1. World Health Organization
20 April, 2017
Most frequent GMP deficiencies observed in sterile production facilities
Ian Thrussell, MHRA, UK
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
Nanjing, November 2009

2. World Health Organization
Session Outline
20 April, 2017
Inspection Findings - Aseptic Processing
Inspection Findings – Terminally sterilised Products
Questions

3. Poorly designed processes
World Health Organization
20 April, 2017
Poorly designed processes
Materials transferred into Aseptic area with insufficient sterility assurance
Poor transfer of partially stoppered vials to lyophiliser
Excessive holding times for sterile equipment or filtered solutions
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 3

4. Poorly designed processes
World Health Organization
20 April, 2017
Poorly designed processes
Single filtration
Filtration not performed as close as practicable to the filling point
Inadequate response to leaking containers – no limits set to prompt an investigation
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 4

5. What happened when these filters are vented!
World Health Organization
20 April, 2017

6. Poorly designed processes
World Health Organization
20 April, 2017
Poorly designed processes
Raw material suppliers not audited but acceptance of side samples e.g. sterile API side samples accepted with no justification
Prefilled syringe assembly sterilisation sites never audited
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 6

7. Poor clean room and aseptic practices
World Health Organization
20 April, 2017
Poor clean room and aseptic practices
Filling needles installed & left unprotected while remainder of line set up still taking place Not routinely recorded/documented
No monitoring during equipment set up
Allowed interventions into aseptic zone are not derived from risk based process review
Systems/Procedures not clear what to do upon intervention
Interventions not linked to batch release process
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 7

8. Poor clean room and aseptic practices
World Health Organization
20 April, 2017
Poor clean room and aseptic practices
Interventions not linked to batch release process
Excessive numbers of manipulations
Excessive numbers of people
People routinely located in the class A zone
Failure to use isolation and closed techniques
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 8

9. World Health Organization
20 April, 2017
“Any intervention or stoppage during an aseptic process can increase the risk of contamination.  The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.” 
“Even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices.”

10. World Health Organization
20 April, 2017
Aseptic processing operator touches floor when picking up settle plates, sanitizes hands, and then performs intervention immediately afterward
Operator removes sterile forceps from aseptic processing zone (Class 100), carries them through the surrounding Class 10,000 area, and places them on a trolley in the class 10,000 room. These were the only sterile forceps sterilized and available for aseptic manipulations. Later, the operator retrieves forceps and uses them again at the aseptic processing line to manipulate sterile product.

11. Poorly designed or maintained equipment
World Health Organization
20 April, 2017
Poorly designed or maintained equipment
Viewing ports on sterilising tunnels not adequately sealed
Lyophilisers not sterilisable or not sterilised sufficiently frequently
Vial capping performed under uncontrolled conditions
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 11

12. Construction activities
World Health Organization
Construction activities
20 April, 2017
Major construction in cleanroom next to personnel entry airlock (e.g., gowning).
Construction occurred over approximately one-month period and coincided with continued production
Media Fill Failure 2 weeks later
Construction not considered to be the cause. Root causes identified by investigation considered corrected.
New Media Fill performed
Second Media Fill Failure Occurred
Contamination attributed to construction

13. Examples of misplaced stoppers from real case lines
World Health Organization
20 April, 2017

14. Vision systems for raised stopper detection
World Health Organization
20 April, 2017

15. Poorly designed or maintained equipment Blow fill seal machine
World Health Organization
20 April, 2017
Poorly designed or maintained equipment Blow fill seal machine
Cooling water
Chills mold plates used to form the container-closure into which the sterile drug is filled.
Demineralized potable water. Held in tank, chilled (when sampled, yields very high microbial counts)
Sterility failure and media fill failure
Pseudomonas, sp. and Acinetobacter, sp. found in media fill
Stenotrophomonas maltophilia identified as Sterility Failure isolate
Several lots rejected
Both the sterility failure and media fill failure attributed to cooling water contamination
Root cause of non-sterility was leak/s/ in aseptic filling machine’s mold plates. Cooling water directly contaminated product.
CAPA Issue: Exact date of problem occurrence unknown.
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 15

16. Poorly designed or executed PM monitoring
World Health Organization
20 April, 2017
Poorly designed or executed PM monitoring
Samples points inappropriately positioned
Alarm systems do not feedback to filling operators.
Alarms and procedures unclear and confused
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 16

17. Poorly designed or executed PM monitoring
World Health Organization
20 April, 2017
Poorly designed or executed PM monitoring
Length of tubing to particle counter too long & even kinked!
PMS data not reviewed as part of batch release process
Overseas-use of manifold systems and no 5 micron monitoring
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 17

