Regulatory workflow for Registration of Biosimilar products in Egypt BVA-050713-004-20070901-SP-v6 Regulatory workflow for Registration of Biosimilar products in Egypt Presented by: Dr/Mona Saleh Biologicals Registration Directorate Central Administration for Pharmaceutical Affairs www.eda.mohealth.gov.eg biosimilars@eda.mohealth.gov.eg

Topics discussed in the presentation Establishment History Mandate Legal Frame Work Structure of regulatory bodies Biologicals in Egypt Similar Biological products Development of a Biosimilar product Registration of a Biosimilar Product Reference guidelines

Establishment History Presidential decree (398/1995) For NORCB establishment. Presidential Decree (244/2009) executive aspect for NORCB functions. Administrative decree (16/2009) Establishment of Biological Products Registration Department Administrative decree (3/2009) Establishment of Biological Products Inspection Directorate Ministerial Decree (297/2009) Rules & procedures for Registration of Biological products , vaccines, serums & blood derivatives.

Mandate Legal Frame work Pharmacy Law (127/55) Specially Article 58 , 59 ,60 ,61. Ministerial Decree (95/2005) Assignment responsibility of approving clinical protocols to the Ethics committee of clinical research Ministerial Decree (297/2009) Rules & procedures for Registration of Biological products , vaccines, serums & blood derivatives. Ministerial Decree (26/2009) For the charges(fees) rendered for CAPA services. Ministerial Decree (399/2010) Assignment responsibility of approving protocol & following up the process of clinical trials to NORCB Ministerial Decree (632/2010) Instruction of evaluation working parties of biological

Structure of regulatory bodies Minister of Health Minister Assistant for Pharmaceutical Affairs Central Administration for Pharmaceutical Affairs “CAPA” National Organization for Research & Control of Biological “NORCB” General Registration Directorate General Inspection Directorate Biological Products Registration Directorate Biological products Inspection Directorate

Biologicals in Egypt Biological products are defined as: Medicinal products made of substances extracted from or produced by living sources whether they are genetically modified living organisms or Liquids and tissues extracted from various human or animal sources

Classes of Biological products Scope of this presentation is Biologicals in Egypt Classes of Biological products Blood derived products Vaccines & Sera Epoetins Interferons Heparins Monoclonal Antibodies Cytokines Hormones Insulins Miscellaneous Scope of this presentation is All Biological product Classes other than Blood Products and their recombinant analogues, Vaccines and Sera

Biosimilars Biosmilar product is defined as: Biological product (other than blood derived products and their recombinant analogues, vaccines and sera) having the same active substance, dosage form, Strength and route of administration of a reference biological product and has proven through a comparability program that its quality, safety and efficacy is equivalent to a reference biological product when prescribed in a claimed indication

Development of a similar biological product Two approaches for development can be applied Standalone approach complete product development program (Quality, Preclinical and Clinical) Excluded from the scope of this guidelines Biosimilar approach complete product CMC development in addition to: comparability quality exercise, reduced preclinical and clinical comparability studies Inorder to demonstrate biosimilarity of the proposed biosimilar product with the reference biologicalproduct

Reference Vs. Biosimilar Clinical Pre-clinical Quality (CMC) Clinical Pre-clinical Quality + comparability Reference Biosimilar

How to develop a biosimilar product Step wise Biosimilar development process: Reference selection Data collection CMC development Preclinical development Clinical development Comparability exercise is part of the development process of the biosimilar product

How to develop a biosimilar product continue Data Collection Collect all possible accessible data on the reference product from the literatures before developing the manufacturing process to understand the reference product characteristics regarding the quality, safety and efficacy. Select different batches of the reference product and document its data (batch no., expiration date,…) in order to perform extensive analytical characterization for the reference product, this would enable the applicant to: - Detect batch to batch variation within batches of the same reference product. - Specify the acceptance criteria for biosimilarity with justification

How to develop a biosimilar product (cont.) Reference selection A single reference product must be used for all comparability exercises during the development process (i.e. quality, safety and efficacy). The reference product should be justified by the manufacturer of the biosimilar product according to the following criteria: Should be authorized on basis of complete dossier (full Quality, Preclinical and Clinical data), Therefore an approved biosimilar cannot be considered as a reference product. Should have the same dosage form, strength, and route of administration of the biosimilar product intended to be developed

How to develop a biosimilar product (cont.) Reference selection (cont.) The Reference product should be either licensed in Egypt Or Licensed and widely Marketed in a reference country for at least 4 years

Registration of a biosimilar product Two approaches are applied for biosimilar product registration Final dossier approach (for imported products) Development process has been already done under supervision of the manufacturer country’s health authority and only evaluation of the final product is done Stepwise approach (for local products) Development and registration processes proceed side by side The manufacturer evaluate the development process at phases

Final dossier approach (Imported product) Phase 1 (Box Approval) Phase 2 (Pricing) Phase 3 (Complete CTD Submission & Evaluation) M2, M4 & M5 (Biologicals evaluation committee)) M3 (NORCB) SMFs, M.P & process validation (inspection department) Stability studies (stability committee) PSUR, RMP & DDPS (PVC) Phase 4 (Reports Collec., review and Tech. Committee subm.) (EWP decision, PVR, Stability R, TAR, Analysis report, Insert, Pack, Price) Issue Registration license

