Presentation on theme: "World Health Organization"— Presentation transcript:
1World Health Organization 1 April, 2017Inspections of Manufacturers of Sterile ProductsSpecific Areas of ConcernsIan Thrussell, MHRA, UKManufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,Nanjing, November 2009
2World Health Organization Contents1 April, 2017Provide a general introduction to the rest of the workshop and a taster for what is to followWhy are sterile products different?To consider what is special about Sterile products GMP?Some of the history of problems with Sterile ProductsWhat are the challenges for the industry and the Inspector?What are the hot topics of interest?
3Why are sterile products different? World Health OrganizationWhy are sterile products different?1 April, 2017Sterile product means the “Complete Absence of Organisms”BUT THIS IS IMPOSSIBLE TO PROVE EVEN IF YOU TESTED EVERY CONTAINERNon-sterile products when injected can kill and history tells us they do when GMP has failed!
4Why are sterile products different? World Health OrganizationWhy are sterile products different?1 April, 2017Sterility of a batch can not be tested for in End product testingA passing “Sterility Test DOES NOT PROVE A BATCH IS STERILESterility of a batch can only be assured from a robust programme of “Contamination Control” and a robust process
5World Health Organization Overview 1World Health Organization1 April, 2017Terminal sterilisationSterilised in final container post fillingPreferred method to manufacture sterile products as lower riskAseptic processingAll components, productand contact equipmentare sterilised pre fillingProduct would typicallybe damaged by heat“Contamination control”TS must be consider if the product can withstand heatIt can only reduce by a certain level so we must make sure that we keep that level low by still controlling the manufacturing areaComponent sterilisation will be discussed later in the courseMust follow validated and written procedures to maintain contamination control. Deviations from these procedures is likely to have severe implications to the patient and could result in death.
6The possible contaminants World Health OrganizationThe possible contaminants1 April, 20174 types of potential contaminants:Living / viable cells / microorganismsInert / non-viable particlesChemicalsPyrogens (Most commonly endotoxin)
7The Contaminants – Overview 2 World Health OrganizationThe Contaminants – Overview 21 April, 2017Microorganisms Warmth, food & moistureCool, clean & dry environmentsHabitatsAlmost any environmentWaterSoilSkinStomach & intestines3 groupsBacteria (cocci, bacilli, vibrio, spiral)Yeasts & MouldVirusesCan cause dangerous diseases. Some are usually benign but can be fatal if administered to an already ill patientActive measures are taken to control bacteria, fungi & mould in pharmaceutical areas.Viruses require a living host to survive so are controlled by default. We also do not allow people into clean rooms with viral diseases.Not necessary to know the difference between the different groups of microorganisms but important to know they are there.SHOW PICTURE OF SETTLE PLATEANY MORE HABITATS???DOES ANYONE KNOW OF ANY GOOD / BAD MICROORAGNISMS??
8The Contaminants – Overview 3 World Health Organization1 April, 2017Non-viablesDustFibres from clothingPaint flakesMetal filingsRubberGlassOur skin sheds millions of cells every day which go to make up the dust in the air. This is the major cause of particulate contamination in the clean rooms.IN YOUR ROLES, CAN YOU THINK OF OTHER MAJOR POSSIBLE CAUSES OF PARTICLE GENERATION?Cephs powder!Paper
9The Contaminants – Overview 4 World Health Organization1 April, 2017Our skin sheds millions of cells every day which go to make up the dust in the air. This is the major cause of particulate contamination in the clean rooms.IN YOUR ROLES, CAN YOU THINK OF OTHER MAJOR POSSIBLE CAUSES OF PARTICLE GENERATION?Cephs powder!Paper
10The Contaminants – Overview 5 World Health Organization1 April, 2017Non-viablesCan be used to transport airborne microorganisms so therefore need to be tightly controlled and monitoredSpecific GMP monitoring requirements for 0.5μm and 5.0μm particles.Facility Monitoring System - FMS
11The Contaminants – Overview 6 World Health Organization1 April, 2017ChemicalsCross contamination can be due to:Improper removal or incorrect use of cleaning & disinfection agentsMix-up of raw materialsPyrogensGenerate a high fever in patients if injectedPyrogens primary concern is endotoxin3.Importance of following correct clean down procedures4.The word pyrogen, which can be traced to the Greek pyro, meaning fire, is now used as an apt description for substance that produce elevated body temperature.Pyrogens are usually bacterial products and remains or decaying products of the bacterial cell walls. A lot smaller than a bacteria.
