GOOD MANUFACTURING PRACTICE FOR BIOPROCESS ENGINEERING (ERT 425) School of Bioprocess Engineering UniMAP

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.

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.

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

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.

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.

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

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.

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, cleaning, 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.

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)

6) Validation Strategy issues 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).

Quality Assurance and Quality Control QA Is defined as the sum total of organized arrangements made with the objective of ensuring that the products are of quality required for their intended use. QC It is the part of GMP which is concerned with sampling, specifications, testing, documentation and release which ensures that necessary and relevant tests are carried out and that materials/products are released For use/ sale only after their quality is judged to be satisfactory. 12

What QA systems should includes? GMP and GLP are taken into account during designing and developing products. All production and control operations are clearly specified and documented. Key personnel responsibilities are clearly defined. All arrangements for procurement and use of correct starting materials and packaging materials are made. In process checks and validations are carried out in a defined manner. The final product is manufactured, packed and checked as per defined procedures. Regulatory aspects and internal requirements for the final product are fulfilled. Storage, handling and distribution procedures for the final product are followed to ensure maintenance of quality throughout shelf life. Self-inspection procedures are defined to regularly monitor the effectiveness of the quality assurance system. Corrective actions Statistical process control 13

What QC systems should includes? Appropriate procedures, training personnel and adequate facilities for sampling, inspection and testing of starting materials, intermediate, bulk and finished products. Validated test methods Maintenance of records to demonstrate that all procedures have been carried out. Certification of starting materials to be of specified quality and purity, and their storage and adequate labeling before use in final product. Release of batch of product ONLY after certification by qualified person that it meet required criteria or specifications. Maintain sufficient samples of starting materials and final product for future examination, if necessary. Recording and investigation of out of specification results, changes, incidents and deviations. 14