Brought

to you by Sponsored by

Increase Uptime of Manufacturing Equipment

by Using TOC for Cleaning Validation

February 22, 2017

Jenny Watson
Global Pharmaceutical Applications Manager
GE Analytical Instruments

Jenny Watson is the Global Pharmaceutical Applications Manager for GEs

Analytical Instruments division. She has 20 years of validation experience in
the pharmaceutical and biopharmaceutical industry with a focus on cleaning
validation. Most recently she was at Amgen where she served as the site
program owner for cleaning validation and a commercial product stability
representative. Jenny holds a Bachelor of Science in Chemical Engineering.
Agenda

TOC and Cleaning Validation

Implementation/ Conversion
Method Development
Method Validation
Cleaning Limits
Return on Investment

3
TOC and Cleaning Validation

4
Cleaning Validation

The purpose of cleaning validation is to establish

documented evidence with a high degree of
assurance that the cleaning process will
consistently yield results that meet
predetermined specifications and quality
characteristics.

5
History of Regulations in US

1938 The Federal Food, Drug, and Cosmetic Act was passed
after a legally marketed toxic elixir killed 107 people, including
many children.
1962 The Kefauver-Harris Amendments were passed, which
were inspired by the thalidomide tragedy in Europe (and the
FDA's vigilance that prevented the drug's marketing in the
United States)
1988 recall of a finished drug product, Cholestyramine Resin
USP

6
Since then..

1988 recall of a finished drug

product, Cholestyramine Resin USP

Guide to Inspections Validation of

Cleaning Processes (1993)

EMEA Annex 15 & PIC/S Annex 15

(2015)

7
 Detection of Residues
Then and Now

Existing HPLC
Refined for lower Specific Method
1993 Methods for final
level detection for CV
product

New Analytical Focus Shift to Allowed Use of

Where we
Methods in cleaning of the Non-Specific
are Now
Pharmacopeia Whole Product Methods for CV

8
Analytical Method Considerations

Organic vs inorganic Speed of Analysis (throughput)

Soluble in water or other Operational Cost
solvents
On-line Adaptability
Is it stable in the cleaning
environment? Available Instrumentation

Does it hydrolyze or oxidize at a pH?

Does it degrade due to temperature

during cleaning?

The goal should be to use the simplest technique that is appropriate and can
be justified
9
 Analytical Method Choices
Analytical
Specific Methods Non-Specific Methods
Techniques

HPLC TLC IC CE GC TOC UV/Vis pH Conductivity

Gravimetric
AA ICP XRF Analysis

IR (MIR, NIR, Probe) Organoleptic (visual, smell)

Titrations
MS IMS
Light Microscopy; SEM
ELISA
Microbial Test Methods (Most Compendial)

Endotoxin Biofilm
Bioburden

10
What testing is performed?

Method Type Attribute Test

Specific Active Ingredient Only HPLC, ELISA, Mass Spectrometry,

Cleaning Agent Only Atomic Adsorption, Gas
Chromatography, etc.
Non-Specific Organics / Active Ingredient / Cleaning TOC
Agent

Ionic / Buffer / Cleaning agent / Conductivity, UV-Vis

Inorganics / Acid / Alkali

Acid / Alkali pH
Microbial Microbes Bioburden

Breakdown of Microbes Endotoxin

11
What is in the equipment after manufacturing
or cleaning?

API

Contamination
in next batch

Specific method

Microbiological method

12
What is in the equipment after manufacturing
or cleaning?

API
Excipients
Contamination
Cleaning Agents
in next batch
Degradants

Specific method

Non-specific method

Microbiological method

13
Why switch from HPLC to TOC?

HPLC methods TOC methods

Costly to develop
Costly to maintain
Time consuming to execute
Difficult to streamline
Simplified Method Development
Lower Cost of Maintenance
Faster Analysis
Streamlined Equipment Release
Capture a Complete Picture

Using TOC Improves Process Understanding and

Efficiency
14
TOC vs HPLC

HPLC TOC
Inst. Qualification Similar approach
Method validation Similar approach
Sampling Similar approach
Recovery study Similar approach
Limit Calculations Similar approach
CV Protocol & Report Similar approach
Sample preparation Time consuming Run Neat
Analytical method Complex Simple
Analysis Time 10-30 min <12 min
Proof of cleaning API only All compounds
Overall risk Medium Low
15
Method Development

HPLC TOC
1. Examine and identify your 1. Run a sample neat in auto-
analyte(s) and matrix in terms of reagent mode to determine
hydrophobicity, polarity & optimal acid and oxidizer
ionization (pKa & pH). settings
2. If needed adjust sample
2. Column choice is based on a preparation
retention mechanism that will
separate an analyte given the
unique character of analyte and
sample matrix.
3. Select a mobile phase that will
compliment column selection.
4. Optimize LC parameters
Repeat this for every analyte Broad grouping possible
16
Common Cleaning Validation Reality

