VALIDATION & QUALIFICATION Engr Syed Ali Haider (PEC & IEP Regd ) Validation Engineer | Helix Pharma (Pvt) Limited Pakistan FLOW OF PRESENTATION GMP History of GMP Timeline What is Validation [.]
VALIDATION & QUALIFICATION Engr Syed Ali Haider (PEC & IEP Regd.) Validation Engineer | Helix Pharma (Pvt) Limited Pakistan FLOW OF PRESENTATION GMP History of GMP- Timeline What is Validation Why Validation Four (4) Approaches to Validation CMA, CPP, CQA What is Qualification Phases of Qualification Types of Validation/Qualification Validation Documentation Protocol & Reports) (VMP, Significance of Validation Role of Engineers in Validation Syed Ali Haider- Copyright © 2022 Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization ~ WHO TRS 961 ANNEX Syed Ali Haider- Copyright © 2022 Good Manufacturing Practice GMP States that every step in the Production including “Who” did “What” and “When” must be documented and fully traceable or It is the documented way of using your “COMMON SENSE” Syed Ali Haider- Copyright © 2022 HISTORY OF GMP Concept of Biologics Control Act 1902 Bureau of Chemistry becomes FDA • • Proof of Safety Pure Food & Drug Act Consumer Protection Law Bureau of Chemistry “Validation“ introduced by Ted First GMP Buyer & Bud Regulations issued Loftus in mid 1937 Sulfonamide Elixir Tragedy Diethylene Glycol (DEG)- Poisonous Solvent was added 1970’s 1963 1938 1930 1906 • Federal Food, Drug & Cosmetic Act 1956 Thalidomide Tragedy Caused Congenital Disabilities Syed Ali Haider- Copyright © 2022 1969 WHO adopted GMP with a draft text 1987 First “Process Validation” Guideline-FDA What is Validation? According to European Commission: • “Act of proving, in accordance of GMPs that Any process actually leads to expected results” (1991) • “Documented evidence that the process operated in accordance with established parameters can effectively and reproducibly produce a medicinal product in accordance with its predetermined specifications and quality attributes.” (2000) According to US FDA: "Process validation provides documented evidence that provides a high degree of assurance that a specified process will consistently produce a product that meets its pre-determined specifications and quality features." According to ICH (International Conference on Harmonization): "Process Validation is the means to ensure and provide documentary evidence that processes within their design parameters can produce a finished product of the required quality repeatedly and reliably." According to WHO: "The documented act of proving that any procedure, process, equipment, material, activity, or system actually results in the expected outcome." Syed Ali Haider- Copyright © 2022 Why Validation? Let’s just rephrase the question, “Validation, Why Not?” Validation is based on, but not prescribed by, regulatory requirements and is best viewed as an important and integral part of cGMP (Current Good Manufacturing Practices) It plays a vital role in Pharmaceutical and Medical Device Industry specifically Validation simply means an evaluation of validity or an intervention to show effectiveness Syed Ali Haider- Copyright © 2022 APPROACHES TO VALIDATION There are four (4) approaches to Validation according to NAFDAC (National Agency for Food and Drug Administration and Control)- Nigeria PROSPECTIVE VALIDATION • Prospective validation occurs before the system is used in production • It is proactive approach of documenting the design, specifications and performances before the system is operational • New Facility, New Equipment, New Product and New Process CONCURRENT VALIDATION • Concurrent validation occurs simultaneously or parallel with production • Existing Facility, Existing Equipment, Existing Product and Process RETROSPECTIVE VALIDATION • Based on review and Analysis of Historical data • The source of this data is Production and QA/QC record Syed Ali Haider- Copyright © 2022 RE-VALIDATION Required when there is are changes in, • Any of the critical process parameters (CPP) • Formulation • Primary Packaging Components • Raw Material • Change in major component of Equipment or Premises • Failure to meet product and process specifications in batches would also require process revalidation or re-qualification Syed Ali Haider- Copyright © 2022 CMA, CPP, CQA CRITICAL MATERIAL ATTRIBUTES (CMA) A physical, chemical, biological or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of output material CRITICAL PROCESS PARAMETERS (CPP) Any parameter whose variability has direct impact on Quality of product Example: Temperature, Humidity, Mixing time, drying Temperature, machine Speed, Mesh Size, Steam pressure of autoclave, Sterilization temperature (According ICH Q8) CRITICAL QUALITY ATTRIBUTES (CQA) Any Physical, Chemical, Biological or Microbiological property or characteristics which should be within appropriate limit, range or distribution to