??F?? - 5? ??????FO???? S????????

1
??F?? - 5? ??????FO???? S???????? ??
??s???µe?a??? Fa?µa??p???? st? ?eta??µ?? t??
???a??? st?? ??e?a
???atast?se?? - ???p??sµ??
Sta???? ????t?? MSc, PhD, ?ate???a ??????p? MSc,
??µ?t???? ????a? MSc, PhD ?µ?µa Fa?µa?e?t????
???? spolitis_at_pharm.uoa.gr
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
2
???atast?se?? - ???p??sµ??

• Ste???? ?????
• S??t?µ? ?st????? a?ad??µ?.
• ?? ?e????te?? p?a?s?? ?a????? pa?a?????
  fa?µa?e?t?-??? p?????t?? (cGMPs).
• ?d?a?te??t?te? t?? ste???? ?????
• ??d??? ??µata

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
3
Ste???? ?????

• S??t?µ? ?st????? a?ad??µ?
• ?st???a gt120 et?? ?? ?????a.
• 2?? ?? S?st?µata e?ae??sµ?? p??? e??tt?s?
  ep?µ????se??. F??t?a HEPA.
• 1955 ß??µ??a???? efa?µ??? ??a dust free
  environment, Western Electric.
• 1960-1 ?? p??te? ap?pe??e? ??µat???? ???? se
  ?e??????e?a (Blowers and Crew Vs
  Charnley-Howorth).

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
4
Ste???? ?????

• S??t?µ? ?st????? a?ad??µ?
• 1961 Willis Whitfield, Mr. Clean
• ???a?? p??s????s?? (The Whitfield Ultra-Clean
  Room, Time Magazine April 1962).

Willis Whitfield Original laminar flow room
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
5
Ste???? ?????

• ???sµ??
• ???sµ?? EN/ISO 14644-1
• ??a? ?????
• - e?t?? t?? ?p???? e????eta? ? s?????t??s? t??
  ae???e??? s?µat?d???,
• - ? ?p???? e??a? s?ed?asµ???? µe t?t??? t??p?
  ?ste ?a e?a??st?p?????ta? ?? ???d???? d?µ??????a?
  ?a? ?ata???t?s?? s?µat?d???,
• - ?a? st?? ?p??? ???? ?? s?et???? pa?????te?, ??a
  pa??de??µa, ? ?e?µ???as?a, ? ???as?a ?a? ? p?es?
  e??????ta? ?at?????a.

A room in which the concentration of airborne
particles is controlled, and which is constructed
and used in a manner to minimize the
introduction, generation, and retention of
particles inside the room and in which other
relevant parameters, e.g. temperature, humidity,
and pressure, are controlled as necessary.
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
6
Ste???? ?????

• ?fa?µ???? (Clean rooms)
• Fa?µa?e?t??? pa?a???? (ste??a p?????ta,
  pa?e?te????, ?f?a?µ???)
• ?????-??e?t?????? (pa?a???? ts?p ??e?t???????
  ?p?????st??), a?t?µat?p???µ??a s?st?µata
  (e?t?p?s?? ?.?.)
• ??ast?µ??? (d?ast?µ??? ???µata, d???f????)
• ??s???µe?a

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
7
Ste???? ?????

• ?d?a?te??t?te? ste???? p?????t?? (pa?e?te????
  S?)
• ?e???? p????? p??t?te ste???.
• ?a?as?e?? se ?????? µe e?d???? p??d?a??af??
  (ste???? - ?a?a??? ?????, cleanrooms).
• ???s?p??? ??d?s?, ?at?????? e?pa?de?s?.
• ??s?e? e??e???µ??e? ??a pa?e?te???? ??????s?.
• ??a??te?, ß????t???? ??s?e? (???µ?st???,
  s??t???t???) p??pe? ?a e??a? e?d???? p??d?a??af??
  (p.?. ?????? ?a?a??t?ta?).
• ?e????te? s???e???µ??e? p??d?a??af??
  a?st???te?e? µ? ste???? s?e?asµ?t??.

Se??? e?e?d??e?µ???? p??t?p?? ????µ??e?
apa?t?se?? ep?????s?? (validation) d?e??as??? ?a?
e?????? ?ata?????t?ta? (qualification) e??p??sµ??
- ?????
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
8
Ste???? ?????

• ????t?ta ste???? p?????t?? (pa?e?te???? S?)
• ??? e?asfa?????ta?? ?e ßa?e?? ???s? ???? t??
  a?????-e?a?t?µe??? µe??? t?? e?se???µ???? st?
  d?e??as?a pa?a????? t???.

???a??µata Machines
?????p?? Men
????d?? Methods
µ??a??µata d?a?e???s? ?e?µ???as?a? ?a? ???as?a?,
p?es??, ae???e??? s?µat?d???
µ???d?? pa?a?????
????se??
s?µpe??f???
???e???
µ??a??µata pa?a?????
DQ, IQ, OQ, PQ
e?pa?de?s?
f??t?a
?atas?e?ast???? pa?eµß?se?? ?a? d?aß??µ?s? ?????
??. S?s?e?
????sµ???
? ??e?
µ??a??µata
sta?e?? ?e?µ???as?a ?a? ???as?a
S?st?µata pa?a- ???????s?? ?a?
e?????? Measurements
????? Materials
?e??ß????? Environment
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
9
Ste???? ?????