Preset
Validation Change
Cleaning
(3 runs) Control
Procedure

Very little understanding of cleaning chemistry

Cleaning is not a process
Sometimes more work is done than needed

17
The Shift in Thinking

Cleaning
Validation is In US: Guide to Inspections
a one time Validation of Cleaning
event Processes (1993)

Cleaning 2011 US Process Validation

Recognized Guide & 2014 EU Guideline
as a Process on process validation

2015 Europe & PIC/S Annex 15

refers to cleaning as a
Lifecyle process
Approach

18
Cleaning Validation Program Expectations
Cleaning
Process
Stage 1 Development/
Evaluation Stage 2
Process Design
Process Verification

Change
Cleaning
Management/
Validation or
Continuous
Verification
Improvement

Cleaning
Monitoring

Stage 3
Continuous Process Verification
19
Types of Cleaning Studies

Cleaning Cleaning Cleaning
Validation Verification Monitoring
Frequency 1 time 1 time Every product cleaning

Duration 3 runs or more 1 run Ongoing

Type of Commercial & Commercial & Commercial &

Product Phase 3 Clinical Phase 1 or 2 Clinical Phase 3 Clinical

Drivers New product or major change Minor change to product, Required by global regulatory
to existing product, equipment, or cleaning guidance (EU Annex 15, PIC/S,
equipment, or cleaning process ICH)
process Many small batches of Assurance of consistent
clinical material cleaning

20
Testing for Cleaning Monitoring

Method Type Attribute Test

Specific Active Ingredient Only HPLC, ELISA, Mass Spectrometry,

Atomic Adsorption, Gas
Chromatography, etc.
Non-Specific Organics / Active Ingredient / Cleaning TOC
Agent

Ionic / Buffer / Cleaning agent / Conductivity, UV-Vis

Inorganics / Acid / Alkali

Acid / Alkali pH
Microbial Microbes Bioburden

Breakdown of Microbes Endotoxin

21
 Equipment Cleaning and Usage

Production

Production

Production
Production
Monitoring
Cleaning & Cleaning & Cleaning &
with
Waiting for Waiting for Waiting for
specific
Release Release Release
methods

Monitoring
with TOC

Monitoring
with
At-line or
On-line
TOC

22
At-line TOC: What it looks like on the floor
Step 1
TOC instrument to production equipment
Production
Equipment

Step 2
Analyze and generate result

23
Online TOC: Connection to vessel outlet to
drain
1. Pre-rinse WFI Vessel
or
2. Hot WFI Rinse Parts washer
3. Hot WFI Final rinse

iO
TOC S
Cond
NOTE: This is a basic
representation of the engineering
configuration and possible location
of the TOC analyser

24
Example connection for flow and
communications

25
On-line TOC: Practical Guide

1
Same technology as lab method
Control
system starts Integrated into automation system
instrument
2
Sample
analysed 3
Results
reported to
control
Clean to a pre-determined level 4
system
Equipment
Show process capability
released
automatically
Online = 4 step release
26
Implementation

27
Conversion from HPLC to TOC

The Process

Instrument Method Swab & Rinse

Method
Qualification Development Recovery
Validation
IQ/OQ/PQ & Feasibility Study

SOP and Cleaning Validation Program Updates

28
Variables of a Sievers TOC Method

Acid Flow Oxidizer

Rate Flow Rate

Sample
Preparation
29
Method Development & Feasibility

Why?
To assure and demonstrate that products can be recovered with
TOC
How?
Prepare a stock solution (check for particulates)
Dilute it to multiple concentrations
Run samples anticipated to be above 1 ppm C in Autoreagent
mode
30
Method Development & Feasibility

If linearity is achieved, recovery can be calculated for

each of the concentrations and the recovery can be
determined as the average across the range of solutions.
Or
Triplicate prep of concentration of
product at the cleaning limit

100

31
Method Development & Feasibility
What if the recovery is non-linear?

Yes: run sample (goal >80% recovery)

Stock is No: Heat and stir
particle free?

Yes: run sample (goal >80% recovery)

Solution is No: Sonicate
particle free?

Yes: run sample (goal >80% recovery)

Solution is No: Prepare fresh stock and titrate with phosphoric acid to between 0.5 and 2.0
particle free?

Yes: run sample (goal >80% recovery)

Solution is No: Need another method
particle free?

