GUIDELINES ON ENVIRONMENTAL MONITORING FOR ASEPTIC DISPENSING FACILITIES

PRODUCED BY

A WORKING GROUP OF THE SCOTTISH QUALITY ASSURANCE SPECIALIST INTEREST GROUP

THIRD EDITION

November 2002

Contents
1. 2. 3. Introduction Definition of Terms Guidelines on frequencies and types of monitoring for aseptic dispensing facilities Guidelines on action levels for monitoring of aseptic dispensing facilities Actions when results deviate from action levels References

Page 2. 2. 3.

4. 5. 6.

4/5. 6. 7.

Appendix 1

Abnormal Event Log

-1-

1.

Introduction

Due to ongoing changes in Guidelines, and the need for periodic review, the 3rd edition of Guidelines on Environmental Monitoring for Aseptic Dispensing Facilities has been produced. In May 1995, the Association of Scottish Trust Chief Pharmacists established a Task Team with the following aim: "To address those issues arising from the Report 'Aseptic Dispensing for NHS Patients' which can be considered on a national basis to facilitate the Report's introduction at local hospitals". [1] The document "Guidelines on Environmental Monitoring for Aseptic Dispensing Facilities" (first edition) prepared by the Task Team, formed part of the Team's final report. It was stressed that the information it contained should not be considered alone and attention was drawn to "The Quality Assurance of Aseptic Preparation Services" (now in its 3rd edition and published on behalf of the NHS QC Committee). [2] In keeping with the aim of the Task Team, an updated version (3rd edition) of the guideline document has been prepared by a Working Group of the Scottish Quality Assurance Specialist Interest Group, in consultation with the Scottish Aseptic Services Specialist Interest Group, to accommodate changes made to practice since preparation of the original document. The information contained within the enclosed guidance is available from various reference sources, but it was felt that the collation of the information into one document was still essential to facilitate standardised good practice. It is recommended that the guidance set out in this document be adopted locally for the monitoring of aseptic dispensing facilities and personnel. Details of individual reference sources are contained within this document. Areas where this Guideline Document has previously quoted more stringent limits or increased testing frequencies, compared to other reference sources, remain unchanged. The monitoring guidelines contained within this document should be considered as minimum requirements, which may be increased as local conditions demand. This Guideline Document complements Guidelines on Test Methods for Environmental Monitoring for Aseptic Dispensing Facilities. [3]

2.

Definition of Terms.

These are as detailed in the Quality Assurance of Aseptic Preparation Services. [2]

-2-

3.

Guidelines on frequencies and types of monitoring for Aseptic Dispensing Facilities

3.1 Sessional Tests (record duration of session) Finger dabs in critical zones (e.g. LAFC/Isolator) in the operational state Settle plates in critical zones (e.g. LAFC/Isolator/Transfer Devices) in the operational state (a) Glove integrity test/visual inspection of glove and sleeve assembly (b) 3.2 Daily Tests Record pressure drop across filter, isolator pressure differential and airflow rate (isolators with appropriate gauges) Record pressure drop across HEPA filter (LAFC) Record pressure differential between aseptic rooms and adjacent areas Alarm test (isolators) 3.3 Weekly Tests Settle plates at test sites in the background environment and change facility in the operational state (c) User pressure decay test (all isolators) (d) Microbiological surface samples in LAFC/Isolator, Transfer Devices and background environment 3.4 Monthly Tests Airborne viable organisms in LAFC/isolator, transfer devices, background environment and change facility in the operational state (f) 3.5 3-Monthly Tests Airborne particle count in LAFC/isolator, transfer devices, background environment and change facility in the operational state (f) Air change rate in aseptic rooms Air velocity in LAFC Inlet air velocity into controlled work zone for laminar air flow isolators Volume flow rate in turbulent flow isolators Operator aseptic transfer tests for all operators 3.6 Annual Tests Integrity and efficiency of all HEPA filters Leak detection test (e.g. Helium Test (all isolators)) KI discus operator protection test (e) Calibration of gauges and critical equipment (e.g. automatic dispensing systems) Process simulation tests for aseptic processes 3.7 Notes (a) (b) (c) (d) (e) (f) Settle plates (90 mm plates filled with a suitable medium) should be exposed during each working session, irrespective of the length of the session, and the time of exposure recorded. For isolators in which it is not possible to perform a glove integrity test, a visual inspection of the glove and sleeve assembly should be performed sessionally. Settle plates should be exposed for a period of not less than 1 hour in the operational state or a full dispensing session, and the time of exposure recorded. Only isolators fitted with appropriate equipment will be able to be tested. This test applies to safety cabinets only. The final stage of change should equate to the grade of room being entered.

