assuring sterility – a cmos approach

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A3P 16th Annual conference

November 2012

Assuring sterility – A CMO’s approach



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Introduction

Patheon Inc. is a leading global provider of contract development andmanufacturing services to the global pharmaceutical industry.

We provide products and services to approximately 300 of the world's leadingpharmaceutical and biotechnology companies.

Our services range from preclinical development through commercial

manufacturing of a full array of solid and sterile dosage forms, includingsoftgels.

As the site Microbiologist at Patheon UK, (based in Swindon) I amresponsible for the Microbiology and sterility assurance functions at two sites,

serving a total of 10 sterile filling lines and 3 non sterile filling lines for bothcommercial and pre-clinical development batches.



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Assuring sterility – Introduction



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Our goal in the production process is to assure the absence of microorganisms from every container. However, what available means do wehave to demonstrate such an absolute negative?

• Sterility testing - is severely limited statistically (20 containers tested perbatch)

• Media fills (process simulations) - are point in time assessments of thecapabilities of an aseptic process and even then only support a maximumcontamination rate, not a level of sterility assurance.

• Environmental monitoring - can only recover a small percentage of themicroorganisms present. (contact plates recover an average of 29% of S.

epidermidis from a stainless steel surface)

Absence of growth does not mean the absence of microorganisms!



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SterileContainer

Sterile

Closure

SterileExcipient

Sterilefinal

product Aseptic

processing

Drugproduct

Container

Closure

Excipient

Sterilisation

Sterilisation

Sterilisation

Sterilisation

Steriledrug

product



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The essence of aseptic processing is the assembly of previously sterilised

materials into a sealed container using procedures, controls and equipment that preserves their most

critical attribute - sterility


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Six blind men and an elephant!




The six pillars of a robust aseptic process:

–Facilities design

–HVAC validation –Material / component transfer

–Process simulation (media fills)

–Personnel training & monitoring

–Environmental monitoring




Like the elephant, theaseptic process must

be considered

holistically



Assuring sterility – Facility and design




In terms of the general design of cleanrooms, it is imperative that:

• They are built of an airtight structure

• As a minimum it should be an ISO 5 / Grade A environment

• The internal surfaces should be smooth and suitable for cleaning

•

The internal surface finish should be sufficiently resilient to resist chippingor powdering

• The surfaces should be resistant to the cleaning agent used.

The designs for manned cleanrooms have undergone constant revisions with

many of these designed to increase the separation between the operator andthe aseptic portions of the process.

The culmination of this progression is the closed isolator which affords thehighest degree of physical separation from the operator.



“Open” Gowned Operator Access

Increasing confidence in sterility assurance

Reducing

probabilityof unitsbeingcontaminated

The Aseptic Processing Spectrum




RABS = R estricted Access Barrier System

Process improvements like RABS are aimed at

separating people from the process.

If successful the risk posed by people

contaminating the area will be greatly reduced



Assuring sterility – Facility and designPatheon RABS approach

Filling Line

HEPA

Grade AFixed BarriersGlove ports

Overspill of Grade A Air below thecritical zone of operation

HEPA

HEPA HEPA HEPA HEPA

“Open operation” Doors can be opened butonly for predefined / risk

assessed activities

Grade Btraditional cleanroom



Assuring sterility – HVAC



Assuring sterility – HVAC

The HVAC (Heating, Ventilation and Air Conditioning) system controls the roomparameters including temperature and humidity.

This is important not only for operator comfort but also for minimising microbialcontamination.

– High temperatures can lead to excessive perspiration which can reduce the efficiencyof the cleanroom suit and result in the increase of shedding of micro-organisms

– Certain mould species cannot grow in areas of low humidity, therefore keeping theroom humidity low will ensure that contamination will be kept to a minimum.

Guidance would suggest that the temperature should be maintained at 18oC ±

2oC and humidity at 45% ± 15

We use a building management system to control these parameters constantlyto show that the room is in control



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Assuring sterility - HVAC



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Assuring sterility – Material and Component transfer



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Materials and components should wherever possible enter your cleanroom as

sterile, in order to achieve this they can go via a hierarchy of controls whichaims to eradicate the microbial contamination.

– Autoclaving – usually at 121oC for a minimum of 15 minutes (validated bydemonstration of a 106 log reduction of a biological indicator)

– De-pyrogenation – (validated by demonstration of a reduction of endotoxin level)

–

Gamma irradiation – usually 25kGy (validated by dose mapping) – Ethylene Oxide - (validated by demonstration of a 106 log reduction of a biological

indicator)

• Whatever method you use you must ensure that all sterilisation andsanitisation processes are properly validated

• Recognise that premium equipment, package components and materialsshould offer enhanced reliability over lesser quality items.

• Aim to reduce the assembly time required for all sterilised materialsthrough pre-fabrication or use of disposable assemblies.



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How the material has been sterilised will determine how it enters thecleanroom:

• In the ideal situation some components will be steam sterilized directly intothe Grade B cleanroom (the problem here will be how to get it to the Grade

A environment (we use Grade A mobile LAF carts)).

