Conducting Supplier Audits: Ensure Validation · PDF fileConducting Supplier Audits: Ensure...

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Conducting Supplier Audits:

Ensure Validation Compliance

Presented by: Gamal Amer, Ph. D.

Principal

Premier Compliance Services, Inc.


Outline

• Why audit your supplier.

• Who will audit your supplier.

• When will you audit your supplier.

• What will you audit.

• How will you conduct the audit;– Pre-audit questionnaire

– Areas to be audit and using check lists

– Close out meeting

– The advantages and disadvantages of using numerical audit scores.

– Issuing observation reports and recommendations to your management and to your potential supplier.


Why Audit Your Supplier?

• It is a regulatory requirement

• To assure yourself that your supplier can provide the required services by virtue of its expertise, technical knowledge, operating capability, financial stability, and sufficient manpower.

• To ensure that they apply the principles of GXP to your standards since they will become an extension of your operation.


Why Audit Your Supplier?

• To ensure that your supplier remains in

compliance.

• Ensure that your supplier is living-up to

commitments made (e.g. to fix things).

• To investigate issues that may arise during

the relationship.


Three Types Of Audits

• Pre engagement audit, or audit to qualify supplier

• Post engagement audit, or audit to ensure supplier remains viable and in compliance with your requirements.

• Tactical Audits to address specific concerns or issues.

• The first two audits are conducted similarly. However, the objectives will differ. The third type focuses on the issue or concern and actions taken to alleviate or correct it.


ICH Requirements

• Q7: Manufacturers should have a system in place to evaluate suppliers, should audit their supplier and they should be approved by the quality unit. Proceeds to detail how an audit maybe conducted.

• Q9: Quality Risk Management as Part of Materials Management includes assessment and evaluation of suppliers and contract manufacturers to provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing, supplier quality agreements).


Example 483

• Reports of analysis from component suppliers are accepted in lieu of testing each component for conformity with all appropriate written specifications, without establishing the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

• Procedure “Vendor Qualification System”, QSOP 020, version October 25, 2000, states "Vendor qualification is established thorough audits, testing and certificates of analysis," however, several suppliers of critical raw materials and components have never been audited. For example :

– contract testing laboratory for USP raw materials used in production.

– contract laboratory that conducted validation of endotoxin testing for drug substance and drug product.

– raw material supplier.

– supplier of intermediate used in manufacture of drug substance

– filter supplier for the drug substance purification.


FDA 483 Examples

• Purity, strength and quality of some critical

components in the manufacturing are not

tested to validate the supplier’s test

results.

• No SOP for supplier audits.

• No audits performed for water, steam or

gas suppliers.


When to Audit

• During the supplier qualification process.

• During the contract negotiation process.

• Prior to awarding the project.

• Regularly during the contract period.

• When an issue arises during contract

period.


Who Audits

• Your quality organization is responsible for final approval.

• They should either audit directly or delegate the audit to third party.

• Using third party is advantageous in that it eliminates any direct arguments, confrontation, or semblance of favoritism and provide appropriate and current expertise.

• Auditor must have expertise in:– The regulatory and Quality issues associated with project

– The technical issue relevant to the project

– Experience in conducting the required type of audit.


How to Audit

• Audits should be documented.

• Audits should be transparent.

• Auditor must prepare before hand.

• Should be conducted using a check list or plan document.

• Use score or pass fail in grading check list.

• Audit the facility from which the services will be provided.

• Observe operation and conduct interviews.

• Review documentation.

• Talk to the management.


How to Audit

• Pre-audit questionnaire

– Info from previous audits if possible

• Define areas to be audit and use check

lists

• Initial and close out meeting

• The advantages and disadvantages of

using numerical audit scores.


How to Audit

• Some useful techniques:

– Follow problems as you identify them.

– Look at the organization of all paper work.

– Check spelling and grammar, they can be an

indication of sloppy record keeping.

– Keep an eye open on manual transcribing.

– Transparent audit by letting them know ahead

what your plan is, what you find as you find it,

do not use gotcha techniques, etc.


Conducting The Audit

• Arrive at your supplier facility and announce yourself and sign in. Pay attention to the reception area.

• Expect to be escorted to a meeting room and introduced to the management of the organization. Look for cooperative attitude.

• Conduct initial meeting:– What are your objectives.

– What you will be focusing on.

– How long do you expect the audit to last.

– Define who from the supplier’s end will accompany you through the audit.


Conducting The Audit (Cont.)

• During initial meeting, request and review some basic documents that may relate to your objective and confirmation of GMP compliance:

– Facility Layout Diagram and people, and material, Flow Diagrams.

– Organizational Chart for the Facility Management Team.

– Position description of responsible personnel.

