Requirements, Qualification and Validation of new or upgraded Clean Rooms for Medical Devices 1 Objective Definition of the procedure for the initial qualification, the requalification and the routine monitoring from clean rooms to proof the sequential agreement with the fixed classification of the particle purity and the number of germs in the air. 2 Scope This SOP applies to all the production sites of the Hospital Care Division of the B.Braun Melsungen AG, where medical devices are manufactured. 3 References/Literature EC Guide to GMP, Annex 1 ISO 14644-1 Cleanrooms and associated controlled environments (Part 1) ISO 14644-2 Cleanrooms and associated controlled environments (Part 2) ISO 14644-3 Cleanrooms and associated controlled environments (Part 3) ISO 14644-4 Cleanrooms and associated controlled environments (Part 4) ISO 14644-5 Cleanrooms and associated controlled environments (Part 5) ISO 14698-1 Cleanrooms and associated controlled environmentsBiocontamination control (Part 1) ISO 14698-2 Cleanrooms and associated controlled environmentsBiocontamination control (Part 2) ISO 14698-3 Cleanrooms and associated controlled environmentsBiocontamination control (Part 3) VDI 2083-1 Cleanroom technology Particulate air cleanliness classes VDI 2083-3 Cleanroom technology Metrology and test methods Document-ID: BPP HC-DIV 160 -> HC-DDDD-G-5-4-07-160 Validation Document-ID: BPP HC-DIV 197 -> HC-DDDD-M-5-4-05-197 Monitoring of manufacture of medical devices FDA 21 CFR Part 820 Quality System Regulation FDA 21 CFR Part 11 Electronic Records; Electronic Signatures FDA 21 CFR Part 211.46 Heating, Ventilation and Air Conditioning (HVAC) ISPE-Baselines Guides for new Facilities: Sterile Manufacturing Facilities FED-STD-209E NEBB Sections 1 & 2 4 Definitions 4.1 Area class D Area class where production and primary is carried out and which is in accordance with classification of the GMP-Guideline (PIC/S) DIN ISO 14644. With that the necessary measurements are defined for the air-supported particles by DIN EN ISO 14644 or by the GMP-Guideline for already existing production rooms. At global productions sites of B. Braun clean rooms which have to be build newly or existing clean rooms which have to be rebuilt, have always to be in accordance with area class D/100.000, DIN EN ISO 14644 (ISO 8) in operational state at rest. The defined values of ISO-class 9 are for operational state in operation. 4.2 Clean Room Area with defined concentration of airborne particles, which is designed and used in a way that the number of particles introduced into the area and the number of developing respectively deposited particle is the smallest possible and in which other purity-relevant parameters such as temperature, humidity and pressure are regulated as required. 4.3 Clean Range Ranges within an area, a plant or machine, whose conditions are specified like a clean room and which can be enclosed by a wider range. 4.4 Classification Organization of the particle purity of air on the basis of class borders. The class border represents the maximum value of the permitted particle concentration for a certain particle size. 4.5 Air Purity Categories The definition of the classes of an area considers the necessary degree of purity for a certain production process. Categories of air purity are specified by the European Union GMP Guide, Annex 1, the DIN EN

ISO 14644-1 and the VDI 2083-1. 4.6 Turbulent Mixed Current Air distribution, with which the air, that penetrates the clean range, is mixed with interior air by induction. 4.7 Low Turbulence Displacement Current (laminar flow) Regulated air flow with homogeneous speed and almost parallel flowlines over the entire cross section of the clean range. 4.8 Operation state : as built Clean room in function, without inserted production mechanisms, without personnel. 4.9 Operation state : at rest Clean room in function with inserted production mechanisms in standby mode, without personnel. 4.10 Operation state : in operation Clean rooms and production mechanisms in function, with intended personnel occupation. 5 General Requirements of Clean Rooms for the Production of Medical Devices For medical devices of the class 1, 2a, 2b and 3 the clean room must fulfill the GMP class D/100'000. This corresponds to the ISO class 8 according to ISO 14644 for operating state "at rest" and/or ISO class 9 for operating state "in operation". 5.1 Requirements for Technical Building Aspects These requirements can be extracted from the following table.

6 Qualification and Validation Activities When planning a new production building the activities cover the following ranges, for which the execution of separate qualifications offers itself:

Clean room, including cleaning validation Monitoring system Utilities Operating facilities

On changes of an existing clean room the range of the qualification activities is accordingly smaller. 6.1 Clean Room A separate QMP should cover the HVAC(Heating, Ventilation and Air Conditioning)-system and the pure space covering (wall, cover, soil of the clean room), however without production equipment and their process. The following documents (inputs) must be present for the compile of the QMP: List of the product specifications for the security of the necessary area class D material flow and personnel flow (concept) due to requirements: o Avoidance of cross contamination o One-way-flow Risk analysis for clean rooms for recognition of hazard potential, in particular definition of the preventive measures and security measures (maintenance plans, SOP's etc..) Zone concept Specification of the requirements of areas, in particular definition of the categories of purity (range classes, air-locks) Room equipment catalog conversion of the zone concept, summary of all process requirements

6.2 Cleaning Validation The cleaning validation refers to the cleaning of the surfaces of wall, soil, window, doors of the clean room as well as the air-locks with the goals: Identification of possible weak points of the cleaning process Identification of the cleaning and disinfection achievement of the individual cleaning steps Determination of the influences of different process parameters on the cleaning process The cleaning validation is to accomplish during PQ phase of the clean room in case of Change of the cleaning agents Change of the surface substance (material) for wall, soil, window and doors For the implementation the following steps are to be considered: Definition of a measuring point controller for the monitoring Cleaning schemes and instructions must be present

Preliminary tests for the re-demand rate of the colony-forming units (CFU) Description of the sampling procedure sample "after the cleaning" for the examination of the efficiency of the process

sample "before the cleaning" for the examination of the inspection frequency Acceptance criteria in accordance with. ISO 14698-1: 200 CFU/plate (plate = 25 cm2) 6.3 Monitoring System for Pressure, Temperature and Humidity The room air characteristics pressure, temperature and humidity must be supervised. In accordance with FDA demands in particular the over pressure level must be continuously noted. Thus with the implementation of a monitoring system 21 CFR part 11 is to be considered. 6.4 Operating Facilities In the case of displacement of the operating facilities into a new clean room a requalification of the operating facilities as well as a revalidation of the associated processes are to be accomplished. The range of these qualification / validation activities is defined in the context of a risk analysis. Remarks: These activities must be considered as interface in the total concept, but do not count among the extent of this SOP. However the acceptance criteria for product-affecting surface must be considered. 7 Requalification A requalification is to be accomplished: Routine-Requalification frequency has to be assessed based on the conditions/changes/monitoring data after conclusion of a rectification, which was accomplished, in order to repair the disregard of the critical values after a change of the clean room or changes of the HVAC-system after a significant change of the valid performance specification, e.g. change of the operational use after maintenance work, which affects the operation of the plant significantly (e.g. change of terminalfiltration filters with a filter surface 20% of the total filter surface) The extent of the requalification is identically with a new qualification (without recovery test). For this the data from the monitoring can be consulted. 8 Clean Room Monitoring Monitoring measurements are accomplished during operation for technical and micro-biological control of the clean room plants and parameters in the production level. The monitoring covers the following points: Microbiological monitoring in accordance with local defaults and/or minimum requirements of Monitoring of manufacture of medical devices. Technical monitoring with control, maintenance and repair of the HVAC-system. End of document