• Many others arrive pre-sterilized (irradiation or EtO) and enter the via aseries of airlocks.

Patheon procedure requests that components arrive sealed inside 3 PE bags.

This allows us to operate an effective decontamination process that controlsthe risks posed by the outer surfaces of these items.

– Eg. Post sterilization the components usually arrive inside a cardboard box;cardboard can get damp during transport and can allow proliferation of moulds.

– Moulds are a risk to our processes.



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Support Area

Grade C Grade BGrade A

(eg RABS)

1 2

Remove Cardboard Box Vacuum clean if dust presentDisinfect Bag

Remove Outer Bag ANDDisinfect Inner Bag

Remove Outer BagOrDisinfect Outer Bag

Contaminationon outersurface

Nocontamination

Process for transfer of pre-sterilised components:



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Assuring sterility – Material and Component transferComponent Chute

FILLINGLINE

HEPA HEPA

Overspill of Air

Component chute pivots toopen & close

Positioned relatively high toprevent operator leaning in

Components opened in

“outer A” and poured downthe chute. Chute closesimmediately



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Assuring sterility – Media fill simulations



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The main contamination risk evaluation tool capable of including all thedifferent aspects and variables of the aseptic process is a process simulation (ormedia fill).

The design of a media fill simulation should consider the following factors:

• Media selection

• Frequency and number of runs

• Size and duration of runs

• Line speed, container size, closure type and fill volume

• Process/line configuration set up• Number of persons, activities and interventions (including line clearance)



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Choosing the media

The media fill should mimic as closely as possible your production of product.

If you have a powder filling process you should use a sterile placebo (we usePEG, polyethylene glycol)

As most clean room contaminants are strict or facultative aerobes any step inthe process where oxygen content is kept low could cause a potential growthinhibition and could mask contamination routes. (ie by the use of Nitrogen).If your process does use Nitrogen then this should be substituted during themedia fill with compressed air.

If this is not possible then evidence that growth of typical processcontaminants is not affected by this step should be considered.

If on the other hand your manufacturing process is a totally anaerobicprocess then you should consider the use of an anaerobic media such as Alternative Fluid Thioglycollate medium



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Frequency and number of runs

At least three consecutive separate successful runs are necessary for:

• Initial line qualification

• Revalidation following major changes to the equipment and/or process• Whenever there are doubts about the ability of the aseptic process toexclude contamination (extended shutdowns, trends in environmentalmonitoring, sterility test failures etc)

For routine re-qualification, one run per line with a semi-annual frequency (ortwice a year, as reported in the Annex 1) is recommended.



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Size and duration of runs

Ideally, the most accurate simulation would be to mimic exactly the commercialprocess in terms of batch size and total duration. In practice, provided that theyaddress all the potential risks of contamination occurring during commercialproduction a different model can be used.

5,000 to 10,000 units is a generally acceptable starting point for run size (FDA guidance), however, for commercial products with batch sizes much bigger than10,000 units it could be difficult to justify that a simulation run smaller than10,000 units is considered representative of the actual process.

The run size must be big enough to allow all of the manipulations andinterventions occurring during the commercial process to be captured.



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Size and duration of runs

From a practical point of view the problem is how to combine a duration equalor longer than the longest commercial process with a media fill run size that ismuch smaller than the product batch size.

At Patheon we perform the process simulation running the line intermittentlytaking care to include line set up, all the planned interventions and maximumoperator levels.

Interventions

Interventions are generally divided into two main categories:

• Intrinsic to the process (normal interventions)

• Extrinsic to the process (non-routine interventions)



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Routine Interventions

These include all the interventions that are necessary for running the processas it is designed.

• Line set up

•

Aseptic connection(s)• Container/Closure feeding

• Product sampling

• Weight checks

• Environmental monitoring



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Non routine interventions

These include all the other interventions that are not strictly necessary forrunning the process, but that can occur due to expected or unexpectedproblems during the operation.

• Removal of jammed containers/closures

• Removal of broken containers/product residues

• Replacement of a dosing device

• Adjustment to the line set-up (guides, star wheels etc)

• Breakdowns (sensors, switches, belts etc)

The ‘perfect’ intervention is one that doesn’t exist



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Assuring sterility – Media fill simulationsInterventions into the RABS

A standard list of pre assessed interventions is published for each RABS

Each new intervention must be risk assessed prior to being performed. A. Amount of microbial contamination on source; 0-2 (eg a sterilized tool or a person’s hand)

B. Risk of dispersion, 0-2 (vigorous movements required. Working above the product or product handling?)

C. Proximity to product, 0-2 (distant from the product or close by?)

D. Effectiveness of control measures, 0-2 (localised clean, discard of exposed product & components)

A x B x C

A x B x C x D

Risk posed by intervention

Residual risk after controlmeasures taken

Defines controlsrequired e.g.•Terminate the batch•Localised clean

H, M, L or NDefines the EMRequired e.g.•Take fingerdabs•Take extrasterility samples

Duration defined



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Assuring sterility – Facility and designExample of an intervention

M 302M 303

L 304N 305

H 301Codes are located oneach door of the RABS

These are the onlyroutine interventionsthat the operator canperform.

