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Challenges In Evaluation Of Biosimilar Products



      Prepared by pharmacist
             Lina Bajjali
   Head of Registration Department
       Jordan Food and Drug
            Administration
Biologics biologicals (what does it mean?)


Biotechnology products?
  A biotechnology product is one manufactured by
  recombinant DNA technology, one where genetic
  manipulation of cells is required, or a monoclonal
  antibody.
Biological products?
  They include those where the starting material
  may be human or animal tissues or of microbiological
  origin also included are those where a complex
  bioassay system is required to monitor potency .
   they need complex processes for ensuring integrity/
  reproducibility and for removing/isolating/purifying/and
  formulating the biological products
                                                  USAID Jordan Economic
                                                  Development Program
                                              2
• What are Allergenic extracts
• Extract (usually containing protein) from
  various sources, pollen, dust, mould,
  insect, venom, food, containing the
  immunogenic or allergenic compound;
  may be used for skin testing or
  desensitization.

                                     USAID Jordan Economic
                                     Development Program
How do biologics differ From Conventional drugs ?



   •Most drugs consist of pure chemical substances
   and their structures are known ,most biologics ,
   however , are complex mixture that are not easily
   identified or characterized .
   •Biological Products differ from conventional drugs
   in that they tend to be heat-sensitive and
   susceptible to microbial contamination
   •This requires sterile processes to be applied from
   initial manufacturing steps.
                                                    USAID Jordan Economic
                                                    Development Program
Manufacturing process
The Process is the Product
Biological Products derived from completely different manufacturing
    processes are not identical
• In contrast to uniform small molecule products, Biological Products are
    composed of complex protein molecules

• Each stage of the complex manufacturing process confers unique properties
   to the resulting Biological Product

• Biological Products produced using completely different manufacturing
    processes cannot be identical

– Data on one Biological Product, with respect to quality, efficacy or safety,
   cannot be extrapolated to a biosimilar product that is produced using a
   completely different manufacturing process without the demonstration of
   similarity in terms of quality, safety and efficacy


                                                                   USAID Jordan Economic
                                                                   Development Program
Challenges facing Biosimilars
 Production Issues
 • Development of a manufacturing process for
   Biosimilars involves many steps (Reverse
   engineering).
 • Process knowledge is key.
 • Choice of cell line is important, impurity
   profiles.
 • The quality development of Biosimilars
   follows the same route as for new biologics.
                                       USAID Jordan Economic
                                       Development Program
Manufacturing process
•    The complexity of biopharmaceuticals means that the process of
    producing a biopharmaceutical is also extremely complex.
•   • The specific combination of steps in the process generates the final
    product.
     • One of the first steps involves the cloning of the appropriate genetic
    sequence into an expression vector, followed establishment of a cell
    expression system
•   • The protein expression system needs to be scaled-up to produce large
    amounts
•   • The desired biopharmaceutical must then be processed and purified
•   • The final product needs to be formulated to ensure consistent and reliable
•   delivery to the patient
•   • Each of these stages involves many checkpoints and quality control steps


                                                                  USAID Jordan Economic
                                                                  Development Program
Contaminants

• Bacterial
e.g. Streptococcus, Staphylococcus,
     Pseudomonus
• Viral
   HIV
    Hepatitis (e.g. Hep B Hep C)
• Prions
  Bovine Spongiform Encephalopathy Agent
  (BSE) Other (non bovine) prions………..

                                      USAID Jordan Economic
                                      Development Program
The chemistry, manufacturing and controls
(CMC) aspect of drug development CMC aspect

 Important factors

 1-What is the source of raw material /Banks for
   biologics /biopharmaceutical.
 2-Production process of biologic/biopharmaceutical
 3-Purification of biologic( most culture media are
   complex with over 50 defined components)
 3-Formulation and drug product manufacture
 4-Demonstrating of product comparability .
 5-Stability –indicating methods and how much
   change is acceptable

                                              USAID Jordan Economic
                                              Development Program
continue
Demonstration of Similarity:

• Product knowledge is critical for designing an analytical
   testing.
• Lack of experience and data makes defining acceptance
    margins difficult.
• All aspects (quality, pre-clinical and clinical) of testing are
  important for approval.
• Advances in physicochemical techniques enable thorough
  characterization of proteins.
• However some unknowns remain and pre-clinical and clinical
   testing is needed to assess the safety and efficacy of
   biosimilars.
                                                      USAID Jordan Economic
                                                      Development Program
continue
Limitations of Analytics for Characterization of Biologics

Only the combination of analytical, non-clinical and clinical testing allows
  the comprehensive characterization of Biological Products

• In contrast with small molecule products, Biological Products are complex
    mixtures of protein molecules with potential for multiple modes of action.

