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?