Regulatory Pathway for Novel Vaccines - Quality requirements European Network on Viral Vaccine Processes 1st Workshop, 14-15 October 2010 Dr. Heidi Meyer Section Viral Vaccines

Agenda  Specific characteristics of vaccines  Risk minimization  Quality requirements for IMP

 Quality requirements throughout clinical development         

General considerations From viral clones to finished product Requirements for raw and starting materials Efficient process and product control Setting specifications adequately Appropriate tests and assays for product release Stability testing Virus safety aspects TSE compliance

Specific characteristics of vaccines  Prophylactic use to prevent infection or infectious disease or post exposure prophylaxis (PEP)  May be intended for use in entire population or  Intended for use in particularly vulnerable age and risk groups  Infants as of 6 weeks of life  The elderly  Individuals with underlying acute or chronic disease

 High expectations of target populations  Threat of infectious diseases not immediately recognizable (e.g. polio)  Many presumed risks of vaccination  Vaccines are expected to have virtually no side effects

 False, misleading or confusing information spread by anti vaccination campaigners and media (e.g. tumorogenicity potential of vaccines due to the use of specific cell lines)

Specific characteristics of vaccines  A very sensitive and publicly discussed topic (e.g. HPV, pandemic flu)  Very precise benefit-risk analyses required  Best possible risk minimization (e.g. adventitious agents, product or process related impurities, excipients, preservatives)  Stepwise definition of optimal use

 Specific goals of vaccination  First priority – individual benefit  Protection from infection or disease  Second priority – population effects  National (public health considerations)  Regional (harmonization of vaccination schedules)  Global (herd immunity, elimination of disease, eradication of pathogen)

Varity of viral vaccine production systems  Type of vaccine     

Inactivated vaccines (e.g. Influenza, Rabies, TBE, JEV, HAV, IPV) Live attenuated vaccines (e.g. MMRV, YFV, Flu, OPV, Vaccinia) Recombinant derived antigen vaccines (e.g. HBV, HPV) Live recombinant viral vectored vaccines (e.g. MVA, chimeric YFV) DNA vaccines

 Host system      

Embryonated eggs Primary cells Human, animal or insect cell lines Yeast E. coli Plants

Risk minimization during clinical evaluation of vaccines 

„*Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products“ applicable for vaccines?

FIM- principles

 In principle yes, if one or more of the following facts apply  Use in extremely vulnerable groups (e.g. newborns, pregnant women)  New antigens  New adjuvanting systems  New manufacturing process for known antigens  New method of administration of known antigens  New combination of known antigens  etc.  Flexible interpretation of „first in man (FIM)“- Guideline  Depends on product and concept  National scientific advice Nat Biotechnol. 2010 Sep;28(9):910-6

Quality requirements for Investigational Medicinal Products (IMP) throughout clinical development

Vaccine – Investigational Medicinal Products (IMP) – quality requirements  General requirements for all clinical trial phases  General EP Monograph 01/2008:0153 „Vaccines for human use“ applies as regards  Viral, bacterial, recombinant vector seed materials  Cell banks  Manufacturing

 Pivotal aim and minimum requirement:  Absence of adventitious agents and compliance to TSE regulations Virus Safety Evaluation of Biotechnological Investigational Medicinal Products; EMEA/CHMP/BWP/398498/05 (recombinant subunit vaccines)

Vaccine – Investigational Medicinal Products (IMP) – quality requirements Specific requirements  Cell substrate  EP monographs  CPMP/ICH guidelines Q5B and Q5D  WHO guidelines WHO guideline: Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks (replacement of TRS 878, Annex 1; expected to be approved in Q4/2010)

 Type of vaccine  EP monographs for specific vaccines  WHO Technical report series for specific vaccines

Vaccine – Investigational Medicinal Products (IMP) – quality requirements  Guideline on the Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials; EMA/CHMP/BWP/534898/2008  End of consultation period: 31st August, 2010

From viral clones to finished product  Clone selection and preparation of Master Virus Seed  History and Traceability of virus strains/vector constructs  Method and level of attenuation  Relevance to circulating wild type virus

 Working Virus Seed  Adventitious agent testing  Neutralizing antibodies against vaccine virus  EP test or PCR? (e.g. seasonal Flu vaccines)

 Neurovirulence  Neurovirulence test required for live attenuated vaccine (e.g. Measles)  Neuroinvasiveness (e.g. nasal administration)

