CleanroomTestingandCertification_inhouseGHPtraining

Cleanroom Testing & Certification GHP in-house training(Knowledge transfer from external training) 1

วตั ถุประสงค์ เพอื่ ถา่ ยทอดความรทู้ ไี่ ดร้ บั จากการประชมุ วชิ าการเรอื่ ง CleanroomTesting and Certification ซงึ่ จดั โดยสมาคมเภสชั กรอตุ สาหการ (ประเทศไทย)รว่ มกบั International Society for Pharmaceutical Engineering (ISPE) เมอื่วนั ที่ 2-3 พฤษภาคม 2560 ใหแ้ กผ่ ทู้ างานทเี่ กยี่ วขอ้ งของบรษิ ทั เยเนอรลั ฮอสปิ ตลัโปรดคั ส์ จากดั (มหาชน)• ทราบความขอ้ กาหนดดา้ น GMP ของคลนี รมู• สามารถออกแบบและตดิ ตง้ั คลนี รมู ไดถ้ กู ตอ้ งเหมาะสมในการผลติ ยาแตล่ ะประเภท• เรียนรูว้ ธิ กี ารตรวจสอบความถกู ตอ้ ง (validation) วา่ ไดร้ ะดบั ความสะอาดของ อากาศตามทกี่ าหนดในสถานะตา่ งๆ ไดแ้ ก่ at rest / in operation• เรยี นรกู้ ารบารงุ รกั ษาคลนี รมู ใหอ้ ยูใ่ นสภาพทใี่ ชง้ านไดต้ ามวตั ถปุ ระสงค์• ทราบวธิ กี ารตรวจประเมนิ เรอื่ งคลีนรมู จากเจา้ หน้าทตี่ รวจประเมนิ GMP ของ อย. 2

BACKGROUND AND OBJECTIVEHVAC problems can be difficult to fix or improve, not like asmall piece of equipment. To prove cleanroom is built asintended use, it cannot be done by visual check. Acleanroom can fail one although it looks very nice by ourown eyes. To prove a cleanroom, we need to do cleanroomtesting and the right cleanroom testing must followsinternational standards ISO / IEST / NEBB. Most important,cleanroom must be designed for the right cleanroom testingotherwise we cannot ensure the cleanroom meets therequirements. So we have to know how a cleanroom istested and certified before we can design the cleanroomand qualify the cleanroom. 3

BACKGROUND AND OBJECTIVEThe program will be benefit for the design team who wantsto do the best design, the validation team who wants toperform the right cleanroom qualification, the service teamwho wants to maintain the cleanroom at validated state.Also In a regulated pharmaceutical facility, someone inQuality Assurance must sign off on the cleanroom testreports. Although they do not test, they must know if thetesting procedure is correct and as per SOP’s Many problemcases will be presented e.g. improper airflowmeasurements, HEPA Filter mismatched installation for leaktesting, Clean-up time ambiguity, etc. SPEAKER: Mr.Dan C.Milholland, NASA Consultant 4

SPEAKER• Mr. Dan C. Milholland, NASA Consultant• เภสชั กรหญงิ คดั นางค์ ปอแกว้ , สานกั งานคณะกรรมการอาหารและยา 5

MR. DAN C. MILHOLLAND• He is the cleanroom expert in USA. He has more than 35 years of experience in cleanroom and contamination control. He was the working group of US cleanroom standards e.g. IEST and Federal Standard 209 and served US Expert Council for ISO 14644. He consulted for NASA for multiple space missions and he is the NEBB Cleanroom Instructor and Committee to certify cleanroom certifiers which is world recognized accredit program in cleanroom certification.• He completed both his undergraduate and graduate studies at North Carolina State University where he was awarded a Master's degree in biochemistry.• Milholland began in the air filtration business in the mid-1970's as a service manager for a company that sold air filters. That experience was the springboard for founding Biocon in November 1980. – Awarded the IES Maurice Simpson Technical Editors Award in 1994 and the IEST Willis J. Whitfield Award in April 2002 – Consulted at NASA for Mars samples containment design – Served on the Expert Council for United States for ISO 14644-1 – Presented to the FDA for the \"Barrier Users Group Symposium\"• Since selling his company in 1999, Dan has remained active as a consultant in the contamination control industry. 6

