GMP PDF - Good Manufacturing Practices Notes

GOOD MANUFACTURING PRACTICES (GMP) TOPIC 1 Part A – Background & Rationale Part B – Regulations 1 Pharmaceutical Products 2 3 Categories of Pharmaceutical Drugs Natural products Obtain/extract naturally from...

GOOD MANUFACTURING PRACTICES (GMP) TOPIC 1 Part A – Background & Rationale Part B – Regulations 1 Pharmaceutical Products 2 3 Categories of Pharmaceutical Drugs Natural products Obtain/extract naturally from herbs, plants, roots, vines and fungi E.g., Turmeric Small molecule drugs (SMDs) Chemically synthesize products inspired from natural products Molecular size < 900 Dalton E.g., Aspirin or Acetylsalicylic Acid is a reproduction of salicin, which Aspirin is found in willow bark (MW = 180 g/mol) 3 3 Categories of Pharmaceutical Drugs Biologics aka Biopharmaceuticals Produced by genetically engineered organisms (i.e., utilize living cells) Molecular size > 900 Avastin: C6638H10160N1720O2108S44 Dalton (MW ≈149000 g/mol) Includes vaccines and recombinant proteins for cancer treatment 4  Comparing SMD to Biopharmaceuticals (in terms of size and complexity) Small Molecule Small Protein Large Protein Aspirin 21 atoms 180 Da Antibody (IgG) e.g., Avastin ~ 25000 atoms Growth Hormone ~ 149 kDa Abilify e.g., Protropin 57 atoms ~3000 atoms 448 Da ~22 kDa Bicycle 10 kg Business Jet Car 2000 kg 15000 kg 5 GOOD MANUFACTURING PRACTICES (GMP) TOPIC 1 Part A – Background & Rationale 6  What is GMP?  A quality assurance system to ensure products intended for human consumption are produced in consistent and controlled manner according to quality standards.  Procedures used to ensure product safety, purity, quality & efficacy are constantly being met.  Designed to minimize risks (e.g., contamination, mix-up and errors) during the production. 7  What is GMP?  Often seen or written as cGMP, where the ‘c’ means current. cGMP = Current Good Manufacturing Practices Using up-to-date technologies and systems to comply with the most updated regulations and changes. 8  Where does GMP apply? 1. In the manufacturing of:  Biologics and Pharmaceutical Drugs  Medical Devices and Implants E.g., prostheses, diagnostic instruments etc.  Cosmetics  Food 9  Where does GMP apply? 2. In all the manufacturing steps from start to end. Culture Fluid Stock Culture Shake Flask Seed Production Fermentor Fermentor Supernatant Medium Cell Separation Product Sterilization Extraction Biomass Note: Risks cannot be Medium Product Formulation Purification eliminated by a final product testing. Medium Fill & Finish Raw Material Packaging 10  Where does GMP apply? 3. Within the company: Organization and Buildings and Facilities Personnel – Design, Construction and Maintenance – Responsibilities and Qualifications Equipment – Calibration and Preventive Maintenance Production Controls – Process Limits – Contamination Control 11  Where does GMP apply? 3. Within the company: Quality Control Packaging and – Samples and Retains Labelling Records and Reports – Expiration dating – Traceability – Evidence of tampering Inspections and Audits Warehousing and Documentation Distribution Validation 12 Who benefits from GMP? 13  Why the need for GMP?  Prevention of tragedy!  Prevent taking shortcuts  Inculcate attitudes and actions towards producing quality products 14  Why study GMP? Production of biopharmaceutical products and medical devices are governed by GMP requirements Important knowledge to have if wants to work in the related industries 15  Pharmaceutical Practices Can be summarised into GxP – Good Manufacturing Practice (GMP) – Good Laboratory Practice (GLP) – Good Documentation Practice (GDP) – Good Distribution Practice (GDP) – Good Dispensing Practice (GDP) – Good Clinical Practice (GCP) 16  Events That Shaped GMP BEFORE 1962: A WORLD WITHOUT GMP! 1962 GMP 1960 Regulations & Amendments 1938 Thalidomide, EFFICACY 1937 Federal marketed as Food Drug “So safe you 1906 Elixir of can take Death and 1905 Food and Cosmetic handfuls of Drugs Act Act it” The Jungle PURITY SAFETY BIRTH OF MODERN DAY FDA  1900s – The Jungle The Jungle was written about Chicago’s meat packing industry Animals were slaughtered and processed under insanitary conditions Sales of rotten/diseased meat to public Ground meat tainted with remains of poisoned rats and unfortunate workers who fell into machinery Adulterated products 18  1906 – Food and Drug Act In 1906, Pure Food and Drug Act was passed Became illegal to sell (adulterated) contaminated food/meat Requirement for truthful labelling and no “misbranding” – E.g., product content (alcohol, opium, morphine that are addictive), product description (misleading statements or pictures) Created one of the first government regulatory agencies (FDA) Allowed for seizure & prosecution 19 1937 – The Elixir Sulfanilamide Tragedy Elixir of Sulfanilamide More than Manufacturer For 100 people used diethylene treatment died, glycol in of including