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  1. 1. USFDA Approval Process For Drug Products & Biological Product [NDA Vs. BLA] By: • Girish A. Swami, (M.Pharm, PGDIPR, PGDDRA) • Mob.: +91-9881492626 • Email-
  2. 2. Outline • • • • • • Overview of USFDA Framework Biological Products How are Biologics different? Therapeutic Biologicals - Examples Biologics in CBER or CDER Regulation for Drugs & Biologics – – – – – – Comparison to drugs Inspection Team Overview & Review Process NDA and BLA (Similarities and Differences) NDA/BLA Dossier content BLA Post-approval requirement
  3. 3. Overview of Regulatory Framework - USFDA Introduction: • The FDA is part of the Health and Human services Department of the US Government. • The FDA’s authority is based upon various laws and statutory documents. • The Food and Drug Administration (FDA) has responsibility for regulation of drugs and Biological products which are manufactured and / or sold in the US.
  4. 4. Organizational Structure The FDA divided into following main Divisions or Centers.  Center for Drug Evaluation and Research (CDER)  Center for Biological Evaluation and Research (CBER)  Center for Devices and Radiological Health (CDRH)  Center for Veterinary Medicine (CVM)  Office of Regulatory Affairs (ORA)  Center for Food Safety and Applied Nutrition (CFSAN)  National Center for Toxicological Research (NCTR)  Center for Tobacco Products (CTP)
  5. 5. Regulatory Submission
  6. 6. Center for Drug Evaluation and Research (CDER) The CDER is responsible for the regulation of Chemically – derived and most therapeutic Biological products, both New Drugs and Generics.
  7. 7. Center for Biologics Evaluation and Research (CBER) The Mission of CBER is to protect and enhance public health through the regulation of certain therapeutic Biological Products as well as Blood Products, Vaccines, Tissue and Gene Therapy Products.
  8. 8. Center for Devices and Radiological Health (CDRH) The CDRH regulation of is responsible Medical for Devices Radiation Emitting products the and
  9. 9. Center for Veterinary Medicine (CVM) The CVM regulation is of responsible Animal Medicinal Products or for the Veterinary
  10. 10. Office of Regulatory Affairs (ORA) The ORA is the lead office for all field activities of the FDA. The duties and functions of ORA are divided between four main offices: • Resource Management • Regional Operation • Criminal Investigations • Enforcement. ORA regions are the Pacific, Southwest, Central, Southeast and Northeast regions of the US. Each region supports a number of local FDA offices.
  11. 11. Office of Combination Products (OCP) The OCP is responsible for general oversight of the agency’s regulation of combination products. The primary responsibilities for regulating specific combination products remain in one of the product centers – CDER, CBER, CDRH. The OCP also oversees multi center reviews of combination products, ensures consistent and appropriate post-approval regulation of combination products, and resolves disputes relating to combination products.
  12. 12. Biological Product (Biologic / Biologics / Biological) Biological Product – a “Virus, Therapeutic Serum, Toxin, Antitoxin, Vaccine, Blood, Blood Component or Derivative, Allergenic product, or Analogous product, applicable to the Prevention, Treatment or Cure of a Disease or Condition of human beings.” - As per Section 351 PHS Act
  13. 13. Biologics vs. Drugs Biologic products generally more complex • Many innovative products. – Virtually every new biologic is a novel product (NME) • Demonstration of product comparability is more difficult. • Changes in manufacturing and scale-up can impede (obstruct) overall approval process.
