Quality Manual

ABC CO., Ltd.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 1 of 16

QUALITY MANUAL Function:

Quality Assurance Department

Title:

Quality Manual

Document:

QM

Version:

Replaces:

N/A

Next Review Date: 9 May 2008

Reason for Change:

Effective Date: 9 May 2006

First Issue

Prepared by: Date: [Title] Reviewed by: Date: [Title] Approved by: Date: [Title] Copy No:

Issued to:

Distribution:XXX Department: XXX Department: XXX Department: XXX Department:

Managing Director Head of XXX XXX Manager XXX Manager

01

ABC CO., Ltd.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 2 of 16

TABLE OF CONTENTS SECTION

TITLE

PAGE

ABC Quality Policy Statement

3

1

Introduction

3

2

Organization

3

3

Manufacturing Facility

4

4

Quality System

4

5

Management Responsibility

5

6

Design and Change Control

5

7

Document Control

5

8

Purchasing and Vendor Assurance

6

9

Material and Product Identification and Traceability

6

10

Process Control Programmes

6

11

Inspection and Testing Programmes

6

12

Calibration Programmes

7

13

Inspection and Test Status

9

14

Control of Non-Conforming Product

9

15

Corrective and Preventive Action Systems

9

16

Handling and Storage of Materials and Products

10

17

Control of Quality Records

10

18

Internal Quality Audits

11

19

Training Programmes

12

20

Statistical Techniques

12

21

Computer Systems Management

13

22

Facility Control

13

23

Management of Equipment and Critical Process Utilities

14

24

Validation Programmes

15

25

Occupational Safety and Health Programmes

16

ISO 9001 CLAUSE

ABC CO., Ltd.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 3 of 16

ABC Quality Policy Statement

1.

2.

Introduction 1.1

Purpose of Quality Manual The purpose of this Quality Manual is to outline the Quality Management Systems used by ABC Co., Ltd. to manage the quality of its products. ABC business is the manufacturer and sales of a range of products including medicines and cosmetics.

1.2

Scope of the Quality Manual This manual covers the quality system that ABC has in place for the commercial supply of its products. It refers to supporting documentation, procedures, quality plans and work instructions associated with the manufacture, storage and distribution of product.

Organization Managing Director

QA Manager

Production Manager

Engineering Manager

Regulatory Manager

Personnel Manager

Financial Manager

ABC CO., Ltd.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 4 of 16

3.

Manufacturing Facility 3.1 Premise ABC Co., Ltd. is located at XXX. The facility consists of XXX. The Company is licensed by Thai FDA under GMP Certificate No. XXX with a valid date from XXX to XXX to manufacture of XXX. Manufacturing area and packing area where products expose are controlled to comply with Class 100,000. The areas maintain their contamination control using a “validated HVAC” system. 3.2 Equipment All major pieces of equipment used in the GMP manufacture of the product should be listed here, such as autoclaves, washers, bioreactors, chromatography systems. All major pieces of equipment used in the QC lab to test raw materials, product or inprocess or environmental testing should be listed here, such as TOC, ELISA reader, Spectrophotometer. All major pieces of equipment in the Utilities should be listed here, such Purified Water Systems, WFI generator, Clean steam generator.

4.

Quality System The Quality System ensures that the product complies with its specified requirements and is manufactured in accordance with appropriate standards. 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. Quality Procedures (such as SOP’s and Manufacturing Directions, 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. 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, Quality Improvements) • Implementation and maintenance of GMP Quality System • Review of Quality System • Planning, 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, XXX and XXX.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 5 of 16 5.

ABC CO., Ltd.

Management Responsibility The role of the Management team as well as the responsibilities and authorities are as follows: Managing Director is responsible for XXX. QA Manager is responsible for XXX. Production Manager is responsible for XXX. XXX is responsible for XXX. 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.

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,…. Flow chart of Change control is as follows:

7.

