PHA111 QA-1.pdf

MPharm Programme Good manufacturing practice: Quality assurance aspects Cheng Shu CHAW 1 1 Good Manufacturing Practice (GMP) • Objective: – Assure the quality of the product for safety, well‐being and protection of the patients • Principles and guidelines: – Orange Guide ‘Rules and guidance for...

MPharm Programme Good manufacturing practice: Quality assurance aspects Cheng Shu CHAW 1 1 Good Manufacturing Practice (GMP) • Objective: – Assure the quality of the product for safety, well‐being and protection of the patients • Principles and guidelines: – Orange Guide ‘Rules and guidance for pharmaceutical manufacturers & distributor’ – EC directives – Enforced by law • GMP regulations are constantly monitored and improved – cGMP (‘current GMP’) • Concept of GMP: – Reduce the risk of making mistakes during all stages 2 2 What made us do GMP? • Clothier Report (Devonport Incident) • A dextrose 5% drip feed solu on BP → non sterile and resulted in the death of 5 patients • Manufactured by Evans Medicals Ltd (Liverpool) and distributed to hospital in May 1971 • The total batch consisted of 4,000 bottles • one particular sub‐batch of 612 units • Approximately one third of the sub‐batch was contaminated • The fault was detected 10 months after the manufacture MPharm 3 3 The Devonport Incident • 6th April 1971: Evans Medical manufactured 5% Sterile Dextrose Solution, Lot D1192/C • May 1971: Lot D1192/C distributed • 29th Feb 1972: 2 deaths at Devonport Hospital • 1st Mar 1972: 2 further deaths • 2nd Mar 1972: 1 further death • 6th Mar 1972: Investigation begins • 12th Jul 1972: Clothier Report issued 4 4 Reported deaths of patients though to be related to the use of 5% dextrose solution • Taken from The Lancet, November 24, 1973 5 5 Sterilisation of Sterile 5% Dextrose MPharm MPH117 6 6 What had happened in the company? • Faulty temperature recorders had been used in the drains of the autoclave • A blocked drain or a lack of use of vacuum to remove all the air from the inner of the autoclave • Some debris was found in the autoclave drain • The company decided that the vacuum was ok • Recommended to run the autoclave for 40 min at maximum temperature 7 7 The list of serious faults leading to the incident Gross negligence to repair and investigate Main fault not identify Dubious decisions bypass the problem Batches were released by the production staff not by the quality control department • Selection of samples for sterility and pyrogen tests by production staff without adequate procedure or training • Samples were taken from the layer of bottles near the dial, problem could not be detected • Quality control tends to detect extreme failure • • • • 8 8 Findings of the Clothier Report • Lack of instrument calibration • Lack of maintenance activities and maintenance logs • Inadequate and lack of operational procedures • Inadequate equipment • Inadequate equipment cleaning • Poor staff training • No batch records review 9 9 Effects of the Clothier Report • Ensure that critical instruments were functional and calibrated regularly • Prove that SOP’s were accurate • Prove that operators had been trained • Test and prove that the process would work time and time again • Document that this had been done 10 10 Good Manufacturing Practice (GMP) • • • • Planning Documentation Equipment and facility Quality control 11 11 Basic requirements of GMP • Manufacturing process (defined, reviewed and consistently manufacture to the required quality and complying with specifications) • Critical steps of manufacturing process and changes to the process are validated* • Facilities are provided: qualified and trained personnel; premises and space; equipment and services; correct materials, containers and labels; approved procedures and instructions; s, in accordance with the Pharmaceutical Quality System; suitable storage and transport • Instructions and procedures are written in clear and unambiguous language 12 12 Basic requirements of GMP • Operators are trained to carry out procedures correctly • Records are made during manufacture demonstrate that all the steps required were taken and the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated • Records of manufacture e.g. distribution, batch history (traceble and retained) • Distribution (wholesaling) of the products minimises any risk to their quality and takes account of Good Distribution Practice • System to recall any batch of product, from sale or supply • Complaints about marketed products are examined, the causes investigated and appropriate measures taken to prevent re‐ occurrence. 13 13 What is a qualified person? (QP) • Responsible for releasing products onto the market or for clinical trials • Assure that the products have been prepared according to all relevant requirement, including GMP and meet specifications • Is actively involved in all aspects relating to quality in the organisation • Must be registered as having correct experiences and trainings • May be a pharmacist, chemist or biologist • A well paid job with huge responsibility 14 14 Quality control Quality Control (QC): part of GMP Sampling, specification, testing Documentation, release procedures Release for supply and sale by QP Objective of QC – Defined process, when followed, will yield a product complying with its specifications • Product – Contains correct ingredients complying with the qualitative and quantitative compositions – Has been correctly processed according to the defined procedures – Is of the purity required – Is enclosed in proper container which bear the correct label – Is stored, distributed and subsequently handled so that its quality is maintained throughout its designated or expected shelf life • • • • • 15 15 GMP: examples of documentation • Equipment cleaning and use record • Records of raw materials, intermediates, API labelling and packaging materials • Master production and control record: a document that describes the procedures for the preparation of a specific product • Batch production and control record: an exact copy of approved MPCR issued for each production batch to record the data for that particular batch • Standard operating procedure: a document that describes a routine procedure of general use which is not specific to one product • Laboratory control records • Product review 16 16 Quality assurance and GMP • Quality needs to be built into the product • Quality control can only detect extreme failure • GMP is important part in quality assurance (QA) • QA: ‘Total sum of the organised arrangements made with the object of ensuring that medicinal products are of the quality required by their intended use’ 17 17 References • Rules and Guidance for Pharmaceutical Manufacturers and Distributors (use the latest version) • Green Guide (Rules and Guidance for Pharmaceutical Distributors) ( use the latest version) • http://www.gmp‐compliance.org/ 18 18