PDA: A Global Association

Matrix Approach to Media Fills

(c) 2012 Catalent Pharma Solutions. All rights reserved.

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§ Guidance Overview

§ Matrix Introduction

§ Why Matrix Media Fills

§ Sample Matrix

§ New Products & Technologies

§ Biologics

§ Scheduling Media Fills

§ Handling Matrix Media Fill Failures

§ Innovations in Media Fills

Overview

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Criteria PDA EU FDA Selection Numer of runs & frequency

3 runs for validation routine 2/Y

3 runs per shift for validation routine 2/Y

3 runs for validation routine 2/Y

3 runs per shift for validation routine 2/Y

Matrix Considerations

Risk assessment to set worst case No worst case, run at extremes of range

Evaluate # of interventions

Evaluate: range of speeds # of interventions # of personnel

Use largest container with widest mouth at slowest speed and smallest vial with highest speed

Incubation temperature

20 - 35°C for 14 days

20 - 25°C for 7 days followed by 30 -35°C for 7 days

20 - 35°C for 14 days. If 2, incubate at lower temp first

20 - 25°C for 7 days followed by 30-35°C for 7days

Qualification of staff

Initial, then once per year

Frequency not specified

Initial, then once per year

Frequency not specified

Guidance

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Reason for matrix approach

§ Most efficient compliant method validating multiple products.

§ Best Coverage: § Microbiological assurance confirmed by worst case conditions § Systematic program including Risk Assessment forces examination of all

products and parameters annually

§ Cost Savings: § Raw Materials § Indirect Costs - Testing, Disposal and Clean up § Equipment costs: purchase and maintenance of incubators § Additional capacity for production § Manpower costs

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§ Risk Assessment utilized to determine critical to sterility parameters

§ Risk Assessment determines worst case value for critical to sterility parameters (fill duration, # of interventions, # of personnel, # of aseptic connections during set up)

§ Where a worst case value can not be justified, the extreme values of the range are used to bracket the parameter (container size, closure size, fill speed)

Introduction of matrix

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Filling Line is used for 3 products

Conventional Media Fill Schedule

Product Vial Size

Closure Size fill speed staff Fill time interventions

# of Media Fills

Initial Routine

1 2mL 13mm 200/min 3 6 hour 10 3 2/yr

2 5mL 20mm 150/min 2 7 hour 15 3 2/yr

3 20mL 20mm 120/min 2 8 hour 20 3 2/yr

# of Media Fill required without using matrix approach 9 6/yr

Matrix Media Fill Schedule

1 2mL 13mm ≥200/min 3 8 hour 20 3 1/yr

2 20mL 20mm ≤120/min 3 8 hour 20 3 1/yr

# of Media Fill required using matrix approach 6 2/yr

Example of a simple matrix

Reduction of 67 %

§ New Product is compared to current limits to determine fit § If not covered within existing limits a separate

media fill is required § If covered by the existing limits, the Generic Validation

Protocol is updated to include new products placement, including risk assessment completion & documentation

§ New Technology requires risk assessment; most likely will require separate matrix

New products & technologies

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§ Due to Biologics process variability, no single / standard process set up is possible

§ It may be more practical to validate the various segments of the process individually

§ The frequency of revalidation should relate to the process of regular, commercial production

§ determined to use worst case conditions

Biological products

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§ Foundation of schedule is worst case condition

§ Program schedule reviewed and approved annually

§ Schedule updates for new products deployed through risk assessments and implemented via change control

§ Different approaches can be used : § Alternate to cover each end of the set limits § Randomize to cover each end of the set limits

and mid level processes

Schedule

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Frequency of media fills within the fence actually increases, reducing risk to any specific product

Human failures should always be treated with full CAPA, fence should be the same in matrix vs. non-matrix program

MYTHS TRUTH

Media fill myths

Fence determination via brackets can lead to larger potentially impacted population

Human error failures impact larger population

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Vegetable Based Media § Optimized performance with non-animal

origin § Eliminates TSE risk § Available irradiated § Available with color indicator § Possible recovery for anaerobic media

fill use

Irradiated Dehydrated Media § Eliminates Bioburden &

Mycoplasma risks § Reduced contamination risk

CONSIDERATIONS § Validation in use (eg. Recovery vs. TSB) § Maturity in use § Fit for purpose for individual needs § Supplier Qualification

Cold Filterable Media § Filterability § Formulation in facility § Safety (no hot WFI) § Mimics process § No pre-use sterilizing/testing

Innovations in media fill

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Matrix approach to Media Fills

§ A systemic, risk based method utilizing worst case conditions

§ Meets guidance requirements for equipment and validation of staff

§ Provides coverage at lowest cost

§ A structured way to review new products, and technologies; including Biologics

Summary

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Acknowledgements - Catalent Pharma Solutions: G. Delestrait, D. Diels-Vandepoel, E. Hoppenbrouwers, H. Jeffreys, J. Krewer, K. Schmidt, J. Spiers

Thank you for your attention

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