Presented by: Shabana Chaudhry, CQA

Allergan Inc.

This presentation is made at the request of IVT.

The information provided and opinions expressed during this presentation are those of the presenter and are not the position of and may not be attributed to Allergan, Inc.

The presenter is a full-time employee and stockholder of Allergan, Inc.

Lab audits should be performed as part of the firm’s Internal Audit Program

Consists of Lead Auditor and Trainee

Covers aspects of Quality System:◦ Laboratory Controls System

Scope: 1)To ensure the Microbiology Lab processes and practices are in compliance with cGMP, (your company requirements), and applicable regulations

2)To verify the efficacy of the Quality Systems in the Microbiology Laboratory

Reference previous audits

Performing regular audits of the Microbiology Laboratory is essential to certifying that the lab and all of it’s associated functions report accurate results

Comply with FDA cGMPs, ISO, EU, ICH and other regulatory bodies

Good idea for auditor to take a Micro101 course

THE LAB SHOULD BE

PREPARED!

Prepare a Plan

Contact the Manager

Set a Date

Discuss the Scope of the Audit

Gather and review the Dept. SOPs

Prepare a checklist

Perform audit of lab areas with an escort

Ask questions to individuals performing the tasks

Document Concurrently

Follow-up if clarification is needed

Treat as a regulatory agency audit

Training

Document

Control

Control of Media

Inspection,

Measuring and

Test Equipment

Receiving/In-

Process/

Finished Product

Acceptance

Non-conforming

Product

Deviations,

Corrective and

Preventive Action

(CAPA)

Labeling

Controls

Statistical

Techniques

Data Integrity

Computer

Systems

COMPANY HEADER Form No ./ Ver. No.

Pre-Audit Meeting

Date: ___________________ Start Time: ______________ End Time: _________________

Area/Dept. /Process Audited:_____________________________________

Location of Audit: ________________________________________________

Date(s) of Audit/Time: ___________________________________________

Audit Purpose:

Audit Scope:

References (Procedures and Documents to be audited):

Auditee Signature/Date:____________________________________________________________

Auditor Signature/Date: ____________________________________________________________

QA Manager Signature/Date: ________________________________________________________

COMPANY HEADER Form No ./ Ver. No.

Area/Dept. Audited: ________________________________ Area/Dept. Mgr. or Sup:_________________________________________

Auditor(s): _________________________________________ Area/Dept. Guide(s):____________________________________________

Date(s) of Audit: ____________________________________

Observations: Category: (Critical, Major, Minor,

Area of Concern, Recommendation

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Auditee Signature/Date:________________________

Auditor Signature/Date:________________________

(Use more pages as needed)

Organization and Personnel◦ CFR 211.22 Responsibilities of quality control unit◦ CFR 211.25 Personnel qualifications

Laboratory Controls◦ CFR 211.60 General Requirements

Specs, Standards, Sampling Plans, Test Procedures and Lab Control Mechanisms Approved by Quality Control Unit

Scientifically sound

◦ CFR211.165 Testing for release and distribution◦ CFR 211.166 Stability Testing◦ CFR 211.167 Special testing requirements

CFR 211.180 Records and reports◦ CFR 211.194 Laboratory records

BA/BS Science, Biology, Microbiology, Laboratory experience

GMP & GLP (Good Laboratory Practices) TRAINING

Is there a Training SOP?

Responsibilities/Competencies are clearly defined Demonstrated competency-person performing test is “trained in task” Personnel qualified and trained in accordance with their function Not only read & understood

Verification of competency ◦ Demonstration◦ Side-by-side◦ Observation

Basic calculations/measurements/conversions Ability to Interpret Data

Definitions:

GMP-the practices required in order to confirm the guidelines recommended by agencies that control authorization and licensing for manufacture and sale of food, drug products, and active pharmaceutical products. These guidelines provide minimum requirements that a pharmaceutical or a food product manufacturer must meet to assure that the products are of high quality and do not pose any risk to the consumer or public =Lot/batch release.

GLP-a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed for pharmaceuticals (only preclinical studies), agrochemicals, cosmetics, food additives, feed additives and contaminants, novel foods, biocides, detergents etc.... GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments = Data Integrity (accurate, concurrent, consistent, legible, original)

FDA “The basic principles of training, aseptic technique, and personnel qualification in aseptic manufacturing also are applicable to those performing aseptic sampling and microbiological laboratory analyses. Processes and systems cannot be considered to be in control and reproducible if the validity of data produced by the laboratory is in question”Guidance for Industry- Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice

USP A good resource is USP <1117> Microbiological Best Laboratory Practices

Logbook or LIMS

Sample submitted by

Sample received by

Sample storage (ex. room temp. or refrigerated)

Sample tested

Sample disposition: released/destroyed

Retain samples submitted?

Material/Media Receipt process flow

Vendor is qualified

C of A’s for sterile materials

Each lot is qualified

Is media prepared in house?

Autoclave records

Pre-incubation

Growth Promotion of Media

Stock Cultures used

Expiration dates defined

SOPs- Are they following the procedure as written? Reproducibility Linearity (if applicable) USP Chapters:

◦ <51> AET◦ <61> Microbiological Examination of Non-sterile Products: Microbial Enumeration Tests ◦ <62> Microbiological Examination of Non-sterile Products: Tests for Specified Microorganisms◦ <71> Sterility Testing◦ <81> Antibiotics Microbial Assays “Antibiotic Potency Testing”◦ <85> Endotoxin Testing◦ <1072> Disinfectants and Antiseptics◦ <1229.3> Monitoring of Bioburden

Acceptance Criteria Product Specifications defined Appropriate media used Use of neutralizers Suitable sampling containers Appropriate sample size/retains Positive and Negative Controls QC Testing for release- No experimental or “Testing

into Compliance” Utilization of Environmental isolates Investigation procedure for failure # of retests, why? Validation performed with 3 lots/batches