Document Control SOP XXX: Document Control The Document Control Centre in Quality Assurance department is responsible for controlling documentation and records. The route of approval and issuing documents are as follows:

Document /Version: QM/01 Effective Date: 9 May 2006 Page 6 of 16

8.

ABC CO., Ltd.

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. Therefore it is important that vendors and raw materials meet the required specifications. An overview of the Quality Checks and procedures to ensure that the vendors meet the specifications, such as audits, testing etc. are required. Approved supplier list is defined and maintained.

9.

Material and Product Identification and Traceability SOP XXX: Lot Numbering System All raw materials, packaging materials, and finished products are identified with a unique code which described in the SOP XXX. All unique codes that are used for the identification could provide full traceability. Batch documentation Traceability back to starting materials will be defined by Quality Assurance according to regulatory requirements on Batch documentation, such that in the event of a product recovery/recall that finished goods lots can be identified and retrieved.

10.

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, equipment and computer systems used for quality critical activities will be suitably validated and records maintained of this validation.

11.

Inspection and Test Programmes 11.1 • • • • •

Receiving Inspection and Testing All materials and components supplied in accordance with a Purchase Order shall be inspected on receipt for damage, completeness, identification and compliance with the procurement documentation. All materials and components shall be verified against the Delivery Order, Specification Record, and/or Certificate of Analysis (C of A). Selected incoming materials shall be tested as described in the Specifications Record and Certificates of Analysis with specific batch test results obtained as appropriate. A QC Officer will perform sampling and testing if testing is required. Rejected materials shall be returned to the supplier. Materials and components meeting the specifications will be labelled with a

Document /Version: QM/01 Effective Date: 9 May 2006 Page 7 of 16

•

11.2 • •

11.3 • • •

12.

ABC CO., Ltd.

"RELEASE" label and stored in the designated area under appropriate storage conditions. Materials and components rejected on receipt will be placed in a separate quarantine area and identified accordingly, 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. These in-process tests are described in standard operating procedures and recorded in production Batch Records and QC Test Records. Final Inspection and Testing The QC Manager will organise final quality control analysis on batch samples according to specifications in Test Methods. The results of the tests shall be recorded and retained. If the results are not acceptable, the QA Manager will be responsible to activate a non-conformance report. 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. Results are released by the QA Manager as per defined Standard Operating Procedure.

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, calibrated at appropriate intervals and maintained according to documented procedures and a schedule. Control of Inspection, Measuring and Test Equipment (Calibration) Proper and periodic calibration ensures that the selected measuring equipment and instruments continue to have the desired accuracy, and precision can be relied upon. 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. Remedial action includes recalibration and evaluation of the impact of out-of-tolerance measurements. Calibration Requirements Analytical instruments in the Quality Control Laboratory are calibrated according to published methods / procedures. These methods / procedures include specific directions and limits for accuracy and precision. Routine calibration programme is carried out to a schedule. Measuring equipment and instruments associated with production and critical utilities in manufacturing areas are calibrated according to published methods/procedures. These methods/procedures include specific directions and limits for accuracy and precision.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 8 of 16

ABC CO., Ltd.

Routine re-calibration (performance check) programme are carried out according to a schedule. 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, purpose, and degree of usage of the equipment. Intervals between calibrations can be shortened as required to assure prescribed accuracy as evidenced by the results of preceding calibrations. Calibration is performed according to the frequency specified in respective standard operating procedure. 13.

Inspection and Test Status Inspection and Test Status Laboratory evaluation is performed to show with documented evidence that an incoming material, intermediate or finished product was manufactured according to the Product Specification. Finished product evaluation, as documented in standard operating procedures, requires that the company establishes and maintains procedures for finished product acceptance, to ensure that each production lot of finished product meets the specifications stipulated in the Product Specification. Finished products shall be held in quarantine or otherwise adequately controlled until release. 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. If there is a query or discrepancy they are held in the quarantine area until the issue has been resolved. Finished product is held in quarantine until released by the Quality Assurance Department. 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 9 of 16

ABC CO., Ltd.

