cGMP

cGMP Introduction, Objectives and Policies of cGMP, Components of cGMP,Layout of buildings,Services, Equipments and their maintenance.

1. cGMP BY:- GARIMA S. SINGH MPHARMA (1 st sem ) DEPARTMENT OF PHARMACEUTICS 1

2. CONTENTS Introduction Objectives and Policies of cGMP Components of cGMP Layout of buildings Services Equipments and their maintenance. 2

3. 1 INTRODUCTION cGMP  refers to the Current Good Manufacturing Practice regulations enforced by the FDA. cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. The cGMP requirements were established to be flexible in order to allow each manufacturer to decide individually how to best implement the necessary controls by using scientifically sound design, processing methods, and testing procedures. The flexibility in these regulations allows companies to use modern technologies and innovative approaches to achieve higher quality through continual improvement. Accordingly, the “c" in cGMP stands for "current," requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been "top-of-the-line" to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today's standards. Current Good Manufacturing Practice ( cGMPs )  is the main regulatory standard for ensuring pharmaceutical quality. Adherence to the  c GMP regulations  assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations.  As per WHO GMP’s main function is to avoid mix-ups and contamination risk.

4. Tragedies preceding cGMP regulation 1902- development of biological control act 1906- development of pure food and drug act 1906 Pure Food and Drug Act Creates one of the first government regulatory agencies (now known as FDA); the culmination of 25 years of lobbying, this act makes it illegal to sell “adulterated” or “misbranded” food or drugs. 1938 Federal Food, Drug and Cosmetic (FD&C) Act Tragedy: Sulfanilamide made with poisonous solvent causes 107 deaths. Result: Requires manufacturers to prove the safety of products before marketing. 1941 Two unrelated events Insulin Amendment requires FDA to test and certify purity and potency of insulin. Tragedy: nearly 300 deaths and injuries from distribution of sulfathiazole tablets tainted with phenobarbital. Result: FDA revises manufacturing and quality controls drastically, the beginning of what will later be called GMPs. 1962 Kefauver-Harris Drug Amendments Tragedy: Thalidomide causes birth defects in thousands of European babies. Result: Manufacturers must prove efficacy of products before marketing them and ensure stricter control over drug testing. 1978 CGMPs Final rules for drugs and devices (21 CFR 210–211 and 820) Establishes minimum current good manufacturing practices for manufacturing, processing, packing, or holding drug products and medical devices. 4

5. Tragedies preceding cGMP regulation 1979 GLPs Final Rule (21 CFR 58) Establishes good laboratory practices for conducting nonclinical laboratory studies that support applications for research or marketing permits for human and animal drugs, medical devices for human use, and biological products. 1982 Tamper-resistant packaging regulations issued for OTC products Tragedy Acetaminophen-capsule poisoning by cyanide causes seven deaths. Result: revision of GMPs to require tamper-resistant packaging. 1983 Two unrelated regulatory events The Guide to the Inspection of Computerized Systems in Drug Processing initiates tighter controls on computers and computer validation. Federal Anti-Tampering Act makes it a federal crime to tamper with packaged consumer products. 1987 Guideline on General Principles of Process Validation Agency expectations regarding the need for process validation are outlined. 1992 Generic Drug Enforcement Act Precipitated by illegal acts involving abbreviated new drug applications. Result: Creates debarment penalty. 1996 Proposed Revision to US CGMPs for Drugs and Biologics (21 CFR 21–211) Adds detail for validation, blend uniformity, prevention of cross-contamination, and handling out-of specification results. 1997 Electronic Records Final Rule (21 CFR 11) Requires controls that ensure security and integrity of all electronic data. 1998 Draft guidance's Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients and Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. 5

6. Tragedies preceding cGMP regulation 2001 ICH Q7A API Guidance ICH’s “Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (APIs)” 2019 Ranitidine can rise cancer Ranitidine have been caught of having NDMA ( nitrosodimethylamine ) which is cancer causing agent. 6