The number and typesof interventions arecompared during batch

release to those thathave been performedduring a Media Fill

Colour indicatesRisk and indicateshow to perform theintervention

Letters indicatesthe residual risk after the correctiveactions are takenand specifies whatEM is required

Numbers are linkedto a writtendescription of the interventionwithin the SOP andthe batch record



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Assuring sterility – Facility and designIntervention Matrix

Colour = Risk BlueDo not record

GreenRecord in BMR

OrangeRecord in BMR

RedRecord in BMR

Sanitise HandsUse glove ports

Use tools

Sanitise HandsUse glove ports

or hatchUse tools

Sanitise HandsOpen door or use

hatchUse tools

Sanitise HandsOpen door or use

hatchUse hands

Also how it isdone

Code = Risk remaining afterthe intervention

Code specifies

the EM andsamples required

N = negligible

No EM or Samples

L = Low

No EM or Samples

M = Medium

Finger-dabs

H = HighFinger-dabs,

sterility test samples

Maximumallowed time is

specified

Duration Exceeded

No action required

Duration Exceeded

BNF

Duration Exceeded

BNF

Duration Exceeded

BNF + Risk Assessment



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Media fill

Intervention

checklist



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Assuring sterility – Training of personnel



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The biggest source of contamination in a cleanroom is people, and levels of contamination will be highest when their training is poor.

Gowns, masks, gloves and goggles can reduce the incidence of contaminationbut the risk remains.

The closer the people get to the product and the more they interact with theline and the product the more likely that contamination will be transferred.

It is therefore essential that adequate training is conducted before anindividual is allowed to enter the cleanroom to perform aseptic manipulations.



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As a minimum the training of the operator should include education in:

• GMP

• Personal hygiene

• Gowning and comportment training

• Basic Microbiology• Knowledge of how a cleanroom functions

• The impact their behaviours can have on the product



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Assuring sterility – Environmental monitoring



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Introduction

• The Patheon site at Swindon has ten Grade A (Class 100) manufacturinglines.

• Environmental monitoring is performed at defined frequencies and locationsusing Settle plates, Active air samples and contact plates.

• The locations for the EM monitoring has been defined based on risk assessment of the operation in conjunction with smoke visualisationfootage and trend data.



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Environmental monitoring - Frequency

Grade A B

Settle plates Continuous monitoring Each operational shift

Contact plates End of eachbatch/campaign

Daily

Active air sample Every shift Each operational shift

Routine Finger Dab After every exit After every exit

Intervention Finger Dab After every high andmedium risk intervention

N/A

Sleeve monitoring At the end of each entry ahigh risk intervention is

performedN/A

Gown Monitor After every exit After every exit

Swabs End of eachbatch/campaign

N/A

(An operational shift is defined as an 8 hour period)

l h h l



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Environmental monitoring – Choosing the location

EM locations are primarily selected based on an assessment of the processwith respect to risk from microbial contamination using the followingequation:

Risk from microbial contamination (Risk rating) = A x B x C x D

Where:

• A = Microbial contamination on, or in, a source.

• B = Ease of dispersion and transfer of contamination.

• C = Proximity and ease of contaminating source from the critical area.

• D = Effectiveness of contamination control method.

E i l i i Ch i h l i



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Environmental monitoring – Choosing the location

A committee should be set up to carry out the risk assessment and comprisethe following people:

– Risk management expert

– Microbiologist

–

Quality Assurance manager – Facilities manager

– Production manager

The risk scores should be assigned to hazards by an aggregation of opinion

from the committee individuals and you should all establish a method of scoring to suit your facility.

We use the scoring system 0 – 2 with

0 = nil, 0.5 = very low, 1.0 = low, 1.5 = medium and 2.0 = high

E i l i i Ch i h l i



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Environmental monitoring – Choosing the locations

Environmental monitoring is increased or decreased basedon the risk assessment score. ie Red ratings would requireenvironmental monitoring to be performed during thatactivity or intervention

E i t l it i Ch i th l ti



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• The number of points to be sampled in a given area should be related torisk, therefore the sampling points should be concentrated in the criticalareas, and as the risk of contamination in the surrounding areas becomesless (ie corridors and other support areas) then there should be fewersampling points.

• Transfer areas may be the exception and require more sampling because of the higher risk associated with the materials and personnel that moving tothe critical area.




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Assuring sterility – Conclusion

A i t ilit C l i



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Assuring sterility – Conclusion

Like the elephant, theaseptic process must

be considered

holistically

Thank o fo listening!



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Thank you for listening!

References



References

• Risk Management of Contamination (RMC) During Manufacturing Operations In Cleanrooms – TechnicalMonograph No. 14 by the Pharmaceutical and Healthcare sciences society (PHSS) and the Scottish society forcontamination control

assuring sterility – a cmos approach

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