Adoption of TOC in CV - Insatech€¦ · GE Analytical Instruments Seminar Info •Who am I?...

Confidential. Not to be copied, distributed, or reproduced without prior approval.

Adoption of TOC in CV

March 27, 2017

Confidential. Not to be copied, distributed, or reproduced without prior

approval.

Info

GE Analytical Instruments Seminar Info

• Who am I?

• Daniel Kellner-Steinmetz

• EMEA UPW Application

Specialist

• Based in Vienna

• Who are You?

• Areas?

• Know-How?

• Expectations?


approval.

Analytical Methods for Cleaning Validation

3


approval.

Detection of Residues

4

Then and Now

Existing HPLC Methods for final

product

Refined for lower level detection

Specific Method for CV

New Analytical Methods in

Pharmacopeia

Focus Shift to cleaning of the Whole Product

Allowed Use of Non-Specific

Methods for CV

1993

Where we

are Now


approval.

Goal of the Analysis

5

Demonstrate that the residues of your

products, active ingredients, detergents, and

microbial levels are adequately reduced and

controlled to acceptable levels by your

cleaning process.


approval.

Analytical Target

6

Product

Active Ingredient(s)

Specific

HPLC Mass Spectrometry

Gas ChromatographyAtomic Adsorption

ELISA

Non-Specific

Total Organic CarbonUV-Vis

pHConductivity

Excipients/ Formulation

Specific



Non-Specific


pHConductivity


approval.

Analytical Target

7

Detergent

Specific



Non-Specific


pHConductivity

Microbial

Live Microbes

Bioburden

Microbe Breakdown

Endotoxin


approval.

Analytical Method Considerations

8

Organic vs inorganic

Soluble in water or other

solvents

Is it stable in the cleaning

environment?

• Does it hydrolyze or oxidize at a pH?

• Does it degrade due to temperature

during cleaning?

Speed of Analysis (throughput)

Operational Cost

On-line Adaptability

Available Instrumentation

The goal should be to use the simplest technique that is appropriate and can

be justified


approval.

Most Common CV Methods

10

Test Attribute Method Type

HPLC, UV-Vis,

ELISA

Active Ingredient Only

Cleaning Agent Only

Specific

TOC

Conductivity

pH

Organics / Active Ingredient / Cleaning Agent

Ionic / Buffer / Cleaning agent / Inorganics /

Acid / Alkali

Acid / Alkali

Non-Specific

Bioburden

Endotoxin

Microbes

Breakdown of Microbes

Microbial


approval.

Most Common CV Methods

11

Test Attribute Method Type

HPLC, UV-Vis,

ELISA

Active Ingredient Only

Cleaning Agent Only

Specific

TOC

Conductivity

pH

Organics / Active Ingredient / Cleaning Agent

Ionic / Buffer / Cleaning agent / Inorganics /

Acid / Alkali

Acid / Alkali

Non-Specific

Bioburden

Endotoxin

Microbes

Breakdown of Microbes

Microbial


approval.

What is in the equipment after manufacturing or cleaning?

12

API

Specific method

Microbiological method

Contamination

in next batch


approval.

What is in the equipment after manufacturing or cleaning?

13

API

Excipients

Cleaning Agents

Degradants

Contamination

in next batch

Specific method

Non-specific method

Microbiological method


approval.

Specific versus Non-specific

• Specific tells you how well you are cleaning your target analyte only

• Non-specific tells you how well you are cleaning your whole product

and degradants

14

The goal should be to use the simplest technique that is

appropriate and can be justified


approval.

Sampling Methods for Cleaning Validation


approval.

What is required by regulations

FDA, EU, and PIC/S prefer direct sampling methods:

• Rinse water

• Soaking/ Sonication

• Swabs

• Visual Inspection

Justification is required for:

• Selected sampling methods

• Worst case swab sites


approval.

Rinse Sampling

17

Benefits:

• Large surface areas

• Limited access surfaces (pipes, filling needles, etc.)

Limitations:

• Solubility dependence

• Volumes

• Sample ports

• Potential for safety issues (hot water, solvents, etc.)


approval.

Swab/Wipe Sampling

18

Benefits:

• Not dependent on solubility alone

• Maximizes recovery from surface

Limitations:

• Technique must be qualified

• Swab material and extractables must be examined

• Swabbing may contaminate clean equipment


approval.

Visual Inspection

19

Benefits

• It’s easy

• Cost Effective

• 100% Inspection of equipment surface

Limitations

• Lack of specificity

• Subjective

• Dependent on lighting, angle of view, surface finish, etc.

Sample Modes for Cleaning Validation, Verification, and Monitoring Samples


approval.

Sampling Modes

21

• Off-line: Samples taken from a system, transported to a lab and

analysed in the lab.

• At-line: Sample is taken from a system and analysed in close

proximity to the sampling point or process stream.

• On-line: Sample is diverted from the manufacturing process, and

may be returned to the process stream.

• In-line: Sample is not removed from the process stream. Can be

invasive or non-invasive (e.g. non-destructive methods NIR or UV/Vis)


approval.