-3-

4.

Guidelines on action levels for monitoring of Aseptic Dispensing Facilities

The source document for each of the tests is referenced and if clarification is required, these documents should be consulted. 4.1 Non-viable particle counts[2],[4],[5],[6]: Maximum permitted number of particles/m equal to or above At rest Operational 5m 10m 25m 0.5m 5m 10m
(note 1) (note 1) (note 1)

EC GMP Grade A

Location Examples LAFC (a) Isolator (a) Transfer device Background to LAFC Background to isolator (b) Clean support Room Background to isolator (c)

0.5m

25m
(note 1)

3 500

ND

ND

3 500

ND

ND

3 500

ND

ND

350 000

2 000

450

B C D

350 000
3 500 000

2 000 20 000

450 4 500

0 500

3 500 000

20 000 200 000

4 500 45 000

500 5 000

NS

ND = Not defined. 4.2 Pressure differentials[2]:

Note 1: Referred to as Macro Descriptors [6]

> 10 Pa between classified area and adjacent area of lower classification > 15 Pa between classified and unclassified area 4.3 Airflow velocity[4],[5],[7],[8]: Horizontal LAFC Vertical LAFC Safety Cabinet Laminar air flow isolators 0.45 0.1 m/s 0.30 0.05 m/s Inward air flow > 0.4m/s; Downward air flow 0.25 - 0.5m/s * 0.3 - 0.6m/s *

* No value may deviate from the mean by more than 20% 4.4 Air change rate[2]: Aseptic room: Clean support room: 4.5 Operator protection factor[7],[8]: Safety Cabinet: OPF > 1 x 105 4.6 Settle plates[2],[4],[9]: Diameter 90mm, 4hr exposure (d). EC GMP Grade A B C D Location Examples LAFC (e) Isolator (e) Transfer device Background to LAFC Background to Isolator (b) Clean support room Background to Isolator (c) At rest cfu (average value) 1 per 2 plates 1 per 2 plates <1 <1 <1 5 50 Operational cfu (average value) 1 per 2 plates 1 per 2 plates 5 5 5 50 100 > 20 air changes per hour > 20 air changes per hour

-4-

4.7

Active viable air sampling[2],[4],[9]: Location Examples LAFC (a) Isolator (a) Transfer device Background to LAFC Background to Isolator (b) Clean support room Background to Isolator (c) At rest cfu/m3 (average value) <1 <1 <1 <1 <1 10 100 Operational cfu/m3 (average value) <1 <1 10 10 10 100 200

EC GMP Grade A B C D 4.8

Finger dabs[2],[4],[9]: Glove print 5 fingers, cfu/glove (average value) <1 (in critical workzones)

4.9

Surface samples [2],[4],[9]:

Diameter 55mm plate (surface area 25cm)/surface swabs (f). EC GMP Grade A B C D Location Examples LAFC Isolator Transfer device Background to LAFC Background to Isolator (b) Clean support room Background to Isolator (c) At rest
cfu/25cm (average value)

Operational
cfu/25cm (average value)

