Evaluation and Qualification of Contract
Analytical Laboratories (CALs)
Joan Ruan
Bristol-Myers Squibb
1
Outline

Selecting a CAL

Importance and key factors of sponsor audits

Method transfer

Case studies

Summary
2
Selecting a CAL
3
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
4
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
5
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.
6
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
7
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
8
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
9
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
10
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
11
Technology Transfer
12
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
13
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
14
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
15
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
16
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
17
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
18
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.
19
Case Studies
20
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)
Before
Samples
After
Samples
Injection
Standard 1
(Unfiltered)
Standard 2
(Unfiltered)
1
503392
157713
2
472141
180786
3
474968
196388
4
259267
153616
5
384634
153717
6
277188
165114
Mean
395265
167889
Stddev
106,305.77
17,287.81
%RSD
26.89
10.30
21
Case 2 - Troubleshooting
0.44

Column #1 (protected
from light)
0.40
0.38
0.36
0.34
0.32
0.30
0.28
0.26
0.24
Imp A
(RRT 0.79)
AU
0.22
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
-0.02
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
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
10.50
7.50
8.00
9.00
9.50
10.00
10.50
Minutes
0.44
0.42
0.40
0.38
Column #2 (Ambient)
0.36
0.34
0.32
0.30
0.28
0.26
0.24
0.22
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
-0.02
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
Minutes
0.45
0.40
0.35
0.30
Column #2 (protected
from light)
0.25
Imp A
(RRT 0.79)
0.20
0.15
0.10
0.05
4.637

0.42
AU

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

0.00
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
Minutes
7.00
8.50
22
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
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
Dessicator Stored Standard vs.
Freshly Dried Standard: 88.5%
w/w L-arginine.
Need to follow the specific instructions!
23
Case 4 – Cross Contamination

Expert Lab
0.030
AU
Issue
–
0.040
0.020
0.010
Several unidentified
peaks were found by the
receiving lab & numbers
of the peaks varied
between sample preps
0.000
0.00
2.00
0.040
8.00
10.00
Receiving Lab
Prep-1
0.030
Syringe filters were rinsed
and reused by the
receiving lab resulting in
sample contamination
6.00
0.050
Finding
–
4.00
Minutes
AU

0.050
Tech transfer of an HPLC
method for potency and
degradants
0.020
0.010
0.000
0.050
0.040
Prep-2
0.030
AU

0.020
0.010
0.000
0.00
1.00
2.00
3.00
4.00
5.00
Minutes
6.00
7.00
8.00
9.00
10.00
24
Case 5 – Follow Lab Best Practices

Method comparison study

Issue
–

Low and variable assay results were
observed by the receiving lab
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
Single standard preparation (method
requested for duplicate)
Sample Prep -3
100.2
95.3
Sample Prep -4
99.8
98.6
Used graduated cylinder instead of
volumetric flask for volume control in
sample preparation
Sample Prep -5
99.6
95.1
Sample Prep -6
100.4
93.0
Average:
99.85
96.15
%RSD:
0.40
2.15
Investigation & finding
–
–
–
Sample Precision
Standard weight was too low for 5 place
balances (5 mg in 10 mL vol. flask)
which increased system error
Expert and receiving labs should communicate
extensively to agree on specific lab practices.
25
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
26
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
27