32
Method Development Tips

Make sure the glassware is clean and rinsed with low

TOC water
Perform feasibility testing with moderate GMP controls
to enable use of the data generated
Feasibility performed for every product or compound
Small molecule companies take advantage of grouping for
feasibility
Data from feasibility testing assessed for acid and
oxidizer flow rates; compare sample preparation
33
Conversion from HPLC to TOC

The Process

Instrument Method Swab & Rinse

Method
Qualification Development Recovery
Validation
IQ/OQ/PQ & Feasibility Study

SOP and Cleaning Validation Program Updates

34
Method Validation per ICHQ2R1

Analytical Procedure Identification Testing for Impurities

Characteristics Quantitative Limit
Accuracy - + -
Precision - + -
Repeatability - + (1) -
Interim Precision + + -
Specificity (2) - + +
Detection Limit - - (3) +
Quantitation Limit - + -
Linearity - + -
Range - + -

- Signifies that this characteristic is not normally evaluated

+ Signifies that this characteristic is normally evaluated
(1) In cases where reproducibility (see glossary) has been performed, intermediate precision is not needed
(2) Lack of specificity of one analytical procedure could be compensated by other supporting analytical
procedure(s)
(3) May be needed in some cases
35
Method Validation

Acid Flow Oxidizer Sample

Rate Flow Rate Preparation

Products that require the similar acid flow rate, oxidizer

flow rate, and sample preparation
Enables Method Platforms for similar types of
compounds

36
Options for Groups/ Matrices/ Bracketing

Sample Types of
Similar Ease of Prep Water Used
Formulation Cleaning Method for Cleaning

Cleaning Shared Solubility

Acceptance Equipment Category
Criteria

You can
Cleaning
Manuf. Area Product Type Agent use more
than one

37
What does it really look like?
Sample Acid &
Product Cleaning
Prep Oxidizer
Type Sample Type
Method Setting
Acid: 1.0
Oxidizer: 0.7
Swab Run Neat
Acid: 1.0
Oxidizer: 1.0

Small Acid: 1.0

Molecule Oxidizer: 0.7
Dilution
Acid: 1.0
Oxidizer: 1.0
Rinse

Acidify & Acid: 1.0

Dilute Oxidizer: 0.7

Acid: 1.0
Oxidizer: 1.0

38
Summary

Three TOC method variables:

Acid flowrate
Oxidizer flowrate
Sample preparation
Insoluble does not mean that TOC cannot be used
Use feasibility to enable grouping for method validation

39
Recovery of Difficult to Oxidize or
Solubilize Compounds

40
Summary of Test Plan
Laboratory TOC Analyzer with Autosampler
GE M9 UV/Persulfate TOC instruments located in GE
Analytical Instruments Applications Laboratory,
Boulder, CO USA

Calibration of Analyzer:
Single-point 10 ppm calibration using KHP
Turbo Multi-Point calibration using KHP
Compounds in this study:
APIs: Lidocaine, Azithromycin, Finasteride,
Pancreatin
Excipients: Starch, Methyl Cellulose, Polyethylene
Glycol 6000
Biological: Bovine Serum Albumin

All compounds purchased through chemical manufacturers

(AstaTech, MP Biomedicals, Spectrum Chemicals, TCI)

41
Summary of Test Plan
Why these compounds?:
APIs:
Lidocaine Practically insoluble in H2O
Azithromycin Practically insoluble in H2O
Finasteride Very slightly soluble in H2O
Pancreatin Difficult to oxidize
(combination of three
different enzymes)
Excipients:
Starch
Methyl Cellulose
Polyethylene Glycol 6000

Biological:
Bovine Serum Albumin

42
Summary of Test Plan
Why these compounds?:
APIs:
Lidocaine Practically insoluble in H2O
Azithromycin Practically insoluble in H2O
Finasteride Very slightly soluble in H2O
Pancreatin Difficult to oxidize
(combination of three
different enzymes)
Excipients:
Insoluble in cold H2O and
Starch large molecule
Methyl Cellulose High molecular
weight, large
Polyethylene Glycol 6000 molecules, difficult
to oxidize
Biological:
High molecular
Bovine Serum Albumin weight, large
molecule, difficult
to oxidize

43
Summary of Test Plan

Testing:
Recovery studies: Make 10 ppm
solutions of the compounds and use
percent carbon for each compound
to calculate recovery

Linearity Studies: Dilute each

compound to 5 ppm, 3 ppm, 1 ppm,
and 0.5 ppm and use TOC results to
calculate linearity

44
Compounds Requiring Pre-treatment

Compound Pre-treatment Performed

Azithromycin Sonicated for one hour, then heated at 60C and stirred for
another hour

