aseptic processing cuc 2014

Asep%c Processing

Mrs Robyn Isaacson Manufacture of sterile medicines – Advanced workshop for SFDA GMP

inspectors - Nanjing, November 2009

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Asep%c Processing -‐ LO

•  Able to describe specific issues rela%ng to the manufacture of asep%cally prepared products: 1.  Manufacturing environment

§  Clean areas §  Personnel

2.  Prepara%on and filtra%on of solu%ons 3.  Pre-‐filtra%on bioburden 4.  Filter integrity/valida%on 5.  Equipment/container prepara%on and steriliza%on 6.  Filling Process 7.   Valida(on of asep(c processes 8.   Specific issues rela(ng to BFS

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Introduc%on •  Why certain products need to be sterile?

–  There is special danger of causing serious infec%ons if they are not

–  Injected products by-‐pass the body’s natural defenses against microorganism and consequences of injec%ng even slightly contaminated products can be serious

–  Can cause death •  Why use parenterals if there is such a poten%al danger?

–  Ac%ve substance is destroyed in GIT –  When rapid ac%on is required –  When it is necessary to target part of the body

e.g. intra-‐cardiac, intra-‐thecal, etc –  When pa%ent cannot swallow, unconscious

Incidents of Non-‐Sterility of Parenterals

•  1964: Sweden –  8 pa%ents developed post-‐opera(ve eye infec%ons, one became

blind; eye ointment contaminated with Pseud. aerugenosa •  1970-‐1: Rocky Mount, USA

–  40 deaths; non-‐sterile infusion fluids contaminated by Enterobacter cloacae and other enterobact. spp

•  1971-‐2: Devonport, UK –  5 deaths of post-‐opera(ve pa(ents a^ributed to

non-‐sterile dextrose infusions contaminated with Kleb. aerogens •  2001: DOC’s Pharmacy Walnut Creek, California

–  3 deaths following spinal injec(on of Betamethasone (Serra(a spp)

•  2002: Urgent Care Pharmacy, South Carolina –  1 death following spinal injec%on of methylprednisolone (fungus)

Asep%c processing relies on:

•  the exclusion of microorganisms from the process stream •  the preven(on of microorganisms from entering open

containers during filling •  product bioburden •  microbial bioburden of the manufacturing environment •  All of the above are important factors rela%ng to the level

of sterility assurance of these products

1. Manufacturing Environment Clean Areas

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Grade At rest In operation

maximum permitted number of particles/m3 0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm > 5 µ

A 3 500 0 3 500 0

B 3 500 0 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 500 000 20 000 not defined not defined

“At rest” - production equipment installed and operating

“In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present

Four Grades of Clean Areas

•  Grade D (equivalent to Class 100,000, ISO 8): –  Clean area for carrying out less cri%cal stages in manufacture of

asep%cally prepared products eg. handling of components aKer washing.

•  Grade C (equivalent to Class 10,000, ISO 7): –  Clean area for carrying out less cri%cal stages in manufacture of

asep%cally prepared products e.g. prepara(on of solu(ons to be filtered.

•  Grade B (equivalent to Class 100, ISO 5): –  Background environment for Grade A zone, e.g. cleanroom in

which laminar flow worksta%on is housed.

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Four Grades of Clean Areas

•  Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5 (ISO 14644-‐1): –  Local zone for high risk opera%ons e.g. product filling, stopper bowls,

open vials, handling sterile materials, asep(c connec(ons, transfer of par%ally stoppered containers to be lyophilized.

–  Condi(ons usually provided by laminar air flow worksta(on.

•  Each grade of cleanroom has specifica%ons for viable and non-‐viable par(cles –  Non-‐viable par%cles are defined by the air classifica%on (See Table 2)

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Viable Par%cles

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Grade Air sample (CFU/m3)

Settle plates (90mm diameter)

(CFU/4hours)

Contact plates (55mm

diameter) (CFU/plate)

Glove print (5 fingers)

(CFU/glove)

A < 3 < 3 < 3 < 3 B 10 5 5 5 C 100 50 25 - D 200 100 50 -

–  These are average values –  Individual settle plates may be exposed for less than 4 hours

•  Values are for guidance only - not intended to represent specifications •  Levels (limits) of detection of microbiological contamination should be established for alert and action purposes and for monitoring trends of air quality in the facility

