Quality Systems and GMPin Pharmaceutical Manufacturing. Marleine Akl Quality Assurance Algorithm SAL

Transcription

1 Session s Outline 1. Bio-equivalence 2. A 30-minute DVD on GMP Break 3. Quality Systems and GMPs in Pharmaceutical Manufacturing 4. Good Distribution Practices 5. Questionnaire (could not go through due to time limitation) FMRI - Education Program - LU - Jan 31,

2 Quality Systems and GMPin Pharmaceutical Manufacturing Marleine Akl Quality Assurance Algorithm SAL FMRI - Education Program - LU - Jan 31,

3 Introduction & Definition 3 subjects go hand in hand with the basic concept of Quality: - Quality Assurance - Quality Control and - Good manufacturing Practices QUALITY has its Origin in a Latin word Qualitas = General Excellence or Distinctive feature FMRI - Education Program - LU - Jan 31,

4 Introduction & Definition Quality most simple definition remains Fitness for Use or for the Intended Purpose ie the patient/user is at focus FMRI - Education Program - LU - Jan 31,

5 Main Goal and Intent of a Quality System Ensuring consistent production of safe and effective products Ensuring full compliance with cgmp regulations Providing the framework for achieving stated requirements thru Quality by Design, Continuous Improvement and Risk management Is based on the fact that Quality is Built in & NOT Tested in Is the responsibility of management and requires staff commitment FMRI - Education Program - LU - Jan 31,

6 Characteristics of a Successful Quality System Science-Based Responsive deviation and investigation systems Sound method for assessing risk Decisions based on an understanding of the intended use of a product Well-defined processes, starting from development and extending throughout the product life cycle FMRI - Education Program - LU - Jan 31,

7 Current Good Manufacturing Practices Serie of principles governing every aspect of producing a drug It is that part of QA aimed at ensuring that products are consistently manufactured to a quality appropriate to their intended use FMRI - Education Program - LU - Jan 31,

8 Global GMP/Quality System Consists of the following core GMP systems, each covering a specific aspect of the manufacturing process with many interactions between each of the systems: Premises: Facilities and Utilities Equipment Materials Production Operations Packaging & labeling Laboratory Quality The Quality system provides the foundation for the other systems linking them together. FMRI - Education Program - LU - Jan 31,

9 How do GMPs of different Countries compare? At a high level, GMPs of various regulatory authorities US 21 CFR Parts 210/211 EU Eudralex volume 4 Directive 2003/94/EC WHO cgmp International Conference on Harmonization (ICH) Lebanon GMP - Issue of 2009 (Decision 212/1) have practically the same global requirements: Equipment & facilities being properly designed, maintained, & cleaned SOPs be written & approved An independent Quality unit Well trained personnel & management FMRI - Education Program - LU - Jan 31,

10 GMP Facilities, Utilities, & Equipment Lifecycle Lifecycle follows below model: 1. Assess Need & Impact Applies to all GMP areas including the laboratory equipment 2. Define requirements 3. Design 4. Design Review 5. Test & Release (IQ/OQ/PQ) Design and test results need approval prior to start of use 6. Operate 7. Maintain 8. Retire Steps 1 5 (Qualification phase) need to be completed prior to start of cleaning and process validations ie prior to use for product manufacturing FMRI - Education Program - LU - Jan 31,

11 PREMISES Facilities Any building used in the manufacture, processing, packing, or holding of a drug product shall be: Of suitable size, construction, and location to facilitate cleaning, maintenance, and proper operation. Designed in line with the intended manufacturing operations and type of products (solid dosage forms, liquid forms, sterile forms etc ) Facilities for highly sensitizing or toxic products shall be completely separate from those for other drug products for human use. FMRI - Education Program - LU - Jan 31,

12 PREMISES Facilities Design should ensure: a. Prevention of contamination from surrounding environment and pests b. Prevention of mix up of materials and products c. Ancillary areas such as change rooms, Laundry, Rest and refreshment rooms should be separated from production & QC laboratory areas, and should be easily accessible & appropriate for the number of users. d. Quality Control Laboratories should be designed to suit the operations to be carried out in them, be separate from production areas, and areas where biological, Microbiological or radioisotope test methods are employed should also be separate from each other. e. Defined areas for certain activities (e.g material sampling & dispensing) f. Storage areas of adequate space g. Finishing: Wall, ceiling, drains, lighting, pipe work and light fitting, sewage and refuse FMRI - Education Program - LU - Jan 31,

