1. World Health Organization
1 April, 2017
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. World Health Organization
Contents
1 April, 2017
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. Why are sterile products different?
World Health Organization
Why are sterile products different?
1 April, 2017
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. Why are sterile products different?
World Health Organization
Why are sterile products different?
1 April, 2017
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. World Health Organization
Overview 1
World Health Organization
1 April, 2017
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”
TS must be consider if the product can withstand heat
It can only reduce by a certain level so we must make sure that we keep that level low by still controlling the manufacturing area
Component sterilisation will be discussed later in the course
Must 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.

6. The possible contaminants
World Health Organization
The possible contaminants
1 April, 2017
4 types of potential contaminants:
Living / viable cells / microorganisms
Inert / non-viable particles
Chemicals
Pyrogens (Most commonly endotoxin)

7. The Contaminants – Overview 2
World Health Organization
The Contaminants – Overview 2
1 April, 2017
Microorganisms
 Warmth, food & moisture
Cool, clean & dry environments
Habitats
Almost any environment
Water
Soil
Skin
Stomach & intestines
3 groups
Bacteria (cocci, bacilli, vibrio, spiral)
Yeasts & Mould
Viruses
Can cause dangerous diseases. Some are usually benign but can be fatal if administered to an already ill patient
Active 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 PLATE
ANY MORE HABITATS???
DOES ANYONE KNOW OF ANY GOOD / BAD MICROORAGNISMS??

8. The Contaminants – Overview 3
World Health Organization
1 April, 2017
Non-viables
Dust
Fibres from clothing
Paint flakes
Metal filings
Rubber
Glass
Our 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

9. The Contaminants – Overview 4
World Health Organization
1 April, 2017
Our 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

10. The Contaminants – Overview 5
World Health Organization
1 April, 2017
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.
Facility Monitoring System - FMS

11. The Contaminants – Overview 6
World Health Organization
1 April, 2017
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 3.
Importance of following correct clean down procedures 4.
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.

12. World Health Organization
Production – Overview 1
1 April, 2017
Whilst design of premises and equipment are very important production staff have the vital role in ensuring good contamination control

13. World Health Organization
Monitoring – Overview 1
World Health Organization
1 April, 2017
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)
USE EXAMPLES OF PLATES
Settle Plates
Major 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 room
Always check expiry on plates
1m3 for grade A & 200cm3 for Grade B

14. World Health Organization
Monitoring – Overview 2
World Health Organization
1 April, 2017
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!
What is the data used for?
Release each batch
Increased levels of contamination will affect patient safety and so the batch could be rejected

15. People & Sterile Production – Overview 1
World Health Organization
People & Sterile Production – Overview 1
1 April, 2017
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. People & Sterile Production – Overview 1
World Health Organization
1 April, 2017
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
SEPRATE TRAINING COURSE FOR HOW TO GOWN
Suits can only be worn for a maximum of 4 hours

17. People & Sterile Production – Overview 3
World Health Organization
1 April, 2017
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
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
Tego 2000 is used where there is a naked flame (e.g. ampoule lines) as this is not flammable
2 pairs of gloves to increase protection.
IPA could cause chemical contamination if not allowed to dry by dripping over product

18. People & Sterile Production – Overview 4
World Health Organization
1 April, 2017
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
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)
Imagine trying to walk in water for movement
Cleanroom operations are uncomfortable!!!

19. People & Aseptic Production – Overview 9
World Health Organization
1 April, 2017
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
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
If 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)

20. Cleaning & Disinfection – Overview
World Health Organization
1 April, 2017
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
Show Green status label card

21. Preparation & Processing – Overview 1
World Health Organization
1 April, 2017
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?
WFI is maintained constantly at 80oC
All types of water are tested for contamination, endotoxin, conductivity and TOC or total organic carbon

22. World Health Organization
1 April, 2017
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

23. World Health Organization
Disclaimer
1 April, 2017
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. The Devonport Incident
World Health Organization
1 April, 2017
The Devonport Incident
6th April Lot D1192/C manufactured
May Lot D1192/C distributed
29th Feb 1972: 2 deaths at Devonport Hospital
1st Mar 1972: further deaths at Devonport
2nd Mar 1972: 1 further death at Devonport
6th Mar 1972: Investigation begins
12th Jul 1972: Clothier Report issued

25. Sterilisation of Sterile 5% Dextrose
World Health Organization
1 April, 2017
Dial
1.7 Bar
115°C T T
Drain P
Steam
1.7 Bar
115°C
Chart
115°C at 1.7 Bar for 30 minutes

26. Sterilisation of Batch D1192/C
World Health Organization
1 April, 2017
Dial
1.7 Bar
115°C T P
115°C
Steam
1.7 Bar
47°C
47°C T
Drain
Chart

27. World Health Organization
1 April, 2017
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

28. World Health Organization
1 April, 2017
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.

29. Findings of the Clothier Report
World Health Organization
Findings of the Clothier Report
1 April, 2017
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. Effects of the Clothier Report
World Health Organization
Effects of the Clothier Report
1 April, 2017
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

31. World Health Organization
1 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.

32. World Health Organization
Pre-vacuum Process
1 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.

33. World Health Organization
1 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. 33

34. World Health Organization
Equilibration Time
1 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.

35. World Health Organization
1 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. 35

36. World Health Organization
1 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). 36

37. World Health Organization
And for later……..
1 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.

38. Validation – Media Fill
World Health Organization
1 April, 2017
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.
Always be aware of manipulations that you perform during a batch and ensure they are covered in a media fill

39. World Health Organization
Recontamination
1 April, 2017
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. World Health Organization
Current issues
1 April, 2017
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