Basic Principles of GMP Production, SelfInspection and quality audits Module 7 | Slide 1 of 17 2012 Self-Inspection Objectives To identify the role of self-inspection in the quality management system To review the way in which a self-inspection programme should be carried out To discuss what to inspect and verify in a company’s selfinspection system Module 7 | Slide 2 of 17 2012 PRODUCTION PROCEDURES Module 7 | Slide 3 of 17 2012 BASIC PRODUCTION PRINCIPLES Starting materials - tested and approved according its specification Production equipment - cleaned, safe, appropriate in size, and appropriate for product type to be manufactured Operation on different products should not be carried out simultaneously in the same room, unless there is no potential risk of mix-up and contamination All materials should bear clear labels and batch numbers Limited access in production area, only authorized personnel Handling of materials and products should be based on written instruction/procedure, and where necessary, recorded All work instructions/procedures should be written and approved Batch manufacturing records (BMR) should be well recorded by qualified and responsible personnel. Module 7 | Slide 4 of 17 2012 PROCESSING GUIDANCE (1) There are several guidelines that should be followed prior, during and after each production activities. These are: Area clearance or lines clearance should be done, to avoid mix up of starting materials or finished products In-process and environmental controls should be carried out and recorded. Indication of failure of equipment or services should be monitored and only equipments in good condition should be available in the production area. Cleaning procedures should be written and approved Containers should be cleaned prior to use Any deviation from requirements and expected result should be recorded and investigated prior to start of production and prior to release of the finished product Module 7 | Slide 5 of 17 2012 PROCESSING GUIDANCE (2) Any significant deviation from the expected yield should be recorded and investigated. Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. Measuring, weighing, recording, and control equipment should be serviced and calibrated at pre-specified intervals and records are maintained. Repair and maintenance operations should not present any hazard to the quality of the products. Module 7 | Slide 6 of 17 2012 BULK QUARANTINE LABEL ( Company name ) QUARANTINE LABEL Formula Number Product Name Manufacturing No Batch Size Processing Date Transfer date & Time Bulk transferred to Bulk Valid until Chemical Approval : : : : : : : : Microbioogical Approval Sample Finished Product Micro ( ( HOLD Module 7 | Slide 7 of 17 2012 ) Yes ) No EQUIPMENT LABEL Cleaning Status of Equipment Company Name EQUIPMENT STATUS : : Cleaning Status of Equipment Company Name : EQUIPMENT STATUS : : SANITIZE D CLEANED Checked and Verified by : Valid until : Date : Checked and Verified by: Valid until Date : Both labels should be attached to the BMR Module 7 | Slide 8 of 17 2012 : WEIGHING & MEASUREMENT Weighing should be carried out : -in defined areas -using calibrated equipment. All weighing and measurement carried out should be: -recorded -counter checked Module 7 | Slide 9 of 17 2012 IN-PROCESS CONTROL Done within the production area and by production people and/or Quality Control Should be recorded and done as per approved/written SOP Sampling done to verify: physical aspects (weight, volume, amount, etc) text on labels other performance requirements Sampling maybe conducted based on need: : during processing activity during packaging (filling & packing) activities • random, • sequential, or • statistical Samples takenaway from the packaging line should not be returned if containers were opened Record of in-process control should be part of the BMR Module 7 | Slide 10 of 17 2012 RECONCILIATION Any deviation from the procedures should be avoided as much as possible. If deviations occur, they should be approved in writing by a designated person, with the involvement of the quality control department. Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. These are some points to be considered in the reconciliation of the batch: quantity of starting materials, output of finished products, machine efficiency All activities concerning reconciliation should be conducted based on written standard operating procedures. Module 7 | Slide 11 of 17 2012 BATCH NUMBERING SYSTEM (1) A product identification number/batch number should be assigned to: every finished product every bulk and semi finished product which enables the history of the product to be traced. A batch numbering system should be specific for the product non repetitive for the same product unique Creation of batch number should be based on written guideline (SOP) Module 7 | Slide 12 of 17 2012 BATCH NUMBERING SYSTEM (2) The batch number should be printed on: primary packaging secondary packaging (as necessary) A batch number may give information on : date and year of production country, manufacturer or subcontractor sequence of production Records of batch number should be kept and maintained for every finished product until at least 