Environmental Monitoring - IVT Network

36 Journal of GXP Compliance

ASQ CPGP BASICS

ASQ CPGP

Basics

Environmental Monitoring

“ASQ CPGP Basics” discusses various good manufacturing practice (GMP) topics from the American Society for Quality (ASQ) Body of Knowledge for the Certified Pharmaceutical GMP Professional (CPGP) program. We intend this column to provide basic theory and application of GMP topics useful to quality professionals and be a valuable resource for daily work applications. The key objective for this column: Useful information.

Reader comments, questions, and suggestions are requested. Please send your comments and suggestions to column coordinator Alice Krumenaker at [email protected] or to journal coordinating editor Susan Haigney at [email protected].

KEY POINTSThe following key points are discussed:

• Environmental monitoring is a proceduralized recurring set of activi-ties for evaluating air and surfaces for viable or non-viable particles as well as other environmental variables.

• The chief function of environmental monitoring is informational feed-back on environmental control, disinfection and sanitization activities, and personnel gowning, hygienic, and aseptic practices.

• Environmental monitoring works in parallel with cleanroom facility qualification.

• Cleanrooms are classified according to the maximum count per cubic meter of particles at or above a specified diameter.

• Most of the world’s pharmaceutical cleanroom regulations and guid-ance recommend the use of international standard ISO 14644-1 and related ISO standards. Comparative standards from other regulatory documents are also provided.

• Viable particulate monitoring and methodologies are described.• Although personnel monitoring is not a component of environmen-

tal monitoring, it is treated identically because of its inclusion in the above specification tables by the competent authorities and inspection conventions.

• Compressed gases are also addressed in ISO standards. Monitoring data should also be routinely reviewed and trended.

Robert D. Seltzer

Winter 2011 Volume 15 Number 1 37

Rob e r t D . S e l t z e r



• Inter-suite pressure differentials, room tempera-ture, and humidity are important environmental control variables governing pharmaceutical (and active pharmaceutical ingredients for sterile phar-maceutical) manufacturing.

• Compliance professionals must be well versed in these topics and assure that their areas of respon-sibility meet regulatory requirements and main-tain manufacturing standards.

• A glossary of related terms is provided.

INTRODUCTIONEnvironmental monitoring, also referred to as an environmental monitoring program or environmental monitoring plan (EMP), is a proceduralized recur-ring set of activities for evaluating air and surfaces (including personnel, where applicable) for viable or non-viable particles as well as other environmental variables that can affect pharmaceuticals. The terms “particulates” or “particulate matter” are interchange-able with “particles.” For completeness of coverage, EMP encompasses the following:

• Defined space temperature, relative humidity, pressure differential, HEPA-filtered air velocity, nonviable particulate counts, viable passive air and active air counts, compressed gases active air counts

• Personnel and surface viable particle counts.

These EMP measurements are performed in real time or non-real time and online or offline with respect to the manufacture, packaging, or holding of active pharmaceutical ingredients (APIs) or finished pharmaceuticals. Environmental monitoring is distinct from environmental control, with the latter referring to facility (infrastructure) and equipment de-sign, qualification, and maintenance that collectively provide varying degrees of protection from microbial and other particulate contamination. Environmen-tal control devices such as heating, ventilation, and air-conditioning (HVAC), high efficiency particulate air (HEPA) filters, water, and pure steam generation systems are covered in chapters dealing with infra-structure, facilities, utilities, and equipment.

The EMP’s chief function is that of informational feedback on the effectiveness or adequacy of the fol-lowing:

• Environmental control• Disinfection and sanitization activities• Personnel gowning, hygienic, and where neces-

sary, aseptic practices.

The EMP is qualified in parallel with cleanroom facility qualification. EMP qualification methodology or acceptance criteria are not described in competent authority regulations or guidance. However, the US Food and Drug Administration, in its 2004 aseptic processing guidance (1), describes the output of such qualification as follows:

“All environmental monitoring locations should be described in SOPs [standard operating procedures] with sufficient detail to allow for re-producible sampling of a given location surveyed. Written SOPs should also address elements such as frequency of sampling, when the samples are taken (i.e., during or at the conclusion of opera-tions), duration of sampling, sample size (e.g.,

ASQ CERTIFIED GMP PROFESSIONAL BODY OF KNOWLEDGE

VI. STERILE AND NONSTERILE MANUFACTURING SYSTEMSE. Requirements for Critical Unit Processes6. Environmental Monitoring Requirements

Differentiate between environmental monitoring requirements for different manufacturing area clas-sifications

7. Monitoring Tools Describe and use various monitoring tools to mea-sure viable and nonviable particulates, pressure dif-ferentials, temperature, humidity, etc.

VII. FILLINGB. Environmental Monitoring Use various monitoring techniques (active air sam-

pling, settle plates, nonviable particle counting, contact plates for surfaces and people, etc.) to de-termine that appropriate environmental conditions are maintained in various operations.


ASQ CP GP BASIC S

surface area, air volume), specific sampling equip-ment and techniques, alert and action levels, and appropriate response to deviations from alert of action levels” (1).