  14. 14. Biologics - Unique Aspects ! Source material for biologics – Potential for transmission of adventitious agents – Bacteria, mycoplasma, fungi, viruses, TSE agents – Need for in-process controls, validation process validation Heat Sensitive & susceptible to microbial contamination – Controlled temperature during production – Aseptic processing throughout – Cannot terminally sterilize Formulations – Majority Parenteral – Issues with concentration, Multi-use vials
  15. 15. Pharmacokinetics – Not well established – May not be able to measure Potential Immunogenicity – Desirable in vaccine strategies – Unwanted effects in other settings (single or chronic-dosing) • Altered PK • Allergic, serum-sickness reactions • Cross reactivity to normal, essential protein – Limitations of non-clinical studies • Species-specific antibody development
  16. 16. Therapeutic Biologicals Examples • Cytokines – Interferons- α, β, γ – Interleukins- IL2, IL11 • Hematopoietic growth factors – Erythropoietins – CSFs (Colony-stimulating factor) • Enzymes – Thrombolytics (e.g. streptokinase, TPA) – Aldurazyme
  17. 17. Monoclonal Antibodies and related products – Anti-EGFR (Cetuximab, Panitumumab) – Anti-Alpha4 integrin (Natalizumab) Fusion proteins – TNFR linked to Fc portion of human IgG (Etanercept) Fab Fragments – Anti-VEGF (Ranibizumab) – Anti-TNFα (certolizumab pegol)
  18. 18. Oncology – Herceptin (trastuzumab) breast cancer, ushers in new area of highly targeted therapy – Rituxan (rituximab) targets some lymphomas – Zevalin (ibritumomab tiuxetan), monoclonal antibody targeted radiotherapy – Campath (alemtuzumab) for CML (Chronic Myeloid Leukaemia) – Avastin (Bavacuzimab Bavacuzimab) first line metastatic colorectal Cancer
  19. 19. CBER or CDER An applicant must determine which division of the FDA to submit its application, as the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) share responsibility for BLAs.
  20. 20. Products Regulates by CBER • Allergenics Patch tests used to diagnose the causes of contact dermatitis. Extracts used to diagnose and treat rhinitis ("hay fever"), allergic sinusitis and conjunctivitis, and bee stings. • Blood Blood and blood components used for transfusion, such as red blood cells, plasma, and platelets.e.g Immunoglobuilns. • Devices Medical devices and tests used to safeguard blood, blood components, and cellular products from HIV, hepatitis, syphilis, and other infectious agents. Machines and related software used to collect blood and blood components. • Gene Therapy Gene therapy products that replace a person's faulty or missing genetic material. • Human Tissues and Cellular Products Human tissues for transplantation, such as skin, tendons, ligaments, and cartilage. Cellular products, such as human stem cells and pancreatic islets. • Vaccines Vaccines used for the prevention of infectious diseases, such as mumps, measles, chicken pox, diphtheria, tetanus, influenza, hepatitis, smallpox, and anthrax. • Xenotransplantation Products Xenotransplantation products use nonhuman tissues or organs into human recipients to treat human diseases such as liver failure, where human materials are not always available.
  21. 21. Products Regulates by CDER Therapeutic Biological Products Transferred to CDER • Monoclonal antibodies for in vivo use. • Proteins intended for therapeutic use, including cytokines (e.g. interferons), enzymes (e.g. thrombolytics), and other novel proteins, This category includes therapeutic proteins derived from plants, animals, or microorganisms, and recombinant versions of these products. • Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or modifying a pre-existing immune response). • Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the production of hematopoietic cells in vivo.
  22. 22. About Combination Products Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. Combination products involve components that would normally be regulated under different types of regulatory authorities, and frequently by different FDA Centers like CBER, CDER & CDRH. (i.e.,Drug/Device, Biologic/Device, Drug/Biologic, or Drug/Device/Biologic) Examples: – Orthopedic implant with growth factors, – Prefilled syringes – Metered dose inhalers – Transdermal patches – Catheter with antimicrobial coating
  23. 23. Regulation for Drugs & Biologics
  24. 24. Product Type FD & C Act PHS Act Component Jurisdiction Generic Equivalence Establishment Standards 21 CFR Part 211 21 CFR Part 312 21 CFR 600 21 CFR 314 Drugs Biological Products Products √ √ √ √ √ √ √ √ √ √ √ √ √
  25. 25. Law or Act. Drug Products fall under the Food, Drug and Cosmetic Act. While Biological Products fall under the Food, Drug and Cosmetic act, & Public Health Service Act.
