PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME
PI 032-2 8 January 2010
RECOMMENDATION
GMP ANNEX 1 REVISION 2008, INTERPRETATION OF MOST IMPORTANT CHANGES FOR THE MANUFACTURE OF STERILE MEDICINAL PRODUCTS
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Index
0. 1. 2. 2.1 2.2 2.3 3. 4. 4.1 4.2 4.3 4.4 4.5 4.6 5. 2 Purpose and scope ............................................................................................ 2 Basics ................................................................................................................ 3 Legal requirements (binding) ............................................................................. 3 Regulatory guidance (to be justified if not applied) ............................................. 3 Relevant international norms (to be justified if not applied) ................................ 3 Definitions and abbreviations ............................................................................. 3 New texts and 4 Clean room / clean air 4 Clean room / clean air device monitoring ........................................................... 5 7 Media simulations .............................................................................................. 7 Pre-sterilisation bioburden monitoring ................................................................ 7 Provisions for environmental conditions for the handling of aseptically filled vials after leaving the aseptic processing area up until 8 Revi
sion history ............................................................................................... 11
0. Document history
The present technical interpretation of Annex 1 to the PIC/S GMP Guide (PE 009) on the manufacture of sterile medicinal products (hereinafter referred to as GMP Annex 1) was initially drafted by Switzerland / Swissmedic and then commented by PIC/S Participating Authorities. It was agreed that the technical interpretation of GMP Annex 1 should be the same between the EU and PIC/S 1. Adoption by Committee of PI 032-1 Entry into force of PI 032-1 Entry into force of PI 032-2 3 November 2009 1 December 2009 1 January 2010
1. Purpose and scope
In order to assure a harmonised conduct of inspections, with respect to the 2008 revision of GMP Annex 1 2, this document summarises the interpretations which an inspector of the competent regulatory authority should adopt when performing an inspection of a manufacturer of sterile medicinal products. This document reflects the most important changes and also addresses the feedback from industry concerning the GMP Annex 1 Revision. It is not meant to address all changes within the Revision.
1
Annex 1 of the PIC/S GMP Guide is identical to Annex 1 of the EU GMP Guide (Eudralex Volume 4 GMP). Both Guides are equivalent in terms of GMP requirements. 2 The revision of Annex 1 to PIC/S GMP Guide was adopted on 12 November 2008 by the PIC/S Committee and entered into force on 1 March 2009. PI 032-2 2 of 11 8 January 2010
2. Basics
2.1 Legal requirements (binding)  Refer to national legislation 3
2.2 Regulatory guidance (to be justified if not applied)  For EEA countries: Eudralex Volume 4 GMP, GMP Annex 1, revision of November 25th, 2008 For non-EEA countries: PIC/S GMP Guide (PE 009), Annex 1 or equivalent
2.3 Relevant international norms (to be justified if not applied)      EN ISO 14644-1 EN ISO 14644-2 EN ISO 14644-3 EN ISO 14644-4 EN ISO 14644-5 EN ISO 14644-6
The relevant international norms used in the context of this paper were applicable at the time this document was drafted. Future revisions of these norms do not automatically apply to this document. T
he GMP Annex 1 Revision came into effect on March 1st, 2009; the provisions for crimp capping for all vials will come into effect in March 1st, 2010. However, especially for new installations with respect to crimp capping, conformance with the revised GMP Annex 1 is to be encouraged already today.
3. Definitions and abbreviations
Room Classification Room classification is part of the initial qualification of a facility and is also normally performed during routine re-qualification. Both, classification activities and the final / to be achieved classification status for clean rooms / clean air devices are meant. This Annex directly links to clean room / clean air device classification according to ISO 14644. For qualification and validation and re-qualification see also PIC/S GMP Guide Annex 15. Restricted Access Barrier Systems
RABS
3
< for Switzerland: Federal Law on Medicinal Products and Medical Devices (Law on Therapeutic Products - LTP), SR 812.21 and Ordinance on Establishment Licenses (ELO), SR 812.212.1.
