An Audit Approach to Address Microbial Contamination in Process Equipment

Transcription

1 An Audit Approach to Address Microbial Contamination in Process Equipment Presented By Paul Lopolito, Technical Services Manager and Elizabeth Rivera, Technical Services Specialist STERIS Corporation

2 Agenda Regulatory Perspective Pre-inspection Work Inspection Summary

3 Why should we worry about this? From years there were 642 recalls involving microbiological contamination being 15% 72% of the citations were Med Sterile Devices, 15% Pharmaceuticals, Products with primary cause 11%being OTC,packaging 7% Cosmetics, andand 2% concerns 22% of thesupplements. citationserrors. were NonDietary manufacturing Sterile Products with primary cause being objectionable microorganisms (B. cepacia).

4 Regulatory References Control of Microbial Contamination 21 CFR Drug 21 CFR Dietary Supplements 21 CFR Medical Device 21 U.S.C. 361 Cosmetics Contamination =

5 Agenda Regulatory Perspective Pre-inspection Work Inspection Summary

6 Pre-Inspection work Auditor s check list: Assemble team Be prepared Collect information Assess risk

7 Types of Microbial Contamination Yeasts, molds, bacteria, viruses or other similar microscopic organisms. Includes species that: May have public health significance May cause product to decompose May be indication that product contaminated with filth May cause product to be adulterated

8 Importance of Microbial ID Helps to focus on the source (s) of the contamination Intrinsic vs. Extrinsic sources History of microbe on site Understand risk and concerns

9 Understanding Microbial Resistance Vegetative Bacteria (Staphylococcus) Enveloped Viruses (Herpes, Hepatitis, HIV) Larger non-enveloped viruses (Adenoviruses, Rotovirus) Vegetative Fungal Cells (Trichophyton) Fungal spores (Aspergillus niger) Small non-enveloped viruses (polio, parvo) Mycobacterium (Mycobacterium tuberculosis) Bacterial Endospores(Bacillus, Clostridium) Prions R e s i s t a n c e Gerald McDonnell, Antisepsis, Disinfection, and Sterilization: Types, Action, and Resistance 2007, ASM Press

10 Cleaning and Process Review Product, personnel, and waste flow diagrams Equipment P&ID s Cleaning procedures

11 Cleaning Practices Lab Studies Cleaning Critical Parameters: Time (wash, rinse, etc.) Action Cleaning agent Cleaner concentration Temperature (wash, rinse, etc.) Water quality Environmental factors (e.g. humidity) Rinsing Verghese, G. (1998). Selection of Cleaning Agents and Parameters for cgmp Processes, Proceedings of the INTERPHEX Conf., Philadelphia, Reed Exhibition Co, Norwalk, CT, pp

12 Agenda Regulatory Perspective Pre-inspection work Inspection Summary

13 Inspection Auditor s Check List Detect Interrogate Confirm

14 Potential Sources of Microbial Contamination Raw materials actives and non-actives Packaging components Personnel Environment air, room Utilities water Equipment Pre-setting microbial limits or sterilizing them Establishing cleanroom disinfection and gowning procedures Qualifying and maintaining USP Water generation system, compressed air, N 2, etc Establishing robust cleaning procedures, addressing design issues, and setting sterilization or sanitization parameters.

15 Raw Material, Processing Aids and Packaging Components Case Study 1: Change in Formulation (Eco-friendly)

16 Warning Letters Cosmetics, Ohio (2012) During the inspection several insanitary practices were observed that have the potential to cause your product to be contaminated with filth or become injurious to health. For Example: 1. The microbial safety of starting materials does not appear to be routinely evaluated. Materials are not sampled and tested or examinedin conformance with procedures assuring the absence of contamination with filth, microorganisms or other extraneous substances to the extent necessary to prevent adulteration of finished products. 2. Fixtures, ducts and pipes are not installed in such a manner that drip or condensate does not contaminate cosmetic materials, utensils, cosmetic contact surfaces of equipment, or finished products in bulk. The FDA investigator was advised that during summer month s condensation may form on piping above manufacturing kettles which may subsequently drip into kettles. This condition may result in microbial contamination of the product

17 Personnel and Room IEST RP-CC027: Personnel Practices and Procedures in Cleanrooms IEST RP-CC018: Cleanroom Housekeeping ISO Cleanroom Classifications USP <1072> Disinfectants and Antiseptics

18 Warning Letters Finished Pharmaceuticals, Florida (2012) The following observations are examples of insanitary conditions observed by FDA investigators during the inspection of your Hollywood, Florida facility. 1. In preparation for and during your firm s aseptic compounding process for DRUG X on September 19, 2011, you were observed to incorrectly don shoe covers, improperly wash your hands and forearms and dry them with kitchen-grade paper towels, wear a gown which exposed approximately one inch of skin on the wrist area between your gloves and the gown sleeves, and frequently lean your head and torso inside the LAF and over the product. 2. On September 19, 2011, one of your employees was observed inside the clean room performing a demonstration of the bubble point test in the Class 5 LAF. The employee s hairnet was donned improperly, exposing approximately fifteen inches of the employee s hair to the environment throughout the entirety of the demonstration. The supervisor did not instruct the employee to correct the deficiencyuntil the demonstration was completed, after FDA personnel brought it to his attention.

