Qualification and Validation Aspects of Single-use Technologies

Isabelle Uettwiller and Marie-Chrsitine Menier

CONFIDENCE® Validation ServiceSartorius Stedim Biotech S.A.

• Regulatory overview

• Validation approach | Risk analysis

• Interaction studies description

31/05/2011

Current Guidance with a ...

Focus on Containers:

• EC Guideline on Plastic Immediate Packaging Materials CPMP/QWP/4359/03 and EMEA/CVMP/205/04 (2005)

• FDA Guideline on Container Closure Systems for Packaging Human Drugs and Biologics (1999)

• ISO 15747 “Plastic Containers for I.V.”

• ICH Q8 Guideline Pharmaceutical Development – 2.4 Container Closure System

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Guideline on Plastic Immediate Packaging MaterialsEMEA/CVMP/205/04

� Issued by the European Medicines Agency in May 19, 2005

� Is applicable to storage of Active Substances or Drugs

� Comparable to the FDA CDER guideline: “Container

closure Systems for packaging Human drug and

biologics” issued in 1999

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Regulatory RequirementsFDA CDER 1999 « Container closure systems »

�Applicable to the primary packaging of drugs but but but but alsoalsoalsoalso to the containers for to the containers for to the containers for to the containers for bulkbulkbulkbulk drugdrugdrugdrugsubstances and substances and substances and substances and productsproductsproductsproducts....

�This regulation lists the required information by type of dosage form and route of administration: Inhalation aerosols and Injectable are of highest concerns

�A specific paragraph is dedicated to the bulk containers for

drug substances and drug final products.

�Drug Master Files applied to the Flexboy® and Flexel® bag ranges

have been submitted to the FDA

• Regulatory overview

• Validation approach | Risk analysis

• Interaction studies description

31/05/2011

Finding the right approach: Risk Assessment

� Identifies important parameters such as storage time, process T°, potential aggressive conditions....

� Helps to categorize validation requirements based on impact to product, process and equipment components

� Used to reduce the overall workload of validation

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Risk Analysis: Process parameters to be considered

• Location in process

• Specific processes with higher risk

• Nature of drug product or process fluid

• Compatibility of processing and packaging materials

• Contact temperature and time

• Volume / surface area ratio

• Pre-treatment steps

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Location in the process: Proximity to Final Product

� Location directly before final filling has direct risk to final product

� Direct contact with the Final bulk or the Active substances

� Upstream process steps may have a reduced risk

� Steps where contaminants can leave the process (e.g. diafiltration)

� Critical process parameters

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ia Prepa

ration

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Ferm

entation

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Specific applications or processes with higher risks

• Surface decontamination:

� Thawing step in a hypochlorite solution

� Vaporized Hydrogen Peroxide (VHP) decontamination

� Vaporisation of decontaminant on the container surfaces...

• Specific applications:

� Freezing and Thawing

� Dynamic mixing....

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Nature of Product | Solvent and Compatibility | Resistance of Material

Solution Composition :Solution Composition :Solution Composition :Solution Composition :

• Extreme pH

• Organic content like PEG or DMSO with high concentration

• Alcohols

• Surfactants like Tween, Triton etc.

• Lipids

Material :Material :Material :Material :

• Material should have passed relevant Pharmacopoeia tests, like USP <661> USP <87> or USP <88>

• Obtain manufacturer’s specifications and recommended operating parameters, such as pH, temperature

• General resistance of a material (stainless steel, glass, PTFE, PP, rubber, etc.)

• Compatibility in relation to the process fluid

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Contact Time | Contact Temperature

• Cold or ambient temperature processing conditions – several hours to up to one week (usually low risk)

• Storage at higher temperature than ambient could be evaluated depending on the storage time and the solution composition in contact

� High process temperature: 60°C / 24h can be applicable for filtration of viscous products (would be considered high risk)

� Solution or WFI introduction in bags at temperature up to 50°C

• Long storage time has to be evaluated depending on the solution formulation

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Surface Area | Volume Ratio

• For container application: the surface area per volume of solution cm²/mL is considered

• Smaller bag capacities usually presents a higher ratio of film surface/Volume and therefore a higher risk

• Containers partially filled presents a higher ratio of film surface per volume of solution

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Sterilization | Flushing

• In general sterilization tends to increase the potential to extract: Validation program performed on sterilized single use systems

� Radiation due to release of breakdown products from polymer materials

� Steam sterilization due to high temperature exposure

� Ethylene oxide due to residual ethylene oxide compounds

• Rinsing / flushing of equipment prior to use (if applicable) can reduce extractable substances entering the product

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Risk assessment: Exemple of Table of evaluation

• Regulatory overview

• Validation approach | Risk analysis

• Interaction studies description

31/05/2011

CONFIDENCE® Validation Services

CONFIDENCE® test Program:

� Chemical Compatibility Test

� Extractables | Leachables Test

� Mechanical Integrity Test

� Microbial Integrity Test: Bacteria Challenge Test

� Physico- Chemical Test USP<661>

� Particle Release Test

� Bacterial Endotoxin Test

� Bioburden TestProduct & Process SafetyEconomical aspects

RegulatoryRequirements

Process Validation

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Chemical compatibility | Resistance

Objective: To prove the mechanical resistance of Objective: To prove the mechanical resistance of Objective: To prove the mechanical resistance of Objective: To prove the mechanical resistance of container assemblies in contact with specific solutionscontainer assemblies in contact with specific solutionscontainer assemblies in contact with specific solutionscontainer assemblies in contact with specific solutions

According to ASTM D543-06 Method for Resistance of Plastic to Chemical Reagents

Tested conditions : Customer’s storage conditions (Temperature and time) and specific customer’s solutions

� Visual inspection (transparency, britleness…)

� Drop test

� Physical properties : Tensile strength (film, seals, connections) and or integrity

� Physico chemical properties : Infra red analysis on films, weight test

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Extractables - Leachables

ObjectivesObjectivesObjectivesObjectives

� Identification and quantification of potential molecules Identification and quantification of potential molecules Identification and quantification of potential molecules Identification and quantification of potential molecules migrating from the film material into the stored solutionmigrating from the film material into the stored solutionmigrating from the film material into the stored solutionmigrating from the film material into the stored solution

� Allows a Toxicological analysis in relation to the type of Allows a Toxicological analysis in relation to the type of Allows a Toxicological analysis in relation to the type of Allows a Toxicological analysis in relation to the type of extractable and the quantity of extractable quantified.extractable and the quantity of extractable quantified.extractable and the quantity of extractable quantified.extractable and the quantity of extractable quantified.

---- ICH standards and EP StandardsICH standards and EP StandardsICH standards and EP StandardsICH standards and EP Standards

---- Toxicological assessmentToxicological assessmentToxicological assessmentToxicological assessment

Polyethylenemolecule

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The most sensitive analytical methods

� Get accurate molecular identification (CAS number)

� Get low detection and quantification (ppb)

� Allow Identification and quantification of extractables

� Conclusion on Toxicological assessment

Two options: Process conditions or Scale down conditions

Analytical Methods

� pH

� Conductivity

� Total Organic Carbon

� Non volatile residue

� HPLC

� Gaz Chromatography-MS

� Liquid Chromatography-MS

� Metal ICP

Extractables – Leachables : Analytical Methods

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Mechanical Integrity testing

Post use integrity testing

• Pressure decay for Flexboy Bags according to the process conditions

• Pressure and immersion

• Red Ink penetration test on film sealing

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GoalGoalGoalGoal

• To demonstrate impermeability to microorganisms of Single Uses Systems

• ISO 15747 “Plastic container for IV injection

Microbial integrity test: Ingress testing

Rationale and samplingRationale and samplingRationale and samplingRationale and sampling

• Why Bacillus atropheus ? To meet the requirements of the ISO 15747

• Worst case with regards of the process application, in liquid phase with a very high concentration

• Representative configuration of Flexel® and Flexboy® Bags

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• Decision tree orients the bacterial Decision tree orients the bacterial Decision tree orients the bacterial Decision tree orients the bacterial challenge method challenge method challenge method challenge method

• Aerosol bacterial challenge for Aerosol bacterial challenge for Aerosol bacterial challenge for Aerosol bacterial challenge for tortuous path : tubing / connection tortuous path : tubing / connection tortuous path : tubing / connection tortuous path : tubing / connection assemblyassemblyassemblyassembly

• Liquid bacterial challenge for Liquid bacterial challenge for Liquid bacterial challenge for Liquid bacterial challenge for contiguous container : thermal seal, contiguous container : thermal seal, contiguous container : thermal seal, contiguous container : thermal seal, adhesive bondadhesive bondadhesive bondadhesive bond

Ingress testing on customer product design

Standard reference PDA Technical report N°27 : Pharmaceutical package Integrity

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Shipping test according to ASTM D4169-08

Standard practice for Performance Testing of Shipping Containers and Systems

• Applicable to shipment of filled Containers

• Provides a list of distribution cycles to be selecteddepending of the shipping conditions (truck, air, boat...stacking, handling)

• Provides different levels of criticity (I, II and III) depending of the shipment conditions whichdefines parameters such as height, weight, frequency of Vibration....

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Regulatory Risk | Increasing Validation Requirements

Vendor’s ValidationPackage

(Extractables GuideValidation Guide)

Upstream / Cell Culture / Downstream / Final filling

Commercial production

Phase 3

Clinical

Ph 1 & 2

Preclinical

Increa

sing r

equire

ments

Vendor‘s Validation Package

Plus Qualitative Leachables Test and Chemical Resistance Test

Vendor‘s Validation Package

Plus Qualitative Leachables Test and Chemical Resistance Test

Vendor‘s Validation Package

Plus Qualitative Leachables Test and Chemical Resistance Test Plus Quantitative Leachables Test

31/05/2011