Document /Version: QM/01 Effective Date: 9 May 2006 Page 1 of 16ABC CO., Ltd. QUALITY MANUAL Function: Title: Document: Replaces: Quality Assurance Department Quality Manual QM N/A First Issue Date: [Title] Reviewed by: Date: [Title] Approved by: Date: [Title] Copy No: Distribution:XXX Department: XXX Department: XXX Department: XXX Department: Managing Director Head of XXX XXX Manager XXX Manager Issued to: Version: 01 Effective Date: 9 May 2006 Next Review Date: 9 May 2008 Reason for Change: Prepared by: Ltd.. TABLE OF CONTENTS SECTION TITLE ABC Quality Policy Statement PAGE 3 3 3 4 4 5 5 5 6 6 6 6 7 9 9 9 10 10 11 12 12 13 13 14 15 16 ISO 9001 CLAUSE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Introduction Organization Manufacturing Facility Quality System Management Responsibility Design and Change Control Document Control Purchasing and Vendor Assurance Material and Product Identification and Traceability Process Control Programmes Inspection and Testing Programmes Calibration Programmes Inspection and Test Status Control of Non-Conforming Product Corrective and Preventive Action Systems Handling and Storage of Materials and Products Control of Quality Records Internal Quality Audits Training Programmes Statistical Techniques Computer Systems Management Facility Control Management of Equipment and Critical Process Utilities Validation Programmes Occupational Safety and Health Programmes .Document /Version: QM/01 Effective Date: 9 May 2006 Page 2 of 16 ABC CO. ABC Quality Policy Statement 1. Ltd. Scope of the Quality Manual This manual covers the quality system that ABC has in place for the commercial supply of its products. quality plans and work instructions associated with the manufacture. It refers to supporting documentation. Introduction 1. ABC business is the manufacturer and sales of a range of products including medicines and cosmetics.. 1. procedures. to manage the quality of its products. storage and distribution of product. Organization Managing Director QA Manager Production Manager Engineering Manager Regulatory Manager Personnel Manager Financial Manager ..1 Purpose of Quality Manual The purpose of this Quality Manual is to outline the Quality Management Systems used by ABC Co. Ltd.Document /Version: QM/01 Effective Date: 9 May 2006 Page 3 of 16 ABC CO.2 2. Manufacturing area and packing area where products expose are controlled to comply with Class 100. is located at XXX. All major pieces of equipment in the Utilities should be listed here.1 Premise ABC Co. ELISA reader. . XXX and XXX. The Company is licensed by Thai FDA under GMP Certificate No. WFI generator. such Purified Water Systems.. bioreactors. Quality Improvements) • Implementation and maintenance of GMP Quality System • Review of Quality System • Planning..Document /Version: QM/01 Effective Date: 9 May 2006 Page 4 of 16 ABC CO. The QA Manager is responsible to liaise with the relevant departments to carry out the following activities in order to meet necessary requirements for the products: • Preparation of various quality plans (including training. Ltd. All major pieces of equipment used in the QC lab to test raw materials. such as autoclaves. 3. scheduling and co-ordination of internal and external quality audits • Identification and preparation of quality records The performance of the Quality Management System is examined at least once a year by Management Review team which consists of XXX. Ltd. product or inprocess or environmental testing should be listed here. Spectrophotometer.000. chromatography systems. Manufacturing Facility 3. such as TOC. Quality Procedures (such as SOP’s and Manufacturing Directions.2 Equipment All major pieces of equipment used in the GMP manufacture of the product should be listed here. Test Procedures) that have been defined and documented are issued to all personnel listed in the controlled distribution list and are used at the work place as references. 4. Clean steam generator. The areas maintain their contamination control using a “validated HVAC” system. The Quality System is documented on four levels: Level 1 Level 2 Level 3 Level 4 Quality Policy Quality Manual Standard Operating Procedures Quality Records and Logbooks The QA Manager (as a Management Representative) shall ensure that the Quality System is being effectively implemented and maintained. washers. 3. The facility consists of XXX. XXX with a valid date from XXX to XXX to manufacture of XXX. Quality System The Quality System ensures that the product complies with its specified requirements and is manufactured in accordance with appropriate standards. Flow chart of Change control is as follows: 7.…. The route of approval and issuing documents are as follows: . Ltd.. ABC CO. The Management team is clearly defined in with a view to: • Ensure approved procedures and instructions are adhered to in all facets of production • Initiate action to prevent occurrence of product non-conformity • Identify and record any product quality problems • Provide solutions through designated channels • Verify the implementation of solutions 6. Management Responsibility The role of the Management team as well as the responsibilities and authorities are as follows: Managing Director is responsible for XXX. XXX is responsible for XXX. Design and Change Control SOP XXX: Change Control Change control is applied to the changes in design and facility. Change control process begins with XXX. QA Manager is responsible for XXX.Document /Version: QM/01 Effective Date: 9 May 2006 Page 5 of 16 5. Production Manager is responsible for XXX. Document Control SOP XXX: Document Control The Document Control Centre in Quality Assurance department is responsible for controlling documentation and records. Specification Record. Inspection and Test Programmes 11. Materials and components meeting the specifications will be labelled with a . 