CGMP guidelines

CGMP guidelines, CFR, CDER and CBER, PIC/S, Environment control in pharma industry, plant layout, maintenance of sterile area, Clean room classification, Environmental monitoring, Types of contaminants in pharma industry & Good Warehousing Practices.

1. CGMP Guidelines According to Schedule M

2. WHO defines Good Manufacturing Practices (GMP) as “that part of quality assurance which ensures that quality products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization” GMP is aimed primarily at diminishing the risk inherent in any pharmaceutical production types of risks : cross-contamination (in particular, with unexpected contaminants) mix-ups (example, false labeling)

3. An FDA 483 is a form used by an FDA investigator following an inspection of your plant It lists deficiencies in your quality system and potential noncompliance issues with GMP’s The guiding principle of GMP is that quality is built into a product, and not just tested into a finished product Therefore, the assurance is that the product not only meets the final specifications, but that it has been made by the same procedures under the same conditions each and every time it is made

4. August 2002, the FDA announced the Pharmaceutical CGMPs for the 21st Century Initiative Intent to integrate quality systems and risk management approaches CGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product The Form 483 is officially known as the Notice of Inspection Observations

5. is compilation of federal laws is divided into 50 titles for different fields, titles are further divided into chapters and chapters are divided into parts CGMP guidelines are defined in Title 21 of the U.S. Code of Federal Regulations (21 CFR), which appears in several parts CFR (Code of Federal Regulations) 21 CFR part 314 : For FDA approval to market a new drug

6. 21 CFR part 210 : Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs 21 CFR part 211 : Current Good Manufacturing Practice for Finished Pharmaceuticals 21 CFR part 600 : Biological Products

7. Most influential and most frequently referenced GMP guidelines for pharmaceuticals: The US Current Good Manufacturing Practices for Finished Pharmaceuticals regulations (the US cGMPs ) The Guide to Good Manufacturing Practice for Medicinal Products of the European Union (the EC GMP Guide) The ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients The World Health Organization (WHO) good manufacturing practices

8. The other guidelines and regulations referred by the pharmaceutical manufacturers are: Schedule M ‘Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products,’ The Drugs and Cosmetics Act and Rules, India PIC/S Guide to Good Manufacturing Practice for Medicinal Products Center for Drug Evaluation and Research (CDER): Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

9. GMP includes a) General considerations b) Personnel c) Production area d) Equipment e) Sanitation f) SOP’s g) Raw Materials h) Self Inspection And Audit i ) Master Formula Records

10. j) Batch Manufacturing Records k) Warehousing Area l) Labels And Other Printed Materials m) Quality Control System

11. General considerations Location and surroundings: shall be so situated that it avoid risk of contamination from external environmental including open sewage, drain, public lavatory. Building and premises: shall conform to the conditions laid down in the Factories Act, 1948 (63 of 1948) Water system: shall be validated system for treatment of water in accordance with standards specified by the Bureau of Indian Standards or Local Municipality or Pharmacopoeial specification Disposal of waste: be in conformity with the requirements of Environment Pollution Control Board

12. b) Personnel Qualified and experience in relevant field Written duties of technical and Quality Control personnel shall be laid and following strictly Appropriate number Medical examination prior to employment & periodically after personnel hygiene training

13. c) Production Area Orderly and logical positioning of equipment and materials and movement of personnel Separate dedicated and self-contained facilities shall be made available for the production of sensitive pharmaceutical products d) Equipment shall be located, designed, constructed, adapted to suit the operations and logbook shall be maintained shall be calibrated and checked on a scheduled basis in accordance to SOP and maintain records

14. e) Sanitation manufacturing premises shall be cleaned and in an orderly manner f) SOP For Equipment, sampling, Testing, Process and Packaging shall be retained for at least one year after the expiry date of the finished product g) Raw materials Keeping an inventory of all raw materials to be used and maintain records as per Schedule U Should be purchased from approved sources Must be checked by QC department and shall be labelled

15. h) Self inspection and Audit To detect shortcomings in the implementation of GMP and to recommend the necessary corrective actions shall be performed routinely and on specific occasions i) Master Formula Records There shall be Master Formula records relating to all manufacturing procedures for each product and batch size shall be prepared and endorsed by head of production and quality control

16. j) Warehousing Area should be designed and adapted to ensure good storage conditions There shall be a separate sampling area in the warehousing area for active raw materials and excipients Should be clean, dry and maintained with acceptable temperature limits Every Material stored should be labeled properly

17. k) Labels & other printed materials Labels are necessary for identification of the drugs and their use The Printing shall be done in bright colours and in a legible manner l) Quality Control System QC lab. May be divided into Chemical, Instrumentation, Microbiological and Biological testing QC department shall conduct stability studies of the products to ensure and assign their shell life All instruments shall be calibrated and validated before adopted for routine testing

18. CDER (Centre for Drug Evaluation & Research) It is a part of USFDA Performs essential public health task by making sure that safe and effective drugs are available to improve the health of people in U.S. Regulates OTC and prescription drugs, including biological therapeutics and generic drugs (more than medicines) Ex. Fluoride toothpaste, antiperspirants, dandruff shampoos and sunscreens FDA CDER also develops standards for CGMP, clinical and Good Laboratory Practices and Industry practices

