OK_Fall_2024_-_W2_-_Introduction_to_GMPs.pdf

GMP I MINIMIZING RISK MAXIMIZING SAFETY IMPROVING QUALITY Week 2 1 Lecture Outline ▪ Introduction to GMPs ◦ Basic Standards in the Drug Development Process ◦ Requirement for Pharmaceutical Products Quality Management System Quality...

GMP I MINIMIZING RISK MAXIMIZING SAFETY IMPROVING QUALITY Week 2 1 Lecture Outline ▪ Introduction to GMPs ◦ Basic Standards in the Drug Development Process ◦ Requirement for Pharmaceutical Products Quality Management System Quality Assurance Etc. ◦ What are the GMPs? The Risks involve GMPs are Everyone’s Responsibility Without Implementation of GMPs ◦ An American GMP History (Before 1963) ◦ An American GMP History (After 1963) ◦ GMPs are Everywhere Four Most Important Principles of GMP GMP requirements ◦ Pharmaceutical Laws and GMP Legislations, Regulations & Guidelines Etc. 2  Basic Standards in the Drug Development Process Discovery Development Delivery NR GLP/GDP GCP GMP NR: not regulated 3 Requirement for Pharmaceutical Products Production 4 Quality Management System (QMS) ▪ Definition: o A Quality Management System is a collection of documented policies, procedures, plans, resources, processes, practices, and the specification of responsibilities and authority of an organization designed to achieve product and service quality levels, customer satisfaction and company objectives. o Quality Policy: It describes the organizations approach to quality. It provides a framework for quality objectives and includes a commitment to meet applicable requirements (Standards, customer, statutory (lawful), or regulatory) as well as to continually improve. o Quality Procedure: A step by step of what the company does to meet its policy. For example, if a fast-food business doesn't have a written procedure for preparing menu items, the quality of the food may suffer. ▪ In which document the QMS is described? o The Quality Manual describes the quality management system of an organization. ▪ Types of QMS: ISO 9001, ICH Q10 ( PQS), SQF (Safe Quality Food) Code, etc. 5 Quality Assurance (QA) ▪ Definition: o It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. o Quality assurance therefore incorporates GMP and other factors such as product design and development (manufacturing or production). ▪ QA o It is an advisory function that plans, reviews and approves quality activities to ensure alignment with the QMS implemented in an organization. o It provide the confidence that the standards will be met. By ensuring the regular evaluations of the quality of pharmaceutical products is be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement. By ensuring that deviations are reported, investigated and recorded. 6 Quality Assurance (QA) ▪ Video 1: oQuality Assurance Associate ohttps://www.youtube.com/watch?v=yhZ6Mg3FQSI o4:17 min. ▪ Video 2: oFood Scientist – Quality Assurance Manager ohttps://www.youtube.com/watch?v=RFE9ByZ_oUo o5:56 min. 7 What are the GMPs? ▪ Health Canada defined GMPs as: ◦ “Part of quality assurance. They ensure that drugs are consistently produced and controlled. Drugs must meet the quality standards for their intended use - as outlined in the marketing authorization, clinical trial authorization and product specification.” ▪ GMP requirements are focus on “What” to do, not “How” to do. ◦ Because of the complexity of the development process between companies. Type of process, dosage form, big pharma vs specialty pharma, etc. ▪ Apply to human & animal drugs, biologics, processed tissues medical devices (ISO 13485), dietary supplements (NPN GMP), food (HACCP). ▪ Failure to comply = adulteration ◦ The products or the company will be subject to regulatory action/sanction. Withdraw the product from marking until corrective action is not implemented. 8 What are the GMPs? ▪ A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufacture will have the required quality. ▪ GMPs provide only a minimum manufacturing and control practices and sometimes a prefix “c” (for cGMP) is added for current good manufacturing practices. 