Points to Consider for Cleaning Validation

1 BethesdaTowers4350 EastWestHighwaySuite200 Bethesda, MD20814 USATel:1 (301)656-5900 Fax:1 Report No. 29 (Revised 2012) Points to Consider for Cleaning ValidationParadigm Change in Manufacturing Task Force on Technical Report No. 29 (Revised 2012): Points to Consider for Cleaning ValidationAuthorsDestin A. LeBlanc, Cleaning Validation Technologies (Chair)Gretchen Allison, PfizerJennifer L. Carlson, GenentechKoshy George, ConsultantIgor Gorsky, ConcordiaValSourceIrwin S. Hirsh, Novo Nordisk ASJamie Osborne, Siegfried (USA), Randall, Baxter BiosciencePierre-Michel Riss, Eli LillyGeorge Verghese, STERIS CorporationJenn Walsh, Bristol-Myers SquibbVivienne Yankah, Sanofi-Pasteur, content and views expressed in this Technical Report are the result of a consensus achieved by the authorizing Task Force and are not necessarily views of the organizations they to Consider for Cleaning Validation Technical Report No.

2 29 (Revised 2012)ISBN: 978-0-939459-48-3 2012 Parenteral Drug Association, Inc. All rights , MD20814 USATel:1 (301)656-5900 Fax:1 Change in Manufacturing Operations (PCMOSM)PDA launched the project activities related to the PCMO program in December 2008 to help imple-ment the scientific application of the ICH Q8, Q9 and Q10 series. The PDA Board of Directors ap-proved this program in cooperation with the Regulatory Affairs and Quality Advisory Board, and the Biotechnology Advisory Board and Science Advisory Board of PDA. Although there are a number of acceptable pathways to address this concept, the PCMO program fol-lows and covers the drug product lifecycle, employing the strategic theme of process robustness with-in the framework of the manufacturing operations.

3 This project focuses on pharmaceutical Quality Systems as an enabler of Quality Risk Management and Knowledge the Parenteral Drug Association s (PDA) membership expertise, the goal of the Paradigm Change in Manufacturing Operations Project is to drive the establishment of best practice docu-ments and /or training events in order to assist pharmaceutical manufacturers of Investigational Medicinal Products (IMPs) and commercial products in implementing the ICH guidelines on Phar-maceutical Development (ICH Q8, Q11), Quality Risk Management (ICH Q9) and pharmaceutical Quality Systems (ICH Q10). The PCMO program facilitates communication among the experts from industry, university and regula-tors as well as experts from the respective ICH Expert Working Groups and Implementation Working Group.

4 PCMO task force members also contribute to PDA conferences and workshops on the follows the product lifecycle concept and has the following strategic intent: Enable an innovative environment for continual improvement of products and systems Integrate science and technology into manufacturing practice Enhance manufacturing process robustness, risk based decision making and knowledge manage-ment Foster communication among industry and regulatory authorities Product DiscontinuationCommercial ManufacturingTechnology TransferPharmaceutical DevelopmentThe Product Life CycleFor more information, including the PCMO Dossier, and to get involved, go to Introduction .. Purpose/Scope.

5 Glossary of Terms .. Definition of Acronyms .. Cleaning Process Design and Development .. Cleaning Process Design .. Cleaning Process Overview .. Physical-chemical Aspects .. Design Considerations .. Location of Cleaning .. In-Place Cleaning .. Clean-in-Place (CIP) Systems .. Solvent Reflux Cleaning .. Placebo Batches as a Cleaning Method .. Out-of-Place Cleaning .. Clean-Out-of-Place Systems .. Automated vs. Manual Systems .. Manual Processes .. Semi-Automated Processes .. Automated Processes .. Soil Evaluation and Categorization .. Soil Categories .. Soil Equipment Considerations .. Dedicated Nondedicated Manufacturing Equipment .. Nonproduct Contact Product Contact Surfaces.

6 Low-Risk Sites High-Risk Sites . Materials of Construction .. Operational Considerations .. Cleaning Agent Selection .. Product Product Risk Considerations .. Cleaning Development Laboratory Experiments .. Soil Selection .. Parameter Selection .. Parameter Interactions .. Measurements to Determine Cleaning Effectiveness .. Cleaning Process Scale-Up .. Setting Process Controls .. Applying the Design Space Concept to Cleaning Processes .. Standard Operating Procedures .. Operator Training for the Cleaning Process .. Introduction of New Products to a Validated Cleaning System .. Qualification .. Protocol Elements .. Key Protocol Issues .. Number of Runs in a Protocol.

7 Mock Soiling .. Worst-Case Process Conditions .. Disposition of Products and Equipment during Validation .. Grouping/Family Approach .. Product Grouping .. Equipment Grouping .. Introduction of a New Product or Equipment into a Group .. Cleaning Verification Documentation .. Residue and Limits .. Considerations for Developing Limits .. The Basis for Quantitative Limits .. Acceptable Concentration of Residue in Next Product .. ARL Based on Drug Active Dose .. ARL Based on Toxicity .. ADE Determinations Based on ISPE s Risk-MaPP .. Toxicity Calculations Based on LD50 Data .. Other ARL Determinations .. Acceptable Total Carryover .. Surface Area Limit .. Limit in Protocol Samples.

8 Limit per Swab .. Concentration Limit in Extracted Swab Solvent .. Concentration Limit in Rinse Sampling Solution .. Consolidated Expressions .. Example Calculations .. Other Considerations .. Multiple Next Products .. Next Product in Verification Approach .. Default Limits ..37 Table of Use of Different Safety Factors .. Different Routes of Different Doses for Adults and Children .. Human and Veterinary Products Manufactured on the Same Equipment .. Residues of Genotoxic and Other Highly Hazardous Active Ingredients .. Limits Based on Analytical Detection Limits .. Degradation of the Active Ingredient . Limits Not Measureable .. Limits for Organic Solvents .. Dedicated Equipment.

9 Dividing a Limit among Various Pieces of Equipment .. Limits for Preferential Transfer to a First Portion of the Next Product .. Limits for Biotechnology Manufacture .. Products with More Than One Active Ingredient .. Bioburden Limits .. Endotoxin Limits .. Visually Clean Criterion .. Sampling .. Sampling Method Selection .. Direct Sampling Methods .. Visual Inspection .. Instrumental Methods .. Rinse Sampling .. Extraction Rinse Sampling for Small Parts .. Solvent Reflux Sampling .. Swab and Wipe Sampling .. Placebo Sampling .. Sampling for Microbial and Endotoxin Analysis .. Additional Sampling Recovery Studies .. General Considerations .. Swab/Wipe Recovery.

10 Rinse Recovery .. Recovery in Visual Inspection .. Recovery for Bioburden and Endotoxin Sampling .. Training and Qualification of Samplers .. Key Issues for Training for Swab Sampling .. Key Issues for Training for Rinse Sampling .. Training for Visual Inspection .. Analytical Methods .. Purposes of the Analytical Methods .. Practical Considerations in Selecting Analytical Methods .. Specific vs. Nonspecific Analytical Methods for Validation Protocols .. Regulatory Status of Specific and Nonspecific Methods .. Most Commonly Used Analytical Techniques Liquid Chromatography (LC) .. UltraViolet/Visible Spectrophotometry (UV/Vis) .. Total Organic Carbon (TOC) .. Conductivity.