12World Health Organization Production – Overview 11 April, 2017Whilst design of premises and equipment are very important production staff have the vital role in ensuring good contamination control
13World Health Organization Monitoring – Overview 1World Health Organization1 April, 2017People present the most risk to a sterile product: >80% of airborne contamination comes from personnelEnvironmental Microbial MonitoringSettle plates(exposed continuously and changed every 4 hours)Contact plates(monitors the surface of certain areas)Air sample(quantity of air sampled on to a plate to detect contamination)USE EXAMPLES OF PLATESSettle PlatesMajor likely source of contamination is when the plates are put down and picked up so ensure this activity is performed as aseptically as possible.We look for the type of microorganism that is recovered – this provides us with information as to its possible source or entry route into the clean roomAlways check expiry on plates1m3 for grade A & 200cm3 for Grade B
14World Health Organization Monitoring – Overview 2World Health Organization1 April, 2017NO amount of monitoring – improves the manufacturing environment and…….In practice performing monitoring especially in aseptic processing introduces a risk of contamination!In a well designed aseptic process as many as 80% of the interventions into the critical zone are to perform monitoring!Good micobiological monitoring data does not mean there are no problems!What is the data used for?Release each batchIncreased levels of contamination will affect patient safety and so the batch could be rejected
15People & Sterile Production – Overview 1 World Health OrganizationPeople & Sterile Production – Overview 11 April, 2017Health Problems Prohibited from Aseptic AreasLarge open wounds or burnsCold soreSevere DandruffDermatitis, eczemaSun burn (peeling skin)AcneFungal/bacterial infectionsCoughRunny nose or sneezingConjunctivitis
16People & Sterile Production – Overview 1 World Health Organization1 April, 2017Comportment - “Particular ways of working in aseptic areas”Dress CodeCorrect garment sizeDo not mix garment type (disposable & non-disposable)Undamaged garmentsNo jewellery (including wedding rings)No make upNo nail varnish (including false nails)No watchesSEPRATE TRAINING COURSE FOR HOW TO GOWNSuits can only be worn for a maximum of 4 hours
17People & Sterile Production – Overview 3 World Health Organization1 April, 2017GlovesRegularly spray hands with 70% IPASpray before AND after touching anythingAllow hands to dry before continuing (approx 10 seconds)Do NOT disinfectant gloves before taking a finger dabDamaged gloves must be replaced immediately outside the aseptic areaEye ProtectionWear goggles appropriately at all times in the aseptic area, not on top of your head or at an angleDemisting of goggles should occur with IPA wipes in the changing room onlyYou are allowed to wear your reading/distance glasses under the gogglesTego 2000 is used where there is a naked flame (e.g. ampoule lines) as this is not flammable2 pairs of gloves to increase protection.IPA could cause chemical contamination if not allowed to dry by dripping over product
18People & Sterile Production – Overview 4 World Health Organization1 April, 2017PostureDo not lean against surfacesDo not put pressure on the gownKeep body away from productStand up straight to minimise disruption to airflowKeep arms at waist level or aboveMovementDeliberate, slow and smoothDo not rushNon-essential movements should be avoidedOperators should stand or sit when not involved with the process(es)Imagine trying to walk in water for movementCleanroom operations are uncomfortable!!!
