most frequent gmp deficiencies observed in sterile...

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 inspectors

Nanjing, November 2009 2 |

Session Outline Session Outline

� Inspection Findings - Aseptic Processing

� Inspection Findings – Terminally sterilised Products

� Questions



Raw Materials

Personnel

Procedures Validated processes

Equipment

Premises

Environment

Packing Materials

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

Environment

Packing Materials



� 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

Environment

Packing Materials



� 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

Environment

Packing Materials

Poor 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

Environment

Packing Materials



� 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

Environment

Packing Materials

Poorly 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 activities Construction 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 detection Vision systems for raised stopper detection



Raw Materials

Personnel


Equipment

Premises

Environment

Packing Materials


Blow fill seal machine


Blow 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

Environment

Packing Materials

Poorly 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

Environment

Packing Materials



� 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

Environment

Packing Materials



� 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

Environment

Packing Materials

Poorly designed or executed micro monitoring

Poorly 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

Environment

Packing Materials

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

Environment

Packing Materials

Media fills! Media fills!

� Interventions allowed in

procedures but not

covered by simulations

� Excessive interventions

not prohibited



Raw Materials

Personnel


Equipment

Premises

Environment

Packing Materials

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

Environment

Packing Materials

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 Time 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.



Sterilization Process Development

Equilibration Time



1 Prevacuum - Tyvek Wrapped Materials l

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

Deg 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 Process 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.



Raw Materials

Personnel


Equipment

Premises

Environment

Packing Materials

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

Environment

Packing Materials

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

Environment

Packing Materials

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

Environment

Packing Materials

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,

ledgesKK.

� Sterility starts here!



Bulk lyophilisation Bulk 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

� E:\Training Materials\Bulk Lyophilisation Videos\Bulk

Lyophilisation\Orchid videos\LYO Unloading - 3 (Frames 21-

26).mpg

� Qilu Video

� E:\MHRA BAck ups\MHRA Laptop back ups\16_11_09\MHRA

Documents\Qilu Autoloading\Video for unloading-

20081210160000[4].dav