do you have confidence in your data? considerations for ... · (oos) results in pharmaceutical qc...
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©2018 Waters Corporation 1
Do you Have Confidence in your Data? Considerations for Minimising Out-of-Specification
(OOS) Results in Pharmaceutical QC
Waters Pharma & Biopharmaceutical LC-MS Forum
Eschborn, Wednesday June 20th 2018 Hélène Boiteux
©2018 Waters Corporation 2
Industry and Regulatory Trends – Background and the need to ensure product quality – What are inspectors looking for? – Lifecycle management of analytical methods
Developing Robust Analytical Methods & Minimising OOS & OOT results
– Key areas where Waters products can help you
Outline
©2018 Waters Corporation 3
Key Trends in Regulatory Audit (483 Observations)
0%
5%
10%
15%
20%
25%
30%
35%
WrittenProcedures
SpecificationDetermination
Change ControlProcess
Investiagation(OOS)
& documentation
Cleaning Related Calibrationrecords &
Procedures
Stability protocol,statistical data
Method Validation Traininingrequirements
LaboratoryControls
Frequency has grown by 3% in 4 yrs
Laboratory Analytics (EDS 365)
Qualification &
Compliance
Project Mgmt &
Consultation
Nugenesis SDMS
Nugenesis Sample Mgmt
Nugenesis ELN
Training Services
Validation Services
Empower &
MVM
Consumables &
ASR
How can Waters Help?
Instrument Services
Instruments
©2018 Waters Corporation 4
Insights Gained from US FDA 483 Citations
14.6% 18.3% 18.2%
14.4%
0.6%
0.7% 0.6%
0.4% 3.3%
4.0% 3.2%
3.6%
5.9%
6.9% 4.3%
4.1%
5.0%
3.2%
2.6%
2.7%
2.8%
2.2%
1.9%
1.6%
3.7%
4.4%
4.5%
2.9%
0
50
100
150
200
250
300
2014 2015 2016 2017
Proportion of 483 Observations Related to OOS Investigations
Investigation extent
Failed to reject product not meetingspecifications
No written record
Incomplete written record
Inadequate QC review of records
Incomplete or missing investigation/CAPA
Investigation failures
36%
18.4%
6.8%
22% 22%
18.5%
6.9% 10.1%
10.9%
30%
40% 35%
©2018 Waters Corporation 5
Global Financial and Regulatory Implications of Poor Quality
Regulatory Overview (from FDA website) Beginning in January 2008, Baxter Healthcare Corporation recalled various lots of heparin, a blood thinning drug, following a spike in reports of adverse events, including deaths, associated with the product. …able to establish a link between a contaminant found in heparin, oversulfated chondroitin sulfate, and the serious adverse events seen in patients given heparin. We have been able to trace the contaminant to 12 different Chinese companies and it has been found in heparin batches shipped to 11 countries.
> 80 recorded deaths in US alone
Recall costs: Regulatory penalty Recall notification Product retrieval Product liability
Baxter stock dropped 16% from Jan 2008 to Dec 2010
©2018 Waters Corporation 6
Exponential Growth of Recalls Spawns Product Quality Focus
“When manufacturing problems arise in drug manufacturing facilities, drug shortages may follow... 65 % of all drug shortages are caused by manufacturing and quality issues This underscores the need for a safe and reliable drug supply chain.”
©2018 Waters Corporation 7
“I’ll be blunt: In the inspection realm, we find too many, disturbing examples of firms providing us with false information, and doing so deliberately”. “In order for those of us at FDA to do our jobs, we must receive accurate information from firms. Quality metrics based on false data are meaningless”. “I will tell you that the trend for the future has been established today – prevention, risk-based inspections, quality metrics, data integrity, and corporate accountability”.
FDA 2015 – “New Carrots and New Sticks”
http://www.fda.gov/NewsEvents/Speeches/ucm444088.htm
Remarks of Howard Sklamberg Deputy Commissioner for Global Regulatory Operations and Policy U.S. FDA 2015 Annual Conference April 21, 2015 Washington, D.C.
©2018 Waters Corporation 8
Regulatory Bodies Need to Trust the Data they are Seeing Data integrity guidances
– Focused on chromatography Review of audit trails as in Annex 11 Focused inspections
– Continual training of regulators – Expect to look at the electronic data, not just printouts
Ensuring the bad as well as the good data is available – Specifically for reanalysis and reprocessing
Find the root cause of issues and OOS – Right scaled lab error and full OOS investigations
Data Integrity is Key for Quality Assurance
©2018 Waters Corporation 9
If analysts are ‘cherry picking’ only the good results If failing results are being deleted, hidden or ignored If samples are being ‘tested into compliance’ Is the instrument functioning properly and providing accurate results? Are the appropriate methods being used?