9 What are the GMPs? ▪ That part of QA that ensures that products are consistently produced and controlled, and they are reliable as required by: ◦ Quality standards. ◦ Clinical trial authorization. ◦ Marketing authorization and/or product specification. ▪ The aim is to: ◦ Minimize risks that cannot be controlled by testing of product. These risks can best be controlled by having a properly managed system of working that takes them into account. This means that there must be good design, sound operation, and planned maintenance of facilities. ▪ A basic principle of GMP is that quality cannot be tested into a batch of product but must be built into each batch of product during all stages of the manufacturing process. 10 The Risks involve ▪ GMPs are designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product such as: ◦ Unpredicted contamination of products, causing damage to health or even death. Contamination/cross-contamination (from facility, facility supports, equipment, personnel, etc.) Mix-ups (confusion) ◦ Incorrect labels on containers, which could mean that patients receive the wrong medicine. ◦ Insufficient or too much active ingredient, resulting in ineffective treatment or adverse effects. ◦ API degradation and change of drug product properties over time. ▪ GMPs also mean that the quality checking system must be designed with these risks in mind and set out to find whether any errors have occurred. ◦ If do not know what it is how can you eliminate or minimize it. 11 GMPs are Everyone’s Responsibility ▪ Products can be considered adulterated. ▪ Regulator enforcement actions – e.g. DEL suspension, Form 483, Warning Letter, Consent Decree, Recalls, Seizures, Injunctions. ▪ For malicious acts, “persons” can be fined or incarcerated. o A “person” may be: the Company, the President, the CEO, a Director, a Manager, a Supervisor, or even the Operator/Technician who failed to follow GMPs. o “Persons” can be debarred from working in the industry. 12 Without Implementation of GMPs ▪ The implementation or application of GMP principles are so fundamental during the drug development process that a drug development without GMP principles as its foundation will lead to: ◦ A poor-quality medicine that may contain toxic substances which have been unintentionally added. ◦ A medicine that contains little or none of the claimed ingredient and will not have the intended therapeutic effect. 13 An American GMP History (Before 1963) ▪ 1902 – the Poison Squad ◦ By the close of the Industrial Revolution, the American food supply was infected with frauds, fakes, and legions of new and untested chemicals, dangerously threatening the health of consumers such as: Na2B4O7*10H2O (borax) C6H4(OH)COOH (salicylic acid) H2SO4 (sulfuric acid) NaC6H5CO2 (sodium benzoate) CH2O ( formaldehyde) ◦ As the Chief Chemist of the Agriculture Department's, Dr. Harvey Washington Wiley has decided to perform a series trials named the "hygienic table trials,“ in order to prove that certain of those chemicals could be dangerous for the health. His advocacy led to the creation of the FDA (or the “Pure Food & Drug Act or Wiley Act”). 14 An American GMP History (Before 1963) ▪ Pure Food & Drug Act or Wiley Act ◦ Foremost concern of the legislation: correct product labeling. Prohibited manufacturing & sale of adulterated, misbranded, poisonous, or deleterious foods, drugs, medicines. Banned their interstate transport. ◦ Authorized legal enforcement of USP standards. ◦ Required Rx (common abbreviation for medical prescriptions) from licensed doctors for some drugs. ◦ However, the legislation was incomplete. Several flaws such as: Therapeutic claims were not limited. Did not require pre-market inspections and approvals. Etc. 15 An American GMP History (Before 1963) ▪ 1933 – America’s Chamber of Horrors ◦ FDA exhibited authentic products to pressure the legislative branch to fix the 1906 law’s flaws. For their campaign, FDA used tragedies that happened since the Wiley Act of 1906. A weight loss drug that caused death. A hair remover that caused baldness, even if not used on the head. An eyelash dye that blinded women (next slide). Lotions & creams that caused mercury poisoning. However, the legislation was incomplete. ◦ First Lady Eleanor Roosevelt presented the same argument as FDA to the White House and appealed to American women to campaign for stronger protections for consumers. ◦ All the proof presented were not enough to change the law. It