QC2LECMIDTERM

• Organizations responsible for ensuring drug product quality

  • International Organization for Standardization (ISO)
  • World Health Organization (WHO)
  • Association of Southeast Asian Nations (ASEAN)
  • Pharmaceutical Inspection Co-operation Scheme (PICS)
  • International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
• ISO


  An independent, non-governmental internal organization with a membership of 164 national standards bodies
• ISO 9001: 2015 Quality Management Systems


  • Management System: A way in which an organization manages the interrelated parts of its business in order to achieve its objectives
  • 7 Quality Management Principles: Customer focus, Leadership, Engagement of people, Process approach, Improvement, Evidence-based decision making, Relationship management
• ISO 31000:2018 Risk Management

  Guidelines, provides principles, framework and a process for managing risk
• World Health Organization (WHO) established on April 7, 1948
• Quality System Essentials (QSEs)


  12 building blocks for managing quality
• GxP includes


  • Good Manufacturing Practice (GMP)
  • Good Laboratory Practice (GLP)
  • Good Clinical Practice (GCP)
  • Good Documentation Practice (GDP)
  • Good Storage Practice (GSP)
  • Good Distribution Practice (GDP)
• ASEAN established in 1967, founding members: Indonesia, Malaysia, Philippines, Singapore, Thailand
• ASEAN guidelines


  • ACTD Organisation Dossier
  • ASEAN Variation Guideline for Pharmaceutical Products
  • ASEAN Guideline for the Conduct of Bioequivalence Studies
  • ASEAN Guideline on Stability Study of Drug Product
  • ASEAN Guideline on Analytical Validation
  • ASEAN Guideline on Process Validation
  • ASEAN Guideline to Conduct the BA/BE Studies
  • ACTD and ACTR (Pharmaceutical technical documents)
  • ASEAN Labelling Requirements for Pharmaceuticals
• ACTD Parts


  • Part I: Table of Contents, Administrative Data, and Product Information
  • Part II: Quality Document
  • Part III: Nonclinical Document (Preclinical)
  • Part IV: Clinical Document
• ACTD Part I Sections


  • Section A: Introduction
  • Section B: Overall ASEAN Common Technical Dossier Table of Contents
  • Section C: Documents required for registration
• ACTD Part II Sections


  • Section A: Table of Contents
  • Section B: Quality Overall Summary
  • Section C: Body of Data
• ACTD Part III Sections


  • Section A: Table of Contents
  • Section B: Nonclinical overview
  • Section C: Nonclinical written and Tabulated summaries
  • Section D: Non clinical study reports
• ACTD Part IV Sections


  • Section A: Table of Contents
  • Section B: Clinical Overview
  • Section C: Clinical Summary
  • Section D: Tabular listing of All clinical studies
  • Section E: Clinical Study Reports
  • Section F: List of Key Literature References
• Pharmaceutical Inspection Co-operation Scheme (PIC/S)


  Non-binding, informal co-operative arrangement between Regulatory Authorities on the field of Good Manufacturing Practice (GMP) of medicinal products
• PIC/S

  • To lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of inspectorates in the field of medicinal products
• ICH

  International non-profit Association under Swiss law, established on October 23, 2015
• ICH Mission


  • To make recommendations towards achieving greater harmonisation in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration and the maintenance of such registrations
  • To maintain a forum for a constructive dialogue on scientific issues between regulatory authorities and the pharmaceutical industry on the harmonisation of the technical requirements for the pharmaceutical products
  • To contribute to the protection of public health in the interest of patients from an international perspective
  • To monitor and update harmonised technical requirement leading to a greater mutual acceptance of research and development data
  • To avoid divergent future requirements through harmonisation of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products
  • To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices
  • To encourage the adequate implementation and integration of common standards through the dissemination of the communication of information about and coordination of training on, harmonised guidelines and their use
  • To develop policy for the ICH Medical Dictionary for Regulatory Activities Terminology (MedDRA) whilst ensuring the scientific and technical maintenance, development and dissemination of medDRA as a standardised dictionary which facilitates the sharing of regulatory information internationally for medicinal products used by humans
• ICH Quality Guidelines


  • Q1 Stability
  • Q2 Analytical Validation
  • Q3 Impurities
  • Q4 Pharmacopoeias
  • Q5 Quality of Biotechnological Products
  • Q6 Specifications
  • Q7 Good Manufacturing Practice
  • Q8 Pharmaceutical Development
  • Q9 Quality Risk Management
  • Q10 Pharmaceutical Quality System
  • Q11 Development and Manufacture of Drug Substances
  • Q12 Lifecycle Management
  • Q13 Continuous Manufacturing of Drug Substances and Drug Products
  • Q14 Analytical Procedure Development
• Compendial Requirements for Solid and Semi-solid Dosage Forms


  • Powders and Granules: Angle of repose, Compressibility index and Hausner ratio, Flow rate through an orifice, Shear cell, Particle size determination
  • Other Solid Dosage Forms: Tablet thickness, Tablet breaking force, Tablet friability, Disintegration test, Dissolution test, Uniformity of Dosage Units, Minimum fill