Authority to Change Status Only authorised personnel are allowed to change status of any material, component and bulk and finished product. 14.

Control of Non-Conforming Product • • • • • •

• •

• • • • •

15.

All non-conforming materials and products shall be quarantined and investigated. They will be properly identified, labelled, segregated, documented and evaluated for appropriate action. The control of non-conforming product procedure has been established to manage any material and product that does not conform to specifications. The procedure includes identification, documentation, evaluation, segregation, and disposition of nonconforming material and product. 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. All evaluation and investigations are documented. All GMP operational staff are trained to recognise material and product nonconformance and take appropriate action, including identifying product as nonconforming, documenting and evaluating the non-conformance, segregating and disposal of non-conforming product. Any non-conforming incoming material shall be immediately identified and segregated. The discrepancy shall be clearly documented and the cause investigated. 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. The results are documented in the Batch Records and other relevant forms or reports. Disposition of the non-conforming material and product is documented, 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. The decision to use, rework or reject a non-conforming material and product is made by the QA Manager. Standard operating procedure for rework, retesting and re-evaluation of the nonconforming product to ensure that the product meets its current approved specifications has been established. All rework and re-evaluation activities, including the determination of any adverse effect from the product rework, must be documented in Batch Records. Disposal of non-conforming product is the responsibility of the QA Manager and its disposal is documented.

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. The need for corrective / preventive action is identified from the following sources:

Document /Version: QM/01 Effective Date: 9 May 2006 Page 10 of 16

• • • •

ABC CO., Ltd.

product non-conformances process non-conformances (manufacturing deviations) deficiencies arising from internal or external (customer or regulatory) audit or review processes accidents, error or incidents within the plan

If the event is an isolated incident (not systemic), the cause is well defined and not likely to occur again, then the issue may be dealt with according to the individual quality system element and documented on the form specific to the issue. 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. 16.

Handling and Storage of Materials and Products 16.1 •

Handling After receipt by appropriately trained personnel, orders are reviewed immediately and reconciled against delivered Lots. All materials and finished products are handled according to the company’s handling and safety procedures.

16.2 •

Storage Designated areas and conditions are provided to minimise deterioration and ensure easy selection of correct stock, stock rotation as well as segregation of nonconforming, rejected and returned materials. All storage areas are temperature controlled and monitored Incoming material movements are consumed and transferred on a First In First Out (FIFO) basis. The stock is monitored periodically for shelf life expiry, and action shall be taken to remove and destroy stock that has short shelf life or has passed expiry or has deteriorated.

• • •

16.3 • •

16.4 •

17.

Packaging Products are delivered to customers using methods that minimise the effect of transport conditions on product viability. Products are packaged in approved packaging material referenced in the Product Specifications with due regard to product stability, approved storage conditions, cleanliness, environment and in such a manner as to prevent damage and deterioration. Preservation Appropriate steps shall be taken to ensure that the conditions of storage and transport are within the limits set by the customer, regulatory or other specifications or are according to supplier’s recommendations.

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.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 11 of 16

ABC CO., Ltd.

Quality Records include, but are not limited to: • Records which demonstrate that products supplied by the company meet technical, regulatory and contractual requirements. This may include production Batch Records as well as records from suppliers and subcontractors that relate to current Good Manufacturing Practices. • Laboratory Test Records, and Specifications Records including raw data and any electronic records if applicable • Logbooks • Records pertaining to product development. • Equipment calibration records • Validation and Commissioning records. • Equipment history files. • Records which demonstrate that all Quality Assurance activities have been effectively implemented. The Quality records are archived in secure storage, preserved during storage and are readily retrievable in readable form for the entire retention period. Records are documented and stored in designated locations that provide proper accessibility. The retention period of quality records is documented. At the end of the retention period, they are destroyed within a designated time period or relocated to other storage areas. The quality records shall be reviewed and analysed periodically to identify trends and to implement continuous improvement of the systems. All electronic records are backed up regularly. Access to archived GMP records is strictly controlled. These records are maintained and documented by the responsible department personnel and the QA Manager, Staff undergo training to ensure they complete both Batch Records and QC Test Records in compliance with GMP requirements during operation. A register of staff signatures and initials is maintained. 18.