took another tragedy to change the law. 16 An American GMP History (Before 1963) ▪ A “lash beautifier” of the time called Lash Lure lured women in with the promise of darker, fuller-looking eyelashes - but instead of delivering lush lashes, Lash Lure delivered mascara that caused women to go blind, and in some extreme cases, to die. https://www.ranker.com/list/lash-lure-fatal-mascara/jessica-defino 17 An American GMP History (Before 1963) ▪ 1937 – Elixir Sulfanilamide ◦ In 1932, the first sulfonamide, trade-named Prontosil, was sole by Bayer AG. At that time, the new drug was the first medicine ever discovered that could effectively treat a range of bacterial infections inside the body. ◦ In 1937, S. E. Massengill Company, a pharmaceutical manufacturer, decided to created an oral preparation of sulfanilamide for children. Chief pharmacist and chemist, Harold Watkins, created a children dosage that content 10% of sulfanilamide, 72% diethylene glycol (DEG), 16% water, “elixir flavor”, raspberry extract, saccharin solution amaranth and, amaranth, and caramel. The company called the preparation "Elixir Sulfanilamide.” ◦ DEG is poisonous to humans and other mammals, but Harold Watkins was not aware of this. ◦ Animal testing was not required by law, and S. E. Massengill performed none. ◦ There were no regulations at the time requiring premarket safety testing. 18 An American GMP History (Before 1963) ▪ 1937 – Elixir Sulfanilamide ◦ Also, no regulation required toxicity testing. ◦ 107 deaths and 248 survivors. ◦ Only one law was broken. What was it? ◦ However, this tragedy led to a need for pre-market drug safety testing. ◦ In 1938 the legislative branch adopted the Food, Drug & Cosmetic (FD&C) Act which have given the power to FDA to: Requires new drug pre-marketing safety studies (Now “NDS”). Prohibits false therapeutic claims. Authorizes factory inspections. Allows FDA to request court injunctions. Extends control to cosmetics and devices. Requires safe tolerances for unavoidable poisonous substances. 19 An American GMP History (Before 1963) ▪ It took the Sulfathiazole Tragedy in 1941 to finally see the birth of the GMP principles. ▪ FDA drastically revises rules on manufacturing & quality controls. ▪ 23 years later GMP regulations were issued. ◦ During those 23 years more tragedy was occurred including the Thalidomide Tragedy: This antiemetic (morning sickness), anxiety, tension and sleeping aid medication has been sole in more than 40 countries. Since it release in 1957, the drug was believed to be safe in pregnancy, concerns regarding birth defects arose until in 1961 the medication was removed from the market in Europe. The total number of embryos affected by use during pregnancy is estimated at 10,000, of which about 40% died around the time of birth. Over the years, this medication has been used many other treatment including HIV-associated conditions. Wikipedia: https://en.wikipedia.org/wiki/Thalidomide 20 An American GMP History (After 1963) ▪ 1963 – First Drug GMPs (28 FR 6385) ◦ For “manufacturing, processing, packing or holding finished pharmaceuticals” ◦ From 1970 and 1980, the scope and control have been increased: 1975 – cGMPs for blood & blood components finalized. 1976 – Proposed GMPs for LVPs. 1976 – Medical Device Amendment. Dalkon Shield incident (intrauterine device (IUD) marketed as safe by AH Robins). Aggressive marketing despite knowledge of safety problems led to the “largest tort liability case since asbestos”. Billions of dollars in settlements! (Bought out by AHP (now Wyeth). By 1978, device GMPs (21 CFR 820) finalized. 1978 – Drug GMPs (21 CFR 210-211) expanded. 1986 – Food GMPs (21 CFR 11) finalized. 