ISPE NORDIC COP CLEAN UTILITIES COPENHAGEN, DENMARK ...€¦ · ISPE Baseline Guideline – Vol. 4...

ISPE NORDIC COP CLEAN UTILITIESSEPTEMBER 6 & 7, 2016COPENHAGEN, DENMARKTUUSULA, FINLANDPablo MorenoProcess Control & Validation [email protected]

Jack Egelund MadsenDirector, Business [email protected] BioPharma Product Testing Denmark

DETECTING ANDMEASURING ROUGE INPHARMACEUTICALWATER

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Eurofins BioPharma Product Testing Capabilities§ Founded in 1987

§ IPO in 1997 in Paris at EUR 1.83 per share

§ Network of over 235 laboratories in 39 countries

§ Over 150,000 reliable analytical methods

§ Over 23,000 employees

Key figures 2015 2010-2015 CAGR

Revenues EUR 1.95bn 23%

Food

Environment Pharmaceuticals

Clinical

Eurofins provides testingservices in four main areas

that have a strong impact onhuman health:

“Recent trends in global food production, processing,distribution and preparation are creating an increasingdemand for food safety research in order to ensure asafer global food supply.” World Health Organisation

Mid-term (2020) EUR 4bn revenues

Eurofins Objectives

FY 2016 >EUR 2.5bn Revenues


Eurofins BioPharma Services

Genomics DiscoveryPharmacology

Pre-clinical/Early

Development

Clinical(Central

Laboratory/Bioanalytical)

BioPharmaProductsTesting

Spanning the Entire Drug Development Cycle

SequencingOligonucleotides

PharmacogenomicsTranscriptomics

GenotypingSNP-analysis

PharmacologyBioanalytical analysis

Translationalmedicine

Phase I studies

BiomarkersBioanalysis

ImmunogenicityProteomics

Microbiological andAnti-infective analysis

BioavailabilityBioequivalence

Pharmaceuticals,biologics, medical

device: safety,characterization,quality control,

Process developmentHygiene Monitoring

Packaging

High-throughput-screeningMolecular-

pharmacologycell-based assaysin vitro screeningin vitro profilingin vivo safety

in vivo efficacy

SpecialtyClinical

Diagnostics

CardiovascularDiseases

ImmunodiagnosticsInfectious DiseasesSpecific, fast-TAT

testing for transplantpatients

PhasesI - III

Phase IV,Surveillance, Quality Control

Basic Research, Discovery,Combinatorial,

Biological Product Libraries, etc

Pharmacology, ExploratoryToxicology, PK, Metabolism, etc


- Method Development & Validation- Facility & Process Validation- Product Release & Stability Testing

Small Molecules

- Raw Materials- Residuals/Impurities- Comparator ProductTesting

- Extractables & Leachables- Aerosol Product Testing

- Sterile Products Testing(isolator technology)

- Non-sterile products- Endotoxin- Environmental Monitoring- Organism Identification

Large Molecules

- Cell Bank Manufacturing & Storage- Cell Bank Characterization- Viral Clearance- Biochemistry Protein Characterization- Residual Impurity Testing- Molecular & Cell Biology (PCR)

• Fee-for-Service• FTEs (full time employees) - working exclusively for one client• PSS (Professional Scientific Services) - Client’s facility, equipment, procedures, and quality systemsNote: Largest Clients Use Multiple Tiers

Our Global Capabilities in GMP Testing


Outsourcing & Insourcing LocationsThe Largest Network of Harmonized Bio/Pharmaceutical GMP Product TestingLaboratories Worldwide

§ 13 Countries§ 24 Laboratory Locations§ > 65,000 m2 / 700,000 ft2

§ > 60 PSS sites§ > 3,000 Employees


Harmonization between Eurofins laboratories


Profile EBPT Denmark

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·Site is GMP approved by Danish authorities and regularly audited

·Site is registered in FDA database and regularly audited by FDA

·All equipment is qualified in GMP environment

·All software is US FDA part 11 compliant and qualified

·Audit trailed database to warrant historical re-calculations

·Broad coverage of sample prep techniques & analytical instruments

·Very experienced staff

·Super low level detection (ppt), enabled by high pressure room

·Dual site strategy enables backup and identical testing in Europe & USA

Metal Competence Center (Europe) - Uniqueness

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Key Offering – Rouge package

LOGISTICAL SOLUTIONS AND CENTEALISED TESTING AS A PACKAGED SOLUTION

To ensure fast and easy handling as well as stability of the samples Eurofins BiopharmaProduct Testing´s Metal Competence Centre can offer the following solution incollaboration with TNT:

• Pre-shipped sample containers and sample vials from Eurofins and a local TNT contactnumber so all that is needed is packing samples and call for the pickup

• Shipment time in 1-2 days (Europe) & 2-4 days (worldwide)

• TAT time for the analysis 5 working days


Detecting and measuring rouge in Pharmaceutical WaterOverview

Connecting Pharmaceutical Knowledge ispe.org

ISPE Baseline Guideline – Vol. 4 – Water & Steam Systems (2011), Chapter 10:

• Even though neither USP nor EP address the topic, potential catalytic impact on products /API´s could have serious patient impact.

• Concern should be focused on drug products, rather than its repercussions on equipmentprotection.

ICH Q3D Framework:

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Why rouge might be critical for patient safety?


