1. GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICALS 2014/02/181 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics Faculty of Pharmacy Omer Al-Mukhtar University Tobruk, Libya. E-mail: nanjwadebk@gmail.com

2. CONTENTS Current GMP in manufacturing processes Packaging and holding of drugs Finished pharmaceuticals General provisions Organization and personnel Building and facilities Equipment Control of components Containers and closures Production and process control Packaging and labeling control Holding and distribution Records and reports Returned savaged drug products The inspection for compliance with GMP regulations Controlled substances safeguards References 2014/02/182 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

3. Introduction 2014/02/183 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

4. What is GMP ? (Good Manufacturing Practices) GMP is that part of Quality assurance which ensures that the products are consistently manufactured and controlled to the Quality standards appropriate to their intended use A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufacture will have the required quality. 2014/02/184 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

5. Good Manufacturing Practices A basic tenet of GMP is that quality cannot be tested into a batch of product but must be built into each batch of product during all stages of the manufacturing process. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. 2014/02/185 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

6. Some of the main risks are – Unexpected contamination of products, causing damage to health or even death. – Incorrect labels on containers, which could mean that patients receive the wrong medicine. – Insufficient or too much active ingredient, resulting in ineffective treatment or adverse effects. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 6

7. Why GMP is important A poor quality medicine may contain toxic substances that have been unintentionally added. A medicine that contains little or none of the claimed ingredient will not have the intended therapeutic effect. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 7

8. QC GMP QA GMP 2014/02/188 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. QA: Quality Assurance GMP: Good Manufacturing Practices QC: Quality Control

9. QA, GMP & QC inter-relationship It is the sum total of the organized arrangements with the objective of ensuring that products will be of the quality required for their intended use QA 2014/02/189 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

10. GMP Is that part of Quality Assurance aimed at ensuring that products are consistently manufactured to a quality appropriate to their intended use GMP 2014/02/1810 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

11. QA, GMP & QC inter-relationship Is that part of GMP concerned with sampling, specification & testing, documentation & release procedures which ensure that the necessary & relevant tests are performed & the product is released for use only after ascertaining it’s quality QC 2014/02/1811 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

12. QC and QA QC is that part of GMP which is concerned with sampling, specifications, testing and with in the organization, documentation and release procedures which ensure that the necessary and relevant tests are carried out QA is the sum total of organized arrangements made with the object of ensuring that product will be of the Quality required by their intended use. 2014/02/1812 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

13. QC and QA Operational laboratory techniques and activities used to fulfill the requirement of Quality All those planned or systematic actions necessary to provide adequate confidence that a product will satisfy the requirements for quality 2014/02/1813 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

14. QC and QA QC is lab based QA is company based 2014/02/1814 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

15. GMP The Quality of a formulation or a bulk drug depends on the Quality of those producing it GMP is the magic key that opens the door of the Quality In matter of GMP, swim with the current and in matter of Quality stand like a rock! 2014/02/1815 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

16. GMP helps boost pharmaceutical export opportunities Most countries will only accept import and sale of medicines that have been manufactured to internationally recognized GMP. Governments seeking to promote their countries export of pharmaceuticals can do so by making GMP mandatory for all pharmaceutical production and by training their inspectors in GMP requirements. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 16

17. GMP Covers… All aspects of production; from the starting materials, premises and equipment to the training and personal hygiene of staff. Detailed, written procedures are essential for each process that could affect the quality of the finished product. There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process - every time a product is made. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 17

18. GMP guidelines GMP as per Schedule “M” GMP as per WHO GMP as per MCA now known as MHRA GMP as per TGA GMP as per US FDA GMP as per ICH guidelines WHO: World Health Organization MHRA: Ministry of Health and Regulatory Affairs TGA: Therapeutic Goods Affairs FDA: Food And Drug Administration ICH: International Conference on Harmonization 2014/02/1818 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

19. GMP guidelines GMP as per Schedule “M” www.cdsco.nic.in GMP as per WHO www.who.int GMP as per MCA now known as MHRA www.mca.gov.uk GMP as per TGA www.tga.gov.au GMP as per US FDA www.fda.gov GMP as per ICH guidelines www.ich.org 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 19

20. GMP GMP in solid dosage forms GMP in semisolid dosage forms GMP in Liquid orals GMP in Parenterals Production GMP in Ayurvedic medicines GMP in Bio technological products GMP in Nutraceuticals and cosmeceuticals 2014/02/1820 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

21. Ten Principles of GMP 1.Design and construct the facilities and equipments properly 2.Follow written procedures and Instructions 3.Document work 4.Validate work 5.Monitor facilities and equipment 6.Write step by step operating procedures and work on instructions 7.Design,develop and demonstrate job competence 8.Protect against contamination 9.Control components and product related processes 10.Conduct planned and periodic audits 2014/02/1821 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

22. List of important documents in GMP Policies SOP (Standard Operating Procedure) Specifications MFR (Master Formula Record) BMR (Batch Manufacturing Record) Manuals Master plans/ files Validation protocols Forms and Formats Records 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 22

23. 10 attributes of a good document 1.Accurate 2.Clear 3.Complete 4.Consistent 5.Indelible 6.Legible 7.Timely 8.Direct 9.Authentic 10.Authorized 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 23

24. API Manufacturing Process 2014/02/1824 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

25. Secondary Manufacturing Dosage Forms 2014/02/1825 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

26. Secondary Manufacturing Process - Tablets 2014/02/1826 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

27. Secondary Manufacturing Process – Sterile parenteral for injection 2014/02/1827 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

