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

Session Outline

 Inspection Findings - Aseptic Processing  Inspection Findings – Terminally sterilised Products  Questions

2 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed processes

 Materials transferred into Aseptic area with insufficient sterility assurance

Validated processes Personnel Procedures

 Poor transfer of partially stoppered vials to lyophiliser

Raw Materials

 Excessive holding times for sterile equipment or filtered solutions

Packing Materials Premises Equipment Environment 3 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed processes

 Single filtration  Filtration not performed as close as practicable to the filling point

Validated processes Personnel Procedures

 Inadequate response to leaking containers – no limits set to prompt an investigation

Raw Materials Packing Materials Equipment Environment Premises 4 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

What happened when these filters are vented!

5 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed processes

 Raw material suppliers not audited but acceptance of side samples e.g. sterile API side samples accepted with no justification

Validated processes Personnel Procedures Raw Materials Equipment

 Prefilled syringe assembly sterilisation sites never audited

Packing Materials Environment Premises 6 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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

Validated processes Raw Materials Personnel Packing Materials

 Interventions not linked to batch release process

Procedures Equipment Environment Premises 7 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poor clean room and aseptic practices

 Interventions not linked to batch release process  Excessive numbers of manipulations  Excessive numbers of people

Validated processes Personnel Procedures Raw Materials Equipment

 People routinely located in the class A zone  Failure to use isolation and closed techniques

Packing Materials Premises Environment 8 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

 “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

personnel.

” of aseptic interventions by  “

Even successfully qualified systems can be compromised

by poor operational, maintenance, or personnel practices.

”

9 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

 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.

10 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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

Validated processes Personnel Procedures Raw Materials Packing Materials Premises Equipment Environment 11 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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 12 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Examples of misplaced stoppers from real case lines

13 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Vision systems for raised stopper detection 14 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed or maintained equipment 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) Validated processes Personnel 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 contaminated product. ’s mold plates. Cooling water directly

–

CAPA Issue: Exact date of problem occurrence unknown. Raw Materials Packing Materials Premises Procedures Equipment Environment 15 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed or executed PM monitoring

 Samples points inappropriately positioned  Alarm systems do not feedback to filling operators.

 Alarms and procedures unclear and confused

Validated processes Personnel Procedures Raw Materials Packing Materials Equipment Environment Premises 16 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed or executed PM monitoring

 Length of tubing to particle counter too long & even kinked!

Validated processes Personnel Procedures

 PMS data not reviewed as part of batch release process

Raw Materials Equipment

 Overseas-use of manifold systems and no 5 micron monitoring

Packing Materials Environment Premises 17 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Poorly designed or executed PM monitoring

 Reliance on the use of contact plates and no use of swabs  Reliance on active air monitoring and inadequate use of settle plates

Validated processes Personnel

 “Averaging into compliance” – inadequate attention to the individual high count  Acceptance of effective.

“good pattern” of very low contamination and failure to evaluate whether the programme is

Raw Materials Packing Materials Premises Procedures Equipment Environment 18 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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

Validated processes Personnel Procedures Raw Materials Packing Materials Premises Equipment Environment 19 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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 Media Fills!

“passing”  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

Validated processes Raw Materials Packing Materials Personnel Premises Procedures Equipment Environment 20 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Media fills!

 Interventions allowed in procedures but not covered by simulations

Validated processes Personnel Procedures

 Excessive interventions not prohibited

Raw Materials Equipment Packing Materials Premises Environment 21 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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

Validated processes Raw Materials Personnel Procedures Equipment

 Engineering work not recorded  No trial runs after major breakdowns to show autoclave still meets validated parameters

Packing Materials Premises Environment 22 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Steam Sterilisation!

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

Validated processes Personnel Procedures Raw Materials Equipment Packing Materials Premises Environment 23 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors 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.

24 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors 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.

25 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors 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. 26 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Sterilization Process Development Equilibration Time 27 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

1 Prevacuum - Tyvek Wrapped Materials

l 125 124 123 122 121 120 119 118 117 116 115 114 113 112 111 110

Time 28 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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.

29 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors 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.

30 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Steam Sterilisation & SIP systems!

 Air removal from equipment not adequately considered

Personnel

 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

Validated processes Raw Materials Packing Materials Premises Procedures Equipment Environment 31 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Oven designs!

 No overpressure in hot air ovens  No HEPA filters on the exhaust side of the oven

Validated processes Personnel Procedures Raw Materials Equipment Packing Materials Premises Environment 32 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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.

Validated processes Personnel Patients Infected:

multiple blood cultures yield

Enterobacter cloacae

. At least one lot “directly implicated” in septicemia

Raw Materials Over 25 Septicemia Reports

lot or “unknown” naming the

Class 1 Recall:

Eleven Lots ( “strong likelihood that product will cause serious adverse health consequences or death ”)

Packing Materials

Cultures of

unopened vials

Enterobacter cloacae

grew Several

water samples

from the water hose/sink found

Enterobacter cloacae

collected at firm

Premises Procedures Equipment Environment 33 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Sterile API – unacceptable process design!

 Huge Grade A/B rooms poor differential pressures  Masses of pipe work  Redundant equipment

Validated processes Personnel Procedures Raw Materials Equipment

 Cracks, crevices, ledges …….

 Sterility starts here!

Packing Materials Environment Premises 34 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

Bulk lyophilisation

35 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

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.

36 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009

 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

37 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, November 2009