1 year after the expiry date for traceability factor Module 7 | Slide 13 of 17 2012 Example of batch number: M001S09A The 1st prefix - M represent for MALAYSIA Products The 2nd - 4th digit – Batch Number The 5th alphabet - Product format code: S (Sachet), C (Capsule), T (Tablet), P (Powder) and L (Liquid). The 6th – 7th digit - Year of product manufactured: 08 (Year 2008), 09 (Year 2009), 10 (Year 2010), etc The last alphabet - Month of production manufactured: A (JANUARY), B (FEBRUARY), C (MARCH), etc. Module 7 | Slide 14 of 17 2012 REPROCESSING Reprocessing is a delicate/tedious activity for a rejected product. There should be a written policy which clearly states that such action is allowed to be done. Reprocessing of rejected product should only be done in exceptional cases. It should only be allowed if the quality of the product is not negatively affected and the product quality still complies with the specifications. It should consider additional testing of reprocessed product, e.g. stability testing of the batch. Complete records should be maintained for reprocessed product A reprocessed product should be given a new batch number. Module 7 | Slide 15 of 17 2012 WET PRODUCT HANDLING Liquids and creams should be produced in such a way as to protect the product from microbial and other contamination. The use of closed systems of production and transfer is recommended. Where pipe-lines are used for delivery of ingredients or bulk products, care should be taken to ensure that the systems are easy to clean. Module 7 | Slide 16 of 17 2012 FINISHED GOOD PRINCIPLES While awaiting approval, finished products should be placed & kept under quarantine area at the finished product warehouse. Quarantine label indicates : Date Product name Batch No Quantity Number of pallets Module 7 | Slide 17 of 17 2012 FINISHED PRODUCT STATUS All label concerning with the status of finished products should be shown clearly Quarantine status can be in the form of: • physical (rope, racks layers, pallet) • computer system Rejected products : • identified and physically separated • taken out from the stock • further process (destruction, reworked, etc) Module 7 | Slide 18 of 17 2012 Type of Audits 1st Party Audit • Self-Inspection (Internal) Audit 2nd Party Audit • External provider audit • Other interested party audit • Certification and/or accreditation audit • Statutory, regulatory and similar audit 3rd Party Audit Module 7 | Slide 19 of 17 2012 Self-Inspection Principle (1) Purpose of self-inspection is to evaluate whether a company’s operations remain compliant with GMP Assists in ensuring quality improvement The programme should cover all aspects of production and quality control be designed to detect shortcomings in the implementation of GMP 8.1 recommend corrective actions set a timetable for corrective action to be completed Module 7 | Slide 20 of 17 2012 Self-Inspection Principle (2) Performed routinely Also on special occasions such as Recalls Repeated rejections When a GMP inspection is announced by the national drug regulatory authority 8.1 Module 7 | Slide 21 of 17 2012 Self-Inspection Principle (3) Self-inspection team should consist of personnel who: Are objective and have no revenge in mind Have no conflict of interest (That is, normally not from the same department as the one being inspected) should have experience as observers of a self-inspection team before becoming a team member The team should be led by an experienced person Procedure should be documented 8.1 Effective follow-up programme (CAPA implemented) Module 7 | Slide 22 of 17 2012 Self Inspections/ Internal Audits • Performed in-house most often by a team and involve people with different expertise • Could be carried out within a single facility or organised by Head Office to be done over a range of facilities Module 7 | Slide 23 of 17 2012 Inspector attributes • Knowledgeable • Being able to identify and focus on areas of high risk • Being well trained in inspecting • Having appropriate personal skills Module 7 | Slide 24 of 17 2012 Self Inspections/ Internal Audits Self Inspections done by external experts Could be full self audit of a facility or system specific audit External expertise, a fresh set of eyes No politics Module 7 | Slide 25 of 17 2012 Self-Inspection 1. Self-inspection - informal (daily) 2. Self-inspection - formal (quarterly) | Slide 26 of 17 Improve systems Confirm compliance 3. QC - Internal (half-yearly) Module 7 Immediate correction 2012 Self-Inspection Items for Self-Inspection (1) Written instructions provide minimum and uniform standard Covering all aspects of GMP: personnel premises including personnel facilities maintenance of buildings and equipment storage of starting materials and finished products equipment production and in-process controls quality control 8.2 Module 7 | Slide 27 of 17 2012 Self-Inspection Items for Self-Inspection (2) documentation sanitation and hygiene validation and revalidation programmes calibration of instruments or measurement systems recall procedures complaints management labels control results of previous self-inspections and any corrective steps taken Module 7 | Slide 28 of 17 2012 8.2 Self-Inspection