the manufacture, conduct NON-REGULATORY AUTHORITIES of clinical trial, distribution, importation, exportation, International Organization for Standardization and retailing of drug products) World Health Organization ○ AO 2016-0003 (Guidelines on the Unified Licensing ICH Requirements and Procedures of the FDA) PIC/s ○ AO 2016-004 (Procedure on the Use of the New Application Form for LTO thru the FDA Electronic INTERNATIONAL ORGANIZATION FOR Portal) STANDARDIZATION (ISO) Pre-Market Assessment General; Not specific to pharmaceutical industry ○ Product types: A non-governmental organization that identifies what New Chemical Entities (NCE) - not previously international standards are required by business, marketed for any pharmaceutical use government, and society Biotechnological products (including biosimilars A network of national standards institutes of 163 countries and vaccines) with a Central Secretariat in Geneva, Switzerland Generic drugs ○ Philippine member: Bureau of Product Standards, Traditionally-used Herbal Products Department of Trade and Industry Herbal Medicines World’s largest standards developing organization Household Remedies Published more than 21,000 international standards for OTC preparations different industries ISO 9000 series ○ ISO 9001:2015: Quality Management Systems - Requirements ○ ISO 9000:2015: Quality Management Systems - Fundamentals and Vocabulary (definitions) ARCANGEL, AREL, BARBARONA, CHUA, NARBONETA 3 bit.ly/TransDatabase  ○ ISO 9004:2018: Quality Management - Quality of an ○ Clinical Trials Organization - Guidance to Achieve Sustained ○ Pharmacogenomics Success (continuous improvement) Multidisciplinary ○ ISO 19011:2018: Guidelines for Auditing ○ topics that do not belong to SEQ Management Systems ○ Medical Terminology ○ Common Technical Document (CTD) – type of INTERNATIONAL CONFERENCE ON HARMONIZATION document submission followed by ASEAN for quality, (ICH) safety, and efficiency Non-regulatory authority that is more specific for health ○ Gene Therapy products Formed in April 1990 in Brussels ICH QUALITY GUIDELINES ○ (members/countries constituting the guidelines: US, Concerns regarding products Europe, Japan) A joint initiative involving both regulators and Q1A – Q1F Stability research-based industry representatives of the European Union, Japan and the USA in scientific and Q2 Analytical Validation technical discussions of the testing procedures required Q3A – Q3E Impurities to assess and ensure the safety, quality and efficacy of medicines. Q4A – Q4B Pharmacopeias Use of ICH guidelines ○ Industry and governments in ICH and non-ICH Q5A – Q5E Quality of Biotechnological Products countries can use the ICH guidelines to address technical issues during the product development Q6A – A6B Specifications process ○ In addition to providing state-of-the-art guidance, the Q7 Good Manufacturing Practice guidance may well also serve as teaching tools ○ Harmonized ICH guidelines can reduce duplication Q8 Pharmaceutical Development in meeting technical requirements, thereby saving Q9 Quality Risk Management financial and material resources because if ibang guidelines, iaassess pa nila if Q10 Pharmaceutical Quality System okay ba yung guidelines or testing procedures that you perform on your product Q11 Development and Manufacture of Drug Substances Quality Safety Q12 Lifecycle Management (stability, analytical validation, (Carcinogenicity, Genotoxicity, impurities, pharmacopeias, Quality toxicokinetics, Pk, Reproductive of Biological products, GMP, etc.) toxicology, immuntoxicology studies, Q13 Continuous Manufacturing of Drug etc.) Substances and Drug Products Efficacy Multidisciplinary Q14 Analytical Procedure Development (Clinical Safety, Clinical study (Topics not under S/E/Q categories: reports, GCP, Clinical Trials, Medical Terminology, Common Pharmacogenomics, etc.) Technical Document (CTD), Gene therapy, etc.) Q7 focuses more on the GMP of the API Q8 – Q10 is important in the product life cycle Q14 – There will be product development first before the Quality validation ○ The quantity aspect of medicines ○ Stability WORLD HEALTH ORGANIZATION (WHO) ○ Analytical Validation Specialized agency of UN (194 member states as of ○ Impurities 2014) ○ Pharmacopeias Functions: ○ Quality of Biological Products ○ To give worldwide guidance in the field of health ○ GMP not only for medicines, but health in general Safety ○ To set global standards fro health ○ Everything related to toxicological studies ○ To cooperate with governments strengthening ○ Carcinogenicity national health programs ○ Genotoxicity ○ To develop and transfer appropriate health ○ Toxicokinetics technology, information, and standards ○ Pharmacokinetics (Pk) WHO works with regulatory authorities in member states ○ Reproductive Toxicology in setting up policies and training programs to ensure ○ immuntoxicology Studies drugs are safe, pure, and effective and are being Efficacy distributed and administered as specified ○ everything related to clinical trials ○ includes supply chain management and guidelines on ○ Clinical Safety the administration of drugs – found in the WHO TRS ○ Clinical Study Reports ○ GCP ARCANGEL, AREL, BARBARONA, CHUA, NARBONETA 4 bit.ly/TransDatabase  WHO Technical Report Series (TRS) ○ Annual reports with adopted guidelines in the form of Annexes Ex: GMP, GDP, GSP, anything related about public health and medicines ○ Makes available the findings of various international groups with the latest scientific and technical advice on a broad range of medical and public health subjects PIC/S Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation Scheme International instruments between countries and pharmaceutical inspection authorities, which provide together an active and constructive co-operation in the field of GMP A forum for: ○ Networking and confidence building for inspectors ○ Exchange of information and experience on GMP ○ Focus on Quality systems for Inspectorates ○ Focus on training of GMP inspectors ○ International harmonisation of GMP PIC/S GMP Prior to following the PIC/S GMP, we have our own GMP under AO 2012-0008 (adapted from other GMPs of other countries). But since we are under ASEAN, it is already stated in the law that we are to follow PIC/S GMP. ARCANGEL, AREL, BARBARONA, CHUA, NARBONETA 5 bit.ly/TransDatabase