  26. 26. Generic Equivalence Generics : Abbreviated New Drug Application (ANDA) A generic drug product is one that is comparable to an innovator drug product in Dosage form, Strength, Route of administration, Quality, Performance characteristics and Intended Use. While Follow-on Biologic or Biosimilar A follow-on biologic is similar but not identical to the brandname, or innovator, product made by the pharmaceutical or biotechnology industry; biosimilar is the term used in the European Union.
  27. 27. Establishment Standards General Information – (i) Product, personnel, equipment, waste and air flow (ii) Illustration or indication of which areas are served by each air handling unit (iii) Air pressure differentials between adjacent areas. Water System – (i) General description of W/S (ii) Validation summary (iii) Routine w/s monitoring program. HVAC System – (Heating, Ventilation and Air Conditioning Systems), (i) General description (ii) Validation summary (iii) Routine monitoring program. Computer Systems – The application should contain information on computer systems which control critical manufacturing processes. Contamination/Cross Contamination Issues – The application should contain the following information regarding methods to prevent contamination and cross contamination to supplement information requested in the CMC (i) Cleaning procedures and validation (ii) Containment features.
  28. 28. USFDA Pharmaceutical Team (Inspectorate) FDA’s Pharmaceutical Inspectorate was established under the agency’s Pharmaceutical cGMP’s for the 21st century: A Risk-Based Approach and Reporting to CDER
  29. 29. USFDA Biologics Team The FDA team biologics was established in 1997 to assure the quality and safety of Biological Products. It consists of a core team of, 1. Certified ORA investigators, 2. CBER certified inspectors, and 3. Specially trained compliance officers representing both ORA and CBER
  30. 30. Overview & Review of NDA & BLA
  31. 31. NDA & BLA (Similarities and Differences)
  32. 32. NDA and BLA - Similarities There are many similarities – Regulations – Guidance documents – PDUFA
  33. 33. NDA and BLA - Similarities Specific Similarities Include • IND regulations, Fast Track designation, Special Protocol Assessment (SPA) • Financial Disclosure, CTD format • Labeling and Advertising (21CFR 201-202) • Pediatric study requirements and waivers • Accelerated Approval • Orphan Exclusivity
  34. 34. Most differences are due to Type of Product Not due to which FDA Center Regulates The Product
  35. 35. Unique to NDAs • Patent Exclusivity (Generics, 505b2, & Orange Book) • Pediatric Exclusivity (written requests) • NDA Field Copies • Regulations more detailed (NDA content; Filing criteria etc.)
  36. 36. Unique to BLAs U.S. License • Product and facility must meet “Product standards” prior to license issuance • Review includes – – – – • Application review Facility inspection (Pre-approval, review members participate) Method validation (complete) Compliance check Cooperative manufacturing arrangements permitted – Divided, Shared, Contract FDA “official” release (21 CFR 610.2) of each product lot (at discretion of FDA) Container & Pkg. Label Requirements Specific information will be required depending on the type of BLA (e.g., Blood, Vaccines).
  37. 37. NDA & BLA Application NDA and BLA are applications to market a new product. NDAs are used by CDER (center for drugs) and BLAs are used by CBER (center for biologics) – The BLA requires close scrutiny of the and facilities, because of the greater products. manufacturing process variability of biological – The application will include complete reports on all studies including patient listings, analysis according to the original statistical analysis protocol (SAP) as well as any exploratory analysis.
  38. 38. – Although there is no regulatory mechanism in the U.S. to approve a generic version of a product that is marketed under a BLA, it is possible that a generic version of a biotech product that has been approved under an NDA could be approved. – This confusing situation results because some biotech products are approved under NDAs while others are approved under BLAs. – Review and approval of an NDA or BLA are based on the demonstration of safety and efficacy assessed from detailed reports of the clinical trials; particularly randomized controlled studies. – Biological products are a subset of drugs; therefore both are regulated under provisions of the FDC Act. However, only biological products are licensed under section 351 of the PHS Act. (As previously noted, some therapeutic protein products are approved under section 505 of the FDC Act, not under the PHS Act.) – Among other things, safety and purity assessments must consider the storage and testing of cell substrates that are often used to manufacture biologics. A potency assay is required due to the complexity and heterogeneity of biologics.