assure product of desired quality Example: Assay, Content Uniformity, pH, Osmolarity, Sterility, F˚ etc (According ICH Q8) Syed Ali Haider- Copyright © 2022 FACILITY/AREA QUALIFICATION Facilities Qualification validates the overall manufacturing / testing / production environment • “The requirement is as usual driven from the product processes” Where the product process calls for specific room condition, as defined in ISO 14644 and was in Federal Standard 209E, the engineers must design the respective process area to enable these conditions to be achieved and maintained Good engineering principles and practice must be used to protect this conditions as required, using • • • • • Approved Area Dimensions & Specs Quality of Air Filtration Temperature & Humidity control Air Flows Control Differential Air pressures Controls Syed Ali Haider- Copyright © 2022 UTILITY QUALIFICATION All Utilities must pass a string of Qualitative and Quantitative specifications to be considered satisfactory • • • • Steps in Utility System Qualification include: Implementing strong operating procedures Establishing extensive quality control systems Extensive Sampling on regular intervals Maintaining dependable testing labs Some Critical Utilities at Pharmaceutical Plant: HVAC System Water System (i.e DI, WFI) Pure Steam Nitrogen System Compressed Air System Note: All the above utilities directly have an impact on Product Quality (affecting Quality Attributes) Syed Ali Haider- Copyright © 2022 EQUIPMENT QUALIFICATION • As per definition, Equipment Qualification is a documented evidence which provides assurance that the equipment or system is commissioned properly, operates and performs consistently as per their intended purpose • Qualification starts from URS to the Decommissioning of Equipment LEVELS OF EQUIPMENT/SYSTEM Level I Equipment systems with highest degree of Product Quality & Regulatory impact Eg Steam Sterilizers, Dry Heat Sterilizers etc Level II Equipment System that may not have a direct impact on product quality, but typically will support Level I Equipment E.g Compressed air Level III Equipment systems representing processes with low Regulatory and Product Quality impact Syed Ali Haider- Copyright © 2022 PROCESS VALIDATION • Process Validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products The process validation activities can be described in three stages Stage – Process Design This is the R&D phase and involves defining a process for manufacturing the product It usually includes the following: • Creation of a Quality Target Product Profile (QTPP) • Identifying Critical Quality Attributes (CQAs) • Defining Critical Process Parameters (CPPs) • Conducting risk assessments Syed Ali Haider- Copyright © 2022 Stage – Process Validation or Process Qualification Stage – Continued Process Validation This stage evaluates/qualifies the process designed earlier to ensure it can reproduce consistent and reliable levels of quality Continued Process Verification involves ongoing validation during production of the commercial product to ensure the process designed and qualified in the previous stages continues to deliver consistent quality It involves collecting and evaluating data on all aspects and stages of the manufacturing process This includes: • The building and facilities, i.e ensuring they adhere to local regulations as well as pharmaceutical manufacturing regulations • Transportation & Storage of raw materials • Training of production line employees One of the main aims of this stage is to detect and resolve process drift The stage involves product sampling, analysis, and verification at various points in the manufacturing process, and requires the involvement of employees with quality control training • Every step of the process to turn raw materials into the finished product This includes having predefined sampling points at various stages of the process • Finished product packaging, storage, and distribution Syed Ali Haider- Copyright © 2022 How many Product Batches could be taken for Process Validation? Answer: Three consecutive batches are enough to identify trend analysis and provide adequate evaluation and reproducibility data 1) First batch quality assumes to be accidental (CO-INCIDENTAL) 2) Second batch quality assumes as regular (ACCIDENTAL), 3) Third batch quality shows the Validation (CONFORMATION) Nevertheless, According to regulatory authorities, batches no longer required – other approaches can be used based on the Manufacturer, while providing a sound scientific rationale Quality Myths!!!! 