 Genetic stability throughout all passage numbers

From viral clones to finished product  Cell substrates  Master Cell Stock  Working Cell Stock  Post Production Cells

Identity, viability and purity of cells must be ensured Absence of adventitious agents

 Are tumorigenic cell substrates acceptable?  In principles yes, however, some important points to consider  Type of vaccine (inactivated versus live attenuated)  Capacity of the process to remove viable cells, host cell proteins and nucleic acid

From viral clones to finished product  Inactivated viral vaccines  Unchanged serological properties of vaccine antigens (e.g. Influenza virus HA and NA)

 Live attenuated viral vaccines  Level of attenuation (e.g. oral polio vaccines)

 Recombinant viral vaccines  Genetic stability of the expression vector/construct throughout fermentation

 Live recombinant viral vaccines (e.g. MVA, YF vectors)  Guidance recently completed Quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines EMEA/CHMP/VWP/141697/2009

 DNA vaccines (e.g. prime – boost concepts)  Guidance under preparation

Requirements for raw and starting materials  Biological starting materials  Viruses, cells, vectors as discussed before

 Raw materials  All other substances used during fermentation, purification and formulation      

Highest available quality Apply same standards as for finished products How about reagents to produce raw materials? Sterilization, microfiltration before use Serum-free culture conditions preferred Reduce or avoid substances of animal or human origin

Efficient process and product control  Manufacturing processes and their control strategies are continuously being improved and optimized especially during early phases of clinical trials  Traceability of batches used in non-clinical and clinical trials  Full description of process improvements and adjustments of product control required  Depending on the consequences of the changes introduced and the stage of development a comparability exercise as described in ICH Q5E to may become necessary  Is there an anticipated potential safety risk for the patient due to the changes introduced  Are the batches intended for the use in clinical trials comparable to the batches investigated in non-clinical studies  Any changes to the formulation of the final product should be documented and justified with respect to their impact on quality, safety, clinical properties, dosing and stability of the finished product

Efficient process and product control 

Process Validation – a staggered approach  Validation of process and analytical procedures according to ICH-Guidelines (Q2, Q6B)  Phase I: describe suitability of process and procedures  Phase II: document suitability of process and procedures  Phase III: provide full validation data

 Critical process steps to be validated before entering into Phase I    

Product safety (adventitious agents) Virus inactivation (vaccine virus) Removal of toxic agents used in the manufacturing process (e.g. formaldehyde) Removal of host cell impurities (e.g. cellular DNA)

 Process and product must be sufficiently described for each clinical trial phase  Dynamics of pharmaceutical development are acknowledged  Comparability of clinical trial lots used in different phases of the clinical development program

 Product must be stable regardless of clinical trial phase

Efficient process and product control  Critical Process Parameters           

Product safety Fermentation Harvest Clarification Concentration/Purification Inactivation Vaccine specific processing steps Formulation Filling Lyophilization Packaging

Staggered approach during clinical development To be fully validated before Marketing Authorization (MA) is granted

Efficient process and product control  Critical Quality Attributes  Drug Substance (up to final bulk vaccine)      

Consistency of harvests (single and pooled) Viability (live attenuated) Completeness of inactivation (inactivated) Sterility Absence of mycoplasms Stability of intermediates

 Drug Product (from final bulk vaccine to finished product)      

Well controlled final formulation steps Efficient lyophylization process Completeness of adsorption Sterility Potency Stability  Cumulative age of components

To be fully validated for MA

Efficient process and product control  Analytical test procedures  Validation of analytical procedures during clinical development is an evolving process  In principle, analytical procedures described in Ph. Eur. or any national pharmacopoeia are considered validated  For phase I clinical trials  Suitability of the analytical method used should be confirmed  Acceptance limits and parameters for performing validation of the analytical methods should be presented in a tabulated form

 For phase II and III clinical trials  Suitability of the analytical method used should be demonstrated  Summary of the results of the validation should be provided  No full validation reports are expected

Efficient process and product control  Reference standards or materials  Use international or Ph. Eur standards, if available  Should be used as primary reference material to calibrate in-house reference materials

 Well characterized reference material is essential  to ensure consistency between different batches of the IMP  To allow comparability of the IMP used in all stages of the clinical development and the product to be marketed

 Information on the production and characterization of the reference material  Using state-of-the-art analytical methods

Setting specifications adequately  Right balance between too wide and too tight specifications  Too wide – process and product cannot reliably be controlled  Too tight – high risk of OOS results