  39. 39. Law Regulation (21 CFR) IND FD & C Act 25, 50, 211, 312 BLA FD & C Act. & PHS Act. 25, 201-2, 207, 211, 600 NDA FD & C Act. 25, 201-2, 207, 211, 314 Post BLA FD & C Act. & PHS Act. 201-2, 211, 600 FD & C Act. PDUFA 25, 201-2, 207, 211, 314 POST NDA ________ Same Same Where, CFR – Code of Federal Regulations PDUFA – Prescription Drug User Fee Act. IND – Investigational New Drug Application BLA – Biologics License Applications NDA – New Drug Application PART 25 Environmental Impact Considerations PART 50 Protection of Human Subjects PART 201 Labeling PART 211 Current Good Manufacturing Practice for Finished Pharmaceuticals PART 312 Investigational New Drug Application PART 207 Registration of producers of Drugs and listing of Drugs in Commercial Distribution PART 600 Biological Products: General PART 314 Applications for FDA approval to market a New Drug
  40. 40. 21 CFR PART 600 BIOLOGICAL PRODUCTS: GENERAL Licensed biological products regulated by the Center for Biologics Evaluation and Research (CBER) Examples of such submissions include: Biologics license applications (BLAs) and their amendments and supplements, adverse experience reports, biological product deviation reports, fatality reports, and other correspondence.
  41. 41. 21 CFR Part 600 BIOLOGICAL PRODUCTS: GENERAL • Subpart A: Definitions • Subpart B: Establishment Standards – Personnel – Facility, equipment, animals – Retention samples – Biological Product Deviations • Subpart C: Establishment Inspections • Subpart D: Reporting of Adverse Events – Postmarketing reporting – Distribution reports
  42. 42. 21 CFR Part 610 GENERAL BIOLOGICAL : PRODUCT STANDARDS • Release – 610.1– lot release (manufacturer) – 610.2– Samples for “Official” FDA testing and release • Testing – – – – – Potency General Safety Sterility Purity (including moisture) Mycoplasma • Dating Periods • Labeling
  43. 43. 21 CFR PART 314 Applications for FDA approval to market a New Drug Scope of this part. (a) This part sets forth procedures and requirements for the submission to, and the review by, the Food and Drug Administration of applications and abbreviated applications to market a new drug under section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and postmarketing reports to them. (b) This part does not apply to drug products subject to licensing by FDA under the Public Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201et seq. ) and subchapter F of chapter I of title 21 of the Code of Federal Regulations. Ref: 50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999
  44. 44. Current Laws Public Health Service Act (1944) – Section 351 - Licensure of biological establishments and products. FFD&C Act (1938, 1962) – Interprets that “biological products” are also “drugs” – The FFD&C Act. applies to a biological product, except no application required under section 505.
  45. 45. PHS Act The Secretary shall approve a biologics license application: – On the basis of a demonstration that • Product is safe, pure and potent • The facility (ies) meet standards designed to assure that it continues to be safe, pure, and potent – If the applicant consents to the inspection of the facility(ies) – Each package of biological product must bear the U.S. license number
  46. 46. Product Standards CFR Standards for Biologics include: (p) “Safety” means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time. (r) “Purity” means relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances. (s) “Potency” is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result. - 21 CFR 600.3 and Part 610
  47. 47. ‘Approval Letter’ “This letter hereby issues Department of Health and Human Services U.S. License No. XXXX to ___________ in accordance with the provisions of Section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products. This license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.”
