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Inspections of Manufacturers of Sterile Products Specific Areas of Concerns Ian Thrussell, MHRA, UK Manufacture of sterile medicines – Advanced workshop.

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Presentation on theme: "Inspections of Manufacturers of Sterile Products Specific Areas of Concerns Ian Thrussell, MHRA, UK Manufacture of sterile medicines – Advanced workshop."— Presentation transcript:

1 Inspections of Manufacturers of Sterile Products Specific Areas of Concerns Ian Thrussell, MHRA, UK Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009

2 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |2 | Contents Provide a general introduction to the rest of the workshop and a taster for what is to follow Why are sterile products different? To consider what is special about Sterile products GMP? Some of the history of problems with Sterile Products What are the challenges for the industry and the Inspector? What are the hot topics of interest?

3 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |3 | Why are sterile products different? Sterile product means the Complete Absence of Organisms BUT THIS IS IMPOSSIBLE TO PROVE EVEN IF YOU TESTED EVERY CONTAINER Non-sterile products when injected can kill and history tells us they do when GMP has failed!

4 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |4 | Why are sterile products different? Sterility of a batch can not be tested for in End product testing A passing Sterility Test DOES NOT PROVE A BATCH IS STERILE Sterility of a batch can only be assured from a robust programme of Contamination Control and a robust process

5 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |5 | Overview 1 Terminal sterilisation –Sterilised in final container post filling –Preferred method to manufacture sterile products as lower risk Aseptic processing –All components, product – and contact equipment – are sterilised pre filling –Product would typically – be damaged by heat –Contamination control

6 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |6 | The possible contaminants 4 types of potential contaminants: Living / viable cells / microorganisms Inert / non-viable particles Chemicals Pyrogens (Most commonly endotoxin)

7 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |7 | The Contaminants – Overview 2 Microorganisms Warmth, food & moisture Cool, clean & dry environments Habitats Almost any environment a.Water b.Soil c.Skin d.Stomach & intestines 3 groups a.Bacteria (cocci, bacilli, vibrio, spiral) b.Yeasts & Mould c.Viruses

8 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |8 | The Contaminants – Overview 3 lNon-viables Dust Fibres from clothing Paint flakes Metal filings Rubber Glass

9 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November |9 | The Contaminants – Overview 4

10 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | The Contaminants – Overview 5 lNon-viables Can be used to transport airborne microorganisms so therefore need to be tightly controlled and monitored Specific GMP monitoring requirements for 0.5μm and 5.0μm particles.

11 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | The Contaminants – Overview 6 Chemicals –Cross contamination can be due to: Improper removal or incorrect use of cleaning & disinfection agents Mix-up of raw materials Pyrogens –Generate a high fever in patients if injected –Pyrogens primary concern is endotoxin

12 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Production – Overview 1 Whilst design of premises and equipment are very important production staff have the vital role in ensuring good contamination control

13 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Monitoring – Overview 1 People present the most risk to a sterile product: >80% of airborne contamination comes from personnel Environmental Microbial Monitoring –Settle 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)

14 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Monitoring – Overview 2 NO 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!

15 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | People & Sterile Production – Overview 1 Health Problems Prohibited from Aseptic Areas –Large open wounds or burns –Cold sore –Severe Dandruff –Dermatitis, eczema –Sun burn (peeling skin) –Acne –Fungal/bacterial infections –Cough –Runny nose or sneezing –Conjunctivitis

16 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | People & Sterile Production – Overview 1 Comportment - Particular ways of working in aseptic areas Dress Code Correct garment size –Do not mix garment type (disposable & non-disposable) –Undamaged garments –No jewellery (including wedding rings) –No make up –No nail varnish (including false nails) –No watches

17 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | People & Sterile Production – Overview 3 2.Gloves –Regularly spray hands with 70% IPA –Spray before AND after touching anything –Allow hands to dry before continuing (approx 10 seconds) –Do NOT disinfectant gloves before taking a finger dab –Damaged gloves must be replaced immediately outside the aseptic area 3.Eye Protection –Wear goggles appropriately at all times in the aseptic area, not on top of your head or at an angle –Demisting of goggles should occur with IPA wipes in the changing room only –You are allowed to wear your reading/distance glasses under the goggles

