Celsis Master Sales

PRESERVATIVE REDUCTION
With Increasing Regulatory Framework
EVERY STEP OF THE WAY
The main regulatory framework for finished cosmetic products placed on the EU market is Regulation (EC) 1223/2009 on cosmetic products (EU Cosmetics Regulation)
Governance on substances that may, or may not, be included in cosmetic products.
Annex II – Prohibited substances
Annex III – Restricted Substances
Annex IV – Colorants
Annex V – Preservatives
Annex VI – UV-Filters

ANNEX V - PRESERVATIVES
Allowable & Unallowable
Governs the use of list of allowable preservatives in 28 countries.
By default, this list also indicates which preservatives are not allowed by exclusion
Ex: Methylisothiazolinone, commonly used but no longer allowed.
Governs acceptable use under certain concentrations.
Ex: Poly hexamethylene biguinide hydrochloride (PHMB) must now be used at < 0.1%
While list contains 50+ approved preservatives, few options exist.
Preservatives must be compatible with formulation

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5
THE PROBLEM WITH PRESERVATIVES…
Dwindling options
Preservatives that are not aligned with Annex V must be discontinued or used in reduced concentrations.
Allowed preservatives are often pH-dependent, temperature sensitive or specific to formula.
Sometimes requires re-formulation around the preservative alone.
Introduces risk of failure if not properly evaluated for antimicrobial activity, sensitivity, and long-term stability.
Alternative preservatives do not have the long term data that the old, standby preservatives have.
Additional requirements and longer time-to-market to allow for proper risk assessment.

the old methods of dirty manufacturing are
no longer acceptable

Cosmetic manufacturers must be concerned about the safety of their ingredients while ensuring
their product is free of contamination.

KEEPING PACE WITH REGULATORY EXPECTATIONS
…and responding to the pressures of business
EVERY STEP OF THE WAY
Pressure to release product to market as fast as possible, while ensuring the safety of its ingredients and from adulteration.
Consumer demands are trending toward preservative-free, all natural formulation claims, while they still expect a clean product.
Regulatory requirements continue to increase, while the amount of allowable preservatives in your product continues to decrease, with few new options coming to market.
Production can no longer rely on their preservatives to keep their product clean and free of microbial contamination and must adapt or fail in the eyes of regulators and the consumer.

ANTIMICROBIAL ACTIVITY BEGINS IN PRODUCTION
Not with Formulation
EVERY STEP OF THE WAY
Antimicrobial activity is a primary criteria in selection of a preservative system.
Microbial contamination is primarily introduced through three main points, both of which are in your manufacturing process:
Water used in production.
The raw materials and ingredients of your product.
Your environment and your personnel.
These initial sources of contamination, lead to continual sources of contamination in your equipment.

EVERY STEP OF THE WAY
Is unknown or uncontrolled microbial contamination during production making you
preservative-dependent?
Why not control your process instead?

ACHIEVING A STATE OF CLEAN-BY-DESIGN
Reducing Risk by Proactive Quality
EVERY STEP OF THE WAY
Manufacturers need to adapt to increased regulatory demand and consumer expectations by adopting cGMP (current Good Manufacturing Practices) standards for their production process.
cGMP’s involve consistent, well-documented, and proven practices for inspection of:
Environmental sampling of equipment, personnel, and manufacturing areas.
Microbial testing of water, raw materials, and finished products.
Secure, complete, and appropriate documentation of results and records.

ADDITIONAL GUIDANCE
EVERY STEP OF THE WAY
Guidance can be found in:
ISO 22716:2007 - Cosmetics - Guidelines on Good Manufacturing Practices
FDA Guidance For Industry - Cosmetic Good Manufacturing Practices

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Raw materials, in-process samples, and final product testing should be implemented as part of a
good manufacturing process
addressing contamination earlier and faster.

ALTERNATIVE MICROBIAL DETECTION METHODS
Rapid microbial detection technology allows companies to quickly and accurately determine whether a product is contaminated, identify the exact organism, and confirm the quality of the product.
EVERY STEP OF THE WAY

EVERY STEP OF THE WAY
Just being rapid isn’t enough. Your RMM needs to be the
Right Microbial Method.
Choosing a rapid method takes more time, energy, and money than ever before. And that’s even before you consider what you’ll need to implement it and ensure it works with your products and methods.