Regarding “action levels,” these are usually inter-preted as the regulatory limits reproduced in the following tables (Tables I-VI), whereas “alert levels” are statistically based environmental monitoring, early warning out-of-trend values.

NONVIABLE PARTICULATE (OR AIRBORNE) MONITORINGCleanrooms are classified according to the maximum count per cubic meter of particles at or above a speci-fied diameter. Particles counted for size and concentra-tion are referred to as non-viable particles or particu-late because the vast majority of such particles have no associated live or culturable organisms. Non-viable particulate is defined as solid or liquid contaminant generally between 0.001 and 1000 micrometers in size that includes dust, fumes, smoke, fog, and mists. United States Pharmacopeia (USP) informational general chapter <1116> “Microbial Evaluation of Clean Rooms and Other Controlled Environments” (2) states that when fewer particulates are present in a cleanroom, the less likely it is that airborne microorganisms will be present because airborne microorganisms are less likely free-floating or single cells and more frequently associated with non-living airborne particles. FDA’s Guidance on Sterile Drug Products Produced by Aseptic Processing states that particulate matter in the air also poses a risk of extraneous contamination to aseptical-ly-filled pharmaceuticals.

USP <1116> is undergoing title and content change. Its new draft title is “Microbiological Control and Monitoring of Aseptic Processing Environments.” The logic behind which is that pharmaceutical cleanrooms are most commonly used for aseptic processes than for non-sterile or terminally sterilized pharmaceuti-cal manufacturing. The new <1116> recommends initially certifying cleanrooms to ISO 14644 and then qualifying them via smoke studies and an appropriate biological indicator challenge, which Ljundqvist and Reinmuller have developed as the L-R method. The

pass/fail criteria for such studies are not readily de-fined and are not specified in any competent authority or inspection convention regulation or guidance. FDA frequently requests such qualification and valida-tion data (including videotapes) during preapproval inspections of new or significantly changed aseptically manufactured products.

ISO 14644-1, -2, -3, and -4Most of the world’s pharmaceutical cleanroom regula-tions and guidance documents recommend the use of international standard ISO 14644-1, “Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness.” The requirements for initial and successive testing of cleanrooms for conformance to non-viable air cleanliness classes are provided in ISO 14644-1 as well as 14644-2, “Specifi-cations for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1.” This chapter’s five-cleanroom specification Tables 10.1–10.5 are charac-terized by four distinct cleanliness classes or grades.

The European Commission (EC) GMP Annex 1 defines the following relationship between its Grades A to D and ISO 14644-1 Classes. EU Grade A for par-ticles ≥5 μm is equivalent to ISO Class 4.8. EU Grade B (at rest) is equivalent to ISO 5 for the ≥0.5 and ≥5 μm. EU Grade C (at rest) is ISO 7, while EU Grade C (in operation) is ISO 8. EU Grade D (at rest) is ISO 8. Cleanliness classification and grading are based solely on non-viable particulate specifications; however, all the competent authorities (e.g., European Medi-cines Agency [EMEA], Australia’s Therapeutic Goods Administration [TGA], FDA, and Japan’s Ministry of Health, Labour and Welfare [MHLW]) or inspection conventions (e.g., Pharmaceutical Inspection Conven-tion and Pharmaceutical Inspection Co-operation Scheme [PIC/S] and World Health Organization [WHO]) additionally provide viable particulate speci-fications, as reflected in the five specification tables.

Classification of cleanrooms and clean air devices, based on non-viable particulate concentration (par-ticles per cubic meter of air) depends on proper use of ISO 14644-1, -2, and -3 “Cleanrooms and Associated Controlled Environments.” The glossary contains many of the terms defined in this series of ISO stan-



dards. ISO 14644-1 “Classification of Air Cleanliness” describes and defines cleanrooms and occupancy states with increasing probability of non-viable par-ticulate generation. It gives an equation for calculating the maximum cleanroom particle concentration for cleanrooms classified in rational numbers between 1 and 9 based on the minimum particle size (microm-eters) that will be measured. 14644-1 Annex B gives formulas for the minimum number of sampling points in a cleanroom (square root of footprint area in m2) and the minimum sample volume that must be taken at each point. Annex C gives statistical formulas for characterizing the mean and dispersion of particle concentration data (3).

ISO 14644-2 “Specifications for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1” defines standard and additional requalifica-tion tests as well as the time intervals or events that lead to requalification (4). ISO 14644-3 “Test Methods” (5) prescribes the following qualification or requalifi-cation tests for pharmaceutical cleanrooms:

• Airborne particle count• Airflow test• Air pressure difference test• Installed filter system leakage tests• Airflow direction test and visualization

• Temperature and humidity uniformity tests• Recovery test • Containment leak test.

Several tests (e.g., electrostatic and ion generator tests, and particle deposition tests) apply only to the semiconductor industry. The details of all these tests are provided informatively in ISO 14644-3 Annexes A, B, and C as well as in other standards (e.g., IEST [Insti-tute of Environmental Sciences and Technology] and ASTM [American Society for Testing and Materials]).

