Jordan FDA - BioAsia 2013

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Jordan FDA - BioAsia 2013

  1. 1. Challenges In Evaluation Of Biosimilar Products Prepared by pharmacist Lina Bajjali Head of Registration Department Jordan Food and Drug Administration
  2. 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. 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. 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. 5. Manufacturing processThe Process is the ProductBiological 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. 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. 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. 8. Contaminants• Bacteriale.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. 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. 10. continueDemonstration 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. 11. continueLimitations of Analytics for Characterization of BiologicsOnly 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 contextof 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. 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. 13. Pharmacovigilance – Practical Implications for BiosimilarsPharmacovigilance and a risk management plan are key pillars inany adequate biosimilars concept• Pharmacovigilance is an essential follow-up requirement for thelicensing of any new Biological and biosimilar Product.• Long-term safety follow-up may identify adverse events that were notidentified during clinical trials.• Commitment to a systematic pharmacovigilance programdemonstrates a manufacturer’s commitment to safety for patients.•PSUR and RMP are required according to regulations. USAID Jordan Economic Development Program
  14. 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. 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. 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. 17. New draft for biological & biosimilar products registrationcriteria 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. 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. 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. 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. 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. 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 JFDAs reference countries should be provided. USAID Jordan Economic Development Program
  23. 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. 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. 25. New draft for biological & biosimilar products registration criteria in Jordan JFDA has the right to take any or all of thefollowing measures: prohibit importation,discontinue the distribution, discontinue the sale,prohibit the marketing, suspension orcancellation of registration , revoke theregistration or recall the biological product If thedrug’s toxicity ,inferior quality, reduced efficacyor in-efficacy becomes evident to the Committeeor due to other reasons mentioned in theregulations . USAID Jordan Economic Development Program
  26. 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. 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. 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. 29. New draft for biological & biosimilar products registrationcriteria in Jordan/ AnnexesContents 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. 30. New draft for biological & biosimilar products registrationcriteria 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. 31. New draft for biological & biosimilar products registrationcriteria 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. 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. 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 studiesProvided 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. 34. continue CLINICAL safety• Immunogenicity :• The issue of immunogenicity can only be settled through clinical trials ofsufficient duration, i.e. at least 12 months using subcutaneous administration.• The comparative phase of this study should be at least 6 months, to becompleted pre-approval.•Data at the end of 12 months could be presented as part of post-marketingcommitment.•The primary outcome measure should be the incidence of antibodies to thetest and reference medicinal product.PHARMACOVIGILANCE PLAN•A risk management program / pharmacovigilance plan should be presented.•This should take into account risks identified during product developmentand potential risks. USAID Jordan Economic Development Program
  35. 35. Nonclinical Requirements for BiosimilarsProduct PD in Vitro PD in Vivo ToxicologyInsulin 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. 36. Clinical Requirement for BiosimilarsProduct class Efficacy study duration Safety and immunogenicityInsulin None, if comparability 12 months (6 months can be concluded from pre-approval) the submitted PK and PD USAID Jordan Economic Development Program
  37. 37. Heparin case FDA recalled a shipment of heparin because of growth ofserratia marcescens in several unopened syringe of thisproduct .the bacteria serratia marcescens can lead to life –threatening injuries and /or death.In march 2008 ,major recalls of heparin due tocontamination of the raw heparin stock imported from chinaContaminated 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. 38. Thank You USAID Jordan Economic Development Program

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