19People & Aseptic Production – Overview 9 World Health Organization1 April, 2017SpeechNo unnecessary talkingDo not shout unless absolutely requiredDo not communicate through holes, ports or airlocksTurn away from the product if sneezingActivitiesNever touch the floor. If an item falls and does not present a hazard leave until end of day cleanCritical area items that have left the zone should be re-sterilised or sanitised where appropriate before rebuilding the lineUse sterilised tools wherever possibleIf an urgent item falls then spray it and the surrounding area. Pick up with forceps spraying all of hands. Change gloves immediately after.Interventions (separately trained)Green (glove port)Orange (non-exposed product)Red (exposed product)
20Cleaning & Disinfection – Overview World Health Organization1 April, 2017All product contact parts should be cleaned, dried and then disinfected or sterilisedCIP & SIP (Clean In Place & Steam In Place)Status labellingEnsure potential mix-up of cleaned and uncleaned items are preventedIt is essential that staff ALWAYS follow the procedure in the SOPShow Green status label card
21Preparation & Processing – Overview 1 World Health Organization1 April, 2017Double ended autoclave to get sterilised items into an aseptic areaValidated time intervalsWashingDryingSterilisationSolution preparationTerminal sterilisationIs the sterilisation media (the steam) of the right quality and does it reach all the parts of equipment that it needs to? And if not?WFI is maintained constantly at 80oCAll types of water are tested for contamination, endotoxin, conductivity and TOC or total organic carbon
22World Health Organization 1 April, 2017Devonport IncidentEvans Medical in Speke, UKTues 6th April 1971,Transfusion Unit manufacture 5% Sterile Dextrose SolutionLot D1192Intravenous Injection therefore required to be sterileTerminally Sterilised at 115 °C for 30 minutes
23World Health Organization Disclaimer1 April, 2017At that time Evans Medical was a subsidiary of Glaxo and was one of the largest manufacturer of generic pharmaceuticals in the UK.Other companies have traded under the name of Evans Medical, however subsequent companies are in no way related in ownership, management, or operations to the Evans Medical that existed then.
24The Devonport Incident World Health Organization1 April, 2017The Devonport Incident6th April Lot D1192/C manufacturedMay Lot D1192/C distributed29th Feb 1972: 2 deaths at Devonport Hospital1st Mar 1972: further deaths at Devonport2nd Mar 1972: 1 further death at Devonport6th Mar 1972: Investigation begins12th Jul 1972: Clothier Report issued
25Sterilisation of Sterile 5% Dextrose World Health Organization1 April, 2017Dial1.7 Bar115°CTTDrainPSteam1.7 Bar115°CChart115°C at 1.7 Bar for 30 minutes
26Sterilisation of Batch D1192/C World Health Organization1 April, 2017Dial1.7 Bar115°CTP115°CSteam1.7 Bar47°C47°CTDrainChart
27World Health Organization 1 April, 2017Report of the Committee appointed to inquire into thecircumstances, including the production, which ledto the use of contaminated infusion fluids in theDevonport Section of Plymouth General HospitalChairmanC. M. CLOTHIER, ESQ., Q.C., B.C.L., M.A. Oxon.Presented to Parliament by theSecretary of State for Social Servicesby Command of Her MajestyJuly 1972
28World Health Organization 1 April, 2017Principle conclusions1. The Committee concludes that the fundamental cause of this disaster is to be found in human failings at Evans Medical, ranging from simple carelessness to poor management of men and plant.2. The Committee heard of no imminent technological advance in the field of production of intravenous fluids which will eliminate the need for skillful men devoted to their work.3. The Committee considers that too many people believe that sterilization of fluids is easily achieved with simple plant operated by men of little skill under a minimum of supervision, a view of the task which is wrong in every respect.4. The Committee considers that the lessons of the past are apt to be forgotten and that public safety in this as in many other technological fields depends ultimately on untiring vigilance both in industry and by government. Forthcoming regulation of the industry by license and inspection will not of itself guarantee freedom from similar disasters.
