Moderated By Eyal RivlinLev Hakongressim, Weizmann Science Park, Ness Ziona

May 2008

• The new annex will be implemented by 1st March 2009,Capping requirement March 2010.

• GMP Annex 1 has been revised and updated in four main areas: – Classification table for environmental cleanliness of

clean rooms

– Guidance on media simulations

– Guidance on bioburden monitoring

– Guidance on capping of liquid and freeze-dried vials

Introduction

Editorial changes

• Laminar air flow becomes uni-directional air flow.

• Clean room becomes cleanroom.

• Capping of freeze dryed and liquid vials.

Classification table for environmental cleanliness of clean rooms – Annex 1(2003)

Classification table for environmental cleanliness of clean rooms

• The continued requirement for monitoring 5 micron particles generated the most comments.

• A Non EU agency (FDA) does not require this monitoring.

• An occasional indication of ≥5 micron particle counts may be false counts due to electronic noise, stray light, coincidence, etc.

Why not remove it ?

• Lack of scientific rationale to remove this requirement.

• Published papers provide data to support continued requirement to monitor 5 micron particales.

monitoring ≥5 micron particles (advantages)

• Consecutive or regular low levels of ≥5 micron particles is an indicator of a possible contamination event and should be investigated.

• Such events may indicate early failure of the HVAC system, filling equipement or bad practice during routine operation or machine set-up.

• An important diagnostic tool for early detection of failure.• Not monitoring ≥5 micron particles would indicate the

company has a High risk appetite.

monitoring ≥5 micron particles - decision

• It was accepted that the previous limits were not statistically valid.

• The limits have been changed to 20 for grade A and 29 for grade B.

• Alert limits and out of trend limits may need to be revised when implementing cont. monitoring.

Classification table for environmental cleanliness of clean rooms- Revised Annex 1 (2008)

≥5 micron particles- summary

20032008

gradeAt restoperationalAt restoperational

A112020

B12000292900

Guidance on media simulations

• The limits were brought to line with the FDA aseptic guidance.• The updated limit appears to have been well accepted by inspectors and industry

2003:

2008:

Filled unitsInvestigationInvestigation following revalidation

Fewer than 5000 Units-1

5000-10000 Units12

More than 10000 Units12

Guidance on capping of freeze-dried and liquid vials

1. Partially stoppered vials should be maintained under grade A conditions at all times until the stopper is fully inserted.

2. The container closure system for aseptically filled vials is not fully integral until the aluminium cap has been crimped into place on the stoppered vial. Crimping of the cap should therefore be performed as soon as possibly after stopper insertion

Guidance on capping of freeze-dried and liquid vials

3.Vial capping can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic core. where this later approach is adopted, vials should be protected by grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped.

Guidance on capping of freeze-dried and liquid vials

4.Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is required at the capping station, appropriate technology should be used to prevent direct contact with the vials and to minimize microbial contamination.

5. Restricted access barriers and isolators may be beneficial (it is more than a recommendation) in assuring the required conditions and minimizing direct human intervention into the capping operation.

Bioburden prior to sterilization

Clarification of requirements:• The bioburden should be monitored before

sterilization. There should be working limits on contamination immediately before sterilization, which are related to the efficiency of the method to be used.

• Bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilized products.

Q&A?

THE END !