Airborne particle counters operate by using vacuum to pull in a sample of air to test. They use a laser or white light shining across the air sample onto photo detection electronics. The light is either absorbed or reflected by particles in the air. The light reacts in a pattern depending on the size of the particle floating in the air sample. Photo detection electronics can in-terpret this pattern and thus find the size and number of particles. ISO 21501-4 “Determination of Particle Size Distribution—Single Particle Light Interaction Methods—Part 4: Light Scattering Airborne Particle Counter for Clean Spaces” is required by the EU for calibrating airborne particle counters (6).

ISO 14644-4 “Design, Construction and Start-up” is a baseline guidance for the commissioning and

TABLE I: ISO 14644-1 cleanroom specifications.

Clean Zone Classification 4.8* or 5 5 7 8

EMP Requirement

At rest max air nonviables ≥0.5 μm per cubic meter 2,220 3,520 352,000 3,520,000

Operational max air nonviables ≥0.5 μm per cubic meter Not used in ISO 14644 / Not applicable

At rest max air nonviables ≥5 μm per cubic meter 18.5 29 2,930 29,300

Operational max air nonviables ≥5 μm per cubic meter Not used in ISO 14644 / Not applicable

Active air CFU per cubic meter Not used in ISO 14644 / Not applicable

90 mm settle plate CFU per 4 hours Not used in ISO 14644 / Not applicable

*4.8 is the classification number corresponding to EU and PIC/S Grade A for particles ≥5 μm. ISO 14644-1 permits intermediate ISO class numbers, with 0.1 the smallest permitted increment. Also, ISO 14644-1 states that, due to particle measuring device sensitivity, no more than three significant figures are used in classification fields above. The above table values for Class 4.8 are calculated directly from the equation given in ISO 14644-1 Section 3.1 on allowable airborne non-viable particulate concentration, while those for Classes 5, 7, and 8 are taken directly from ISO 14644-1 Table 1.


ASQ CP GP BASIC S

installation qualification of a new cleanroom prior to particulate testing described in Parts 1-3. It represents a template for a detailed technical agreement between an engineering design or construction company and the ultimate owner or manufacturer (e.g., pharmaceu-tical company). Many details for personnel gowning room layout, airlocks, vacuum-cleaning equipment, wall, floor, and ceiling construction have been ad-opted from this standard into actual or de facto good manufacturing practices of various competent authori-ties and inspection conventions (7).

EC GMP Annex 1The EC GMPs Annex 1 (8) is the most prescriptive regulatory document (compared to those of FDA, WHO, Japan, and USP <1116> [9, 10]) with regard to requirements for measuring cleanroom non-viable particulate matter. It is the first regulation to set specifications for 5 μm and larger non-viable particles and for manufacturing “full duration” or continuous particle monitoring in Grade A. EC GMPs Annex 1 permits the use of independent particle counters (with short sampling tubes) or use of a network of

TABLE II: EC GMPs, PIC/S, and TGA GMPs Annex 1 cleanroom specifications.

Clean Zone Classification A B C D

EMP Requirement

At rest max air nonviables ≥0.5 μm per cubic meter

3,520 3,520 352,000 3,520,000

Operational max air nonviables ≥0.5 μm per cubic meter

3,520 352,000 3,520,000 Not Defined

At rest max air nonviables ≥5 μm per cubic meter

20 29 2,900 29,000

Operational max air nonviables ≥5 μm per cubic meter

20 2,900 29,000 Not Defined

Frequency Full duration of critical processing

Frequency may be less than in A

According to risk management


Active air CFU per cubic meter <1 10 100 200

Frequency “Frequent” Operating Shift Not Specified Not Specified

90 mm settle plate CFU per 4 hr <1 5 50 100

Frequency Operating shift Operating shift According to risk management


55 mm contact plate CFU <1 5 25 50

Frequency “After critical operations” Operating shift According to risk management


Personnel gown CFU Not specified Not specified Not specified Not specified

Frequency N/A N/A N/A N/A

Personnel gloves CFU <1 5 Not specified Not specified

Frequency “After critical operations” Operating shift N/A N/A



continuously or sequentially accessed sampling points connected by a manifold to a single particle counter. The latter is known in the cleanroom industry as a se-quential facility monitoring system (FMS) or sequen-tial FMS. There are no universally accepted design specification standards or validation methods for the manifolds comprising an FMS. FDA’s aseptic guideline supports the use of a remote counting system over portable particle counters, owing to the former being less invasive of the aseptic processing area. That same guideline mandates a monitoring location within one foot of the work site, within the airflow, and during filling and closing operations (1).