What are Regulators Looking for?
Culture of Compliance
“Quality means doing it right when no one is looking.” -Henry Ford
Culture of Quality
VS
©2018 Waters Corporation 10
Perform Testing
Within Spec Report Results
Preliminary Investigation
Error Identified
?
CAPA
Reprocess Batch
Re-analysis
No
No
No
Yes
Yes
Analytical Protocol
Followed?
CAPA (*)
Batch re-analysis
Yes Initiate lab investigation
Phase I: Lab investigation Batch Quarantine
QA/QC to determine the fate
of the batch
Phase II: Full scale investigation
Source of OOS^: Abberation in
measurement Abberation in manufacture
No
Yes
Lab error identified
?
Process investigation
A View of the Regulators Expected Investigation Workflow
(*) Corrective Action Preventive Action ^Out-of-specification
US FDA OOS Guidance link
©2018 Waters Corporation 11
Review of data and records
Demonstrating Ongoing Product Control and Improvement
Analytical method
Supply chain
Manufacturing process
Pharmaceutical Quality System
Analytical method robustness is critical to assessing
manufacturing process or supply chain robustness
- Design space - In-process controls - Identify areas for improvement / change management
Identify/Control variations - Batch - Supplier - Grade
- Analytical design space - Critical factors and interactions - Specifications and “fit” - Lifetime robustness
©2018 Waters Corporation 12
Adherence to Data Quality Standards Throughout the Product Lifecycle
QC
checks System
suitability tests
Analytical method validation
Analytical instrument qualification
Source: USP <1058> Analytical Instrument Qualification
Evidence that instrument performs suitably for intended purpose
Evidence that analytical procedure is suitable for its intended use
Evidence that the system will perform in accordance with established criteria e.g. UPS<621>
Evidence of ongoing assurance of test suitable performance during test sample analyses
Sensitivity Precision Accuracy Specificity Linearity Range Peak asymmetry
©2018 Waters Corporation 13
Developing Robust Analytical Methods & Minimising OOS & OOT Results
Laboratory Analytics (EDS 365)
Qualification &
Compliance
Project Mgmt &
Consultation
Nugenesis SDMS
Nugenesis Sample Mgmt
Nugenesis ELN
Training Services
Validation Services
Empower &
MVM
Consumables &
ASR
How can Waters Help?
Instrument Services
Instruments
©2018 Waters Corporation 14
Analyst Instrument Sample & Method Material Data Review & Calculation
• Procedure details sufficient to produce intended result? • Performance verification –Benchmarking method? • Data review • Training requirement
• Qualification/PM • Leaks, detector performance • Electrical spikes • Instrument setting, parameters & configuration • Missing vial, # of injections • Robustness
• Solution stability (degradation) • Robustness • Retention time shifts • Missing peaks • Unexpected/system peaks • Interference/Distortion (peak shape)
• Contamination from glassware, vials • Reference standard – purity, expiration, proper characterization • Column – robustness, shelf-life, other application use
• Integration parameters • Calculation • Historical data
OOS & OOT Investigation Workflow
Potential Sources of OOS / OOT
With an understanding of root cause, actions can be taken to prevent future events
©2018 Waters Corporation 15
What is Contributing to Chromatographic Variability?
Instrument
• Pumps/Flow • Connections • Voids • Detector
Sensitivity • Column
Condition
Reagents
• Mobile Phase pH
• Additives • Contamination • Dilutions • Solvent Quality
Workflow
• Mobile Phase Preparation
• Sample Preparation
• Method operation
Inconsistencies in any one category can result in Out-of-Specification (OOS) data Hence the need for benchmarking practices, diligence and well trained staff
©2018 Waters Corporation 16
Quality instrumentation contributes to repeatable performance Reliable, robust instrumentation = reproducible results Instrument to instrument performance consistency (and across multi-site
operations) Improved resolution facilitates peak integration
1. Ensure Quality and Consistency of Analytical Results
©2018 Waters Corporation 17
2. Ensure Consistency in Column Packing Materials & Process
Controlling the manufacturing of the column from the very beginning mitigates reproducibility risks
Understanding column packing provides equivalent column performance across all column dimensions
Recommendations! - Minimise the risk of method variation by developing methods on a quality column - Test 3 columns – same chemistry, different batches, using Waters method validation kits to validate long term method reliability
Waters is a primary manufacturer of silica and hybrid particles – from starting materials to finished product
Small 1-2 kg batches are manufactured to closely monitor parameters that impact process variability
©2018 Waters Corporation 18
Trend in instrumentation and applications – More sensitive method requirements – Smaller volumes and more valuable samples – Customers can’t afford failed assays and re-assay costs
Samples are PRECIOUS and EXPENSIVE – The vial is the LAST surface that the final sample
encounters
3. Don’t Underestimate the Importance of Vials – Autosampler Consumables
©2018 Waters Corporation 19
4. Be Proactive, Use Quality Control Reference Materials
System Performance Benchmarking – After installation / After maintenance – Reference point – Establish control limits – Compare systems – Record/trend retention factors etc.