13 PREMISES Defined Areas for Certain Activities WEIGHING & SAMPLING AREAS: Should be separate Specially designed for that use and operated to prevent cross-contamination and mix-ups. STORAGE AREAS of materials/ products should ensure adequate: a. Space, design, security and cleanliness b. Storage of quarantine stocks, Rejects, Recalled or Returned products c. Storage of hazardous substances and controlled substances d. Environmental conditions of storage area (e.g. T C & RH) e. Receiving of incoming materials FMRI - Education Program - LU - Jan 31,

14 PREMISES Facilities ALL FACILITY COMPONENTS NEED TO: COMPLEMENT EACH OTHER TO ENSURE A LOGICAL FLOW OF MATERIALS AND PERSONNEL i.e Product Areas should preferably be laid out in such a way to: Allow production to take place in areas connected in a logical order corresponding to the sequence of the operations and the required cleanliness levels Avoid crowding and disorder, Allow effective communication and supervision. FMRI - Education Program - LU - Jan 31,

15 PREMISES UTILITIES Qualified Utilities and Equipment mainly consisting of: Power Supply System Water Treatment System: Ensuring the required Quality of Water to be used in the manufacture of the product and complying with current compendia eg USP, EP and for the intended purpose. Air Handling and Treatment System: Ventilation, Air Filtration, Air Heating and Cooling for adequate control of air balancing, dust, humidity, and temperature throughout the manufacture, processing, packing, or holding of a drug product. Compressed Air System Steam All necessary Equipment to operate in Production, QCL, warehouses etc Computer Systems (as applicable) Good compliant periodic Calibration and Maintenance program Adequate Personnel Dress Code & Access Control FMRI - Education Program - LU - Jan 31,

16 Materials Quality System (Raw materials, Packaging Components and Finished products) Four Key elements: Materials management: all activities, for materials and product, related to receipt, storage, status control, warehouse practices (wooden vs plastic pallets, physical segragation, controlled storage conditions etc ) and inventory management (FIFO / FEFO) Distribution of the Finished product: Preparation of Orders, Picking/Packing, Transport monitoring (Environmental conditions - T C/RH, safe adequately labeled containers), Traceability, Documentation and Reconciliation Supplier Quality Management (Supplier evaluation/qualification: Certified vs non-certified etc ) GMP Service providers & Consultants (Supplier evaluation) FMRI - Education Program - LU - Jan 31,

17 Production Operations All Manufacturing operations follow the same pattern ie Dispensing the correct material for a batch, Compounding then subdividing into unit doses They accordingly should be designed to ensure: Contamination Control (product protection and contamination control to address bioburden, chemical & physical sources of contamination operators dress code, reusable pallets cleaning & storage, Environmental monitoring, processing highly toxic or sensitizing materials etc ) Adequate preparation, Set-up & Processing (line clearances, dispensing operations, in-process controls, Metal detection for capsules & tablets etc ) Post processing activities (yield verifications vs the theoretical expected yield ranges, reconciliation, equipment cleaning and line closing etc ) Re-processing rules They consequently should be carried out according to the related: Master Production records (detailed manufacturing and packaging instructions, including safety, environmental and contamination control instructions, and complying with marketing authorization) Batch production records (must be issued from the approved master record with unique identification etc ) FMRI - Education Program - LU - Jan 31,

18 Packaging & Labeling Packaging materials: Must conform to established specifications and regulatory requirements Suitability of the primary packaging for the product must be supported by data Access to pre-printed packaging material should be limited to authorized personnel Quantities of printed materials must be reconciled Packaging operations: Lot number and expiration date are mandatory on primary and secondary packaging (date format MM/YYYY) Encoding is critical (datamatrix, track and trace system) 100% verification of printed materials identity on line 100% verification of encoding on line 100% verification of market pack integrity on line FMRI - Education Program - LU - Jan 31,