  48. 48. BLA / NDA Dossier Content • • • • • • • • A copy of the cover letter attached to the archival copy A completed application Form FDA 356h A copy of the summary A copy of the general index of the entire application A letters of reference or authorization, if appropriate Patent Information Manufacturer Information Product/Manufacturing Information (CMC) – – – – – – • • • Source material / raw material Manufacturing process and controls Formulation Facility information Contamination / cross-contamination information Environment assessment or categorical exclusion Pre-clinical Studies Clinical Studies Labeling
  49. 49. Application Forms FDA 356h – Application to Market a New or Abbreviated new drug or biologic for Human Use FDA-3356 – Establishment Registration and listing for Human cells, Tissues, And Cellular and Tissue based products (HCT/Ps) FDA-3486 – Biological Product deviation report Vaers form – Vaccine Adverse Event Reporting System
  50. 50. Patent Information An applicant must submit information on each patent that claims the drug or a method of using the drug that is the subject of the BLA and with respect to which a claim of patent infringement could reasonably be asserted. An applicant must submit basic information about each patent, including the following: (i) Patent number and the date on which the patent will expire; (ii) Type of patent; (iii) Name of patent owner; (iv) If the patent owner or applicant does not reside or have a place of business within the U.S., the name of the agent of the patent owner or applicant who resides or maintains a place of business within the U.S. authorized to receive notice of patent certification.
  51. 51. Labeling Label should include: (i) The proper name of the product; (ii) The name, address and license number of the manufacturer; (iii) The US License number must appear on the product labeling. (iv) The expiration date; (v) The recommended individual dose, for multiple dose containers; (vi) The statement “Rx only” for prescription Biologicals; and (vii) Minimum potency of product expressed in terms of official standard of potency or, if potency is a factor and no U.S. standard of potency has been prescribed, the word “No U.S. standard of potency”
  52. 52. Biologic License Application (BLA) Under the Public Health Services Act, the Federal Food and Drug Administration (FDA) has been given the authority, concurrent with its authority under the Food Drug and Cosmetic Act, to regulate biologics. The FDA regulates a wide range of biologics, including, but not limited to, vaccines, blood and blood by-products, certain monoclonal antibodies, tissue and cellular products. Within the FDA, the Center for Biologics, as well as the Center for Drug Evaluation and Research, can be responsible for the regulation of biologics.
  53. 53. – Biologics are evaluated for market by the FDA through the filing of a Biologic License Application (BLA). – A BLA, although similar to a New Drug Application (NDA), has its own set of intricate requirements. – Applicant has to provided the information in an acceptable format, under the applicable regulations. However, applicants must be cognizant that unique and specific information will be required depending on the type of BLA (e.g., blood, vaccines).
  54. 54. Archival and Review Copies of BLA Federal regulations require the submission of two copies of a BLA – Archival and Review. Archival Copy The archival copy is a complete copy of an application submission and must be bound in a BLUE cover jacket. The archival copy should include a cover letter to: (i) confirm any agreements or understandings between the FDA and the applicant; (ii) identify a contact person regarding the application; (iii) identify the reviewing division of the FDA and the HFD number; and (iv) convey any other important information about the application.
  55. 55. Review Copy The review copy is divided into six technical sections (“review sections”) and should be submitted with each review section separately bound in a specific color: (i) Chemistry, Manufacturing and Controls (CMC) – RED; (ii) Nonclinical Pharmacology and Toxicology – YELLOW; (iii) Human Pharmacokinetics and Bioavailability – ORANGE; (iv) Microbiology (if required) – WHITE; (v) Clinical Data – LIGHT BROWN; (vi) Statistical – GREEN. eCTD format starting no later than two years after the publication of the final guidance in the Federal Register, and final guidance is likely to enforce in mid-to-late 2015
  56. 56. BLA Post-Approval Requirements • Required Annual Reports: – Post Marketing Commitment (PMC) status (601.70) • Other required submissions: – Adverse Events (600.80) – Distribution summary (600.81) – Biologic Deviation Reports (600.14) – Advertising and Promotional Labeling • Periodic cGMP inspections
  57. 57. Changes to be Reported (21CFR 601.12) Manufacturing Changes – Pre- Approval Supplements (PAS) – 30 day Supplements (CBE30) – Annual Reports - only if reportable changes Labeling Changes – Pre Approval Supplements – Changes Being Effected (CBE) Supplements – Annual Reports - only if reportable changes
  58. 58. Thank You ------ O -----GIRISH A. SWAMI Asst. Manager – DRA & DQA Serum Institute of India Ltd.