Lecture 2: GMP; Premises & Contamination Control (PHEN 502) - PDF

Pharmaceutical Engineering and Biotechnology Department of Pharmaceutical Technology Good manufacturing Practice & Quality Management System (PHEN 502) Lecture 2: GMP; Premises & Contamination...

Pharmaceutical Engineering and Biotechnology Department of Pharmaceutical Technology Good manufacturing Practice & Quality Management System (PHEN 502) Lecture 2: GMP; Premises & Contamination Control Course Instructors: Dr. Shahir Aziz Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 1 Intended Learning Objectives (ILOs)  Arrange the order of different levels of clean areas within a pharmaceutical facility.  Apply general GMP guidelines for premises, personnel, documentation, and validation.  Assess a work station if it is following the correct standards and guidelines at different environmental conditions (i.e.: as built, at rest or operational).  Identify different quality assurance aspects in regards of personnel in manufacturing (i.e.: Safety, Training & Hygiene) Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 2 Recall: What is Quality Assurance? Introduction to Quality Quality Assurance: Is the planned and systematic “Proactive” activities necessary to prevent problems and making certain that medicinal products are fulfilling the quality required for their intended use. Quality Assurance therefore incorporates all the following interconnected essential elements in a collection of regulations Called “GXP”; A. Good manufacturing B. Good Laboratory C. Good Clinical Practices practices (GMP) practices (GLP) (GCP) 1. Personnel and training 2. Validation and 3. Materials, Equipment Qualification and Premises 4. Complaints and Product 5. Sanitation and hygiene 6. Documentation Recalls 7. Self-inspection and 8. Contract production quality audits and analysis Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 3 Outline Premises and personnel Introduction: Industrial Layout examples Manufacturing process flow Premises: General guidelines Different areas (i.e.: Storage, Production, Weighing, Quality control, Ancillary) Heating, ventilation and air-conditioning Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 4 Manufacturing process – Industrial Layout Example Introduction Roche Campus Layout in Basel, Switzerland Dr. Shahir Aziz – GMP & QMS course (PHEN 5 502) – Winter 2024 Manufacturing process – Flow through Layout Introduction Pharmaceutical Factory Layout Example 3rd Unit for Liquid E Administrative Offices R&D Production x t e Intermediate products r 2nd Unit for Special Products / Biologics / n Quality Control Antibiotics…etc. a Raw Material Finished goods Packaging l R Approved Final In process Warehouse Coating Tablet Compression o Product Quarantine a GMP Solid Production Unit Shipping Receiving d Area Area Receiving Approved Material Dispensing Granulation Quarantine warehouse External Road 6 Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 6 Manufacturing process - videos Introduction Advertisement Video of an Indian Pharmaceutical company showing different manufacturing process, Quality guidelines and premises; https://www.youtube.com/watch?v=hA01pSBPgr4 7 Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 7 Definition and general guidelines Premises Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. 1. The layout and interior design of premises:  Must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt.  Where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of powder), measures should be taken to avoid cross-contamination and facilitate cleaning. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 8 Definition and general guidelines Premises 2. Premises Location  should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products. (i.e.: Climate, Altitude, local noise and pollution…etc.) VS. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 9 Definition and general guidelines Premises 3. Premises structure ensure the logical flow of materials and personnel. 4. Premises Utilities:  Electrical supply, lighting, temperature, humidity and ventilation 5. Premises Designed with maximum protection against the entry of insects, birds or animals. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 10 Storage areas Premises 1. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products with proper separation and segregation 2. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry, sufficiently lit and maintained within acceptable temperature limits. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 11 Storage areas Premises 3. Receiving areas should be designed and equipped to allow containers of incoming materials to be cleaned if necessary before storage. 4. Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. 5. Highly active and radioactive materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas with special precautions. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 12 Production areas Premises 1. Minimize the risk of a serious medical hazard due to cross contamination;  Isolated, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms). 2. Connected in a logical order  corresponding to the sequence of the operations and to the requisite cleanliness levels. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 13 Production areas Premises 3. Interior surfaces  Walls, floors and ceilings should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection. 4. Utilities:  Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 14 Weighing areas Premises  The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas designed for that use, for example with provisions for dust control. Such areas may be part of either storage or production areas. E.g.: Laminar Flow workplace for the weighing of large quantities under clean- room conditions, Installed in the pharmaceutical production Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 15 Quality Control areas Premises 1. Separated from production areas. 2. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents and records. 3. Suitable construction materials.  Floor materials should be non-absorbent, skid- proof, resistant to wear, and resistant to the adverse effects of acids, solvents, and detergents.  Materials may be monolithic (sheet flooring) or have a minimal number of joints such as vinyl composition tile (VCT) or rubber tile. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 16 Quality Control areas Premises 4. A separate room may be needed for instruments  To protect them against electrical interference, vibration, contact with excessive moisture and other external factors, or where it is necessary to isolate the instruments. