GOOD MANUFACTURING PRACTICE FOR BIOPROCESS ENGINEERING (ERT 421)

1. GOOD MANUFACTURING PRACTICE FOR BIOPROCESS ENGINEERING(ERT 421) Huzairy Hassan School of Bioprocess Engineering UniMAP

2. What is Bioprocess Engineering? Bioprocess Engineers work at the frontiers of biological and engineering sciences to “Bring Engineering To Life” through the conversion of biological materials into other forms needed by mankind. • What separates them from other engineers is their understanding of how every engineering field relates to living materials. The demand for bio-process engineers continues to grow. They provide a bridge between the research lab and the economic, large-scale implementation of biotechnologies and food production systems. Application areas associated: poduction of biofuels, design and operation of fermentation systems, development of food processing systems, application and testing of product separation technologies, design of instrumentation to monitor and control biological processes. 

5. GMP Basic Requirement What is GMP ? • Part of Quality Assurance (QA) which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by marketing authorization or product specification. • Engineering for cGMP: those activities performed throughout the project life- cycle, which ensures that it will be easy and natural to operate the completed facility in accordance with current Good Manufacturing Practice.

6. Project Life-Cycle means from project inception through feasibility studies / conceptual design, engineering, construction, installation, start-up, operation, maintenance to final plant decommissioning or modification. GMP is controlled by the US Code of Federal Regulation (CFR) 21 in the USA.

7. Various regulatory authorities produce different types of applicable documentation: • Directives, rules, regulations - US Code of Federal Regulations CFR 21 Parts 210 and 211 (Drugs and products) - EU GMP Directive 91/356/EEC, Commission Directive Laying Down the Principles and Guidelines of GMP . 2) Guides, guidelines, point to consider - FDA Guide to Inspection of Bulk Pharmaceutical Chemical Manufacturing - FDA Guide to Inspection of Validation of Cleaning

8. General GMP requirements • The establishment and maintenance of an effective quality assurance system; • Control of the process; • Personnel that are suitably qualified, trained and supervised; • Premises and equipment that have been located, designed, installed, operated and maintained to suit intended operations; • Maintenance of adequate records of all aspects of the process so that in the event of a problem being identified, an investigation can trace the complete history of the process, including how, when, and where it was produced, under what conditions and by whom (i.e. an audit trail); • The prevention of contamination from any source, in particular from components, environment, premises and equipment by the use of suitable premises and equipment and through standard operating procedures.

9. Project assessment to determine applicable standards • Stage of product development; • Stage of production; • Category of the product and production processes employed; • Facility location and location of the markets that the facility will serve.

10. Stage of product development • Laboratory trials (pre-clinical animal trials) – cGMPs regulations not applicable, may be applied cGLPs • Clinical trials – Basic cGMPs, may be applied cGCPs • Routine production – full cGMPs • Stage of production - means what the facility is used for • Bulk Pharmaceutical Chemicals (BPCs) manufacturing • Finished product manufacturing • Packaging • Warehousing / holding

11. 3) Category of the product and production processes employed - most active ingredients are manufactured by; • chemical synthesis • biotechnology • blood derived • animal or plant extraction 4) Facility and Market locations - cGMPs regulations are produced by a number of different countries or groups of countries world-wide, in addition to WHO. Clarification should be sought from the pharmaceutical manufacturer before the design commences.

12. GMP Design requirements 1) Process issues - closed or open (piping and equipment, expose to environment- measure to prevent contamination) - level of batch to batch integrity required (simultaneous filling self-emptying vessels, or cleaning, or drying, sterilization between batches?) 2) Layout issues - site location and layout – existing site, brown and green field, and overall site layout - facility layout – cored vs. linear layout, transfer corridor, segregation of areas, environment, containment strategy, security etc.

13. 3) Automation Strategy issues - level of technology, use of design tools and models - availability / redundancy, modularization / expansion - instrumentation / cabling / field devices - paperless batch records, electronic signatures. 4) Flow issues - people (security, access, occupancy level) - equipment (mobile or fixed, use of hard piping, cross- contamination) - components / materials (materials handling systems, cross- contamination / mix-ups)

14. 5) Regulatory issues - stage of development and production, category of the product (sterile medical, biological medical, herbal medicinal, medical gases, liquid, creams, tablets etc) and production process employed, facility location etc. 6) Validation Strategy issues - validation required, validation team(s), validation plan(s).

15. Refine basic requirements for the various aspects of the project to allow the facility to be engineered. • Categories suggested for guidance; • Facilities and environment • Services and utilities • Personnel flows • Material flows • Equipment flows • Equipment design • Computerized systems • Maintenance and services • Waste management • Procedure and documentation

16. 1) Facilities and environment facility - local environmental considerations - suitability / acceptability of physical segregation of processes for manufacturing and holding products - overall layout of the facility - general layout of production processes environment - assessment of the environmental classification of the various areas against the level of quality required by the product - airflow regime (turbulent or laminar) - air pressure differentials between areas - humidity, etc.

17. 2) Services and Utilities example: high purity water systems – WFI systems - assessment of the proposed water quality against the level of quality required by the product - materials of construction (piping, gaskets, valve diaphragms) - internal surface finishes (electropolishing, passivation) - water pre-treatment and control - system sizing - key design considerations (flow rates, minimum deadlegs with no cavities, vents, drainage air gaps) - use of security devices - instrumentation and control of critical process parameters (T, velocity, etc.) - adverse operating conditions

18. Typical GMP criteria for WFI - quality to conform to compendia requirements (USP) - production to be by distillation (ex: RO) from purified water and to conform to USP - WFI to be sterile and pyrogen free with an action limit set to less than 10 CFU/100ml (Colony Forming Units) with a sample size of between 100 and 300 ml and an endotoxin level < 0.25 EU/ml.

19. 3) Personnel Flows --> the influence personnel have on the quality of the product that might be caused by their contact with the product. • Clothing requirements • Changing facilities (washing facilities, doors, vision panels) • Security and access control – potential short cuts and back doors • Types of movements within the area, etc. 4) Material Flows  all the movement of materials • General flow of materials through the area (linear flow through with no cross-over of production streams) • Methods of handling and prevention of cross-contamination • Frequency of movements and available space

20. 5) Equipment Design - pedigree of the machine (established for pharmaceutical use/ specially developed prototype) - pedigree of the manufacturer - materials of construction and surface finishes of primary and secondary contact parts (i.e. primary – direct product contact; secondary – contact with local environment) - equipment sizing - instrumentation and control of critical process parameters - methods and adequacy of cleaning and sanitization - maintenance  For equipment and pipework that does not come into contact with the product components, there are no specific GMP requirements.

21. GMP reviews of Design 1) Organizing the GMP design review team 2) Information required to perform the review - specification of the pharmaceutical product and manufacturing process - specification of the equipment and facility 3) Divide-up the facility into manageable sized areas - Bulk pharmaceutical chemical manufacturing - secondary manufacturing

22. Standard Operation Procedure (SOP) • SOPs are detailed, written instructions to achieve uniformity of the performance of a specific function. • SOPs help government organizations, emergency response operation, and clinical research organization achieve maximum safety and operational efficiency. • A well-written SOP can be used to satisfy compliance requirements. SOPs are recommended for all procedures that pose a potential risk to the health and safety of personnel. • http://www.epa.gov/quality/qs-docs/g6-final.pdf

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