Pharmaceutical Quality System in regard to Good Engineering Practice Quality Director, R-Pharm GC

1. Pharmaceutical Quality System in regard to Good Engineering Practice Quality Director, R-Pharm GC T.M. Vyazmina

2. Normative documents • Council of the Eurasian Economic Commission Resolutionas of 03.11.2016 No. 77 “Concerning approval of  the Good manufacturing practice of EAEU” • Order of the Ministry of Industry and Trade of the RF as of 14 June, 2013 No.916 “On the Approval of Good Manufacturing Practice Rules” • ISPE Good Engineering Practice Guidelines • GOST R52896-2017. National standard of the Russian Federation. Manufacturing of medicinal products. Manufacturing systems and equipment for the production of medicines. General requirements. • ISPEHeating, Ventilation and Air Conditioning Guidelines • ISPE Process Gases Guidelines • ISPE“Pharmaceutical Engineering Guides for New and Renovated Facilities. Oral solid dosage form” Guidelines • ISPE“Pharmaceutical Engineering Guides for New and Renovated Facilities. Sterile Product Manufacturing Facilities” Guidelines • ISPE“Pharmaceutical Engineering Guides for New and Renovated Facilities. Water and Steam Systems” Guidelines • ISPE“Commissioning andQualification of Pharmaceutical Water and Steam Systems” Guidelines

3. GEP definition • GEP (Good Engineering Practice). • Established engineering procedures and standards used throughout the whole ‘lifecycle’ of the project for the purpose of getting cost-effective solutions. • System used by the qualified personnel for the implementation of individual solutions, and documentary support of the latter, which allows to track the events from customer’s demands to the final project (design). GEP documentation studies the goal, parties responsible, references, suppositions, calculation methods, conclusions and impact on other sides of the project (design). Requirements of Good Engineering Practice take in account industry-driven activities, performance specifications and safety requirements, as well as economic and normative requirements. • GEPguarantees that technical (engineering) project satisfies the customer’s requirements, is cost-effective, meets the norms, regulatory requirements and has explicit documentary support. • At the same time, philosophy, principles and approaches, engineering methods and standards related to technological equipment, engineering systems, clean rooms are applied throughout the whole lifecycle of the project.

4. Relation to other ISPE documents ISPE guidelines ISPE GAMP: Validation of process control systems ISPE Guide: Commissioning and qualification Critical engineering systems ISPE Guide: HVAC systems ISPE Guide: Maintenance ISPE Guide: Pharmaceutical engineering for new and renovated facilities Good engineering practice

5. Pharmaceutical engineering for new and renovated facilities management structure PV PQ Risk identification, analysis and management OQ Chapter1 Introduction PQS Chapter2 Key definitions and philosophy URS IQ Chapter4 Good engineering practice Chapter5 Commissioning Chapter6 Qualification procedures Chapter3 Impact assessment Chapter7 Enhanced project review Chapter9 OQ Chapter8 IQ Chapter10 PQ SAT Selection of supplier References Glossary Utility programs Annexes Commissioning Project documentation Project specifications FAT Regulation and registration documents for each stage

6. GEP – Good Engineering Practice Customer’s requirements Project evaluation С1 Invitation to participate in a tender In-house standards for engineering activities С3 Enhanced evaluation of the project С4 Offers In-house standards for engineering activities Project plan Contract, purchase order and payment schedule Training materials Registration of assets Project analysis Functional specification of the project С2 Records on training of maintenance personnel Calibration master list Maintenance tasks Records on training of operating personnel Payments Bill of materials Design specification Project analysis FAT Production plan Calibration and maintenance schedule Spare parts inventory Payments Commissioning Maintenance historical data Production activities Project analysis SAT Final payment Acceptance KPI data Configuration record Improvement request Assessment of change impact С1>Requirements С2>Project С3>Time-cost relationship С4>Maintenance use С2 Any source Change approval Change request Change implementation С1 С4 С3

7. Key definitions • Three main aspects of Good Engineering Practice: • Project engineering • Conventionally practiced actions • Operations and maintenance • Project engineering:actions related to the launch of new or heavily modified equipment or facilities. • Conventionally practiced actions:actions, which are a part of project engineering and of common maintenance activitiesand operations. • Operations and maintenance:actions required for maintaining the equipment and facilities in due state and their use for production purposes.

8. Scope of Good Engineering Practice Project engineering Operations and maintenance Conventional practices • Standards and procedures • Documentation practices • Change control • Innovations and continuous improvement • Calibration • Asset management • Supplier management • Equipment storage • Project infrastructure • Project organization • Profit analysis • Planning and monitoring • Engineering • Project analysis • Construction • Compliance with GxP norms • Commissioning • andqualification • Handover • Documentation • Manuals and records • Routine maintenance • Maintenance after breakdown • Internal audit • Waste management • Equipment decommissioning • Equipment and facilities inheritance

9. Quality project plan • Quality project plan should determine acceptable quality standards and how the required quality will be attained and assessed (e.g. analysis stages, approval, supplier quality management). • Quality project plan needs to cover: • Change control procedure and its implementation • Application of risk management strategy (how to manage risks and when to perform their assessment) • Review, agreement and approval of documents before their issuance at predefined stages (concept, approved for design engineering and approved for construction) • Identification, coding of documents and version control • Identification of equipment and control and measuring instruments • Project analysisand progress analysis • Distribution and control of documents

10. Comparison of non-conformities

11. Comparison of non-conformities, %

12. Non-conformities • Differences in identification of production area objects for qualification and in technical and process documents of the project. • HEPA-filters remain unidentified in clean production premises, which impedes traceability of their preventive maintenance. • Absence of filters on exhaust devices in clean production premises, which bears the risk of contamination of internal surfaces of HVAC ducts. • Airtight installation of grids on exhaust systems during dusting production stages implies lack of technical availability of periodic cleaning of the space between the air grid and the filter. • Technical means for the control of air flow resistance in HEPA filters letting the air in clean production premises are unavailable, which does not allow to keep the level of filter cleanliness under control. • Equipment operation logbook does not allow to track down all stages of lifecycle of technological equipment (FAT/SAT/IQ/OQ/PQ/PV, shutdowns, breakages, repairs, etc.)

13. Non-conformities • Construction, operation and maintenance of air handling systems do not allow to feed sufficiently purified air to production premises.In the solids and liquid dosage areas, premises are not classified according to cleanness grades. No purification of the incoming air. • No continuous monitoring of aerosol particles in the aseptic core area of sterile production. • Dispensing room for raw materials in non-sterile production department does not have air cleaning system. • Room surfaces are made of materials, which do not allow to clean and disinfect them repeatedly. It creates a risk of product contamination.

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