19 Laboratory Quality System Management and handling of Samples: safeguard at all times the identity and integrity of samples storage, security, safety etc Management of reference standards and reagents: safeguard at all times identity and integrity of standards/reagents/media/solutions, validity, security and safety Testing: Glassware handling, Methods used, Equipment used cleaning, validation, Qualification, periodic calibration, etc Documentation: safeguard at all times the identity and integrity of all data Reporting, Recording, verifications, compliance with cglp/cglp, retention, security, safety (archiving system), etc Data Review, Analysis and Evaluation: Comprehensive review, interpretation and assessment by a qualified person Investigation of Suspect Results: first in the lab than extending if need be to manufacturing; practically same elements as deviations with requirements for allowing re-sampling/retest, specific points for investigations in microbiology, etc FMRI - Education Program - LU - Jan 31,

20 Quality System The Quality system provides the foundation for the other systems linking them together. It contains the key elements of: Quality Management cgmp Expectations for: Documentation Personnel qualification Deviation Change Management Auditing & Self-assessment Product Quality Assurance and Patient safety assurance FMRI - Education Program - LU - Jan 31,

21 Quality Management Quality Systems Responsibilities & Governance Quality Systems Definition Sustaining & Improving Quality Systems Personnel Responsibilities Management Responsibilities Risk Management Standards, Procedures & Quality manual Management Reviews of Quality Systems Delegation Quality Unit Monitoring & Evaluation Preventive & Corrective actions Quality Plans Product Quality Assessment FMRI - Education Program - LU - Jan 31,

22 Quality Unit Responsibility in Brief INDEPENDENT OF PRODUCTION FULFIL QUALITY ASSURANCE AND QUALITY CONTROL RESPONSIBILITIES; MAYBE COMBINED OR SEPARATE RESPONSIBLE FOR ENSURING ALL PRODUCTS AND MATERIALS MEET REQUIREMENTS FOR INTENDED USE GMP DECISIONS ARE FINAL AND CAN NOT BE OVERRULED BY OTHER FUNCTIONS MUST APPROVE ALL APPROPRIATE QUALITY RELATED DOCUMENTS MUST BE INVOLVED IN ALL QUALITY RELATED MATTERS HAVE THE AUTHORITY TO ACCESS AREAS AND RECORDS NECESSARY TO EXECUTE THEIR RESPONSIBILITY HAVE THE AUTHORITY TO HALT PRODUCTION AND PLACE PRODUCTS ON HOLD OR QUARANTINE STATUS TO ENSURE RESOLUTION OF QUALITY ISSUES FMRI - Education Program - LU - Jan 31,

23 Documentation Fundamental Principle: every action will only be undertaken by following approved written procedures Maintenance Periodic review (routinely 2-3 years) Safeguard history of Doc. Ensure no use of superseded docs Design Prepare Review Approve Distribute ALL TYPES of DOCS: Procedures Instructions Plans Reports Records Title Document code Version & Page numbering Reason for revision Purpose Authors & Approvers Described by SOP Content verification Signed/dated by authors Accurate description of activity performed Acceptance criteria Approval by area supervision, technical services & Quality PRIOR to Execution Other Practices to be ensured eg: 2 nd person verification, proper and timely recordings, proper corrections, entries in chronological order, date format, etc Data Integrity and Traceability to be safeguarded/maintained at all times Only current versions available for user Specified Retention Period Legibility of Doc. thru retention At the end of the specified Retention Period Document destruction Archive Destroy FMRI - Education Program - LU - Jan 31,

24 Personnel Qualification Personnel must be qualified PRIOR to performing assigned tasks/duties Qualification is achieved based on: Education Experience and Training of the individual Qualification program to be based on cgmp regulations and appropriate standards related to the job requirements The Quality Unit and appropriate area supervision must approve the qualification requirements and the training material Trainers Must be Qualified Training Records should be retained for each employee Training appropriateness and effectiveness to be re-assessed periodically and, if needed, corrective action taken Continuous Training is critical FMRI - Education Program - LU - Jan 31,