IMPACT OF CELSIS® RAPID MICROBIAL METHODS
EVERY STEP OF THE WAY
Release product from micro hold faster
Reduce Inventory & Working Capital Requirements
Shorten production cycles
Improve warehouse utilization
Respond to and Recover from contamination faster
z
Improve Lab Efficiency & Data Integrity Compliance

EVERY STEP OF THE WAY
BUILT FOR SIMPLICITY
Celsis® Rapid Microbial Detection Instruments
Easy integration
Into your current test protocols.
Use your validated method.
Eliminate days of incubation.
Objective results
replace manual eye counts
or visual turbidity checks with automated, instrument based
analysis.
Secure data integrity
and control through on-board,
regulatory compliant software.
Automated reporting. Multiuser
management.
Microbial Limits results in 24 hours.
Let your data work
for you, instead of
against you.
Because finding
nothing ultimately
means everything.

SAME FEATURES. DIFFERENT SIZES.
Celsis® Rapid Microbial Detection Instruments
EVERY STEP OF THE WAY
the Celsis Advance II™
High capacity. High efficiency.
Up to 120 Assays per Hour
the Celsis Accel®
Everything you need. Nothing you don’t.
Up to 30 Assays per Hour
Provides the critical results necessary for critical decisions. Shorten production cycles. Detect contamination events sooner and respond even faster.
Provides the same high-performance detection and reagent compatibility as the Advance II for labs with workloads that are smaller, but no less important.

EVERY STEP OF THE WAY
Celsis® ATP-Bioluminescence Reagents
Adenosine triphosphate (ATP) is present in all living cells, including bacteria, yeasts, and fungi.
Standard ATP assays use enzyme luciferase to catalyse microbial ATP and produce light
Light generated is measured using a luminometer.
Intracellular
ATP extracted
Light signal generated
Contaminated sample
Celsis LuminEX™ Added
Celsis LuminATE® added
50 uL sample
CELSIS LUMISCREEN™
STANDARD ATP BIOLUMINESCENCE

EVERY STEP OF THE WAY
Celsis® ATP-Bioluminescence Reagents
Two-phase, proprietary enzyme reaction
All living organisms also contain the enzyme adenylate kinase (AK) as part of their biochemical processes
Microbial enzymes convert ADP into ATP
Amplification of ATP levels beyond naturally occurring level.
Enzymes are not depleted by reaction
Ability to generate almost unlimited amounts of ATP
CELSIS AMPISCREEN®
AMPLIFIED ATP BIOLUMINESCENCE
Intracellular
ATP and components extracted
Contaminated sample
Celsis LuminEX™ & Celsis LuminAMP™ Added
Celsis LuminATE® added
50 uL sample
AMPLIFIED light signal generated

EVERY STEP OF THE WAY
ROBUST REAGENTS.
RAPID RESULTS.
Celsis® ATP-Bioluminescence Reagents
A rapid microbial detection instrument is only as good as the reagents that power it.
Celsis® utilizes the most advanced class of adenosine triphosphate (ATP) bioluminescence reagents, unlocking new efficiencies for your QC workflow and a new level of confidence in the safety of your product.
Don’t settle for less. Charles River manufactures Celsis AMPiScreen® Pharma reagents to the same high-level quality you build into your own products.

CELSIS APPLICATIONS
EVERY STEP OF THE WAY
Celsis® Method Overview
microbial limits
STERILITY
contamination response

PRIMARY CONSIDERATIONS
EVERY STEP OF THE WAY
When Choosing an RMM
SUPPLIER EXPERIENCE & SUPPORT
TIME TO RESULT
PRODUCT COMPATIBILITY
ASSAY THROUGHPUT
NON-DESTRUCTIVE
ASSAY REQUIREMENTS

EVERY STEP OF THE WAY
ADAPTS TO CURRENT TEST PROTCOLS
Minimizes Changes to Current Preparation Method
Culture Media
Compatible with a wide variety of common media: such as TSB, TAT, and FTM
Incubation Time
Microbial Limits and Bioburden in 24 Hours versus 5-7 days. Sterility results in 6 days versus 14 days