System Diagnosis / Troubleshooting – Predictable nature of QCRM – Identifies mismatch between
o Expected – Benchmarking o Observed – Qualification
– Pattern changes in QCRM parameters help target troubleshooting
System Qualification – Routine analysis – Confirmation system qualify for analysis – Comparing results to benchmark data – Monitoring changes in QCRM parameters – Compiling qualification data overtime allows creation of
control chart
Types of Monitoring – System Components
o Pumps, injector, detectors, column Manager, columns – Analyst error – Use QCRM to ensure proper performance when
switching between separation methods
©2018 Waters Corporation 20
Decision Tree for Choosing Benchmarking Standards
What Separation Technique is being used? HILIC
Preparative Reversed Phase
LC
Analytical Reversed Phase
LC
SFC
HILIC QCRM (186007226) UPC2 QCRM
(186007950)
Separation Method? Separation Method?
Gradient Isocratic
Prep. Chromatography
Mix Standard (186006703)
Autopurification System Standard
(716000765)
Gradient
Isocratic
Neutrals QCRM (186006360)
What type of detection?
UV only & UV/MS MS only
Reversed Phase QCRM (186006363)
LCMS QCRM (ToF) (186006963)
QDa QCRM (186007345)
Quad LCMS QCRM (186007362)
©2018 Waters Corporation 21
Method development processes can be streamlined to produce the best method in a short timeframe – Screen multiple eluents and columns to identify the most robust method – Benefit from tools that prepare buffers consistently (reduce errors) & check pH
robustness of the method – Use Empower built-in/custom calculation and custom reporting to make the best
decisions wrt method development and avoid manual errors in calculations – Benefit from fit for purpose QbD software and Empower data link – Apply modern technologies to ensure data quality and regulatory confidence
5. Use Fit-for-Purpose Analytical Tools to Develop Robust, Reliable Methods
©2018 Waters Corporation 22
Streamline Method Development Develop Robust Methods
Applicable to all LC systems • Systematic approach to define
Knowledge Space • Independant from particle size UPLC Benefits - 6x improvement in productivity • Reduce overall development time • Reduce cost per sample • Reduce time per analysis • Improve separation integrity • Improve resolution Compatible with QbD & DoE guidelines (ICH Q8 (R2)) • Using Fusion software to automate the
method development workflow & establish the Design Space
©2018 Waters Corporation 23
Applying a QbD Approach to Analytical Methods Method Operable Design Region (MODR)
MODR benefits: Flexibility of movement within validated
method operation design region - No need for revalidation within the
design space
Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change ICH Q8(R2) Guidelines
©2018 Waters Corporation 24
The Fusion QbD Approach to Method Development
Define Experimental
Design
• Run experiments & process data
• Analyze results & variable effects
Develop Knowledge
Space
• Define best method conditions
• Define method robustness Establish
Design Space
1.
2.
3.
• Select study variables & define ranges – Columns, solvents, temperatures...
• Generate Design of Experiments (DoE) Fusion works seamlessly
with Empower & ACQUITY UPLC H-Class
- Experimental design from Fusion is automatically reconstructed in
Empower
- Sample set and all methods are instantly generated, saving time
and REDUCING MANUAL ERROR
- Processed analytical data is automatically imported into Fusion
for statistical analysis
©2018 Waters Corporation 25
US FDA - Emphasis on New Technologies
Over the life cycle of a product, new information (e.g., a better understanding of product CQAs or awareness of a new impurity) may warrant the development and validation of a new or alternative analytical method. “New technologies may allow for greater understanding and/or confidence when ensuring product quality. Applicants should periodically evaluate the appropriateness of a product’s analytical methods and consider new or alternative methods.”
VIII. LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES
©2018 Waters Corporation 26
Use mass detection to: – Confirm spectral purity in method development – Allow detection of low level process/product-related
impurities (lower LODs than UV) – Ensure detection of non chromophoric peaks – Run LC(/UV) SIM methods for accurate quantification of low
level impurities in routine testing. Better LODs can facilitate integration
Benefit from Mass Information to Help Reduce Investigations and Save Valuable Time
Thereby reducing the risk of problems in routine QC testing
©2018 Waters Corporation 27
Are your instruments fit for purpose? Is all data coming from qualified & validated systems? Are users well trained (general education and equipment/method-specific)? Are methods validated? Do you have procedural control in place? Where is all of your electronic data?
