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.
ALERT AND ACTION LEVELS:
Alert and action levels need to be established for all areas. Action levels are based upon published standards, guidelines, and policy. All action levels must be in compliance with USP<1116> requirements and European Union and other Boards of Health standards. See Tables C, D, and E.
Alert levels are based on historic data. These levels must be able to detect trends or drifts from expected EM results. There are several methods for calculating Action levels.
- Cut Off Value – all data for a particular area are arranged in a histogram and alert and action levels are set values whose results are respectively 1% and 5% higher than levels selected. (Per PDA Technical Report No. 13).
- Normal Distribution – this is best used for high-count results only. The means and standard deviation of the data are calculated and alert and action levels are set at the mean plus 2 or 3X the standard deviation. (Per PDA Technical Report No 13).
- Non-parametric Tolerance Limits – alert and action levels are set using non-parametric methods. (See PDA Technical Report No. 13 for a discussion of the method).
- New Facilities – procedures use data from base line, start up, and summarized within the first qtr. of the year the facilities are started. Alert levels are established by calculating the average of each data point for all rooms in a given classification. The new specification will be the average plus two standard deviations from the prior year norm.
CHARACTERIZATION OF ISOLATES:
It is an important requirement to characterize microorganisms isolated from both the environment and personnel-monitoring program. Written standard operating procedures (SOP) must be developed by the Quality Control Microbiology laboratory. All microorganisms isolated from critical controlled (ISO 5/6, class A/B) areas must be identified. This identification should be to the genus and species level if possible. All other isolates in controlled areas are to be identified whenever alert or action levels are exceeded. Summary of all identified microorganism should be tabulated and circulated to the appropriate quality management.
Change control programs must be established per company and regulatory agency expectations. This program must have written SOP’s and documentation programs to track, approve, and control all changes that may affect the EM program. In addition, a follow up after implementation of the change should be reviewed for any deviations.
There shall be written and approved investigation programs in place. These programs will communicate whenever alert/action levels are exceeded. This should include notification of exceeding alert or action levels to senior level management as part of your Quality System program. All corrective actions must be documented and follow up reviews to assess the effectiveness of the corrective actions.
All systems associated with the sterilization process and environmental controls must be monitored, validated, and controlled to insure product sterility and integrity. A list of some of the systems that need to be controlled under the EM program include the following:
- Aseptic filling
- Water monitoring
- Compressed gas monitoring
- Air monitoring
- Non-viable monitoring
- Viable monitoring
- Personnel monitoring
- Training/certification of personnel
- Product bioburden
- Product and intermediate release
- In-process testing
- Stability testing
VALIDATION/QUALIFICATION OF EM SYSTEMS:
Validation/qualification is a regulatory expectation for all critical controlled areas and controlled areas. All systems must be validated. The validation requirement includes an expectation of acceptance criteria and detailed description of each process, equipment, or system being validated. Some of the critical validation systems should include:
HVAC system. Testing of classified areas in both static and dynamic conditions. Also, standards in this area are in the process of changing regulation from to ISO 14644 standards.
Utilities. These systems are required to be validated and monitored routinely.
Aseptic Process. Process simulation using media fills are expected to be conducted to evaluate the total system of aseptic filling for clinical trail material and production. Issues such as worst case, media growth promotion, incubation times, documentation, acceptance criteria, and investigation programs need to be in place..
The study recommendations in this reported is summarized as follows:
- Replace Fed. Std. 209E Classification of Air Cleanliness with ISO 14644-1, Classification of Air Cleanliness and ISO 14644-2, Specifications for Testing &Monitoring for all areas that have room classifications. (Example: Class 100 rooms will be referred to as ISO 5 rooms). FDA recognizes the ISO designations. In addition, Grade A, B, C, and D room classifications may be used for those locations that are required to meet other government regulations. (On 29 November 2001, the GSA-FSS issued a notice of cancellation of Fed. Std. 209E and states it had been superseded by the International Organization for Standardization (ISO) standard “Cleanrooms and Associated Controlled Environments,” ISO 14644-1 and ISO 14644-2.).
- Risk Assessment needs to be performed to identify and assess risk to the process, product and personnel, and to mitigate against that risk. The risk assessment should be carried out according to established methods such as Failure Modes Effects Analysis (FMEA), Hazard Assessment of Critical Control Points (HACCP) or Hazard Assessment in Operation (HAZOP). Once risk are identified and assessed, risk reduction measures can be introduced. This process will serve to address potential risk, focus validation efforts and establish a scientific rational for the environmental monitoring program.