What is A Cleanroom?• From clean rooms to cleanrooms 7

Clean room to CleanroomClean room \ two words, an adjective and the noun itdescribes.1. Something you hope to find in a cheap hotel2. Something your mother experts from you.• Early standards and Microsoft use “clean room”Cleanroom \ klen-rum \ n: a room that is maintained ata high level of cleanliness using HEPA filters, etc.• A multi-billion dollar industry• All standards after 1983 have used the compound word “cleanroom” 8

What Do You Think?• A 0.3  particle in a cubic meter of air.• … is the equivalent of one golf ball in a cube that is how large?• A 0.3  particle in a cubic meter of air is the equivalent of on golf ball 19,000 square kilometer cube• Bangkok is only 1570 sq. kilometers 9

How Big are Bacteria? 0.3 m sphere 10

0.3 m Particles Cannot be Seen with a Microscope 11

What Limits the Microscope? 12

How Clean Is Clean? It Depends… ISO Cleanroom Standards maximum particles / m3 FED STD14644-1  0.1 m  0.2 m  0.3 m  0.5 m  1 m  5 m 209E Class equivalent1 102 100 24 103 1,000 237 102 35 Class 1 Class 104 10,000 2,370 1,020 352 83 Class 1005 100,000 23,700 10,200 3,520 8326 1,000,000 237,000 102,000 35,200 8,320 293 Class 1,0007 352,000 83,200 2,930 Class 10,0008 3,520,000 832,000 29,300 Class 100,0009 35,200,000 8,320,000 293,000 Room a1ir3

How Do We Establish a Clean Area?• A supply of clean air• A barrier or boundary• Reduce particle generation 14

How Do We Establish a Clean Area?• A supply of clean air – HEPA filters – Airflow 15

Two Types of “Clean” Airflow• Unidirectional • Non-unidirectional• Formerly “laminar flow” • Formerly “turbulent flow”• Uses the principle of flushing • Uses the principle of dilution 16

Unidirectional Airflow• Formerly “laminar flow”• Uses the principle of flushing 17

Non-unidirectional Airflow• Formerly “turbulent flow”• Uses the principle of dilution 18

How Dilution Works• We keep introducing clean air into a room over time• It lowers the particulate level in the room• Finally, it reaches a stasis – Clean air coming in is offset by particulates being introduced into or generated in the room. 19

Where Is Non-Unidirectional Flow Used?• Typically used in less clean cleanrooms – ISO 6 to ISO 9 20

What Do You think?• Are particles evenly disbursed throughout a cleanroom using non-unidirectional flow? – Yes – No 21

What Do You think?• Are particles evenly disbursed throughout a cleanroom using non-unidirectional flow? – Yes – No (Answer is Yes) 22

How Do We Establish a Clean Area?• A supply of clean air• A barrier or boundary – Pressurization – Airflow again• Reduce particle generation 23

Dan’s Rule• Everything Leaks• It might leak… – In or out – A little or a lot – Measurably or immeasurably• But It Leaks! 24

Even The Space Station!!! 25

Pressurization• Negative pressure – air leaks in • Positive pressure – air leaks out• The cleanliness of the room or • The cleanliness of the room or area is DEPENDENT on the area is INDEPENDENT of the cleanliness of the surrounding cleanliness of the surrounding area area 26

What Do You Think?• If everything leaks, a cleanroom should be pressurized… – With positive pressure – With negative pressure 27

How Much Pressure Is Recommended?“… a positive pressuredifferential of at least 10-15 Pa(1.0 to 1.5 mm wg) should bemaintained between adjacentrooms of differing classificationwith doors closed.” – Guideline for Industry – Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (Sept.2004) 28

How Do We Establish a Clean Area?• A supply of clean air• A barrier or boundary – Pressurization – Airflow again• Reduce particle generation 29

How Do We Establish a Clean Area?• A supply of clean air• A barrier or boundary – Pressurization – Airflow again • Establishes pressurization • Removes internally generated particles• Reduce particle generation 30