VIABLE PARTICULATE MONITORINGCulturable bacteria or fungi in air or on surfaces and personnel are clearly the more direct threat to steril-ity of aseptically prepared pharmaceuticals than are airborne particulates; although visible particulate matter in parenteral products is its own basis for 100% inspection per many GMPs and compendia. The com-petent authorities and the inspection conventions, to varying extents, define the action limits and minimum acceptable testing frequencies of viable monitoring (see Tables I–VI). They also expect alert levels, tighter than the regulatory or guidance action limits, to be set by pharmaceutical manufacturers based on histori-cally achievable viable monitoring results. Methods for creating, periodically reviewing, and revising alert

limits for all forms of viable particulate monitoring (e.g., air, surface, and personnel) may be found in PDA Technical Report No. 13 “Fundamentals of an Environmental Monitoring Program,” which describes several statistical approaches and data management and trending (11).

Test MethodologyViable particulate air sampling consists of both active air and settle plate (passive air) monitoring in all the world’s GMP regulations and inspection conventions except Japan’s, which specifies only active air monitor-ing. Active air samplers can provide CFU/m3 (i.e., vol-ume-normalized quantitative counts of airborne viable particles versus non-normalized counts of CFU on a settle plate) usually after a four-hour exposure time. Settle plate exposure within and underneath a laminar airflow (LAF) device must be validated for non-des-iccation/acceptable growth promotion characteristics if a four-hour exposure time is used. Both active air sampler media and settle plate media require validated incubation conditions (time and temperature). The incubation conditions for active air sampler exposed media are almost always validated and prescribed by the air sampler equipment manufacturer, relieving the pharmaceutical manufacturer of method validation questions from competent authorities. On the other hand, settle plate media (usually trypticase/tryptic soy agar = soybean-casein digest agar = soybean-casein

TABLE III: FDA Sterile Drug Products Produced by Aseptic Processing cleanroom specifications.

Clean Zone Classification 5 6 7 8

EMP Requirement

Operational max air nonviables ≥0.5 μm per cubic meter

3,520 35,200 352,000 3,520,000

Frequency Regular monitoring each production shift

Not specified Not specified Not specified

Active air CFU per cubic meter 1 7 10 100

Frequency Not specified Not specified Not specified Not specified

90 mm settle plate CFU per 4 hr 1 3 5 50



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digest medium or SCDM) are purchased or prepared in-house, either of which requires sterilization valida-tion, growth promotion, and expiration dating studies by the preparer. Incubation conditions for settle plate media have been a source of controversy among mi-crobiologists, competent authorities, and manufactur-ers, especially with regard to sequential and biphasic incubation at temperatures conducive to fungi and to bacteria. Commercially available active air samplers are described in the PDA Technical Report No. 13 and in USP <1116>.

One common denominator among all EMP media is the need for growth promotion testing (GPT) on a per-lot and/or per-delivery or per in-house prepara-tion-and-sterilization-basis, prior to use. None of the competent authorities or compendia have permitted, in writing, the certification of EMP media or the con-current GPT to actual usage (i.e., run at risk). Differ-ent guidance documents, particularly those of FDA, require using local microbiological isolates among the microbes used in GPT. Creating and re-creating a library of air and surface environmental isolates is a general worldwide expectation of competent authori-ties and inspection conventions. These organisms are then used in GPT, sanitization process validation.

An expectation of all competent authorities and inspection conventions is that manufacturers have procedures governing what events or time frequencies require cultivating and identifying flora found in air, on product contact equipment, primary surfaces (see glossary), or on personnel. This identification aids in assessing effectiveness of plant sanitization, hygiene, and overall environmental control. It also helps manu-

facturers control organisms that would be considered objectionable were they to contaminate non-sterile drug products.

Product-contact equipment and primary surfaces must be sampled at frequencies stated by the com-petent authorities or as determined by the manufac-turer’s EMP risk assessment (initial and ongoing). Flat surfaces and personnel gown sampling may be performed with a contact plate (see glossary). Gloved fingers are usually sampled with a 90 mm regular TSA plate. Irregular critical surfaces (e.g., a filling needle) should be sampled with swabs. Method validation of the touch plate and swab sampling must be preceded by sourcing both with appropriate neutralizers for site-specific disinfectant residue. Although microbio-logical recovery from inanimate objects and surfaces can show 200% or higher swings in precision, initial recovery studies are expected by some competent authorities, even if the study is done at only one of the many sites within a multi-site corporation.

Although personnel monitoring is not, classically speaking, a component of environmental monitoring, it is treated identically because of its inclusion in the specification tables presented herein by the competent authorities and inspection conventions. Compressed gas utility, on the other hand, is neither classically part of EMP nor specified alongside air, surface, and personnel monitoring specifications in the tables. Yet their inclusion in this chapter is logical because pharmaceutical manufacturing management should additionally review trended compressed gas monitor-ing data on a periodic basis along with data on air, surfaces, and personnel. Also, PDA Technical Report

TABLE IV: 2009 Draft Revision of USP <1116> Microbiological Control & Monitoring of Aseptic Processing Environments, recommended initial EMP viable contamination recovery rates.