preparation of infections children the drug Elixir Sulfanilamide: 10% sulfanilamide, 72% diethylene glycol, In 1938, Federal Food, Drug and 16% water. Raspberry extract, Cosmetic Act was enacted caramel, etc. 20 1960s – The Thalidomide Scandal Thalidomide [thal-lid-oh-mide] As sleeping pill and treat morning sickness Over 10000 cases of Flipper Babies 21 1960s – The Thalidomide Scandal US avoided tragedy as an FDA physician Dr Francis Kelsey blocked thalidomide’s entry due to incomplete information. She was hailed a national heroine and received a president award from John F. Kennedy. She passed away at the age of 101, in 2015. Thalidomide is still in use today, as it is extremely effective in the treatment of certain cancers, leprosy and other inflammatory diseases.  1962 Drug Amendments and GMP Today Thereafter, more stringent legislation imposed for proving drug safety and effectiveness before market release. Example in clinical testing and trials  Testing on animals before human  Informing participants about drug trial purposes  Obtaining participants’ consent  Reporting any adverse drug reaction  Providing evident of drugs safety and efficacious First set of GMP regulations published in 1963. Continual revision of GMP regulations are in place to ensure being current and still protecting us. GOOD MANUFACTURING PRACTICES (GMP) TOPIC 1 Part B – Regulations 24  The Regulatory Bodies So, who regulates GMP today? Regulatory Bodies Role: to license and control the manufacture and sale of healthcare products, ensuring systemic conformity through GMP. Each country has its own authority that sets its own standards. 25  The Regulatory Bodies Food and Drug Administration European Medicines Agency (FDA, USA) (EMA, EU) Health Sciences Authority (HAS, SG) 26  The Regulatory Bodies Medicines and Healthcare Therapeutic Goods Administration Products Regulatory Agency (UK) (TGA, Australia) The overall principles of GMP are the same between them. But differs in their approach Pharmaceuticals & Medical and guideline enforcement Devices Agency (Japan) 27  The Regulatory Bodies  Manufacturers will have to obtain approval from country specific authorities before they can sell their products in that country  Inspectors from the regulatory agencies will visit manufacturing plants to check on compliance to GMP. Such inspection are also called audit. o FDA will visit manufacturing sites in USA without notice. While sites outside USA are issued with a 90- days advance visit notice. o HSA will visit Singapore plants with advance notice. 28  GMP Regulations & Guidance Country / Agency Guidance Document Region Title 21 Code of Federal Regulations (CFR) USA FDA – Parts 210, 211, 820 FDA Guidelines EU GMPs – Annex 1, 2, 13 EU EMA EU Directives – 2003/94/EC, 2004/23/EC Australia TGA Australian Code of GMP PIC/S Guide to GMP for Medicinal Singapore HSA Products FDA Code of Federal Regulations: https://www.ecfr.gov/ 29  GMP Document Pyramid Regulations: 21 CFRs, PIC/s guide, Australia code of practices, etc Increasing Company What we must do Level of Quality At corporate level Detail Policies (From How we must do General to Company SOPs Procedures outlining how Specific) to execute the process What was done Records Documentation history E.g., batch record, training history 30  cGMP Requirements Harmonization  Potential danger of gaps between different countries (and their GMP standards) over time  Need to prevent widening difference  Efforts must be made to harmonize the standards from different countries. 31  ICH The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)  A platform to harmonize standards between the EU, USA and Japan.  Developed over 40 guidelines. One of the most important one is ICH Q7A GMP Guidance for Active Pharmaceutical Ingredients (APIs) 32  PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S)  Established in 1995  Non-legal cooperative arrangement between regulatory countries  60 members as of Oct 2024  HSA became a member of PIC/S in Jan 2000 33  Benefits of Joining PIC/S International GMP Training opportunities harmonization PIC/S provides a forum for the Develop and harmonise of training of GMP inspectors through international GMP guides and attending PIC/S Seminars and Joint guidelines. Visits Programme. The PIC/S Committee also actively No other international training promotes the uniform interpretation forum run jointly by Regulatory of GMP and Quality Systems for Authorities. GMP Inspectorates. 34  Benefits of Joining PIC/S Networking High standards Contact and exchange of GMP PIC/S members comply with PIC/S related information. standards at all times GMP inspectors meet, discuss issues Increased efficiency of the GMP of mutual concern and share inspectorate. experiences and information. 35  Benefits of Joining PIC/S Sharing of information Rapid Alert System Voluntary sharing of GMP inspections Member Regulatory Authorities reports. automatically included of the PIC/S Rapid Alert and Recall System arising from quality defects of batches of medicinal products distributed on the market. 