GMP AND PHARMACOVIGILANCE OF A PHARMACY

GMP and vigilance of pharmacology

1. Dr. Shibabrata Behera ProfESSOR & Head Dept. of Rasasastra & Bhaishajya Kalpana Govt. Ayurvedic College & Hospital, Balangir GOOD MANUFACTURING PRACTICE (GMP) & PHARMACOVIGILANCE IN AYURVEDA

2. ( Good manufacturing practices) GMP Schedule “T ’’ of drugs and cosmetic rule 1945 GMP-A set of principles and procedures which, when followed by manufactures for therapeutic goods, helps ensure that the products manufactured will have the required quality.

3. What is GMP? Good Manufacturing Practices or GMP is a system that consists of processes, procedures and documentation that ensures manufacturing products, such as food, cosmetics, and pharmaceutical goods, are consistently produced and controlled according to set quality standards. Implementing GMP can help cut down on losses and waste, avoid recall, seizure, fines and jail time. Overall, it protects both company and consumer from negative food safety events.

4. GMPs examine and cover every aspect of the manufacturing process to guard against any risks that can be catastrophic for products, such as cross-contamination, adulteration, and mislabeling. Some areas that can influence the safety and quality of products that GMP guideline and regulation address are the following : Quality management Sanitation and hygiene

5. Building and facilities Equipment Raw materials Personnel

6. Validation and qualification Complaints Documentation and recordkeeping Inspections & quality audits

7. What is the difference between GMP and cGMP? GMP is the basic regulation promulgated by the US Food and Drug Administration (FDA) under the authority of the  Federal Food, Drug, and Cosmetic Act  to ensure that manufacturers are taking proactive steps to guarantee their products are safe and effective.

8. cGMP, on the other hand, was implemented by the FDA to ensure continuous improvement in the approach of manufacturers to product quality. It implies a constant commitment to the highest available quality standards through the use of up-to-date systems and technologies.

9. 1. People All employees are expected to strictly adhere to manufacturing processes and regulations. A current GMP training must be undertaken by all employees to fully understand their roles and responsibilities. Assessing their performance helps boost their productivity, efficiency, and competency. The 5 P’s of GMP

10. 2.Products All products must undergo constant testing, comparison, and quality assurance before distributing to consumers. Manufacturers should ensure that primary materials including raw products and other components have clear specifications at every phase of production. The standard method must be observed for packing, testing, and allocating sample products.

11. 3.Processes Processes should be properly documented, clear, consistent, and distributed to all employees. Regular evaluation should be conducted to ensure all employees are complying with the current processes and are meeting the required standards of the organization.

12. 4.Procedures A procedure is a set of guidelines for undertaking a critical process or part of a process to achieve a consistent result. It must be laid out to all employees and followed consistently. Any deviation from the standard procedure should be reported immediately and investigated.

13. 5.Premises Premises should promote cleanliness at all times to avoid cross-contamination, accidents, or even fatalities.

14. All equipment should be placed or stored properly and calibrated regularly to ensure they are fit for the purpose of producing consistent results to prevent the risk of equipment failure. The factory premises will have minimum covered area of 1200sq.ft. + 200sq.ft. for furnaces and Bhatti purposes.

15. The manufacturing plant must have adequate space for: Receiving and storing raw materials Manufacturing process area Quality control section Finished goods store Office Rejected goods and drugs store Minimum requirements

16. 10 PRINCIPLES OF GMP- Create Standard Operating Procedures (SOPs). Enforce / Implement SOPs and work instructions. Document procedures and processes. Validate the effectiveness of SOPs. Design and use working systems .

17. 6 .Maintain systems, facilities, and equipment. 7.Develop job competence of workers. 8.Prevent contamination through cleanliness. 9.Prioritize quality and integrate into workflow. 10.Conduct  GMP audits  regularly.

18. QUALITY CONTROL Quality control is a part of Good Manufacturing Practice that focuses on sampling, specification, and testing. It checks the organization, documentation, and release procedures to ensure that products go through the required tests before being released for sale or supply. 

19. QUALITY RISK MANAGEMENT Quality risk management is a systematic process of assessing risks that can affect the quality of the product. According to its principles, quality risk management should ensure that: The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient and users.

20. The level of effort, formality, and documentation of the quality risk management process is commensurate with the level of risk. 

21. Patent The patent gives a drugmaker exclusive rights to produce and sell the drug for a limited time. The average time a brand-name drug is protected by the patent after it hits the market is  12 years .