  
• Angle of repose


  Frictional forces in a loose powder, maximum angle possible between the surface of a pile of powder and the horizontal plane

  
• Compressibility index or Hausner ratio


  Measures both the bulk volume and the tapped volume of a powder

  
• Flow rate through an orifice


  Useful only with free-flowing materials, measures mass flow rate or volume flow rate
• Shear cell


  Measures shear stress-shear strain relationship, angle of internal friction, confined yield strength, tensile strength, flow factor and other flowability indices
• Particle size determination methods

  • Optical microscope
  • Sieving

  
• Angle of repose


  Formula: tan^-1 (height / radius)
• Compressibility index (CI) or Hausner ratio (HR)

  • Application: measuring both the bulk volume and the tapped volume of a powder
  • CI = (Vo - Vf) / Vo x 100
  • HR = Vo / Vf
• Flow rate through an orifice

  • Application: useful only with free-flowing materials
  • Measure: mass flow rate or volume flow rate using any types of containers (cylinders, funnels, hoppers)
• Shear cell


  • Parameters that can be obtained: shear stress-shear strain relationship; angle of internal friction; confined yield strength tensile strength; flow factor and other flowability indices
  • Types: Cylindrical, Annular, Plate-type
• Particle size determination methods

  • Optical microscope
  • Sieving
  • Light Diffraction Measurement

  
• Tablet thickness


  • Equipment: Caliper / Vernier caliper
  • Measure diameter, depth, width
• Tablet breaking force


  • Tablet hardness
  • The resistance of tablet to problems such as chipping, abrasion or breakage depends on its hardness
  • Instruments: Monsanto hardness tester, Strong-Cobb hardness tester, Pfizer hardness tester, Erweka hardness tester, Schleuniger hardness tester, Vankell 2000
• Tablet hardness acceptable specifications

  • Ordinary compressed tablet: 4-10 kg
  • Sublingual: 2 kg
  • Chewable: 2 kg
  • Buccal: 10 kg
• Tablet friability


  • "Ability of tablet to withstand abrasion"
  • Applicable to compressed tablet - uncoated
  • Sample: 650 mg or greater: 10 whole tablets, Less than 650 mg: 6.5 g
  • Friabilator: 25 rpm, 4 minutes (100 revolutions)
  • Formula: % loss on weight = (weight before - weight after / weight before) x 100 or %loss = 1 - (weight after / weight before) x 100
  • Specifications: A weight loss of not more than 1.0% is considered acceptable for most products
• Disintegration test


  • Complete disintegration: The state at which any residue of the unit, except fragments of a soft mass having no palpably firm core
  • Apparatus parts: 1L Low form beaker, Heater/Thermostatic arrangement, Device for raising and lowering the basket, Basket-rack assembly
  • Basket-rack assembly: Six open ended transparent tubes, Two plastic plates, Mesh screen, Accessory Disk
• Disintegration test procedure for uncoated/plain coated tablets

  1. 1 tablet is placed in each of the six tubes of the basket rack assembly and operate the apparatus using water/specified medium maintained at 37±2 Celsius. At the end of the time specified, lift the basket rack assembly and observe the tablet. All tablets should have disintegrated completely. If 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets.

  2. Criteria: If 6 tablets are tested, all 6 of the tablets are disintegrated. If 18 tablets are tested, the requirement is met if not fewer than 16 of the total of 18 tablets are disintegrated.
• Disintegration test procedure for delayed-release tablets and capsules

  1. 1 tablet is placed in each of the six tubes of the basket. If the dosage units are not sugar-coated, proceed to the acid stage.

  2. Acid stage: Immersion fluid: 0.1 M hydrochloric acid or simulated gastric fluid TS, Temperature: 37±2 Celsius, Time: 1 hour. If after 1 hour no dosage unit shows evidence of disintegration, cracking or softening, proceed with the buffer stage.

  3. Buffer stage: Immersion fluid: pH 6.8 phosphate buffer, or simulated intestinal fluid TS, Temperature: 37±2 Celsius, Time: as specified in the individual monograph.

  4. Criteria: Acid stage: no dosage unit shows evidence of disintegration, cracking or softening. Buffer stage: Apply the criteria for uncoated or plain-coated tablets.

  
• Disintegration time requirement


  • Plain uncoated tablet: 30 minutes
  • Coated tablet: Up to 2 hours
  • Sublingual tablets: 3 minutes
  • Buccal tablets: 4 hours
  • Orally disintegrating tablet: <1 min
• Dissolution test


  • The process of which a solid substance enters in the solvent to yield a solution
  • Controlled by the affinity between the solid substances and the solvent
  • A physical test to predict drug delivery to a target area in the proper amount at the right time

  
• Factors that influence the dissolution characteristics of a drug

  • Wettability of a dosage unit - surfactant & wetting agent
  • Penetration ability of the dissolution medium
  • The swelling process
  • Disintegration and deaggregation of dosage forms