Conducting Supplier Audits: Ensure Validation Compliance

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. All rights reserved. Do not copy without permission. 2

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. All rights reserved. Do not copy without permission. 3

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. All rights reserved. Do not copy without permission. 4

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. All rights reserved. Do not copy without permission. 5

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). All rights reserved. Do not copy without permission. 6

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. All rights reserved. Do not copy without permission. 7

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. All rights reserved. Do not copy without permission. 8

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. All rights reserved. Do not copy without permission. 9

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. All rights reserved. Do not copy without permission. 10

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. All rights reserved. Do not copy without permission. 11

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. All rights reserved. Do not copy without permission. 12

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. All rights reserved. Do not copy without permission. 13

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. All rights reserved. Do not copy without permission. 14

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. All rights reserved. Do not copy without permission. 15

Conducting The Audit (Cont.) 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. All rights reserved. Do not copy without permission. 16

Conducting The Audit (Cont.) 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 All rights reserved. Do not copy without permission. 17

Conducting The Audit (Cont.) Packaging and Labeling Appropriate Procedures. Label Controls. Label count reconciliation. Validation of automated systems Confirmation of use of proper labels on packaged product. All rights reserved. Do not copy without permission. 18

Conducting The Audit (Cont.) 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. All rights reserved. Do not copy without permission. 19

Conducting The Audit (Cont.) 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 All rights reserved. Do not copy without permission. 20

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 All rights reserved. Do not copy without permission. 21

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 All rights reserved. Do not copy without permission. 23

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 commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. All rights reserved. Do not copy without permission. 24

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. All rights reserved. Do not copy without permission. 25

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) All rights reserved. Do not copy without permission. 26

The Life Cycle Approach to Process Validation Planning & Design (ICH Q8) PAT Continuous Verification & Improvement ICH Q9, CAPA, PAT & Change Control ICH Q9 Implementation & Qualification ICH Q10 The Quality System All rights reserved. Do not copy without permission. 27

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 All rights reserved. Do not copy without permission. 29

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 All rights reserved. Do not copy without permission. 30

Auditing Validation Practice 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). All rights reserved. Do not copy without permission. 31

Auditing Validation Practice 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. All rights reserved. Do not copy without permission. 32

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 All rights reserved. Do not copy without permission. 33

Auditing Validation Practice 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. All rights reserved. Do not copy without permission. 34

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%. All rights reserved. Do not copy without permission. 37

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. All rights reserved. Do not copy without permission. 38

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. All rights reserved. Do not copy without permission. 39

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) All rights reserved. Do not copy without permission. 40

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 All rights reserved. Do not copy without permission. 41

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. All rights reserved. Do not copy without permission. 42

OSD Process Excipient Wetting agent Active Weighing & Dispensing Mixing Granulation Wet Milling Drying To Packaging Coated Tablets Coating Binder Tablet Press Additives Blending Air Milling & Screening Coating Material All rights reserved. Do not copy without permission. 44

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. All rights reserved. Do not copy without permission. 45

The Equipment Drying: Charging equipment Bowl Invertors Lifts Conveying system Fluid bed with associated air handling and dust collection Microwave Oven Vacuum All rights reserved. Do not copy without permission. 48

The Equipment Blending and Tablet presses: Charging equipment Lifts Conveying system Blenders Tablet press Coating Drum Coating Spray coating Totes and tablet handling equipment All rights reserved. Do not copy without permission. 49

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 All rights reserved. Do not copy without permission. 50