most frequent gmp deficiencies observed in sterile production facilities ian thrussell, mhra, uk...

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

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

Session OutlineSession Outline

Inspection Findings - Aseptic Processing

Inspection Findings – Terminally sterilised Products

Questions


Raw Materials

Personnel

ProceduresValidated processes

Equipment

Premises

EnvironmentPacking Materials

Poorly designed processes 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


Raw Materials

Personnel


Equipment

Premises



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


What happened when these filters are vented!

What happened when these filters are vented!


Raw Materials

Personnel


Equipment

Premises



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


Raw Materials

Personnel


Equipment

Premises


Poor clean room and aseptic practicesPoor 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


Raw Materials

Personnel


Equipment

Premises


Poor clean room and aseptic practicesPoor 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


“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.”


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.


Raw Materials

Personnel


Equipment

Premises


Poorly designed or maintained equipmentPoorly 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


Construction activitiesConstruction activities

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


Examples of misplaced stoppers from real case lines

Examples of misplaced stoppers from real case lines


Vision systems for raised stopper detectionVision systems for raised stopper detection


Raw Materials

Personnel


Equipment

Premises


Poorly designed or maintained equipmentBlow fill seal machine

Poorly designed or maintained equipmentBlow 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.


Raw Materials

Personnel


Equipment

Premises


Poorly designed or executed PM monitoringPoorly designed or executed PM monitoring

Samples points inappropriately positioned

Alarm systems do not feedback to filling operators.

Alarms and procedures unclear and confused


Raw Materials

Personnel


Equipment

Premises



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


Raw Materials

Personnel


Equipment

Premises



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.


Raw Materials

Personnel


Equipment

Premises


Poorly designed or executed micro monitoringPoorly 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


Raw Materials

Personnel


Equipment

Premises


Media fills!Media fills!

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


Raw Materials

Personnel


Equipment

Premises


Media fills!Media fills!

Interventions allowed in procedures but not covered by simulations

Excessive interventions not prohibited


Raw Materials

Personnel


Equipment

Premises


Steam Sterilisation!Steam Sterilisation!

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


Raw Materials

Personnel


Equipment

Premises


Steam Sterilisation!Steam Sterilisation!

Long heat times during validation not investigated as no limits for heat up times = potential sterility issues


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.


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


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.


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.


Raw Materials

Personnel


Equipment

Premises


Steam Sterilisation & SIP systems!Steam Sterilisation & SIP systems!

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


Raw Materials

Personnel


Equipment

Premises


Oven designs!Oven designs!

No overpressure in hot air ovens

No HEPA filters on the exhaust side of the oven


Raw Materials

Personnel


Equipment

Premises


Packaging and post sterilisation damage!Packaging and post sterilisation damage!

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


Raw Materials

Personnel


Equipment

Premises


Sterile API – unacceptable process design!Sterile API – unacceptable process design!

Huge Grade A/B rooms-poor differential pressures

Masses of pipe work

Redundant equipment

Cracks, crevices, ledges…….

Sterility starts here!


Bulk lyophilisationBulk lyophilisation


Risk of contamination 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.


Orchid Video

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Qilu Video

E:\MHRA BAck ups\MHRA Laptop back ups\16_11_09\MHRA Documents\Qilu Autoloading\Video for unloading-20081210160000[4].dav