9. equipment and computer systems used for quality critical activities will be suitably validated and records maintained of this validation. completeness. and finished products are identified with a unique code which described in the SOP XXX. and/or Certificate of Analysis (C of A). Batch documentation Traceability back to starting materials will be defined by Quality Assurance according to regulatory requirements on Batch documentation.. packaging materials. Material and Product Identification and Traceability SOP XXX: Lot Numbering System All raw materials. 8. Rejected materials shall be returned to the supplier. Purchasing and Vendor Assurance SOP XXX: Purchasing Procedure SOP XXX: Vendor Audit Procedure Quality of a pharmaceutical product depends as much on the quality of the raw materials and equipment as it does on operations. identification and compliance with the procurement documentation. such as audits. An overview of the Quality Checks and procedures to ensure that the vendors meet the specifications. All unique codes that are used for the identification could provide full traceability. testing etc. Process Control Programmes SOP XXX: Validation: Principles and Strategy SOP XXX: Production Process Validation SOP XXX: Analytical Method Validation SOP XXX: Equipment Validation SOP XXX: Cleaning Validation SOP XXX: Computer Validation All facilities. Therefore it is important that vendors and raw materials meet the required specifications. A QC Officer will perform sampling and testing if testing is required. 11. Selected incoming materials shall be tested as described in the Specifications Record and Certificates of Analysis with specific batch test results obtained as appropriate.1 • • • • • Receiving Inspection and Testing All materials and components supplied in accordance with a Purchase Order shall be inspected on receipt for damage. such that in the event of a product recovery/recall that finished goods lots can be identified and retrieved.Document /Version: QM/01 Effective Date: 9 May 2006 Page 6 of 16 ABC CO. are required. 10. Approved supplier list is defined and maintained. All materials and components shall be verified against the Delivery Order. Ltd. 11. Routine calibration programme is carried out to a schedule. The results of the tests shall be recorded and retained. Final Inspection and Testing The QC Manager will organise final quality control analysis on batch samples according to specifications in Test Methods..Document /Version: QM/01 Effective Date: 9 May 2006 Page 7 of 16 ABC CO. Materials and components rejected on receipt will be placed in a separate quarantine area and identified accordingly. Control of Inspection. Measuring equipment and instruments associated with production and critical utilities in manufacturing areas are calibrated according to published methods/procedures. Ltd. Calibration Programmes All measuring and test equipment and instrument used to demonstrate the conformance of the product to specifications shall be of the appropriate precision and accuracy required for the test. Results are released by the QA Manager as per defined Standard Operating Procedure. These in-process tests are described in standard operating procedures and recorded in production Batch Records and QC Test Records. Calibration programmes ensure: • routine calibration is performed and completed according to written procedures • calibration of each measuring equipment and instrument is documented • specifications of accuracy and precision limits are provided • use of standards traceable to a national or international standard • remedial action is available to evaluate whether there was any adverse effect on the product's quality. calibrated at appropriate intervals and maintained according to documented procedures and a schedule. pending investigation In-process Inspection and Testing The QA Manager and the Production Manager shall ensure that in-process inspection and test activities are carried out in accordance to the relevant SOP’s and master batch instructions. Measuring and Test Equipment (Calibration) Proper and periodic calibration ensures that the selected measuring equipment and instruments continue to have the desired accuracy. Calibration Requirements Analytical instruments in the Quality Control Laboratory are calibrated according to published methods / procedures. Remedial action includes recalibration and evaluation of the impact of out-of-tolerance measurements. . the QA Manager will be responsible to activate a non-conformance report. These methods / procedures include specific directions and limits for accuracy and precision.2 • • 11. These methods/procedures include specific directions and limits for accuracy and precision.3 • • • 12. All finished product lots are released based on verification of the validity of the results and/or observation obtained from the in-process and final QC analysis. If the results are not acceptable. • "RELEASE" label and stored in the designated area under appropriate