• ????t?ta ste???? p?????t?? (pa?e?te???? S?)
• ??? e?asfa?????ta?? ?e ?µß???s? t?? pa?a???t??
  d?a???d??e?s??.

Risk from Manufacturing site
High
Q10 Pharm. Quality Systems
Risk from Product
Low
Q8 Pharmaceutical Development
Low
High
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
10
Ste???? ?????

• ???atast?se??
• ??d???? apa?t?se?? se
• S?ed?asµ?, ??e??? ?ata?????t?ta?
• ?????
• S?st?µata e?ae??sµ?? (HVAC)
• ??af????? p?es? a??µesa se ??????
• ???p??sµ??
• ?a?a?????
• ?a?a???????s?? ?a? e??????

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
11
?a????µ?s? Ste???? ????? (Classification)

• ?a?µ?de? (???se?? ? ???e?)
• A µ?a pe?????sµ??? ???? ??a e??as?e? ??????
  ep????d???t?ta? p.?. p????s?, sf????s?, ???s?
  a????t?? f?s????? ?a? f?a??d???, ep?te??? ?s?pt??
  s???????. ???s? ??se?? e??as?a? µe ??µat??? ???
  (a??a sta?e??? ta??t?ta? 0,45m/s st? ??s?
  e??as?a?)
• B pe??ß????? ßa?µ?da? ? ??a ?s?pt? pa?a???? ?a?
  p????s?.
• G ????te?? ???s?µe? f?se?? pa?a????? ste????
• ? ?µ??a µe G

• Ta µp????se ??a? ?a?a??? ????? ? ?a s????e?e? µe
  ??a? µ? e?e???µe?? ????
• ? ße?t??s? t?? p??d?a??af?? t?? ????? ???eta?
  stad?a?? ?a? f?s??? µeta?? ?e?t?????? ????? ?p?
  d?af??? p?es??.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
12
?a????µ?s? Ste???? ????? (Classification)

• ISO-Classes 5,6,7,8
• ISO 14644-11999, Cleanrooms and associated
  controlled environments -- Part 1 Classification
  of air cleanliness.
• http//www.iso.org/iso/home/store/catalogue_tc/cat
  alogue_detail.htm?csnumber25052
• http//acquisition.jpl.nasa.gov/rfp/JSL-52404/ISO1
  4644-11999.pdf

• EU-Classes Classes A,B,C,D
• EC - EudraLex, Volume 4, EU Guidelines to Good
  Manufacturing Practice, Medicinal Products for
  Human and Veterinary Use, Annex 1, Manufacture of
  Sterile Medicinal Products, (cor.vers., Nov
  2008).
• http//ec.europa.eu/health/files/eudralex/vol-4/20
  08_11_25_gmp-an1_en.pdf