Verify Procedures are current Change Controls

Sterility TestingBioburden Testing Water/Endotoxin TestingPE/Antibiotic TestingMET TestingDisinfectant study- are all surfaces present in aseptic manufacturing

represented?Growth Promotion Environmental MonitoringSub-culturing and Identification of IsolatesRefrigeration Hold-time studiesLaboratory Inspections- adequate lighting, ex. black/white background (media)Previous CAP Survey Results- may be a good indication of Technician

competency Data Storage-

◦ Includes Backing up of data

GDP (Good Documentation Practices)◦ Governing procedure

◦ Controlled forms-user friendly, room for comments

◦ Clear and Concise

◦ Errors/Cross-outs must be explained if not obvious

◦ No extraneous marks, strange comments

◦ No sticky notes

◦ Factual, no speculation

◦ Proper cross-referencing (ex. retesting)

◦ Traceable Results

◦ No forward/back-dating

◦ Secondary “qualified” Reviewer

◦ Logbook reviews conducted in a timely manner!

◦ Investigations adequately documented

EQUIPMENT CALIBRATION Calibrations Current Hoods (LAF/BSC) Small equipment◦ Scales◦ Weights◦ Pipettes◦ Microscopes◦ Thermometers◦ pH meter

Daily Calibrations Limited Calibration

Reagents Changed

IQ/OQ/ PQ Protocol & Report◦ Incubators◦ Refrigerators◦ Freezers◦ Isolators◦ Automated equipment◦ Autoclaves

Verify validated fixed load cycles are used for dry goods claimed as sterile.

Mass load approach can be used for decontamination of testing supplies and materials but cannot claim sterility.

Equipment PMs (Requals) Cleaning schedules Equipment malfunction, documented and CA

ex. Power outage, Incubation extendedEvery piece of equipment should have a Maintenance Log

No food, candy, etc.

Wearing proper PPE as applicable Lab Coats Gloves Masks Hairnets Shoe Covers

Main Lab Controlled Areas:

◦ Badge access?

High Bioburden-BSC Low Bioburden-LAF (ex. Grade A/Background B)

◦ Prevention of cross-contamination

Sterility Testing Suites (ex. Isolator Grade A/Background D) Environmental Monitoring Waste Management/Decon.

Grade A/B – completely covered including face, SterileGrade C- Hair, beard & arms covered, shoe covers, non-sterile coverallGrade D- Hair, beard & arms covered, shoe covers, lab coat

Segregation of media pending Growth Prom.

Approved and Quarantine labels

FIFO

Cleaning Regimen outlined in SOP

General Lab Cleaning

Frequency of Cleaning

Solutions used (Does it include a sporicide?)◦ Contact time

◦ Concentration

◦ Disinfectant study available

Test areas-Cleaning before and after

Cleaning of Incubators and Refrigerators

Look inside Water Bath

Work orders/Repairs◦ No dust, rust, clutter, growth, etc.

BLEACH

What types of organisms are being recovered?

What are the sources? ◦ People

◦ Water

◦ Environmental

Is yeast/mold being recovered?

Evidence of cross-contamination?

What actions are being taken?

TRENDING

Alert and Action Limits◦ What action was taken when Alert Levels are reached?◦ Supervisor notified?◦ Closely monitored?◦ Low levels of contamination should be included in trend

Importance of Sterility Test Results-Sterility Test Failures?

Water System Investigations Adverse Trends (# of hits in X amount of time) Quarterly Reports Annual Reports Root Cause Analysis QA Involvement CAPA/Effectiveness Checks

If some of the micro. testing is outsourced,

Reports should be reviewed for accuracy

Proof that reagents/media are qualified

Sample Storage

Evidence that B/F studies were performed

Sterile Supplies/Cleanroom gowning supplies

Should be audited regularly

Prepare a Report

◦ Include findings

◦ Classify as Critical, Major, Minor, Area of Concern, or Recommendation

Critical- Direct Impact to product, patient safety

Major- Potential Impact to product, patient safety

Minor- No impact to product, patient safety but conflicts with CFR, ISO, Ministry of Health regulations, etc.

Area of Concern-meets min. requirements but could be improved to mitigate future risk

Recommendation-just a suggestion

Discuss Findings with Dept. Manager and Supervisors

Request a response

Set a reasonable due date for closure

21 CFR 210, 211, and 820 (2015)

ISO 11737-1 Sterilization of Medical Devices-Microbiological Methods-

Part 1: Determination of Population of Microorganisms on Products-April 2006

ISO 11737-2 Sterilization of Medical Devices- Microbiological Methods- Part 2: Tests of Sterility Performed in the Definition, Validation, and Maintenance of a Sterilization Process Nov 2009

ISO 9000 Quality Management

ISO 17025:2005 General Requirements for the Competence of Testing and Calibration Laboratories

FDA Guidance for Industry- Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice 2004

FDA Compliance Program Guidance Manual, Sterile Drug Process Inspections Program Chapter 56- Drug Quality Assurance

World Health Organization (WHO) Good Manufacturing Practices for Sterile Pharmaceutical Products and Water for Pharmaceutical Use

PIC/S GMP Guide PE 009-10 Guide to Good Manufacturing Practice for Medicinal Products Part I

PICS/Inspection of Aseptic and Sterile Manufacturing

ISO 13485 (2003) Medical Devices-Quality Management

EU Medical Device Directive MDD/193/42/EEC

Health Canada GUI-0001 Good Manufacturing Practice

US Pharmacopeia 38 NF 33 (2015)

USP Chapter 1117 Microbiological Best Laboratory Practices

Wikipedia.org

Contact info. chaudhry_shabana@allergan.com