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 17 Ancillary (Additional) areas Premises 1. Rest, refreshment, eating, and meeting rooms should be separate from manufacturing and control areas. 2. Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not communicate directly with production or storage areas. 3. Maintenance workshops should if possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 4. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air-handling facilities. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 18 Heating, ventilation and air-conditioning (HVAC) Premises 1. HVAC system design influences architectural layouts with regard to airlock positions, clean areas, doorways and lobbies. The architectural components have an effect on room pressure differential cascades and cross-contamination control. 2. The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system. 3. The design of the HVAC system should be considered at the concept design stage of a pharmaceutical manufacturing plant. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 19 Heating, ventilation and air-conditioning (HVAC) Premises 4. Temperature, relative humidity and ventilation should be appropriate and should not adversely affect the quality of pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment. 5. The HVAC Guidelines are set based on the type of manufactured products; sterile or non sterile, solid or liquid or semisolid dosage form fulfilling the GMP requirements. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 20 Heating, ventilation and air-conditioning (HVAC) Premises Ad. For a company that provide Cleanroom Design, Clean Construction, Cleanroom Services: https://www.youtube.com/watch?v=F1dfb9t1D8s Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 21 Heating, ventilation and air-conditioning (HVAC) Premises Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 22 Heating, ventilation and air-conditioning (HVAC) Premises A typical cleanroom is designed to keep the outside environment from getting in. Once an environment has been built, the two things that cause contamination in it are the People and the Process. So, what contamination is generated by people, and what contamination is generated by the process is what needs to be determined. When setting a clean room specification; There are three main questions to ask in order to determine what classification is needed for a particular cleanroom application: 1. What are my sources of contamination? 2. What size particles do I need to filter out? 3. How much air do I have to circulate to get that contamination out? Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 23 Heating, ventilation and air-conditioning (HVAC) Premises Based on level of protection, Areas are classified into 3 main levels as shown in table. Further sublevels can be introduced according to more specific standards such as the number of airborne particulates and their sizes in micron (µm). Level Condition Example of area Area with normal housekeeping and maintenance (e.g. Level 1 General warehousing, secondary packing). Area in which steps are taken to protect the exposed pharmaceutical starting material or product from Level 2 Protected contamination or degradation (e.g. manufacturing, primary packing, dispensing). Area in which specific environmental conditions are defined, controlled and monitored to prevent Level 3 Controlled contamination or degradation of the pharmaceutical starting material or product (e.g.: Sterile production process) Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 24 Heating, ventilation and air-conditioning (HVAC) Premises “As-built” condition “At-rest” condition “Operational” Condition In classifying the environment, the manufacturer should state whether this is achieved under “as-built” , “at-rest” or “operational” conditions. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 25 Heating, ventilation and air-conditioning (HVAC) Premises Detailed Classification Examples: Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 26 Heating, ventilation and air-conditioning (HVAC) Premises The degree to which air is filtered plays an important role in the prevention of contamination and the control of cross contamination. The process core is regarded as the most controlled clean zone which is protected by being surrounded by clean areas of a lower classification. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 27 Heating, ventilation and air-conditioning (HVAC) Premises Some of the typical HVAC system parameters that should be qualified for a pharmaceutical facility may include: 1) Temperature and Relative humidity 6)Microbiological air and surface counts 2) Return air or exhaust air quantities 7) Room air-change rates and pressure differentials 3) Room airflow patterns and velocities 8) Room clean-up rates 4) HEPA filter penetration tests 9) Room particle counts 5) Operation of de-dusting 10) Warning/alarm systems 28 Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 28 Heating, ventilation and air-conditioning (HVAC) Premises HEPA Filter: high-efficiency particulate arresting or high-efficiency particulate air 3) How to correctly wipe floors and ceiling in clean area: https://www.youtube.com/watch?v=XqCk1JMBuJE 29 Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 29 References Premises & Personnel 1. EUROPEAN COMMISSION - HEALTH AND CONSUMERS DIRECTORATE-GENERAL. 2012. The Rules Governing Medicinal Products in the European Union. Brussels : EUROPEAN COMMISSION, 2012. Ref. Ares(2012)778531 - 28/06/2012. 2. GAD, SHAYNE COX. 2008. PHARMACEUTICAL MANUFACTURING HANDBOOK; Regulations and Quality. New Jersey : John Wiley & Sons, Inc., 2008. ISBN: 978-0-470-25959-7. 3. World Health Organization. 2007. Quality assurance of pharmaceuticals : a compendium of guidelines and related materials. Geneva : WHO Press, 2007. ISBN 92 4 154708 1. 4. World Health Organization. 2009. Handbook: good laboratory practice (GLP): quality practices for regulated non-clinical research and development -. Geneva : WHO Library, 2009. ISBN 978 92 4 154755 0. 5. U.S. Department of Health and Human Services Food and Drug Administration. 2009. Guidance for Industry Q10 Pharmaceutical Quality System. Silver Spring : Food and Drug Administration (FDA), 2009. Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 30  “If you are not willing to learn, no one can help you. If you are determined to learn, no one can stop you.” - Zig Ziglar American author (1926 – 2012) THANK YOU Dr. Shahir Aziz – GMP & QMS course (PHEN 502) – Winter 2024 31