US-Classes 100, 1000, 10000, 100000 FDA -
Guidance for Industry, Sterile Drug Products
Produced by Aseptic Processing - Current Good
Manufacturing Practice, Sep 2004 (replaced 1987
guideline) http//www.fda.gov/downloads/Drugs/.../
Guidances/ucm070342.pdf
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
13
ISO 14644-11999, Cleanrooms and associated
controlled environments -- Part 1 Classification
of air cleanliness.????st? s?????t??s?
(s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e??? ap?
?a????µ?s? Ste???? ????? (Classification)
ISO ?at?ta?? ????st? s?????t??s? (s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e??? ????st? s?????t??s? (s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e??? ????st? s?????t??s? (s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e??? ????st? s?????t??s? (s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e??? ????st? s?????t??s? (s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e??? ????st? s?????t??s? (s?µat?d?a/m3 a??a) s?µat?d??? µe µ??e???
ISO ?at?ta?? 0,1 µm 0,2 µm 0,3 µm 0,5 µm 1,0 µm 5,0 µm
ISO Class 1 10 2
ISO Class 2 100 24 10 4
ISO Class 3 1 000 237 102 35 8
ISO Class 4 10 000 2 370 1 020 352 83
ISO Class 5 100 000 23 700 10 200 3 520 832 29
ISO Class 6 1 000 000 237 000 102 000 35 200 8 320 293
ISO Class 7 352 000 83 200 2 930
ISO Class 8 3 520 000 832 000 29 300
ISO Class 9 35 200 000 8 320 000 293 000
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
14
EC - EudraLex, Volume 4, EU Guidelines to Good
Manufacturing Practice, Medicinal Products for
Human and Veterinary Use, Annex 1, Manufacture of
Sterile Medicinal Products, (cor.vers., Nov
2008).????st?? ep?t?ept?? a???µ?? ae???e???
s?µat?d??? a?? ???s?
?a????µ?s? Ste???? ????? (Classification)
Se et??µ?t?ta Se et??µ?t?ta Se ?e?t?????a Se ?e?t?????a
???s? ????st?? a???µ?? s?µat?d??? /m3 ?s?? ? µe?a??te??? ap?... ????st?? a???µ?? s?µat?d??? /m3 ?s?? ? µe?a??te??? ap?... ????st?? a???µ?? s?µat?d??? /m3 ?s?? ? µe?a??te??? ap?... ????st?? a???µ?? s?µat?d??? /m3 ?s?? ? µe?a??te??? ap?...
0.5µm 5µm 0.5µm 5µm
A 3 520 20 3 520 20
B 3 520 29 352 000 2 900
G 352 000 2 900 3 520 000 29 000
? 3 520 000 29 000 ?e? ????eta? ?e? ????eta?
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
15
(EC - EudraLex, Volume 4, EU Guidelines to Good
Manufacturing Practice, Medicinal Products for
Human and Veterinary Use, Annex 1, Manufacture of
Sterile Medicinal Products, (cor.vers., Nov
2008).???a µ????ß?a??? ep?µ????s??
?a????µ?s? Ste???? ????? (Classification)
S???S?O???? ???? ??????????S ????????S?S S???S?O???? ???? ??????????S ????????S?S S???S?O???? ???? ??????????S ????????S?S S???S?O???? ???? ??????????S ????????S?S
?a?µ?da ?e??µa a??a CFU/m3 ????e? ?a????se?? (d?aµ.90 mm) CFU/4??e?) ????e? epaf?? (d?aµ.55 mm) CFU/p???a ?p?t?p?µa ?a?t??? µe 5 d??t??a CFU/???t? (?e????t??)
A lt1 lt1 lt1 lt1
B 10 5 5 5
G 100 50 25 -
? 200 100 50 -
() ????e?ta? ??a µ?se? t?µ?? () ???sµ??e?
p???e? ?a????se?? µp????? ?a e?te???? ??a ???????
d??st?µa µ????te?? t?? tess???? ????.
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
16
FDA - Guidance for Industry, Sterile Drug
Products Produced by Aseptic Processing - Current
Good Manufacturing Practice, Sep 2004???a
a???µ?? s?µat?d??? ?a? µ????ß?a??? ep?µ????s??
?a????µ?s? Ste???? ????? (Classification)
?at?ta?? (S?µat?d?a 0,5 µm/ft3) S?s??t?s? µe ISO 14644-1 S?µat?d?a 0,5 µm/m3 ?????ß??????-?? de??µa a??a (cfu/m3 ) ????e? ?a????se?? (d?aµ.90 mm) CFU/4??e?)
100 5 3 520 1 1
1000 6 35 200 7 3
10 000 7 352 000 10 5
100 000 8 3 520 000 100 50
() ?a de??µata se a?t? t? ßa?µ?da p??pe? ?a
eµfa?????? µ?de???? µ????ß?a?? f??t??.
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
17
FDA - Guidance for Industry, Sterile Drug
Products Produced by Aseptic Processing - Current
Good Manufacturing Practice, Sep 2004???sµ??
Critical Area Class 100 (ISO 5)
?a????µ?s? Ste???? ????? (Classification)
A critical area is one in which the sterilized
drug product, containers, and closures are
exposed to environmental conditions that must be
designed to maintain product sterility ...
Activities conducted in such areas include
manipulations (e.g., aseptic connections, sterile
ingredient additions) of sterile materials prior
to and during filling and closing operations.
This area is critical because an exposed product
is vulnerable to contamination and will not be
subsequently sterilized in its immediate
container. To maintain product sterility, it is
essential that the environment in which aseptic
operations are conducted be controlled and
maintained at an appropriate quality. One aspect
of environmental quality is the particle content
of the air. Particles are significant because
they can enter a product as an extraneous
contaminant, and can also contaminate it
biologically by acting as a vehicle for
microorganisms. Appropriately designed air
handling systems minimize particle content of a
critical area. Air in the immediate proximity of
exposed sterilized containers/closures and
filling/closing operations would be of
appropriate particle quality This level of air
cleanliness is also known as Class 100 (ISO 5).
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
18
S?????s? d?af??et???? s?st?µ?t??
?a????µ?s? Ste???? ????? (Classification)

• Ge???? ?p???e? d??at?t?ta a?t?st????s??.
• ?p???e? s?????s? ????p?? ?µe????? ????
  e?a?µ???s?? (ICH).
• ?? p??t?p? ISO af??? µ??? se s?µat?d?a.
• ???s??? p?? a?af????ta? ta ???a p? ?at?stas?
  ?e?t?????a? ? µ?
• - ISO14644-1 Occupancy state As
  Built/At-Rest/Operational.
• - EU At rest/In operation.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
19
???s???!
?a????µ?s? Ste???? ????? (Classification)

• ?? ?d???e? pe???aµß????? ?????S??S apa?t?se??.
• ?p?????? d?af???? µeta?? t?? ?d?????, p??t?µ?s?
  a?st???te??? a?????a µe ???a efa?µ????.
• ?? ?d???e? a???????-ep??a???p?????ta?!

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
20
???s???!
?a????µ?s? Ste???? ????? (Classification)

• ?????? pe??pt?se?? ?a? ?d?a?te??t?te? a?????a µe
  d?e??as?a ?a? e??at?stas? (p?, te???? ap?ste???s?
  ? ???s? Isolators a?t?st???a).
• ???s??? se µe??d??? µ?t??s?? (p?te, p?? ?a? µe
  p??? t??p?).
• ?e? ?e???µe t? ?e????te?? ?a????st??? p?a?s?? (p?
  ICH Q7A-GMP guidance) ?a? ???e? p????
  p????f???s?? (p? IEST recommended practices and
  guides, WHO, Feb 2011).

Institute of Environmental Sciences and
Technology.
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
21
S?ed?asµ?? ???at?stas??