03 Batches- Not appropriate 30 Batches required for 90% reliability & 95% confidence (Practically Impossible) Syed Ali Haider- Copyright â 2022 ANALYTICAL METHOD VALIDATION ã Method Validation confirms that the analytical procedure employed for a specific test is suitable for its intended purpose Strategy for Method Validation Develop Validation Protocol and define scope of the method Define Performance parameters and acceptance criteria Define Validation Experiments Select Quality Material- (Standards & Reagents) Perform Full Validation Experiments & Develop SOP’s for method execution routinely Define criteria for revalidation Define type & frequency of system suitability tests and/or Analytical Quality Control (AQC) Document Validation Experiments and Generate Validation Report Syed Ali Haider- Copyright © 2022 COMPUTER SYSTEM VALIDATION Computer Systems Validation (CSV) – is a process used to test, validate and formally document that a regulated computer-based system does exactly what it is designed to in a consistent and accurate manner that is secure, reliable and traceable Usually, while validating computer systems, companies stick to the Good Automated Manufacturing Practice V-Model, also known as GAMP-5 Step-by-Step Breakdown of Computer System Validation • Planning — at this stage, deadlines and the budget needed to carry out CSV are set Also, all stages are broken down by time and monetary estimates in form of Gantt Chart • Defining URS- Basically, this includes all the functions a system needs to carry out • Design Specifications At this point, a team involved in CSV decides the look of a given function and the way it should function in order to complete all tasks outlined during the previous stage • Configuring a System build This stage consists of writing configure scripts that will design the software for a computer system • IQ tests test a range of scripts to determine if they have chosen the correct way to install the system into the user environment • PQ tests — test worst-case scenarios to ensure a system would still work properly under poor conditions • Reporting All planned activities are reviewed A tester has to document the result of validation and organizes them as proof that a system is ready for release Syed Ali Haider- Copyright â 2022 CLEANING VALIDATION ã Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size Cleaning Validation Sampling Methods: Worst Case Selection: Visual Inspection Toxicity Swabbing Method Difficult To Clean (Cleanability) Rinse Sampling Therapeutic Dose Placebo Sampling Method Solubility Syed Ali Haider- Copyright © 2022 VALIDATION MASTER PLAN • Validation Master Plan (VMP) is a document which outlines the principles tied to the qualification of a certain facility, defining the systems and areas which need validation and provides a written guideline on how to achieve and then maintain a qualified facility Syed Ali Haider- Copyright © 2022 COMPONENTS OF VMP Syed Ali Haider- Copyright â 2022 SIGNIFICANCE OF VALIDATION ã Improve the use of Technology • Improve Operational Efficiency • Improve compliance with Regulations • Increase Productivity • Reduce the risk of Failure • Reduce the Cost • Process Optimization • Increased Customer Satisfaction Syed Ali Haider- Copyright © 2022 ROLE OF ENGINEERS IN VALIDATION Engineers contribute a significant portion to the Validation Team They are entitled with the following responsibilities: • Commissioning and Qualification of Equipment/Utilities • Monitoring Area/System/Equipment/Utilities Specifications • Directing Validation Activities and Preparing Compliance Reports • Auditing and Calibrating Equipment • Analyzing test results and compiling of technical reports • Providing evidence of regulatory compliance • Bridge the Gap between Quality Operations and Engineering Department Syed Ali Haider- Copyright © 2022 REFERENCES [1] Drug Act 1976, Drugs Licensing, Registering and Advertising Rules, 1976, Schedule B [2] USP-NF General Chapters [3] British Pharmacopoeia [4] The International Pharmacopoeia [5] EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation [6] FDA Current Good Manufacturing Practice for Finished Pharmaceuticals , 21 CFR, Part 211 [7] WHO TRS 937, Annex 4, Supplementary Guidelines on Good Manufacturing Practices: Validation [8] Baseline Guide Volume 5, ISPE Commissioning and Qualification [9] Good Manufacturing Practices (GMP) Guidelines – 2009 Edition, Version 2, Health Canada, GUI-0001 [10] PIC/S Guide to Good Manufacturing Practice for Medicinal Products, Annex 15, Qualification and Validation Syed Ali Haider- Copyright © 2022 ... Timeline What is Validation Why Validation Four (4) Approaches to Validation CMA, CPP, CQA What is Qualification Phases of Qualification Types of Validation/ Qualification Validation Documentation... TYPES OF VALIDATION/ QUALIFICATION • Facility/Area Qualification • Analytical Method Validation • Utility Qualification • Computer System Validation • Equipment Qualification • Process Validation. .. Validation Develop Validation Protocol and define scope of the method Define Performance parameters and acceptance criteria Define Validation Experiments Select Quality Material- (Standards &