This compilation of the complex

Manufacturing in a Global Marketplace Reference Matrices on Regulations for Classified (Environmentally Controlled) Areas Betty Seawell, William Miele, and Jean Huxsoll The complex world of international regulations, standards, and guidelines on sterile manufacturing of parenteral products is deciphered and reduced to a set of matrix tables. Collecting the data in a single reference may not make developing aseptic controls easy but it does illustrate the dilemma faced by professionals setting those standards and illuminates the variety of inputs they can use in implementing monitoring programs. Betty Seawell is QA/QC director at Monsanto, Augusta, GA; William Miele is compliance manager, corporate quality assurance, at Bayer HealthCare, Clayton, NC; and corresponding author Jean Huxsoll is a member of the BioPharm International editorial advisory board and senior director quality assurance at Chiron Corporation, 4560 Horton Street, M/S Q-314A, Emeryville, CA 94603-2916, fax 510.923.2323, jean_huxsoll@chiron.com. 32 BioPharm International SEPTEMBER 2003 This compilation of the complex requirements for aseptic processing from a variety of regulatory and industry references is presented to serve as a ready reference to those who are drowning in the deluge of information we receive on a day-to-day basis. We present a collection of references some are legal requirements, some are guidelines that have evolved into standard practices within the industry, and others are either in the process of that evolution or are perceived as raising the bar on standards with their basis in current technology or management philosophy. These matrices are intended to place major relevant references in a single location. They are set according to accepted standard air classifications, with published requirements for common aseptic activities listed according to designated reference. However, these matrices are only references and are not intended to be used as an unequivocal selector. They do show the variety of inputs from worldwide sources that can be used when defining an approach to aseptic control in the manufacture of sterile parenteral products. They also illustrate the dilemma facing professionals in this industry who are charged with the development and implementation of environmental monitoring programs. Clearly, the way government agencies administer and legally require compliance to these documents differs significantly from country to country and also within a country, depending on whether a company manufactures drugs, biologics, or devices. We recommend you use these matrices as a guide for setting action levels (that is, the potential for a drift from operational parameters); alert levels (the possible drift from operational parameters) should be set at less than action levels. The general recommendation is that these levels be set based upon historical data and looked at on a routine basis (such as yearly). One standard may not fit all, and even within a single location, individual assessments based on the facility and on the processes may be necessary. Table Description The matrix information has been accumulated in four tables to make the information easier to use. The data are separated into Critical Class A (Table 1), Aseptic Class B (Table 2), Controlled Class C (Table 3), and Class D (Table 4). Reference documents are listed across the top of each table (in short form), and the corresponding parameters are listed beneath. For those documents lacking specific criteria, a not specified comment has been listed. The tables are otherwise self-explanatory and should be used for reference. The References for Environmental Monitoring Quality System Guidelines sidebar provides complete references to the documents referred to in the tables and to additional resources that can be used for locating environmental monitoring guidelines. These matrix tables indicate the complexity of the environmental control parameters established by worldwide standards and guidelines and the difficulty manufacturers have in establishing their own routine guidelines and standards. Manufacturers need to set alert and action levels that not only meet the regulatory requirements, but are reflective of their facilities normal operating parameters. If or when historical data are lacking, individual guidelines should be set from the most conservative information published, with adjustments made after sufficient data have been collected. Deviations should be dealt with case by case, using a consistent rationale backed by principles outlined in the environmental monitoring program. Conclusions should be risk-based, supporting both the safety and the quality of the product. BPI