• Ge????
• ??st? ??tas?, ?atas?e??, f???????a, ?p?d?µ?.
• ???at??? d??aµ??? d?a?es?µ?t?ta ?a? ?p?ßa???.
• ?p?st????? d?a??µ?? µetaf????.
• ?a???? e????e?a?.
• ?d?? (p???t?ta).
• ???a? (p???t?ta).
• ?p?ß??ta (p???t???).
• S?ed?asµ?? se s??s? µe t?? ?p????p? e??at?stas?.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
22
S?ed?asµ?? Ste???? ?????

• ?????te?e? apa?t?se??.
• ?e??ste??? ?atas?e??.
• ????? a??e?t??? se f???? ?a? pa?a???? s?µat?d???.
• ?e?e? ep?f??e?e? ??a e????? ?a?a??sµ?.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
23
S?ed?asµ?? Ste???? ?????

• Teµe???d??? s?µas?a? t? s?st?µa HVAC
• Heating
• Ventilation
• Air-Conditioning
• ??? ßas???? µ??a??sµ?? t??p?? ep?te????
  ?a?a??t?ta? st? es?te????
• ??? ?a? e?a??a??? a??a
• ??af??? p?es?? a??µesa st??? ??????
  (?e??f???te?)

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
24
S?ed?asµ?? Ste???? ?????

• ????? t?? s?st?µat?? HVAC
• ap?µ?????s? ep?µ????t?? (s?µat?d??? ?a?
  µ???????a??sµ??)
• ???µ?s? ?e?µ???as?a? (???? / ???µa?s?)
• ???µ?s? ???as?a? (ef???a?s? / af???a?s?)
• e?asf???s? d?af???? p?es?? (??)
• pa???? a??a µe ?at?????? ta??t?ta / e?a??a???
  a??a a?? µ???da

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
25
S?ed?asµ?? Ste???? ?????

• ?? ??? µp??e? ?a ???e? t? s?st?µa HVAC
• ?a?a??sµ? ß??µ???? ep?fa?e???...!
• µe??s? p??ß??µ?t?? p?? d?µ????????ta? ap? t?
  p??s?p??? p?? de? a??????e? t?? d?ad??as?e?...!
• ?a?µata...!!!

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
26
S?ed?asµ?? Ste???? ?????

• ?? ??? µp??e? ?a ???e? t? s?st?µa HVAC

VIDEO
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
27
S?ed?asµ?? Ste???? ?????

• ?as??? st???e?a s?et??? µe ta s?st?µata HVAC
• ?as???? ?at?????e? a??a
• f??s??? a??a? (µ??? µ?a f??? e?s???eta? st? ????)
• ??a t????? ?????
• ??a e?f?e?ta ?????
• ??a p??? d?ast??? ?????
• a?a??????µe??? a??a? (µ???? t?? a?a??????eta?)
• p?? ??????µ??? ??s?
• ?a??te?? ?ata???t?s? ap? f??t?a
• p??a??t?ta d?asta????µe??? ep?µ????s??

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
28
S?ed?asµ?? Ste???? ?????

• ?as??? st???e?a s?et??? µe ta s?st?µata HVAC
• ????µ??? pa???? a??a
• ??afe?? ? ?at?st?µa pe??p?? 2-10 a?a?e?se??/??a
• se ??a? ?a?a?? ???? p??? pe??ss?te?e? p.?. 60-90
  e?a??a??? (ßa?µ?da G)
• ??d??? f??t?a ?????? ap?te?esµat???t?ta?
• se ??a ??afe?? ? ?at?st?µa, ap?? f??t?a
• s?????? ??PA f??t?a epa?????
• T?s? te????? f??t???
• ??afe?? ? ?at?st?µa, f??t?a µet? ap? t?? pa????
  a??a (s???? st??? a??????)
• se ??a ?a?a?? ???? a???ß?? st? s?µe?? pa?????
  a??a
• Tet??? p?es? p?? ?a?a??? ????? se s??s? µe t???
  ????te?? ?a?a????
• p?? apa???? ????te??? a??a ap? a?t?? p??
  e?s??eta? ? apa???? t?? a??a se ?e?t???????
  ??????
• ??st??

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
29
S?ed?asµ?? Ste???? ?????

• ??? a??a st??? ste????? ??????

• S?µßat??? ??? a??a
• µe?????t?µa ? p??a??t?ta d?µ??????a? st??ß????
  se ???sµ??e? pe?????? t?? ?????
• ??? a??a p??? µ?a ?ate????s?
• laminar flow or unidirectional flow.
• 90fpm20. ???tas? ap? t?? ep??? t?? Whitfield.
• ???t? ???
• s?µßat??? ?a? d?aß?ßas? ???? a??a p??? µ?a
  ?ate????s? st?? ???s?µe? ??se?? e??as?a?.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
30
S?ed?asµ?? Ste???? ?????

• ??? a??a st??? ste????? ??????

S?µßat??? ??? a??a
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
31
S?ed?asµ?? Ste???? ?????

• ??? a??a st??? ste????? ??????

??µat??? ??? p??? µ?a ?ate????s?

• ???et? (ap? ep??? p??? ta ??t?)
• p?? ap?te?esµat???
• ??????t?a (ap? t???? se t????)
• p?? ??????µ???

