FDA & Regulatory Compliance: Focus on Cleaning Ole T. Madsen Chief Technology Officer, McFlusion

FDA & Regulatory Compliance: Focus on Cleaning Ole T. Madsen Chief Technology Officer, McFlusion 1

Agenda FDA Background CFR Rules FDA organization Actions FDA and Cleaning 2

Agenda FDA Background CFR Rules FDA organization Actions FDA and Cleaning 3

GMP Goal: Quality Product How is that achieved? ORGANISATION FACILITY/EQUIPMENT DOCUMENTATION Qualified personel Maintenance, validation Prove, document, trace PRODUCT DEVELOPMENT Improve product PROCEDURES QUALITY (PRODUCT) CONTROL Describe process Product quality, safety Build quality into the product via the process and personnel 4

What is GMP? GMP Good Manufacturing Practice GMP is part of the law text in Code of Federal Regulations CFR (21CFR 210 and 211) CGMP C means current Interpretations t ti Preamble Inspection Guides Industry Guidelines Current CGMP notes 5

Background BEFORE 1978: Adulteration USP requirements not fulfilled No standard for test and verification AFTER 1978: Focus on the manufacturing process and quality control not the conformity of the final product compendia standards FDAdecides what good practice is not USCongress 6

Agenda FDA Background CFR Rules FDA organization Actions FDA and Cleaning 7

21CFR Part 210/211 Proposed in 1962 Final rule 1979 Proposed amendments may 1996 8

GMP Rules Drugs part 210 & 211 Biologics part 600 Medical devices part 820 Foods part 110 9

Agenda FDA Background CFR Rules FDA organization Actions FDA and Cleaning 10

FDA Organization CBER Center for Biological Evaluation and Research CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health ORA Operation of Regulatory Affairs FOI FDA s Freedom Of Information Inspection Guides Guidance documents 11

Agenda FDA Background CFR Rules FDA organization Actions FDA and Cleaning 12

FDA Actions 483 Observations Warning Letters Consent decrees 13

Agenda FDA Background CFR Rules FDA organization Actions FDA and Cleaning 14

FDA points of view 1988 Recall of a pharmaceutical product attracts the attention of FDA. 1992 FDA issues a warning against import from a foreign pharmaceutical company. 1992 Barr Laboratories denies that the cleaning validation is a requirement according to cgmp. FDA Inspection Guideline Guide to Inspections of Validation of Cleaning Processes (1993) 15

Guidelines FDA guidelines CFR 211 FDA Inspection Guide (1993) FDA API Guide (draft 1998) Industrial guidelines PDA Cleaning and Cleaning Validation: A Biotechnology Perspective (1996) PDA Technical Report No. 29: Points to Consider for Cleaning Validation (1998) Books, articles, etc. Destin LeBlanc: Articles, technical tips, books, e.g. Validated Cleaning Technologies for Pharmaceutical Manufacturing Bill Hall: Articles, courses Michael Mullen: Articles 16

Legislation Code of Federal Regulations (21 CFR) 211.63 Design, size and placement of equipment Equipment for manufacturing, processing, packaging must be designed d with a view to facilitating ti the cleaning to the greatest t possible extent 211.67 Cleaning and maintenance of equipment Cleaning for the sake of avoiding forgery In compliance with written procedures Recordings of cleaning 211.182 Cleaning of equipment and recording of usage Most recently produced batch Personnel performing the cleaning Chronological record of activities 17

cgmp Part 211.67 - Equipment Cleaning and Maintenance 211.67 Equipment cleaning and maintenance. (a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. (b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (1) Assignment of responsibility for cleaning and maintaining equipment; (2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules; (3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance; (4) Removal or obliteration of previous batch identification; (5) Protection of clean equipment from contamination prior to use; (6) Inspection of equipment for cleanliness immediately before use. (c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in 211.180 and 211.182. 18

FDA - Guide to inspection of validation of cleaning processes Part 1 Validation protocols prior to test of equipment evaluation of cleaning validation when is a production system clean? which level variations must be expected between each batch test sample procedures Analytical methods Implementation of validation test Validation report to be approved by the management proves that the cleaning process is valid the report must contain data substantiating the fact that the cleaning has removed ed the product or cleaning residues to an acceptable level.

FDA - Guide to inspection of validation of cleaning processes Part 2 Cleaning processes must be validated Data must prove that the process passes off as expected in a consistent way. The process produces a result which continuously meets the stipulated requirements Instructions for cleaning processes Procedures for validating cleaning processes Who is responsible for implementing the validation? Who is responsible for approving? Who is responsible for outlining/approving criteria for acceptance? When must revalidation take place?

FDA Guidance for Industry Manufacturering, Processing, or Holding Active Pharmacautical Ingredients (draft March 1998) Where feasible, clean in place (CIP) methods should be used to clean process equipment and storage vessels. CIP systems should be subjected to cleaning validation studies to ensure that they provide consistent and reproducible results. During cleaning validation should be disassembled to facilitate inspection and sampling of inner product surfaces for residues or contamination, even though the equipment is not normally disassembled during routine use. IV Process Equipment (F) Clean in Place Methods. 21

In a report published by ECA analyzing FDA Warning Letters in 2004 the 21CFR 211.67 Equipment Cleaning and Maintenance is one of the most frequent Warning Letter citations. 22

Typical 483 observations during FDA inspections 9-13% of all cgmp defects observed by FDA in Europe in 1999 and 2000 can be referred to the area Cleaning of equipment - Inadequate equipment cleaning and - Residue limits for potential contaminants validation protocols not established - Cleaning methods for common equipment not validated - Inadequate sampling and testing of equipment surfaces - Specificity and sensitivity of analytical methods not established - No testing for residues of solvents used in API production - No record to document alarms with the - The CIP validation did not include studies cleaning equipment to determine or evaluate what are the most difficult ( Hot Spot ) locations to - CIP record sheets that document the CIP of clean. the manufacturering equipment are not reviewed by Production or Quality Assurance Staff. 23

Cleaning Documentation The cleaning validation must document the efficiency of a cleaning procedure The cleaning procedure must be reliable with regard to removal of contamination (e.g. products, cleaning agents, microorganisms) to a predetermined acceptable level Procedures for cleaning of areas in product contact must be validated (with consideration to areas out of product contact). The intervals between use and cleaning of equipment as well as between cleaning EudraLex and Volume reuse 4 of Annex equipment 15 subsection must be 36validated. 24

Cleaning Documentation Recordings Preceeding product Batch to batch cleaning or product to product cleaning The cleaning documentation for equipment which is considered to be critical for the product Samling of equipment which is considered critical for the product Applied cleaning agents and concentrations (batch no.) Time of cleaning date of performance and signature Observations during inspection of equipment prior to production 25

Increased FDA Focus on Cleaning-Related Issues: 1) Inadequate, inconsistent manual cleaning. 2) Inadequate scientifically-based cleaning cycle development rationale. Analytical methods Recovery studies Worst-to-Clean definitions in current cleaning validation processes 3) Cleaning related issues in existing, validated d (CIP) processes. 4) Lack of consistency in CIP recipe cleaning methods on identical products within the same company. 26

FDA & Regulatory Compliance: Focus on Cleaning Ole T. Madsen Chief Technology Officer, McFlusion 27