Introduction to Medicines Inspections Technical Updates: GMP inspections of Active Pharmaceutical Ingrédients and Finished Pharmaceutical Products (including Reproductive Health Products) Vimal Sachdeva, Technical Officer (Inspector) WHO Prequalification Team (PQT), WHO/HIS/EMP/RHT 20 Avenue Appia, CH - 1211, Geneva 27, Switzerland Tel.: +41-22-791 13615 Fax: +41-22-791 4730 e-mail: sachdevav@who.int 1
This Presentation Includes: International Norms, Standards and Guidelines WHO Prequalification GMP Inspection Process API and FPP manufacturing sites inspected Compliance status and inspection outcome Top ten observations (including reproductive health product) Discussion on commonly found top three observations Recommendations Concluding remarks 2
http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2 3
Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide applicability USP BP Ph. Eur. Ph. Int. Other guidelines e.g. ICH, ISO 4
WHO Prequalification Medicines Inspections Process-1 Manufactures are inspected by WHO-PQT on a routine basis using an SOP, and based upon a risk based approach; As part of pre-approval activity Post approval surveillance For special cause e.g. serious complaints Before inspection, inspector is required to verify objective of inspection to be carried out; Inspector determines what the scope and depth of the inspection will be based on product dossier assessment report(s) and findings of previous inspection, if applicable and other intelligence; 5
WHO Prequalification Medicines Inspections Process-2 WHO-PQT inspections may be conducted purely as WHO-PQT inspections, and may be joint inspection with other authorities (e.g. API cooperation scheme); WHO PQ conducts system based inspection but also covers product specific elements (e.g. dossier integrity); It is possible to prequalify a product which was not specifically covered during an inspection (e.g. same site, same QMS, same production facilities, based on more recent inspection, and depending on specific product risk); Up-to-date Site Master File (SMF); Review of variation list, complaint register; Preparation of tentative inspection plan; 6
WHO Prequalification Medicines Inspections Process-3 Opening meeting covering introduction and brief presentation of site Inspection to cover an on-site verification of dossier accuracy and data verification Assessment of robustness of Quality System and GMP compliance, what the company is good at and where there are gaps and weaknesses Observations are based on RED Requirement Evidence Deficiency Review of the company CAPA, and Final compliance decision and recommended inspection re-interval. 7
WHO-PQT Medicines Inspections-1: Number of GMP Inspections in 2014 40 35 30 25 20 39 32 Number of Inspections Number of GMP Inspections in 2015 (Jan-Jun) 15 10 25 21 5 20 0 API FPP 15 14 Number of Inspections 10 5 0 API FPP 8
WHO-PQT Medicines Inspections: Break-up of API sites Break-up of FPP Sites 30 30 18 18 25 16 14 20 12 11 15 API sites 10 8 FPP Sites 10 5 0 5 New 4 Routine Requires Follow-up 0 Special 6 4 2 0 New Routine Requires Follow-up 3 0 Special 9
WHO-PQT Medicines Inspections (API): Final Compliance Status of API Sites in 2014 Inspection Outcome for API sites inspected in 2014 8 5 26 Compliant Noncompliant Requires Follow-up 11 28 Immediate Compliant After 1st round of CAPA After 2nd or more round 10
WHO-PQT Medicines Inspections (FPP): Final Compliance Status of FPP Sites in 2014 Inspection Outcome for FPP sites inspected in 2014 5 1 Compliant 1 3 Immediate Compliant 25 Noncompliant Requires Follow-up 27 After 1st round of CAPA After 2nd or more round 11
WHO-PQT Medicines Inspections: Compliance Status of API sites during Jan-Jun 2015 Compliance Status of FPP sites during Jan-Jun 2015 8 1 10 Compliant 5 Compliant 2 Awaits CAPA 2 7 Noncompliant Noncompliant Awaits CAPA 12
API Sites: Top 10 Areas for Improvements 1. Design, Maintenance and Cleaning of Equipment 2. Product Quality Review (PQR) 3. Process Validation 4. Computerised Systems data integrity 5. Change Controls 6. Production and Packaging Operations 7. Design, Maintenance & Cleaning of Production Premises 8. Documentation Control 9. Investigation of out of specification (OOS), Deviations 10.Quality Risk Management 13
FPP Sites: Top 10 Areas for Improvements 1. Product Quality Review (PQR) 2. Design, Maintenance and Cleaning of Equipment 3. Computerised Systems data Integrity 4. Contamination & Cross Contamination (physical/chemical) 5. Investigations of Deviations, out of specification (OOS) 6. Contamination & Cross Contamination (microbial) 7. Change Controls 8. Design & Maintenance of HVAC system 9. Design, Maintenance & Cleaning of Production Premises 10.Documentation Control 14
RH (API & FPP sites): Top 10 Areas for Improvements 1. Quality Management Product Quality Review 2. Contamination & Cross Contamination 3. Computerised Systems data integrity 4. Duties of key personnel 5. Hygiene and Clothing 6. Supplier and Contractor selection/monitoring/audit 7. Warehousing and Distribution activities (temp. control & monitoring) 8. Documentation Control (general, manufacturing & procedures) 9. Quality Risk Management 10. Management Review 15
Product Quality Reviews (PQR)-1 The quantity of data being collected was not adequately and critically reviewed; The selection of those criteria to be trended was not well explained and linked to product and process risk. There was no risk assessment documented to justify critical in process parameters o There was no appropriate review and trending of the API quality attributes, excipients, and packaging components; o No robust tool used to assess any trend and or variation e.g. Trends were not adequately evaluated using appropriate statistical means. 16
