regulatory pathway for novel vaccines · quality requirements throughout clinical development...
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Regulatory Pathway for Novel Vaccines- Quality requirements -
European Network on Viral Vaccine Processes1st Workshop, 14-15 October 2010
Dr. Heidi Meyer Section Viral Vaccines
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
Agenda
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)
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)
Specific characteristics of vaccines
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?
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
FIM-
principles
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
Type of vaccine EP monographs for specific vaccines WHO Technical report series for specific vaccines
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)
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
Cell substrates Master Cell Stock Working Cell Stock Post Production Cells
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
Identity, viability and purity of cells must be ensured Absence of adventitious agents
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
DNA vaccines (e.g. prime – boost concepts) Guidance under preparation
Quality, non-clinical and clinical aspects of live recombinant viral vectored vaccinesEMEA/CHMP/VWP/141697/2009
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
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
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 duringclinical 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 befully
validatedfor 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 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 Accelerated design
Early developmental phase Help to understand the degradation profile of the product and may support extension of shelf life
Real time - real condition design 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 vaccinesBiologicals, Volume 37, November 2009WHO 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.dewww.ema.europa.euwww.ec.europa.eu/health/documents/eudralex/www.who.int/biologicals/publications/trs/areas/enwww.ich.org/
Questions?