Sterile Product Manufacturing
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manufacture of of sterile sterile products •
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The overall objective is to produce product that has a high assurance of of sterility sterility (and which meets all other quality parameters) This presentation: Summarises the
general approach general approach
Gives
a framework for other for other detailed detailed guides guides on specific specific aspects aspects of sterilisation & sterile manufacturing
Illustrates the Provides
unde un derl rl in
rinc ri ncii le less
advice and and gives gives recommendations.
General Principles of Sterile Manufacturing • •
o s ea er za on Dry Heat Sterilization
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Environmental Monitoring
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Sterile Filtration
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Sterility testing
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Visual Inspection
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ter ty s t e a sence o v ng organ sms This is an absolute definition The robabilit of of achievin sterilit de ends on the overall rocess It is generally generally accepted that a terminally terminally sterilized sterilized product should have a probability of ‐ 6 non‐sterility of of less than 10 (i (i..e., a lower probability than one in a million of of having a non‐ ster e un t This is often expressed as an SAL Sterility Assurance Level of of 106 This is a worst‐case figure (with a challenge challenge more resistant than product bioburden) bioburden). Real confidence levels are generally very much higher gure a as some mes een quo e or asep ca y e pro uc s pro a y o non‐ ‐ 3 sterility of of less than 10 . However, However, this is harder harder to analyse as contamination contamination does not follow a clear clear statistical distribution distribution.. Potential Potential contamination sources are not randomly distributed.. distributed
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e test or ster ty cannot con rm t at t e w o e batch is sterile statistical limitations statistical non‐sterile
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It is thus necessary to recognize and understand every aspect that could lead to loss of of sterility assurance Such conditions should be prevented by the application of of carefully designed barriers and/or control measures. measures.
Development – Validation and Control •
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It s mportant t at t e pro uct an process are designed to maximise sterility assurance Wherever possible, the product should be developed to withstand sterilization in the final container Once the product product design is defined, defined, a suitable suitable production process must be developed This is installed and validated The process must then be tightly tightly controlled to assure reliabilit and consistenc consistenc .
or ew ro uc ss:: Define product product and and processing processing requirements Define Consider stability stability of of product product to the sterilization conditions Consider Base the process process on achieving the required required sterility sterility assurance level Base Where possible possible choose terminal terminal sterilization in final final container Where Define process process flow flow and and the important important microbiological microbiological aspects Define Ensure changes Ensure •
are subject subject to strict strict change control
For reviewing existing (marketed) products products:: should be by by compendial compendial procedures procedures Preferably, sterilization should Where other other procedures procedures are registered, assess SAL Where process and and maybe re‐register Require justification justification & validation validation.. Require
us e n comp ance w example: Must minimise Must minimise
company po c es an proce ures, or
the risk of contamination at all critical stages Requ re Gra es o C ean Rooms : nee to e appropr ate or t e process ‐‐ e.g. for Terminal Sterilization e.g. for Terminal Sterilization or Aseptic Fill Personnel Access and Material Flow Personnel Restr cte access, correct gown ng Materials flow, air locks, decontamination, segregation Materials flow, HVAC ‐System HVAC Segregation/Dedicated HVAC of correct standard Segregation/Dedicated HVAC of correct standard Requires control of Filtration/ Requires ΔP/Air Flow/Temp./Pressure/Humidity Air flow patterns demonstrated Air No sinks and drains in Zone A/B areas, air breaks to drains in others Surfaces and ease of cleaning: smooth unbroken impervious surfaces Surfaces
Cleaning and disinfection of the Facility •
ean ng an
s n ec on s mpor an n env ronmen a con ro
Efficacy needs to be validated
Validated procedures, conducted consistently Validated •
In c ass A sterilized
B areas, t e c ean ng an
s n ectant mater a s must e
And need to minimise contamination risk in other areas And need to •
Operating proce ures must inc u e, at minimum: Preparation of cleaning materials (and sterilization Exact procedure of cleaning &
if applicable)
disinfection.
Responsibility & scheduling. Responsibility & Type and concentration of detergents and disinfectants. Type of cleaning tools. • •
Training is required for cleaning and disinfection of clean of clean rooms Routine decontamination using formaldehyde gas should be avoided.
wa er sys ems requ re goo
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T
es gn an va
a on
icall , for harmaco oeial rades, validation includes
Two studies over a total of 4 weeks to assess against the acceptance criteria, Additional 11 months to verify that the system remains under control Additional 11
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required quality Physico‐chemical,
Biological (endotoxin endotoxin, , Biological (
where applicable)
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defined written monitoring plan based on results of the validation studies.
