VALIDATION AS A KEY TOOL IN SUCCESSFUL TRANSFER OR ESTABLISHMENT OF A MEDICAL DEVICE COMPANY IN A NEW FACILITY

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1 VALIDATION AS A KEY TOOL IN SUCCESSFUL TRANSFER OR ESTABLISHMENT OF A MEDICAL DEVICE COMPANY IN A NEW FACILITY Oren Levin, Diane Gordon VisionCare Ophthalmic Technologies, POB 3879, Petah Tikva 49130, Israel Abstract Medical Device and Pharmaceutical companies are sometimes required to transfer their manufacturing plant or set up operational activities in a new facility. Advance planning of the transfer or the beginning of operational activities will help ensure conformance to mandatory requirements and the achievement of a high level of quality during manufacturing activities. This paper will present the activities required by the Medical Device Company for planning and implementation of validation activities in the event of a company or manufacturing facility transfer. The proposed planning and implementation activities are based on International Standards, current FDA QSR part 820 and CE MDD requirements as well as the valid experience of VisionCare Ophthalmic Technologies Ltd. The planning was based on a process risk approach and analysis. Validation steps and the master validation plan illustrate the required activities from inception to completion including installation, operation and process qualification. Several examples of plans, templates of test protocols and reports, checklists, and requirements for calibration of instruments and equipment will be offered. The methods and experience presented may be useful both for companies planning the establishment of a new facility and for those planning the transfer of an existing operation. In addition this paper will describe the activities for the full validation of a Clean Room from Installation, Operation and Process Qualification through determination of microbial limits (bioburden) to validation of the software controlling the environment in the Clean Room. A short overview of questions asked by the CE notified body and FDA investigator regarding validations during their audits will be presented. VisionCare Ophthalmic Technologies Ltd believes that the integration of the risk based approach, process analysis, quality planning and implementation of good validation practices are the keys to assure the quality of the product and processes in the new facility and contributed to the successful conclusion of both the FDA Pre-market approval audit and the CE notified body audit and that it may be used as a valid model by other Medical Device and Pharmaceutical Companies. Introduction In the life cycle of a medical device manufacturing company it is necessary to establish a manufacturing facility and it is sometimes necessary, for sound business reasons, such as expansion of the business, to expand the facility or move to a new facility. For a new or upgraded facility commissioning and facility validation is the foundation for assuring success in further manufacturing process validation. The purpose of this presentation is to detail the facility, equipment and process validations required for the completion of the transfer of a manufacturing facility to a new location or during the establishment of a new facility. In general when moving to a new facility it is the Company s intention to transfer its personnel, quality system, and operating procedures as previously implemented. Existing procedures should be reviewed and those requiring revision or new procedures specifically related to the new facility and equipment noted. These procedures should be revised or written and issued in compliance with the Quality System change control procedures. In the case of the

2 establishment of a new facility, recruitment of personnel, building of the Quality System and establishment of operating procedures need to be implemented This presentation describes the validations required to bring the facility into compliance with the Quality System. It is good practice to write and implement a Quality Plan to define the changes in the Quality System required as a result of a facility transfer. Qualification And Validation Overview Before beginning the validation of the manufacturing process the appropriate facility and the supporting utilities and equipment must be in place. It is advisable to document and establish in a Validation Master Plan (VMP) the requirements for qualification and validation of the manufacturing and quality assurance of the products, equipment, processes, methods, and software early in the project. (see example of a Validation Master Plan Matrix Appendix 1). The scope of the validation can be based on a risk analysis of the impact of a system on the product quality and critical systems identified. The medical device company needs to qualify and validate the facility design, installation and function, critical process support utilities, process equipment design, installation and operation. When the facility has been validated the next step is to train the operating staff and to validate the manufacturing process. For each IQ/OQ/PQ to be performed, a written protocol should be established, including the specific acceptance criteria. In some cases, IQ, OQ and PQ activities may be combined and should be defined in the protocol. It is helpful to use standardized documentation templates to reduce the time required to write, review and approve validation protocols and reports. Installation Qualification (IQ) IQ should be performed to ensure that equipment for the new facility and the transferred equipment has been properly installed and operates as intended. The qualification could include a review of the manufacturers diagrams, installation specifications, and certificates of installation by the contractors. Operational Qualification (OQ) Establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements. OQ for equipment used should be performed according to defined protocols. Performance Qualification (PQ) Establishing by objective evidence that the process under anticipated (normal) operating conditions, consistently produces a product that meets all predetermined requirements. To conclude the qualification process, a process validation for the Medical Device shall be carried out and usually includes the complete manufacture of more than 2 consecutive lots or a relevant quantity of the device. A separate protocol should be established detailing the acceptance criteria. Finished product should be manufactured and inspected in accordance with the relevant DMR and the product should meet all predetermined requirements. Pre and post validation, the equipment used should be calibrated and found in a calibrated state, for the intended purpose. If post validation calibration fails then metrological correction needs to be performed followed by revalidation. Organization and Personnel A Quality System ("QS") should be established or adapted and implemented to assure compliance with the requirements of the QSR as defined in 21 CFR Part 820, ISO 9001:2000, ISO 13485:2003, and the Medical Device Directive (full Quality System, annex II or any other applicable directive). It is often helpful to document a detailed analysis of the changes required to the quality system due to the move in a Quality Plan Matrix, as part of the Quality Plan for the validation and verification activities required for the facility transfer or establishment.