storage conditions. and precision can be relied upon. as documented in standard operating procedures. Calibration and Performance Check Records Calibrated equipment and instrument are labelled to include: • equipment identification • calibration date • initial of the calibrator • date the next calibration is due Calibration Schedules Equipment and instruments are calibrated at periodic intervals established on the basis of stability. Finished product evaluation. Finished product is held in quarantine until released by the Quality Assurance Department. Ltd. Inspection and Test Status Inspection and Test Status Laboratory evaluation is performed to show with documented evidence that an incoming material. Finished products shall not be released for distribution until: • activities required in the Master Batch Record (MBR) are completed • associated data and documentation is reviewed • release is authorised by signature of the Authorised Person Change of Status and Location of Materials On receipt Incoming materials are held in the quarantine receiving area until the documents have been checked and the lot inspected. 13.. Whenever a lot of material or finished product changes status it must be labelled with one of the following status labels: • QUARANTINE (Lot under test – not available for use or release) • RELEASE (Lot approved for use or release) • HOLD (Lot under investigation – hold processing) • REJECT (Lot failed specifications – not available for use) If any lot does not have a status label it must not be used or released under any circumstances.Document /Version: QM/01 Effective Date: 9 May 2006 Page 8 of 16 ABC CO. Intervals between calibrations can be shortened as required to assure prescribed accuracy as evidenced by the results of preceding calibrations. If there is a query or discrepancy they are held in the quarantine area until the issue has been resolved. purpose. Routine re-calibration (performance check) programme are carried out according to a schedule. requires that the company establishes and maintains procedures for finished product acceptance. Finished products shall be held in quarantine or otherwise adequately controlled until release. to ensure that each production lot of finished product meets the specifications stipulated in the Product Specification. . Calibration is performed according to the frequency specified in respective standard operating procedure. intermediate or finished product was manufactured according to the Product Specification. and degree of usage of the equipment. All rework and re-evaluation activities. All evaluation and investigations are documented. Authority to Change Status Only authorised personnel are allowed to change status of any material. must be documented in Batch Records. Ltd. In-process products and finished products not meeting specifications shall be clearly labelled and held in a separate quarantine area until the discrepancy has been investigated and resolved. segregated. evaluation. Disposition of the non-conforming material and product is documented. 14.. and disposition of nonconforming material and product. Standard operating procedure for rework. The evaluation of material and product non-conformance includes a determination of the need for an investigation and notification of the persons or organisations responsible for the non-conformance. including identifying product as nonconforming. including the determination of any adverse effect from the product rework. The discrepancy shall be clearly documented and the cause investigated. rework or reject a non-conforming material and product is made by the QA Manager. They will be properly identified. The results are documented in the Batch Records and other relevant forms or reports. Control of Non-Conforming Product • • • • • • All non-conforming materials and products shall be quarantined and investigated. Any non-conforming incoming material shall be immediately identified and segregated. documentation. Corrective and Preventive Action Systems Corrective and Preventive Action (CAPA) programmes to: • detect systemic problems and implement corrective actions in order to prevent release of the non-conforming product to customer • implement preventive actions to continuously improve the Company’s processes and products Some actions resulting from a customer complaint may be handled by CAPA. Disposal of non-conforming product is the responsibility of the QA Manager and its disposal is documented. documented and evaluated for appropriate action.Document /Version: QM/01 Effective Date: 9 May 2006 Page 9 of 16 ABC CO. segregation. All GMP operational staff are trained to recognise material and product nonconformance and take appropriate action. retesting and re-evaluation of the nonconforming product to ensure that the product meets its current approved specifications has been established. The procedure includes identification. The decision to use. The need for corrective / preventive action is identified from the following sources: . labelled. segregating and disposal of non-conforming product. documenting and evaluating the non-conformance. • • • • • • • 15. component and bulk and finished product. The control of non-conforming product procedure has been established to manage any material and product that does not conform to specifications. and includes the justification for the use or rework of any non-conforming product after cause of non-conformance is determined and the authorisation for use is approved. . 