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4. New texts and their interpretation
4.1 Clean room / clean air device classification General interpretation: The GMP Annex 1 Revision distinguishes very clearly between clean room / clean air device classification which is described in sections 4 to 7, and clean room monitoring, which is described in sections 8 to 20. Section 3 defines at rest and in operation states, which is not new. However, it should be noted that the company needs SOPs to define at rest and in operation states, which might be specifically required per production room. These SOPs should include a definition of equipment to be installed and running, number of operators to be present. In general, clean room / clean air device classification is required to be performed according to EN ISO 14644-1 with the applicable limits for particle counts defined in the table in section 4 of GMP Annex 1. Probe-locations should be chosen in order to demonstrate the homogeneity across the room. A classification report should be prepared according to section 4.4 of ISO 14644-1 and section B.1.4 of ISO 14644-3. Monitoring, on the other hand, does not need to be performed according to EN ISO 14644-1. It can be performed for a reduced number of sampling points
and sampling volumes. A formal risk analysis study based on experiments and analysis of the monitoring data (over at least 6 month operation) should provide a basis for the determination of frequencies and limits. Frequencies and limits should be processbased and the results of the initial qualification and on going monitoring should be taken into account when setting operational alert and action limits. These limits and sample locations should be periodically reviewed for on-going validity of the risks initially considered. Those frequencies and limits should be process-based and the results of the qualification should be taken into account. Section 4: New text: Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. Interpretation: Classification of clean rooms / clean air devices should be done according to provisions in EN ISO 14644-1. Compared with the prior version, the values for maximum permitted particles have been changed in this section. Especially the values for the maximum permitted number of 5 m particles / m3 for grade A have been changed from 1 to 20. For grade A, the corresponding ISO class is 4.8, based on the 5 m counts. For grade D, no in operation limits are defined; the company should establish in operation limits based on a risk analysis and on historical data where applicable. Section 5: New text: For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sampling locations and the sample size.
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Interpretation: Minimum amount of sampling points and sampling volume and also interpretation of the results are defined in EN ISO 14644-1 (confidence interval). See also provisions for outliers in appendix B 6.2 of EN ISO 14644-1. ISO 14644-1 Annex f has an informative section on the use of sequential sampling techniques for non-viable particle monitoring. This technique may be useful in reducing the time needed for sampling very large clean-room areas, at rest. This method would not be considered suitable for "in operation" classification. The application of this method may be acceptable but it is unlikely to be the preferred method since most pharmaceutical facilities do not normally have the very large clean rooms of the type discussed in Annex f and therefore it is unlikely that significant time would be saved. Section 6: New text: Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥ 5 m in remote sampling systems with long lengths of tubing. Interpretation: This section implies that old central particle counters with long tube lengths will no longer be acceptable for clean room classification, as they absorb too many particles (especially 5 m particles). Therefore, modern portable particle counters with short tubes or (even preferable when possible) those without tubes sho
uld be used for classification purposes. The certificate of calibration of the particle counter should mention the tube length and nature of material (inox or polymer). When calibration of the particle counter is performed outside by an external laboratory, the particle counting system should be qualified on site with a comparative measurement with an isokinetic probe. For impact on monitoring, see also section 11. Section 7: New text: EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications. Interpretation: This provision concerns clean room re-qualification. The company may choose to perform re-qualification of clean rooms according to provisions in EN ISO 14644-2 (including the proposed frequencies). For re-qualification of grade A areas, it is generally expected to carry out the following activities also performed during initial classification: air velocity, filter integrity, differential pressure every 6 months. Other examples for frequencies: grade B: every 6 months at rest, once a year in operation; other grades: once a year, with maximum delay defined. If the company takes another approach, this should be justified, e.g. based on monitoring data. 4.2 Clean room / clean air device monitoring Section 8: New text: Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.
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