3 It is good practice at the start of the project for the company to appoint a validation coordinator and where necessary interdepartmental team members to be responsible for assuring that the validation master plan and the quality plan are completed adequately. It is important that all staff involved in the validation should be adequately trained. Facility Before establishment or transfer a detailed document (BOD - Basis of Design, URS - User Requirement Specifications or similar document) describing the new facility should be written and approved. This should include general business and special facility requirements, with reference to the reason for the transfer or establishment of the facility, specific environmental requirements, placement of personnel, location of major equipment and detailed diagrams of all of the areas in the facility. A detailed description and architects plan of the facility should be included or referenced in the validation master plan. If the facility is required to comply with international standards these should be defined and taken into account during the validation activities. Special conditions such as restricted entrance, gowning or behavior in the manufacturing area should be described. Areas designated for special activities, such as packaging, laser operation that require different conditions should be described separately. The facility should comply with local building, fire, and safety regulations. Strict attention should be paid to production, material, and personnel flow in the facility. Suitable procedures should be written to describe the flow of production, personnel and materials in the new facility and any special behavior required (for example gowning). Below is a sample checklist of elements to be considered when designing a facility 1. Wall and floor surfaces that are smooth, crevice free and pit free. The walls and floor corners are rounded to facilitate cleaning. 2. Floor surface is easily cleanable, welded anti-static PVC sheet. 3. Electrical and control units are flush with the wall. 4. Exposed pipe works are polished stainless steel. 5. Furniture in the gowning room includes step-over bench, clean room type lockers, hand washing, disinfection and drying facility (paper free), full-length wall mirror and refuse basket. 6. Furniture in the clean rooms is stainless steel and HPL type and is compliant with ECD requirements for floors and Furniture. 7. Use of wood is forbidden. 8. Chairs are clean room type with non-particle shedding covering 9. Doors and pass-thrus are equipped with leak tight seals and are fitted flush with the wall and with minimum crevices. Active pass-thru may be required for ISO class 7 or lower class facilities. 10. The gap between the doors and the floor are controllable according to environment control designer instructions. 11. The hinges are adjustable type. The doors are equipped with mechanical closers. 12. Illumination of the working areas should comply with the BOD/URS or is recommended to be between LUX for assembly and test facility areas. Controlled Environment Area (Cleanroom, surrounding controlled areas and utilities) The CEA including the air handling system should undergo full validation (IQ, OQ, PQ). The purpose of the IQ is to verify the following: 1. Facility design, construction and finishes are in accordance with the approved facility Engineering file and drawings. 2. The Heat Ventilation and Air Conditioning (HVAC) system within the facility, with all kits sub-parts and components, is installed according to the vendor s requirements and company pre-determined specifications, as set in approved layouts and system drawings as well as the Engineering file. 3. All supporting utilities are adequate and connected properly.

4 4. The spare part list is complete and accurate. 5. The manuals for operation and maintenance of the equipment are on file and are adequate. 6. Verification of equipment, instruments, valves and fittings 7. Critical instruments have been calibrated The scope of the IQ should cover verification of the Air Handling Unit (AHU) system and its parts to all the controlled areas, including: 1. Air handling units, 2. Air supply ducts, 3. Fan Filter Units 4. Filters 5. Air return ducts 6. Supply of Chilled Water and its returns 7. Water system pipes and components directly connected to the AHU 8. The boundaries of the System are from the points where air enters the system from, the various filters, heat exchangers, heating elements, blowers with their motors, to the clean rooms out to the exhaust. The purpose of the OQ and PQ is to verify the following: 1. All instruments which are not part of the system but which are used during the operation and process qualification must be calibrated/ certified or verified before performing tests. 2. If a computerized control system is used it should be verified that analog and digital inputs and outputs of the PLC operate as designed including alarms. 3. Static pressure tests, differential pressure is measured between the ambient/outside the clean room and the inner room(s). 4. Flow rate test/air changes tests should be carried out to ensure that they meet the specifications. They should cover all the filter areas and be carried out in accordance with approved standards. 5. Particle Count test should be carried out to ensure that it meets the specifications, the number of particles and their size in every room should be checked in accordance with approved standards. This test should be carried out in "As-built", "At-Rest" and "Operational" conditions (see ISO 14644). 6. Filter integrity test (known as DOP test) checks the efficiency of the HEPA filters according to their predefined efficiency (at least 99.97%) for particles larger then 0.3micron. 7. The level of microbial contaminations in the production and control facilities under dynamic and static conditions. The data received should be analyzed and serves as a foundation to determine the limits for the Bioburden monitoring in the CEA. In addition the microbial bioburden on the product should be evaluated to ensure that acceptable levels are achieved. The results of the above validation are used as a basis for defining sampling sites in the new facility, test procedures and their frequency, alert and action levels, and investigative and corrective actions to be implemented if levels are exceeded. In addition differential pressure and temperature monitoring should be performed routinely. The CEA gas delivery system should undergo full validation (IQ, OQ, PQ). The check list below can be used for IQ of the gas delivery system: 1. Provide description of the Gas system and its major components 2. Provide description of the Gas system operations 3. Provide mechanical specifications of the Gas system components 4. Provide description, specifications and mode of action of the controls and indication gauges 5. Provide Gas system construction "as built" drawings 6. Verify that proper junctions of the cylinders have been installed properly. 7. Verify that piping is leak free using water and soap or leak detector. 8. Ensure Maintenance Procedures maintained next to the compressed gas balloon. 9. Provide Gas filter specifications 10. Verify that gauges and filters are installed in according to the relevant procedure