• Comparative analytical data of finished products alone can never serve as a
   substitute for preclinical and clinical testing in biosimilarity assessments.

• Analytical testing of biosimilar products must be assessed in the context
of preclinical and clinical data to obtain a full product profile.

• All analytical methods used must meet regulatory standards for selectivity,
    sensitivity and reproducibility



                                                                    USAID Jordan Economic
                                                                    Development Program
Limitation of Analytical Testing:

• Small changes to large protein molecules may be
  functionally important but difficult to detect.
• Product characteristics may change during
  storage and it is important to investigate such effects.
• The definition of what constitutes a significant
  difference can change.
• May not discriminate all variants and impurities.
• May change the product, thereby giving irrelevant
  results.

                                                USAID Jordan Economic
                                                Development Program
Pharmacovigilance – Practical Implications for Biosimilars



Pharmacovigilance and a risk management plan are key pillars in
any adequate biosimilars concept

• Pharmacovigilance is an essential follow-up requirement for the
licensing of any new Biological and biosimilar Product.

• Long-term safety follow-up may identify adverse events that were not
identified during clinical trials.

• Commitment to a systematic pharmacovigilance program
demonstrates a manufacturer’s commitment to safety for patients.

•PSUR and RMP are required according to regulations.



                                                             USAID Jordan Economic
                                                             Development Program
Situation at JFDA
• All biological products and biosimilars
  should be submitted as new DRUGS and
  should take NDA number.
• Biological products and Biosimilars are
  evaluated by two committees :
-Vaccine and sera registration committee.
- New drugs registration Committee.

                                  USAID Jordan Economic
                                  Development Program
New draft for biological & biosimilar products registration criteria in Jordan



 Articles :
  It is forbidden/prohibited to register a biological product
  before the approval of its manufacturing site(s).
• What do we mean by manufacturing sites?
• Manufacturing site of the active ingredient(s).
• Manufacturing site of the finished product.
• Manufacturing sites involved in any of the manufacturing
  processes of the active ingredient and the finished
  product.
• Manufacturing site responsible for batch release.


                                                                           USAID Jordan Economic
                                                                           Development Program
New draft for biological & biosimilar products registration criteria in Jordan




   New definition for Biologicals
   They are materials intended for human consumption and
   may contain any of the following:
   •Vaccines
   •Allergens
   •Antigens
   •Blood and plasma derivatives
   •Specific Immuno-Sera
   •Antisense (RNA, DNA)
   •Gene Therapy
   •All proteins ( i.e. Hormones, Cytokines, Enzymes,
   Immunoglobulin and monoclonal antibodies
   •Recombinant DNA.
                                                                         USAID Jordan Economic
                                                                         Development Program
New draft for biological & biosimilar products registration
criteria in Jordan


•    And are produced by any of the following methods:
1.   Development of microbial strains (Prokaryocytes).
2.   Development of Eukaryocytes cells.
3.   Extraction of materials from bio-tissues including
     Human, Animal, Plant tissues or Genetically-
     Engineered tissues.
4.   Recombinant DNA.
5.   Methods of Hybridization of Cells.
6.   Development of micro-organisms in embryos or
     animals.
7.   Any other related methods.
                                                              USAID Jordan Economic
                                                              Development Program
New draft for biological & biosimilar products registration
 criteria in Jordan


- For allergens, a registration dossier for each of the below groups
   should be submitted in accordance with the requirements stated in
   Annex (1). The technical dossier must contain all the required
   technical details for each class included within a group:

1- Pollens:
        * Trees.
        * Grass.
        * Weeds.
2- Animals, insects and venoms.
3- Food.
4- Mites.
5- Others.


                                                               USAID Jordan Economic
                                                               Development Program
New draft for biological & biosimilar products registration criteria in Jordan

    Biologicsbiologicals (according to WHO)
    that can be produced by one of the following methods
    -Growth of strains of microorganisms and eukaryotic cells.
    - Extraction of substances from biological tissues , including human, animal
    and plant tissues ( allergens).
    - Recombinant DNA (rDNA) techniques.
    - Hybridoma techniques.
    - Propagation of microorganisms in embryos or animals.
    -Biological products manufactured by these methods include allergens,
    antigens, vaccines, hormones, cytokines, enzymes, human whole blood and
    plasma derivatives, immune sera, immunoglobulins ( including monoclonal
    antibodies), products of fermentation (including products derived from rDNA)
    and diagnostic agents for in vitro use.