- Critical control area and control area are to be used to describe room areas located within an ISO classified room. (Example: ISO 5 room that has both critical controlled zone, inside laminar flow area and controlled zone, outside laminar flow area).
- Research & Development (R&D) facilities will incorporate the appropriate environmental monitoring specifications based on a sound scientific rational, risk assessments, and regulatory requirements. Environmental monitoring requirements increase as research and development moves the product into clinical trial material.
- Alert and action levels must be included in all environmental monitoring requirements. (See Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice, September 2004).
- Responsibilities for the EM program need to be assigned. Quality Assurance has
responsibility to ensure control of all matters that influences the quality of
the product. This includes management responsibility for assuring all cGMP
procedures and regulatory requirements are in place for the environmental
monitoring program. Quality Control is responsible for performing sampling
and testing of the environment, tracking and trending of data, and reporting results
to senior management. Additional site functions need to be assigned various
responsibilities to ensure full compliance with all regulatory and quality
- Sterilize vs. sanitize tanks – sanitization of buffer tanks and sterilization of all tanks used for intermediate holding of sterile product should be validated for both hold times, storage times and acceptability of use.
- Pre and Post integrity testing – post integrity test for 0.45-micron filters and pre and post integrity testing for all 0.22 micron filters. Pre and post testing of 0.22 micron filters is recommended in report from F.D.A. in, “Sterile Drug Product by Aseptic Processing”, Sept. 2002.
- Training needs to be provided for all personnel whose duties involve any aspect
that could have an effect on the environmental monitoring and control program.
This training should include assessment as to the effectiveness on a periodic bases.
- Types of gowning – recommendation is based on room classification. In class ISO 8, D area (class 100,000) hair and beard cover required. A plant uniform that should be a polyester blend, safety glasses, and dedicated shoe or overshoe cover should be worn. In class ISO 7, C (class 10,000) area safety glasses, hair and beard cover is suggested. A single piece suit gathered at the wrists and high neck cover, gloves, and polyester hood should be worn
- ISO 5/6, Grade A/B (100/1000) – Sterile headgear should totally cover hair, beard, and moustache. A single sterile piece suite gathered at the wrists and high neck cover, gloves, and shoe cover is needed. Also, facemasks and safety glasses are worn. All protective clothing should shed no fibers or particulate matter.
- Environmental Monitoring Trending – recommendation is based on cGMP, PDA technical report 13 and International Organization for Standardization (ISO) standard “Cleanrooms and Associated Controlled Environments,” ISO 14644-1 and ISO 14644-2.). An Environmental Monitoring software application such as that provided by Novatek International can effectively capture this massive quantity of data and provide various trending.
- Investigation- Recommendation is based on the fact that many out of alert and out of actions are not investigated. Lack of timely adequate investigation will eventually lead to bigger problems and sterility failures. An environmental monitoring software with a good data mining and filtering capabilities can be used for route cause analysis in case of out of alert or out of action limits.
LISTS OF REFERENCES
*Pharm. Eng., Using New Cleanroom Standards with Sterile GMPs. Nov./Dec. 2002
*Pharm Technology, Envir. Control and Monitoring in Bulk Mfg. Facilities for
Biological Products”, May 1998
*Annex 1, Manufacture of Sterile Medicinal Products
*FDA concept guide, Sterile Drug Products Produced by Aseptic Processing Sept. 04
*European Commission, Annex 15, EU Guide to GMPs.
*PDA Technical Report No. 13, Fundamentals of EM Program
*PDA Letter, Has ISO 14644-1 replaces Fed. Std. 209E, August 2002
*Kohn and Riveria, Establishment of an EM Master Plan for Biological Mfg., PDA
Spring meeting, 2001.
LISTING OF REFERENCES/ SUMMARY TABLES:
*Table A: Excerpts from Sterile Drug Products Guidance Table 1-
Air Classifications and action levels of microbiological quality
*Table B: List of ISO 14644 Parts (sections)
*Table C: Excerpts from ISO 14644-1 Table 1-Airborn Particulate Cleanliness
Classes for Cleanrooms and Clean Zones
*Table D: Excerpts from EC GMPs Guide, Annex 1-Table on Airborne
Particulate Classification Grades
*Table E: Excerpts from EC, GMPs Guide, Annex 1-Table on Limits for