Frank S. Kohn, PhD, SM(NRM),ASCP,CCM
FSK Associates, Inc.
Manson, Iowa 50563 USA
This two part technical report will put forward series of recommendation for a quality management program for Environmental Monitoring and Control. This included an evaluation of industry practices, regulatory requirements, and current methods utilized by Biopharmaceutical plant sites. The result of this effort has developed into a listing of several recommendations for potential implementation at plant sites. These recommendations include environmental monitoring controls at all stages of product development and supply chain production.
The management and control of an acceptable environmental program is extensive and comprehensive. This is the reason for a brief over view of the subject to assist in understanding the recommendations provided.
The purpose of this report is to provide the reader with a background on the complex subject of environmental monitoring and a summary review of the PDA Technical Report No.13 and Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing, CGMP, September 2004. This report discusses the microbiological and particulate control concepts as they relate to the manufacturing of biopharmaceuticals. This paper represents a global view of methods, terminology, and practices of procedures to track, trend, control, and manage an environmental monitoring program. Several of the recommendations are a reflection of the current changing regulatory requirements and standards from various regulatory agencies. (Examples – FDA, MCA, Canada, and EU). In all cases the recommendations represent a guide to meet current Good Manufacturing Practices (cGMP) requirements.
The management and control of an acceptable environmental program is extensive and comprehensive. This is the reason for a brief over view of the subject to assist in understanding the recommendations provided..
A consistent acceptable environmental monitoring control program should include the following:
- Environmental Classification
- Risk Analysis
- Surveillance Information
- Data Collection Program
- Alert and Action Levels
- Characterization of Isolates
- Change Control
- Investigation Program
- System Surveillance
A consistent approach should be followed while establishing an environmental monitoring program for biological manufacturing facilities. A proposed classification based on risk analysis and defined as critical control areas and controlled areas can provide suitable environmental conditions for Research, Development, and Manufacturing of biological products and their intermediates.
* Critical controlled areas are those in which process steps are carried out when the product cannot tolerate microbial contamination. Example – final intermediate and final filling of product.
*Controlled areas encompass non processing support areas and processes which can tolerate minimal levels of microbial contamination due to either short processing times, low temperatures, or subsequent bioburden reduction steps. Example – Glassware preparation or media preparation processing.
Critical and support areas of the aseptic processing operations should be classified based on ISO classification and supported by microbiological and particulate data obtained during qualification studies of the facilities. While initial clean room qualifications include some assessments of microbial quality under static conditions, final room and area classifications should be obtained from data generated under both static and dynamic conditions. Example- personnel present, equipment in place, and operations ongoing. See Table A 1. Air Classifications.
Measurements of air cleanliness in aseptic processing zones should be taken with particulate counting probe oriented in the direction of on coming airflow and where sterilized product and container-closure are exposed. Regular monitoring should be performed during each shift.
Air in critical controlled areas should be supplied at the point of use HEPA filtered laminar flow air at a velocity sufficient to sweep particulate matter away from the filling/closing area and maintain laminarity during operations.
Biopharmaceuticals and components are produced in closed systems with no personnel exposed to live bacterial or viral pathogens. The purification process are usually performed in ISO 7, (class C) controlled areas. Controlled areas are designed to protect the product from direct environmental contact. Clean connections are used to transfer product from the different process tanks. The final stages of production are in critical controlled ISO 5/6, class A/B environment. See Area Classification Summary.
Data should be collected, tracked, and trended in compliance with current Good Manufacturing Practices (cGMP). Personnel should be adequately trained in order to evaluate the data to make appropriate decisions. All equipment must be calibrated and appropriately validated.
Sampling must be performed under both static and dynamic conditions. Sampling during inactivity must be in compliance with room classifications. The primary purpose of sampling should be to provide meaningful interpretable data that can assist actual or potential contamination problems associated with specific procedures, equipment, materials, personnel, and processes. Frequency of sampling should be based on risk
assessment and regulatory requirements.
Factors to consider in selecting sampling sites for routine surveillance are:
- Laminar flow hoods
- Hood curtains
- Room floor surfaces
- Gloves of personnel
- Equipment surfaces
Detailed descriptions of all sample sites should be included in standard operating procedures (SOP). Establish action and alert limits for sampling sites and frequency of sampling should be considered during validation. Sites having the greatest opportunity (risk) for contributing to bioburden of the product should be sampled and monitored.
ENVIRONMENTAL MONITORING COLLECTION OF DATA:
Environmental monitoring programs must have a system in place that will have the ability to track, trend, and analyze collected data. Also, any system must be in full compliance with all governmental and regulatory requirements .The system should be capable of communicating to designated departments such as QA, Mfg., and QC. An alert and action level notification and trending data needs to be sent to appropriate senior management for evaluation on timely bases. Because of the magnitude of the environmental monitoring data, FDA believes a computerized system, such as that provided by Novatek International is invaluable.
Table A – Air Classifications
|Clean Area (old)
|MicrobiologicalSettling Plate Action Levels
Table B – List of ISO 14644 Parts
|14644-1||Classifications of Air Cleanliness|
|14644-2||Specification for testing & monitoring to prove
Continued compliance with ISO 14644-1
|14644-3||Metrology & test methods|
|14644-4||Design, construction and start-up|
|14644-6||Terms, definitions & units|
|14644-7||Separative Enclosures (clean air hoods, glove boxes,
Isolators and mini-environments)
Table C: Excerpts from ISO 14644-1, Table 1 – Airborne Particulate Cleanliness (at rest)
|ISO class 5||3500||1* (20)|
|ISO class 6||35,000||1 *(20)|
|ISO class 7||350,000||2,000|
|ISO class 8||3,500,000||20.00|
- “the maximum permitted number of particulates at >5.0 microns
is established at 1/ M3 but for reasons related to the false counts associates with electronic noise, etc. a limit of 20/M3could be considered.”
Table D: Excerpts from EC GMPs Guide, Annex – 1, Table on Airborne Particulate
Classification Grades. (MHRA Guidance)
Maximum permitted number of particles per meter cube equal to or above
At Rest In Operation
|0.5 um||5.0 um||0.5 um||5.0 um|
|D||3,500,000||20,000||Not defined||Not define|
Table E: Excerpts from EC, GMPs Guide, Annex 1 – Table on Limits for Microbial
(dia. 90 mm),
(dia. 55 mm).