Product Quality Reviews (PQR)-2 o Stability data were not trended for any adverse trends; o No mentioning of media simulation studies; o No mentioning of use of contractual services (calibration, qualification, requalification); o No comment was made on post/marketing; commitments for new dossiers and variation to the dossiers; o Environmental monitoring of production areas and purified water were not included as part of PQR review for all products inspected. 17
What makes a Good PQR-1 The SOP should include clear objectives of PQR or regular reviews. The objective is not to look into whether batches manufactured during a year were within specification or not, but to verify consistency of the process and identify where there is a need for improvement; Wisely use data collected for review. It is not for the inspectors, but for you and your company to improve the processes; It is important to identify trends, interpret data and draw conclusions from the data. 18
What makes a Good PQR-2 Control Charts (Shewhart control charts enables manufacturers to determine upper and lower control limits, and identify trend & shift in mean etc) and, Process Capability Study (to determine whether a process is stable and capable, Cp is used to evaluate variation of the process whereas CpK is used to evaluate centering of process) are recommended to verify process variability, where applicable; Conclusion should be based on the critical review of data, and should propose recommendations for further improvements. 19
Computerised Systems Data Integrity-1 Inadequate number of software licences for the number of workstations; Sharing of common password not attributable Trial system suitability was not included in the sample set, not mentioning in analytical report and chromatogram not filed; Procedure not in place giving details of how manual integration be performed and control over such events; Audit trail on HPLC systems were disabled without justification; Audit trials were not reviewed as part of CDS data. 20
Computerised Systems Data Integrity-2 It was noted that during testing of related substances that there was shift in the retention time which necessitated redesignation of integration events. Whilst in this case the correction was scientifically justified and could be tracked in the software audit trial, the changes were not discussed and reported in the relevant test record; Allocation of access rights presented potential conflict of interest. Laboratory supervisor had system administrator rights to the CDS software; No procedure and practice in place for scientifically sound, timely back-up and archive of the e-data generated by Empower software; 21
How to establish and run Good Data Management Practices Understand and learn our expectations WHO draft Guidance on Good Data and Record Management Practices, and other guidelines (e.g. MHRA); Set realistic and achievable expectations Monitor process capabilities Provide necessary resources Reduce pressure and possible source of error Adoption of Quality Culture within the company; Design a system to improve detection of errors/changes; Training of personnel on computerised systems and review of electronic data. 22
Design, Maintenance and Cleaning of Equipment There was no de-duster and metal detector for compression machines; The scoops for transferring granule to the vibratory sieve were in a very poor condition and had uncleanable recesses in the welding; The blender seal was in a poor condition and staff had been using sealing tape to contain leakage; Some punches were stored unprotected in a drawer due to inadequate locations in frame. There was therefore a risk that tips could crash and it was noted that some punches appeared to have attrition damage; Not all dust collector extracts could be properly adjusted. There was a build-up of residues and the some of the flaps were jammed. There was no enough water to perform cleaning of equipment No non-return valves were installed in nitrogen supply pipelines to prevent backflow. There was no integrity test (such as spark test) performed for glasslined reactors as part of the initial equipment qualification and preventive maintenance program. 23
Reduce Risks of Cross-contamination by better Design of Processes, Maintenance & Cleaning of Equipment Aim to have closed processes & equipment whenever appropriate. Always aim to have equipment which minimizes risk of errors, permit effective cleaning and maintenance. Always ensure parts of the production equipment that come into contact with product are not reactive, additive or absorptive. Equipment, especially if non-dedicated should be cleaned according to validated cleaning procedures. Remember, one of the most important processes in a pharmaceutical plant is often assigned to the lowest paid staff. CLEANING 24
Concluding Remarks Understand requirements and expectations Have good quality metrics and monitoring processes Keep systems up to date, and perform robust investigations Financial incentives don t reduce errors. Employees must be passionate about eliminating mistakes Have pride in whatever work assigned - small or big Celebrate success of not doing things twice 25
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