18. Poorly designed or executed PM monitoring
World Health Organization
20 April, 2017
Poorly designed or executed PM monitoring
Reliance on the use of contact plates and no use of swabs
Reliance on active air monitoring and inadequate use of settle plates
“Averaging into compliance” – inadequate attention to the individual high count
Acceptance of “good pattern” of very low contamination and failure to evaluate whether the programme is effective.
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 18

19. Poorly designed or executed micro monitoring
World Health Organization
20 April, 2017
Poorly designed or executed micro monitoring
Viable sample points not close to point of fill
The whole process is not monitored
Viable sampling does not cover all key areas under Grade A e.g. vial turntable, stopper hopper
Monitoring is not risked based and “too routine”
High pre-filtration bioburden not adequately investigated and bioburden limits >> 10cfu/100ml and no justification
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 19

20. World Health Organization
Media fills!
World Health Organization
20 April, 2017
The belief that some contamination is OK!
Acceptance criteria does not meet Annex 1 & allows 1 failure to be accepted with no effective investigation
Poor practices accepted as covered & justified by “passing” Media Fills!
Good history does not mean failures/growth need not be investigated
Implications to batches on the market or in stock subsequent to failures are not always considered fully
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 20

21. World Health Organization
Media fills!
World Health Organization
20 April, 2017
Interventions allowed in procedures but not covered by simulations
Excessive interventions not prohibited
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 21

22. World Health Organization
Steam Sterilisation!
World Health Organization
20 April, 2017
Leak test/Bowie Dick test not performed sufficiently frequently on equipment sterilisers and failures fully investigated.
Poor control of checking acceptability of autoclave cycles
Engineering work not recorded
No trial runs after major breakdowns to show autoclave still meets validated parameters
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 22

23. World Health Organization
Steam Sterilisation!
World Health Organization
20 April, 2017
Long heat times during validation not investigated as no limits for heat up times = potential sterility issues
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 23

24. World Health Organization
20 April, 2017
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.

25. World Health Organization
20 April, 2017
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.
Gravity displacement processes should only be used for surface sterilization applications, where air removal is not a consideration. 25

26. World Health Organization
Equilibration Time
20 April, 2017
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.

27. World Health Organization
20 April, 2017
Sterilization Process Development
Equilibration Time
Component 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. 27

28. World Health Organization
20 April, 2017
1 Prevacuum - Tyvek Wrapped Materials l
This 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). 28

29. World Health Organization
20 April, 2017
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.

30. World Health Organization
Pre-vacuum Process
20 April, 2017
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.

31. Steam Sterilisation & SIP systems!
World Health Organization
20 April, 2017
Air removal from equipment not adequately considered
Steam quality not assessed adequately
Non-condensable gases
Wet steam (Dryness fraction)
Superheat Clean steam quality tests are not performed at distal points of the distribution system. Steam quality test not performed following modifications
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 31

32. World Health Organization
Oven designs!
World Health Organization
20 April, 2017
No overpressure in hot air ovens
No HEPA filters on the exhaust side of the oven
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 32

33. Packaging and post sterilisation damage!
World Health Organization
20 April, 2017
Failure to meet GMP:
Rough handling of bulk finished vials resulted in difficult to detect and hairline cracks in bottle. “Washdown” of vials with potable water was apparent contamination source.
Patients Infected: multiple blood cultures yield Enterobacter cloacae.
At least one lot “directly implicated” in septicemia
Over 25 Septicemia Reports naming the lot or “unknown”
Class 1 Recall: Eleven Lots (“strong likelihood that product will cause serious adverse health consequences or death”)
Cultures of unopened vials grew Enterobacter cloacae
Several water samples collected at firm from the water hose/sink found Enterobacter cloacae
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 33

34. Sterile API – unacceptable process design!
World Health Organization
20 April, 2017
Huge Grade A/B rooms- poor differential pressures
Masses of pipe work
Redundant equipment
Cracks, crevices, ledges…….
Sterility starts here!
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises 34

35. World Health Organization
Bulk lyophilisation
World Health Organization
20 April, 2017

36. World Health Organization
20 April, 2017
Risk of contamination
Extent of human manipulation of sterilised filtrate and lyophilisate during loading and unloading of the large number of trays typically used in these processes.
Extent of exposure of sterilised filtrate to controlled environmental conditions during filling, lyophilisation and unloading of lyophiliser compared to lyophilisation in the final container.
Extent of aseptic operations subsequent to the sterilisation step at both drug substance and finished product manufacturer in the ‘open tray’ process compared to lyophilisation in the final container.

37. World Health Organization
20 April, 2017
Orchid Video
E:\Training Materials\Bulk Lyophilisation Videos\Bulk Lyophilisation\Orchid videos\LYO Unloading - 3 (Frames ).mpg
Qilu Video
E:\MHRA BAck ups\MHRA Laptop back ups\16_11_09\MHRA Documents\Qilu Autoloading\Video for unloading [4].dav