GF2007 RUIZ WFH biosimilars min

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					Track Listings                          Track Listings
{PRIVATE}1. Sunny - Bobby Hebb          {PRIVATE}1. Sunny - James Brown And Dee Felice Trio Feat
2. Sunny - Arthur Lyman Group           Marva Whitney Montez
                                        2. Sunny - Chris
3. Sunny - Georgie Fame                 3. Sunny - Les McCann
4. Sunny - Booker T. & The MG's         4. Sunny - Shirley Bassey
5. Sunny - Dusty Springfield            5. Sunny - Jose Feliciano
6. Sunny - John Schroder Orchestra      6. Sunny - The Four Tops
7. Sunny - Robert Mitchum               7. Sunny - Marian Love
8. Sunny - Stan Kenton                  8. Sunny - The Walker Brothers
                                        9. Sunny - Paul Kuhn
9. Sunny - Herbie Mann & Tamiko Jones
                                        10. Sunny - Trini Lopez
10. Sunny - Stanley Turrentine          11. Sunny - Young Holt Trio
11. Sunny - Andy Williams               12. Sunny - Marvin Gaye
12. Sunny - The Ventures                13. Sunny - The Electric Flag
13. Sunny - Cher                        14. Sunny - Leonard Nimoy
14. Sunny - Jimmy Smith                 15. Sunny - Ella Fitzgerald
15. Sunny - Wilson Pickett              16. Sunny - Gary Lewis And The Playboys
16. Sunny - Nancy Wilson                17. Sunny - Brother Jack McDuff And David Newman
                  Biological Product
due to its complexity it cannot be           fully
characterized by analytical testing alone
quality determined by a combination of physico-
chemical and biological testing, together with the
production process and its control

bioactivity and immunogenicity are dependent
upon all its “structural features”
                 Chemical Product
well defined   molecular   structure,   ‘easy’   to

impurity profile depending on the synthetic and
degradation route
safety and efficacy independent on the origin of
the product
            rDNA Product
 proteins and glycoproteins
 large and complex molecules
 inherent microheterogeneity due to post-
  translational modification (ICH Q6B)
'Pharmed' goats seek drug license

 Imagine you could get life-saving
 medicines from milking a common
 farmyard animal.

 That idea moves a step closer to
 becoming a reality this week, as the
 European Medicines Agency (EMEA)
 considers the final stages of an
 application to license a natural human
 protein extracted from the milk of

  22 February 2006
EU funding for GM plant vaccines
 European scientists have launched a project
 to make pharmaceutically useful products in
 genetically modified crops. The consortium,
 called Pharma-Planta, wants to produce
 vaccines and other treatments for major
 diseases, such as HIV/Aids, rabies and TB.
 The EU has put 12 million euros (£8m) into
 the project, which hopes to start clinical trials
 by 2009.
 The first product, possibly grown in maize, is
 likely to be an antibody that can be used to
 block HIV transmission.
 It would be incorporated into a microbicidal
 cream that could be used in the vagina.

                                                     12 July 2004
Change in a given
                     New MAA
production process
                      compared to a
    development     reference product
    after MA
The extent of the studies to demonstrate comparability will
  depend on:

 The production step where the changes are introduced
 The potential impact of the changes on the purity as
  well as on the physicochemical and biological properties
  of the product, particularly considering the complexity
  and degree of knowledge of the product (e.g. impurities,
  product related substances)
 The availability of suitable analytical techniques to
  detect potential product modifications and the results of
  these studies, and
 The relationship between quality attributes and
  safety and efficacy, based on overall non-clinical and
  clinical experience.
Change in a given    New MAA
production process
                      compared to
 development
                       a reference
 after MA             product
Independent development will result in
inherent differences in:

 source materials, expression systems, culture
  process details
 purification process (scheme, scale, operation...)
 In-process controls, test methods, specifications...
  Comparison based on a pharmacopoeia monograph
  is not sufficient
•   rDNA products   •   rhuFVIII
•   EPO             •   alteplase (rtPA)
•   insulin         •   calcitonin
•   somatropin      •   HBsAg
•   IFN alfa        •   molgramostim (GM-CSF)
•   IFN gamma       •   MoAbs
•   glucagon
Affinity chromatography

                            - bioburden
                            - pH

CE chromatography

                            - bioburden

AE chromatography

                             - bioburden
                             - endotoxin

                             - bioburden
                              - endotoxin
                             - CHOP
Add Polysorbate 20