16. error or incidents within the plan If the event is an isolated incident (not systemic). The stock is monitored periodically for shelf life expiry. orders are reviewed immediately and reconciled against delivered Lots.Document /Version: QM/01 Effective Date: 9 May 2006 Page 10 of 16 ABC CO. All storage areas are temperature controlled and monitored Incoming material movements are consumed and transferred on a First In First Out (FIFO) basis.3 • • 16. regulatory or other specifications or are according to supplier’s recommendations. environment and in such a manner as to prevent damage and deterioration. cleanliness. Control of Quality Records The company maintains quality records required by the GMP standards to demonstrate that the requisite manufacturing and testing control has been achieved.4 • 17. approved storage conditions. .2 • • • • 16. rejected and returned materials.1 • Handling After receipt by appropriately trained personnel. Preservation Appropriate steps shall be taken to ensure that the conditions of storage and transport are within the limits set by the customer. Storage Designated areas and conditions are provided to minimise deterioration and ensure easy selection of correct stock. • • • • product non-conformances process non-conformances (manufacturing deviations) deficiencies arising from internal or external (customer or regulatory) audit or review processes accidents. All materials and finished products are handled according to the company’s handling and safety procedures. Ltd. 16. the cause is well defined and not likely to occur again. Products are packaged in approved packaging material referenced in the Product Specifications with due regard to product stability. If the event however is systemic (has other related incidents or is likely to re-occur in the future if corrective or preventive action is not put in place) then it should be resolved and documented. stock rotation as well as segregation of nonconforming. Packaging Products are delivered to customers using methods that minimise the effect of transport conditions on product viability. and action shall be taken to remove and destroy stock that has short shelf life or has passed expiry or has deteriorated. then the issue may be dealt with according to the individual quality system element and documented on the form specific to the issue. Handling and Storage of Materials and Products 16. These records are maintained and documented by the responsible department personnel and the QA Manager. to determine the effectiveness of the Quality System and verify compliance with GMPs. • Equipment history files. they are destroyed within a designated time period or relocated to other storage areas. Procedures for the stages of internal audit are: • Planning and Scheduling • Preparing for the Audit • Conducting the Audit . but are not limited to: • Records which demonstrate that products supplied by the company meet technical. Records are documented and stored in designated locations that provide proper accessibility. Every element of the quality system is audited at least once per year.Document /Version: QM/01 Effective Date: 9 May 2006 Page 11 of 16 ABC CO. Internal Quality Audits This is done to verify whether quality activities comply with the Quality Plan. The quality records shall be reviewed and analysed periodically to identify trends and to implement continuous improvement of the systems. • Records which demonstrate that all Quality Assurance activities have been effectively implemented. Quality Records include.. At the end of the retention period. A register of staff signatures and initials is maintained. The actual frequency of such audits is determined according to the results of previous audits and the importance of the activity. preserved during storage and are readily retrievable in readable form for the entire retention period. The retention period of quality records is documented. • Equipment calibration records • Validation and Commissioning records. The Quality records are archived in secure storage. Staff undergo training to ensure they complete both Batch Records and QC Test Records in compliance with GMP requirements during operation. • Laboratory Test Records. This may include production Batch Records as well as records from suppliers and subcontractors that relate to current Good Manufacturing Practices. All electronic records are backed up regularly. and Specifications Records including raw data and any electronic records if applicable • Logbooks • Records pertaining to product development. regulatory and contractual requirements. Access to archived GMP records is strictly controlled. Ltd. 18. Training is carried out by appropriate internal and/or external personnel. the company shall establish and maintain procedures for identifying valid statistical techniques required for controlling and verifying the acceptability of process capability and product characteristics.making. but is not limited to.. are agreed between the auditor and the auditee and reported. Statistical Techniques Statistical techniques and methods are used to measure the inherent variability in these processes in order to estimate the confidence levels associated with data and provide information for effective decision. Test Methods and Master Batch Records Department Manager shall prepare a training plan to be used for organising relevant training sessions for the employee.These records link training to SOPs and other relevant documents. • • Audit Reports and Corrective Action Requests (CARs) Follow Up Audits are carried out by approved auditors who are independent of the department being audited. . The GMP training will include. Records will be kept in accordance with established policies and procedures. 