Evaluation and Qualification of Contract Analytical Laboratories (CALs)
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Transcript of Evaluation and Qualification of Contract Analytical Laboratories (CALs)
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Evaluation and Qualification of Contract Analytical Laboratories (CALs)
Joan RuanBristol-Myers Squibb
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Outline
Selecting a CAL Importance and key factors of sponsor audits Method transfer Case studies Summary
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Selecting a CAL
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Outsourcing Analytical Work to CAL
• Why sponsors choose to outsource their work? Free internal resources Utilize CAL expertise Add flexible capacity Reduce cost
• Sponsor’s expectations on selecting a CAL CAL’s ability to perform analytical testing with
technical excellence & superior quality Low cost
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Analytical Outsourcing Process
Establishing scopes of work Choosing a CAL
– Due diligence process– Request for proposal/FTEs program– Site visit – preliminary audit– Capabilities of the CAL– Negotiation of agreement (include price negotiation)– Formal inspection/QA audit– Issuance of certification
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Things Sponsors Look for During Site Visit - Preliminary Audit
Business in general Management team/technical personnel & experience Facility - size, location, zoning, accessibility & security Analytical capabilities - analytical instruments &
technology Regulatory experience Quality system
Do not take the preliminary inspection lightly.
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Formal Inspection / QA Audit
What to audit?– Organization & personnel
• Responsibilities and functions• Qualification, training and adequacy of staff
– Quality management system • Procedures & their adequacy (SOPs)• Documentation control• Change control• QA• Internal monitoring/auditing program
– Analytical facility, procedures, and documentation
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Formal Inspection / QA Audit – An Example Audit Plan
Overview of the business, capabilities, facility & personnel, including organizational structure & regulatory experience – provided by CAL
Tour of facility Auditing lab control system
– Special facilities for analytical services– Qualification, Calibration and Maintenance of equipment– Sample receipt / storage– Data management (e.g. laboratory notebooks, worksheets)
/ report writing / archival
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Formal Inspection / QA Audit – An Example Audit Plan – Cont.
Quality System– Role of the quality unit– Review of standard operating procedures (SOP)– OOS / OOA investigation procedures– Personnel training records, job descriptions and CVs– Documentation: Master documents, change control,
document control and retention– Validation - Process, method and computer (EU Annex 11,
21 CFR Part 11 compliance)– Outsourcing activities– Disaster recovery, business continuity plans
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Formal Inspection / QA Audit – An Example Audit Plan – Cont.
Facilities and Equipment System– General housekeeping: pest control, facility security, and
cleaning– Calibration / maintenance and engineering programs (i.e.
scales, timers, etc.)– Equipment qualification– Environmental controls / auxiliary systems: HVAC, air
filters, pressurization of rooms, compressed gases, purified water, steam systems, air supply / extraction
– Capability of handling high potency compounds
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Preparation Tips for CAL
Be well prepared– Request audit plan from sponsor in advance & confirm
audit date– Notify all staff working in the laboratory about the audit– Assemble all the requested documents in One place
• SOPs• Organization chart, staff responsibilities & training
record• A copy of the equipment list• Notebooks/OOS or OOA investigations, etc. if a mock
study was conducted prior to the formal inspection– Conduct an internal audit
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Technology Transfer
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Technology Transfer
Once a CAL is certified as a preferred vendor, sponsor needs to qualify the CAL to perform specific task or study by performing technology transfer
Depending upon the nature of the projects, procedures for the tech transfer can be categorized as follows:– CAL performs method validation – sponsor
establishes acceptance criteria – Formal tech transfer – transfer protocol required– CAL performs method comparison study
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CAL Performs Method Validation
Method developed & validated by expert lab Method validation will be performed at the receiving lab in
place of method transfer– Acceptance criteria determined by expert lab– Validation protocol prepared by the receiving lab and
approved by the expert lab No transfer protocol required This approach usually applies to early stage projects
and/or IND stability studies
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CAL Performs Method Validation - Typical Process
Duration: typically 4-8 weeks depending on projects Pre-transfer activities (ship materials, provide training, etc) Prepare method validation plan Receiving lab executes the plan Expert lab reviews the data Remedial actions as needed Receiving lab issues the validation report
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Formal Tech Transfer
The requirements for transferring analytical methodology for late stage projects is formal and stringent
Method developed & validated by expert lab Require method transfer protocol The receiving lab will perform the method performance
verification tests following the protocol This approach usually applies to late stage projects, e.g.
registrational stability studies
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Formal Tech Transfer – Typical Process
The formal tech transfer process is usually more extensive and time consuming, ~ 3 months
The expert lab prepares a detailed transfer protocol The receiving lab performs the method performance
verification tests following the protocol Testing must be completed on the selected test samples.
Deviation must be justified and approved by both expert and receiving labs
The receiving lab provides copies of raw data to the expert lab for evaluation
The expert lab issues a final Transfer Report and a letter to authorize the receiving lab to conduct testing
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CAL Performs Method Comparison Study
Method developed & validated by expert lab Transfer protocol is required
– Selected tests– The expert lab establishes the acceptance criteria
Both expert and receiving labs should test the same lots of samples within an acceptable time period
Expert lab prepares the final report and issues a certification of conformance
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Investigations
Conduct investigation if receiving lab could not meet acceptance criteria: – Expert and receiving labs will need to work closely to determine
root causes of the failure – Expert lab will guide receiving lab to determine the cause of
failure– Determine what additional test(s) or training should be
conducted– Make sure these actions are documented in notebooks and in
transfer report and approved by designated personnel at expert and receiving labs
Communication is the key to successfully identify the root causes of failure during the method transfer.