– Process flow diagram (PFD) for the product of interest.

– Confirm the existence of major regulatory documents (NDA, ANDA, 510K, Etc.)

– The latest process abnormality reports, ensure that proper investigation and appropriate conclusions were reached.



• Begin by going through the quality

systems.– Review quality policy and manual document(s)

– Review some of the basic procedures (OOS,

Deviation, Change Control, CAPA, etc.)

– Do they have a comprehensive list of SOPs

– Calibration, maintenance, and environmental

monitoring programs.

– Look at the standards (Analytical, design, etc.)

– Training and documentation of such.



• Next follow the operation of interest.– Start at the Raw Material receiving, storage and warehousing

– Follow the process flow

– Pay attention to how the operation is laid-out, clutter, operator stations adequacy, general house keeping, etc.

– Batch sheet and batch records, Batch Sheets properly executed

– Review the various procedures and how well they are followed

– Gowning and degowning

– Cleanliness and general maintenance of the facility

– Labeling of processing equipment and transfer lines

– Do operators appear to know what they are doing, ask questions

– Has the process and facility been validated and what is the quality of the validation documents



• Packaging and Labeling– Appropriate Procedures.

– Label Controls.

– Label count reconciliation.

– Validation of automated systems

– Confirmation of use of proper labels on

packaged product.



• Facility and Utility Systems

– Are the critical utilities well documented?

– Have the critical utilities been validated?

– Facility cleanliness, maintenance, and orderly progression of the operation.

– Is there too much clutter?

– Do they have an environmental monitoring program?

– Is it too hot? Too cold? Too Humid? Too Noisy? Too tight? Etc.



• Warehousing, storage and materials handling facilities– Segregation and well labeled areas.

– Record keeping

– Validation of Materials Resource Planning (MRP) system and all other computerized systems

– Cleanliness and organization

– Rodent and pest control program

– Procedures for destruction and disposal of rejects and waste


Outline supplier audit (Cont.)

• Laboratories– Validation of instruments and controlled temperature

chambers

– Validated analytical procedures

– Training and training documentation

– Labeling of samples, reagents, etc. as to content, expiration dates, date of receipt

– Cleanliness and organization

– Note book or record keeping and its adequacy and reviews

– Procedures for destruction and disposal of rejects and waste


Outline supplier audit (Cont.)

• Other Issues:

– Financials

– Safety

– Environmental stewardship

– Stand Alone Computerized Systems


Auditing Validation Practice

• Qualification and process validation are

critical requirements.

• Audit your supplier practice based on the

new FDA guidance issued in January

2011.

• Ensure that vendor uses the appropriate

systems which follow the guidance

recommendations


Process Validation: General

Principles and Practices

• Guidance to industry issued by the FDA in January 24, 2011.

• Outlines the life cycle approach to validation.

• Inline with the principles advanced in ICH Q8, ICH Q9, ICH Q10 and in ASTM E2500.

• Defines PROCESS VALIDATION as the collection and evaluation of data, from the process design stage throughout commercialproduction, which establishes scientific evidence that a process is capable of consistently delivering quality products.


FDA Guidance:

Process Validation: General

Principles and Practices

• Replaces the guidance issued in 1987

• Quality of the product cannot be assured by simply inspecting or testing in-process and finished products. It must be built into the product-process a-priori.

• Focusing exclusively on the qualification effort without understanding the process and ensuring the process is maintained in a state of control may not lead to adequate assurance of quality.


FDA Guidance To Industry

January 2011

• Three Stages of Process Validation

– Process Design Stage (process is defined based on development and scale-up)

– Process Qualification Stage (Design is confirmed as being capable of reproducible production)

– Continued Verification and improvement (Continuously gaining assurance the process remains in a state of control)


The Life Cycle Approach to

Process Validation

Planning &

Design (ICH Q8)

Implementation

& QualificationContinuous

Verification &

Improvement

ICH Q9

ICH Q9, CAPA, PAT &

Change Control

PAT

ICH Q10

The Quality System


Stage 1: Process Design

• Understanding the science

• Understanding the risk

• Building Quality into the process

• Establishing Control Strategy


Stage 2: Implementation and

Process Qualification

• Implement the process and Facility

• Qualification of utilities and equipment

• Performance qualification and PQ protocol

• Protocol execution and report


Stage 3: Continued Process

Verification

• Monitoring appropriate parameters to ensure process in a validated state of control.

• Use CAPA, PAT and Change control as well as data collected in monitoring to continually improve the process.

• Proper maintenance of the facility, utilities, and process equipment



• Verify documentation of risk analysis during facility, utility systems, and process design

• Ensure principles of quality by design were applied in addressing the design of risky components of such systems and that design rational is properly documented.