19. CBER (Centre for Biologics Evaluation & Research) regulates biological products for human use under applicable federal laws, including Public Health Service Act and Federal Food, Drug and Cosmetic Act Responsible for assuring safety, purity, potency and efficiency of biologics and related products biologics are drugs derived from humans, animals and microorganisms BLA (Biologic License Application) is request for permission to introduce biologic product into interstate commerce BLA is a form from FDA 356

20. PIC/S (Pharmaceutical Inspection Convention/ Pharmaceutical Inspection CO-operation Scheme) provides the pharmaceutical GMP guidelines for industries mainly guidelines for sterile pharmaceuticals and also QA guidelines PIC/S guidelines are applicable for member countries was established to harmonize, educate and update aspects relating to GMP among member countries

21. PIC was established by European Foreign Trade Agency under the title ‘The Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products’ Goal: To lead the international development, implementation and maintenance of harmonized GMP standards of inspectorates in the field of medicinal products PIC/S (Pharmaceutical Inspection Convention/ Pharmaceutical Inspection CO-operation Scheme)

22. PIC/S (Pharmaceutical Inspection Convention/ Pharmaceutical Inspection CO-operation Scheme) Objectives: to harmonize GMP requirements to bring about uniform mutual valid inspections to educate & exchange information among different countries to attain mutual confidence of drug regulatory authorities to safeguard public health by providing good quality medicines by bringing harmonization in GMP among countries

23. PIC Established in 1970 Convention 18 countries Formal agreement Focus on inspection PICS Established in 1995 Scheme 49 agencies Informal agreement Focus on training and developing guidelines

24. Environment Control Clean areas should be ventilated with air passed through appropriate filter ( HEPA) Temperature and relative humidity in clean areas should be controlled within limits compatible with properties of materials and products being handled therein Air pressure in clean areas should be maintained higher than that in adjacent or lower cleanliness levels areas with different levels of cleanliness should be separated by airlocks

25. Plant Layout

26. Maintenance of Sterile Area Sterile products are produced by 2 ways----- Aseptic processing: is processing & packaging of sterile products into previously sterile containers followed by hermetic sealing with a sterilized closure in a manner that prevents viable microbial recontamination of sterile product Terminal sterilization: a product is sterilized in its final container or packaging which permits the measurement & evaluation of quantifiable lethialty

27. Cleanliness of area in processing areas is defined by the no. of airborne particles greater or equal to 0.5 µm in diameter per unit volume of air Filling and sealing areas Direct support areas Other areas Air Cleanliness

28. Filling and sealing areas: products and container- closure systems are directly exposed to env. During filling and sealing process these processes include installation and connection of container components to container- closure systems cleanliness should be Grade C or higher 2) Direct support areas: supporting areas of filling & sealing areas cleanliness should be Grade C or higher

29. 3) Other areas: areas for preparing pharmaceutical solutions prior to sterilization & areas for washing & cleaning manufacturing equipments & apparatus weighing & preparation processes of solutions are conducted in Grade C areas; if contamination preventive measures are implemented then can be performed in Grade D area Air in clean areas should be controlled by designing, instituting and managing suitable Heating, ventilating and Air Conditioning Systems (HVAC) to maintain atm. Conditions at appropriate levels

30. Classification of Clean Areas

31. Environmental Monitoring to control the levels of microbes and airborne particles within specified limits predict damage to env. evaluate efficiency of cleaning, disinfection & decontamination in filling & sealing areas & other support areas Purpose of env. Monitoring classified as: 1) microbial control 2) particle control

32. Airborne particles that are greater than 0.5 µm in diameter Bacteria & fungi Not only airborne microbes but also include those on surface of wall, floors, equipments, gowns, etc. Containment : dedicated production area for highly sensitive materials, materials of infectious nature, high pharmacological activity or toxicity Targets for Monitoring

33. Testing frequency for environmental monitoring

34. Control of Contamination Presence of unwanted materials viz., dust & particles during manufacturing & transportation time Functional contamination: has detrimental effect on product or process 2) Nuisance contamination: does not have functional effect on product or process but interferes with orderly management of cleanroom

35. 5 main classes of contaminants found in pharma industry Particles, metallic ions, chemicals, bacteria, airborne molecular contaminants (AMCs) Contamination sources: Air, production facility, cleanroom, personnel, process water, process chemicals, process gases and static charge

36. Good Warehousing Practices Large building where raw materials or manufactured goods may be stored prior to their distribution for sale is called warehouse GWP means storing of supplies so that products are always available, accessible & in good conditions It is an operation that preserve the integrity of drugs

37. Objectives of GWP: to optimize resources available for a large scale storage in a specified a manner to save time & effort in identifying & locating goods to maintain safe, clean & segregated environment

38. References CDER and CBER Experience, ACDRS Special Workshop: Substantial Evidence in 21 st Century Regulatory Science, UC- Washington Center, 2016. https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations (09/05/2021) WHO Technical Report Series, No. 961, 2011.