                             - bioburden

 Bulk filtered into tanks

                              - bioburden
                               - endotoxin
                              - protein concentration
     Store frozen
Impurity          Residual level
Host cell DNA     < 2.5 ng/max. dose
CHO Proteins      < 0.375 µg/max. dose
Insulin           < 17 ng/mL (below the LOQ)
Gentamicin        < 2.5 ng/mL (below the LOQ)
Anti-foam agent   < 12.5 µg/mL

Protein A         < 0.4 ng/mL
TRIS              < 83 µM (10 g/mL)
                                     Product-related   Product-related
                                     substances (%)    impurities (%)
Aggregates                                   <3
N-terminal variant                            2
C-terminal variants                          5-7
Unpaired VH loop disulfide variant                           15 - 20
IsoAsp variant                                                2-8
Succinimide variant (light chain)                             1-3
Deamidated                                   6-8
     Extensive characterization               GMP
    during the development of the          compliance

                                                        In process
Control of starting                                      controls

validation                      Specifications
                             SAFETY & EFFICACY
     depending on the
 nature of the drug substance and formulation
 complexity of its molecular structure
 differences with the reference product
   Authorization through the centralized procedure
   Same pharmaceutical form, dose and route of
    administration as the reference product
   No extrapolation between different administration
   The reference product should be the same throughout
    the dossier and it should be available in the EU
   Preclinical Comparative studies in vitro and in vivo

    –   PK
    –   PD
    –   Immunogenicity
    –   Toxicity

   Efficacy and safety data showing comparability
   Immunogenicity
   Pharmacovigilance system and risk management plan
                   QUALITY                      CLINICAL

                  ICH Q5E                   EMEA/CPMP/3097/02

                                             Guideline on similar
                                             biological products
          Guideline on similar biological containing biotechnology-
              products containing         derived proteins as active
             biotechnology-derived         substance: Nonclinical &
          proteins as active substance:         Clinical Issues
                  Quality issues
                                         Product-specific guidelines

Guideline on Similar Biological Products (CPMP/437/04)
Product-specific guidelines
A similar biological medicinal product is defined by

 related to the molecule (including product related
  substances/impurities), and
 related to its process (which may affect molecular
  characteristics and includes process related impurities).
The Applicant should demonstrate the consistency and robustness
of his own process according to existing guidelines.
                        EU Approach
                              Directive 2003/63

Overarching    Guideline on Similar Biological Medicinal Products

               Guideline on Similar Biological Medicinal Products
Quality       Containing Biotechnology-Derived Proteins as Active
                           Substance: Quality Issues

Nonclinical    Guideline on Similar Biological Medicinal Products
              Containing Biotechnology-Derived Proteins as Active
& Clinical          Substance: Nonclinical & Clinical Issues

Annexes        rHuEPO      rHuG-CSF        rHuINS         rHuGH
 Two comparative studies minimum (renal anemia)
 Anemia correction and maintenance phase should be
 Separate studies for pre-dialysis and dialysis patients
 Separate studies to evaluate SC and IV routes
 Efficacy data can be extrapolated to other indications
 Safety data from at least 300 patients
 Immunogenicity data for at least one year
   PK/PD
   Minimum one comparative study, double blind
   Pre-pubertal naive children with GH deficiency
   Evaluation of efficacy for at least 6-12 months
   Efficacy data can be extrapolated to other indications
   Immunogenicity data for at least one year
 Minimum one comparative study, double blind
 Prophylaxis of neutropenia after cytotoxic
 Efficacy data can be extrapolated to other indications
 Safety after repeated dosing (according to the
  conventional chemotherapeutic treatment). FU for at
  least 6 months
 Immunogenicity data
   PK/PD. It may be sufficient
   Immunogenicity data for at least 6 months
    (12 months post-authorization)
 ADVATE is a modification of Recombinate (approved on 12
  May 1993)
 Both drug substances are produced by the same CHO cell line
 Protein free production process. Modifications to the
  fermentation, the purification process and the drug product
  formulation were introduced
 A S/D viral inactivation step was also introduced

 Both quality and PK/PD studies showed comparability
 between these two products
 The applicant submitted an application comprising
  pharmacokinetic, clinical efficacy, and safety data required for
  a completely new product.
 Primary objective of the pivotal study: Advate is bioequivalent
  to Recombinate.
 A stepwise approach was followed. Results indicated that:
 i) Recombinate and Advate pilot scale are bioequivalent
 ii) Advate pilot and Advate commercial scale are bioequivalent

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