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Best Practice for Clean Room Monitoring

Guidance on clean room monitoring with reference to EU-GMP Annex 1 and ISO 14644 Part 1:2015 & ISO14644 Part 2:2015

John Wallingford and Janice Wallace (PHSS & Pharmagraph )

The Pharmaceutical and Healthcare Sciences Society (PHSS) exists as a science based forum for individuals active in the fields of Pharmaceutical and Healthcare Sciences.

Industry-leading guidance on regulation and GMP best practice in the international pharmaceutical sector;

Best Practice for Clean Room MonitoringPHSS

As an independent not-for-profit society well-respected by regulatory bodies the PHSS provides:

Special Interest Group collaboration and networking to generate best practice guidelines;

A voice for all stake-holders in the industry, including suppliers and customers;

Impartial advice and guidance;

A bridge between industry and regulatory bodies

Best Practice for Clean Room MonitoringScope

Advice on non-viable particle monitoring systems used in pharmaceutical facilities governed by EU GMP Annex 1.

Non-viable particle counting systems should be part of suite of environmental monitoring measures, including microbiological monitoring (viable particles),temperature monitoring and differential pressure monitoring.

Best Practice for Clean Room MonitoringEU GMP- Annex 1

GMP Annex 1 – Good manufacturing practice – manufacture of sterile medicinal products was first issued in 1972 with 5 subsequent partial revisions ( 1996, 2003, 2005,2007 and 2009) A full revision of Annex 1 was proposed in 2014. Since its initial issuance and subsequent revisions there has been a change in technologies and GMP.

A working group was formed from PIC/S /EMA to work on the full revision. Essentially EU GMP and PICS are now aligned. This is the first time that PIC/S have been directly involved with Annex 1.


Pharmaceutical Inspection Co-operation Scheme PIC/S aims at harmonising inspection procedures worldwide by developing common standards in the field of GMP


Annex 1 has been written and has been approved for public consultation by IWG,EMA, WHO and PIC/S. It is currently with the European Commission and requires a legal review before being published by the European Commission.

Clean room monitoring for continued compliance

Best Practice for Clean Room MonitoringGMP Requirements- Orange Guide

The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination.

Should be carried out in clean areas and these clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through appropriate filters.

• Grade A- High risk operations, filling zones, open ampoules & vials, aseptic connections

• Grade B- Aseptic preparation, background to Grade A• Grade C/D- background for Grade B, or isolators, also

used for preparation

The clean areas are classified according to

the required characteristics of the

environment. The four grades of area are:-

Cleanroom and clean air devices should be classified in accordance with ISO 14644 Part 1:2015

Sterile Products

Sterile products are products that are going to be infused directly into the bloodstream or body tissue.

Best Practice for Clean Room MonitoringSterile Products

Best Practice for Clean Room MonitoringSterile Products

Types of sterile products can be:-

Injectable

Radiopharmaceuticals

Compounding

Ophthalmic

( CBTF ) Cell Preparations

Producing sterile drug

Terminally Sterilised Products -The process of sterilising a product that is in its final package

Best Practice for Clean Room MonitoringSterile Product Category

Two categories of Sterile Products:-

Aseptic Processing-Those that can not be terminally sterilised but be aseptically prepared

ISO 14644

ISO 14644-1 and ISO 14644-2 specify procedures for classifying, testing and monitoring cleanrooms and clean air facilities.

Best Practice for Clean Room MonitoringISO 14644

New ISO Classification Table- sees the removal of the 5um particle size.

New ISO14644 specifically requires the use of ISO 21501-4 compliant particle counter

Best Practice for Clean Room MonitoringISO 14644:1

The limits were removed for Class 5 because there were too few particles to be statistically significant.

Best Practice for Clean Room MonitoringISO 14644:1

The 5um particle size should still be monitored during routine production. Such particles sizes are well recognised as carriers of microorganisms.

Best Practice for Clean Room MonitoringISO14644:2

Specifications for testing and monitoring to prove continued compliance with ISO14644-1

The updated ISO 14644-2 defines the types of Cleanroom monitoring

Sequential – Typically Semiconductor and not recommended for Pharmaceutical applications

Best Practice for Clean Room MonitoringISO14644:2

Continuous- multiple particle counters, one per individual location

Periodic

Counts 0.5 and 5.0 micron particles simultaneously

Able to detect fast, random events

Avoids effects of long tubing runs (>5.0um particle drop out)

ISO 14644-2 & SystemBest Practice for Clean Room Monitoring

System Design

Sample tubing length is not specified, but generally agreed not to be more than 2-3 metres or as specified by the particle counter manufacturer.

