Specific Areas of Concerns: Inspections of Manufacturers of Sterile Products

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?
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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!
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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
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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
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The possible contaminants

4 types of potential contaminants:
Living / viable cells / microorganisms
Inert / non-viable particles

Chemicals Pyrogens (Most commonly endotoxin)
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The Contaminants Overview 2

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

a. b. c. d. Water Soil Skin Stomach & intestines
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l Non-viables
Dust Fibres from clothing
Paint flakes
Metal filings Rubber Glass
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l Non-viables
Can be used to transport airborne microorganisms so therefore need to be tightly controlled and monitored
Specific GMP monitoring requirements for 0.5m and 5.0m particles.

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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
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Production Overview 1
Whilst design of premises and equipment are very important production staff have the vital role in ensuring good contamination control
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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)
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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!
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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
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Comportment - Particular ways of working in
aseptic areas Dress Code

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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

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
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4. 5. 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)
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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
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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
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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?................
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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
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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.
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The Devonport Incident

6th April 1971 Lot D1192/C manufactured
May 1971 29th Feb 1972: 1st Mar 1972: Lot D1192/C distributed 2 deaths at Devonport Hospital 2 further deaths at Devonport
2nd Mar 1972: 1 further death at Devonport 6th Mar 1972: Investigation begins 12th Jul 1972: Clothier Report issued
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Sterilisation of Sterile 5% Dextrose

P
1.7 Bar
115C
Dial
Steam 1.7 Bar
115C Chart
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Drain 115C at 1.7 Bar for 30 minutes
Sterilisation of Batch D1192/C

P
1.7 Bar
115C
Dial
115C
Steam 1.7 Bar 47C 47C Chart
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T
Drain
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
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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.
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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
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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
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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.
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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.
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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.
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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.
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Sterilization Process Development
Equilibration Time
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1 Prevacuum - Tyvek Wrapped Materialsl
TC1 Drain
125 124 123 122 121 120 119 118 117 116 115 114 113 112 111 110
TC 5 TC 6 TC 7 TC 8
TC 9
TC 10
Deg C
TC 11
TC 12 TC 13 TC 15 TC 16
TC 17
TC 18
Time
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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.
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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.
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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 nonsterile 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.
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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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Specific Areas of Concerns: Inspections of Manufacturers of Sterile Products

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Specific Areas of Concerns: Inspections of Manufacturers of Sterile Products

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Inspections of Manufacturers of Sterile Products

Specific Areas of Concerns

To consider what is special about Sterile products GMP?

Why are sterile products different?

Why are sterile products different?

The possible contaminants

Inert / non-viable particles

The Contaminants Overview 2

Habitats Almost any environment

The Contaminants Overview 3

The Contaminants Overview 4

The Contaminants Overview 5

Specific GMP monitoring requirements for 0.5m and 5.0m particles.

The Contaminants Overview 6

People & Sterile Production Overview 1

People & Sterile Production Overview 1

People & Sterile Production Overview 3

People & Sterile Production Overview 4

People & Aseptic Production Overview 9

Cleaning & Disinfection Overview

Preparation & Processing Overview 1

Transfusion Unit manufacture 5% Sterile Dextrose Solution

The Devonport Incident

Sterilisation of Sterile 5% Dextrose

Steam 1.7 Bar

Drain 115C at 1.7 Bar for 30 minutes

Sterilisation of Batch D1192/C

Findings of the Clothier Report

Effects of the Clothier Report

Prove that SOPs were accurate

When sterilising equipment and components there is just one objective

Gravity Displacement Process

Sterilization Process Development

1 Prevacuum - Tyvek Wrapped Materialsl

And for later..

Validation Media Fill

Vial Capping operations

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