                                                                     USAID Jordan Economic
                                                                     Development Program
New draft for biological & biosimilar products registration criteria in Jordan



   • Reference Biological Product: It is the first biological
     product to be registered internationally. Contains a new
     biological active ingredient. Has proven quality, efficacy
     and safety through preclinical ( toxicity ) and clinical
     studies.

   • Reference Biological Product should be mentioned
     clearly in comparative studies .

   • Biosimilars: Are biological products that are similar to the
     reference biological products in aspects of their efficacy,
     safety and quality .
                                                                 USAID Jordan Economic
                                                                 Development Program
New draft for biological & biosimilar products registration criteria in Jordan



   • If the submitted biological product is
     manufactured by contract, the applicant must
     fulfill the requirements stated in Annex (5) along
     with the dossier requirements stated in Annex
     (1).

   • If the submitted biological product is
     manufactured under license, the applicant must
     fulfill the requirements stated in Annex (3) in
     addition to those stated in Annex (1).


                                                                 USAID Jordan Economic
                                                                 Development Program
New draft for biological & biosimilar products registration criteria in Jordan



• The committee shall depend on the following criteria upon the
  registration of the drug:

 1- The efficacy of the drug.
 2- The safety of the drug intended.
 3- The quality of the drug.
 4- The drug to be registered must be actually marketed in the
   country of origin with the same composition. In case it is not
   marketed, the reasons of such should be clarified and a
   certificate of pharmaceutical product (CPP) from one of JFDA's
   reference countries should be provided.




                                                             USAID Jordan Economic
                                                             Development Program
New draft for biological & biosimilar products
           registration criteria in Jordan



• The drug to be registered should be
  marketed in the country of origin or any
  reference countries for at least a year, it is
  entitled to exempt the biological products
  used for the treatment or prevention of
  epidemics and endemics and the
  biological products that own a therapeutic
  advantage from this stipulations.
                                            USAID Jordan Economic
                                            Development Program
New draft for biological & biosimilar products
          registration criteria in Jordan



• The committee is to decide on any
  submitted and complete biological product
  application within a period that does not
  exceed 180 days from the date of
  submitting a complete registration request.



                                           USAID Jordan Economic
                                           Development Program
New draft for biological & biosimilar products
         registration criteria in Jordan

  JFDA has the right to take any or all of the
following measures: prohibit importation,
discontinue the distribution, discontinue the sale,
prohibit the marketing, suspension or
cancellation of registration , revoke the
registration or recall the biological product If the
drug’s toxicity ,inferior quality, reduced efficacy
or in-efficacy becomes evident to the Committee
or due to other reasons mentioned in the
regulations .
                                          USAID Jordan Economic
                                          Development Program
New draft for biological & biosimilar products registration criteria in Jordan




    • Upon changing the source of the active
      ingredient or pharmaceutical form, the
      biological product must be submitted and
      registered as a new product .
    • Upon changing in the production site of
      the active ingredient the production site
      must be approved by the relative
      committee.
                                                                                 USAID Jordan Economic
                                                                                 Development Program
New draft for biological & biosimilar products registration criteria in Jordan




    •     The approval of the Committee must be
          obtained upon conducting any of the following
          changes/variations on the registered drug:
         – Manufacturing site of the finished product.
         – Site responsible for batch release.
         – The name of the manufacturer of the active
           ingredient and finished product.
         – Major steps of the manufacturing process of the
           active ingredient, intermediate and finished product.
         – The inactive ingredients in the product’s
           composition.
                                                                                 USAID Jordan Economic
                                                                                 Development Program
New draft for biological & biosimilar products registration criteria in Jordan



         - Primary packaging materials ( type, size, and form ) of the
         finished product.
           -Shelf life and storage conditions of the active ingredient,
           intermediates and finished product.
           - Information mentioned in the insert leaflet.
           - Information mentioned on the outer and inner packs which are
         related to the insert leaflet.
           - Specifications and method of analysis of the active ingredient,
         intermediates and finished product.
          - Trade name of the product.
          - Any changes in the batch numbering system or information
         within the production and quality control files.
          - Change in the batch size ( Scale up ).
          - Any updates or changes in the plasma master file.