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a er or n ec ons For injectables formulation For formulation Final rinse water water or or roduct ‐contact contact items or or in ectables Final Freshly prepared prepared or or from from a validated validated hot hot (e (e..g. ,, >75 75° °C) C) storage Freshly /distribution system or or otherwise protected protected from from microbial contamination
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Highly Purified Water (HPW)
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To European Pharmacopoeia
Purified Water (PW)
For initial For initial washing of of product product ‐contact contact items , and prevent and prevent microbiological microbiological proliferation, proliferation, following following the relevant company relevant company procedures. procedures.
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ases Specification equivalent to the Specification
room air quality where it is to be used In aseptic applications, gases are to be filter sterilized Consider sterile filtering non‐ product contact gases for aseptic Consider sterile filtering applications. (But, note safety considerations, e.g. avoidance of leakage) All gas filters to be integrity tested on installation and at defined All gas filters intervals •
Vacuum S stems Sometimes used for cleaning Sometimes
and dust control May be mobile units, fitted with exhaust HEPA filters On these, use dedicated vacuum pumps’ protected against back ‐ flow Design to prevent unprotected route into the aseptic suite. Design
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qu pmen
ua
ca on
To include the critical aspects for sterile product processing Qualification of critical aspects of moist heat sterilization, aseptic Qualification processing, dry heat sterilization etc.
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Cleaning and Sanitization of Equipment For Terminal Sterilization applications, low microbial challenge. Where possible, critical surfaces should be sterilized , sterilized before use. In exceptional cases where this is not possible (e.g., some stopper bowls), they should be sanitized by a validated method Cleaning validation must show effectiveness and absence of residues. Cleaning
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Equ pment Ster zat on an
an
ng
Sterilization
must must follow follow a validated validated procedure procedure Aseptic processes processes designed designed to minimise aseptic Aseptic assembly and assembly and intervention Unavo a e asept cc assem y y nee s c ear ear prec prec se procedures ‐
media fill fill simulation trials
possible – – must be validated validated..
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ra n ng ‐ personne appropr a e y ra ne or s er er e processing, including assessment and documentation documentation:: Basic GMP Basic Fundamenta s o micro io ogy Personal hygiene, health and and cleanliness Personal Behaviour and and aseptic aseptic working techniques Behaviour own ng an en ry ry proce proce ures and disinfection Cleaning and procedures, validation and and routine operation Sterilization procedures, . . loss of of power, power, equipment equipment interventions etc etc.. ))
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Personnel participating in aseptic processing must have
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manipulations They must have participated in a successful media fill run run..
Personnel must correctly wear appropriate clean
room garments Detailed, easily understood, gowning procedure (preferably illustrated) •
Aseptic Techniques Personnel in
the aseptic manufacturing area, must understand the principles
They must only be
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considered qualified after appropriate training, working under supervision and demonstration of competence The supervisor should observe technique & correct as necessary All personnel directly involved in aseptic processing must participate in a media fill at least once per year
ove
s n ect on
Sterile
disinfectants must be available (e.g., alcohol based) Glove disinfection must be reasonably frequent, defined in SOP.
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The scope of environmental monitoring includes: Non‐viable particulates,
Differential pressures Temperatures Humidities Air flows
on or ng ur ng oom
ua
ca on
Operational Qualification (OQ)
at rest conditions to verify operation Performance Qualification (PQ) in worst case operational conditions Action levels should meet USP or Euro GMP as applicable Alert levels tight enough to detect deterioration, but not so tight that they become meaningless due to frequent transgression PQ must cover a sufficient period to establish consistency •
Routine Monitoring Ensures
area remains satis actor . Results should be within alert level Results above alert levels need review and perhaps corrective actions Above action levels, must trigger appropriate actions (described in uide , Results must be assessed for trends so that progressive or sudden changes in the results may be observed. This should be reviewed regularly.