29Findings of the Clothier Report World Health OrganizationFindings of the Clothier Report1 April, 2017Poor staff trainingInadequate procedures/ Lack of proceduresNo effective batch record reviewInadequate equipment / facilityInadequate equipment cleaningLack of effective instrument calibrationLack of maintenance activity/Lack of maintenance logs
30Effects of the Clothier Report World Health OrganizationEffects of the Clothier Report1 April, 2017Ensure that critical instruments were functional and calibrated regularlyProve that SOP’s were accurateProve that operators had been trainedTest and prove that the process would work time and time againDocument that this had been doneValidation became a fundamental requirement
31World Health Organization 1 April, 2017When sterilising equipment and components - there is just one objectiveTO KNOW UNEQUIVOCALLY THAT ALL PARTS OF THE LOAD ARE SUBJECT TO DRY SATURATED STEAM AT THE REQUIRED TEMPERATURE FOR THE REQUIRED TIME.
32World Health Organization Pre-vacuum Process1 April, 2017A sterilization process in which air is removed from the chamber using a vacuum pump or other mechanical system before the exposure phase begins. This method is particularly suited to load items that can trap air such as tubing, filters and filling machine assemblies.
33World Health Organization 1 April, 2017Gravity Displacement ProcessA sterilization process based on the principle that cold air within the chamber is heavier than the steam entering and will sink to the bottom of the chamber. As steam enters the chamber, air is pushed out the bottom drain and exits, with the condensate, through a steam trap.Gravity displacement processes should only be used for surface sterilization applications, where air removal is not a consideration.33
34World Health Organization Equilibration Time1 April, 2017The equilibration time is the period that elapses between attainment of the minimum specified sterilizing temperature in the chamber (chamber reference temperature - typically in the drain) and attainment of the minimum specified sterilization temperature in the load, as measured by the slowest-to-heat penetration probe. This period is an indication of the ability to properly condition the load through air removal and load heating.
35World Health Organization 1 April, 2017Sterilization Process DevelopmentEquilibration TimeComponent Mapping studies are commonly referred to as “cold spot mapping” because it is done to determine the location within the item or package that is the most difficult to heat.Component Mapping: When conducting component temperature mapping, it is important to distinguish between the type of challenge (air removal vs. significant mass) the item represents and to position the temperature probes accordingly. For items that pose air removal challenges, the probes should be placed within the wrapped item but with the tip of the sensor placed to measure the temperature immediately adjacent to the item being sterilized. The objective of this temperature distribution measurement is to evaluate the effectiveness of air removal by determining the equilibration time.Load Patterns:Parameters: One of the more crucial aspects of the cycle development effort is the determination of the required operating parameters to meet the process objectives and to determine if they are critical or key parameters.35
36World Health Organization 1 April, 20171 Prevacuum - Tyvek Wrapped MaterialslThis cycle was performed with an induced leak and you can see how it greatly widened the temperature spread and lengthened the equilibration time (to approximately 2 minutes and 40 seconds).36
37World Health Organization And for later……..1 April, 2017Short equilibration times can be achieved with appropriate pre-vacuums to pre-condition (remove air and heat) the load.With appropriate load preconditioning, any surface temperature measurement method should yield acceptable results.With minimal load pre-conditioning, the heat penetration probes covered with autoclave tape were influenced the most.
38Validation – Media Fill World Health Organization1 April, 2017A ‘media fill’ or ‘process simulation’ is used to demonstrate the robustness of the operators, equipment, facility and systems. Microbial growth media (TSB or tryptone Soya broth) is used instead of productThe standard is zero contaminated vials.All routine or planned events must be simulated during a media to evaluate potential impactMedia fills performed on a routine basis depending on line and/or processA successful media fill should NOT be used as a reason for not applying good contamination practices 100% of the time.Always be aware of manipulations that you perform during a batch and ensure they are covered in a media fill
39World Health Organization Recontamination1 April, 2017Recontamination of a sterilised item either in subsequent processing or distribution is a major and often underestimated problem …… It has killed patientsLeaking vials e.g. during autoclaving and then cooled with non-sterile water or washed to remove cytotoxic residuesVials not stoppered effectively and capped in low grade environments with ineffective faulty stopper placement detection and rejection.
40World Health Organization Current issues1 April, 2017Increasing use of isolator & Restricted Access Barrier technologiesOver confidence in the technologiesConservativism restricts uptakeVial Capping operationsChanges to EU and PIC/s Annex 1