36 QUALITY MANAGEMENT SYSTEM TOPIC 2 1  What is QUALITY?  Totality of all features and characteristics that exhibit a product meets the pre-defined specifications and satisfies its fitness-for-use.  In other words, every aspects that allows a product to be fit (effective, pure, safe and stable etc.) for its intended use.  At times, simply referred as fitness of product for intended purpose. 2  Drug Quality Attributes Identity Is the drug what it is? How many percent is free from Purity impurities? How much is needed? Potency What is the lethality? Safety Relative freedom of consumer from risk Does it work for its intended Efficacy indication? Product quality remains the same on Stability expiration date as when first packaged Is the product reproduced batch after Consistency batch with meeting specifications? 3  What is QUALITY? Match the desirable product feature to their correct product quality attribute Desirable product feature Product quality attributes Lasts till use by date Safety No side effects Effectiveness Free from contaminants Identity Correct label Purity 4  What is Quality Management? 1. The basic elements are:  Appropriate infrastructure or “quality system” encompassing the organization structure, responsibilities, procedures, processes and resources.  Systematic actions to bring quality policy to life (i.e., having adequate confidence on a product/service to satisfy/meet its given “Quality” requirements). 2. Overall intention and direction regarding quality are authorized by the top management of organization. All add up to be termed “Quality Assurance” 5  Quality Relationships Quality Management Overall policy of the organization towards quality (supersedes everything) Quality Assurance Concept that ensures the policy is achieved GMP Deals with the risks that cannot be tested, helps build quality into product Quality Control (Production & Lab) Focuses on testing of environment and facility, as well as materials, components, product according to standards 6  Quality Management Quality Policy  Statement of company’s objectives and commitment to quality Example: 7 Quality Assurance (QA) Principles  Wide-ranging concept – Covers all matters that individually or collectively influence the quality of a product  Totality of the arrangement – To ensure that the drug is of the right quality for the intended use  GMP incorporated – Including product design and development QA is the responsibility of all employees who in any way can influence product quality. 8  Appropriateness of QA System 1. Responsibilities and Authorities  For managerial and personnel  Properly defined in job descriptions 2. Quality Standards  The approach and applications  Complying to same standards (e.g., GMP, GDP, GLP and current regulatory guideline) 9  Appropriateness of QA System 3. Production & Control Operations  Properly defined in documentations Manufacturer, supplier and use of materials (e.g., start to packaging) Controls to be performed (calibration and validation, including on intermediates and bulk items) Checks on finished product Storage, distribution and handling 10  Appropriateness of QA System 4. Product Sales  Need to comply with marketing authorization, production and QC requirements  Only after reviewed by the authorized person 5. Self-inspection and/or Quality Audits  Regular evaluation of product quality  Verify consistency and continued improvement 11  Appropriateness of QA System 6. Deviation/Incident, Investigation and Records  Deviation/incident reporting & documentations  Investigation execution  Decision makers 7. Change Control & Approval  Status and duration tracking (open, pending, closed)  Types of change (document, procedure, equipment etc.) 12  Roles of Key Personnel The establishment and maintenance of a satisfactory system of quality assurance rely upon PEOPLE (even cleaners) For this reason, there must be ① sufficient and ② qualified personnel to carry out all the tasks for which the manufacturer is responsible. 13  Training Requirements  Personnel must be adequately trained to perform their assigned responsibilities.  Trained prior to assuming assigned duty.  New hires MUST receive training on cGMP and procedures prior to be assigned duties in GMP areas.  All employee trained on cGMP awareness and practices.  Regular refresher training conducted to stay current.  Training documented and records retained. 14 Example of Biopharmaceutical Organization Structure Site Head Science & Human Quality Operations Technologies …… Resources Documentation Control Manufacturing Validation Recruitment Technology Compensations Quality Assurance Engineering Transfer and Benefits Utilities & Employee Quality Control Automation Maintenance Development Material Regulatory Affairs Management Sales Change Control Office 15  Roles of Key Personnel Key personnel include the heads of various departments – Manufacturing / Operation – Quality – Sales / Distribution – Other functions as required Full-time personnel should occupy key postions. The heads of Operation and Quality should be independent of each other. 