BIOLOGICS IN EUROPEAN UNION SLIDESHARE..

Stability, safety, advertising , labelling and packaging of biologics in EU

1. STABILITY, SAFETY, ADVERTISING, LABELLING & PACKAGING OF BIOLOGICS IN EU Presented By: Tanisha Jain 2308212170005 Guided By: Dr. Hiral Dave Associate Professor

2. ADVERTISING OF BIOLOGICS 2

3. PK - Pharmacokinetics PD - Pharmacodynamics ADME - ( A bsorption, D istribution, M etabolism, E limination) EFD - E mbryo F etal D evelopment NHP - Non-H uman P rimates GCP - G ood C linical P ractice EMA - E uropean M edical A gency EU - E uropean U nion CTD - C ommon T echnical D ocument ABBREVIATIONS: 3

4. INTRODUCTION BIOLOGICS: They are medical products . Many biologics are made from a variety of natural sources (human, animal or microorganism).Like drugs, some biologics are intended to treat disease & medical conditions. Other biologics are used to prevent or diagnose diseases . Example – Vaccines, Blood & Blood Products, gene therapies, cellular therapies . 4

5. STABILITY OF BIOLOGICS Stability: A bility of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf-life. Manufacturers should provide- stability indicating profile which helps to detect changes in the product. Applicants should provide sufficient validated data of stability and review it properly. 5

6. STABILITY OF BIOLOGICS: Protocol : It includes all the necessary information which depicts the stability of the biological product also about the expiration date of the product. Also describes specifications of the product. Potency : Ability or capacity of the product to achieve its intended effect . 6

7. STABILITY OF BIOLOGICS Product’s Characteristics : Visual Appearance ( colour/opacity of solutions/suspensions PH Moisture Levels (powders, lyophilised products) Sterility testing of the container closure – to get the proper shelf life of the product. 7

8. STABILITY OF BIOLOGICS: Storage Conditions: Temperature: M ost biologics need defined storage temperatures. Humidity: Biologics are distributed in containers protecting against humidity. Stability data is mandatory if container are not protecting against humidity. Light: Depends on type of the product. 8

9. TYPES OF STABILITY STUDIES: 1. Long term Testing : K nown as Real Time Testing . performed for longer duration . Test period depends upon the stability of the product which is long and can indicate that no degradation occurs . 2. Accelerated Testing : Helps to predict shelf-life or used to compare stability of alternative formulation . 7

10. TYPES OF STABILITY STUDIES: 3 . Intermediate Testing : This test is performed when accelerated test fails at 25°C for a longer duration . 4 . Stress Testing : Helps to identify the degradation of the product. 10

11. STABILITY TESTING REQUIREMENTS Sr.No Parameters Drug Substance Drug Product 1. Stress Testing Temperature: 50°C, 60°C,70°C Humidity: 25°C/75%RH & 25°C/90% RH Oxidation: Required according to the condition. Photo stability : Should be carried out on a single batch . Temperature: 50°C, 60°C for 1 month. Humidity: 40°C/75%RH & 25°C/80% RH Photo stability should be carried out.   11

12. STABILITY TESTING REQUIREMENTS Sr.No Parameters Drug Substance Drug Product 2. Selection of batches Data should be provided on at least 3 primary pilot scale batch. Data should be provided on at least 3 primary batches. 2 should be at least pilot scale batches. 3. Container Closure System Stability testing should be carried out in the same container closure system as that proposed for storage & distribution. Container closure system for testing should be same as that proposed for marketing including any secondary packaging. 12

13. 4. Specification It is the list of tests & proposed acceptance criteria which the drug substance should meet. It is the list of tests & proposed acceptance criteria which the drug product should meet. 5. Testing Frequency : Long Term studies: 0, 3, 6, 9,12,18,24 months & annually through the proposed re-test period. Accelerated : 0, 3, 6 months Intermediate : 0, 6, 9, 12 months Long Term studies: 0, 3, 6, 9,12,18,24 months & annually through the proposed re-test period. Accelerated : 0,3,6 months Intermediate : 0,6,9,12 months STABILITY TESTING REQUIREMENTS 13

14. 6. Storage Conditions: General Case: Long Term- 25°C/60%RH or 30°C/ 65%RH Intermediate- 30°C/65%RH Accelerated -40°C/ 75% RH Freeze condition: Long Term- 5°C Accelerated Term- 25°C/ 60% RH Freezer: -20°C   Storage condition for general case for the product intended to be stored in refrigerator & freezer is same as for drug product.   7. Stability Commitment If the data does not cover the proposed retest period granted at the time of approval a committed should be made to continue the stability testing.   If the data does not cover the proposed shelf-life granted at the time of approval committed should be made to continue the long term studies through proposed shelf-life, the accelerated studies for 6 months.   STABILITY TESTING REQUIREMENTS 14

