Get documents about "1-1_Inspections Manufacturers Sterile Products
Document Sample
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