Internal Quality Audits This is done to verify whether quality activities comply with the Quality Plan, to determine the effectiveness of the Quality System and verify compliance with GMPs. Every element of the quality system is audited at least once per year. The actual frequency of such audits is determined according to the results of previous audits and the importance of the activity. Procedures for the stages of internal audit are: • Planning and Scheduling • Preparing for the Audit • Conducting the Audit

Document /Version: QM/01 Effective Date: 9 May 2006 Page 12 of 16

• •

ABC CO., Ltd.

Audit Reports and Corrective Action Requests (CARs) Follow Up

Audits are carried out by approved auditors who are independent of the department being audited. An audit schedule is maintained and controlled by Quality Assurance, and communicated to the relevant function heads. The audit schedule may vary according to non-conformances found and changing circumstances. The audit findings, corrective actions, timings and any requirements for follow up audits, are agreed between the auditor and the auditee and reported. The Management review meeting assesses internal audit and follow up report summaries in order to help evaluate the effectiveness of the system. Records will be kept in accordance with established policies and procedures. 19.

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 - SOPs, Test Methods and Master Batch Records Department Manager shall prepare a training plan to be used for organising relevant training sessions for the employee. Training is carried out by appropriate internal and/or external personnel. This includes training on specific tasks relating to the job performed as well as quality awareness. The GMP training will include, but is not limited to, 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.These records link training to SOPs and other relevant documents.

20.

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- making. Where appropriate, 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.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 13 of 16

ABC CO., Ltd.

Statistical techniques are applied in the area of process control and quality control activities to ensure that process capability and product characteristics are acceptable. Appropriate statistical techniques will be applied to data generated from process monitoring and testing. These shall be used to analyse trends and variability and provide a basis for modifying processes, if these are necessary. Training in the use and application of statistical techniques are recognised as important. 21.

Computer Systems Management The control of computer systems which impact GMP activities is important to ensuring control of processes, assessment of data, accuracy of manufacturing and control records and compliance with industry regulations. The following general requirements and policies apply to GMP related computer systems • Persons with appropriate expertise should be responsible for the design, introduction and regular review of a GMP related computer system. • Where a computer is used in connection with any procedure or process associated with the production of clinical trial material, the computer system employed should meet applicable GMP requirements for those manual functions, which it replaces. • 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. • 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, its purpose and its date of effect and should provide for a check to confirm that the change has been applied correctly. Security of Computer Systems • A hierarchy of permitted access to enter, amend, read, or print out data shall be established according to user needs. Suitable methods of preventing unauthorised entry shall be available, such as pass cards or personal user-identity codes. • The recovery procedure to be followed in the event of a system breakdown shall be defined in writing

22.

Facility Control The access to manufacturing facility is restricted. All staff must enter via designated locked entry doors secured by key codes. On termination of employment, staff must surrender all access key cards and access passwords must be deleted. 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. No contractor or visitor may remove any sample, equipment, product or remove or copy any document without the approval of the management.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 14 of 16

ABC CO., Ltd.

Facility Security: Monitoring and Alarms • The facility shall be access-controlled to prevent illegal entry and is also firealarmed. In the event of power failure, the local and main alarm panels shall be activated. • There is written procedures for facility evacuation and response to power failure. Restrictions on Entry to Cleanroom and Manufacturing Areas • Within the manufacturing area, certain rooms are designated cleanroom areas. • 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. • All visitors to restricted areas must be accompanied at all times by a staff member. 23.