Classification in 3 groups:

• Class I – Migratory Rouge

• Class II – In-Situ Oxidation of Non-Passive surfaces

• Class III – Black Oxide Produced by Hot-Oxidation

Chemical composition:

• predominant iron oxides and hydroxides

• low proportion of chromium oxide and very little nickel oxide

At least 5 known mechanisms about rouge formation

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Rouge composition, body of knowledge 2015


CO2 and Temperature

Others:

• O2

• N2

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Influencing variables , body of knowledge 2015

http://www.google.dk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwig14iJmfbOAhUJiRoKHZvgC6AQjRwIBw&url=http://www.seafriends.org.nz/issues/global/acid.htm&bvm=bv.131783435,d.ZGg&psig=AFQjCNF6HgTFhPUNiK2jIm5hYKIOSiEhdA&ust=1473095097998781


ISPE Baseline Guideline – Vol. 4 – Water & Steam Systems (2011), Chapter 10

• Process Fluid Analyses for the Identification of Mobile Constituents (table 10.2)

• Ultra Trace Inorganic Analysis (Inductively coupled plasma mass spectrometry from here on ICP/MS)

• Standard Particulate Analysis (via Light Obscuration), USP <788>

• Ultra Trace Inorganic Analysis (by SEM/EDX)

• Fourier Transform Infrared Spectroscopy (FTIR)

* emerging area of technology, improved techniques may be available

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Rouge detection methods mobile constituents


Rouge detection methods Solid Surface Analyses

ISPE Baseline Guideline – Vol. 4 – Water & Steam Systems (2011), Chapter 10

• Solid Surface Analyses for the identification of surface layer composition (table 10.3 *)

• Microscopic and Human Visual Analysis

• Scanning Auger Microanalysis (SAM), or (Auger)

• Small Spot Electron Spectroscopy for Chemical Analysis (ESCA) or X-ray Photoelectron Spectroscopy (XPS)

• Electrochemical Impedance Spectrometry

• Reflection Grade Elipsometry

* emerging area of technology, improved techniques may be available


ICP-MS is a type of mass spectrometry which is capable of detecting metals and several non-metals.

This is achieved by ionizing the sample with inductively coupled plasma and then using a massspectrometer to separate and quantify those ions.

Everything reaching the detector, obstacles:

• Sample introduction system

• Plasma

• Vacuum interface

• Quadrupole

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ICP-MS, what is measured?


Everything reaching the detector!

• Metals in water e.g. oxides/hydroxides

• Metal ions in the water

• Metals in undissolved molecules < 5µm

• Metals in nanoparticles

What will NOT reach the detector?

• Particles ≥ 10 - 20 µm

• Metals embedded in large molecules

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ICP-MS, What is measured?


The original scope of the analytical method wasto include as many elements as feasible.

Focus is mainly on the ICH Q3D elements.

BOLD MARKED ELEMENTS ARE TYPICALROUGE TESING PARAMETERS

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ICP-MS, the validated analytical methodElement(Q3D class)

LOQ(µg/l)

Upper range(µg/l)

Li (3) 0.5 50Be 0.8 50Mg 1 50Al 3 50V (2A) 0.4 50Cr (3) 0.5 50Mn 0.4 50Fe 1 50Co 1 50Ni (2A) 0.2 50Cu (3) 5 50Zn 1 50As 0.2 50Se (2B) 0.4 50Rb 0.3 50Mo (3) 0.8 50Ru (2B) 0.2 50Rh (2B) 0.07 50Pd (2B) 0.1 50Cd (1) 0.4 50Sn (3) 0.2 50Sb (3) 0.2 50Ba (3) 0.4 50Ir (2B) 0.1 20Pt (2B) 0.1 50Tl (2B) 0.1 50Pb (1) 0.08 20


Validation of transport and storage scenarios

Scope:

Test of stability of metal ions in water samples stored at conditions between -18ºC and +40 ºC for up to 4 weeks

Storage conditions and timeframe were selected to illustrate different transportscenarios

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ICP-MS, sample stability and transport


• Water samples can be considered stable for at least 4 weeks when stored at

+5±3 °C

+20±5 °C

• Water samples can be considered stable for at least 3 weeks when stored at:

-18±5 °C

+40±5 °C

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ICP-MS, sample stability conclusions


REMEMBER: we are talking about trace elements à avoid false positive !

Sampling:

Use same precautions for sampling of water for metal analysis as for sampling for TOC analysis –e.g. use powder free gloves, do not sterilize valve, etc.

Containers:

Use ultra low trace element containers… validated !

Sample volume: ≥ 12 ml

Leave enough headspace in the vial for the water to expand if there is a risk of freezing duringtransportation

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ICP-MS analytical criticalities


ICP-MS analytical criticalities

REMEMBER: we are talking about trace elements à avoid false positive !

Testing facility:

Only work with validated/verified methods.

Sample preparation in clean areas free of particles (dust is known to release several elements toweak acidic solutions)… don´t forget acid resistant ventilation system !

Metal free acids for sample preparation AND metal free water for preparation of calibration standards(to go down in limits of detection / quantification).

Personnel specially trained for working in clean environment and capable to operate very complexand sensitive instruments like ICP-MS.


1) Baseline testing to establish control limits

2) Trend analysis

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Strategy to keep under control (discussion)

ISPE NORDIC COP CLEAN UTILITIES COPENHAGEN, DENMARK ...€¦ · ISPE Baseline Guideline – Vol. 4...

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