20. timings and any requirements for follow up audits.Document /Version: QM/01 Effective Date: 9 May 2006 Page 12 of 16 ABC CO. Ltd. Training Programmes Training of Company staff is categorised into the following areas: • Induction and basic hygiene training for all new employees and contractors who are required to enter the manufacturing area • GMP principles training on a regular basis • Skills or Competency training . Where appropriate. The Management review meeting assesses internal audit and follow up report summaries in order to help evaluate the effectiveness of the system. where applicable: • Regulatory standards and GMP requirements • Principles of cleaning and sanitation • Basic microbiology • Good Laboratory Practices • Good aseptic practices • Company documentation (SOPs) Training records are held for each employee. corrective actions. This includes training on specific tasks relating to the job performed as well as quality awareness. 19. and communicated to the relevant function heads. An audit schedule is maintained and controlled by Quality Assurance. The audit findings.SOPs. The audit schedule may vary according to non-conformances found and changing circumstances. • Any change to an existing GMP computer system should be processed in accordance with a defined change control procedure which should document the details of each change made. These shall be used to analyse trends and variability and provide a basis for modifying processes. Suitable methods of preventing unauthorised entry shall be available. All staff must enter via designated locked entry doors secured by key codes. All contractors and visitors must sign an entry register. . report to a designated employee when entering the facility and be supervised at all times while in the facility. Training in the use and application of statistical techniques are recognised as important. • When a computer system is in process of replacing a manual operation the computer system should show that it operates correctly and meet the specified requirements. its purpose and its date of effect and should provide for a check to confirm that the change has been applied correctly. equipment.Document /Version: QM/01 Effective Date: 9 May 2006 Page 13 of 16 ABC CO. the computer system employed should meet applicable GMP requirements for those manual functions. accuracy of manufacturing and control records and compliance with industry regulations. • The recovery procedure to be followed in the event of a system breakdown shall be defined in writing 22. staff must surrender all access key cards and access passwords must be deleted. amend. read. • Where a computer is used in connection with any procedure or process associated with the production of clinical trial material. Facility Control The access to manufacturing facility is restricted. or print out data shall be established according to user needs. if these are necessary. The following general requirements and policies apply to GMP related computer systems • Persons with appropriate expertise should be responsible for the design. 21. No contractor or visitor may remove any sample. such as pass cards or personal user-identity codes. Security of Computer Systems • A hierarchy of permitted access to enter. On termination of employment. Appropriate statistical techniques will be applied to data generated from process monitoring and testing. which it replaces. introduction and regular review of a GMP related computer system. assessment of data. Computer Systems Management The control of computer systems which impact GMP activities is important to ensuring control of processes. Ltd.. product or remove or copy any document without the approval of the management. Statistical techniques are applied in the area of process control and quality control activities to ensure that process capability and product characteristics are acceptable. HVAC Systems – Maintenance and Monitoring • The HVAC systems servicing all GMP cleanrooms shall be regularly maintained to a written schedule. operation. The V model requires development of user. shutdown. testing and reporting results. Qualification of equipment. For minor items this model may be varied. • Equipment and utilities history logs shall be maintained for all critical items. Calibration and Control of Equipment • All critical equipment and process utilities shall be monitored and controlled during use according to the approved written procedures and schedules for preventive maintenance. Records of maintenance shall be retained.Document /Version: QM/01 Effective Date: 9 May 2006 Page 14 of 16 ABC CO. certain rooms are designated cleanroom areas. Water and Clean Steam System Control and Monitoring • The purified water system and associated clean steam system shall be regularly monitored according to a written sampling and testing programme under the control of the laboratory. the local and main alarm panels shall be activated. cleaning. Management of Equipment and Critical Process Utilities Manufacturing and QC equipment and process utilities are uniquely identified during installation. shall be tagged and removed from use when under repair maintenance and shall not be used until cleared by the authorised person. In the event of power failure. 