16  Roles of Key Personnel Quality Unit  Given responsibility and authority to approve or reject all incoming components and products manufactured  Concerned with organization structure, documentation, sampling, specifications, testing, release procedures and process non-conformance management etc.  Not confined to simply laboratory operations  Involved in all decisions concerning the quality of the product (e.g., final approval on relevant documentation)  Ensures that the necessary and relevant tests are carried out 17 GMP Documents Requiring Quality Approval  Policies  Standard operating procedures (SOPs)  Product specifications  Validation protocols  Change control records  Batch records  Analytical testing methods  Raw material certificates of analysis  Calibration and maintenance documents  Non-conformity investigation reports  Product release package  Complaint records 18  Quality Assurances (QA) Entails a systematic analysis of each process to preplan and document how every activities will be undertaken Ensures the outcome will be as expected Legislative (have last say!) – Iike law enforcement officers! 19  Quality Control (QC) Provides the physical verification (by analytical testing) that quality has been met 20 How to check for Quality? 21 Detection Not Ideal Model  Usually rely on inspectors  Weeded out some inferior products  Found and corrected some mistakes  Does not improve the quality of the system or products  If certain amount of defective item is found,  the WHOLE batch to be reworked or thrown away 22  Preventive Model output Process Shipment Improve Inspect with SPC Analyze Usually automated Collected statistical signals (data) along production lines Statistics analyzed at appropriate points  Statistical process control (SPC) Process control and improvement achieved efficiently based on analysis 23  Quality Audit  A systematic, independent examination of the quality system.  Purpose: - To ensure continuous effectiveness of the quality system and its compliance with GMP / quality system requirements  Requirements: - Performed at defined intervals and at sufficient frequency. - Performed by personnel with no direct responsibility for the matters being audited 24  Quality Audit Team from Independent Regulatory company specialist Agencies Internal External Audit Audit AUDIT Production Warehouse QC Suppliers Contractors Training 25  Quality Audit  To determine whether both quality system activities and the results of such activities comply with quality system procedures. FDA (21 CFRs), EU (PIC/s guide), TGA (Australia code of practices), etc  Are the procedures implemented Company quality policies What we must do effectively? Increasing Level of Details  Are the procedures Company SOPs How we must do suitable to achieve quality system Records objective? e.g. batch record, What was done training history 26  Quality Audit  Any non-conformances (non-compliance matters) highlighted in an audit will require action(s) from the company. Such actions  are called Corrective Actions and Preventive Actions (CAPAs)  must be documented and implemented within a promised timeframe  are verified in Quality Re-audit (or Surveillance Audits), where necessary 27 DOCUMENTATION AND RECORDS TOPIC 3  GMP Document Pyramid Regulations: 21 CFRs, PIC/s guide, Australia code of practices, etc Increasing Company What we must do Level of Quality At corporate level Detail Policies (From How we must do General to Company SOPs Procedures outlining how Specific) to execute the process What was done Records Documentation history E.g., batch record, training history 2  Documentation  A significant feature in a company complying to cGMP requirement  Provides assurance that quality related activities are carried out exactly in the way they have been planned and approved  Can be in electronic or paper form BUT only the original copies are to be used  Documentation includes – Procedures (SOP) – Records, logbooks, datasheets – Protocols, reports – Labels 3  Importances of Documentation  As evident to assure regulators that the manufacturing process complies with the legal requirements and the approved marketing authorization prove that procedures have been followed and that actions or events took place  A form of traceability that provides complete history of finished batches makes investigations of raised problems smoother FDA stance is “What hasn’t been documented, hasn’t been done!” 4  Personnel Signature Policy 1. Handwritten signature (including initials) 2. Electronic signature = computer data compilation of symbol or series of symbols, executed, adopted or authorized by the individual to be the legally binding equivalent of the individual’s handwritten signature MJ 5  Personnel Signature Policy Types of electronic signature:  Biometric – employing a person's unique physical and other traits (e.g., fingers, iris, voice etc.)  