Reference European Commission USP 26/NF 21 Documentation GMP Vol. 4, Annex 1 Chapter <1116> Parameter Grade A FS Class M 3.5 a Operational particles 3,500 3,530 per m 3 ( 0.5 mm) Monitoring frequency not specified, just Monitoring frequency suggested as each states frequent. operating shift, but it is to be dynamic and Operational particles 0 Not specified Monitoring frequency not specified, just states frequent. At rest particles 3,500 Not specified per m 3 ( 0.5 mm) At rest particles 0 Not specified Active air sample 1 3 (cfu/ m 3 ) c Average value; frequency not specified Monitoring frequency suggested as each during operations, just states frequent ; operating shift, but it is to be dynamic and also required outside of production Settle plate 1 Not to be used for quantitative measurements 4-hr. exposure time Average value; frequency not specified States that settling plates are not to be used (diameter 90 mm) during operations, just states frequent ; for quantitative estimates of the microbial (cfu/plate) c also required outside of production contamination of critical environments. Individual settle plates may be exposed for 4 hr. Surface samples 1 3 (contact plates and swabs) Average value; frequency not specified Monitoring frequency suggested as each (cfu/25 cm 2 ) c during operations, just states frequent ; operating shift, but it is to be dynamic and also required outside of production based upon trending performance; area stated as 24 30 cm 2. Personnel glove print 1 3 (four fingers and thumb) Average value; frequency not specified Monitoring frequency suggested as each (cfu/glove) c during operations; also required outside operating shift, but it is to be dynamic and of production operations (such as after based upon trending performance; area stated cleaning, as 24 30 cm 2. Personnel gown Not specified 5 (contact plates and swabs) Monitoring frequency suggested as each (cfu/25 cm 2 ) c operating shift, but it is to be dynamic and based upon trending performance; area stated as 24 30 cm 2. a Federal standard (FS) classification; Système International (SI) M 3.5; in United States customarily 100. Table 1. Critical environmental areas Class A regulations (full references for the cited documentation are listed in the References for Environmental Monitoring Quality System Guidelines sidebar, using the reference number in parentheses) from the European Commission (12), USP (29), ISO (15), Japanese Pharmacopoeia (8), and FDA (5); not specified is used for documents without specific criteria. 34 BioPharm International SEPTEMBER 2003

ISO Japanese Pharmacopoeia FDA Draft 14644-1, Part 1 14th Ed., Sec. 8 Aseptic Processing (2002) ISO Class 5 Grade A Class 100 3,520 3,530 3,500 Frequency not specified; states that the Laminar-airflow zone; frequency suggested particulate cleanliness in a cleanroom shall at each shift. be defined in one or more of three occupancy states: as built, at rest, or operational. 29 Not specified Not specified Frequency not specified; states that the particulate cleanliness in a cleanroom shall be defined in one or more of three occupancy states: as built, at rest, or operational. See above 3,530 Not specified Laminar-airflow zone; frequency suggested at each shift. See above Not specified Not specified Not specified 1 3 Maximum acceptable average numbers Alternate microbiological standards may be under each condition; frequency suggested established where justified by the nature as each shift ; minimum air sample is of the operation; samples from Class 100 0.5 m 3. environments should normally yield no microbiological contaminants. Not specified Not to be used for quantitative measurements Not specified States that settling plates are not to be used for quantitative estimates of the microbial contamination of critical environments. Not specified 1 Not specified Frequency suggested as each shift ; area stated as 24 30 cm 2 ; plate diameter listed as 5.4 6.2 cm; average value. Not specified 1 Not specified Frequency suggested as each shift ; area stated as 24 30 cm 2 ; plate diameter listed as 5.4 6.2 cm; average value; put all fingers on the plate. Not specified Not specified Not specified b Original document used unmanned rather than unstaffed. c Colony forming units (cfu). BioPharm International SEPTEMBER 2003 35

