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SME Biotech Consulting

The Evolution of Viral Clearance Evaluation Studies During Development of Biopharmaceutical Products

Barry Rosenblatt, Ph.D.


Phases of Development

Preclinical Proof of concept (POC) Toxicology/Safety

Phase I First in Man (milestone) Safety

Phase II Dosing Efficacy Safety


When is it done in development?


Phases of Development

Phase III Consistency

Efficacy Manufacturing Safety

Phase IV Safety Profile Indication expansion


Process Validation

Why perform process validation studies?

Direct testing may detect only known viruses

Direct testing may fail to detect variants of known viruses

Low concentrations of infectious virus may not be detected by direct testing


General Considerations

In the past, viral clearance guidance varied among the US, EU, and Japanese regulatory control agencies

ICH document now used by all (Sort-of…)

Viral clearance requirements become more stringent as product development progresses toward licensure

Case by case basis Clearance may vary with similar products Changes in process affect clearance


Study Design

Risk analysis Determine clearance objectives

Phase I Phase II Phase III

Select critical steps Scale-down process Virus selection Interpret results


Process ValidationViral Clearance Studies

How much should we do?

When should we do it?


Process Validation Phase I: Emphasis on Safety

More properly termed process evaluation

“What-if” experiments (“Worst Case”)

Assurance of clearance Viruses known or suspected to be present in the

starting materials- expected Viruses that model unknown contaminants-

optional (Required by EU)


Process Validation Phase II: Emphasis on Safety

Re-evaluation of Manufacturing process due to changes Cell line switch Optimization of DSP

Assurance of clearance Preparation for Pivotal Trials Viruses known or suspected to be present in

the starting materials- AND Viruses that model unknown contaminants


Viral Clearance Studies

How Much Should We Do?

Phase I/II(Depends on the Nature, Severity and Stage of the

Disease)



Serious or Immediately Life-threatening Conditions

If the purification scheme includes at least two orthogonal robust steps (low pH, heat, S/D, filtration), viral clearance studies may not be necessary (See new EU directive)

Serious But Not Life-threatening Conditions One virus (retrovirus) may be sufficient


Viral Clearance Studies Therapeutic Proteins “Generally, the process should be assessed for its ability to clear at least three different viruses with differing characteristics” (ICH, Viral Safety Evaluation of Biotech Products)

Consultation with CBER/CDER is strongly advised before viral clearance studies are performed


Process Validation

Phase III: Emphasis on Consistency of Safety Re-evaluation due to changes in manufacturing process True Process Validation

Robustness studies Exploration of manufacturing limits End of lifetime studies Cleaning studies (as appropriate)

Assurance of clearance Viruses known or suspected to be present in the

starting materials Multiple Viruses that model unknown

contaminants



How Much Should We Do? Phase III


Viral Clearance Studies Viral clearance studies should be duplicated

and the statistical variation within and between studies evaluated

Model viruses representing a wide range of biophysical and structural characteristics (Generally, at least 4 viruses are evaluated)

Revaluation of viral clearance Whenever significant changes in the

production or purification process are made, the effect of that change on viral clearance should be considered



Viral clearance studies should be performed as part of the overall process validation plan.

Considerations should be made with respect to the operational limits of the process Evaluation of cleaning procedures for re-used equipment (i.e. chromatography resins) should be incorporated in studies wherever appropriate.


Viral Clearance StudiesStudy Design

Design a scaled-down version of the process

Choose appropriate spiking viruses Select appropriate spiking steps and

sampling points Perform preliminary buffer/product

cytotoxicity and viral interference studies

Perform spiking experiments


Viral Clearance StudiesStudy Design

Determine virus reduction factors for each step (expressed as log clearance)

Sum reduction factors for all steps will give overall clearance factor for the whole process

Interpret results - be aware of study limitations


Viral Clearance StudiesVirus Selection

“Relevant” viruses and “model” viruses Include viruses with a range of physical and

chemical properties Examples:

Rodent Cells - XMuLV, Reo-3, Pseudorabies, MVM

Human Cells - XMuLV, Reo-3, Pseudorabies, SV40

Human Blood Products - HIV, HAV, BVDV, PPV, Pseudorabies


Scale-Down Purification Process

Validity of the scaled-down process must be demonstrated (representative of commercial-scale manufacturing

For chromatographic equipment Column bed-height linear flow-rate flow-rate-to-bed-volume ratio (contact time) buffer and gel types pH temperature concentration of protein


Validation of Assays

For Phase I/II clinical trials, the suitability of the analytical methods applied for viral testing should be demonstrated. A tabulated summary of the results of the validation, carried out according to ICH-methodology, should be provided (e.g. results of values found for specificity, linearity, range, accuracy, precision, quantification and detection limit, as appropriate). It is not necessary to provide a full validation report.


Validation of Assays

Viral tests performed in accordance with the European Pharmacopoeia are normally not (re-) validated by the company.

In addition to the information to be provided for Phase I/II trials, for Phase III studies a full validation report should be held available and should be submitted upon request.



Robust Inactivation and Removal Steps

pH ≤ 3.9 (Reported log virus inactivation = 3-4)

Heat (Reported log virus inactivation = 4) Solvent/detergent (Reported log virus

inactivation = 5) Filtration (15-40 nm) (Reported log virus

removal = 4-8)


Conclusion

Viral Clearance should be treated as an ongoing program of studies that will vary in scope with Phase of development

Early phase studies emphasize safety and are performed as evaluation studies


Conclusion

Late phase studies emphasize consistency (robustness) of the safety and should be treated as part of the overall process validation plan


Regulations and Guidelines Guidance for Industry: For the Submission of

CMC Information for a Therapeutic r-DNA-Derived Product or a mAb Product for In Vivo Use, FDA/CBER/CDER.1996

9 CFR - Animal and Animal Products, Part 113.53, 2002. Requirements for ingredients of animal origin used for production of biologics

Guidance for Industry: Monoclonal Antibodies Used as Reagents in Drug Manufacturing, FDA/CBER/2001


Regulations and Guidelines

ICH Harmonised Tripartite Guideline: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products, 1997

Guidance for Industry: Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin, 1997


Regulations and Guidelines

Note for Guidance on Virus Validation Studies CPMP/BWP/268/95

Guideline On Virus Safety Evaluation Of Biotechnological Investigational Medicinal Products: EMEA/CHMP/BWP/398498/2005-corr

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