Non-biometric – employing at least 2 distinct identification components such as an identification code and password 6  Personnel Signature Policy  Electronic signature and handwritten signature / initial shall be unique to each personnel and shall not be reused by or reassigned to anyone else  If you sign or initial on cGMP documentation, you are responsible for the completed action that you have acknowledged to be true.  Both signature types are legally-binding 7  Personnel Signature Policy  DO NOT sign someone else’s name  DO NOT share your e-signatures  Misuse of signatures can result in termination and legal action  In some work processes or operational steps, a verifier’s signature is required, in addition to the operator’s signature 8  Good Documentation Practices (GDP)  Provides standards and practices to be followed in the execution of GMP documents.  To ensure the reliability and integrity of information and data throughout all aspects of a product's lifecycle From recording, correcting and managing data, documents and filing records.  Complete and accurate records indicate a good quality management system Trust by customers and regulators 9  Guiding Principles of GDP Accurate Permanent Principles Complete Clear of GDP Traceable Timely 10  Guiding Principles of GDP Permanent Clear  Use waterproof blue/black  Free of ambiguity ink  Self-explanatory  Ballpoint pen  No slangs or jargon recommended  Acceptable acronyms only  No pencil/erasable ink  Neat and legible (no  No post-it notes scribbles or write-over or  No correction tape or fluid use of deface document) Timely  Actions documented real time  Use current date, no back-dating or complete before execution 11  Guiding Principles of GDP Accurate Traceable  Attention to detail  Signature traceable to  Do not fabricate data author (can identify the person making any entry)  Traceable to time & Complete material batches used  All required fields to be  Document data directly – filled no transcription  N/A appropriately in non-  All original records must applicable fields be retained-never throw!  Missing data / empty fields  Attachments must be should be escalated labelled and referenced immediately accordingly 12 Data Integrity Principles 13  Rules on ERROR corrections  Cross out error with single line through entire word. – Allow original entry be legible (i.e., do not correct by scribbling over the error)  As near as possible to the original entry, enter – correct information – Initial and date the correction ABC 20 Oct 24 – use current date and proper date format  Do not back-date corrections  Do not leave blank spaces which can potentially be rooms for illegal entries  Enter ‘N/A’ in spaces that are not applicable, with initial/date  When the reason for correction is not self-evident, provide an explanation 14  Rules on ERROR corrections  Do not use correction tape or fluid  When a verifier is required for the original entry, any corrections to this entry need to be initialled and dated by both the operator and verifier  Don’t just line out the middle portion of a word or number. Line and correct the entire entry  No arrows or ditto marks  No ‘inverted carrot’ marks  In electronic systems, any corrections made need to comply with the SOP for that system 15  Causes to Data Integrity Lapses Time Pressure Insufficient education , knowledge & understanding (Why?) Fear of mistakes (or owning up to) Fear of speaking up Reputation Performance Pressure Instructed by leader Money Culture or culturally accepted behaviour 16  Don’t get IT wrong Mistakes can occur… They just should NOT be a result of shortcuts, poor-decision making & fear of speaking up Nothing is worth risking Safety of patients, Data Integrity or Compliance DATA INTEGRITY All deviations from GDP principles should be escalated immediately AND addressed by THE company’s Discrepancy Management System. 17  Standard Operating Procedure (SOP)  Important documentation for all operations  One for every repeated task performed in any area within the company. For examples, – in manufacturing, SOP for making of culture medium in media preparation tank – in warehouse, SOP for handling rejected/damaged goods  Must be available where the work is done 18  Purpose of SOPs 1. Enable personnel to carry out operations correctly and consistently; always in the same manner. 2. Helps to ensure products are always produced in consistent and controlled manner according to quality standards. 