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Case Studies
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Case 1 – Accidental Method Deviation
Transfer of a dissolution method – HPLC finish
Issue– Significant variation in
standard precision Finding
– Receiving lab’s analyst observed precipitation during the testing, but did not inform the expert lab.
– Wrong buffer (pH 6.8 instead of pH 4.5) was used in standard diluent
Communication is the key to resolve this issue.
Dissolution Calculation Data
Run 1 (Acetate Buffer)
Injection Standard 1 (Unfiltered)
Standard 2 (Unfiltered)
Before Samples
1 503392 157713
2 472141 180786
3 474968 196388
After Samples
4 259267 153616
5 384634 153717
6 277188 165114
Mean 395265 167889
Stddev 106,305.77 17,287.81
%RSD 26.89 10.30
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Case 2 - Troubleshooting
Issue– Inconsistent impurity
profiles were observed by the receiving lab
– An unknown impurity (Imp A) was absent when a new column was used
Receiving lab’s conclusion– The new column provided
lower sensitivity. Investigation
– Check sensitivity on the new column by injecting the freshly prepared sensitivity solution
– Imp A was detected in the sensitivity solution
Root cause– The sample solution was
not protected from light as indicated in the method and Imp A was degraded
AU
-0.02
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Minutes2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50 10.00 10.50
AU
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Minutes2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50 10.00 10.50
4.63
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AU
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Imp A (RRT 0.79)
Imp A (RRT 0.79)
Column #1 (protected from light)
Column #2 (Ambient)
Column #2 (protected from light)
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Case 3 – Small Deviation May Cause Issue
HPLC Method Transfer for Arginine Issue
– Arginine is a very hydroscopic compound
– Arginine level obtained by the receiving lab is higher than that by the expert lab
Finding– According the method, the standard
should be dried at 100C for 4 hrs and placed in a dessicator prior to each use
– Receiving lab followed the instruction, but re-used the standard stored in the dessicator
– Dessicator Stored Standard vs. Freshly Dried Standard: 88.5% w/w L-arginine.
Counterion DeterminationTheoretical % Arginine = 26.3
Sample ID % Arginine by
Expert Lab% Arginine by Receving Lab
Sample Prep -1 26.4 29.8
Sample Prep -2 26.4 29.7
Sample Prep -3 26.3 29.7
Sample Prep -4 26.5 29.8
Sample Prep -5 26.4 29.7
Sample Prep -6 26.5 29.7
Average: 26.42 29.73%RSD: 0.28 0.17
Need to follow the specific instructions!
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Case 4 – Cross Contamination Tech transfer of an HPLC
method for potency and degradants
Issue– Several unidentified
peaks were found by the receiving lab & numbers of the peaks varied between sample preps
Finding– Syringe filters were rinsed
and reused by the receiving lab resulting in sample contamination
AU
0.000
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0.050
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0.000
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Minutes0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00
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Minutes0.00 2.00 4.00 6.00 8.00 10.00
Expert Lab
Receiving LabPrep-1
Prep-2
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Case 5 – Follow Lab Best Practices
Method comparison study Issue
– Low and variable assay results were observed by the receiving lab
Investigation & finding– Standard weight was too low for 5 place
balances (5 mg in 10 mL vol. flask) which increased system error
– Single standard preparation (method requested for duplicate)
– Used graduated cylinder instead of volumetric flask for volume control in sample preparation
Expert and receiving labs should communicate extensively to agree on specific lab practices.
Sample Precision
Sample ID
API Purity by Expert Lab
(%)API Purity by
Receiving Lab (%)
Sample Prep -1 99.3 97.1
Sample Prep -2 99.8 97.8
Sample Prep -3 100.2 95.3
Sample Prep -4 99.8 98.6
Sample Prep -5 99.6 95.1
Sample Prep -6 100.4 93.0
Average: 99.85 96.15%RSD: 0.40 2.15
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Things to Keep in mind During Tech Transfer
Follow methods strictly– Understand method requirements– Pay attention to details
Communicate all experimental observations with the expert lab Consult the expert lab for any deviations and document changes Ensure good lab practices are followed
– Use the same materials (column, filter, solvents, etc.) specified in the method
– Avoid glassware contamination– Ensure System Suitability requirements are met – Avoid documentation/data recording/log book entry errors– Double check data rounding and calculations
Inform the expert lab of any OOS results promptly and conduct investigation according to SOPs and expert labs’ instructions
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Summary
CAL selection is a thorough process CALs need to be well prepared for both the site visit and
formal inspection/QA audit by Sponsors Sponsors will qualify the certified CALs for specific tasks
by performing tech transfer Procedure and CAL’s responsibilities of tech transfer
depend on the nature of the task Open communication and cooperation between
Sponsors and CALs are the key for a successful tech transfer
Understanding the many detailed factors in lab practices are critical to ensure the smooth/successful transfer