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
32
S?ed?asµ?? Ste???? ?????

• ??? a??a st??? ste????? ??????

• ?p?f??? st??ß???sµ??
• ?µfas? sta p?? ???s?µa s?µe?a

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
33
S?ed?asµ?? Ste???? ?????

• ??af??? p?es??

• S???st?µe?? t?µ? ??a t?? ????pa??? ???s?
  10-15Pa
• S?s?e??? a?t?µat?? ???µ?s??/d?at???s?? p?es??
  (pressure stabilizers)
• ?????µa p??ta?
• pa??d???
• e?? d?a??e? pe??ss?te??
• µ???? ? d?p??? p??te?
• s???pe?e? s?et????ta? ?a? µe ?e?µ???as?a
• ?p?????sµ?? d?a????? a??a ap? t?? p??te? ?a?
  a?????? pa???? p?s?t?ta? a??a (QAa (??)1/2)

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
34
S?ed?asµ?? Ste???? ?????

• ??af??? p?es?? - ae??f???te?

• ??a??t??? d?? p??te?, ?? ?p??e? de? a???????
  ta?t?????a
• ???a? ?a? ?? ????? e?d?µas?a?
• G?a p??s?p???, ?????, d?af??et???? t?p??
• ?a???? a??a ap? t?? ?a?a??te?? p?e??? t?? ?????
  e?d?µas?a?
• Se t? ???s?µe????
• d?at???s? d?af???? p?es??
• pa?eµp?d?s? e?s?d?? µ???sµ???? a??a

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
35
S?ed?asµ?? Ste???? ?????

• F??t?a (HEPA)

• High Efficiency Particulate Air Filters
• ?ata??at??? s?µat?d?a / e?????aµµ????? ??? a??a
• HEPA 99,97 ap?d?s? a?? 10,000s?µat?d?a
  µe?????? 0,3µm pe????? 3.
• ULPA (Ultra Low Penetration Filters) ?ata??at???
  99,99 s?µat?d??? 0,1-0,2µm.
• ???f??t?a µe??s? ep?ß????s?? ?????? f??t???.
• T?µata ??st???.
• ???s??? ?at? t?? e??at?stas? (e?s?d??
  af??t????st?? a??a).
• ????t?s? ap?d?s?? ap? ??? a??a.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
36
S?ed?asµ?? Ste???? ?????

• F??t?a ?? pa?????ta? d?a???d??e?s?? ??a a??pt???
  µ????ß?a??? f??t???

• ???s??? es?te????? s??te???? pe?????? t??
  f??t??? a??µa ?a? se s????? ???as?a. ????e?ta? ?
  a??pt??? µ???????a??sµ??
• ?ata???t?s? s?µat?d??? µe µ????ß?a?? f??t??
• ???d???? ? µ????ß?a?? µ????s? ?a p?????eta? ap?
  ta ?d?a ta f??t?a
• F??t?a e??s??µ??a ??e?t???? (??F filters) ?
  ?????e? UV s??dedeµ??e? µe ta f??t?a
• S????? ??e???? t?? f??t???

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
37
S?ed?asµ?? Ste???? ?????

• S?ed?asµ?? a?????a µe t?? µ??f??
• ????/?µ?ste?e?/ste?e?
• ??a??µata/e?a????µata/?a?a?t?µata
• Ste?e? (???e??/???f???p???µ??a)
• S?ed?asµ?? a?????a µe d?e??as?e?
• ?s?pt? pa?a???? vs ?e???? ap?ste???s?
• ??e??as?a pa?a????? (a??µe???, d?asp???,
  ?µ??e??p???s? ??p)
• ???s? Isolators ?a? ??e?st?? s?st?µ?t??
• ???f??a
• ????? pa?a?????.
• ?pe?tas?µ?t?ta e??at?stas??.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
38
S?ed?asµ?? Ste???? ?????

• ??? d?e??as???
• ??? p??s?p????
• ??? ??????
• ?????t???? e??as?e? - s??t???s? - ?a?a??sµ??
  (CIP)- ap?ste???s? (SIP)
• ???p??sµ?? ?????? ß????t????
• ?e?t?????e? ????e? ?a? ep?????????
• ICH Q7A The facility to be designed to provide
  sufficient space as to perform the operations
  within a proper and organized way. Contamination
  and mix up prevention should be also considered
  as a part of the facility design.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
39
S?ed?asµ?? Ste???? ?????
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
40
S?ed?asµ?? Ste???? ?????

• ???s? ? (critical area)
• ??e???ß??? ?a? ??st?ß??? tµ?µa e?a??st?p???s?
  ??tas?? sta µ?t?a t?? d??at??
• ??a??st?p???s? ap?stas?? s?µe??? d?e?pe?a??s??
  ???s?µ?? stad??? ap? HEPA
• ???t?st? ??? a??a ta?e?a ap??at?stas?
  d?ata?a?µ???? s???????
• ??a??st?p???s? apa?t??µe??? p??s?p????

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
41
S?ed?asµ?? Ste???? ?????

• ?et?f?as? t?? a?a????. ???d?a??af?? ??a t??
  ?????? t?? apa?t??µe??? ???s?? (User Requirement
  Specification-URS).

• ?pa?t?t??? ????.
• S??e??as?a µe t??? s?ed?ast?? ?/?a? t???
  p??µ??e?t??.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
42
S?ed?asµ?? Ste???? ?????

