CHALLENGES FOR GLP QA IN AUDITING AND MONITORING OF IN VITRO STUDIES

Dr. Labhu U. Sanghani, and Smit J. Patel, smit.patel@jrfonline.com sanghanilu@jrfonline.com

Jai Research Foundation, India, www.jrfglobal.com

Introduction

In vitro studies are conducted to obtain data on the safety of various chemicals with respect to human health and the environment, mainly in the genetic toxicity testing. The hazard assessment based on data derived from in vitro studies, to a large extent, is gaining prominence as alternative or supplement to in vivo safety testing.

As GLP Principles require QA to inspect especially the critical phases of a study, it is important that QA should be well aware of what constitutes critical phases (and critical aspects) of in vitro. The Standard Operating Procedures (SOPs) for QA inspections should be developed in co-operation with Study Directors, Principal Investigators, and study personnel pertaining to the relevant functions. For a better understanding and effective auditing of in vitro studies, QA personnel should be trained and educated on specific aspects of studies which will help them to recognize potential challenges in specific areas of in vitro testing.

Qa Audits

Audits of raw data, statestical analysis & report

Review of acceptance criteria, interpritation of results

Requirements of Regulatory Guidelines

QA AUDITORS TRAINING FOR IN-VITRO STUDIES

Development of audit checklist, audits of critical phase (s)

Study specific SOPs and safety in in-vitro lab

Study plan verification and identification of critical phase(s)

Equipment/instruments PQ

IN-VITRO FACILITY AUDIT v and acceptance criteria v SOPs/instruction

Manual/guidance documents v Staff training & competency v Test system (maintenance, identification and characterization) v Cryopreservation and reconstitution of cells/tissues v Sterility of materials and supplies v Cleaning and decontamination of facilities/equipment v Adequate separation of activities v Environmental monitoring (pathogens in the air and on surfaces)

IN-VITRO STUDIES STUDY PLAN AUDIT v Regulatory/guidelines requirements v Study acceptance criteria v Criteria for assay repetition v Details of test system & test item v Positive/negative control/vehicle control v Experimental procedure v Special requirement to be considered (sponsor/study plan)

AUDIT OF CRITICAL PHASE(S) OF STUDY v phases

Identification of critical v Availability and adherence of SOPs v Test system record (chronology of custody, passage number of cell lines, culture conditions and sub cultivation intervals, freezing/thawing conditions, etc.) v Procedures for freezing and thawing of cells and tissues v Maintenance of aseptic condition during experimental work v Procedure to check the responsiveness of test system and its records v Raw data documentation

AUDIT OF RAW DATA , CALCULATION AND STATISTICAL ANALYSIS v are attributable, legible, contemporaneous, original, accurate & complete

Establish that the raw data v Verification of doses, calculation and statistics v Record of test system used v Records of test item, positive control, negative control used v Records of disposal of culture, reagents, formulations v Repeatability of assay v Criteria to assess the viability, suitability and responsiveness of test system and records of such evaluation v Documentation of problems with test system, if any and its impacts

AUDIT OF REPORT

COMPLIANCE & CONCLUSION

Accuracy in transfer of v data identification of test system, test item, positive and negative controls v Characterisation status of test system and test items used v Study plan amendment(s) and deviation(s), if any v Acceptance criteria in line with study plan, SOPs and test guidelines v Content of repot in line with respective test guidelines and study plan requirements

Qualified, trained & v competent QA auditor v Well developed QA SOPs v Indepth QA check list for critical phase(s) audit v Data and report review in line with acceptance criteria

FDA 483 Responses: Do You Have What it Takes?

Many Warning Letters are issued by US FDA because a company’s response letter did not address the finding and/or include evidence of the corrective and preventative actions taken for the FDA to evaluate to determine if the situation was appropriately addressed.

When responding to a 483, your objectives should focus on the following three things

Good Response

We have opened CAPA 123 to investigate and fully understand the root cause of this issue and to develop comprehensive corrective actions in order to prevent recurrence. As immediate corrections to this observation, we have taken the following actions:

• We have revised our XYZ procedure to address the specific example in the 483 as well as the other areas where this issue may arise (see Attachment 1 for revised procedure).

• We have retrained all applicable employees on this procedure to ensure it is implemented appropriately (see Attachment 2 for evidence of re-training to the revised procedure).

• We have quarantined the product referenced in the example and will disposition it in accordance with our procedures by 31-Oct 2018.

• We have arranged for a retrospective review of other products that may have been impacted by this same issue to be performed and will ensure they are also appropriately dispositioned. This retrospective review will be completed by 30-Npv 2018 and the results will be provided in our monthly update to this response.

The CAPA 123 root cause investigation is currently underway; a copy of the CAPA investigation and corrective action plan will be provided in our next monthly response.

 Objective evidence provided for completed actions

 Immediate corrections made, timelines provided for longer term corrective actions

Bad Response

 Addressed example in 483, but also looked to see what other product could be impacted

 Commits to providing updates on a periodic basis

 Commits to performing a retrospective review for other potentially impacted product

We have reviewed our process as described in the 483 and we respectfully disagree with this finding as procedure XYZ has been in place for many years with no issue and we believe it to be compliant as is. However, we have revised the procedure to address the specific example listed in the 483 and we have retrained all applicable employees on this procedure to ensure it is implemented appropriately. We have also quarantined the product referenced in the example and will disposition it in accordance with our procedures.