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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

0.00

0.02

0.04

0.06

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0.12

0.14

0.16

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0.22

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0.28

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0.38

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0.42

0.44

Minutes

2.00 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

-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

0.20

0.22

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0.28

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0.44

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

0.00

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0.25

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0.45

Minutes

2.00 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

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 Determination

Theoretical % 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

0.010

0.020

0.030

0.040

0.050

AU

0.000

0.010

0.020

0.030

0.040

0.050

Minutes

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00

AU

0.000

0.010

0.020

0.030

0.040

0.050

Minutes

0.00 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