                                                                                 USAID Jordan Economic
                                                                                 Development Program
New draft for biological & biosimilar products registration
criteria in Jordan/ Annexes



Contents of Annex no1:
Requirements of the Drug Registration File

   module no1 : Regional Requirements, Certificates, Information
    and Administrative Documents .
   module no 2: CTD file summaries.
   module no 3: Quality part (drug substance and drug product)
   module no 4: Non clinical studies
   module no 5:Clinical studies, PSUR and Risk Management
    Plan.
     All modules are according to CTD .

    For Biosimilars :Comparability studies with the Reference Product
    should be submitted

                                                              USAID Jordan Economic
                                                              Development Program
New draft for biological & biosimilar products registration
criteria in Jordan/ Annexes



  • Annex no 2 (content of plasma master file)
  • Annex no3 ( Information required to be mentioned on
    the Primary and secondary container
  • Annex no 4 (Information required to be mentioned on
    inner leaflet)
  • Annex no 5 ( Contract manufacturing requirements).
  • Annex no 6 (Contract manufacturing requirements
    for registered product and re-sourcing
    requirements.
  • Annex no 7 (Re–registration requirements)
  • Annex no 8 (prices certificates)
  • Annex no 9 (Importation certificates for serum and
    vaccines
                                                              USAID Jordan Economic
                                                              Development Program
New draft for biological & biosimilar products registration
criteria in Jordan/ Annexes




  • It is required to submit a separate copy of the
    technical file for analysis purpose at the Drug
    Control Laboratory enclosing:
  • Samples of the finished product, the number of which will
    be determined in accordance with the drug testing
    system.
  • An adequate quantity for analysis of the reference
    primary active substance(s) and degradation products.




                                                              USAID Jordan Economic
                                                              Development Program
Case study - Insulin

       NON-CLINICAL STUDIES:
• These studies should be comparative in nature and should be designed to detect
     differences in the response to the similar biological medicinal product and reference
     medicinal product .
  1-Pharmacodynamic studies
• In vitro studies
    comparative in vitro bioassays for affinity, insulin- and IGF-1-receptor binding assays,
     as well as tests for intrinsic activity should be performed
•     In vivo studies
•     are normally not required as part of the comparability exercise.
    Comparative study(ies) of pharmacodynamic effects would not be anticipated to be
     sensitive enough to detect any non-equivalence not identified by in vitro assays,
   2-Toxicological studies
• Data from at least one repeat dose toxicity study in a relevant species (e.g. rat) should
     be provided. Study duration should be at least 4 weeks.


                                                                           USAID Jordan Economic
                                                                           Development Program
Case study - Insulin

CLINICAL STUDIES
   1-Pharmacokinetic studies:
It is determined in a single dose crossover study using subcutaneous
 administration. Comprehensive comparative data should be provided on the time-
 concentration profile . Studies should be performed preferably in patients with
 type1 diabetes. Factors contributing to PK variability e.g. insulin dose and site of
 injection / thickness of subcutaneous fat should be taken into account.
  2-Pharmacodynamic studies :
-The double-blind, crossover hyperinsulinaemic euglycaemic clamp study is
 suitable for this characterization, The clinical activity of an insulin preparation
 is determined by its time-effect profile of hypoglycemic response
- The choice of study population and study duration should be justified.
  3- Clinical efficacy studies
Provided that clinical comparability can be concluded from PK and PD data, there
 is no anticipated need for efficacy studies on intermediary or clinical variables.


                                                                         USAID Jordan Economic
                                                                         Development Program
continue
      CLINICAL safety
• Immunogenicity :
• The issue of immunogenicity can only be settled through clinical trials of
sufficient duration, i.e. at least 12 months using subcutaneous administration.
• The comparative phase of this study should be at least 6 months, to be
completed pre-approval.
•Data at the end of 12 months could be presented as part of post-marketing
commitment.
•The primary outcome measure should be the incidence of antibodies to the
test and reference medicinal product.
PHARMACOVIGILANCE PLAN
•A risk management program / pharmacovigilance plan should be presented.
•This should take into account risks identified during product development
and potential risks.