Clean Zone Classification Isolator (ISO 5 or better) 5 6 7 8

EMP Requirement

Incident rate of any CFU detection from active air sampling <0.1% <1% <3% <5% <10%

Incident rate of any CFU detection from 90 mm settle plates per 4 hr <0.1% <1% <3% <5% <10%

Incident rate of any CFU detection from contact plate or swab <0.1% <1% <3% <5% <10%

Incident rate of any CFU detection from glove or garment <0.1% <1% <3% <5% <10%



13 Revised includes compressed gases among “prod-uct contact sources” and includes with air, surface, and personnel monitoring.

COMPRESSED GAS MONITORINGCompressed gases are used to overlay, pressurize, or otherwise directly or indirectly contact bulk product or intermediates; and compressed gases are sterile filtered via a hydrophobic 0.2 μm filter. Compressed gases should be included in the EMP according to PDA Technical Report No. 13 Revised to assure that the “gas does not challenge the bacterial retention of the filter.” Various suppliers sell instruments for ex-posing media to compressed gases. The following ISO standards describe tests for content and conditions of compressed air. Part 7 is particularly relevant to microbial content determination, and can be applied to gases other than air:

• ISO 8573-1:2001 Compressed air for general use, Part 1—Contaminants and purity classes

• ISO 8573-2:1996 Compressed air for general use, Part 2—Test methods for aerosol oil content

• ISO 8573-3:1999 Compressed air for general use, Part 3—Test methods for measurement of humidity

• ISO 8573-4:2001 Compressed air for general use, Part 4—Test methods for solid particle content

• ISO 8573-5:2001 Compressed air for general use, Part 5—Test methods for oil vapor and organic solvent content

• ISO 8573-6:2003 Compressed air for general use, Part 6—Test methods for gaseous contaminant content

• ISO 8573-7:2003 Compressed air for general use—Test method for viable microbiological con-taminant content.

TABLE V: WHO Annex 6 GMPs for Sterile Pharmaceutical Products.

Clean Zone Classification A B C D

EMP Requirement

At rest max air nonviables ≥0.5 μm per cubic meter 3,500 3,500 350,000 3,500,000

Operational max air nonviables ≥0.5 μm per cubic meter 3,500 350,000 3,500,000 Not defined

At rest max air nonviables ≥5 μm per cubic meter 0 0 2,000 20,000

Operational max air nonviables ≥5 μm per cubic meter 0 2,000 20,000 Not defined

Frequency “Frequent” Not specified Not specified Not specified

Active air CFU per cubic meter < 3 10 100 200


90 mm settle plate CFU per 4 hr < 3 5 50 100


55 mm contact plate CFU < 3 5 25 50


Personnel gown CFU Not specified Not specified Not specified Not specified


Personnel gloves CFU <3 5 Not specified Not specified



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According to ISO 8573-7 (12), the air (or other gas) sampler should be fitted with a diffuser capable of main-taining laminar flow conditions so that particles pass through the sample head in a controlled flow; any dis-ruptions would have a negative effect on the impaction of the particle onto the contact plate media such as making the particle non-viable or making it bounce off the con-tact plate. A 1 m3 sample is required. Prior to sampling, both the sample head and diffuser must be sterilized.

MACROSCOPIC CLEANROOM VARIABLESAlthough inter-suite pressure differentials, room tem-perature, and humidity are important environmental control variables governing pharmaceutical (and APIs for sterile pharmaceutical) manufacturing, their mea-surement, feedback control, and alarm activation are relatively straightforward.

Except for FDA’s aseptic processing guidance requiring continuous monitoring of differential

TABLE VI: Japanese Guidance for Industry Sterile Drug Products Produced by Aseptic Processing cleanroom specifications.Clean Zone Classification

A B C DEMP Requirement

At rest max air nonviables ≥ 0.5 μm per cubic meter

3,520 3,520 352,000 3,520,000

Operational max air nonvia-bles ≥ 0.5 μm per cubic meter

3,520 352,000 3,520,000 “Dependent on process attributes”

At rest max air nonviables ≥ 5 μm per cubic meter

Not specified* Not specified Not specified Not specified

Operational max air nonvia-bles ≥ 5 μm per cubic meter

Not specified Not specified Not specified Not specified

Frequency “Throughout the entire aseptic procedure”

“Throughout the entire aseptic procedure”

“Once a month” “As appropriate”

Active air CFU per cubic meter < 1 ≤ 10 ≤ 100 Not specified

Frequency “For each shift” “For each shift” “As appropriate” “As appropriate”

90 mm settle plates CFU per 4 hour

Not specified Not specified Not specified Not specified

Frequency N/A N/A N/A N/A

55 mm contact plates CFU ≤ 1 on Equipment; ≤ 1 on Walls; ≤ 5 on Floors

≤ 5 on Walls; ≤ 10 on Floors

≤ 30 on Floors Not specified

Frequency “At the completion of each processing”

“At the completion of each processing”

“As appropriate” “As appropriate”

Personnel gown CFU ≤ 5** ≤ 20** “As appropriate” Not specified

Frequency For Each Shift “Once per day of operation”

“As appropriate” N/A

Personnel gloves CFU ≤ 1 ≤ 5 “As appropriate” Not specified

Frequency For Each Shift “Once per day of operation”

“As appropriate” N/A

*The number of particles larger than 5 μm may be included as a parameter in the control program as appropriate.**Both arms, chest, head, shoulders, etc.



pressures between cleanrooms and adjacent clas-sified or unclassified areas “throughout each shift and frequently recorded,” it provides no guidance on allowable excursions. Compared to excursions in airborne nonviable and viable particle counts, excur-sions in differential pressure, inlet air volumetric flow rate, temperature, and humidity have contributory but indirect effects on aseptically manufactured prod-ucts. Initial cleanroom qualification must determine the allowable excursions in magnitude and duration without the need for process deviation and product impact analysis.

