0. Regulatory workflow for Registration of Biosimilar products in Egypt
BVA SP-v6
Regulatory workflow for Registration of Biosimilar products in Egypt
Presented by: Dr/Mona Saleh
Biologicals Registration Directorate
Central Administration for Pharmaceutical Affairs

1. 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

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

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

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

19. 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

20. 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

21. 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

22. 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

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

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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. BVA SP-v6
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