19 Utilities Water and steam generation systems Routine monitoring results Preventative maintenance Non routine service Compressed gases Heating and cooling systems

20 Walk-through the Areas Visual inspections: Camera Light Magnifier Inspection mirror Boroscope Samples: Rinse Swabs Contact plates

21 Processing Equipment Surfaces and Equipment Design Residue Type and Cleaning Parameters Sterilization/ High Level Disinfection Parameters Elements Affecting Microbial Decontamination

22 Residue Type and Cleaning Parameters Changes: Manufacturing Batch Composition Dirty Hold Time Environmental Others Affects: Residue Characteristics Alters: Soil Condition and Cleanability Evaluate current cleaning practices for effective removal of: Process residue Microbial residue

23 -Case Study 2- Example: Multiproduct facility Finished products Hard to clean Process Soil Product evaluated contains a polymer and insoluble oil CLEANER CONC. TIME/ TEMPERATURE VISUAL OBSERVATION Comparison Test Sodium Laureth Sulfate 2 2 % v/v 15 min / 60 C Trace Formulated Alkaline Cleaner 3 % v/v 60 min / 60 C Trace Formulated Alkaline Cleaner with detergent additive containing hydrogen peroxide 1 % v/v + 1 % v/v 15 min / 60 C Visually Clean Concern about current cleaning practices due to microbial issue (B. cepacia) at one of the companies manufacturing locations

24 Microbial Residue Hyphae, Endotoxin, Biofilm EPS consists of polysaccharides, proteins, nucleic acid and lipids EPS can be harder to clean than process residues Residual organic material can reduce efficacy of biocides Residual EPS can reduce penetration of biocides Pictures provided by Dan Klein and Amanda Deal

25 Microbial Residue Removal P. Aeruginosa Sporicide Formulated Alkaline Detergent Photographs by: Center for Biofilm Engineering, Bozeman, MT 25

26 Surfaces Rouge and Scale Build-Up

27 - Case Study 3 - Situation: Objectionable microbial contaminant, E. cloacae, in piping, transfer tank and filler. Recommendation: Step (1) precleaning with formulated alkaline detergent at 5% v/v + booster 60 to 80ºC for 3-4 hours, Step (2) acid cleaning and passivation with formulated acid detergent at 15% v/v 80ºC for 3-5 hours, Step (3) sanitization with H2O2/PAA formulated blendat25 Cfor30min.

28 Equipment Design Sanitary Cleaning Connections Cleaning Solution solution Coverage Welding coverage Drainability is preferred Profile for connecting pipes. Velocity Profile (~5 ft/s for most pipe diameters) For vertical tanks: Valve Selection Dead-Leg Orientation Gaskets and Tubing Inspection Laminar deformities. Dead-Leg Orientation Surface Non-uniformities Sanitary clamp-type connections for nonpermanent connections. To drain Drainability Turbulent Sanitary connection Welded connection should not have excessive Volumetric Flow rate (in GPM) of 2.5 to 3.0 times circumference in feet cracks, crevices, misalignments, or other surface 1/16 inch/foot (0.5 cm/m)

29 Surfaces & Equipment Design For Manual Cleaning Applications: Manual assembly and disassembly (scratches) Corners and crevices need particular attention (overlooked) Drainability Hard-to-reach areas

30 More About Rouge and Equipment Design Issues Lopolito, P. Addressing Rouge in Biopharmaceutical Manufacturing. Pharmaceutical Technology. jsp?id= Rivera. E. Basic Equipment Design Concepts to Enable Cleaning in Place.Pharmaceutical Technology. il.jsp?id=

31 Sterilization/High-Level Disinfection Methods High Temperature Steam (Moist Heat) Dry Heat Superheated water Gas / Vapor Ethylene Oxide (VHP) Hydrogen Peroxide Chlorine Dioxide Ozone Radiation Gamma Radiation E-Beam X-ray UV Mechanical Filtration Chemical Sporicide/Sterilant High-level disinfectants

32 Sterilization/High-Level Disinfection Methods Type Steam Dry Heat Hydrogen peroxide Critical parameters Time, temperature and saturated steam Time and temperature Vapor concentration, time, humidity and saturation Chlorinedioxide Ozone Gas concentration,time, temperature, humidity and pressure Gas concentration, time, humidity and pressure Chemical sterilization Concentration, time, temperature, water hardness 32

33 Agenda Regulatory Perspective Pre-inspection work Inspection Summary

34 Audit Approach - Summary Identify microbe and history on site Understand the different pathways of the MFG process Understand cleaning practices for process and microbial residues Assess clean-ability of equipment Understand sterilization/disinfection and clean hold practices Identify existing controls and flag concerns

35 For additional information or questions, please contact: Paul Lopolito Manager Technical Services Elizabeth Rivera Technical Services Specialist

36 Lopolito and Rivera, An Audit Approach to Address Microbial Contamination in Process Equipment, Chapter 15 in Contamination Control in Healthcare Product Manufacturing, Volume 1, PDA/DHI Publishing (2013).