Reference European Commission USP 26/NF 21 Documentation GMP Vol. 4, Annex 1 Chapter <1116> Parameter Grade B FS Class M 5.5 a Operational particles 350,000 353,000 per m 3 ( 0.5 mm) Monitoring frequency not specified, just Monitoring frequency suggested as each states frequent. operating shift, but it is to be dynamic and Operational particles 2,000 Not specified Monitoring frequency not specified, just states frequent. At rest particles 3,500 Not specified per m 3 ( 0.5 mm) At rest particles 1 Not specified Active air sample 10 20 (cfu/ m 3 ) c Average value; frequency not specified Monitoring frequency suggested as each during operations, just states frequent ; operating shift, but it is to be dynamic and also required outside of production Settle plate 5 Not to be used for quantitative measurements 4-hr. exposure time Average value; frequency not specified States that settling plates are not to be used (diameter 90 mm) during operations, just states frequent ; for quantitative estimates of the microbial (cfu/plate) c also required outside of production contamination of critical environments. Individual settle plates may be exposed for 4 hr. Surface samples 5 3 (10 for floors) (contact plates and swabs) Average value; frequency not specified Monitoring frequency suggested as each (cfu/25 cm 2 ) c during operations, just states frequent ; operating shift, but it is to be dynamic and also required outside of production Personnel glove print 5 10 (four fingers and thumb) Average value; frequency not specified Monitoring frequency suggested as each (cfu/glove) c during operations; also required outside operating shift, but it is to be dynamic and of production operations (such as after based upon trending performance; area stated cleaning, as 24 30 cm 2. Personnel gown Not specified 20 (contact plates and swabs) Monitoring frequency suggested as each (cfu/25 cm 2 ) c operating shift, but it is to be dynamic and based upon trending performance; area stated as 24 20 cm 2. a Federal standard (FS) classification; Système International (SI) M 5.5; in United States customarily 10,000. Table 2. Aseptic environmental areas Class B regulations (full references for the cited documentation are listed in the Reference for Environmental Monitoring Quality System Guidelines sidebar, using the reference number in parentheses) from the European Commission (12), USP (29), ISO (15), Japanese Pharmacopoeia (8), and FDA (5); not specified is used for documents without specific criteria. 36 BioPharm International SEPTEMBER 2003

ISO Japanese Pharmacopoeia FDA Draft FDA Draft 14644-1, Part 1 14th Ed., Sec. 8 Aseptic Processing Aseptic Processing (2002) ISO Class 7 Grade B Class 1,000 (Optional) Class 10,000 352,000 353,000 35,000 350,000 Frequency not specified; states Nonlaminar-airflow zone; frequency Listed as an option for areas that the particulate cleanliness in suggested at each shift. surrounding Class 100 (critical cleanroom shall be defined in one aseptic processing). or more of three occupancy states: as built, at rest, or operational. 2,930 Not specified Not specified Not specified Frequency not specified; states that the particulate cleanliness in cleanroom shall be defined in one or more of three occupancy states: as built, at rest, or operational. See above 3,530 Not specified Not specified Nonlaminar-airflow zone; frequency suggested at each shift. See above Not specified Not specified Not specified Not specified 10 7 18 Maximum acceptable average Listed as an option for areas Alternate microbiologinumbers under each condition; surrounding Class 100 (critical cal standards may be frequency suggested as each shift ; aseptic processing); alternate established where minimum air sample is 0.5 m 3. microbiological standards may justified by the nature be established where justified of the operation. by the nature of the operation. Not specified Not to be used Not specified Not specified for quantitative measurements States that settling plates are not to be used for quantitative estimates of the microbial contamination of critical environments. Not specified 5 Not specified Not specified Frequency suggested as each shift ; area stated as 24 30 cm 2 ; plate diameter listed as 5.4 6.2 cm; average value. Not specified 5 Not specified Not specified Frequency suggested as each shift ; area stated as 24 30 cm 2 ; plate diameter listed as 5.4 6.2 cm; average value; put all fingers on the plate. Not specified Not specified Not specified Not specified b Original document used unmanned rather than unstaffed. c Colony forming units (cfu). BioPharm International SEPTEMBER 2003 37