28. Biotechnology Manufacturing Process 2014/02/1828 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

29. Current GMP in manufacturing processes (cGMP) 2014/02/1829 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

30. What are cGMPs? cGMP refers to the Current Good Manufacturing Practice regulations enforced by the US Food and Drug Administration (FDA). cGMP provide for systems that assure proper design, monitoring and control of manufacturing processes and facilities. Adherence to the cGMP regulations assures the identity, strength, quality and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 30

31. Why are cGMP so important A consumer usually cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. While cGMPs require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch (for example, a drug manufacturer may test 1000 tablets from a batch that contains 2 million tablets), so that most of the batch can be used for patients rather than destroyed by testing. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 31

32. Packaging 2014/02/1832 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

33. Packaging 2014/02/1833 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

34. Packaging 2014/02/1834 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

35. Packaging and holding of drugs Care shall be taken when using automatic tablet and capsule counting, strip and blister packaging equipment to ensure that all ‘rogue’ tablets, capsules or foils from packaging operation are removed before a new packaging operation is commenced. There shall be an independent recorded check of the equipment before a new batch of tablets or capsules is handled. 2014/02/1835 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

36. Finished pharmaceuticals Appropriate specifications for finished products shall include: - The designated name of the product and the code reference. The formula or a reference to the formula and the pharmacopoeial reference. Directions for sampling and testing or a reference to procedures. 2014/02/1836 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

37. General provisions The processing of dry materials and products creates problems of dust control and cross- contamination. Special attention is therefore, needed in the design, maintenance and use of premises and equipment in order to overcome these problems. Wherever required, enclosed dust control manufacturing systems shall be employed. 2014/02/1837 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

38. Organization and personnel 1.Responsibilities of quality control unit. 2.Personnel qualifications. 3.Personnel responsibilities. 4.Consultants. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 38

39. Building and facilities 1.Design and construction features. 2.Lighting. 3.Ventilation, air filtration, air heating and cooling. 4.Plumbing. 5.Sewage and refuse. 6.Washing and toilet facilities. 7.Sanitation. 8.Maintenance. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 39

40. Equipment 1.Equipment design, size, and location. 2.Equipment construction. 3.Equipment cleaning and maintenance. 4.Automatic, mechanical, and electronic equipment. 5.Filters. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 40

41. Control of components 1.General requirements. 2.Receipt & storage of untested components, drug product containers and closures. 3.Testing and approval or rejection of components, drug product containers and closures. 4.Use of approved components, drug product containers, and closures. 5.Retesting of approved components, drug product containers, and closures. 6.Rejected components, drug product containers, and closures. 7.Drug product containers and closures. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 41

42. Containers and closures All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, absorptive, or leach to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used. 2014/02/1842 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

43. Production and process control 1.Written procedures; deviations. 2.Charge-in of components. 3.Calculation of yield. 4.Equipment identification. 5.Sampling and testing of in-process materials and drug products. 6.Time limitations on production. 7.Control of microbiological contamination. 8.Reprocessing. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 43

44. Packaging and labeling control 1.Materials examination and usage criteria. 2.Labeling issuance. 3.Packaging and labeling operations. 4.Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. 5.Drug product inspection. 6.Expiration dating. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 44

45. Packaging and labeling control 2014/02/1845 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

46. Holding and distribution 1.Warehousing procedures. 2.Distribution procedures. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 46

47. Holding and distribution Prior to distribution or dispatch of given batch of a drug, it shall be ensure that the batch has been duly tested, approved and released by the quality control personnel. Pre-dispatch inspection shall be performed on each consignment on a random basis to ensure that only the correct goods are dispatched. Detailed instructions for warehousing and stocking of Large Volume Parenterals, if stocked, shall be in existence and shall be complied with after the batch is released for distribution. Periodic audits of warehousing practices followed at distribution centers shall be carried out and records thereof shall be maintained. Standard Operating Procedures shall be developed for warehousing of products. 2014/02/1847 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

48. Holding and distribution 2014/02/1848 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

49. Records and reports 1.General requirements. 2.Equipment cleaning and use log. 3.Component, drug product container, closure, and labeling records. 4.Master production and control records. 5.Batch production and control records. 6.Production record review. 7.Laboratory records. 8.Distribution records. 9.Complaint files. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 49

50. Returned savaged drug products 1.Returned drug products. 2.Drug product salvaging. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 50

51. Returned savaged drug products Adequate areas shall be designed to allow sufficient and orderly warehousing of returned or recalled products. Segregation shall be provided for the storage of rejected, recalled or returned materials or products. 2014/02/1851 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

52. The inspection for compliance with GMP regulations Short description of the self inspection system indicating whether an outside, independent and experienced external export was involved in evaluating the manufacturer’s compliance with Good manufacturing Practices in all aspects of production. Periodic inspection of the garments shall be done by responsible staff. 2014/02/1852 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

53. Controlled substances safeguards Hazardous, toxic substances and flammable materials shall be stored in suitably designed and segregated, enclosed areas in conformity with Central and State Legislations. Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall be stored in safe and secure areas. Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authority. 2014/02/1853 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

54. References EU Good Manufacturing Practice (GMP) Guidelines, Volume 4 of “The rules governing medicinal products in the European Union” US FDA current Good Manufacturing Practice (cGMP) for finished pharmaceuticals, 21 CFR, 210 and 211 WHO Good Manufacturing Practices for pharmaceutical products, Annex 4 to WHO Technical Report Series, No. 908, 2003 2014/02/1854 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya.

55. 2014/02/18 Faculty of Pharmacy, Omar Al-Mukhtar University, Tobruk, Libya. 55 E-mail: nanjwadebk@gmail.com