Validation of aseptic fill process - BFS IOA...Typical bioburden of resin is found below

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BFS IOA Training Seminar 2018 Kunming 1 Validation of aseptic fill process Presented by Stefan Kiesel Senior Manager Rommelag Pharma Service BFS International Operators Association Copyright © by BFS IOA

Transcript of Validation of aseptic fill process - BFS IOA...Typical bioburden of resin is found below

Page 1: Validation of aseptic fill process - BFS IOA...Typical bioburden of resin is found below

BFS IOA

Training Seminar 2018 Kunming

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Validation of aseptic fill process

Presented by Stefan Kiesel

Senior Manager Rommelag Pharma Service

BFS International Operators Association

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Overview/Index

I. Regulatory Background

II. Media fill – Method

III. Media fill – Design

IV. Media fill – Evaluation

V. Extruder Challenge Test

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Which guidelines are available?

China, Chinese GMP revised in 2010 Annex 1

EU, EudraLex Volume 4 EU-GMP Guide Annex 1

FDA, Guidance for Industry – Sterile Drug Products produced by aseptic

processing

USP 1116, Operational Evaluation of the Microbiological status of

Aseptically Filled Products in Clean Rooms and Other Controlled

Environments.

PIC/S, PI 007-2 Recommendation on the Validation of Aseptic Processing

Japan, Guidance for Industry - Sterile Drug Products Produced by

Aseptic Processing

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What answers can we find?

What to do?

When to do?

How to do?

How many units?

Specifications?

Which nutrient Medium?

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What to do?

Chinese GMP: Validation of aseptic processing should include a

process simulation test using a nutrient medium

(media fill).

EU-GMP: Validation of aseptic processing should include a

process simulation test using a nutrient medium

(media fill).

FDA: An aseptic processing operation should be

validated using a microbiological growth medium in

place of the product.

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When to do?

Chinese GMP: Process simulation tests should be performed as initial

validation with three consecutive satisfactory simulation

tests per shift and repeated at defined intervals and after

any significant modification to the HVAC-system,

equipment, process and number of shifts. Normally

process simulation tests should be repeated twice a year

per shift and process, one batch at least in each time.

EU-GMP: Process simulation tests should be performed as initial

validation with three consecutive satisfactory simulation

tests per shift and repeated at defined intervals and after

any significant modification to the HVAC-system,

equipment, process and number of shifts. Normally

process simulation tests should be repeated twice a year

per shift and process.

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When to do?

FDA: When a processing line is initially qualified, individual

media fills should be repeated enough times to ensure that

results are consistent and meaningful…

…We recommend that at least three consecutive separate

successful runs be performed during initial line

qualification…

…Subsequently, routine semi-annual qualification

conducted for each processing line will evaluate the state

of control of the aseptic process.

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How to do?

Chinese GMP: The process simulation test should imitate as

closely as possible the routine aseptic

manufacturing process and include all the critical

subsequent manufacturing steps which may affect

the aseptic result.

EU-GMP: The process simulation test should imitate as

closely as possible the routine aseptic

manufacturing process and include all the critical

subsequent manufacturing steps.

FDA: Media fill studies should closely simulate aseptic

manufacturing operations incorporating, as

appropriate, worst-case activities and conditions

that provide a challenge to aseptic operations.

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How many units?

Chinese GMP: The number of containers used for media fills

should be sufficient to enable a valid evaluation.

EU-GMP: The number of containers used for media fills

should be sufficient to enable a valid evaluation.

FDA: The number of units filled during the process

simulation should be based on contamination risk

for a given process and sufficient to accurately

simulate activities that are representative of the

manufacturing process.

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Specifications?

Chinese GMP: When filling more than 10,000 units:

⑴ 1 contaminated unit should result in an investigation;

⑵ 2 contaminated units should result in revalidation ,

following investigation.

EU-GMP: When filling more than 10,000 units:

a) 1 contaminated unit should result in an investigation;

b) 2 contaminated units are considered cause for

revalidation, following investigation.

FDA: When filling more than 10,000 units:

-- 1 contaminated unit should result in an investigation.

-- 2 contaminated units are considered cause for

revalidation, following investigation.

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Which nutrient medium?

Chinese GMP: Selection of the nutrient medium should be made based on

dosage form of the product and selectivity, clarity,

concentration and suitability for sterilisation of the

nutrient medium.

EU-GMP: Selection of the nutrient medium should be made based on

dosage form of the product and selectivity, clarity,

concentration and suitability for sterilisation of the

nutrient medium.

FDA: In general, a microbiological growth medium, such as

soybean casein digest medium, should be used. Use of

anaerobic growth media (e.g., fluid thioglycollate medium)

should be considered in special circumstances.