How Do We Establish a Clean Area?• A supply of clean air• A barrier or boundary• Reduce particle generation – Construction materials – Appropriate practices • e.g., gowning 31

How Do We Know It’s Clean?• Particle counts meets standards• Systems are working properly• Airflow pattern• Also done (not covered here): – Environmental monitoring – Microbial sampling 32

Particle Count Meets Standards• Particle count determines cleanroom classification• Most common standards – ISO 14644-1 and Annex 1 33

Particle Count Meets Standards• Is it as clean as it needs to be?• Is it as clean as it is expected to be?• Is there a trend upward? 34

How Do We Know It’s Clean?• Particle counts meetsstandards• Systems are workingproperly– Pressure relationships– Air velocity and volume We are moving beyond what it is …to whether it can stay that way– HEPA leak test• Airflow pattern 35

Check Pressurization• Positive pressure differential  – 10-15 Pascals – 1.0 to 1.5 mm wg Check Air Velocity / Volume• How much air is being pushed into the room or area to establish pressurization? 36

Check Air Velocity / Volume• Unidirectional rooms / areas – measure air velocity• Non-unidirectional rooms / areas – measure air velocity Check HEPA Filters• Check HEPA filters for leaks – How clean is the supplied air? 37

How Do We Know It’s Clean?• Particle counts meets standards• Systems are working properly• Airflow pattern – Airflow visualization – Recovery time 38

Summary• Cleanrooms are environments with a controlled level of environmental particulate – e.g., dust, airborne microbes, aerosol particles• The level of cleanliness varies with the class of cleanroom.• How a cleanroom achieves the level of cleanliness varies with the design and operation.• All cleanrooms have: – HEPA filtered air – Pressurization relative to the surrounding area – Unidirectional or non-unidirectional airflow – Appropriate construction materials and practices 39

Introduction to HEPA Filters 40

Objectives• At the end of this section, you will be able to: – Explain what HEPA filters are and how they work – Identify components of HEPA filters – Define “efficiency,” “penetration” and “resistance” – Define the “most penetrating particle size” – Describe the difference between “mass median diameter” and “count median diameter” – Distinguish between HEPA and ULPA filters 41

What Does “HEPA” Stand For? High Efficiency Particulate Air 42

HEPA Filter ConstructionFilter pack: Frame: fire retardant woodpleated medium board,and seperators aluminum, stainless steelContinuous Media:sheet of filter borosilicatemedium fibers, acrylicSealants: two- binderspartpolyurethaneSeparator: aluminium, Edge sealant: gasket 43medium, glue, dimples with clamp

Glass and ePTFE HEPA Filter Media Both images magnified 10K 44

HEPA Filter Media Pack 45

HEPA Filter Sealing Gel 46

Definitions• Efficiency: The percentage of particles that arecaptured. For example: 99.97% efficient on 0.3m mass median diameter particles• Penetration: The percentage of particles that findtheir way through the filter media and are notcaptured. For example: 0.03% 0.3 m massmedian diameter particles getting through thefilter.• Resistance (pressure drop): The pressurerequired to move a certain amount of air througha filter. For example: 10 mm wc 47

Count Median vs. Mean Diameter Count Median Mass Median Diameter DiameterDiameter 1 2 3 4 5 67 (cm)Mass ofEach 0.5 4 14 33 65 113 180ParticleAccum 0.5 4.5 18.5 51.5 116.5 239.5 419.5 Mass 48

HEPA Filter Definition: IESTAn extended medium, dry type filter in a rigidframe, having a minimum particle collectionefficiency of 99.97% for 0.3 m massmedian diameter particles of DOP whentested at rated airflow in accordance withMIL-STD-282IEST-RP-CC-001 49

HEPA Filter Efficiency Testing Classical (MIL STD 282)• Tested at Rated Flow• Determines Efficiency Rating• Hot Monodispersed DOP Used (0.3  massmedian diameter particles)• Uses Photometer to Measure Penetration• Different than Leak Testing• Determines Pressure Drop Across Filter• 1950’s technology• Filter Test Penetrometer: ATI TDA-120 ThermalPenetrometer 50