5 11. List the composition of the gas. 12. Provide procedure for operation and maintenance of the system. 13. Provide calibration certificates for gauges, indicators and controls 14. Ensure availability of Event Registration Equipment Log book as per the relevant procedure 15. Provide safety instructions for system components and integrated systems 16. Provide tag list of valves, pipes and control instruments OQ and PQ of the gas delivery system should be carried out to ensure that it meets the predetermined specifications criteria. Equipment Existing Equipment: In order to minimize possible damage during transit it is recommended to contract a professional moving company to pack and transport the existing measuring and manufacturing equipment. All equipment should be tested to be in working order after transfer. The need for calibration and qualification of test, measuring and manufacturing equipment should be evaluated and the results documented as part of the Validation Master Plan. All equipment to be calibrated should be calibrated and qualified at the new facility. All the portable equipment should be qualified for proper operation prior to starting manufacturing work. New Equipment: New equipment should undergo complete validation and calibration as necessary. Where possible it can be time saving to test and inspect systems or new equipment at the vendor's site before delivery as this inspection can reveal problems before the systems or equipment are installed. The results of such an inspection can be included in the validation. Other Aspects of the Facility Transfer Product labels and labeling information should be reviewed and changes made relating to the new address. All changes should be controlled and issued in compliance with the QS requirements. Consideration of any possible changes, resulting from the transfer of facility location such as subassembly procedures, process parameters, final assembly, packaging, QC/QA or device specifications should be taken into account and documented. New software or changes to existing software require risk evaluation and assessment as to whether validation activities are required. The change shall be documented. Questions asked by FDA and CE auditors The FDA inspection is based on the FDA Guide to the Inspection of Quality Systems (QSIT) and is designed to determine the company's state of compliance with the relevant regulations. QSIT leads the auditor through the various parts of the company's Quality System. Note that the company is responsible for the compliance of its subcontractors providing critical services, for example sterilization subcontractor. When reviewing the Device History Record (DHR) the inspector must evaluate the validation study to determine whether the process has been adequately validated, this includes any software that is used to control a process. The CE inspection is based on CE MDD, CE IVD or other Directive relevant to the facility and ISO that like the FDA requires the company to establish and implement verification, validation and monitoring inspection and test activities to ensure that the product meets its specifications. Specifically during the inspection of the cleanroom the CE auditor inspected aspects of the construction, cleanliness, provision for hygiene, equipment, work areas, environmental control, validations and normal monitoring activities and documentation related to the above activities including Procedures, product related specifications, validation documents, training records, maintenance instructions and files, problem records and regular monitoring records.

6 References 21 CFR 820 FDA Good Manufacturing Practices for Medical Devices ISO 13485:2003 Medical devices Quality management systems: requirements for regulatory purposes. GHTF Quality management Systems Process Validation Guidance GHTF/SG3/N99-10:2004. ISO : 1999(E)-Cleanrooms and associated controlled environments-part 1: Classification of Air Cleanliness. ISO 9001:2000 Quality Management Systems-Requirements QSIT- FDA Guide to the Inspection of Quality Systems Facility Qualification: A case study for Integrating and Streamlining the Validation Approach to Reduce Project Resources by Graham C. Wrigley and Jan L. du Preez, Ph.D.

7 Appendix 1: Example of a Validation Master Plan Matrix PROCESS STEP / INSTRUMENT / EQUIPMENT PROCEDURE IQ O Q PROTOCOL # PQ IQ OQ PQ Facility Controlled Environment Area 113 r r r 84R 5002P 5002P Compressed Nitrogen as a cleaning agent 108 r r r 5074P 5046P 5046P Equipment used in manufacturing process Comparator r r r 5069P 5024P 5036P 5067P Labeling machine r r r 5069P 5029P 5054P Equipment used for Quality Control Refrigerator r r r 5069P 5044P Video System r r r 5069P 5039P 5052P Assembly machine r r r 5069P 5028P 5030P Oven r r r 5069P 5076P 4399P Validation of processing methods 3 Lots Product family 5050P Sterilization Validation Process 5077P * r=required

Supplementary Training Modules on Good Manufacturing Practice. Validation. WHO Technical Report Series, No. 937, Annex 4.

Supplementary Training Modules on Good Manufacturing Practice Validation WHO Technical Report Series, No. 937, 2006. Annex 4. Validation Slide 1 of 48 August 2006 Validation! Part 1. General overview on