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 environments–Biocontamination control (Part 1) ISO 14698-2 Cleanrooms and associated controlled environments–Biocontamination control (Part 2) ISO 14698-3 Cleanrooms and associated controlled environments–Biocontamination 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

4. that penetrates the clean range. 2a. 2b and 3 the clean room must fulfill the GMP class D/100'000.ISO 14644-1 and the VDI 2083-1. with intended personnel occupation. without personnel.9 Operation state : at rest Clean room in function with inserted production mechanisms in standby mode. 4. 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 General Requirements of Clean Rooms for the Production of Medical Devices For medical devices of the class 1. 5. 4.1 Requirements for Technical Building Aspects These requirements can be extracted from the following table. 4. 6 Qualification and Validation Activities When planning a new production building the activities cover the following ranges.10 Operation state : in operation Clean rooms and production mechanisms in function. with which the air. is mixed with interior air by induction.6 Turbulent Mixed Current Air distribution.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. for which the execution of separate qualifications offers itself: .8 Operation state : as built Clean room in function. without inserted production mechanisms. without personnel.

1 Clean Room A separate QMP should cover the HVAC(Heating.) Zone concept Specification of the requirements of areas. summary of all process requirements . 6. cover.. SOP's etc. Ventilation and Air Conditioning)-system and the pure space covering (wall. including cleaning validation • Monitoring system • Utilities • Operating facilities On changes of an existing clean room the range of the qualification activities is accordingly smaller. in particular definition of the preventive measures and security measures (maintenance plans. soil of the clean room).• Clean room. air-locks) Room equipment catalog conversion of the zone concept. in particular definition of the categories of purity (range classes. 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. however without production equipment and their process.

soil. 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.2 Cleaning Validation The cleaning validation refers to the cleaning of the surfaces of wall. window. 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 .6.

but do not count among the extent of this SOP. which affects the operation of the plant significantly (e. The monitoring covers the following points: Microbiological monitoring in accordance with local defaults and/or minimum requirements of Monitoring of manufacture of medical devices. 6. Technical monitoring with control.g. Remarks: These activities must be considered as interface in the total concept.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. which was accomplished. In accordance with FDA demands in particular the over pressure level must be continuously noted. 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.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. – End of document – . 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. ISO 14698-1: 200 CFU/plate (plate = 25 cm2) 6. However the acceptance criteria for product-affecting surface must be considered. The range of these qualification / validation activities is defined in the context of a risk analysis. e. Temperature and Humidity The room air characteristics pressure. change of terminalfiltration filters with a filter surface ε 20% of the total filter surface) The extent of the requalification is identically with a new qualification (without recovery test). change of the operational use after maintenance work. 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.3 Monitoring System for Pressure. temperature and humidity must be supervised.g. maintenance and repair of the HVAC-system. Thus with the implementation of a monitoring system 21 CFR part 11 is to be considered. For this the data from the monitoring can be consulted.