Environment Monitoring

•  Viable Par%cles

•  Physical –  Par%culate ma^er

–  Differen%al pressures –  Air changes, airflow pa^erns –  Clean up %me/recovery

–  Temperature and rela%ve humidity

–  Airflow velocity

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Environmental Monitoring -‐ Physical

•  Par%culate ma^er –  Par%cles significant because they can contaminate and also carry

organisms –  Cri%cal environment should be measured not more than 30cm from

worksite, within airflow and during filling/closing opera%ons –  Preferably a remote probe that monitors con%nuously –  Difficul%es when process itself generates par%cles (e.g. powder filling) –  Appropriate alert and ac(on limits should be set and correc(ve

ac(ons defined if limits exceeded

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•  Differen%al pressures –  Posi%ve pressure differen%al of 10-‐15 Pascals should be maintained

between adjacent rooms of different classifica%on (with door closed) –  Most cri(cal area should have the highest pressure –  Pressures should be con%nuously monitored and frequently recorded.

–  Alarms should sound if pressures deviate –  Any devia%ons should be inves%gated and effect on environmental

quality determined

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•  Air Changes/Airflow pa^erns –  Air flow over cri(cal areas should be uni-‐direc(onal (laminar

flow) at a velocity sufficient to sweep par%cles away from filling/closing area

–  for B, C and D rooms at least 20 changes per hour are usually required

•  Clean up %me/recovery –  Par%culate levels for the Grade A “at rest” state should be

achieved ajer a short “clean-‐up” period of 20 minutes ajer comple%on of opera%ons (guidance value)

–  Par%cle counts for Grade A “in opera%on” state should be maintained whenever product or open container is exposed

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•  Temperature and Rela%ve Humidity –  Ambient temperature and humidity should not be uncomfortably high (could cause operators to generate par%cles)

•  Airflow velocity –  Laminar airflow worksta%on air speed of approx 0.45m/s ± 20% at working posi%on (guidance value)

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Manufacturing Environment Personnel

•  Minimum number of personnel in clean areas –  especially during asep(c processing

•  Inspec%ons and controls from outside •  Training to all including cleaning and maintenance staff

–  ini%al and regular –  manufacturing, hygiene, microbiology –  should be formally validated and authorized to enter asep%c area

•  Special cases –  supervision in case of outside staff –  decontamina%on procedures (e.g. staff who worked with animal

%ssue materials)

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Manufacturing Environment Personnel

•  High standards of hygiene and cleanliness –  should not enter clean rooms if ill or with open wounds

•  Periodic health checks •  No shedding of par%cles, movement slow and controlled •  No introduc%on of microbiological hazards •  No outdoor clothing brought into clean areas, should be

clad in factory clothing •  Changing and washing procedure •  No watches, jewellery and cosme%cs •  Eye checks if involved in visual inspec%on

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Asep%c Processing •  In asep%c processing, each component is individually

sterilised, or several components are combined with the resul%ng mixture sterilized. –  Most common is prepara%on of a solu(on which is filtered

through a sterilizing filter then filled into sterile containers (e.g ac%ve and excipients dissolved in Water for Injec(on)

–  May involve asep%c compounding of previously sterilized components which is filled into sterile containers

–  May involve filling of previously sterilized powder •  sterilized by dry heat/irradia%on •  produced from a sterile filtered solu%on which is then asep%cally crystallized and precipitated

–  requires more handling and manipula%on with higher poten%al for contamina%on during processing

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2. Prepara%on and Filtra%on of Solu%ons

•  Solu(ons to be sterile filtered prepared in a Grade C environment

•  If not to be filtered, prepara(on should be prepared in a Grade A environment with Grade B background (e.g. ointments, creams, suspensions and emulsions)

•  Prepared solu%ons filtered through a sterile 0.22μm (or less) membrane filter into a previously sterilized container –  filters remove bacteria and moulds –  do not remove all viruses or mycoplasmas

•  filtra(on should be carried out under posi(ve pressure

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Prepara%on and Filtra%on of Solu%ons

•  Time limits should be established for each phase of processing, e.g. –  maximum period between start of bulk product compounding and

steriliza(on (filtra(on) –  maximum permi^ed holding %me of bulk if held ajer filtra%on prior to

filling –  product exposure on processing line –  storage of sterilized containers/components –  total %me for product filtra%on to prevent organisms from penetra%ng

filter –  maximum %me for upstream filters used for clarifica%on or par%cle

removal (can support microbial a^achment)