7. Worldwide enforcement of GMP 7

8. 1 OBJECTIVES To understand where the regulation come from, who has enforcement authority, and why u need to comply. to understand the “Fundamentals” , “Benefits”, and “Key Parts” of cGMP. As a food handlers we have responsibility to our customers to maintain high standards of food safety. To ensure , only safe and high quality product are produced, employee must follow all GMP listed. 8

9. Components of cGMP cGMP is a part of Q.A. cGMP’s main function is to produce quality product consistently. cGMP must meet legal requirements of country. cGMP must meet both production and Q.C. related issues. 9

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15. personnel 15 Qualified personnel Experienced Sufficient number Written job description Trained Health details

16. Building layout Design pattern Permit effective cleaning Permit effective maintenance Avoid cross contaminations, build-up of dirt and dust. Minimize risk of errors Maximum protection against entry of insects, birds and animals. Separate facilities for other products such as some antibiotics, hormone, cytotoxic product. Finishing of floors ,walls, ceilings should be smooth, impervious, hard wearing ,easy to clean. Specific area Production areas Quality control area Weighing areas Storage areas Ancillary areas Hygiene Eating , drinking , smoking should not be allowed in production areas 16

17. Construction feature :  Regarding buildings and facilities, there are two major areas of concern: the external environment and the internal environment. The external environment must be amenable to the location of well-designed and constructed buildings. It is insufficient that the building in which the production operations are to occur are clean and orderly and of suitable size and construction. If the land, air, or water resources that surround the plant offer the potential for water damage, infestation, or contamination of any type, the facilities are in jeopardy of being judged unsuitable. any building used in the manufacturing ,processing , packing or holding of drug product shall be of suitable size, construction or location to facilitate cleaning , maintenance. The orderly placement of equipment and materials to prevent mix-ups between different component and drug product containers , closures , labeling, in process materials ‘or drug products or to prevent contamination. Lightening: adequate lightening shall be provided in all areas. Ventilation, air filtration ,air heating and cooling: Equipment for adequate control over air pressure , micro organism dust , humidity and temperature shall be provided when appropriate for the manufacturing , processing, packing or holding of a drug product. Air filtration systems, including prefilters and particulate matter air filters ,shall be used when appropriate on air supplies to production areas , there shall be adequate exhaust systems or other systems adequate to control contaminants. Plumbing: Potable water shall be supplied under continuous positive pressure in a plumbing system. Potable water shall meet the standard prescribed in the environmental protection agency’s primary drinking water regulations. Drains shall be of adequate size and where connected directly to a sewer, shall be provided with an air break to prevent back siphon age. 17

18. Sewage and refuse: Sewage ,trash and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner. Washing and toilet facilities: Adequate washing facilities shall be provided including hot and cold water ,soap or detergent, air driers or single service towels and clean toilet facilities easily accessible to working areas. Sanitation: Building shall be free of infestation by rodents, birds, insects and other vermin trash and organic waste matter shall be held and disposed of in a timely and sanitary manner . There shall be written procedure for uses of suitable rodenticides , insecticides, fungicides, fumigating agents and cleaning and sanitizing agents . Maintenance: Any building used in the manufacture, processing , packing or holding of a drug product shall be maintained in a good state of repair. 18

19. 3 cGMP services: 19 cGMP manufacturing of drug substances and drug products Stability testing of drug substances and drug products Release testing and issuance of certificate of analysis (COA) Identity Purity Assay Related substances Total impurities Residual Solvents / Organic volatile impurities (OVIs), USP <467> Moisture by Karl Fischer Potential genotoxicants Loss on drying Bioburden - microbial limits and total endotoxins Heavy metals Specialized testing Batch record writing Batch record review Batch disposition assessment Corrective and Preventive Action Plans (CAPA) Out-of-specification (OOS) investigations Deviation assessment and reporting Vendor assessments / audits SOP writing Raw material procurement Cleaning method development and validation Analytical method development and validation cGMP training Chemistry, Manufacturing, and Controls (CMC) regulatory writing