19  SOP Format Standardization Cover/front page should contain: Company name Unique SOP number and version (revision) number Subject Title Effective Date Total no of pages Checked by Approved by 20  A Well-written SOP  Descriptive  provide sufficient details for personnel to perform task  Concise  clear, accurate instructions (helpful to include any pictorial for illustration) that is followable for execution  Up-to-date  aligned with current practices  Has a desired outcome and measurement 21 Definitions Batch / Lot  A specific quantity of material that is – intended to have uniform character and quality, within specified limits, and – produced according to a single manufacturing order during the same cycle of manufacture 22  Definitions Batch production  each process is completed at a unit operation before they move to the next.  Start to end of a unit operation 23  Definitions Batch / Lot / Control Number - A distinctive combination of numbers and/or letters which uniquely identifies a batch on the labels, its batch records and corresponding certificates of analysis, etc. 24  Records  Documents (either as hardcopies or in electronic form) detailing information related to the production, control or distribution of a batch of product. Original true copies - QA approved photocopies, microfilm, or other accurate reproductions of the primary records - Electronic versions that can be retrieved immediately through a computer or other electronic means from another location 25 General Requirements for Records 1. Retention Period  Maintained till at least 1 year after the expiration date of the batch for these records Production record Quality Control record Distribution record  Actual retention period depends on individual company policies 2. Availability  All records, or copies of such, shall be readily available for authorized inspection during the retention period 26 General Requirements for Records 3. Initialled and dated  All entries should be duly initialled and dated For operation/process:  Initial/signature of operator (who performs the task) and current date as the task was performed  Initial/signature of verifier (who check and/or verify operator had performed the task and filled up required details of the task on the record) and current date as the task and verification was performed For review  Initial/signature of a reviewer (a 2nd or 3rd person, showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards) and current date as review was performed. 27  Types of Records  Equipment cleaning and use log  Component, drug container, closure and labelling records  Master production and control records  Batch production and control records  Laboratory records  Distribution records  Complaint records  Training records 28  Equipment Cleaning and Use Log A written record for individual equipment, showing the various activities that have been performed with / on the equipment / in the room, and equipment status.  Activities/events are recorded chronologically Cleaning and Sterilization Maintenance Batch processing  Details included in record Date and time (start and end) Job number (for automated cleaning) Product and lot no. (for batch processing) Maintenance work order no. Initial/date of operator and verifier 29  Component, Drug Product Container, Closure and Labelling Records For each shipment of each lot of components, drug product containers, closures, and labelling etc., the following details are captured – Identity/Item name and description – Quantity – Supplier and Supplier's lot no. (if known) – Receiving code – Date of receipt – Name and location of the prime manufacturer, (if different from the supplier) 30  Component, Drug Product Container, Closure and Labelling Records Individual inventory record is required to trace the use and reconciliation of raw materials, components, drug product container and closures. Allowing determination of any batch or drug product associated with the use of each raw material, component, drug product container and closure Documents all inspections of labels for conformity with established specifications Documents the disposition of rejected components, drug product containers, closure, and labelling 31  Master Production and Control Records Written description of the manufacturing process of specific drug product, which must consist  Complete manufacturing and control instructions  Sampling and testing procedures  Specifications  Special notations  Precautions to be followed for a batch 32  Master Production and Control Records There’s only one set of original master production and control record for each product. Hence, kept away and not use for execution. The master templates for duplicating batch production and control records (reproduction copies) that are used for processing execution. Ensuring batch to batch consistency for each product. Prepared and signed/dated by one person; independently checked and signed/dated by a second person. Typically approved by Technical, Operations and Quality prior to use 33  Master Production and Control Records Content includes: – Identity of product and dosage description – description of the drug product