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Prepara%on and Filtra%on of Solu%ons

•  Filling of solu(on may be followed by lyophiliza(on (freeze drying) –  stoppers par%ally seated, product transferred to lyophilizer (Grade A/

B condi%ons) –  Release of air/nitrogen into lyophilizer chamber at comple(on of

process should be through sterilizing filter

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3. Prefiltra%on Bioburden (natural microbial load)

•  Limits should be stated and tes%ng should be carried out on each batch

•  Frequency may be reduced ajer sa%sfactory history is established –  and bioburden tes%ng performed on components

•  Should include ac%on and alert limits (usually differ by a factor of 10) and ac%on taken if limits are exceeded

•  Limits should reasonably reflect bioburden rou%nely achieved

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Prefiltra%on Bioburden (natural microbial load)

•  No defined “maximum” limit but the limit should not exceed the validated reten%on capability of the filter

•  Bioburden controls should also be included in “in-‐process” controls –  par%cularly when product supports microbial growth and/or

manufacturing process involves use of culture media •  Excessive bioburden can have adverse effect on the quality of

the product and cause excessive levels of endotoxins/pyrogens

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Asep%c Processing

Filter integrity •  Filters of 0.22μm or less should be used for filtra%on of liquids and

gasses (if applicable) –  filters for gasses that may be used for purging or overlaying of filled

containers or to release vacuum in lyphiliza%on chamber •  filter intergrity shoud be verified before filtra%on and confirmed

ajer filtra%on –  bubble point –  pressure hold –  forward flow

•  methods are defined by filter manufacturers and limits determined during filter valida%on

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4. Filter Valida%on •  Filter must be validated to demonstrate ability to remove

bacteria –  most common method is to show that filter can retain a

microbiological challenge of 107 CFU of Brevundimonas diminuta per cm2 of the filter surface

–  a bioburden isolate may be more appropriate for filter reten%on studies than Brevundimonas diminuta

–  Challenge concentra%on is intended to provide a margin of safety well beyond what would be expected in produc%on

–  preferably the microbial challenge is added to the fully formulated product which is then passed through the filter

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Filter Valida%on –  filter valida%on should be carried out under worst case condi(ons

e.g. maximum allowed filtra(on (me and maximum pressure –  integrity tes%ng specifica%on for rou%ne filtra%on should

correlate with that iden%fied during filter valida%on

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5. Equipment/container prepara%on and steriliza%on

•  All equipment (including lyophilizers) and product containers/closures should be sterilized using validated cycles –  same requirements apply for equipment steriliza%on that apply to

terminally sterilized product –  par%cular a^en%on to stoppers -‐ should not be %ghtly packed as

may clump together and affect air removal during vacuum stage of steriliza%on process

–  equipment wrapped and loaded to facilitate air removal –  par%cular a^en%on to filters, housings and tubing

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Equipment/container prepara%on and steriliza%on

•  heat tunnels ojen used for steriliza%on/depyrogena%on of glass vials/bo^les –  usually high temperature for short period of %me –  need to consider speed of conveyor –  valida%on of depyrogena%on (3 logs endotoxin units)

•  worst case loca%ons –  tunnel supplied with HEPA filtered air

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Equipment/container prepara%on and steriliza%on

•  equipment should be designed to be easily assembled and disassembled, cleaned, sani%sed and/or sterilized –  equipment should be appropriately cleaned -‐ O-‐rings and gaskets should be

removed to prevent build up of dirt or residues

•  rinse water should be WFI grade •  equipment should be lej dry unless sterilized immediately ajer cleaning

(to prevent build up of pyrogens) •  washing of glass containers and rubber stoppers should be validated for

endotoxin removal •  should be defined storage period between steriliza%on and use (period

should be jus%fied)

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Useful References •  PIC/S Recommenda%on on the Valida%on of Asep%c Processes •  FDA Guidance for Industry-‐ Sterile Drug Products Produced by Asep%c

Processing -‐ Current Good Manufacturing Process •  ISO 13408 Asep1c Processing of Health Care Products

–  Part 1: General Requirements –  Part 2: Filtra1on –  Part 3: Lyophiliza1on –  Part 4: Clean-‐In-‐Place Technologies –  Part 5: Steriliza1on-‐In-‐Place –  Part 6: Isolator Systems

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aseptic processing cuc 2014

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