                                                                 USAID Jordan Economic
                                                                 Development Program
Nonclinical Requirements for Biosimilars


Product      PD in Vitro        PD in Vivo     Toxicology



Insulin      Comparative in     Normally not   One repeat dose
             vitro bioassay     required       toxicity in rats,
             (insulin and IGF                  4 weeks (incl.
             binding)                          local tolerance)




                                                   USAID Jordan Economic
                                                   Development Program
Clinical Requirement for Biosimilars




Product class          Efficacy study duration Safety and
                                               immunogenicity




Insulin                None, if comparability   12 months (6 months
                       can be concluded from    pre-approval)
                       the submitted PK and
                       PD




                                                         USAID Jordan Economic
                                                         Development Program
Heparin case

 FDA recalled a shipment of heparin because of growth of
serratia marcescens in several unopened syringe of this
product .the bacteria serratia marcescens can lead to life –
threatening injuries and /or death.

In march 2008 ,major recalls of heparin due to
contamination of the raw heparin stock imported from china
Contaminated heparin killed 81 people in the united states.
The contaminant was identified as an “over-sulphated”
Derivative of chondroitin sulphate .. Popular shellfish –
derived supplement often used for arthritis.


                                                 USAID Jordan Economic
                                                 Development Program
Thank You




            USAID Jordan Economic
            Development Program

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Jordan FDA - BioAsia 2013

  • 1. Challenges In Evaluation Of Biosimilar Products Prepared by pharmacist Lina Bajjali Head of Registration Department Jordan Food and Drug Administration
  • 2. Biologics biologicals (what does it mean?) Biotechnology products? A biotechnology product is one manufactured by recombinant DNA technology, one where genetic manipulation of cells is required, or a monoclonal antibody. Biological products? They include those where the starting material may be human or animal tissues or of microbiological origin also included are those where a complex bioassay system is required to monitor potency . they need complex processes for ensuring integrity/ reproducibility and for removing/isolating/purifying/and formulating the biological products USAID Jordan Economic Development Program 2
  • 3. • What are Allergenic extracts • Extract (usually containing protein) from various sources, pollen, dust, mould, insect, venom, food, containing the immunogenic or allergenic compound; may be used for skin testing or desensitization. USAID Jordan Economic Development Program
  • 4. How do biologics differ From Conventional drugs ? •Most drugs consist of pure chemical substances and their structures are known ,most biologics , however , are complex mixture that are not easily identified or characterized . •Biological Products differ from conventional drugs in that they tend to be heat-sensitive and susceptible to microbial contamination •This requires sterile processes to be applied from initial manufacturing steps. USAID Jordan Economic Development Program
  • 5. Manufacturing process The Process is the Product Biological Products derived from completely different manufacturing processes are not identical • In contrast to uniform small molecule products, Biological Products are composed of complex protein molecules • Each stage of the complex manufacturing process confers unique properties to the resulting Biological Product • Biological Products produced using completely different manufacturing processes cannot be identical – Data on one Biological Product, with respect to quality, efficacy or safety, cannot be extrapolated to a biosimilar product that is produced using a completely different manufacturing process without the demonstration of similarity in terms of quality, safety and efficacy USAID Jordan Economic Development Program
  • 6. Challenges facing Biosimilars Production Issues • Development of a manufacturing process for Biosimilars involves many steps (Reverse engineering). • Process knowledge is key. • Choice of cell line is important, impurity profiles. • The quality development of Biosimilars follows the same route as for new biologics. USAID Jordan Economic Development Program
  • 7. Manufacturing process • The complexity of biopharmaceuticals means that the process of producing a biopharmaceutical is also extremely complex. • • The specific combination of steps in the process generates the final product. • One of the first steps involves the cloning of the appropriate genetic sequence into an expression vector, followed establishment of a cell expression system • • The protein expression system needs to be scaled-up to produce large amounts • • The desired biopharmaceutical must then be processed and purified • • The final product needs to be formulated to ensure consistent and reliable • delivery to the patient • • Each of these stages involves many checkpoints and quality control steps USAID Jordan Economic Development Program