22. MISBRANDED DRUGS A drug shall be deemed to be misbranded:- If it is so colored, coated, powdered or polished that damage is concealed or if it is made to appear of better or greater therapeutic value than it really is. (b) If it is not labeled in the prescribed manner.

23. MISBRANDED DRUGS (c) If its label or container or anything accompanying the drug bears any statement, design or device which makes any false claim for the drug or which is false or misleading in any particular.

24. ADULTERADED DRUGS A drug shall be deemed to be adulterated:- If it consists, in whole or in part, of any filthy, putrid or decomposed substance. If it has been prepared, packed or stored under insanitary conditions whereby it may have been contaminated with fifth or whereby it may have been rendered injurious to health.

25. If its container is composed in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health.

26. (d) If it bears or contains, for purposes of coloring only, a color other than one which is prescribed. (e) If it contains any harmful or toxic substance which may render it injurious to health. (f) If any substance has been mixed therewith so as to reduce its quality or strength.

27. SPURIOUS DRUGS A drug shall be deemed to be spurious:- If it is manufactured under a name which belongs to another drug. (b) If it is an imitation of, or is a substitute for, another drug or resembles another drug in a manner likely to deceive or bears upon it or upon its label or container the name of another drug unless it is plainly and, conspicuously marked so as to reveal its true character and its lack of identity with such other drug.

28. (c) If the label or container bears the name of an individual or company purporting to be the manufacturer of the drug, which individual or company is fictitious or does not exist. (d) If it has been substituted wholly or in part by another drug or substance. (e) If it purports to be the product of a manufacturer of whom it is not truly a product.

29. SPURIOUS COSMETICS A cosmetic shall be deemed to be spurious:- If it is manufactured under a name which belongs to another cosmetic. If it is an imitation of, or a substitute for, another cosmetic/resembles another cosmetic in a manner likely to deceive or bears upon it or upon its label or container the name of another cosmetic unless it is plainly and conspicuously marked so as to reveal its true character and its lack of identity with such other cosmetic.

30. (c) If the label or container bears the name of an individual or a company purporting to be the manufacturer of the cosmetic which individual or company is fictitious or does not exist. (d) If it purports to be the product of a manufacturer of whom it is not truly a product.

31. Pharmacovigilance in Ayurveda

32. Contents 33 Etymology and Definition. Historical Background. Aims of Pharmacovigilance. Pharmacovigilance in India. National Pharmacovigilance Programme for ASU. Reporting Culture. A yu r v edic c on c ept of P V . Need of PV for Ayurvedic Medicines. Challenges in introducing PV in Ayurveda.

33. I s th e pharma c o lo g ic a l s c i e n c e r ela t ed t o the detection , collection , assessment , understanding and p r e v ent i on o f a d v erse ef f e c t s parti c u l a r l y lo n g term, short term side effects of medicine.(WHO 2002). Post-Marketing tool. Pharmakon v i gi l are Greek Latin Drug to be awake or alert, to keep watch Etymology and Definition 34

34. Limitation of Clinical study Data Clinical trials Clinical practice No.of patients Hundreds ( rarely thousands) Thousands to milions Duration Weeks Years Populations Pregnant, children, Elderly excluded ALL Concomitant medication and illnes Avoided Usually present Dose Fixed Variable Condition Rigorous, more information Flexible less information

35. Technical terms 38 Adverse Drug Reactions(ADRs) - A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. Eg. Hypersensitivity rash with intake of guggulu Adverse Event/Experience(AE) - Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with the treatment.

36. Side Effect(SE) - Any unintended effect of a pharmaceutical product occurring at doses normally used in human which is related to the pharmacological properties of the drug . Eg. Use of Atropine in oraganophosphorus poisoning achieves therapeutic action by its anticholinergic activity but at same time causes dryness of mouth & dilatation of pupil which is not noxious. Serious Adverse Event (SAE) – Any adverse event which is fatal, life- threatening, permanently disabling or which results in hospitalisation. 39

37. Expected adverse reaction - As opposed to “unexpected”, an event that is noted in the brochure or labeling. Unexpected adverse reaction - The nature or severity of which is not consistent with the domestic labeling or ma r k et au t hor i zati o n , or e x pec t ed f r om characteristics of the drug. Signal - Reported information on possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than one single report is required to generate a signal 40

38. Historical Background … 41 Thalidomide tragedy (1961)- greatest of all drug disasters. 1960 marketed in 46 countries (hypnotic, prevention of nausea in pregnancy) . Tragically the drug proved to be a potent human teratogen that caused major birth defects in an estimated 20,000 children. Phocomelia (Absence of proximal part of limbs ) was a characteristic feature.

