viral risk in biotechnology products -...

Lara Chris CaminitiUniversità di Milano, 29/11/17

Prevention and detection of Viral contamination

VIRAL RISK IN BIOTECHNOLOGY PRODUCTS

Content01 Sourc e and r isk of V ira l

contam i n a t i o n

02 Regu la t o r y Requ i r em e n t s and Gu idan c e

03Regu la t o r y aspe c t s

SOURCE AND RISK OF VIRAL CONTAMINATION

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Source of adventiatious Agent Contamination

MVM VIRUS

Enterovirus


Advantitious Agents Medical products during their development, and prior to being marketed, must

meet strict criteria of Quality, Safety and Efficacy

Safety consideration are

associated with contaminats in biological products including the following agents:

Bacteria

Fungi

Mycoplasma

Viruses

Trasmissible spongiform encephalopathies (TSE)


Differences between QC control in Chemical and in Biotech process

Chemical Biotech❖Quality control on raw materials: • Car Fisher (API)• Microbiological quality control

❖Quality control performed during a production run:• Microbiological quality control• Water , environmental, operator and surface• Compounding (pH, Bioburden, Sterility)• Integrity of the menbrane filters

❖ Quality control on finished product • Microbiological quality control (Bioburden,

Sterility)• HPLC quantification test• AQL visual inspection• Bacterial Endotoxins - LAL (Limulus Amoebocyte

Lysate Assay)• Visual inspection• Chemical Identity HPLC

❖Quality control on raw materials: •Culture media (TSE)•Cell bank characterization and stability

❖Quality control performed during a production run:•Microbiological quality control•Contaminant control (Virus, Mycoplasma,)•Compounding (pH, Bioburden, Sterility)•Integrity of the menbrane filters•Cell count•Cell viability•DS content – HPLC

❖ Quality control on finished product Determine the biological activity (Potency) Bacterial Endotoxins - LAL (Limulus Amoebocyte Lysate Assay)Visual inspectionChemical Identity HPLCProtein Content

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Biotechnology drugs

QC data are used to improve the process

Chemical drugs

QC activities are part of process. These activities tends not change

Quality control

Aim of the CQ


Three barriers preventing the transmission of pathogens

Sourcing

Selecting and Testing of Starting/Raw Material

(e.g. Cell line, culture media, sera, DS, etc)

Characterization &Testing the product intermediates at appropriate step

(e.g. of cell banks and bulk harvests)

Validation of production process for virus inactivation and removal(e.g Low pH inactivation, Cromatography, Nanofiltration)

MANUFACTURING PROCESS

REGULATORY REQUIREMENTS AND GUIDANCE


Regulatory Requirements and Guidance


Pharmaceutical Research and development process vs Quality Standards

In the pharmaceutical field there are rules regulating the whole drug route from the research to the marketing of the drug


when it is needed to apply the GMP into the biotech process?

EudraLex Volume 4, parte II “ Basic requirements for active substances used as starting materials”.

GMP



EU: 2003/94/EC “Laying down principles and guidelines of GMP in respect of medicinal products for human use and investigational medicinal products for humane use”

directive GMP 2017/1572 as regards the principles and guidelines of good manufacturing practice for medicinal products for human use (entry into force 01/04/2018)

Regulation 2017/1569 specifying principles of and guidelines for GMP for investigational medicinal products for human use and arrangements for inspections( entry into force 2019, may continue to apply national D.L. 219/2006)

Eudralex “EU GMP Guide”

US FDA: 21 CFR part 210 and 211

European and US Pharmacopoeia

D. L. n. 219/2006 Attuazione direttiva 2001/83/CE e direttiva 2003/94/CE.



ICH Q2 R1 - “Validation of analytical procedures: text and methodology”

ICH Q5A - “viral safety evaluation of biotechnology products derived from cell lines of human or animal origin”

ICH Q5B - “quality of biotechnology products: analysis of the expression construct in cells used for production of r-DNA derived protein products”

ICH Q5D -“derivation and characterisation of cell substrates used for production of biotechnological/biological products”

ICH Q7 - “good manufacturing practice guide for active pharmaceutical ingredients”

“viral safety evaluation

of biotechnology

products derived from

cell lines of human or

animal origin”

ICH Q5A



ICH Q5A (R1) Viral absence

Suggests approach for:

- EVALUATION OF THE RISK OF VIRAL CONTAMINATION;

- THE REMOVAL OF VIRUS FROM PRODUCT

thus contributing to the PRODUCTION OF SAFE BIOTECHNOLOGY

PRODUCTS derived from animal or human cell lines


ICH Q5A (R1) Viral absenceHow?a) testing cell lines and raw materials to identify which, if any, viral

contaminants are present;

b) establishment of an appropriate program of testing for adventitious

viruses in unprocessed bulk;

c) assessing the capacity of the production processes to clear infectious viruses;

d) testing the product at appropriate steps of production for absence of

contaminating infectious viruses;

e) design of viral clearance studies using different methods of virus inactivation or removal in the same production process in order to achieve

maximum viral clearance.

no single approach will necessarily establish the safety of a product.


Biological Testing through Bioprocess

Bulk

Harvest

Purified

Product

MCB

Bioreactor

WCB

RAW MATERIALS

BATCH

RELEASE

ExCB

Downstream Process

CELL BANK VALIDATION

IN PROCESS CONTROL

VIRAL CLEARANCEBioassay

Viral Safety

Viral Safety

Regulatory Authorities require Viral Safety monitoring on Cell Banks and on Bulk Harvests (ICH Q5A (R1) Guideline)

http://www.brothers.co.in/images/aboputus.jpg


Viral Clearance: PRINCIPLES

Virus Clearance Studies aim is to

demonstrate the capability of a

downstream process to remove /

inactivate potential viruses

(ICH Q5A)


Viral Clearance: PRINCIPLESDownstream Process Manufacturing Scale


Viral contamination in Biotech Industry

Timeline of the major contaminations events

Quality of biotechnological products: analysis of the expression construct in cells used for production of r-DNA derived protein products

ICH Q5B



ICH Q5BAnalysis of the expression construct (EC)

The purpose of analysing the expression construct is to establish that the

correct coding sequence of the product has been incorporated into the host cell

and is mantained during culture to the end of production.

Genetic sequence of recombinant

proteins

Mutation that could alter the properties of the protein

Potential adverse

consequences to patients


ICH Q5BAnalysis of the expression construct (EC)

Characterization:

The cell line history and production of the cell banks should be described in detail,

including:

- methods and reagents used during culture,

- in-vitro cell age,

- storage conditions.

Master cell bank and working cell bank should be carachterised for phenotypic

and genotypic markers

Cell substrates

ICH Q5D



ICH Q5DCell substrates

The properties of the cell substrate and events linked to the cell substrate can affect resultant product quality and safety.

Must be described:

• Origin, source and history of cells Generation of the cell substrate;

• Cell banking system and procedures (MCB, WCB);

• Characterisation and testing of cell banks ;

• Tests, on cells line, to confirm:

o identity,

o purity,

o suitability or stability


ICH Q5DViral safety


Viral Safety Testing: Current situation

PCR(e.g. MVM, Vesivirus, etc..)

In vitro/ In vivo


Next Generation Sequencing for biosafety quality control

NGS BIOSAFETY to mitigate the business risk


Next Generation Sequencing for biosafety quality control

ANY CONTAMINANT:

1. detection IN ONE RUN minimizes the risk to have large scale extensive

facility contamination

2. can be identified or, if not yet worldwide discovered, correlated to the

existing species

REGULATORY ASPECTS


Regulatory aspects

The process and the quality control tests are registered in the

dossier.

Changes can not be implemented before the evaluation of the change

impact on the product and the comunication to the heath authorities.

Quality Systems management according to regulatory requirements

is very complex


Regulatory aspectsMinimum requirements for GMP

o Personnel (Resp. della Produzione, Persona/e Qualificata/e, Resp. QC)

o Change control system

o Deviation system (by Procedure/Instruction)

o Documentation system (Procedure, Record, Report)

o Quality Control system

o Technology transfer system

o Validation system (Process, Method, Systems, plants)

o Self Audit

o Corrective Actions-Preventative Actions system

o Personnel system (responsibilities, org chart)

o Training system (courses, training file)

o Periodic review (of Product/Process and of quality system management)


Thank:

• Sofia Cerioni

Flavio Peroglio

viral risk in biotechnology products -...

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