  • 8. Contaminants • Bacterial e.g. Streptococcus, Staphylococcus, Pseudomonus • Viral HIV Hepatitis (e.g. Hep B Hep C) • Prions Bovine Spongiform Encephalopathy Agent (BSE) Other (non bovine) prions……….. USAID Jordan Economic Development Program
  • 9. The chemistry, manufacturing and controls (CMC) aspect of drug development CMC aspect Important factors 1-What is the source of raw material /Banks for biologics /biopharmaceutical. 2-Production process of biologic/biopharmaceutical 3-Purification of biologic( most culture media are complex with over 50 defined components) 3-Formulation and drug product manufacture 4-Demonstrating of product comparability . 5-Stability –indicating methods and how much change is acceptable USAID Jordan Economic Development Program
  • 10. continue Demonstration of Similarity: • Product knowledge is critical for designing an analytical testing. • Lack of experience and data makes defining acceptance margins difficult. • All aspects (quality, pre-clinical and clinical) of testing are important for approval. • Advances in physicochemical techniques enable thorough characterization of proteins. • However some unknowns remain and pre-clinical and clinical testing is needed to assess the safety and efficacy of biosimilars. USAID Jordan Economic Development Program
  • 11. continue Limitations of Analytics for Characterization of Biologics Only the combination of analytical, non-clinical and clinical testing allows the comprehensive characterization of Biological Products • In contrast with small molecule products, Biological Products are complex mixtures of protein molecules with potential for multiple modes of action. • Comparative analytical data of finished products alone can never serve as a substitute for preclinical and clinical testing in biosimilarity assessments. • Analytical testing of biosimilar products must be assessed in the context of preclinical and clinical data to obtain a full product profile. • All analytical methods used must meet regulatory standards for selectivity, sensitivity and reproducibility USAID Jordan Economic Development Program
  • 12. Limitation of Analytical Testing: • Small changes to large protein molecules may be functionally important but difficult to detect. • Product characteristics may change during storage and it is important to investigate such effects. • The definition of what constitutes a significant difference can change. • May not discriminate all variants and impurities. • May change the product, thereby giving irrelevant results. USAID Jordan Economic Development Program
  • 13. Pharmacovigilance – Practical Implications for Biosimilars Pharmacovigilance and a risk management plan are key pillars in any adequate biosimilars concept • Pharmacovigilance is an essential follow-up requirement for the licensing of any new Biological and biosimilar Product. • Long-term safety follow-up may identify adverse events that were not identified during clinical trials. • Commitment to a systematic pharmacovigilance program demonstrates a manufacturer’s commitment to safety for patients. •PSUR and RMP are required according to regulations. USAID Jordan Economic Development Program
  • 14. Situation at JFDA • All biological products and biosimilars should be submitted as new DRUGS and should take NDA number. • Biological products and Biosimilars are evaluated by two committees : -Vaccine and sera registration committee. - New drugs registration Committee. USAID Jordan Economic Development Program
  • 15. New draft for biological & biosimilar products registration criteria in Jordan Articles : It is forbidden/prohibited to register a biological product before the approval of its manufacturing site(s). • What do we mean by manufacturing sites? • Manufacturing site of the active ingredient(s). • Manufacturing site of the finished product. • Manufacturing sites involved in any of the manufacturing processes of the active ingredient and the finished product. • Manufacturing site responsible for batch release. USAID Jordan Economic Development Program
  • 16. New draft for biological & biosimilar products registration criteria in Jordan New definition for Biologicals They are materials intended for human consumption and may contain any of the following: •Vaccines •Allergens •Antigens •Blood and plasma derivatives •Specific Immuno-Sera •Antisense (RNA, DNA) •Gene Therapy •All proteins ( i.e. Hormones, Cytokines, Enzymes, Immunoglobulin and monoclonal antibodies •Recombinant DNA. USAID Jordan Economic Development Program
  • 17. New draft for biological & biosimilar products registration criteria in Jordan • And are produced by any of the following methods: 1. Development of microbial strains (Prokaryocytes). 2. Development of Eukaryocytes cells. 3. Extraction of materials from bio-tissues including Human, Animal, Plant tissues or Genetically- Engineered tissues. 4. Recombinant DNA. 5. Methods of Hybridization of Cells. 6. Development of micro-organisms in embryos or animals. 7. Any other related methods. USAID Jordan Economic Development Program
  • 18. New draft for biological & biosimilar products registration criteria in Jordan - For allergens, a registration dossier for each of the below groups should be submitted in accordance with the requirements stated in Annex (1). The technical dossier must contain all the required technical details for each class included within a group: 1- Pollens: * Trees. * Grass. * Weeds. 2- Animals, insects and venoms. 3- Food. 4- Mites. 5- Others. USAID Jordan Economic Development Program