21 Top 10 GMP Deficiencies from 1995-2005 22 Top 20 FDA Observations from 2018 23 Why this History section ▪ George Santayana “Those who cannot remember the past are condemned to repeat it.” ▪ We are living in a reactive, not proactive, society: Laws & regulations born of tragedies, and catastrophes to prevent recurrence. Federal agencies formed or strengthened in their wake. To avoid past tragedies recurrence and to prevent future ones. 24 GMPs are Everywhere ▪ Health Canada https://www.canada.ca/en/health-canada/services/drugs-health- products/compliance-enforcement/good-manufacturing-practices/guidance- documents/gmp-guidelines-0001/document.html ▪ US FDA (21 CFR 211) https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPar t=211 ▪ European Union (in the EUDRALEX) ▪ Japan (PMDA or pharmaceuticals and medical devices Agency) ▪ World Health Organization (WHO) ▪ ICH Q7: GMPs for Active Pharmaceutical Ingredients 25 GMPs are Everywhere ▪ Buildings & Facilities ▪ Manufacturing ▪ Packaging & Labeling ▪ Product Development Laboratory ▪ Quality Control & Laboratories ▪ Quality Assurance ▪ Receiving & Shipping ▪ Regulatory Affairs ▪ Training Department ▪ Validation Department ▪ Documentation 26 Four Most Important Principles of GMP ▪ Every process and every task is described in detail in specific documents (e.g., work instructions, SOPs, checklists). ▪ Every employee (including managers) carries out the work exactly as defined and reports any deviation immediately. ▪ The employee records everything in detail while carrying out the tasks so that it is possible at a later stage to identify the who, what, and when something was happened or was observed. ▪ At regular intervals, the results are compared and evaluated to determine if there are trends or high occurrences of problems (review, trending). When it is the case, the work processes and specifications must be improved before a quality error occurs (continual improvement process, CIP). 27 GMP requirements ▪ Clearly define all manufacturing processes. Review them systematically in the light of experience. Show that they are capable of consistently manufacturing drugs of the required quality that comply with their specifications. ▪ Validate critical steps of manufacturing processes and key changes to the process. ▪ Provide all key elements for GMP, including: o Qualified and trained staff. o Adequate premises and space. o Suitable equipment and services. o Correct materials, containers and labels. o Approved procedures and instructions. o Suitable storage and transport. 28 GMP requirements ▪ Write step-by-step instructions and procedures in clear and direct language, specifically applicable to the facilities used. ▪ Train operators to properly carry out procedures. Ensure they understand the importance of meeting GMP requirements as part of their role in assuring patient safety. ▪ Create records (manually and/or by recording instruments) during manufacture. Show that all the steps required by the defined procedures and instructions were in fact followed and met relevant parameters and/or quality attributes. Show that the quantity and quality of the drug was as expected. ▪ Document any deviations. Investigate significant deviations to determine the root cause and impact. Ensure proper corrective and preventive action is taken. 29 GMP requirements ▪ Keep records of fabrication, packaging, labelling, testing, distribution, importation and wholesaling in an easy-to-understand and accessible form. This allows the complete history of a lot to be traced. ▪ Distribute products in a way that minimizes any risk to their quality and takes account of Canadian good manufacturing practices which incorporate good distribution practice. ▪ Control storage, handling and transportation of drugs and their ingredients to minimize any risk to their quality. ▪ Have a system in place for recalling drugs from sale. ▪ Examine complaints about drugs. Investigate the causes of quality defects. Take appropriate measures to prevent problems from happening again. 30 Documentation In GMPs ▪ Good documentation practices (GDP) is required in order to ensure an auditable account of work performed. ▪ GDP is required for all documentations included in a fully developed quality system. ▪ Example of required documents: Batch records Records Specifications Stability Study Summary Validation & Qualification Report Records Machine Logs Calibration Records Product and sample labels Standard procedure Analytical Methods Room Temperature/ %RH Manufacturing Procedures 31 Example of a Manufacturing Process ▪ API manufacturing process 32 Example of a Manufacturing Process ▪ Drug product manufacturing process 33 Example of a Manufacturing Process ▪ Dosage forms and GMPs: o GMP in solid dosage forms o GMP in semisolid dosage forms o GMP in Liquid orals o GMP in Parenteral