25 Deviations Handling Identify & Report Notify the Quality Unit Investigate & Document Corrective & Preventive Actions (CAPA) Trend Analysis All personnel are responsible for identifying and reporting to supervision Should be noted immediately on relevant GMP doc. As soon as identified (within 1 working day) In written Assess & Assign Criticality of deviation Assess Impact on other batches, materials and processing systems Risk Evaluation Investigate the 5Ms Identify Root cause (s) Corrective action(s) Complete report within a specified timeframe Report to be Approved by area supervision and Quality Develop CAPA plan Follow-up on its implementation/dates Trend and Track all deviations CAPA Evaluate effectiveness of actions FMRI - Education Program - LU - Jan 31,

26 Change Management Changes can be triggered by new standards, Regulatory and or Business requirements, suppliers limitations, or need for improvement (procedural, equipment, facility etc ) A Change management system must be in place to ensure: Changes that could affect the quality of a product or reproducibility of the process are comprehensively planned, fully Identified, Assessed, Documented, Approved, Implemented and Evaluated for Effectiveness Risk management is applied through classification of changes, impact analysis (internal, external) and subsequent levels of control Changes are tracked After implementation, an appropriate number of batches are evaluated according to acceptance criteria to ensure change effectiveness and no unintended consequences FMRI - Education Program - LU - Jan 31,

27 Auditing (Self-Assessment / Self-Inspection) Audit System Self-Assessment Due Diligence Cause Audits Audit Program (type/scope of audit, frequency etc ) Audit Plan (Agenda, auditors, dates, etc ) Audit Preparation (notify party to be audited, logistics etc ) Audit Execution Audit Report Tracking Actions Trend Analysis Documenting & Tracking Observations Report & Categories Audit Response Final report FMRI - Education Program - LU - Jan 31,

28 Product Quality Assurance & Patient Safety Assurance Specifications (including expiration dating) Validation & Qualification Practices (IQ, OQ, PQ need to be finalized and approved before Cleaning and Process validation can start) Batch Disposition (Release) Periodic product and systems reviews Stability Testing Complaints & Recalls FMRI - Education Program - LU - Jan 31,

29 Thank You FMRI - Education Program - LU - Jan 31,

30 30 Good Distribution Practices GDP Marleine Akl Quality Assurance Algorithm SAL GDP FMRI Education Program - LU - Jan 31, 2015

31 31 GDP - FMRI - Education Program LU - Jan 31, 2015 OUTLINE Distribution in Pharmaceuticals Why has GDP become such a hot topic? What has been the Response? Key Elements of Regulations Revised GDP Guidelines

32 32 Distribution in Pharmaceuticals Aims at GDP - FMRI - Education Program LU - Jan 31, 2015 Delivery to pharmacies without alteration of product properties A Quality System that would ensure: Authorised persons/institutions Storage conditions observed (including transport) No contamination or product adulteration Stock turnover Stored safe and secure Right product, right address, satisfactory time period Tracing system to allow recall

33 33 GDP - FMRI - Education Program LU - Jan 31, 2015 WHY HAS GDP BECOME SUCH A HOT TOPIC? Distribution / Supply Chain 1970's: Prevailing simple linear business model, Local market management and predominantely small molecule manufactured by chemical synthesis s: Outsource non-core activities Manufacture, analytics, distribution, storage Storage & Transportation

34 34 GDP - FMRI - Education Program LU - Jan 31, 2015 WHY HAS GDP BECOME SUCH A HOT TOPIC? DIS-Integration of the Supply Chain

35 35 GDP - FMRI - Education Program - LU - Jan 31, 2015 WHY HAS GDP BECOME SUCH A HOT TOPIC? Integrity Issues Economically motivated adulteration Heparin, supplied by Baxter, found to be adulterated, with reports of 574 adverse events and nine patient deaths estimated Recalls associated with supply chain issues (J&J/McNeil) Loss of hundreds of millions $ in manufacturing issues (Novartis) Shortages in US/EU supply chains result in governments and general public questions Security Issues Abbott was hit by $4m diagnostics theft in USA (June 2011) Eli Lilly warehouse thieves make off with $76m haul (March 2011) Counterfeiting Operation Singapore, 2 million doses of counterfeit medicine enter UK supply chain in 2006/7. Persistent concerns that the drug supply is increasingly vulnerable to diversion of legitimate drugs (ie stolen or sold illegally)

36 36 GDP - FMRI - Education Program LU - Jan 31, 2015 WHY HAS GDP BECOME SUCH A HOT TOPIC? Crippling impacts on Patient safety Brand image and reputation Costs of remediation Customer service and confidence. A UNIVERSAL CRY FOR CHANGE!