  • 19. New draft for biological & biosimilar products registration criteria in Jordan Biologicsbiologicals (according to WHO) that can be produced by one of the following methods -Growth of strains of microorganisms and eukaryotic cells. - Extraction of substances from biological tissues , including human, animal and plant tissues ( allergens). - Recombinant DNA (rDNA) techniques. - Hybridoma techniques. - Propagation of microorganisms in embryos or animals. -Biological products manufactured by these methods include allergens, antigens, vaccines, hormones, cytokines, enzymes, human whole blood and plasma derivatives, immune sera, immunoglobulins ( including monoclonal antibodies), products of fermentation (including products derived from rDNA) and diagnostic agents for in vitro use. USAID Jordan Economic Development Program
  • 20. New draft for biological & biosimilar products registration criteria in Jordan • Reference Biological Product: It is the first biological product to be registered internationally. Contains a new biological active ingredient. Has proven quality, efficacy and safety through preclinical ( toxicity ) and clinical studies. • Reference Biological Product should be mentioned clearly in comparative studies . • Biosimilars: Are biological products that are similar to the reference biological products in aspects of their efficacy, safety and quality . USAID Jordan Economic Development Program
  • 21. New draft for biological & biosimilar products registration criteria in Jordan • If the submitted biological product is manufactured by contract, the applicant must fulfill the requirements stated in Annex (5) along with the dossier requirements stated in Annex (1). • If the submitted biological product is manufactured under license, the applicant must fulfill the requirements stated in Annex (3) in addition to those stated in Annex (1). USAID Jordan Economic Development Program
  • 22. New draft for biological & biosimilar products registration criteria in Jordan • The committee shall depend on the following criteria upon the registration of the drug: 1- The efficacy of the drug. 2- The safety of the drug intended. 3- The quality of the drug. 4- The drug to be registered must be actually marketed in the country of origin with the same composition. In case it is not marketed, the reasons of such should be clarified and a certificate of pharmaceutical product (CPP) from one of JFDA's reference countries should be provided. USAID Jordan Economic Development Program
  • 23. New draft for biological & biosimilar products registration criteria in Jordan • The drug to be registered should be marketed in the country of origin or any reference countries for at least a year, it is entitled to exempt the biological products used for the treatment or prevention of epidemics and endemics and the biological products that own a therapeutic advantage from this stipulations. USAID Jordan Economic Development Program
  • 24. New draft for biological & biosimilar products registration criteria in Jordan • The committee is to decide on any submitted and complete biological product application within a period that does not exceed 180 days from the date of submitting a complete registration request. USAID Jordan Economic Development Program
  • 25. New draft for biological & biosimilar products registration criteria in Jordan JFDA has the right to take any or all of the following measures: prohibit importation, discontinue the distribution, discontinue the sale, prohibit the marketing, suspension or cancellation of registration , revoke the registration or recall the biological product If the drug’s toxicity ,inferior quality, reduced efficacy or in-efficacy becomes evident to the Committee or due to other reasons mentioned in the regulations . USAID Jordan Economic Development Program
  • 26. New draft for biological & biosimilar products registration criteria in Jordan • Upon changing the source of the active ingredient or pharmaceutical form, the biological product must be submitted and registered as a new product . • Upon changing in the production site of the active ingredient the production site must be approved by the relative committee. USAID Jordan Economic Development Program
  • 27. New draft for biological & biosimilar products registration criteria in Jordan • The approval of the Committee must be obtained upon conducting any of the following changes/variations on the registered drug: – Manufacturing site of the finished product. – Site responsible for batch release. – The name of the manufacturer of the active ingredient and finished product. – Major steps of the manufacturing process of the active ingredient, intermediate and finished product. – The inactive ingredients in the product’s composition. USAID Jordan Economic Development Program
  • 28. New draft for biological & biosimilar products registration criteria in Jordan - Primary packaging materials ( type, size, and form ) of the finished product. -Shelf life and storage conditions of the active ingredient, intermediates and finished product. - Information mentioned in the insert leaflet. - Information mentioned on the outer and inner packs which are related to the insert leaflet. - Specifications and method of analysis of the active ingredient, intermediates and finished product. - Trade name of the product. - Any changes in the batch numbering system or information within the production and quality control files. - Change in the batch size ( Scale up ). - Any updates or changes in the plasma master file. USAID Jordan Economic Development Program