BSA Dissolved in 8.3mM phosphoric acid

Lidocaine Heated at 60C for approximately one hour

Starch Heated at 60C for approximately one hour

45
Results Summary

Compound Category Linearity (R2) TOC Recovery

Lidocaine Insoluble API 0.9999 100.4%
Azithromycin Insoluble API 0.9994 99.8%
Finasteride Very Slightly Soluble 0.9999 102.4%
API
Starch Insoluble & Difficult to 0.9999 98.7%
Oxidize
Methyl Cellulose Difficult to Oxidize 0.9998 92.3%
Propylene Glycol 6000 Difficult to Oxidize 0.9997 100.4%

Bovine Serum Albumin Difficult to Oxidize 0.9989 99.5%

Pancreatin Difficult to Oxidize 1.0000 97.2%

46
Additional Pharmaceutical Compounds (Prior Study)
Compound Solubility Treats Structure Molecular % Carbon % Recovery
Formula TOC

Metaxalone Practically Spasms C12H15NO3 65% >90%

insoluble

Nifedipine Practically Angina, C17H18N2O6 59% >90%

insoluble hypertensio
n

Tolcapone Very low Parkinsons C14H11NO5 61% >90%

solubility

Tetrabenazine Very low Chorea C19H27NO3 72% >90%

solubility

Topiramate Very low Migraine, C12H21NO8S 42% >90%

solubility seizures

Carbidopa Slightly Epilepsy C10H14N2O4 71% >90%

soluble

Gabapentin Soluble Parkinsons C9H17NO2 53% >90%

47
Calculating Cleaning Limits for
TOC

48
Toxicological Approach to Cleaning Limits
(section 10.6)

10 ppm

Drug Active
Dose
1 2 3 4
LD50
MAC or Limit for Limit for
SAL
Safe Daily STV compound TOC
Intake

ADE (ISPEs ADE = Acceptable Daily Exposure of the residue

Risk-MaPP) PDE = Permitted Daily Exposure
MAC = Maximum Allowable Carryover
Pharmacological and STV = Safe Threshold Value
Toxicological data SAL = Surface Area Limit
(PDE) TOC = Total Organic Carbon

49
Conversion of HPLC Limit to TOC Limit

Calculate the TOC Sample Limit by multiplying the

existing compound limit by the % carbon


()()= ()()%

50
Converting a Compound limit to a TOC limit
I have an HPLC limit. What is the TOC limit?

= %
e.g. Ethanol C2H5OH or e.g. Ethanol= 52% C
C 2H 6O Multiply by 0.52
2 carbon mass = 24.0
6 hydrogen mass = 6.0
1 oxygen mass = 16.0
Total mass = 46.1
% carbon = 52.1%

NOTE: The limit for TOC will be lower value than the HPLC limit,
but represents the same quantity of material
1 ppm = 1 mg/L = 1000 ppb
51
Factors for Return on Investment

52
Considerations
Current State- HPLC Conversion Costs Capital Costs Future State Costs- TOC

HPLC Column Number of TOC Analyzers Vials

Compounds
Guard column Autosampler TOC
Number of New Maintenance
HPLC Vials
Compounds per Consumable
Solvents year Parts
HPLC Method Standards
Maintenance Development
Labor LABOR
Consumable
Parts
LABOR

53
How much could you save?

Parameter Value

# of CV Samples/ week 10 Project Value Estimations (based on savings)

Return on Investment 231%
Instrumentation to Purchase 1 TOC Analyzer w/
Autosampler Payback Period (months) 19
Number of Compounds 40 Payback Period (years) 1.6
NPV (3 year) of Project Benefit $ 35,233
Number of new compounds 2
NPV (5 year) of Project Benefit $ 85,440
per year
Internal Rate of Return (3 yr) 26%
Assumptions Internal Rate of Return (5 yr) 58%
TOC Method Development/Feasibility takes 0.5 days

TOC Method Validation = 1 day

TOC Method groups 5 compounds together

Labor Rate (USD) = $60/ hour
HPLC Method Development takes 5 days per compound

HPLC Method Validation takes 3 days per compound

54
Summary
Cleaning Monitoring Method Development Cleaning Limits Return on Investment

Using TOC TOC methods Your limit is Even with a

provides are easy to based on a large number of
evidence that develop compound compounds to
whole product convert there is
Only 3 method No need to
is cleaned a big benefit to
variables change it
converting from
TOC can be Insoluble does Multiply by the HPLC to TOC
used at-line and not mean that % carbon to get
on-line to TOC cannot be the TOC limit
increase used
equipment
uptime
Q&A
Please submit your questions using the Q&A box located
on your screen.