• Ensure there is a documented control strategy.

• Ensure qualification of facility, utilities and equipment was performed prior to performing Process Performance Qualification (PPQ).



• Ensure PPQ was successfully performed and that there is a certification as to the acceptability of the process.

• Ensure that the vendor has a process as well as an environmental monitoring program.

• Ensure the use of proper statistical techniques in analyzing monitoring data.

• Ensure vendor has the proper quality systems in place which allows for continuous improvement.

• Ensure vendor has a maintenance and calibration program.


Auditing Validation Practice• Review procedures associated with validation, eg.:

– Conducting risk analysis

– Preparing VMP

– Preparation of qualification protocols

– Computer related system validation

– Protocol execution

– Responsibilities for the validation

– CAPA, Deviation reporting & Investigation, Change control

• Review documentation – Sample risk analysis documentation defining validation/qualification

requirements

– Validation/Qualification Master Plan

– Ensure all systems identified in VMP as requiring qualification were qualified

– Sample executed protocol against your own standards to determine their acceptability.

– Sample deviation reports and associated investigation



• When reviewing documents:– Review for completeness

– Review for accuracy

– Review for quality

– Review for consistency

– Review for good documentation practices.

• Ensure that deviations have been addressed and properly resolved prior to closing the protocols.

• Do not forget the Labs.


Example Audit Forms


Scoring The Audit

• Pass – All is well, no major quality or compliance

issues and better than 75% score

• Conditional – Several minor and correctable

quality or compliance issues and score between

60-75%

• Fail – At least one fundamental compliance or

quality issue that is not correctable or indicative

of organizational problems and a score of less

than 60%.


Advantages of Numerical Audit

• Makes the audit more objective and less

subjective.

• Reduces the entire audit to one or two

numbers which are used to make the

decision.

• Has well defined questions upfront and

thus nothing is forgotten.


Disadvantages of Numerical Audits

• Reduces the entire audit to one or two numbers which are used to make the decision.

• May result in a major item being overlooked because of all other issues being excellent (use weighing).

• Could limit the ability to follow issues as they arise since the questions are predefined.


Audit Report Format

• The Audit Final Report will include:– Description of the reason for the audit

– Description of the product / process and its relationship to the audit requisitioner.

– Description of facility, utility systems and process equipment

– Identification of the individuals responsible for the execution of the audit and their qualifications

– Identification of the flow of material / personnel and equipment

– Identification of the programs, controls, systems and processes to be observed and reviewed

– Identification of the questionnaire(s) and site tour agenda to be utilized in the execution of the audit

– Identification of the Supplier Audit Check List and the Results Summary

– Listing of appropriate observations

– Listing of recommendations (if requested by audit requisitioner)


Audit Report Format

• The Final Report Table Of Content:– Objective

– Scope

– General Description

– Product / Process Specific Description

– Responsibilities

– Methodology / Procedure

– Observations

– Supplier Rating

– Recommendations

– Appendices


Summary

• Auditing your supplier is a regulatory

requirement.

• Auditing your supplier is your way of confirming

their capabilities and compliance status.

• Auditor must be experienced and

knowledgeable.

• Use a formal auditing approach and experienced

auditors.

• Conduct transparent audits.


Interactive Exercise

Develop a check list to guide

auditing of Validation of a Oral

Solid Dosage Process.


OSD Process

ExcipientActive

Weighing &

Dispensing

Mixing Granulation Drying

BlendingTablet PressCoatingCoated

Tablets

To

Packaging

Wetting agent

BinderAir

Coating

Material

Additives

Milling &

Screening

Wet

Milling


The Equipment

• Weighing and dispensing:

– Weighing scales (floor scales, Scales,

utensils)

– Directional Air Flow weighing booths

– IBC (Intermediate Bulk Containers)

– Powder conveying equipment

– Lifts, forklifts, skids, etc.


The Equipment

• Mixing

– Mixing tanks

– Mixers

– IBC tumblers

– Dispensing systems


The Equipment

• Granulation:

– Charge tanks

– Granulators

– Feed system

– Conveying system


The Equipment

• Drying:

– Charging equipment

– Bowl Invertors

– Lifts


– Fluid bed with associated air handling and dust

collection

– Microwave

– Oven

– Vacuum


The Equipment

• Blending and Tablet presses:– Charging equipment

– Lifts


– Blenders

– Tablet press

• Coating– Drum Coating

– Spray coating

– Totes and tablet handling equipment


The Equipment

• Laboratory Equipment– Gas Chromatographs

– HPLC equipment

– Dissolution Bath

– General case work

– Laboratory glassware and general support equipment

• Other– Automation

– Monitoring

– Building condition controls

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