  • 29. New draft for biological & biosimilar products registration criteria in Jordan/ Annexes Contents of Annex no1: Requirements of the Drug Registration File  module no1 : Regional Requirements, Certificates, Information and Administrative Documents .  module no 2: CTD file summaries.  module no 3: Quality part (drug substance and drug product)  module no 4: Non clinical studies  module no 5:Clinical studies, PSUR and Risk Management Plan. All modules are according to CTD . For Biosimilars :Comparability studies with the Reference Product should be submitted USAID Jordan Economic Development Program
  • 30. New draft for biological & biosimilar products registration criteria in Jordan/ Annexes • Annex no 2 (content of plasma master file) • Annex no3 ( Information required to be mentioned on the Primary and secondary container • Annex no 4 (Information required to be mentioned on inner leaflet) • Annex no 5 ( Contract manufacturing requirements). • Annex no 6 (Contract manufacturing requirements for registered product and re-sourcing requirements. • Annex no 7 (Re–registration requirements) • Annex no 8 (prices certificates) • Annex no 9 (Importation certificates for serum and vaccines USAID Jordan Economic Development Program
  • 31. New draft for biological & biosimilar products registration criteria in Jordan/ Annexes • It is required to submit a separate copy of the technical file for analysis purpose at the Drug Control Laboratory enclosing: • Samples of the finished product, the number of which will be determined in accordance with the drug testing system. • An adequate quantity for analysis of the reference primary active substance(s) and degradation products. USAID Jordan Economic Development Program
  • 32. Case study - Insulin  NON-CLINICAL STUDIES: • These studies should be comparative in nature and should be designed to detect differences in the response to the similar biological medicinal product and reference medicinal product . 1-Pharmacodynamic studies • In vitro studies comparative in vitro bioassays for affinity, insulin- and IGF-1-receptor binding assays, as well as tests for intrinsic activity should be performed • In vivo studies • are normally not required as part of the comparability exercise. Comparative study(ies) of pharmacodynamic effects would not be anticipated to be sensitive enough to detect any non-equivalence not identified by in vitro assays, 2-Toxicological studies • Data from at least one repeat dose toxicity study in a relevant species (e.g. rat) should be provided. Study duration should be at least 4 weeks. USAID Jordan Economic Development Program
  • 33. Case study - Insulin CLINICAL STUDIES 1-Pharmacokinetic studies: It is determined in a single dose crossover study using subcutaneous administration. Comprehensive comparative data should be provided on the time- concentration profile . Studies should be performed preferably in patients with type1 diabetes. Factors contributing to PK variability e.g. insulin dose and site of injection / thickness of subcutaneous fat should be taken into account. 2-Pharmacodynamic studies : -The double-blind, crossover hyperinsulinaemic euglycaemic clamp study is suitable for this characterization, The clinical activity of an insulin preparation is determined by its time-effect profile of hypoglycemic response - The choice of study population and study duration should be justified. 3- Clinical efficacy studies Provided that clinical comparability can be concluded from PK and PD data, there is no anticipated need for efficacy studies on intermediary or clinical variables. USAID Jordan Economic Development Program
  • 34. continue  CLINICAL safety • Immunogenicity : • The issue of immunogenicity can only be settled through clinical trials of sufficient duration, i.e. at least 12 months using subcutaneous administration. • The comparative phase of this study should be at least 6 months, to be completed pre-approval. •Data at the end of 12 months could be presented as part of post-marketing commitment. •The primary outcome measure should be the incidence of antibodies to the test and reference medicinal product. PHARMACOVIGILANCE PLAN •A risk management program / pharmacovigilance plan should be presented. •This should take into account risks identified during product development and potential risks. USAID Jordan Economic Development Program
  • 35. Nonclinical Requirements for Biosimilars Product PD in Vitro PD in Vivo Toxicology Insulin Comparative in Normally not One repeat dose vitro bioassay required toxicity in rats, (insulin and IGF 4 weeks (incl. binding) local tolerance) USAID Jordan Economic Development Program
  • 36. Clinical Requirement for Biosimilars Product class Efficacy study duration Safety and immunogenicity Insulin None, if comparability 12 months (6 months can be concluded from pre-approval) the submitted PK and PD USAID Jordan Economic Development Program
  • 37. Heparin case FDA recalled a shipment of heparin because of growth of serratia marcescens in several unopened syringe of this product .the bacteria serratia marcescens can lead to life – threatening injuries and /or death. In march 2008 ,major recalls of heparin due to contamination of the raw heparin stock imported from china Contaminated heparin killed 81 people in the united states. The contaminant was identified as an “over-sulphated” Derivative of chondroitin sulphate .. Popular shellfish – derived supplement often used for arthritis. USAID Jordan Economic Development Program
  • 38. Thank You USAID Jordan Economic Development Program