Management of Equipment and Critical Process Utilities Manufacturing and QC equipment and process utilities are uniquely identified during installation. The company generally follows the “V Model” principles for qualification of major critical items of equipment or critical process utilities. For minor items this model may be varied. The V model requires development of user, functional and design specifications, which are used for design qualification. Qualification of equipment, Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) Qualification, shall be documented in preapproved protocols and reports. Routine Monitoring, Maintenance, 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. • Critical equipment and utilities, shall be tagged and removed from use when under repair maintenance and shall not be used until cleared by the authorised person. • There shall be written procedures for start up, operation, shutdown, cleaning, calibration and maintenance of all critical equipment and utilities. • Equipment and utilities history logs shall be maintained for all critical items. • All critical measuring devices/instruments shall be calibrated at defined intervals to a written schedule, if necessary using qualified contract calibration laboratories. Regular checks on the ongoing accuracy and performance of measuring devices shall be conducted. 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. • There shall be written procedures for sampling, testing and reporting results. Action and alert limits are established and documented. HVAC Systems – Maintenance and Monitoring • The HVAC systems servicing all GMP cleanrooms shall be regularly maintained to a written schedule. Records of maintenance shall be retained.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 15 of 16

•

24.

ABC CO., Ltd.

Routine monitoring shall include daily recording and periodic trending of cleanroom pressure differentials, at least quarterly cleaning of pre-filters, quarterly inspection of Air Handling Units, at least annual certification of HEPA filters and routine environmental monitoring programmes.

Validation Programmes The company is committed to validating critical computer systems, equipment and qualifying critical process utilities, validating cleaning procedures and processes, and laboratory methods in accordance with GMP requirements. The company has developed and published a Validation Master Plan (VMP) for the construction and commissioning of the facility, equipment and utilities. This document provides schedules, standards, acceptance criteria and responsibilities for development and execution of protocols. The validation of specific processes, 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. • Wherever common equipment is used in manufacture, cleaning validation studies shall be conducted. • All validations shall be conducted using approved protocols and cleaning methods. • All new products shall be assessed for the suitability of the standard cleaning procedures and whether additional validation studies are required. • All cleaning validation reports shall be prepared and submitted to Quality Assurance for approval. Laboratory Test Method Validation • Laboratory personnel shall be trained to follow standard procedures and specific test methods. • All non-compendial laboratory methods shall be validated with the equipment and reagents specified in the test methods. • All critical laboratory equipment involved in the measurement and testing of starting materials, intermediates and finished product shall be qualified and calibrated. • Any contract testing laboratory shall be qualified, preferably approved by a regulatory agency. Pharmacopoeial Test Methods • The company uses compendial (BP/EP/USP/etc.) methods where applicable. Test methods that are published in the British Pharmacopoeia (BP), and/or the United States Pharmacopoeia (USP) do not require full validation but shall be demonstrated to be accurate, precise and selective before use. • The company recognises it is therefore good laboratory practice to conduct some method transfer ruggedness studies even on compendial methods before use.

Document /Version: QM/01 Effective Date: 9 May 2006 Page 16 of 16

ABC CO., Ltd.

Non Pharmacopoeial Test Methods • Non pharmacopoeial test methods shall be fully validated. The level of validation and responsibility for validation shall be discussed with customers as part of technology transfer. 25.

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. Before operating equipment or handling biologically hazardous materials, staff will be instructed on safety procedures and correct gowning. All biological hazardous materials shall be decontaminated before disposal. The company’s policy and GMPs require that staff undergo the following OS&H procedures: • Pre-employment medical checks. • Periodic medical checks for staff who are required to handle or manipulate biological hazardous materials. • Temporary exclusion of staff from manufacturing areas and cleanrooms if they carry a communicable condition, including respiratory infection or open skin wounds.