FLEXIBLE PROTOCOL FOR BROAD PRODUCT SUITABILITY
Celsis AMPiScreen® Method Overview
EVERY STEP OF THE WAY
W/ or w/o filtration
Varying broth volumes/types
Soluble / Non-soluble products
High pH / Low pH products
Oil / Water based products
Pigmented products
Preserved products
IV Solutions, Antibiotics, Vaccines
Tablets, Syrups, Suspensions
Lotions, Creams, Ointments, Gels
Medical Devices, Packaging
Soaps, Detergents, Fabric Softeners
Toothpaste, Deodorant, Cosmetics
Ink, Pudding, Juices, Nutritionals
Flexible Protocol
Product Matrix Examples

EVERY STEP OF THE WAY
EXAMPLE PROTOCOL – MICRO LIMITS TESTING
Celsis AMPiScreen® Method Overview
Direct Inoculation
Measure and prepare sample in broth media (typically TAT, TSB, or Letheen).
Incubate
Incubate samples for 24 hours
For mold detection, add beads and place on linear shaker for 30 minutes after incubation.
Membrane Filtration
Filter sample according to preparation method and transfer membrane to broth media for incubation.
Analyze
Pipette 50μL of incubated sample into cuvettes and load into instrument.
After ~1 hr automated analysis, collect results.

EVERY STEP OF THE WAY
TRADITIONAL METHOD VS CELSIS RMM
Traditional
Incubation Method
Antiquated, Subjective, Visual readout
5–7 Days Microbial Limits
Labor Intensive
Instrument-based, Enzyme-catalyzed assay
24 Hours Microbial Limits,
Automated Analysis
High Impact, High Cost
Less Than Traditional
DETECTION PRINCIPLE
TIME (DAYS)
EASE OF USE
RELATIVE TOTAL COST
CFU or Presence/Absence
RLU or Presence/Absence
METHOD
Celsis®
Rapid Method
Key Advantages of a Rapid Test Method

DATA INTEGRITY
EVERY STEP OF THE WAY
Subjective evaluation in Tradtional Method
Based on visual, human analysis
Four-eyes principle requires additional personnel
Prone to interpretation and transcription error.
Single canisters compared against control canister for each media type.
A Key Advantage to Rapid Sterility Testing Resulting in Improved Data Integrity position

IMPROVED TEST PERFORMANCE
A Key Advantage to Rapid Testing Resulting in Improved Data Integrity position
EVERY STEP OF THE WAY
An example where turbidity is a poor indicator of microbial contamination.
Which are sterile and which are contaminated?
1
2
3
4
Samples 1 and 2 are sterile.
Samples 3 and 4 are contaminated.

DATA INTEGRITY
EVERY STEP OF THE WAY
Objective Evaluation in Celsis Rapid Detection
Based on instrument analysis.
Automation allows walk-away results.
Automatic results reporting and export removes possibility of interpretation or transcription errors.
Duplicate cuvettes prepared for each sample compared against duplicate control cuvettes.

RESULTS INTEGRITY
EVERY STEP OF THE WAY
ASSAY AUTOMATION
Precisely controls reagent volumes and reaction timing
OBJECTIVE RESULTS:
Interprets results against validated parameters
Provides multiple reporting options
21 CFR Part 11 compatibility
Compatibility up to Windows 10 Pro
Archived data protects data integrity
Administrator right and users roles/permission structure
Subjectivity vs Objectivity: Celsis.im software

YOUR SUCCESS IS OUR SUCCESS
EVERY STEP OF THE WAY
Industry Leading Expertise And Support

Reduced cost of manufacturing
Reduced inventories
Financial Savings
Earlier response to contamination events
Experienced global support through Charles River
OPERATIONAL IMPACT OF CELSIS®

EVERY STEP OF THE WAY
LEADING COMPANIES TRUSTING CELSIS® DETECTION
Proven and In Use by Pharma and Personal Care Product Manufacturers

CRITICAL INFORMATION TO RELEASE PRODUCT FASTER
EVERY STEP OF THE WAY
Increased Efficiencies of a Qualitative Screening Assay

REDUCING INVENTORY AND LEAD TIMES
EVERY STEP OF THE WAY
The Cost Savings from Charles River RMMs

REDUCING INVENTORY AND LEAD TIMES
EVERY STEP OF THE WAY
The Cost Savings from Charles River RMMs
$470,000
Inventory investment
$1,120,000
Inventory investment