6. Ensure the Quality of your Data
©2018 Waters Corporation 28
Traceability in Empower Data & Metadata are Linked
E-Cord: Track info in the
method from batch to batch
The relational db allows full traceability of data – connecting data back to
source... Ensures compliance &
traceability of activities
©2018 Waters Corporation 29
7. Control Chart Analytical Data to Support Product Lifecycle
QCRM Benchmarking White paper Literature/PN 720004535en Link
o Plot quality and laboratory work performance data
o Confirm when a process, instrument or method is running well
o Warn of a drift towards an out-of-specification result before rejectable material is produced
o Upper and lower control limits (UCL, LCL) can provide notification of attention
o Highlight improved performance after intentional changes
Warning control limit Upper control limit
Typical method performance trending •Retention time range or reproducibility •Peak area range or reproducibility •Peak tailing range •Efficiency •Peak resolution •Peak response •System pressure
©2018 Waters Corporation 30
System suitability can be automated Create processing method that can flag on limits in the result Custom calculations can be validated and reduce manual or external data processing Configurable user privileges to support data integrity Audit trails give complete view into data and methods to support the quality system,
Empower uses a relational database to connect all actions to one another (e.g. reprocessed and retested data – data integrity risk)
Pre-configured and tailored trend reports can be created to support benchmarking, monitoring and troubleshooting
With a network deployment, appropriate stakeholders can gain timely access to the data to determine root cause and establish corrective and preventive steps to avoid future occurrences.
8. Use Empower CDS to flag OOS Events
©2018 Waters Corporation 31
Flagging during Review Custom Fields can flag events in the report
Examples of Flagging using Custom Fields
©2018 Waters Corporation 32
Secure, web-based solution that extends the default dashboards found within Empower
Dashboards to monitor specific aspects of how your instruments are being used, and accelerate investigations by reducing the time and cost of collecting data
Additional customized dashboards are also available, based on your need.
9. Take Advantage of EDS365 Dashboards
EDS365 LETS YOU: • Access critical system usage
information
• Maximize system utilization.
• Manage resources
• Identify training needs
• Identify process improvements.
• Plan for capital expenditures
• Identify opportunities to improve sample turnover time using UPLC Technology
• Identify potential areas of Data Integrity concern
©2018 Waters Corporation 33
With this report we can you to help to check…. – Are the technical controls sufficient to meet current data integrity regulations? – Is the data protected from unauthorized modification or access? – Are the analysts following company SOPs for multiple processing and manual
integration? – Are the audit trails configured as per regulatory requirements? – Is the data being managed over it’s life cycle in terms of archival and backup?
10. Request a Data Integrity and Compliance Status Report
©2018 Waters Corporation 34
Proactive rather than reactive maintenance Performance Maintenance is based on knowledge
– A keen understanding of instrument design, component reliability testing, and quality parts manufacturing
– The goal is to optimise instrument reliability by replacing normal wear components before they begin to operate unreliably
Performance Maintenance removes the inherent variability found in Preventive Maintenance that can lead to unbudgeted maintenance costs and lower productivity. – Maximises uptime – Maximises system & laboratory productivity – Improves confidence in the results – Lowers overall cost of ownership by minimizing or even eliminating unscheduled service events
11. Benefit from Waters Performance Maintenance Philosophy
©2018 Waters Corporation 35
Waters Self-Paced eLearning
12. Reduce Human Error through a Structured Training Program
Control the pace: Learn quickly or take your time
Over 100 modules and 25 tracks to
choose from
Available 24/7: Learn at your own
pace and convenience
Flexible Options Buy modules or tracks to fit your
budget needs
Better Focus: Skip what you know or don’t
need. Repeat difficult course sections
Immediate Savings :
Cut travel costs and eliminate
travel expenses
Affordable: Prices ranging from
$50-$1,200
Certified Developers:
Designed by same classroom based quality trainers
Multi discipline Courses
Empower, MassLynx, UPLC, HPLC, Small and Large Molecules
Fundamental, Essential, & Advanced
Techniques
Demonstration of functionality through hands-on exercises
Knowledge Check Quizzes
Perfect Supplement to Waters
Classroom training
©2018 Waters Corporation 36
Prevent Failed Results with Waters Quality Instrumentation, Software, Consumables & Support Services