15. 8. Evaluation Based on evaluation of data re-test period should be established. Based on evaluation of data shelf- life should be established. 9. Labelling A storage statement should be established based on stability evaluation of drug substance . A storage statement should be established based on stability evaluation of drug product . STABILITY TESTING REQUIREMENTS 15

16. SAFETY OF BIOLOGICS: For evaluating safety of biologics preclinical and clinical studies are done . Preclinical Studies : It is also known as non-clinical studies. It is conducted prior clinical trials It contains following of the parameters . 16

17. A) PRECLINICAL STUDIES : 17

18. A) PRECLINICAL STUDIES : 18

19. A)PRECLINICAL STUDIES: 1. Study Design: For conducting any kind of study , study design plays an important role. Helps for easy evaluation and assessment of the results. While designing study , PK-PD approaches should be considered. Clinical Trials should be conducted easily using the study design. 19

20. A) PRECLINICAL STUDIES: 2. Pharmacology Studies: Evaluates the biologics potential adverse effects on vital functions of the body. Special assays and biomarkers are used to access safety concerns of biologics . Helps identify potential risk and gives guidance for selecting a proper dose for clinical trials . Pharmacokinetic properties are also evaluated of the biologics (ADME) data. 20

21. A) PRECLINICAL STUDIES : 3 . Animal Species/Model Selection: Sponsor should select relevant species for preclinical trials. A relevant species is one in which the test material is pharmacologically active . A variety of techniques (e.g., immunochemical or functional tests) can be used to identify a relevant species . 21

22. A) PRECLINICAL STUDIES : 4 . Number/Gender of the animal: The number of animal used per dose should have the ability to detect toxicity. Small sample size – failure to observe toxicity . Both genders should be used and if not justification should be provided. 22

23. A) PRECLINICAL STUDIES : 5 . Dose Selection: Dosage levels – To provide information on dose-response relationship. Ideal dosage range for further trials is based on preclinical evaluation. Optimal dose selection is crucial to ensure more therapeutic efficacy while minimizing potential adverse events. All PK-PD characteristics are also considered. 23

24. A) PRECLINICAL STUDIES : 6. I mmunogenicity: Many biologics intended for human are immunogenic in animals . Evaluations of immunogenicity determine whether a biologics has a capacity to induce into the immune system of the species or not (preclinical trial) . Assessments are done in accordance with regulatory guidelines. Techniques like ELISA, cell based are used for the same. 24

25. A) PRECLINICAL STUDIES : 7. Single Dose Toxicity : Single dose studies may generate useful data to describe the relationship of dose to systemic and/or local toxicity . These data can be used to select doses for repeated dose toxicity studies . 25

26. A) PRECLINICAL STUDIES : 8 . Immunotoxicity Studies : Many biologics are intended to stimulate or supress the immune system. Toxic effects can be caused by formulation vehicle which may result in the toxic changes at the site of infection . Immunotoxicological Testing strategies are required to clarify issues . 26

27. A) PRECLINICAL STUDIES : 9 . Local Tolerance Studies : Studies are done to check the local tolerance of the drug. Data of single dose and repeated dose can also be used to evaluate the study. 27

28. A) PRECLINICAL STUDIES : 10. Reproductive and Developmental toxicity : Provides general advice on reproductive toxicity. Fertility Studies Embryo- Fetal Developmental Studies (EFD) Pre and post natal developmental studies Non-human primates studies (NHP) 28

29. SAFETY OF BIOLOGICS: For evaluating safety of biologics preclinical and clinical tests are done. B) Clinical Studies : Biologics need to undergo clinical trials before a marketing authorization application. Following are the considerations: 29

30. B) CLINICAL STUDIES : 30

31. B ) CLINICAL STUDIES : 1. Clinical Trial Authorization : Trials begins when: Subjects understands the objective and risk of the trial and give their informed consent . The physical and mental integrity of the subjects should be maintained. 31

32. B ) CLINICAL STUDIES : 2 . GCP and other aspects of trials: Clinical trials of biologics must comply with GCP and the ICH E6 . Clinical trial information must be handled, recorded and stored with all the privacy rules. Trials must comply ethical principles (benefits & risk ratio) ensuring safety of subjects. Investigators must obtain freely given consent from every subject before the trial. 32