Production o GMP in Biotechnological products o GMP in Nutraceuticals and cosmeceuticals 34 Pharmaceutical Laws and GMP ▪ Pharmaceutical Laws and Regulations in Canada. Food & Drug Guidelines Regulations Cosmetic Guidelines Food & Drugs Regulations Act Medical Device Guidelines Regulations NNHPs Guideline Regulations Legislation Regulation Non-Legislative 35 Legislations, Regulations & Guidelines ▪ What is Legislation? ◦ Legislation refers to written laws, often referred to as Acts or statutes, which are enacted by Parliament, the legislative arm of government. Draft legislation, called a bill, is introduced to Parliament, and requires the assent of the House of Commons, the Senate and the Crown to become law. 36 Detailed of the Drug Development Process ▪ In Canada o Food & Drugs Act 37 Food & Drugs Act ▪ Prohibited sales of drugs: 8 No person shall sell any drug that: (a) was manufactured, prepared, preserved, packaged or stored under unsanitary conditions; or (b) is adulterated. ▪ Deception, etc., regarding drugs: 9 (1) No person shall label, package, treat, process, sell or advertise any drug in a manner that is false, misleading or deceptive or is likely to create an erroneous impression regarding its character, value, quantity, composition, merit or safety. ▪ Drugs labelled or packaged in contravention of regulations: (2) A drug that is not labelled or packaged as required by, or is labelled or packaged contrary to, the regulations shall be deemed to be labelled or packaged contrary to subsection (1). 38 Food & Drugs Act ▪ Unsanitary manufacture, etc., of drug: 11 No person shall manufacture, prepare, preserve, package or store for sale any drug under unsanitary conditions. ▪ Samples: 14 (1) No person shall distribute or cause to be distributed any drug as a sample. ▪ Marginal note: oException: (2) Subsection (1) does not apply to the distribution, under prescribed conditions, of samples of drugs to physicians, dentists, veterinary surgeons or pharmacists. 39 Legislations, Regulations & Guidelines ▪ What are Regulations? ◦ Regulations are a form of law, sometimes referred to as subordinate legislation, which define the application and enforcement of legislation. Regulations are made under the authority of an Act, called an enabling Act. Regulations are enacted by the body to whom the authority to make regulations has been delegated in the enabling Act, e.g., the Governor in Council, a minister, etc. 40 Detailed of the Drug Development Process ▪ In Canada o Regulations 41 Detailed of the Drug Development Process ▪ In Canada o Food & Drugs Regulations 42 Detailed of the Drug Development Process ▪ In Canada o Food & Drugs Regulations 43 Detailed of the Drug Development Process ▪ In Canada o Food & Drugs Regulations o Other division o Establishment Licences o Radiopharmaceuticals o Vaccines o Drugs for Clinical Trials o Controlled drugs Such as morphine, oxycodone, oxycontin and all related opioids/narcotic drugs. 44 Legislations, Regulations & Guidelines ▪ What are Guidelines? ◦ Guidance documents are non-legislative instruments used to clarify existing legislative instruments (i.e., regulations). Guidance documents cannot be used to compel a certain behavior but rather to guide desired behavior to supplement the regulatory requirements. Important to remember that guidance documents under no circumstances are part of a legislative instrument. If certain behavior is required in a certain way, that prescription goes in a legislative instrument. ▪ Example of Guidelines ◦ GUI-0104, Good Manufacturing Practices for APIs. ◦ GUI-0036, Drugs used in Clinical Trials. ◦ GUI-0102, Good Pharmacovigilance Practices. ◦ GUI-0069, Temperature Control of Drug products during Storage & Transportation. ◦ GUI-0001, Good manufacturing practices guide for drug products. 45 Regulatory Guidance 46 Regulatory Guidance It’s all about the INTERPRETATION of the Agency (or the Regulator) of the Food & Drug Act (FDA) 47 Act, Regulations and GUI-0001 Deception, etc., regarding drugs 9 (1) No person shall label, package, treat, process, sell or advertise any drug in a manner that is false, misleading or deceptive or is likely to create an erroneous impression regarding its character, value, quantity, composition, merit or safety. 48