39. Amendment to Federal Food, drug & Cosmetic Act - required both safety & efficacy data 1 9 6 2 44 Bri t is h C om m i t t ee on Sa f ety of drug monitoring 1 9 6 3 UK starts “yellow cards” system 1 9 6 4

40. National ADR reporting system UK, Australia, New Zealand, Canada, West Germany, Sweden. 1964-65 45 WHO: Programme for International Drug Monitoring 1 968 WHO center moved from Geneva to Uppsala 1 9 7 8

41. UMC(Uppsala monitoring centre) 46 Uppsala monitoring centre(UMC,Swedan) is a field name of the WHO collaborating Centre for International Drug Monitoring. It is responsible for the management of the WHO program for International Drug Monitoring. UMC has >3 million AE case reportes from over 75 countries. The data are supplied by national health authorities Does no t r evi e w or as s ess th e i n d i vidual case s put in t o database, but it does pharmacovigilance analyses and signaling.

42. Aims of Pharmacovigilance 47 Improve patient care and safety. Improve public health and safety. T o c ontribu t e t o th e as s essment of benefit, harm, effectiveness and risk of medicines. T o p r omo t e u n derstandin g , ed u c a tio n and clini c al training.

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44. 1986 ADR monitoring system for India proposed (12 regional centres) 1997 India joined WHO-ADR monitoring programme (3 centres: AIIMS, KEM, JLN) 2004 – 2008 National PV Prog. (2 Zonal, 5 Regional, 24 Peripheral ) overseen by CDSCO 2010 Pharmacovigilance p r o g r amme o f I ndia (PvPI) Pharmacovigilance in India 49

45. Pharmacovigilance in India 50 PV was established since 2003 under the control of Central Drug Standard Control Association(CDSCO) under the aegis of Ministry of H & FW, DGHS (Directorate General of Health Service) New Delhi. WHO emphasized that it should include Traditional medicines in PV system and has published guidelines on safety monitoring of herbal medicines in pharmacovigilance systems in 2004.

46. IPGT & RA ,Jamnagar conducted a two days workshop on 3rd & 4th December 2007, on “Pharmacovigilance for Ayurvedic Drugs: Scope, Limitations & Methods of Implementation”. Based on the recommendations from the workshop, Pharmacovigilance Cell (PV Cell), has been established . Reporting Form for Suspected ADRs of Ayurvedic Formulations has been developed. 51

47. National Pharmacovigilance P r og r amme f or ASU (NP P -ASU) 52 ASU drugs are considered as safe drugs. This perception is likely to change in the light of some recent incidences of ADR during their use. The first National Consultative meet of National Pharmacovigilance Programme for ASU Drugs was organized at Dept. of AYUSH, Ministry of Health & FW, New Delhi on August 2008, sponsored by WHO.

48. Based on the feed back received from the meet, National Pharmacovigilance Programme for ASU drugs was launched on 29 th Sept 2008. The purpose of the programme is to collect and collate data, analyse it and use the inferences to recommend informed regulatory interventions, beside communicating risks to healthcare professionals and the public. 53

49. PV Centres in India AIIA NEW DELHI N BHU BHU S T VM E Gu h w at W NIA C CR AS Chennai B ’lo r e C Bhopal N a t ion a l P V c en t r e 54 8 Regional PV centres 30 Pheripheral P V c ent r es

50. REPORTING CULTURE 55

51. WHAT TO REPORT? 56 All suspected adverse reactions. Lack of effects. Resistance. Drug interactions. Reactions suspected of causing: Death Life threatening (real risk of dying) Hospitalisation (initial or prolonged) Disability (significant, persistent or permanent) Congenital anomaly

52. How do we report ADRs? STEP 1 : Fill out the RED ALERT CARDS PGH FORM # P – 60170 PGH ADVERSE DRUG SURVEILLANCE ALERT CARD (Clip this on chart front cover) Name of patient: Ward & Bed No.: Name of suspect drug: Manufacturer: Lot/ Code No.: (Retain empty vial or container) Describe the reaction: Reporter: (Please Print)

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55. Withdrawals from the market as a result of spontaneous reporting