• ?ata??af? t?? a?a????. ???d?a??af??
  ?e?t???????? s?ed?asµ?? (Functional Design
  Specification FDS) ?a???eta? ap? t?? p??µ??e?t?
  st? f?s? t?? p??sf????. ?a??de??µa ped??? a??
  e?d??

• 1.0 Introduction. 2.0 Overview
• 3.0 Operational Requirements
• 3.1 Commodities, 3.2 Performance, 3.3 Functions,
  3.4, Power Failure and Recovery, 3.5 Emergency
  Stop, 3.6, Alarms and Warnings, 3.7 Data
  Security, 3.8 Interfaces, 3.9 Supervisory
  Interface, 3.10, Data Collection
• 4.0 Environment,
• 4.1 Layout, 4.2 Physical Conditions
• 5.0 Constraints, Milestones and Timelines
• 6.0 Compatibility
• 6.1 Controls, 6.2 Product Contact Parts, 6.3
  Utilities, 6.4 Cleaning, 6.5 Chemical Resistance
• 7.0 Availability
• 8.0 Procedural Constraints, Regulatory Compliance
• 9.0 Maintenance
• 9.1 Instructions, 9.2 Tools, 9.3 Spare Parts
• 10.0 Life-Cycle
• 10.1 Development, 10.2 Testing, 10.3 Delivery,
  10.4 Documentation, 10.5 Support.
• 11.0 Glossary. 12.0 References. 13.0 Approval

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
43
S?ed?asµ?? Ste???? ?????

• ?p?????s? ?ata?????t?ta? s?ed?asµ?? (Design
  Qualification).

- ICH Q7A Design Qualification (DQ) documented
verification that the proposed design of the
facilities, equipment, or systems is suitable for
the intended purpose.

• ?pa?t?t??? ????.
• S??e??as?a µe t??? s?ed?ast?? ?/?a? t???
  p??µ??e?t??.
• ? e????? e??a? t?? a?a??t?, a??? ??s?ast???
  e?te?e?ta? ap? t?? p??µ??e?t?.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
44
???at?stas? Ste???? ?????

• ?p?????s? ?ata?????t?ta? e??at?stas?? (Design
  Qualification).

- ICH Q7A Installation Qualification (IQ)
documented verification that the equipment or
systems, as installed or modified, comply with
the approved design, the manufacturers
recommendations and/or user requirements.

• ?p?????s? ?ata?????t?ta? ?e?t?????a?
  (Operational Qualification).

- ICH Q7A Operational Qualification (OQ)
documented verification that the equipment or
systems, as installed or modified, perform as
intended throughout the anticipated operating
ranges.

• ?p?????s? ?ata?????t?ta? s???????? ap?d?s??
  (Performance Qualification).

- ICH Q7A Performance Qualification (PQ)
documented verification that the equipment and
ancillary systems, as connected together, can
perform effectively and reproducibly based on the
approved process method and specifications.
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
45
???at?stas? Ste???? ?????

• G?at? ??e???eta? ? d?e?pe?a??s? t??
  ep?????s??.

• ?pa?te?ta? te?µ????µ??? ap?de??? p?? pa???e?
  ????? ßa?µ? d?asf???s?? ?t? ???e d?e??as?a (?a?
  e??at?stas?).... ep?te?e? t? s??p? ??a t?? ?p???
  ??e? s?ed?as?e?.
• ??????OS? ????G?S??S G????
• ?ste ?a ap?de????eta? ?t? ???e d?e??as?a
  s?st?µat??? ?a? ad?a?e?pt?? ep?te?e? t? st??? t??
  (ß??s?eta? e?t?? stat?st???? e??????)
• ?ste ?a ?a???????ta? ?? ???s?µe? pa??µet??? t??
  d?e??as?a?, ta ap?de?t? ???? t??? ?a? ??
  apa?a?t?t?? ??e???? ?at? t? d????e?a t??
  d?e??as?a?
• ?ste ?a ße?t?st?p?????ta? ?? d?e??as?e?

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
46
???at?stas? Ste???? ?????

• ?p?????s?.

• ? ep?????s? apa?te? ?µad??? p??sp??e?a, de?
  µp??e? ?a e??a? ?pe?????t?ta e??? at?µ?? ? e???
  tµ?µat??
• ?a??????e?a ???µat?? p?? ?a ?p?st????e? t??
  d?ast????t?te? t?? ?p?????s??
• ?a????st???? apa?t?se??, ?p?st????? ap?
  a?t?st???? tµ?µa.
• ?f???
• S?µµ??f?s? µe ?a????sµ??? cGMP (????? ??a?t????
  ?a?a?????)
• ?e??s? ??st??? (? eµpe???a ?a? ? ????? ??????
  ?p?de??????? ?t? µ?a ep?????µ??? d?e??as?a ??e?
  ?a??te?? ap?d?s?, ????te?e? a?a?ate??as?e?,
  a?a???se?? ??p)
• ????e??? ???f?? ??st??? µ? ep?????µ????
  d?e??as???

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
47
???at?stas? Ste???? ?????

• ?p?????s?.