The ISO standard lists the main items to be taken into account when developing an airborne particle monitoring system:

Locate particle counter probes as close as practically possible to critical zones and should be determined by risk assessment. Typically this will be within 30cm of point of fill.

Location of particle counter to be accessible for maintenance, calibration, and repair

Air sample flow rate and volume 28.3-100L/Min for Portable Counters & 28.3L/Min for continuous particle counters

Sample probe configuration and orientation with respect to airflow (e.g. isokinetic for laminar flow)

Isokinetic probes provides the advantage of harmonizing the sampling flow speed with the typical laminar flow speed ( typically 0.45 m/s). This size of the probe will vary depending on the flow rate of the particle counter.

Best Practice for Clean Room MonitoringSystem Design

The system may be a combination of continuous particle counters and portable counters which can be moved between specified locations.

Annex 1 does not use the term continuous monitoring but specifies that the Grade A zones should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. In practice this can only be achieved by continuous monitoring with individual particle counters per sampling point.

Grade B areas, where they are the background for a Grade A zone, the preference is for continuous particle counters

Periodic monitoring with portable counters is allowed, the test frequency must be specified(i.e. once per week )

Critical AreasBest Practice for Clean Room Monitoring

Critical Areas to Monitor

Point of fill

Component hopper

Loading of freeze dryers

Descrambler tables

Aseptic manipulations

Operator interventions

Stoppering and capping stations

Best Practice for Clean Room MonitoringAseptic Processing in Clean Rooms

There is increased expectation in the new Annex 1 that operators are removed from the critical zone which can be achieved by using Isolators & RABS.

This ensures that pharmaceuticals are not exposed to viable organisms or particulate contamination. When dealing with highly potent formulations, these systems can also protect operators.


RABS Open System Physical separation of operators from the Grade A area, the grade A air from the RABS is exhausted into the room. The RABS must be installed within a Grade B environment

A-ISO5B –ISO7

Photographs courtesy of F Ziel GmbH.


cRABS Closed System Physical separation of operators from the Grade A area, the grade A air within the cRABS is recirculated inside the cRABS and not exhausted into the room.


The isolator has a complete physical separation of operators from Grade A, the grade air is recirculated inside the isolator. Ideally should be installed in a Grade C environment. Access to an isolator is through glove ports and sterile transfer systems



PHSS Contamination control and EM Process monitoringCase studies

1. Aseptic Process Vial filling of Liquid and LYO-Freeze dried products – Vials sterilised in Tunnel – Single use Product pathway, pre-sterilised stoppers. Isolator (Filling/Lyo) and RABS (capping) – Grade C surround. Process includes Off line stand alone Rapid vH202 Decon station for EM plate entry to Filling line via RTP canisters.

2. Aseptic Process filling toxic and Bio-hazard products in pre-sterilised containers – Vials & Syringes with transfer NTT (No-Touch Transfer). Liquid and Lyo products. Modular Isolator system (Capping in Isolator).Pharmaceutical Containment applied for OEL/ ADE containment and operator protection

3. Filling Toxic products into pre-sterilised syringes – Filling pumps sterilised Out-Of-Place with Aseptic transfer and assembly under Barrier conditions, pre-sterilised syringe plugs, syringe tub entry via NTT

4. Sterility Test Isolator with Rapid Decon Transfer Hatch using vH202/ VHP for material load transfers

5. ATMP Aseptic processing in Isolators and Biological safety cabinets with in-process transfers e.g. transfer steps between Grade A zones and Incubator, centrifuge, water bath, freezer, microscope

6. Hospital/ Compounding Pharmacy preparations in Isolators – TPN, Cytos, Antibiotics, MABS etc.

• Clarity of GMP guidance notes support GMP in specific areas that need guidance based on good practice with consensus between users and regulators on the approach.

• The revision of Annex 1 will impact all in sterile and associated non sterile medicinal product manufacture.

• The outcome of guidance’s should be reduced risk in sterile product manufacturing, improved GMP compliance and less risk to patients.

PHSS SUMMARY

Case Study worked example guidance & Clarity in GMP guidance notes

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