Final dossier approach (cont.) CAPA Biological Registeration Directorate Front Office Company Required Docs Approval DisApproval Time Line  15 Working Days

Final dossier approach (cont.) CAPA Pricing Committee Required Docs Company Price Time Line  60 Working Days

Final dossier approach (cont.) CAPA Biological Registeration Directorate Complete CTD Company M2 (Biologicals evaluation committee)) M3,M4, M5 (NORCB) SMFs, M.P & process validation (inspection department) Stability studies (stability committe) PSUR, RMP & DDPS (PVC) Time Line  60 Working Days

Final dossier approach (cont.) (EWP decision, PVR, Stability R, TAR, Analysis report, Insert, Pack) CAPA Biological Registeration Directorate Technical Committee Submission Issue Registration license Time Line  60 Working Days

Stepwise approach (Local products) Phase 1 (Box Approval) Phase 2 (Pricing) Phase 3 (API Evaluation Phase) ASMF Evaluation SMF of API Evaluation Issue Preliminary approval (Valid for 3 Years) (Finished product manufacturing & Control – perform Stability studies – preclinical studies) Phase 4 (CMC, Preclinical studies & Clinical protocol evaluation phase) Stability evaluation (stability committee)CAPA Charact. & Anal. procedure evaluation at NORCB (registration analysis certificate) M.P & process validation Evaluation (inspection department) CAPA Preclinical studies evaluation (NORCB) Clinical protocol evaluation (Ethics committee at M.O.H & NORCB

Stepwise approach (Local Products) (Cont.) Performing Clinical trials (during the 3 years) Supervising the process by NORCB Phase 5 (Complete CTD Submission stability approval + analysis report, M1, Clinical studies & PV system evaluation) M1 evaluation (Front office department) Clinical studies evaluation (Biologicals evaluation committee) RMP & DDPS (PV center) Phase 6 (Reports Collection, review and Tech. Committee submission) (EWP decision, PVR, Stability R, TAR, Analysis report, Insert, Pack, Price) Issue Registration license

Stepwise approach (Local Products) (Cont.) CAPA Biological Registeration Directorate Front Office Company Required Docs Approval DisApproval Time Line  15 Working Days

Stepwise approach (Local Products) (Cont.) CAPA Pricing Committee Required Docs Company Price Time Line  60 Working Days

Stepwise approach (Local Products) (Cont.) CAPA Biological Registeration Directorate Company 1- ASMF 2- SMF of API Technical Committee Submission ASMF NORCB SMF of API CAPA Biological Inspection Directorate (Finished product manufacturing & Control – perform Stability studies – preclinical studies) Time Line  60 Working Days

Stepwise approach (Local Products) (Cont.) During The 3 Years CMC, Preclinical, Clinical Protocal CAPA Biological Registeration Directorate Company Stability evaluation (stability committee) Charact. & Anal. procedure evaluation at NORCB (registration analysis certificate) M.P & process validation Evaluation (inspection department) CAPA Preclinical studies evaluation (NORCB) Clinical protocol evaluation (Ethics committee at M.O.H & NORCB Performing Clinical trials Approval Supervising the process by NORCB

Stepwise approach (Local Products) (Cont.) CAPA Biological Registeration Directorate Complete CTD Company M1 evaluation (Front office department) Clinical studies evaluation (Biologicals evaluation committee) RMP & DDPS (PV center) Time Line  60 Working Days

Stepwise approach (Local Products) (Cont.) (EWP decision, PVR, Stability R, TAR, Analysis report, Insert, Pack) CAPA Biological Registeration Directorate Technical Committee Submission Issue Registration license Time Line  60 Working Days

Re-registration Re-registration process for products Registered before as Generics (i.e. No clinical studies performed on the product) Well established PV system that can prove safety and Efficacy Phase IV comparability studies depend on the Pv system and PSUR Quality Comparability studies on case by case basis No PSUR on the previous registration period (No available data on safety and Efficacy) Phase IV comparability studies is mandatory

Reference guidelines Global: WHO- GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs) ICH guidelines ICH - Pre-clinical safety Evaluation of Biotechnology-derived pharmaceuticals S6 ICH- General consideration for clinical trials E8 ICH- Statistical principles for clinical trials E9 ICH- Quality of Biotechnological products: Stability testing of Biotechnological/Biological products Q5C ICH- Derivation and characterization of cell substrates used for production of Biotechnological/Biological products Q5D ICH- Viral safety evaluation of Biotechnology products derived from cell lines of human and Animal origin Q5A ICH- Development and manufacture of drug substances (chemical entities and biotechnological/biological entities Q11

Reference guidelines EMA-Overarching biosimilar guidelines EMA- Product-specific biosimilar guidelines EMA- Other guidelines relevant for biosimilars EMA- Scientific Guidelines on Biological Drug substances EMA- Scientific Guidelines on Biological Dug Products FDA- Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product FDA- Scientific Considerations in Demonstrating Biosimilarity to a Reference Product CDSCO- Indian Biosimilars Guidelines

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