IMPLICATIONS FOR COMPLIANCE PROFESSIONALSThis brief introduction to environmental monitoring is a recommended starting point for discussion on this critical topic. Environmental monitoring is a critical responsibility supporting manufacturing operations. There are fundamental requirements associated with environmental monitoring activities. Compliance professionals must be well versed in these topics and assure that their areas of responsibility meet regula-tory requirements. Close working relationships with site microbiologists are highly recommended. Aseptic manufacturing areas are often well controlled regard-ing these considerations. Non-aseptic areas, perceived to be of lesser risk, may not be adequately controlled.

Compliance professionals must assure that their EMP is well designed and technically sound. Proce-dures must clearly define operational parameters. Ex-ecution must carefully follow procedures. Compliance professionals should be wary of overlooked details and procedures that have been compromised in favor of cost savings, headcount reductions, or other economic benefit. A comprehensive environmental monitoring program is invaluable in maintaining facility stan-dards. Monitoring data must then be appropriately and routinely reviewed and analyzed with attention to emerging trends and unexpected data.

REFERENCES 1. FDA, Guidance Sterile Drug Products Produced by Aseptic Process-

ing, 2004.

2. USP, <1116> “Microbiological Evaluation of Clean Rooms”

(current title) and “Microbiological Control and Monitoring

of Aseptic Processing Environments” (proposed revised title),

United States Pharmacopeia.

3. ISO, ISO 14644-1, “Cleanrooms and Associated Controlled

Environments—Part 1: Classification of Air Cleanliness,”

1999.

4. ISO, ISO 14644-2 “Specifications for Testing and Monitoring

to Prove Continued Compliance with ISO 14644-1,” 2000.

5. ISO, ISO 14644-3 “Test Methods” 2005.

6. ISO, ISO 21501-4 “Determination of Particle Size Distribu-

tion—Single Particle Light Interaction Methods—Part 4:

Light Scattering Airborne Particle Counter for Clean Spaces”

2007

7. ISO, ISO 14644-4 “Design, Construction and Start-up,” 2001

8. EC, EU Guidelines to Good Manufacturing Practice; Medicinal

Products for Human and Veterinary Use, Annex I, “Manufacture

of Sterile Medicinal Products,” European Medicines Agency,

2008.

9. FDA, 21CFR 211.42(c )(10)(iv), 1978.

10. WHO, Good Manufacturing Practices: Main Principles for Phar-

maceutical Products.

11. PDA, PDA Technical Report No. 13 Revised, “Fundamentals of

an Environmental Monitoring Program” 2001.

12. ISO, ISO 8573-7:2003 Compressed air for general use. Test

method for viable microbiological contaminant content.

GENERAL REFERENCEISO 14698-1 “Cleanrooms and Associated Controlled Environ-

ments—Biocontamination Control—Part 1: General Prin-

ciples” 2003. GXP

GLOSSARYGood definition (≡): Description of a word or multi-word (≡ term) that: a) does not use any form of the word/term itself, b) first places the word/term in a category or genus, c) distinguishes the word/term sufficiently from other category/genus members, and d) satisfac-torily describes the word/term for any English-speaking audience.Working definition: A satisfactory description of a word/term, for use in the discussion at hand or for a very spe-cific audience, which may differ from a customary Eng-lish dictionary or even from some other oft-cited, rigid, preexisting, and non-useful explanation of that term.Note: All definitions in this glossary are working definitions and are strictly words or terms described


ASQ CP GP BASIC S

for pharmaceutical GMP applications. Where words or terms are not further defined, their meaning is that from a common English dictionary.Aerosol generator: Instrument capable of producing particulate matter in an appropriate particle size (e.g., 0.05 to 2 micrometers (μm))Action level: Specification or limit (in fact, more cor-rectly called an action limit rather than an action level) established in published regulation (or a guidance or guideline or standard that is regarded by competent au-thorities as de facto regulation), which when exceeded, requires immediate intervention, including investigation of cause, immediate remediation, and/or corrective action.Air exchange rate: Air changes per unit of time that is calculated by dividing the volumetric flow rate of incoming air by the volume of the space/room.Alert level: Measurement magnitude set by an active pharmaceutical ingredient (API) or finished pharma-ceutical manufacturer that gives early warning of a drift from normal conditions and that, when exceeded, should result in increased attention to the process. Antisepsis: The act or process of chemically reducing viable organisms on living tissue, including skin, oral cavities, and open wounds.Aseptic processing area (APA): Controlled environ-ments in which the air supply, materials, equipment, and personnel are regulated to control microbial and particulate number to acceptable levels. Note: APA consists of “critical (processing) area” and “direct sup-port area.”As-built: Occupancy state in which the installation is complete with all services connected and function-ing but with no production equipment, materials, or personnel present.At rest: Occupancy state in which the installation is complete with equipment installed and operating in a defined manner but zero personnel present. Bioburden: The total quantity of recoverable microbes present on a defined surface, surface area, or within a non-sterile solid, powder, or liquid drug, intermediate, or raw material. Classification: Level (or process of specifying or de-termining the level) of airborne particulate cleanliness applicable to a cleanroom or clean zone, expressed in