23. • There is written procedures for facility evacuation and response to power failure. Maintenance. • There shall be written procedures for start up. • All visitors to restricted areas must be accompanied at all times by a staff member. • All critical measuring devices/instruments shall be calibrated at defined intervals to a written schedule. Action and alert limits are established and documented. Restrictions on Entry to Cleanroom and Manufacturing Areas • Within the manufacturing area. Routine Monitoring. • Gowning standards are to be applied in these areas and no staff may enter these areas unless they are properly gowned according the standard procedures. • There shall be written procedures for sampling. . Ltd. Facility Security: Monitoring and Alarms • The facility shall be access-controlled to prevent illegal entry and is also firealarmed.. calibration and maintenance of all critical equipment and utilities. The company generally follows the “V Model” principles for qualification of major critical items of equipment or critical process utilities. Operational Qualification (OQ) and Performance Qualification (PQ) Qualification. Installation Qualification (IQ). if necessary using qualified contract calibration laboratories. functional and design specifications. which are used for design qualification. • Critical equipment and utilities. shall be documented in preapproved protocols and reports. Regular checks on the ongoing accuracy and performance of measuring devices shall be conducted. . Validation Programmes The company is committed to validating critical computer systems. equipment and utilities. • All non-compendial laboratory methods shall be validated with the equipment and reagents specified in the test methods. The company has developed and published a Validation Master Plan (VMP) for the construction and commissioning of the facility. • Wherever common equipment is used in manufacture. 24. • All new products shall be assessed for the suitability of the standard cleaning procedures and whether additional validation studies are required. Laboratory Test Method Validation • Laboratory personnel shall be trained to follow standard procedures and specific test methods. cleaning validation studies shall be conducted. intermediates and finished product shall be qualified and calibrated. quarterly inspection of Air Handling Units. This document provides schedules. validating cleaning procedures and processes. • Any contract testing laboratory shall be qualified. precise and selective before use. standards. acceptance criteria and responsibilities for development and execution of protocols. Test methods that are published in the British Pharmacopoeia (BP). Ltd. • The company recognises it is therefore good laboratory practice to conduct some method transfer ruggedness studies even on compendial methods before use. • Routine monitoring shall include daily recording and periodic trending of cleanroom pressure differentials. and/or the United States Pharmacopoeia (USP) do not require full validation but shall be demonstrated to be accurate. • All critical laboratory equipment involved in the measurement and testing of starting materials. Pharmacopoeial Test Methods • The company uses compendial (BP/EP/USP/etc. • All cleaning validation reports shall be prepared and submitted to Quality Assurance for approval. The validation of specific processes.Document /Version: QM/01 Effective Date: 9 May 2006 Page 15 of 16 ABC CO. at least annual certification of HEPA filters and routine environmental monitoring programmes. equipment and qualifying critical process utilities. • All validations shall be conducted using approved protocols and cleaning methods. and laboratory methods in accordance with GMP requirements. at least quarterly cleaning of pre-filters.) methods where applicable. cleaning and test methods shall be conducted according to approved protocols.. Cleaning Validation Programmes • The validation of cleaning procedures for common equipment is considered critical to prevent cross–contamination of biopharmaceutical products. preferably approved by a regulatory agency. The level of validation and responsibility for validation shall be discussed with customers as part of technology transfer.Document /Version: QM/01 Effective Date: 9 May 2006 Page 16 of 16 ABC CO. All biological hazardous materials shall be decontaminated before disposal. staff will be instructed on safety procedures and correct gowning. including respiratory infection or open skin wounds. The company’s policy and GMPs require that staff undergo the following OS&H procedures: • Pre-employment medical checks. Non Pharmacopoeial Test Methods • Non pharmacopoeial test methods shall be fully validated. 25. • Temporary exclusion of staff from manufacturing areas and cleanrooms if they carry a communicable condition.. Before operating equipment or handling biologically hazardous materials. Ltd. Occupational Safety and Health Programmes As an integral part of employee induction. all Manufacturing operational staff will be instructed in occupational health and safety policies and procedure. . • Periodic medical checks for staff who are required to handle or manipulate biological hazardous materials.