Example of Off-line (Lab) CVVM process flow

1. Take offline samples

2. Send samples to Quality (QC)

3. Samples wait for analysis

4. Analyse samples

5. Generate results / Printout results

6. Results transferred into LIMS or results book

7. Quality review, approve and release results

8. Operations/Tech Services/Validation print the results

9. Operations/Tech Services/Validation enter the results in CV report or EUR

10. Operations/Tech Services/Validation review and approve the report

11. Personnel release equipment for use

Holdup to release equipment

Delay

Duplication

22


approval.

Downside of Off-line CVVM

24

• Delay to equipment release (large downtime)• Taking samples to the lab

• Waiting on results

• Duplication of steps

• Large number of lab samples

• Risk of failure results from sample handling• OOS results can lead to additional delay and/or samples


approval.

At-line TOC: What it looks like on the floor

25

Production

Equipment

Step 1

TOC instrument to production equipment

Step 2

Analyze and generate result


approval.

What it looks like on the floor

26

Portable Analyzers for At-Line Testing

Production

Equipment

Step 1

TOC instrument to production equipment

Step 2

Analyze and generate result


approval.

At-line CVVM Advantages

27

Reduced failures due to sample handling

Removes delays due to QC workflow

Removes duplication of documentation/review/approval

Reduced turnaround time for equipment

Testing of rinse and swab samples

Easy to transfer out the lab method to the plant

Low capital cost for implementation

= More efficient manufacturing


approval.

At-line CVVM Implementation Drivers

28

Cleaning Validation, Verification and Monitoring

Product and equipment changeover

Troubleshoot a cleaning cycle

Testing of swab and rinse samples

Combined Conductivity and TOC sample

Portable: Allows you to move the instrument within a

suite or from one suite to another


approval.

At-line CVVM: Practical guide

29

Portable Analyzer

Same method as lab for mobility anywhere at anytime1. Start up the analyser

2. Run a check standard

3. Run your samples

4. Document appropriately

It is OK to disconnect the analyser and move it

It is OK to power off when not in use

Not integrated into a SCADA system


approval.

How do you implement At-line CV?

• Like-for-like analytical instrument qualification might be

possible

• Demonstration of method equivalency• Autosampler versus Grab mode

• Periodic verification standards

Ask your TOC Supplier about protocols, guidance and support to assist you.

30


approval.

Process Flow

March 27, 2017Presentation Title 31


approval.

Online TOC: Connection to vessel outlet to drain

32

Vessel

or

Parts washer

TOCiO

S Cond

1. Pre-rinse WFI

2. Hot WFI Rinse

3. Hot WFI Final rinse

NOTE: This is a basic

representation of the engineering

configuration and possible location

of the TOC analyser


approval.

Example connection for flow and communications

33


approval.

On-line TOC: Practical Guide

34

Online = 4 step release

1

Control system starts

instrument2

Sample

analysed 3

Results

reported to

control

system 4

Equipment

released

automatically

Same technology as lab method

Integrated into automation system

Clean to a pre-determined level

Show process capability


approval.

On-line Advantages

35

• Trending and Control (in real-time)

• Regulatory compliance (EP/CP/IP/JP/KP/USP)

• Continuous verification of the validated state

• Reduced sample variability (e.g. sampling error)

• Cleaning process optimization

• Removes delays due to QC workflow

• Faster release of equipment

= Reduced overall costs


approval.

On-line CVVM Implementation Drivers

36

Cleaning validation, verification and monitoring• Option 1: Single measurement

• Option 2: Measure TOC after conductivity is below limit (e.g. 40uS/cm)

• Option 3: Rinse down profile during rinse / process

Efficient way to prove the ability to clean

Product safety

Process optimization• Reducing rinse and cleaning cycle time

• Reducing environmental impact

• Cost saving, increasing production rate


approval.

On-line CVVM: Implementation

1. Engineering project for installation and re-qualification of altered

systems (e.g. piping and automation)

2. Like-for-like analytical instrument qualification may be possible

3. Demonstration of method equivalency• Autosampler versus Onlinesampler

4. Periodic verification standards

Ask your TOC Supplier about protocols, guidance and support to assist you.

37


approval.

Comparison of Sampling Modes for TOC

Advantages Disadvantages

Lab Standard Process

Low cost

Highly flexible

Ability to run swabs

Sample Handling Errors

Delayed equipment release

Duplication of review/approval

Samples queued with other QC

testing

At-Line Lower initial cost

Highly flexible

Instrument dedicated to cleaning

samples

Ability to run swabs

Sample handling (less than lab)

Data must be transferred

On-Line Total automation

Data integration

Rinse down profile

Process Control

Reduced Human Factors

Higher initial cost

Low flexibility

No swabs

38

39

Contact Information: Daniel Kellner-Steinmetz

EMEA Application Specialist

C +43664 2069 153

E daniel.kellner-

[email protected]

Adoption of TOC in CV - Insatech€¦ · GE Analytical Instruments Seminar Info •Who am I?...

Documents

Transcript of Adoption of TOC in CV - Insatech€¦ · GE Analytical Instruments Seminar Info •Who am I?...