 Dynamic approach  Specs can be tightened, widened or even graduated as experience with a given manufacturing process grows  Specs relevant for routine control of the process  Specs relevant for decision making steps whether or not to proceed to the next process step

 Specs need to be regularly reviewed since a process will change over time  Slightly altered equipment  Changes introduced into the process (variation procedures)

 Continuous statistical trend analysis (not non-statistical trending!) required for each individual specification

Appropriate tests and assays for product release  Potency  Tests and assays must always correlate with clinical safety and efficacy (in contrast to serology following vaccination)    

Immunogenicity or challenge assays in animals Titer (live attenuated viral vaccines) Immunogenicity assays (e.g. ELISA, SRD) Combination of in vitro and in vivo tests and assays

 Potential wide variance of in vitro and animal assays  Appropriate statistical models  Particularly crucial for stability studies

 All other release tests are more descriptive as regards consistency of production and usually less predictive as regards compliance with clinical performance

Efficient process and product control  Adjuvanting systems  Owing to the complexity of novel adjuvanting systems (e.g. MPL, MF59, AS03) same rules and principles apply for manufacturing as for the active substance(s), i.e. the vaccine antigens

 Complex excipients (e.g. HSA, rHA)  See above

Stability testing 

Suitable stability protocol covering the proposed storage period of the active substance and final vaccine product    



Accelerated design  

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Early developmental phase Help to understand the degradation profile of the product and may support extension of shelf life

Real time - real condition design  

  

Including information on specifications, analytical methods and test intervals Test intervals and conditions should follow ICH Q5C. Quality of the batches placed into stability program should be representative for clinical trial material used Containers and closure systems used to store the active substance or final vaccine product should be of the same type and material

Early and late developmental phase Long term stability studies to justify shelf life

In-use stability data for presentations intended for use after reconstitution, dilution or mixing For phase III a comprehensive understanding of the stability profile of the active substance is expected Process changes should be monitored by appropriate stability studies

Stability testing of vaccines Biologicals, Volume 37, November 2009 WHO guideline on stability evaluation of vaccines, 2006

Virus safety aspects  Different approach compared to other biologicals  Thorough testing of viral seeds and cells (starting materials)  Additional control thorough control cells (process control)

 Live attenuated vaccines  Process cannot be validated for virus partition or removal  Rely on principles laid down in the first bullet point  Safety records of live attenuated vaccines suggest that these measures are sufficiently robust to ensure virus safety

 Inactivated vaccines  Same requirements as regards starting materials  Process more robust to ensure virus safety, however, relevant process steps (e.g. inactivation, splitting, removal of impurities) have not specifically been validated for many established inactivated viral vaccines  Exception: Flu vaccines (avian leukosis virus, mycobacteria)

 For novel viral vaccines capacity of the production process to remove/inactivate viral contaminants must be demonstrated (e.g. Flu vaccines produced on novel cell substrates, HPV)

Virus safety aspects  Novel cell substrates, novel vaccines  Example given: Flu vaccines produced in new cell substrates (Vero, MDCK)  How to deal with seasonal updates?  Mandatory EP test to demonstrate viral safety of viral seeds (= seasonal updates) not possible due to time constraints

 PCR testing as a suitable alternative?  Sensitivity equivalent to EP test  Process validated for virus removal  Panel of viruses identified that may replicate under culture conditions  Seasonal update dependent on epidemiological situation  Risk based approach acceptable to authorities under these conditions

Virus safety aspects  Through history, only few examples available demonstrating that process controls to ensure absence of contaminating viral agents in vaccines have turned out to be insufficient  SV 40 and sCMV contamination of PMKCs (primary monkey kidney cells) used for production of polio vaccine  Transfer of both viruses into humans? SV40 genome occasionally found in human tumor tissue  Test in susceptible cell lines

 Insufficient inactivation of wild-type poliovirus strains used to produce inactivated polio vaccine (IPV)  “Cutter incident” – vaccine has caused poliomyelitis  Production method and test for completeness of inactivation improved

 PCV1/PCV2 contamination of Rotavirus vaccines (2010)

TSE compliance  Although there is no evidence that TSE agents has ever been transmitted by vaccines  Provide EDQM certificate for compliance with TSE regulations  Or, perform a risk analysis  In case history of starting material contains gaps

Useful links: www.pei.de www.ema.europa.eu www.ec.europa.eu/health/documents/eudralex/ www.who.int/biologicals/publications/trs/areas/en www.ich.org/

Questions?