Reference European Commission USP 26/NF 21 Documentation GMP Vol. 4, Annex 1 Chapter <1116> Parameter Grade C FS Class M 6.5 a Operational particles 3,500,000 3,530,000 per m 3 ( 0.5 mm) Monitoring frequency Frequency for support areas twice per week, unless a no-contact product area, then once per week, but it is to be dynamic and Operational particles 20,000 Not specified Monitoring frequency At rest particles 350,000 Not specified per m 3 ( 0.5 mm) At rest particles 2,000 Not specified Active air sample 100 100 (cfu/ m 3 ) c Average value; frequency not specified Frequency for support areas twice per week, during operations; also required outside of unless a no-contact product area, then production once per week, but it is to be dynamic and Settle plate 50 Not specified 4-hr. exposure time Average value; frequency not specified (diameter 90 mm) during operations; also required outside of (cfu/plate) c production sanitizing, and validating); individual settle plates may be exposed for 4 hr. Surface samples 25 Not specified (contact plates and swabs) Average value; frequency not specified (cfu/25 cm 2 ) c during operations; also required outside of production Personnel glove print Not specified Not specified (four fingers and thumb) (cfu/glove) c Personnel gown Not specified Not specified (contact plates and swabs) (cfu/25 cm 2 ) c a Federal standard (FS) classification; Système International (SI) M 6.5; in United States customarily 100,000. Table 3. Controlled environmental areas Class C regulations (full references for the cited documentation are listed in the Reference for Environmental Monitoring Quality System Guidelines sidebar, using the reference number in parentheses) from the European Commission (12), USP (29), ISO (15), Japanese Pharmacopoeia (8), and FDA (5); not specified is used for documents without specific criteria. 40 BioPharm International SEPTEMBER 2003

ISO Japanese Pharmacopoeia FDA Draft 14644-1, Part 1 14th Ed., Sec. 8 Aseptic Processing (2002) ISO Class 8 Grade C Class 100,000 3,520,000 3,530,000 3,500,000 Frequency not specified; states that the Frequency suggested at twice per week for particulate cleanliness in a cleanroom shall potential product or container contact areas; be defined in one or more of three once per week for no-contact product or occupancy states: as built, at rest, or container areas. operational. 29,300 Not specified Not specified Frequency not specified; states that the particulate cleanliness in a cleanroom shall be defined in one or more of three occupancy states: as built, at rest, or operational. See above 353,000 Not specified Frequency suggested at twice per week for potential product or container contact areas; once per week for no-contact product or container areas. See above Not specified Not specified Not specified 100 88 Maximum acceptable average numbers Alternate microbiological standards may be under each condition; frequency suggested established where justified by the nature as twice per week for potential product of the operation. or container contact areas; once per week for no-contact product or container areas; minimum air sample is 0.2 m 3. Not specified Not to be used for quantitative measurements Not specified States that settling plates are not to be used for quantitative estimates of the microbial contamination of critical environments. Not specified 25 Not specified Frequency suggested as each shift ; area stated as 24 30 cm 2 ; plate diameter listed as 5.4 6.2 cm; average value. Not specified Not specified Not specified Not specified Not specified Not specified b Original document used unmanned rather than unstaffed. c Colony forming units (cfu). BioPharm International SEPTEMBER 2003 41