37 37 What Has Been The Response? Regulators collaborating globally - EU, US, PIC/S... Dramatic tightening of GDP/GMP EU implemented Falsified Medicines Directive (2011/62/EU). EU Revised Guidance on Wholesale Distribution Practice (2013/C 68/01) WHO Revised good distribution practices for pharmaceutical products (WHO technical report series, No. 957, 2010) Annex For US: USP Chapters regarded as FDA benchmark were revised: Chapter<1079> Good Storage & Distribution Practices for Drug Products Chapter <1083> Good Distribution Practices-Supply Chain Integrity GDP - FMRI - Education Program LU - Jan 31, 2015 FDA joined the Pharmaceutical Inspection Co-operation Scheme (PIC/S). FDAs Pathway to Global Safety and Quality for systems to collect and share data between competent authorities across the world. GS1 Global Traceability Standard for Healthcare (GTSH). Track & Trace Serialization implementation Guidelines on Good Storage and Distribution Practices of Pharmaceutical Products in Lebanon - Edition

38 38 GDP - FMRI - Education Program LU - Jan 31, 2015 Key Elements in Regulations Responsible person (oversees Quality System) Written contracts with Suppliers and Representatives Written procedures Checking Bona Fides of suppliers and customers Staff Training Records/traceability Counterfeit Medicines

39 39 GDP - FMRI - Education Program LU - Jan 31, 2015 Directive: Falsified Medicinal Products 2011/62/EU - SCOPE Extending regulation to brokers of medicines Strengthened obligations on wholesale dealers Improving controls on quality of active substances and certain excipients Regulating medicines imported for re-export new term introduced and rules governing access to medicines held in free trade zones & warehouses Requiring safety features for medicines at risk of counterfeiting Addressing the internet supply of medicines Strengthening inspection and ensuring appropriate penalties for counterfeiting are in place in Member States

40 40 Revised Guidelines on GDP Quality Management Senior management commitment Management of outsourced activities Risk management Quality System: Documentation and procedures Traceability of pharmaceutical products Handling Complaints Handling Recalls Handling Returned Goods Personnel Responsible Person Organisation chart Training in GDP GDP - FMRI - Education Program LU - Jan 31, 2015

41 41 GDP - FMRI - Education Program LU - Jan 31, 2015 Revised Guidelines on GDP (Cont d) Premises, warehousing & Storage Storage areas Storage conditions Stock control Operations Shipment containers and container labelling Dispatch and receipt Repackaging and relabeling Qualification of suppliers and customers

42 42 GDP - FMRI - Education Program LU - Jan 31, 2015 Revised Guidelines on GDP (Cont d) Suspected falsified medicines Distributors must inform competent authority and MAH immediately according to a defined procedure. Contract Operations Written Quality/ Technical agreements allocating responsibilities Required between all actors in the supply chain with the Marketing Authorisation Holder (MAH) shouldering more responsibility.

43 43 GDP - FMRI - Education Program LU - Jan 31, 2015 Revised Guidelines on GDP (Cont d) Transportation Delivery drivers identified and trained in GDP Vehicles equipped with location tracing devices and shipment conditions monitoring devices Maximum limit of 24 hours for transport hubs Wholesalers distribution authorisation: More stringent control in storage whereby some actor/logistics providers, holding product for greater that 24 hours, may require a Wholesale Dealer Licence (WL). Specific provisions for Brokers Register and have quality management system

44 44 GDP - FMRI - Education Program LU - Jan 31, 2015 GMP Regulations tightening Traceability reflected in Chapter 5 of GMP Guidelines: requirement for A record of where each active substance (including its critical starting materials) is manufactured, propagated, processed and handled prior to its use in the manufacture of a medicinal product. Tightening of requirements to check Bona Fides of supply sources (qualification of suppliers) and other trading partners. Safety features required for products at risk of counterfeiting (eg. serialisation/authentication) Barrier: Complex and expensive technology options

45 45 GDP - FMRI - Education Program LU - Jan 31, 2015 Questions? Thank You