HIDDEN COSTS ADD TO TRUE COST PER TEST
EVERY STEP OF THE WAY
The Cost Savings from Charles River RMMs
Traditional method
Rapid Method
QC DEPARTMENT
DIRECT COST
INVESTMENT IN
FINISHED GOODS
INVESTMENT IN
SAFETY STOCK
WAREHOUSE SPACE COSTS
CONTAMINATION RECOVERY
SAVINGS PER TEST
cost
Increased costs in QC Department include reagents
and consumables

EVERY STEP OF THE WAY
The Cost Savings from Charles River RMMs
FINANCIAL IMPACT ASSESSMENT
Using readily available financial and QC data, the following can be determined:

SUMMARY AND NEXT STEPS
EVERY STEP OF THE WAY
NEXT STEPS
Establish multi-function team and project timeline
Complete and review Financial Impact Assessment
Review products for validation and implementation

CONTACT US
ENTER CONTACT INFO HERE
Address:
251 Ballardvale Street
Wilmington, MA
01887
Website:
www.criver.com
Email:
[email protected]
Phone:
877.CRIVER.1

APPENDIX
Additional Information

EVERY STEP OF THE WAY
RMM TECHNOLOGY SELECTION
Growth Based Methods Detectable signal is achieved after a period of growth
Amplified ATP Bioluminescence
CO2 Production
Flow Cytometry
Fluorescence-Assisted Colony Counter
Standard ATP Bioluminescence
Digital Imaging Technology
Direct Measurement: Individual cells are differentiated and visualized
Flow Cytometry
Solid Phase cytometry

EVERY STEP OF THE WAY
Industry Leading Expertise And Support
REGULATORY OVERVIEW
Regulators do not pre-approve RMM technologies; the user is responsible for seeking approval of use with their products, process, and method.
Already in Use
A growing number of companies have received approval for the use of Celsis for finished product testing using various submission strategies
Guidance for the Validation of Rapid Microbial Methods
PDA TR33
USP<1223>
Ph. Eur. 5.1.6

PRIMARY CONSIDERATIONS IN SELECTING AN RMM TECHNOLOGY
EVERY STEP OF THE WAY

TIERS OF REGULATORY REQUIREMENTS
Appendix A
EVERY STEP OF THE WAY

PDA TR33 GUIDANCE
Appendix B
EVERY STEP OF THE WAY

EVERY STEP OF THE WAY
PROACTIVE QUALITY SYSTEMS REDUCE RISK
What if you do find a positive result?
The cosmetic products industry has a known history of recall notices that name the following organisms as microbial contaminants: B. cepacia, P. aeruginosa, S. aureus, E. coli., K. pneumoniae, and S. marcescens.
Aside from the obvious concern for consumer safety, a microbial contamination is also costly in terms of immediate financial impact and longer-term damage to the brand’s reputation.
So how can you reduce the risk of a product recall associated with these and other known harmful organisms?
Environmental monitoring
Accurate and reliable microbial identification
Tracking and trending EM data

THE IMPORTANCE OF ACCURATE IDENTIFICATIONS & EM
EVERY STEP OF THE WAY
The first step in most risk-reduction approaches is identification and characterization of the objectionable organism.
The next step is accurate identification, which can only occur if the organism is present in the microbial library that is referenced.
Environmental monitoring (EM) is a fundamental aspect of cGMP compliance and is a proven strategy for contamination risk mitigation for cosmetic manufacturers.
Accurate identification of environmental isolates plays an important role in this strategy because it helps record the routine flora of the facility and allows the quality system managers to detect and analyze any deviations from the norm.
The Environmental Monitoring Program
Measures and documents the State of Control of the facility
Quality of the environment
Acts as early warning surveillance system
The Isolate of Concern
Risk management - Evaluate level of risk
Origin of contamination
Is the isolate objectionable?
CAPA planning to mitigate risk

EVERY STEP OF THE WAY
WHY TREND ORGANISMS?
When you have confidence in your ID results, you can gain a better understanding of your manufacturing environment and the ability to aggregate and trend EM data.
But collecting and managing this data can be difficult and time-consuming, which is why having the right tool to automate these processes can lead to significant time (and cost) savings.
Turning Raw Data into Actionable Information