Environmental Monitoring R Raghunandanan, Mumbai Director – ISPE India 26th February 2011
Agenda • Introduction
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Agenda • Introduction
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Environment includes All the factors impacting quality and safety of pharmaceutical products
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Facility
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Utilities
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Machines
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Personnel
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Why environmental monitoring is important GMP requirement Facilities are designed to protect p rotect products from contamination or deterioration Facility must operate operate to meet the design criteria Only routine monitoring can prove that facilities are functioning as designed. • •
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Why environmental monitoring is important • •
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Regulatory Requirements, US FDA Microbiological control of drug manufacturing areas: Statutory requirement as per 21 CFR 211 as stated in Sections 211.46, 211.56, and 211.113 211 CFR 211.46, Ventilation, air filtration, air heating and cooling: Adequate control over microorganisms, dust, humidity and temperature. Pre filters and particulate matter air filters for air supplies to production areas
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Why environmental monitoring is important • •
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Regulatory Requirements EM is a requirement of GMP as per WHO, MHRA, MCC,TGA etc too. Schedule M requirements Sec 8.2.1. The licensee shall prevent mix-up and cross-contamination of drug material and drug product (from environmental dust) by proper airhandling system, pressure differential, segregation, status labeling and cleaning. Proper records and Standard Operating Procedures thereof shall be maintained.
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Why environmental monitoring is important Schedule M requirement All environmental parameters listed under para 3.1 to 3.10 shall be verified and established at the time of installation and thereafter monitored at periodic intervals. The recommended frequencies of periodic monitoring shall be as follows :• •
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Why environmental monitoring is important Schedule M requirement - recommended frequencies (a) Particulate monitoring in air 6 Monthly. (b) HEPA filter integrity testing (smoke testing) Yearly (c) Air change rates 6 Monthly. (d) Air pressure differentials Daily. (e) Temperature and humidity Daily (f) Microbiological monitoring by settle plates and/or swabs in aseptic areas - daily, and at decreased frequency in other areas •
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What impacts from environment •
Product deterioration Microbiological deterioration Thermal deterioration Humidity induced deterioration Product contamination Particulate contamination Cross contamination Increased bio-burden Sterility failures • •
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Different environments •
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Product exposed areas Aseptic preparation Aseptic filling, blending Preparatory areas Solution preparation Component preparation General areas Component washing
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What need to be monitored •
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Non-viable air monitoring (particulates) Viable air monitoring (microbiological) Surface monitoring (facility and equipment) Personnel monitoring (garments & gloves) Temperature and humidity Pressure differentials (∆p) Gases and other utilities (including water) Disinfectants Detergents and washing agents
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Different classes of environments EU Grade
ISO Class
Class
US FED STD
A
5
100
M 3.5
B
6
1000
M 4.5
C
7
10,000
M 5.5
D
8
100,000
M 6.5
(US FED STD now replaced by ISO 14644-1 though we frequently use the terminology Class 100 etc.) 26-02-2011
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Available standards and guidance EU Annex 1, 2008 USP 32, General Chapter ISO 14644 Schedule M of D&C Act and Rules of India Guidance for industry, US FDA – Sterile Drug Products produced by Aseptic Processing-Sept 2004 21 CFR Part 211.42 21 CFR Part 211.46 (and others) • • • • •
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Available standards and guidance •
It is important to remember that •
All standards are not exactly identical
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Manufacturer to follow the market
requirements as a minimum •
You are free to have tighter in-house
standards
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Area particulates (non-viable) EU Annex 1 Maximum no of particles per cubic meter At rest
In Operation
Grade
0.5 micron
5.0 micron
0.5 micron
5.0 micron
A
3520
20
3520
20
B
3520
29
352,000
2900
C
352,000
2900
3,520,000
29,000
D
3,520,000
29,000
Not defined
Not defined
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‘At rest’ and ‘In Operation’ • ‘At rest’ – Air flow is ON – Equipment installed but not in use – No personnel in the area • ‘In Operation’ – Air flow is ON – Equipment in operation (sometimes simulated) – Specified no. of personnel in the area • Define these for each clean room 26-02-2011
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‘Microbiological monitoring standards (EU Annex 1) Limits for microbial contamination Grade
Air sample Cfu/m3
Settle plate Cfu/4 Hrs
Contact plate Cfu/plate
Glove print Cfu/glove
A