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Overview/Index

I. Regulatory Background

II. Media fill – Method

III. Media fill – Design

IV. Media fill – Evaluation

V. Extruder Challenge Test

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Full filling period

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Different methods for media fills

Media Product Media Product Media Product Media

Media Water Media Water Media Water Media

Media Hold Hold Media Hold Hold Media

Product Product Product Product Product Product Media

Media Media Media Media Media Media Media

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Overview/Index

I. Regulatory Background

II. Media fill – Method

III. Media fill – Design

IV. Media fill – Evaluation

V. Extruder Challenge Test

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Worst case parameters

If machine is used as shared equipment, worst case

parameters should be defined:

Longest fill duration

Widest container opening

Longest exposure time of open container

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Interventions

Interventions must be clearly defined and classified

regarding contamination risk, frequency…

Interventions must be covered during media fill

Duration of media fill to allow performing all defined

interventions

Proper documentation of interventions required (batch

records)

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Interventions

Example for classification of interventions

Minor interventions

Major interventions

Critical interventions

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Other points to consider

Shift regimes to be considered

Fill level of units sufficient for complete wetting of inner

surface

Fill level of units to allow sufficient oxygen for supporting

microbial growth

Max. holding time to be considered

All integral units to be incubated

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Overview/Index

I. Regulatory Background

II. Media fill – Method

III. Media fill – Design

IV. Media fill – Evaluation

V. Extruder Challenge Test

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Incubation / storage

Different possibilities e.g.:

14 days at 20-25°C

7 days at 20-25°C and 7 days at 30-35°C

Heat up period to be considered

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Evaluation/Examination

To be performed or at least supervised by QC personnel

Examination to be done by educated, trained and

experienced personnel

Proper ambient conditions required

Proper documentation required

Growth promotion test to be demonstrated for medium

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Evaluation/Examination

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Overview/Index

I. Regulatory Background

II. Media fill – Method

III. Media fill – Design

IV. Media fill – Evaluation

V. Extruder Challenge Test

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Why to do an extruder challenge test?FDA Aseptic Guideline – Appendix 2 BFS Chapter B

Data gathered during such studies should ensure that BFS containers are

sterile and, if used for parenteral drugs, nonpyrogenic. This can generally

be achieved by validating that time temperature conditions of the

extrusion process are effective against endotoxin or spore

challenges in the polymeric material.

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Literature available Leo, F., Poisson, P., Sinclair, C. S., & Tallentire, A. (2004). Evaluation of

Blow/Fill/Seal Extrusion through Processing Polymer Contaminated

with Bacterial Spores and Endotoxin. PDA Journal of Pharmaceutical

Science and Technology.

Birch,C.J., Sinclair, C.S.(1998). BFS Extrusion of Contaminated

Polymer. BFS-News 9_98;

Molin, O. (1999). Extruder Challenging Test for verifying Production of

Sterile and Endotoxin Free Polypropylene Ampoules. BFS-News 3/1999

Poisson, P.(1999). Spore Polymer Challenge of the ALP Model 624 BFS

Machine. BFS-News 3/99.

Rommelag (2015). Design Space Verification for extrusion process

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Questions to be asked

Is there a reduction of endospores within the BFS-extrusion process?

What are the parameters influencing the process?

Can the reduction-effects be ranked?

Is the extrusions-process equivalent to sterilization?

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How to perform

1. Contamination of resin (homogenous or spotted)

2. Performing a media fill using worst case conditions:

Lowest possible temperature / highest possible extrusion speed

3. Incubation and evaluation of the produced containers

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Contamination of resin (Homogenous)

Transformation

Extrusion process

detail

scrap

container wall

available contamination

= homogeneously

located germs

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Contamination of resin (Spotted)

Transformation

Extrusion process

scrap

container wall

available contamination

= non-contaminated resin

embedded contamination

= germ

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Is there a reduction of endospores within

the BFS-extrusion process?

All available literature is stating that there is a reduction of endospores

(Bacillus atrophaeus ATCC 9372) during extrusion

Reduction factors vary 102 CFU/g to 104 CFU/g

Yes

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What are the parameters influencing the

process?

Kind of contamination (homogeneous / spot)

Container design (product-contacting surface)

Transformation of the contaminated resin surface:

scrap, outer surface, container wall

Product of temperature and retention time

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Can the reduction-effects be ranked?

1. Kind of contamination (homogeneous / spot)

1. Transformation of the contaminated resin surface:

scrap, outer surface, container wall

2. Container design (product-contacting surface)

3. Product of temperature and retention time

Yes Copyright © by BFS IOA

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Is the extrusions-process equivalent to

sterilization?

The extrusion process is not equivalent to a sterilization process

Temperature*Retention Time is too small

Reduction from 102 CFU/g 104 CFU/g

No

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Consequences for BFS-process

Typical bioburden of resin is found below <10¹ CFU/g resin

Transport, storage and distribution is critical, for example damaged

bags, etc.

Handling is critical: opening of bags etc.

Qualification of the supplier

Appropriate design of the handling system, qualification of the

handling system

SOPs and training of operators

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Thank you very

much for your

Attendance!

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