terms of an ISO Class N, which represents the maxi-mum allowable concentrations (in particles per cubic meter of air) for considered sizes of particles [see ISO 14644-1].Classified area or cleanroom: Room or operating area designated by Grades A, B, C, D as defined in EC GMPs guide or designated Class 4.8, 5, 6, 7, or 8 per ISO cleanroom standards; a classified area is constructed (usually of durable walls as opposed to cur-tains—see clean zone below) and used in a manner to minimize the introduction, generation, and retention of particles and in which other relevant parameters, e.g., temperature, humidity, and pressure, are controlled as necessary (see ISO 14644-1). Note: A curtained area satisfying some of the definition of classified area, except its wall construction, is known as a clean zone, the distinction being necessary for purposes of the latter’s moveable/flexible versus permanent nature and the degree of pre-use validation or qualification. Competent authority: A country-specific agency or body designated to administer that country’s laws or statutes governing marketing of safe and effective pharmaceu-ticals, medical devices, foods, dietary supplements, cosmetics, etc.; a competent authority fulfills this role by enacting regulations, guidelines, guidance, etc., in line with those statutes or laws. Note: examples include the US Food and Drug Administration, the US Department of Agriculture (USDA), Health Canada, the UK’s MHRA, the UK’s Veterinary Medicines Directorate (VMD), Japan’s Ministry of Health, Labor, and Welfare (MHLW), and Australia’s Therapeutic Goods Adminis-tration (TGA).Contact plate (also touch plate): A Petri dish usually measuring 55 mm diameter and containing convex-shaped agar that forms a dome above the dish to permit sampling flat surfaces for microorganisms. Note: RODAC is the brand name (stands for Replicate Organism Detection and Counting Plate) of contact plate and which trademark is currently owned by Becton-Dickinson.Contamination: The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, API, finished drug, primary surface, or equipment. Note: a contaminant is any particulate, molecular, and/or



biological entity that can adversely affect a material or process (biocontaminant is a bacterial, mycoplasma, fungal, or protozoa contaminant).Controlled area: A non-classified room or operating area designed to control/minimize the presence, prolif-eration, or ingress of particulates and in which specific environmental conditions (e.g., temp, RH, directional airflow, and viable and non-viable particulate limits) are defined and monitored to prevent contamination of exposed products.Disinfection: The act or process of chemically or physically destroying or removing vegetative pathogens on inanimate objects (a disinfectant is a chemical or physical agent that assists disinfection).Endotoxin: The lipopolysaccharide remnant of the outermost cell wall layer of a dead Gram Negative bacterium, which can be pyrogenic (fever-causing) to mammals, especially humans. Note: endotoxin is a potential contaminant of water, including pharmaceuti-cal water. Note: all (USP, EP, and JP) pharmaceutical water for injection and pure steam have, among other specifications, an upper limit of NMT (not more than) 0.25 Endotoxin Units/ml (EU/ml)Flora: The identified microbes (to species level) found at a specific time in an operating area(s), room(s), or the collection of rooms used in manufacturing, testing, and warehousing; this includes microbes isolated from primary surfaces, air, as well as product, intermedi-ates, raw materials, etc. Tested and determined to be contaminated after a specific area or suite exposure.HVAC: The totality of installed equipment that provides coordinated heating, ventilation, and air conditioning to classified or unclassified areas.Installation (vis-à-vis cleanrooms): The ensemble that includes a cleanroom or one or more clean zones, together with all associated structures, air-treatment systems, services, and utilities.Microbiological contamination: The presence of one or more various bacteria, mycoplasma yeasts, mold, protozoa, or their toxins/by-products (e.g., endotoxins or exotoxins), which could adversely affect product and material or a patient’s health and safety.Microorganisms and microbes: Bacteria, mycoplasma, yeast, mold, protozoa, all of which are organism and living. Note: viruses and prions are not organisms/