<1 <1 <1 <1 <1 5 25

<1 <1 5 5 5 25 50

4.10 Operator aseptic transfer tests[2],[4]: Zero growth 4.11 Process simulation tests[10]: Zero growth 4.12 Notes (a) (b) (c) Test methods used when sampling in the operational state should not interfere with work zone air flow or quality. Limits for background environment for Negative pressure isolators with type A, B, C1 transfer devices or background environment for Positive pressure isolators with type A transfer devices [5] . Limits for isolators to be sited in a grade D[4] background or the background environment for Negative pressure isolators with type C2, D, E, F transfer devices or the background environment for Positive pressure isolators with type B, C1, D, E, F transfer devices[5] . Although it is suggested that certain combinations of isolator type and transfer device may be sited in less stringent background depending on the activity being undertaken[5], the recommendation of GMP[4] is for a minimum of a grade D background. (d) (e) If settle plates have been exposed for less than 4 hours, action levels should be adjusted accordingly. In critical work zones of LAFC/Isolators, 2 plates should be exposed at each work session. If swabs are used quantitatively the surface area being sampled should be recorded in order to relate the count obtained to the action level.

(f)

-5-

5.
5.1 5.1.1

Actions when results deviate from action levels

Physical tests When the results of physical testing are outwith action levels, the Responsible Pharmacist must be informed and the test repeated. A satisfactory repeat test should be confirmed in duplicate. If the repeat test is still outwith the action level, this may indicate a problem such as a blocked HEPA filter, a leak in the isolator, a hole in the glove system, etc., and further action must be taken to identify and rectify the problem, e.g., a failed pressure decay test may require a helium test to pin-point the leak. All corrective actions taken and subsequent results must be fully documented (e.g. in an Abnormal Event Log (Appendix 1)).

5.1.2 5.1.3

5.1.4

5.2 5.2.1

Microbiological tests When the results of a microbiological test are outwith action levels, the action taken will depend on the type, extent and duration of the observed contamination. All abnormal results must be reported to the Responsible Pharmacist. Isolated incidents often require no more than close monitoring of the results of subsequent tests or a repeat test and examination of the control systems. Repeated levels of contamination greater than action levels may require an increase in the frequency of testing, observation of operator technique, investigation of cleaning procedures, etc. In such cases, the causative organism(s) should be identified and the potential source traced. Gross contamination in any test requires immediate action which may include additional microbiological monitoring, identification of the causative organism(s), a complete clean down of the aseptic facility, re-training of staff, repeat testing for an extended period until the contamination has been eliminated. Wherever possible, corrective action should be taken to prevent the recurrence of such an incident. All corrective actions taken and subsequent results must be fully documented (e.g. in an Abnormal Event Log (Appendix 1)).

5.2.2

5.2.3

5.2.4

5.2.5

-6-

6.
[1] [2]

References
Aseptic Dispensing for NHS Patients. Department of Health. 1995. The Quality Assurance of Aseptic Preparation Services (3rd Edition). The Pharmaceutical Press, 2001. Guidelines on Test Methods for Environmental Monitoring for Aseptic Dispensing Facilities. Produced by a Working Group of the Scottish Quality Assurance Specialist Interest Group. (Current Edition) Rules and Guidance for Pharmaceutical Manufacturers and Distributors 1997. Medicines Control Agency, London: The Stationary Office. 1997. (under review) Isolators for Pharmaceutical Applications. Editors Gerard Lee and Brian Midcalf, HMSO. Cambridge. 1995. Clean Rooms and Associated Controlled Environments Part 1: Classification of Air Standards. BS EN ISO 14644-1:1999. London: British Standards Institute, 1999. BS 5726 (1992) Microbiological Safety Cabinets. Keynes, UK. 1992. British Standards Institute, Milton

[3]

[4]

[5]

[6]

[7]

[8] [9]

BS EN 12469:2000 Biological Safety Cabinets Standards. Parenteral Society Technical Monograph No. 2. Environmental Contamination Control Practice. The Parenteral Society, Swindon. 1989. Parenteral Society Technical Monograph No. 4. The use of process simulation tests in the evaluation of processes for the manufacture of sterile products. The Parenteral Society, Swindon. 1993.

[10]

-7-

Appendix 1 Sheet No.: .. Action Taken Initials and Date

ASEPTIC DISPENSING FACILITY

Abnormal Event Log

Date of Test

Test

Result of Test