18 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | People & Sterile Production – Overview 4 4.Posture –Do not lean against surfaces –Do not put pressure on the gown –Keep body away from product –Stand up straight to minimise disruption to airflow –Keep arms at waist level or above 5.Movement –Deliberate, slow and smooth –Do not rush –Non-essential movements should be avoided –Operators should stand or sit when not involved with the process(es)

19 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | People & Aseptic Production – Overview 9 6.Speech –No unnecessary talking –Do not shout unless absolutely required –Do not communicate through holes, ports or airlocks –Turn away from the product if sneezing 7.Activities –Never touch the floor. If an item falls and does not present a hazard leave until end of day clean –Critical area items that have left the zone should be re-sterilised or sanitised where appropriate before rebuilding the line –Use sterilised tools wherever possible

20 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Cleaning & Disinfection – Overview All product contact parts should be cleaned, dried and then disinfected or sterilised CIP & SIP (Clean In Place & Steam In Place) Status labelling Ensure potential mix-up of cleaned and uncleaned items are prevented It is essential that staff ALWAYS follow the procedure in the SOP

21 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Preparation & Processing – Overview 1 Double ended autoclave to get sterilised items into an aseptic area Validated time intervals –Washing –Drying –Sterilisation –Solution preparation –Terminal sterilisation Is 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?

22 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Evans Medical in Speke, UK Tues 6th April 1971, Transfusion Unit manufacture 5% Sterile Dextrose Solution Lot D1192 Intravenous Injection therefore required to be sterile Terminally Sterilised at 115 °C for 30 minutes Devonport Incident

23 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Disclaimer At 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.

24 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | 6th April 1971 Lot D1192/C manufactured May 1971 Lot D1192/C distributed 29th Feb 1972: 2 deaths at Devonport Hospital 1st Mar 1972: 2 further deaths at Devonport 2nd Mar 1972:1 further death at Devonport 6th Mar 1972:Investigation begins 12th Jul 1972:Clothier Report issued The Devonport Incident

25 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Sterilisation of Sterile 5% Dextrose Steam 1.7 Bar T Drain P 1.7 Bar 115°C at 1.7 Bar for 30 minutes T Dial Chart 115°C

26 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Sterilisation of Batch D1192/C Steam 1.7 Bar T Drain P 1.7 Bar 47°C 115°C Chart 47°C T Dial 115°C

27 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Report of the Committee appointed to inquire into the circumstances, including the production, which led to the use of contaminated infusion fluids in the Devonport Section of Plymouth General Hospital Presented to Parliament by the Secretary of State for Social Services by Command of Her Majesty July 1972 Chairman C. M. CLOTHIER, ESQ., Q.C., B.C.L., M.A. Oxon.

28 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | 1. 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. Principle conclusions

29 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Findings of the Clothier Report Poor staff training Inadequate procedures/ Lack of procedures No effective batch record review Inadequate equipment / facility Inadequate equipment cleaning Lack of effective instrument calibration Lack of maintenance activity/Lack of maintenance logs

30 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Effects of the Clothier Report Ensure that critical instruments were functional and calibrated regularly Prove that SOPs 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 Validation became a fundamental requirement

31 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | When sterilising equipment and components - there is just one objective TO KNOW UNEQUIVOCALLY THAT ALL PARTS OF THE LOAD ARE SUBJECT TO DRY SATURATED STEAM AT THE REQUIRED TEMPERATURE FOR THE REQUIRED TIME.

32 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Pre-vacuum Process A 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.

33 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | A 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 Process

34 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Equilibration Time The 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.

35 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Sterilization Process Development Equilibration Time

36 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | 1 Prevacuum - Tyvek Wrapped Materials l

37 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | And for later…….. Short 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.

38 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Validation – Media Fill A 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 product The standard is zero contaminated vials.All routine or planned events must be simulated during a media to evaluate potential impact Media fills performed on a routine basis depending on line and/or process A successful media fill should NOT be used as a reason for not applying good contamination practices 100% of the time.

39 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Recontamination Recontamination of a sterilised item either in subsequent processing or distribution is a major and often underestimated problem …… It has killed patients –Leaking vials e.g. during autoclaving and then cooled with non- sterile water or washed to remove cytotoxic residues –Vials not stoppered effectively and capped in low grade environments with ineffective faulty stopper placement detection and rejection.

40 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November | Current issues Increasing use of isolator & Restricted Access Barrier technologies –Over confidence in the technologies –Conservativism restricts uptake Vial Capping operations –Changes to EU and PIC/s Annex 1


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