Reference European Commission Japanese Pharmacopoeia European Commission Documentation GMP Vol. 4, Annex 1 14th Ed., Sec. 8 GMP Vol. 4, Annex 1 Parameter Grade D Grade D No Additional Grades Operational particles Not defined Not defined Not specified per m 3 ( 0.5 mm) The requirement and limit for The requirement and limit for this area this area will depend on the will depend on the nature of the operations operations being carried out. carried out; frequency suggested at twice per week for potential product or container contact areas; once per week for no-contact product or container areas. Operational particles Not defined Not specified Not specified The requirement and limit for this area will depend on the operations being carried out. At rest particles 3,500,000 3,530,000 Not specified per m 3 ( 0.5 mm) Should be achieved in the Frequency suggested at twice per week unstaffed b state, after a short for potential product or container contact areas; clean-up period of 15 20 min. once per week for no-contact product or after completion of operations; container areas. frequency At rest particles 20,000 Not specified Not specified Should be achieved in the unstaffed b state, after a short clean-up period of 15 20 min. after completion of operations; frequency Active air sample 200 200 Not specified (cfu/m 3 ) a Average value; frequency not Maximum acceptable average numbers specified during operations; under each condition; frequency suggested also required outside of as twice per week for potential product production operations (such as or container contact areas; once per week for after cleaning, sanitizing, and no-contact product or container areas; validating). minimum air sample is 0.2 m 3. Settle plate 100 Not to be used for quantitative measurements Not specified 4-hr. exposure time Average value; frequency not States that settling plates are not to be used (diameter 90 mm) specified during operations, just for quantitative estimates of the microbial (cfu/plate) a states frequent ; also required contamination of critical environments. outside of production operations (such as after cleaning, sanitizing, and validating); individual settle plates may be exposed for 4 hr. Surface samples 50 50 Not specified (contact plates Average value; frequency not Frequency suggested as each shift ; area and swabs) specified during operations, just stated as 24 30 cm 2 ; plate diameter listed (cfu/25 cm 2 ) a states frequent ; also required as 5.4 6.2 cm; average value. outside of production operations (such as after cleaning, sanitizing, and validating). Personnel glove print Not Specified Not specified Not specified (four fingers and thumb) (cfu/glove) a Personnel gown Not specified Not specified Not specified (contact plates and swabs) (cfu/25 cm 2 ) a a Colony forming units (cfu). b Original document used unmanned rather than unstaffed. Table 4. Controlled environmental areas Class D regulations (full references for the cited documentation are listed in the Reference for Environmental Monitoring Quality System Guidelines sidebar, using the reference number in parentheses) from the European Commission (12) and Japanese Pharmacopoeia (8); not specified is used for documents without specific criteria. 42 BioPharm International SEPTEMBER 2003

References for Environmental Monitoring Quality System Guidelines Some of these references are referred to at the top of each table; others are useful resources for environmental monitoring information. (1) Akers, J.E. and Agalloco, J.P., Commentary: Environmental Monitoring Myths and Misapplications, PDA J. Pharm. Sci. Technol. 55(3), 176 184 (May June 2001). (2) Akers, J.E. and Agalloco, J.P., Recent Inspectional Trends: Are Regulatory Requirements for Sterile Product Becoming Scientifically Undoable or Unpractical? PDA J. Pharm. Sci. Technol. 56(4), 179 182 (July August 2002). (3) CDER, Guideline on Sterile Drug Products Produced by Aseptic Processing (FDA, Rockville, MD, June 1987). (4) CDER, Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (FDA, Rockville, MD, August 2001). (5) CDER, Sterile Drug Products Produced by Aseptic Processing Draft (FDA, Rockville, MD, 2002). (6) Committee on Japanese Pharmacopoeia, General Information: Medial Fill Test, Japanese Pharmacopoeia, Vol. 14, Sec 6. (Ministry of Health, Labour, and Welfare, Tokyo, Japan, January 2002), pp. 1307 1310. (7) Committee on Japanese Pharmacopoeia, Microbial Attributes of Nonsterile Pharmaceutical Products, Japanese Pharmacopoeia, Vol. 14, Sec 7. (Ministry of Health, Labour, and Welfare, Tokyo, Japan, January 2002), pp. 1310 1312. (8) Committee on Japanese Pharmacopoeia, Microbiological Evaluation of Processing Areas for Sterile Pharmaceutical Products, Japanese Pharmacopoeia, Vol. 14, Sec 8. (Ministry of Health, Labour, and Welfare, Tokyo, Japan, January 2002), pp. 1312 1316. (9) Council of Europe Directorate for