1-1_Inspections Manufacturers Sterile Products by fjwuxn

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									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
                                               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?
     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
2|   Nanjing, November 2009
     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!
     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
3|   Nanjing, November 2009
     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
     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
4|   Nanjing, November 2009
                                           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”


     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
5|   Nanjing, November 2009
                  The possible contaminants

4 types of potential contaminants:

• Living / viable cells / microorganisms

• Inert / non-viable particles

• Chemicals

• Pyrogens (Most commonly endotoxin)

     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
6|   Nanjing, November 2009
           The Contaminants – Overview 2

 Microorganisms
                                                               3 groups
      Warmth, food & moisture                                        a. Bacteria (cocci, bacilli, vibrio,
      Cool, clean & dry environments                                    spiral)
                                                                      b. Yeasts & Mould
                                                                      c. Viruses
 Habitats

 Almost any environment
     a.   Water
     b.   Soil
     c.   Skin
     d.   Stomach & intestines

     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
7|   Nanjing, November 2009
          The Contaminants – Overview 3

l Non-viables
 Dust

 Fibres from clothing

 Paint flakes

 Metal filings

 Rubber

 Glass




     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
8|   Nanjing, November 2009
          The Contaminants – Overview 4




     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
9|   Nanjing, November 2009
            The Contaminants – Overview 5

l Non-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.

       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
10 |   Nanjing, November 2009
            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



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
11 |   Nanjing, November 2009
                        Production – Overview 1

      Whilst design of premises and equipment are very
important production staff have the vital role in ensuring good
                    contamination control




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
12 |   Nanjing, November 2009
                        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)

       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
13 |   Nanjing, November 2009
                        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!


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
14 |   Nanjing, November 2009
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




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
15 |    Nanjing, November 2009
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

        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
16 |    Nanjing, November 2009
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



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
17 |   Nanjing, November 2009
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)



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
18 |   Nanjing, November 2009
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



        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
 19 |   Nanjing, November 2009
       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
       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
20 |   Nanjing, November 2009
 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?................




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
21 |   Nanjing, November 2009
                                    Devonport Incident
 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




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
22 |   Nanjing, November 2009
                                                 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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
23 |   Nanjing, November 2009
                         The Devonport Incident

 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
       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
24 |   Nanjing, November 2009
       Sterilisation of Sterile 5% Dextrose

                                  P    1.7 Bar                          T         115°C   Dial




                                                                                                 Steam
                                                                                                 1.7 Bar



                             T
          115°C                         Drain
           Chart                                            115°C at 1.7 Bar for 30 minutes
       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
25 |   Nanjing, November 2009
              Sterilisation of Batch D1192/C

                                  P    1.7 Bar                          T         115°C   Dial



                                                  115°C
                                                                                                 Steam
                                                                                                 1.7 Bar

                                                    47°C
                             T
            47°C                        Drain
            Chart
       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
26 |   Nanjing, November 2009
                      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
                                           Chairman
                          C. M. CLOTHIER, ESQ., Q.C., B.C.L., M.A. Oxon.

                                         Presented to Parliament by the
                                      Secretary of State for Social Services
                                          by Command of Her Majesty
                                                    July 1972


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
27 |   Nanjing, November 2009
                                Principle conclusions
 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.



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
28 |   Nanjing, November 2009
                      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

        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
29 |    Nanjing, November 2009
                    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
                   Validation became a fundamental requirement


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
30 |   Nanjing, November 2009
  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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
31 |   Nanjing, November 2009
                                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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
32 |   Nanjing, November 2009
                Gravity Displacement Process
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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
33 |   Nanjing, November 2009
                                    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.


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
34 |   Nanjing, November 2009
Sterilization Process Development


                                                Equilibration Time




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
35 |   Nanjing, November 2009
            1 Prevacuum - Tyvek Wrapped Materialsl


                                                                                      TC1 Drain

                      125                                                             TC 5
                      124
                                                                                      TC 6
                      123
                      122                                                             TC 7
                      121                                                             TC 8
                      120
                      119                                                             TC 9
              Deg C




                      118                                                             TC 10
                      117
                      116                                                             TC 11
                      115                                                             TC 12
                      114
                      113                                                             TC 13

                      112                                                             TC 15
                      111
                      110                                                             TC 16

                                                                                      TC 17

                                                                                      TC 18


                                                                 Time




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
36 |   Nanjing, November 2009
                                   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.

       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
37 |   Nanjing, November 2009
                            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.

       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
38 |   Nanjing, November 2009
                                    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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
39 |   Nanjing, November 2009
                                        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




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
40 |   Nanjing, November 2009

								
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