The data must be analysed Where necessary further investigations initiated
, Outcome •
and detail must be reported
Recommended Methods for Routine Monitoring Physical and microbiological monitoring of the Particles
environment
(viable and non‐viable) in the air
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Micro‐organisms
contaminating surfaces Presence of micro‐organisms on the hands and garments •
Defined monitoring plans:
tests, locations, alert/action levels & frequencies May contain details of water, compressed gas clean steam testing
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All ingredients should have appropriate biological specifications Any limitations to sterilization must be defined Description o origin e.g. viro ogica prion ris
Materials Used in the Process Where
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appropriate, determine bioburden (e.g., ion exchange materials)
Primary Packaging Components Container and the
closure and cleaning / sterilization to be clearly specified Steps such as siliconization may need monitoring If cleaning/sterilization is by supplier, same exigencies apply •
Container‐closure integrity Simulate,
where appropriate: stress from processing Method appropriate to container/closure system
Weighing, Compunding and Sterilization •
Vessels must be cleaned, and sterilized or sanitised as appropriate and stored dry in a way to prevent microbial contamination
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Storage of pre‐sterilization intermediates to be controlled & time limited
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Following aspects to be considered: ‐
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Pre‐sterilization bioburden Appropriate in‐ process controls
Sterilization of product and product contact materials
Selection of a suitable sterilization protocol must be based on SAL
Validation always required
Change control is vital; even apparently minor change must be assessed
By far the most common method for aqueous‐based pharmaceuticals
Preferred cycle is the Pharm Eur reference cycle is 15 minutes at 121°C
Sterilization parameters clearly defined In conjunction with other controls, the required SAL must be demonstrated •
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Validation to confirm sterilization conditions consistently throughout the load
Sterilization by Ionizing Radiation
Common for medical devices, but not for pharmaceuticals.
Pharm. Eur. reference condition, 25 KiloGray (kGy), has been widely accepted. Other
Important to consider susceptibility of the product to radiation damage
Dry Heat Sterilization , exposures. Pharm Eur reference cycle is 2 hours @ 160°C Rarely used for terminal sterilization of pharmaceuticals; in rare cases heat resistant non‐ aqueous products may be terminally sterilized.
Sterilization of Items for Aseptic Fill (1) Widely used,
but careful validation needed – particularly complex items Broadly similar to terminal steam sterilization, but two aspects are critical – –
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Removal of air and subsequent steam penetration
Sterilization by Ionizing Radiation May be used for temperature sensitive primary packaging or components Used for disposables for sterile areas and sterility testing areas Validation includes dosimetry, ‐ correct, even, irradiation of the items
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Dry Heat Sterilization/Depyrogenation Sterilization/Depyrogenation Sterilization/ depyrogenation
of heat resistant primary packaging materials Pharm Eur notes that temperatures in excess of 220 oC have been frequently used, the USP suggests 250 ± 15 oC a a on mus nc u e en o ox n c a enge s u es Dry heat may be used to sterilize non‐aqueous preparations (e.g. Ointment bases) at lower temperature/time relationships, without depyrogenation.
Sterilization of Items for Aseptic Fill (2) y ene x e
er za on
Quite widely used to sterilize heat labile
components European Pharmacopoeia and the European GMP guide indicate that s me o s ou on y e use w ere ere s no su a e alternative Hazardous ‐ toxic, potentially carcinogenic, flammable, potentially Generally conducted by specialized contractors There are
strict regulatory limits on maximum permissible product
Bulk packs for sterilization must be
gas permeable, but sealed
against microbial ingress
, , (ethylene oxide & water vapour), bulk pack integrity Validation and routine monitoring must include Biological indicators.
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Contaminating organisms are not killed, but are retained on the filters. Any faults in the filter structure, may compromise this
Validation includes:
Retention of bacterial challenge: B. diminuta at 107 per cm2
This is correlated with an integrity test value
Validation should address: Filter suitability ‐ toxicity, extractables, shedding of particles Adsorption of product
Compatibility with product solvents
T e requ re ter s ze an su ta ty o t e trat on equ pment Retention of B.diminuta in the actual product under process conditions
Parameters for the physical integrity test
Conducted in line with the validated parameters
Check integrity testing, process time, differential pressure, flow rates, sterilization and reuse of filters.
Performance Qualification of Aseptic Manufacturing •
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Based on simulating the risk of of contamination in all aseptic operations For For a new new process, a minimum of of three consecutive satisfactory media filling trials For aqueous liquid products, simulation trials use a liquid microbiological medium For solid dosage forms, a powder ‘placebo’ is used, followed by aseptic reconstitution into a liquid micro io ogica me ium The following slide gives a general overview overview.... ....
Aseptic Process Simulation (Media Fill Trial) e a
ras
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All process stages simulated as closely as possible Particularly interventions and manual manipulations Must follow routine procedures and include all interventions Regular interventions simulated with the same frequency as actual process In each case, the worst ‐case eventuality must be covered Process must be successfully validated before product filling is permitted Revalidation by media fill must be conducted every half year (each line)
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Manufacturin Environment Microbiological monitoring must be performed during
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Filling Conditions and Equipment Containers
must be passed through all stages.
the trial
Any Questions