• ? ep?????s? ?e???? ap? t? f?s? t?? s?ed?asµ?? t??
  d?e??as?a? ?a? de? e??a? p?t? p????? e?? de? ??e?
  ?e????se? ap? a?t?.
• ?? tµ?µa ??e??a? ?a? ???pt???? (se s??e??as?a µe
  pa?a???? ?a? ??e??? p???t?ta?) ?a p??pe? ?a e??a?
  se ??s? ?a pa???e?
• sta?e??? d?e??as?e? (robust processes) µe
  ?p?-d?e??as?e? ep?????µ??e? (s?µas?a ep?????s??
  p???t???? pa?t?d??)
• ta?t?p???s? ???t???? pa?aµ?t??? d?e??as?a? /
  p?????t??
• p??se?t???? ?a????sµ?? ?????
• µe??d?? ??a t?? ??e??? ???s?µ?? pa?aµ?t???

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
48
???at?stas? Ste???? ?????

• ?p?????s?-s????? eµp?d?a

• ???e??? p??s?p????, p????, µ??a??µ?t??
• ?p?????s? de? e??aµß??eta? ap? ????? ?? apa?t?s?
  ? ep?fe??? d?ast????t?ta
• ??t??eta e??aµß??eta? ??
• pa??µßas? st? ???? t?? pa?a?????
• ?s??p? ?ata????s? ??????, p???? (?a? ??????
  ???µ?t??)
• eµp?d?? ??a p?? pa?a??????? d?ast????t?te?

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
49
???at?stas? Ste???? ?????

• ?p?????s? - s?µµet????te?.

• ?µ?da ap?te???µe?? ap?
• ??????s?
• ?µ?µa pa?a?????, e?????? p???t?ta?, ??e??a? ?a?
  a??pt????
• ?e??????, µ??a?????
• ?µ?µa d?asf???s?? p???t?ta?
• ?µ?µa ?a????st???? ?p???se?? (regulatory affairs)
• ???µ??e?t??
• ??? pe??ss?te??? ? ????te??? ap? ?s???
  apa?t???ta? (4-5 ?t?µa s???st?µe??? a???µ??).
• ???s??? ? ep?????s? de? ap?te?e? at?µ???
  d?ast????t?ta.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
50
???at?stas? Ste???? ?????

• ?p?????s? ???s?µ?? ?a???e?.

1. ??? t? pa???ete p??s?p???.
2. ???a??ste t?? p??sp??e?a ?a? t???ste t?
   p????aµµa.
3. ?p????te s?st? t?? p??te?a??t?te? (p??e? e??a? ??
   ???s?µe? pa??µet??? t?? d?e??as?a?)
4. ??pa?de?ste ????? t??? eµp?e??µe????.
5. ?a e??µe???este s???? ??a t?? e?e???e??.
6. ?? ?????p??-??e?d?? s?????? de? ?ata????? t??
   a?a??a??t?ta t?? ep?????s??.
7. ? ep?????s? a???p?st?a? e??a? µ?a d?e??as?a ap?
   µ??? t??, ??? ??a ?e?????.
8. ? ep?????s? ?a?a??sµ?? de? ?e???? p?t? a??et?
   ?????.
9. ? ep?????s? µp??e? ?a ?????????e? ep?t???? µ???
   ef?s?? ? d?e??as?a ??e? ???ste? p????? ?a? saf??.
   ? ep?????s? ?a? ? ße?t?st?p???s? de? µp????? ?a
   ?????? ta?t?????a st?? ?d?a d?e??as?a, st? ?d??
   µ?????µa, t?? ?d?a st??µ?.
10. ?p?????ste ???e d?ast????t?ta, tµ?µa e??p??sµ?? ?
    ß?µa d?e??as?a? ??e? ep?pt?s? st?? ?a?a??t?ta,
    p???t?ta, asf??e?a, ap?te?esµat???t?ta t??
    p?????t??.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
51
???at?stas? Ste???? ?????

• ?p?????s? Teµe???d? ?a?a?t???st???.

• 3 D (Defined, Demonstrated, Documented)
• Defined (saf?? ???sµ???) ???a? ?d?a?te?a
  s?µa?t??? ?a ?????µe t? ep????????µe ?a? ??at?.
  ??t? apa?te? ?a ???s??µe saf?? t? a?t??e?µe?? t??
  ?p?????s??, ??t? p?? de? e??a? e????? ap? t??
  a???.
• Demonstrated (ap?dede??µ???) ?p?????s? s?µa??e?
  ap?de??? (ap??? ??e???? de? a??e?).
• Documented (te?µ????µ???) ?? ??apt?? ap?de??e??
  t?? ep?????s?? e??a? ?,t? ?a µe??e? te???? ?a
  p??pe? ?a e??a? ???a??µ??e?, p???e??, ??t?? ?a?
  pe??e?t????, ?ste ?a µ? d?µ???????? a??s?d?t??
  e??t?se??.

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
52
???at?stas? Ste???? ?????

• ?p?????s? Teµe???d? ?a?a?t???st???.

• ?a? ??a ? (?????aµµat?sµ???!)
• Validation Master Plan
• Calibration Plan
• Equipment, room utilities qualification plan
• Computer systems Validation
• ?t?s?a a?as??p?s? s?st?µat??

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
53
???at?stas? Ste???? ?????

• ?p?????s? Teµe???d? ?a?a?t???st???.