living and, by the above definition, are not technically categorized among microorganisms.Occupancy state: Status of a classified area with re-gard to presence or absence of equipment and person-nel and operation of the HVAC.Operational: Occupancy state in which the installation is functioning in a defined manner, with a specified number of personnel present and working in a defined manner.Particle or particulate matter: A minute piece of matter with defined physical boundaries. Solid or liquid object that, for purposes of classification of cleanrooms, falls within the size range of 0.1 to 5 micrometers (μm). Note: a viable particle is one that consists of, or sup-ports, one or more live microorganisms; and a non-viable particle is one that consists of zero culturable microorganisms.Particle size: Diameter of a sphere that produces a response, by a given particle-sizing instrument that is equivalent to the response produced by the particle being measured.Pathogenic: Regarding a microbe or microorganism that is harmful to man or animal.Primary surface: The first solid surface contacted in moving away from an exposed product. In a room, this includes the walls, floors, ceilings, and doors, the room side of air diffusers but not the duct side, and floor drain covers, but not the piping system. A primary surface is not a product contact surface.Settle plate: Suitable container (e.g., Petri dish) of appropriate size, containing an appropriate, sterile, culture medium, which is left open for a defined period to collect viable particles depositing from the air.Sanitization: The act or process, physical or chemical, of reducing viable organisms on a surface to a defined acceptance level (a sanitizer is a physical or chemical agent that assists sanitization); sterilization is a subset of sanitization; surface sanitization concerns primary surfaces and product- or other material-contacting equipment surfaces. Note: some countries and regions use the term sanitation instead of sanitization.Sporicide: A chemical agent that destroys bacterial and fungal spores when used in sufficient concentra-tion for a specified contact time; it is expected to kill all vegetative organisms. Note: Health Canada prohib-


ASQ CP GP BASIC S

its a supplier from labeling a non-sporicidal disinfec-tant with claims against the vegetative cells of spore-forming bacteria whose spores may be the primary means of spread of healthcare-associated infections, which reference could mislead users into assuming that the disinfectant has sporicidal effectiveness. Sterilization: The act or process, physical or chemi-cal, of destruction or elimination of all viable organisms (including bacterial and fungal spores, viruses, protozoa) in the inanimate environment; never being considered absolute, it is characterized by a probability of presence of one or more viable organisms and expressed as 10-n; a sterilant is an agent that can assist sterilization; steril-ants are liquid or vapor-phase agents. Note: all steril-ants are sporicides, but not all sporicides are sterilants.TOC = Total organic (or oxidizable) carbon: An indirect measure of organic molecules, measured as carbon, present in pharmaceutical (i.e., compendial) waters.Unclassified area: A room or area not designated by grades but which needs to be designed and maintained such that its environment does not adversely impact the quality, purity, and integrity of the products. Note: Unclassified areas may or may not be controlled areas. Unidirectional airflow: Controlled airflow through the entire cross-section of a clean zone with a steady veloc-ity and approximately parallel streamlines.Working shift: Scheduled period of work or production, usually no greater than 12 hours in length, during which operations are conducted by a single defined group of workers.

ARTICLE ACRONYM LISTINGAPIs Active Pharmaceutical IngredientsASQ American Society for QualityASTM American Society for Testing and MaterialsCPGP Certified Pharmaceutical GMP ProfessionalEC European CommissionEMP Environmental Monitoring ProgramEMEA European Medicines AgencyEU European UnionFDA US Food and Drug AdministrationFMS Facility Monitoring System

GMPs Good Manufacturing PracticesGPT Growth Promotion TestingHEPA High Efficiency Particulate AirHVAC Heating, Ventilation, and Air ConditioningIEST Institute of Environmental Sciences and

TechnologyISO International Organization for StandardizationLAF Laminar Air FlowMHLW Japan’s Ministry of Health, Labour, and WelfarePDA Parenteral Drug AssociationPIC/S Pharmaceutical Inspection Convention and

Pharmaceutical Inspection Co-operation Scheme

SCDM Soybean-casein Digest MediumSOPs Standard Operating ProceduresTGA Australia’s Therapeutic Goods AdministrationUSP United States PharmacopeiaWHO World Health Organization

ABOUT THE AUTHORRobert D. Seltzer has worked in the FDA-regulated pharmaceuti-cal, biopharmaceutical, and medical device industries for the past 21 years. Bob holds an M.S. in biochemistry and bachelor degrees in chemical engineering and biochemistry, all from Rutgers University, New Brunswick, NJ. He is active in the Food, Drug, & Cosmetic Division of the American Society fro Quality (ASQ) as well as the Parenteral Drug Association Metro Chapter, and has five ASQ certifications as Quality Auditor, Quality Engineer, Manager of Quality/Organizational Excellence, Biomedical Quality Auditor, and Pharmaceutical GMP Professional, the last of which he con-ceived and successfully championed to formal adoption by ASQ.

ABOUT THE COLUMN COORDINATORAlice Krumenaker is Process Manager, Quality Systems, at Merial Ltd., North Brunswick, NJ. Alice is a senior member of ASQ and serves as a regional councilor and volunteer chair for the Food, Drug and Cosmetic Division. She holds ASQ certifications for Quality Process Analyst, Manager of Quality/Organizational Excel-lence, Pharmaceutical GMP Professional, and Six Sigma Green Belt. She may be reached by e-mail at [email protected] or by phone at 732.729.5872.

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