33. B ) CLINICAL STUDIES : 3 . Study Design Considerations : Phase I - involves the initial safety and PK studies . Phase II study is a therapeutic exploratory study that explores efficacy . Phase III - involves therapeutic confirmatory studies . 33

34. B) CLINICAL STUDIES : 4 . Consultation with EMA: A sponsor may obtain scientific advice regarding clinical trial protocols from the EMA The agency remarks will only address scientific issues and will focus on matters such as selection of endpoints, comparator, duration of treatment or follow-up . 34

35. C) MARKETING AUTHORIZATION APPLICATION: 1. The requirements of EU centralised procedure: The approval standards for biotechnology products are the same as for chemically synthesized medicines. Both types of products must be safe and effective and have appropriate quality . 35

36. C) MARKETING AUTHORIZATION APPLICATION: 2. MAA for biologics must meet the standard dossier submission requirements: MAA must comply with CTD format Module 1(Administrative info, including labelling). Module 2 (various summaries) Module 3 (chemical, pharmaceutical and biological information) Module 4 (non-clinical reports) Module 5 (clinical study reports ) 36

37. ADVERTISING OF BIOLOGICS: Advertising of medicinal products shall include any information which is designed to promote the prescription, supply, sale or consumption of medicinal products. Advertising is done for general public. Done for qualified personnel which helps them to prescribe or supply the product. Member States prohibits the product which is not according to the regulation. 37

38. ADVERTISING OF BIOLOGICS: All parts of the advertising of a medicinal product must comply with product’s characteristics. Advertising shall encourage the rational use of the product. It should not be misleading . 38

39. ADVERTISING OF BIOLOGICS: Advertisement which include therapeutic indications should be prohibited for example disease like: Tuberculosis Sexually Transmitted D iseases Other serious infectious diseases Cancer and other tumoral diseases Chronic Insomnia Diabetes and many others. 39

40. LABELLING AND PACKAGING OF BIOLOGICS: The following particulars shall appear on the outer packaging of medicinal products or on immediate packaging . 1. Name of the medicinal product. 2. Type of dosage form , weight , volume and dose of the product. 3. List of excipients used in the product. 4. Route of Administration 40

41. LABELLING AND PACKAGING OF BIOLOGICS: 5. Special Warnings about the product 6. E xpiry date in clear terms (month/year ) 7. Special Storage Conditions 8. Special Precautions for disposal of unused or waste products from the product. 9. Name and address of the Market Holder for placing product in the market. 10. Manufacturer’s Batch Number 41

42. LABELLING AND PACKAGING OF BIOLOGICS : 11. The price of the medicinal product. 12. Information about contra-indications . 13. Information about interactions that can cause adverse d rug reaction. 42

43. LABELLING AND PACKAGING OF BIOLOGICS: Warning against using the product after the expiry date. W arning against certain visible signs of deterioration The date on which the package leaflet was last revised. P ackage leaflet must be written in clear and understandable terms for the users and all the regulatory laws should be followed. 43

44. Comparison of Biologics in EU & USA Information About: EU USA Advertising   Direct to consumer advertising is prohibited. Direct to consumer advertising is permitted. EU prioritizes healthcare professionals as the primary audience for drug promotion. FDA require advertisements include fair balance, risks and benefits, along with specific safety standard. Done through conferences, publications and educational materials Done through Television, print, media, social media etc. 44

45. Comparison of Biologics in EU & USA Information About: EU USA Labelling EU labelling requirements focus on providing comprehensive information for healthcare professionals and patients. FDA approved labelling for biologics must adhere to specific regulations outlined in CFR Title 21. EU labels may include information on storage conditions, shelf-life, specific handling instructions. US labels may contain boxed warnings, medication guides for patients , administration, dosage etc. Packaging Involves product details , strength , dosage form, storage form along with Patient Information Leaflet (PIL) Must comply with CFR 21 including details about product along with warnings and storage conditions. PIL gives information about use of medicine, side effects, precautions etc. Packaging involves barcodes for inventory control, tamper-seal and other information about packaging. 45

46. REFERENCES: ICH Topic Q 5 C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products Step 5 note for guidance on quality of biotechnolo-gical products: stability testing of biotechnological/biological products final approval by cpmp december 1995 proposed date for coming into operation ‌ International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use preclinical safety evaluation of biotechnology-derived pharmaceuticals s6(r1) Requirements for quality documentation concerning biological investigational medicinal products in clinical trials - Scientific guideline | European Medicines Agency 46

47. REFERENCES: 4. Non-clinical guidelines | european medicines agency 5. DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 novemeber 2001 on the community code relating to medicinal products for human use. 47

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