Master Plan or Outline of a Process Validation Program Master Plan or Outline of a Process Validation Program
Objective Proving or demonstrating that the process works
Type of validation Prospective, concurrent, retrospective, revalidation
Type of process Chemical, pharmaceutical, automation, cleaning
Definition of process Flow diagram, equipment/components, in-process, finished product
Definition of process output Potency, yield, physical parameters
Definition of test methods Method, instrumentation, calibration, traceability, precision, accuracy
Analysis of process Critical modules and variables defined by process capability design and testing program
Control limits of critical variables Defined by SPC and process capability design and testing program
Preparation of validation protocol Facilities, equipment, process, number of validation trials, sampling frequency, size, type, tests to perform, methods used, criteria for success
Organizing for validation Responsibility and authority
Planning validation trials Timetable and PERT charting, material availability, and disposal
Validation trials Supervision, administration, documentation
Validation finding Data summary, analysis, and conclusions
Final report and recommendations Process validated, further trials, more process design, and testing
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
54
???at?stas? Ste???? ?????

• ?p?????s? ???t?????a.

• G?apt?, e??e???µ??? ?e?µe?? ??a t? s?ed?asµ? t??
  ep?????s??, p?? a?a?e??e?ta? pe???d???
• t? ?d?? t? pe??aµat??? s??d??, s?st?se??
• ?s? p?? ap?? ???eta?
• ??? a?a??t??? ?? µ???d?? e??????, d?a???µµata,
  s??µata de??µat?????a?, a??? pa?ap?µp? se a?t?
• ???s?µe? pa??µet??? d?e??as?a?
• ?e???? apa?te?ta? ep?????s? ??a ?t? e??a? ???s?µ?
  ??a t?? p???t?ta, ?a?a??t?ta, ta?t?t?ta,
  pe??e?t???t?ta t?? fa?µa?e?t???? µ??f??
• ?ata???s? t?? d?e??as?a?, pe??aµat??? ded?µ??a
  (p.?. DOE)
• ?p?de?t? ???a (????? ?aµ???)
• ????µ?? pa?t?d?? p?? ?a e?e?????? (3 t??????st??)

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
55
???at?stas? Ste???? ?????

• ????µas?e? ?a? ??e???? se ste??? ????.

• Airflow uniformity test
• Temperature control test
• Humidity control test
• Pressurization control test
• HEPA filter Leak test (DOP test)
• Airborne particles count test
• Enclosure induction leak test
• Airflow pattern test
• Particle dispersion test
• Recovery test
• Airborne microbial sampling
• Surface sampling

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
56
??de??t??? ??ß?????af?a
White W., Cleanroom Technology Fundamentals of
Design, Testing and Operation, John Wiley and
Sons, 2001. Niazi S.K. Handbook of Pharmaceutical
Manufacturing Formulations, Volume 6, Sterile
Products, CRC Press, 2004 Zhang C. Fundamentals
of Environmental sampling and analysis, John
Wiley and Sons, 2007. Mc Dowall R. Fundamentals
of HVAC systems, Elsevier, 2006. Sugarman S.,
HVAC Fundamentals, Taylor Francis, 2005. Willig
S.H., Good Manufacturing Practices for
Pharmaceuticals , 5th edition, Marcell Dekker
Inc, 2001. Signore A.A., Jacobs T., Good Design
Practices for GMP Pharmaceutical Facilities,
Taylor Francis, 2005. WHO, Quality assurance of
Pharmaceuticals, a compendium of guidelines and
related materials vol 2, 2nd edition, WHO
Library, 2007. Denyer S.P., Baird, R.M.,
Microbiological Control in Pharmaceuticals and
Medical Devices, 2nd Edition, Taylor Francis,
2007. Hickey A.J., Ganderton D., Pharmaceutical
Process Engineering, Marcel Dekker, 2001. Michael
Levin Pharmaceutical Process Scale-Up. Marcel
Dekker, 2001. Nash R.A., Wachter A.H.,
Pharmaceutical Process Validation An
International 3rd Edition, Revised and Expanded.
Marcel Dekker, 2003. Jornitz M.W., Meltzer T.H.
Sterile Filtration A Practical Approach, Marcel
Dekker, 2001. EC, EudraLex Volume 4, EU
Guidelines to Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use,
Annex 1, Manufacture of Sterile Medicinal
Products (corrected version), 2008. FDA,
Guidance for Industry Sterile Drug Products
Produced by Aseptic Processing - Current Good
Manufacturing Practice, 2004. ICH Q7A, Good
Manufacturing Practice Guide For Active
Pharmaceutical Ingredients, 2000. Sutton S.
Qualification of an Environmental Monitoring
Program, Microbiology Topics, Journal of
Validation Technology, vol. 16, 2, 2010. WHO,
Environmental Monitoring of Clean Rooms in
Vaccine Manufacturing Facilities, Draft Document,
2011.
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
57
??t? ep??????

• ??s? s???? ??e???eta? ??a ?a µpe? ??a t?ap???
  se ??a ste??? ?????

?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
58
VIDEO
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012
59
Sa? e??a??st? ??a t?? p??s??? sa?!!!
Sta???? ????t?? MSc, PhD ?µ?µa Fa?µa?e?t????
???? spolitis_at_pharm.uoa.gr
?.?.F.?.?. - 5? ??????FO???? S????????, ???t?
????, 21-23 Septeµß???? 2012