Evaluation and Qualification of Contract Analytical Laboratories (CALs)

1. Evaluation and Qualification of Contract Analytical Laboratories (CALs) Joan Ruan Bristol-Myers Squibb

2. Outline • Selecting a CAL • Importance and key factors of sponsor audits • Method transfer • Case studies • Summary

3. Selecting a CAL

4. 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

5. 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

6. 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.

7. 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

8. 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

9. 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

10. 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

11. 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

12. Technology Transfer

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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.

20. Case Studies

21. 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.

22. Column #1 (protected from light) Imp A (RRT 0.79) Column #2 (Ambient) Column #2 (protected from light) Imp A (RRT 0.79) 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

23. 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 dessicatorprior 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. Need to follow the specific instructions!

24. Expert Lab Receiving Lab Prep-1 Prep-2 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

25. 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.

26. 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

27. 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