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
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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.
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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.
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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
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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.
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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
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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………..
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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
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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 .
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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).
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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.
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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.
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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.
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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 .
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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.
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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.
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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.
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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
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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
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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.
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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.
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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.
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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.
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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)
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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
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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.
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38. Thank You
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