the Quality of Medicines, Microbiological Examination of Non-Sterile Products (Total Viable Aerobic Count) European Pharmacopoeia, Supplement 4.6, Section 2.6.12 (Council of Europe, Strasbourg, France, 17 June 2003). (10) Council of Europe Directorate for the Quality of Medicines, Microbiological Examination of Non-Sterile Products (Test for Specified Micro-organisms) European Pharmacopoeia, Supplement 4.6, Section 2.6.13 (Council of Europe, Strasbourg, France, 17 June 2003). (11) Defense Transportation Regulation, Technical Committee 209, ISO 14698-3, Cleanrooms and Associated Controlled Environments Biocontamination Control: Part 3, Measurement of the Efficiency of Processes of Cleaning and/or Disinfection of Inert Surfaces Bearing Biocontaminated Wet Soiling or Biofilms, 6983 (International Organization for Standardization, Geneva, Switzerland, January 1998). (12) Directorate General III, Good Manufacturing Practices: Medicinal Products for Human and Veterinary Use, Vol. 4 (European Commission, Brussels, Belgium, 1998). (13) Halls, N.A., Practicalities of Setting Acceptance Criteria for Media Fill Trials, PDA J. Pharm. Sci. Technol. 54(3), 247 252 (May June 2000). (14) IEST, IEST-RP-CC006.2: Testing Cleanrooms, 7th ed., V. Kopetz, Ed. (Institute of Environmental Sciences and Technology, Rolling Meadows, IL, 2000). (15) IEST/ISO Technical Committee 209, ISO 14644-1 Cleanrooms and Associated Controlled Environments: Part 1, Classification of Air Cleanliness, 644S (International Organization for Standardization, Geneva, Switzerland, January 1999). (16) IEST/ISO Technical Committee 209, ISO 14644-2 Cleanrooms and Associated Controlled Environments: Part 2, Specifications for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1, 442S (International Organization for Standardization, Geneva, Switzerland, September 2000). (17) IEST/ISO Technical Committee 209, ISO 14644-4 Cleanrooms and Associated Controlled Environments: Part 4, Design, Construction, and Start-up, 444S (International Organization for Standardization, Geneva, Switzerland, May 2001). (18) ISPE Sterile Manufacturing Facilities Guide Team, Pharmaceutical Engineering Guide A Guide for New Facilities: Volume 3, Sterile Manufacturing Facilities, (International Society for Pharmaceutical Engineering, Tampa, FL, June 2000), pp. 26,61 63. (19) Jahnke, M., Introduction to Environmental Monitoring of Pharmaceutical Areas (Parenteral Drug Association, Bethesda, MD, November 2001). (20) Ljungqvist, B. and Reinmuller, B., Microbiological Risk Assessment in Pharmaceutical Clean Rooms, (Parenteral Drug Association, Bethesda, MD, 2001). (21) Moldenhauer, J., An Industry Commentary on Regulatory Issues: Microbiology, PDA J. Pharm. Sci. Technol. 56(2), 60 64 (March April 2002). (22) Moore, B., Air Handling Systems for Cleanroom Control, Sterile Pharmaceutical Products Process Engineering Applications (Drug Manufacturing Technology Series), K.E. Avis, Ed. (Interpharm Press Inc., Buffalo Grove, IL, 1995). (23) PDA, Process Simulation Testing for Aseptically Filled Products: Technical Report No. 22 PDA J. Pharm. Sci. Technol. 50(6) Suppl. 1, 1 16 (1996). (24) PDA, Evaluation, Validation and Implementation of New Microbiological Testing Methods: Technical Report No. 33, PDA J. Pharm. Sci. Technol. 42(3), 2000. (25) PDA, A Proposed Training Model for the Microbiological Function in the Pharmaceutical Industry: Technical Report No. 35, PDA J. Pharm. Sci. Technol. 55(6) (2001). (26) PDA, Fundamentals of an Environmental Monitoring Program: Technical Report No. 13, Revised, PDA J. Pharm. Sci. Technol. 55(5) Suppl, i-iv, 1-35 (September October 2001). (27) PDA Current Practices in the Validation of Aseptic Processes 2001: Technical Report No. 36, PDA J. Pharm. Sci. Technol. 56(3) (2002). (28) PDA Aseptic Processing Task Force, Points to Consider for Aseptic Processing Draft, (Parenteral Drug Association, Bethesda, MD, September 2003). (29) United States Pharmacopeia, Microbiological Evaluation of Clean Rooms and Other Controlled Environments, USP 26 NF 21, Ch. <1116> (U.S. Pharmacopeial Convention, Rockville, MD, 2003). (30) Wilson, J., Environmental Monitoring: Misconceptions and Misapplications, PDA J. Pharm. Sci. Technol. 55(3), 185 190 (May June 2001). (31) Zemler, M. Considerations for Developing and Environmental Monitoring Program: A Laboratory Manager s Perspective, J. GXP Compl. 7(1), p. 29 (October 2002). BioPharm International SEPTEMBER 2003 43