inspections of manufacturers of sterile products specific areas of concerns ian thrussell, mhra, uk...

Inspections of Manufacturers of Sterile ProductsSpecific Areas of Concerns

Ian Thrussell, MHRA, UK

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,

Nanjing, November 2009

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectorsNanjing, November 20092 |

ContentsContents

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?


Why are sterile products different?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!


Why are sterile products different?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


Overview 1Overview 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”


The possible contaminantsThe possible contaminants

4 types of potential contaminants:

• Living / viable cells / microorganisms

• Inert / non-viable particles

• Chemicals

• Pyrogens (Most commonly endotoxin)


The Contaminants – Overview 2The Contaminants – Overview 2

Microorganisms

Warmth, food & moisture Cool, clean & dry environments

Habitats

Almost any environmenta. Water

b. Soil

c. Skin

d. Stomach & intestines

3 groupsa. Bacteria (cocci, bacilli, vibrio,

spiral)

b. Yeasts & Mould

c. Viruses



l Non-viables

Dust

Fibres from clothing

Paint flakes

Metal filings

Rubber

Glass



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.



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


Production – Overview 1Production – Overview 1

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

contamination control


Monitoring – Overview 1Monitoring – 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)


Monitoring – Overview 2Monitoring – 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!


People & Sterile Production – Overview 1People & 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



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



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



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)


People & Aseptic Production – Overview 9People & 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


Cleaning & Disinfection – Overview 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


Preparation & Processing – Overview 1Preparation & 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?................


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

Devonport Incident


DisclaimerDisclaimer

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.


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

The Devonport IncidentThe Devonport Incident


Sterilisation of Sterile 5% Dextrose Sterilisation of Sterile 5% Dextrose

Steam1.7 Bar

TDrain

P 1.7 Bar

115°C at 1.7 Bar for 30 minutes

T Dial

Chart

115°C

115°C


Sterilisation of Batch D1192/CSterilisation of Batch D1192/C

Steam1.7 Bar

TDrain

P 1.7 Bar

47°C

115°C

Chart

47°C

T Dial115°C


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

Presented to Parliament by the

Secretary of State for Social Services

by Command of Her Majesty

July 1972

Chairman

C. M. CLOTHIER, ESQ., Q.C., B.C.L., M.A. Oxon.


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.

Principle conclusions


Findings of the Clothier ReportFindings 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


Effects of the Clothier ReportEffects 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


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.


Pre-vacuum ProcessPre-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.


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 Process


Equilibration TimeEquilibration 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.


Sterilization Process Development

Equilibration Time


1 Prevacuum - Tyvek Wrapped Materialsl

110111112113114115116117118119120121122123124125

De

g C

Time

TC1 Drain

TC 5

TC 6

TC 7

TC 8

TC 9

TC 10

TC 11

TC 12

TC 13

TC 15

TC 16

TC 17

TC 18


And for later……..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.


Validation – Media FillValidation – 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.


RecontaminationRecontamination

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.


Current issuesCurrent 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

inspections of manufacturers of sterile products specific areas of concerns ian thrussell, mhra, uk...

Documents

sterile products gmp

sfda gmp inspectors

sterile sterility

sterile products different

contamination slide

container nonsterile

endotoxin slide

monitoring overview