containers, closures, and packaging materials, including specimen / copy of each label – complete list of raw materials / intermediates designated by names/codes sufficiently specific to identify – quantity or ratio of each raw material / intermediate. If quantity is not fixed, calculation for each batch size should be included 34  Master Production and Control Records Content includes: – statement of theoretical weight or measure at appropriate phases of processing – statement of theoretical yield, including the maximum and minimum percentages of theoretical yield (beyond which requires investigation) – in-process testing and acceptance criteria – complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed (e.g., time limit of steps, location/identity of equipment) 35  Batch Production and Control Records Prepared for every batch of drug product produced [documenting all significant steps in the manufacture, processing, packing, or holding of the batch] Include complete information relating to the production and control of each batch Generated by accurate duplication of the appropriate master production and control record, checked for accuracy, dated, and signed. Only authorized personnel can generate batch production and control records 36  Batch Production and Control Records Things documented in the records are,  Date of step performed/completed  Identity of major equipment and lines used (unique Equipment / Line identification no.)  Lot no. of raw materials, intermediate used  Weights and measures of components used  Sampling details  In-process and laboratory control results  Calculation of the actual yield and comparison to the theoretical yield at appropriate phases of processing 37  Batch Production and Control Records Things documented in the records are,  Inspection (before and after use) of the packaging and labelling area (i.e., line clearance check)  Complete labelling control records, including specimens or copies of all labelling used. (Unused labels should be reconciled)  Identity of operators and verifiers of each significant step in the operation  Deviation / investigation performed  Inspection results 38  Record Review  Upon batch completion, all batch production and control records shall be reviewed and approved by Quality Assurance (QA) before batch is released or distributed.  Any unexplained discrepancy or component failure to meet any specification shall be thoroughly investigated, regardless whether batch has been distributed – Extension of investigation to other batches which may be linked with the discrepancy 39  Laboratory Records  Contains complete sets of data derived from all QC tests necessary to meet established specifications and standards Contain information of – sample to be tested – testing to be done – testing and standardization of laboratory reference standards, reagents, and standard solutions – periodic calibration of laboratory instruments, apparatus, gauges, and recording devices – all stability testing performed 40  Laboratory Records Sample Testing description of content method of testing (SOP ref no.) date/time sample was taken calculations for test (including and received for testing units of measure, conversion factors and equivalency factors) origin/source identification raw data collected quantity received and used results and how the results lot no. of batch compare with established standards of identity, strength, quality, and purity for the component, in-process material, or drug product tested 41  Distribution Records Must contain: – Name and strength of the product and description of the dosage form – Name and address of the consignee – Date and quantity shipped – Lot or control number of the drug product 42 BUILDING & FACILITIES TOPIC 4 Part A – Cleanrooms Part B – Design Considerations 1  Cleanrooms  Controlled environment whereby the environmental conditions (e.g., particle count, temperature, humidity and pressure) are maintained to facilitate specific operations  Classified according to the environmental air cleanliness (measured in terms of particle concentration per volume of air)  With different guidelines (ISO Class, EU Grade), the designation of cleanrooms varies  In additional, microbial limits apply to cleanrooms meant for pharmaceutical applications 2  Cleanrooms  Applicable for: – Laboratory work – Production of precision parts for electronic or aerospace equipment – Manufacture of pharmaceuticals and medical components  Air Conditioning and Mechanical Ventilation (ACMV) systems are designed to regulate air quality, meeting the cleanroom classification 3 What are the possible contaminants? 