The Self-Inspection Team Team appointed by management, with: authority sufficient experience may be from inside or outside the company experts in their own field familiar with GMP 8.3, 8.4 Frequency should be at least once a year Depends on company size, requirements, actrivities Often, departments are inspected according to a calender – one department per month over a one year cycle Module 7 | Slide 29 of 17 2012 Self-Inspection Self-Inspection Report prepared at completion of inspection, including: results evaluation conclusions recommended corrective measures Follow-up action Effective follow-up programme Company management to evaluate both the report and corrective actions Module 7 | Slide 30 of 17 2012 8.5, 8.6 Quality Audit This is an examination of all or part of quality system The aim is to improve it Usually conducted by outside experts or team appointed by management Useful to supplement self-inspection programme with quality audits May be extended to suppliers and contractors Module 7 | Slide 31 of 17 2012 8.7 External Audits – Regulatory Audits • Carried out by national auditing/ inspecting authorities • Verify compliance with the ISO Standards and other national legal requirements • Could be product specific or system audits • Could be triggered by a product recall or other undesired events (unannounced?) • Detailed in scope Module 7 | Slide 32 of 17 2012 External Audits – Contractor Audits • Carried out to determine manufacturer’s technical capability • Carried out by a group of experts from contract giver • Establish line of communications and priorities between involved parties Module 7 | Slide 33 of 17 2012 External Audits – Supplier Audits • Carried out on suppliers of critical raw materials and packaging materials • Verify materials specifications • Could be used to justify reduced raw materials testing Module 7 | Slide 34 of 17 2012 Quality Audit Suppliers’ audits and approvals Quality Unit (e.g. QA or QC) responsible together with other relevant departments for approving suppliers Ensure that suppliers can reliably supply materials that meet established specifications Suppliers should be evaluated and approved before they are included in approved supplier's lists Should take into account the supplier’s history and nature of 8.8, 8.9 materials to be supplied Evaluation may also lead to an audit to assess compliance, e.g. with GMP Module 7 | Slide 35 of 17 2012 Quality Audit Inspecting the Self-Inspection Programme (1) GMP inspectors should preferably check self-inspection programme at end of an inspection Evaluate: SOP, team composition Annual program / schedule Checklists used by the company (are these up to date?) Check that inspections are done as schedules Reports are available CAPAs are taken, implementation is verified, management involvement Module 7 | Slide 36 of 17 2012 Quality Audit Auditing the Self-Inspection Programme (2) The SOP should describe teams, process, items covered, and the frequency of self-inspection Company policy may not permit GMP inspector to see actual deficiency reports and corrective actions GMP Inspectors should be looking for compliance with the selfinspection SOP - not necessarily at actual deficiencies recorded Seek objective evidence of reports and action Module 7 | Slide 37 of 17 2012 Quality Audit Auditing the Self-Inspection Programme (3) Ensure company is not just doing housekeeping or safety audits Check there are “Vertical” as well as normal “Horizontal” audits; both play valuable role in self-inspection Module 7 | Slide 38 of 17 2012 Audit Report Introductio n: Change s: Module 7 | Slide 39 of 17 2012 • Brief description of the company and its activities. • Ensure that you briefly document major changes since the last audit. Audit Report Audit findings: Key for classification of observations / report are : Critical : A deficiency which has produced or leads to a significant risk of producing products that harmful to consumers or manufacturer is involved with fraud or false advertising. Major : A deficiency which has produced which does not comply to specifications or which indicates a major deviation from EU Good Manufacturing Practice or which indicates a failure to carry out satisfactory procedures for release of batches. Other : A deficiency that is not classified as major or critical but deviates from GMP. Recommendation: No GMP violation. Module 7 | Slide 40 of 17 2012 Audit Report ●The name of the organization, department, process or function being audited. ●Audit programme or agenda. ●Obstacles encountered. ●The address of the site audited. ●Statement of confidentiality. ●An overview of all areas observed during the audit. ●Date and duration of audit. ●People at opening and closing meeting. ●Any nonconformities or observations that were raised. ●Reason for performing the audit. ●Names of auditors. ●Any unobserved areas. ●Standard used for assessment during audit. ●Name of the audit host and their contact details. ●A description of any grading of any nonconformities. Module 7 | Slide 41 of 17 2012 ●Instructions for the department or organization to comply upon receipt of the report in order to respond to any nonconformities raised. ●Conclusion.