20. 4 cGMP services in production area Production of Tablets and Capsules Packaging of Clinical Supplies Labeling of Clinical Supplies Study Randomization Formulation Development for: Oral Solids Oral Liquids Topical Creams and Ointments Transdermal Products Consultant Services for: Technology Transfer Formulation Development Technical Operations 20

21. 1 Equipment handling Equipment handling and equipment control should be done by qualified personnel and proof of qualification made available. The handling involves movement, storage and protection. Standardization of all equipments and software makes it possible to perform a wide range of tasks. All equipment in the facility should be clearly identified using markings that are clearly visible. The identification number allotted to equipment or an instrument should correspond with the entry appearing in the equipment log. The maintenance log should be kept near or on the equipment. Equipment should be kept in a room that has sufficient air flow. A measuring device such as a weighing balance must demonstrate its accuracy through qualification. Qualification of instruments is done to determine if a device is suitable and is normally done by quality control laboratories and other professionals trained in the provision of such services. 21

22. Equipment design and placement All the equipment used for the manufacture process or drug holding should be appropriately designed and sized for the intended use. There should be adequate and a clearly designated building or room where all the equipment will be placed and should be under key and lock always. The storage facility should comply with the set CGMP. The location of all the equipment in the facility should be appropriate for each of them. The surfaces of the machines should be made of materials that are non reactive, non-additive and non-absorbent to the raw materials or finished product. Design and operating precautions should be taken to ensure that operating substances such as lubricants, coolants and others do not come in contact with the raw materials or final product. Asbestos filters should not be used for the production of any drug or product. Any idle equipment should be stored in a designated area and its status clearly marked. Written procedures should be available for all equipment that are in the facility that are being used during the manufacturing, holding of raw materials or finished product. 22

23. Equipment maintenance and cleaning All equipment should have written instructions for their maintenance as well as their maintenance schedule and there should be proof that they are being followed to the letter. A written procedure should be established that assigns the responsibility of cleaning and maintenance of equipments to someone and should be adhered to. Validation of the cleaning procedure should be properly done to ensure risks of contamination and cross contamination are removed. The cleaning and maintenance procedures should also identify disassembly or reassembly if any that is required for the maintenance and cleaning. All equipment must be cleaned after use and cleaning records kept as proof of the same. Written procedures on calibration of equipments should be in place and availed as proof if needed. Equipment calibration assures that the results obtained from the equipment are valid. If production is automated by the use of computers, the computer’s program or software should also be validated. The Food and Drug Administration (FDA) requires that firms have written procedures on cleaning validation, entailing aspects of the cleaning process, equipment design, sampling and analytical methods used in a manufacturing factory. FDA is a body that protects the consumers’ health by assuring safety, quality and efficacy of food and drugs. 23

24. conclusion “Pharmaceutical cGMPs for the 21st Century” is intended to jump-start progress into this future. Pharmaceutical manufacturing is evolving from an art form to one that is now science and engineering based. Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes. This initiative is designed to do just that through an integrated systems approach to product quality regulation founded on sound science and engineering principles for assessing and mitigating risks of poor product and process quality in the context of the intended use of pharmaceutical products. In this regard, the desired future state of pharmaceutical manufacturing may be characterized as: Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product specifications based on mechanistic understanding of how formulation and process factors impact product performance Continuous “real time” assurance of quality Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability Risk based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product. Inculcation of cGMP in the organization provides increased quality of products with less wastage ,more profit and customer satisfaction 24

25. reference http://www.pharmatips.in/Articles/Quality-Assurance/GMP/GMP-Buildings-And-Facilities.aspx https://learnaboutgmp.com/good-manufacturing-practices-cgmp/top-tips-for-facility-design-layout-and-equipment-handling/ http://www.newchemicalentity.com/cgmp-services.php https://pharmacy.temple.edu/research/current-good-manufacturing-practices-cgmp-services Ansel’s Pharmaceutical Dosage Forms and Drug Deliver Systems, ninth edition by Loyd V. Allen, Nicholas G. Popovinch, Howard C. Ansels. 25

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