4  Common Contaminants Microorganisms and particulate matters − Can be airborne and/or from resources (e.g. raw materials, process equipment, personnel etc.) − Very important to recognise the need to control them in pharmaceutical cleanrooms (both viable and non-viable) 5  Contaminant Sources Raw materials – Fine powder that get stirred up into the air during dispensing or charging Process Equipment – Metal or rubber shedding from grinding of moving parts Personnel  Human sheds all the time – Skin flakes, aerosols from exhaled gases, clothes fibres, hair etc. 6  Human Particle Emissions 1,000,000 100,000 Sneezing Coughing 10,000 Particles produced Talking 1,000 100 10 1 0.1 1 10 100 1000 10000 Size of particle in micron 7 Cause of Process Contamination in Cleanrooms 85% 10% 5% Equipment failure Filter failure People NYP - SCL - BPA - Topic 5 - © NYP 8  Personnel Hygiene  Health examinations:  Before and throughout employment  Periodic eye & hearing examinations for those who do visual inspections and work under loud/noisy machinery environment  Training:  Induction training – basic practices personal hygiene  Written procedures and instructions  Pictorial instructions and signs in areas 9  Personnel Hygiene  Written procedures and instructions to sanitize hands before entering production areas  Most companies encourage usage of disinfectants 10  Personnel Hygiene  Illness or open lesions (wounds) – May affect the quality of products – Should not handle starting materials, intermediates or finished products etc. – Instruction and encouragement to report to supervisors  Direct contact between product and operator: – Should be avoided – Also includes starting materials, primary packaging materials, intermediate and bulk product 11  Personnel Hygiene  Implementation of cleanroom gowning  prevent personnel contaminating products – Prior to enter each classification of cleanroom – Covering all hair areas (e.g., hair nets and beard cover) – Street clothes replaced by clean scrubs – Gloves should always be worn 12  Number of Particles Generated (per second per person) Jul 2016 NYP - SCL - BPA - Topic 5 - © NYP 13  Personnel Hygiene  Personal hygiene procedures includes wearing protective clothing applicable to everybody entering the production areas:  Full-time employees  Temporary workers  Contractor's employees  Visitors / Auditors  Managers  Inspectors 14  Cleanroom Rules for Personnel  No smoking, eating and drinking allowed in GMP areas – change room, production, laboratories and storage areas.  Chewing gum or eating sweets are also not allowed.  No makeup and painted nails.  No storage of food or drinks allowed.  No plants or other living things allowed except for human. 15  Cleanroom Rules on Design  Change rooms/changing facilities – Hand washing and drying facilities available – Used gowns stored in separate closed containers while waiting to be cleaned – Laundering of cleanroom gowns according to an SOP and in an appropriate facility – Procedure for disinfecting and sterilizing when required (gamma-radiation in biologics) 16  Cleanroom Rules on Design  Rest and refreshment areas should be separate from AIR FACTORY CHANGE ROOM LOCK TOILETS manufacturing and control areas  Toilets should not open directly into CANTEEN production or storage areas 17  Cleanroom Classification Maximum particles/m3 US FED ISO 14644-1 STD 209E Classification > 0.1 µm > 0.2 µm > 0.3 µm > 0.5 µm > 1 µm > 5 µm equivalent ISO 1 10 2 ISO 2 100 24 10 4 ISO 3 1000 237 102 35 8 Class 1 ISO 4 10000 2370 1020 352 83 Class 10 ISO 5 100000 23700 10200 3520 832 29 Class 100 ISO 6 1000000 237000 102000 35200 8320 293 Class 1000 ISO 7 352000 83200 2930 Class 10000 ISO 8 3520000 832000 29300 Class 100000 ISO 9 35200000 8320000 293000 Room air 18  Cleanroom Classification Maximum particles/m3 EU ISO GMP 14644-1 At rest In operation Grade equivalent 0.5 µm 5 µm 0.5 µm 5 µm A 5 3 520 20 3 520 20 B *5 3 520 29 352 000 2 900 C 7 352 000 2 900 3 520 000 29 000 D 8 3 520 000 29 000 Not defined * Requirements for particle counts during operation are different from Class A 19  Cleanroom Conditions As built At rest In operation air air air Complete installation with Complete installation with Installation functioning in all services connected and equipment installed the defined operation functioning No personnel present mode No production equipment, With specified number of materials or personnel personnel at work present 20  Cleanroom Classification FDA (microbes) Cleanroom ISO Designation Micro-biological Micro-biological Classification active air settling plates (based on (based on action levels action levels 0.5 µm ≥ 0.5 µm (∅ 90 mm) particles/ft3) particles/m3) (CFU/m3) CFU/4 h 100 5 3520 1 1 1000 6 35200 7 3 10000 7 352000 10 5 100000 8 3520000 100 50 Note: All classifications are based on data measured in the vicinity of exposed materials/articles during periods of activity FDA Guidelines for Industry Sterile Drug Products Produced by Aseptic Processing 21  Cleanroom Classification EU GMP Annex 1 (microbes) Recommended average limits for microbial contamination Air sample Settle plates Contact plates Glove print Grade (∅ 90 mm) (5 fingers) (∅ 55 mm) CFU/m3 CFU/4 h CFU/plate CFU/glove A