56. Withdrawals from the market as a result of spontaneous reporting

57. Withdrawals from the market as a result of spontaneous reporting

58. List of the unapproved Ayurvedic medicinal products Karela capsules , produced by Himalaya Drug , India Karela tablets , produced by Shriji Herbal Products , India Karela capsules , produced by Charantia , UK (specifically batch #12011) Maha Sudarshan Churna powder , produced by Zandu Pharmaceuticals , Mumbai, India Maha Sudarshan Churna powder , D and K Pharmacy , Bhavnagar, India Maha Sudarshan Churna powder , produced by Chhatrisha , Lalpur , India Maha Sudarshan Churna powder , produced by Dabur India , New Delhi, India Safi liquid , produced by Hamdard -WAKF-Pakistan Safi liquid , produced by Hamdard -WAKF-India Yograj Guggul tablets , produced by Zandu Pharmaceuticals , Mumbai, India Sudarshan tablets , produced by Zandu Pharmaceuticals , Mumbai, India Shilajit capsules , produced by Dabur India , New Delhi, India

59. WHO CAN REPORT ? 67 Any health care professional can report . Shall not accept reports from lay members of the public. Others can report through the physicians under whom he / she had undergone treatment. Consumer can directly report to the concerned PPC / RPC / nearest health centre or physician regarding the suspected ADR.

60. P a t ient Health P r o f e s s i onal R e gion a l Centre Manufacturer Hospital N a ti on a l Centre WHERE TO REPORT? 69

61. WHAT HAPPENS TO THE INFORMATION SUBMITTED ? 72 Confidential. PPC forward the form to the respective RPC (causality analysis). This information shall be forwarded to the NPRC. The data will be statistically analysed and forwarded to the Dept. of AYUSH PPC RPC NPRC AYUSH

62. RESPONSIBILITIES OF CENTRE'S 73 T o c ol l e c t AD R r eport s . T o f il l i n th e AD R f orm p r ope r l y . To forward duly filled in ADR forms to next higher centre. T o mai n tai n a log of all AD R noti f ic a tio n f orm s . To provide general technical support,coordinate and monitor the functioning of Centres. To carry out causality analysis of all ADR forms.

63. T o f or w a r d all du l y - f ille d AD R f or m s as per pre-determined time line. T o r ep o r t all SADRs within 2 4 Hr s . To forward periodic reports to next higher centre. T o o r gni z e and a tt end t r aining p r og r am s / interactive meetings for all lower level centres. Organize the public campaigns. 74

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65. Ayurvedic Concept of PV 76 Term PV does not feature in Ayurvedic texts. Rational drug use are reccurent themes of Ayurvedic pharmacology(DRB) and therapeutics(chikitsa). Along with descriptions related to actions & benefits of medic i ne s , A yu r v edic pha r ma c ol o g y describe s detailed a d v erse r eacti o n s & also h o w t o dea l with w a y s t o minimize adverse effect such as Precaution in manufacture techniques. Time of drug administration. C om p lime n t di e t a n d li f e st y le a n d so o n .

66. Need of PV for Ayurvedic Medicines 77 In ancient times, physicians prepared medicines for their patients themselves. T od a y p r oduction and sale of A yu r v eda drug s is formalized into a thriving industry. Ayurvedic medicines – Classical Ayurvedic formulations 2.Patent and proprietry formulations. This industrialization has brought many challenges about safe use of Ayurvedic medicines.

67. Pippali when used properly alleviates dosas,however their excessive and continous use for long time , leads t o agg r a v ation of dosa s . Kshara is used for dipana,pachan and medo nashak purpose but if used excess proves harmful for hair, eyes,heart and sexual ability. Continous use causes . Lavanam is used for bisransana karma,ruchivardhaka pachak but excess uses it produces glani,durbalata,sithilata in the body. 87 (Ca. vi . 1/1 5 )

68. Challenges in introducing PV in Ayurveda 88 NPP encouraged reporting of all suspected ADRs, But number of reports related to Ayurvedic /herbal drugs are abnormally low. Concept & terminologies related to ADR monitoring are not covered in the Ayurvedic curriculum. Methods to study drug safety problems have not evolved adequately in Ayurveda. Information related to medicines are in the form of slo k as i n th e t ext s , i t i s n ot eas i l y a v a i lable f or g ene r al public.

69. Signal detection is difficult because of inherent belief that Ayurvedic medicines are safe. Patients often use medicines from different systems of medicine concomitantly - difficulty in assigning causality. Lack of quality assurance and control in man u factu r e of A yu r v edic me d ic i ne. M ost A yu r v edic f orm u lations a r e mul t i - ingredient. 89

70. Summary and Conclusion 91 By incoperating PV, we will be able to prepare medicines with good efficacy,,quality, safety and minimum harmful effect. In all, Pharmacovigilance will promote: Systematic and rational use of medicines Boost confidence for safety.

71. THANKS 92