Buffl

Exam Questions

DS
by Daria S.

(6) Steam sterilization processes (4 points)

(a) How is the air removal carried out in the autoclave shown?

Note: the items to be sterilzed are placed in the grid basket.


(b) Name two disadvantages of the autoclave shown in (a) compared to an autoclave with an external steam generator.


(c) Draw the pressure curve of a steam sterilization process using fractionated vacuum for air elimination and a single vacuum phase for drying.



(a) How is the air removal carried out in the autoclave shown?

Steam generation within the chamber – single wall: Batch steam sterilizer

grid basket = Gitterkorb = air can circulated freely but can get unter the basket (enough space between basket & bottom needed for air elimination)

Function:

1) Product placed inside the autoclave

2) water reservoir is direct underneath the plate

3) steam generation with electrical heating (yellow)

4) Elimination of air = steam moves up & displaces the air to the top

 - air gets pressed out via air-removal valve out of the chamber

 - air must be eliminated otherwise steam cannot reach product; no condensation


(b) Name two disadvantages of the autoclave shown in (a) compared to an autoclave with an external steam generator.

picture a) Steam generation within the chamber – single wall: Batch steam sterilizer

disadvantages:

1) slow heat up because steam generation inside the chamber with (cold) product

2) slow cooling because water reservoir inside chamber, takes longer to cool system down (condensate stay inside)


(c) Draw the pressure curve of a steam sterilization process using fractionated vacuum for air elimination and a single vacuum phase for drying.

= combination of fractioned vacuum & single vacuum phase


A) Ventilation phase = generated steam replaces the air via air-separator

 = Risetime & air elimination:

B) Compensation phase = rest of the air gets eliminated

 = Pressure rises: valve get closed & steam accumulates

C) Sterilization time =

D) Cooling & vacuum phase = vacuum helps in drying



(4) (a) What does the z-value tell us about the heat resistance of a microorganism?

(b) What is the relationship between the F value and the SAL value?

(c) For a steam sterilization process at 134 °C, an F0 value of 50 min is achieved. How is the achieved F0 value of 50 min to be interpreted?

(2 points)

a) Z-value = Temperature change in °C required to alter D-value by factor of 10

  • high z-value = means large increase in °C is required to achieve 1 log reduction of D-value = means that germs are more heat resistant to changes of temeprature

  • low z-value = low increase in °C is required to achieve 1 log reduction in the D-value = germs are less heat resistant

    e.g. spores = z-value 10°C & vegetative cells = 5,5 °C

b) Relationship between the F value and the SAL value

F-value = thermal death time = holding time [mins] at a temperature T to reduce population N0 with specific D-value by desired number of poweres (log levels) to final value N

SAL = sterility assurance level = probability that germs may be alive

  • Relationship: with sufficient F-value [holding time in mins] a sterilisation process can ensure that the SAL-value achieves the required standard

  • high F-value = high holding time = low probability of items remaining non-sterile, low probability that germs stay alive = means a better (lower) SAL-value

  • low F-Value = low holding time = high probability that sterilisation is not sufficient & germs stay alive = high SAL-value


(c) For a steam sterilization process at 134 °C, an F0 value of 50 min is achieved. How is the achieved F0 value of 50 min to be interpreted?

F0-value [mins] = 1 min means the lethality of a method that works for 1 minute at 121.1 °C (250 °F) and a z-value of 10 °C (18 °F) or an equivalent temperature-time combination

= makes different steam sterilization comparable -> important for pharmacy


Calculation:

50min (F0-value) at 134°C = process achieves the same microbial lethality as the sterilisation at 121,1°C for 975 mins

(12)

(a) According to GMP Annex 1, every company that manufactures sterile medicinal products requires a CCS. What does the abbreviation CCS stand for?

(b) One of the rules of aseptic working is not to interrupt the laminar air flow. GMP Annex 1 refers to this as the first air principle. Briefly explain why this rule must be followed whenever possible?

(c) Which aseptic working rule should class B personnel follow regarding their gloves?

(2.5 points)

(a) According to GMP Annex 1, every company that manufactures sterile medicinal products requires a CCS. What does the abbreviation CCS stand for?

CCS = contamination control strategy (for Aseptic production of sterile drugs)

= a planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding to assure process performance & product quality.


(b) One of the rules of aseptic working is not to interrupt the laminar air flow. GMP Annex 1 refers to this as the first air principle. Briefly explain why this rule must be followed whenever possible?

= is an important principle for aseptic working

  • Laminar airflow shouldn't be interrupted because:

    1) Contamination control & Sterility maintenance: unidirectional flow of air sweeps away particles from working area -> when interrupted particles/ contaminants can settle on surface (risk of contamination) -> product quality & safety

    2) Important if protection of personal required (hazardous subtances) -> interruption can create a risk for personnel

    3) Laminar airflow is usually connected with controlled envirenmental conditions (°C/ humidity…) -> interruption can cause disturbances in conditions

(c) Which aseptic working rule should class B personnel follow regarding their gloves?


(14) Barrier systems (2.5 points)

(a) Why is a safety cabinet considered less safe as an open RABS?

(b) Which RABS type is most comparable to an isolator?

(c) When is overpressure used within isolators?

(d) How can it be tested whether an inert gas atmosphere is maintained in an isolator?


(a) Why is a safety cabinet considered less safe as an open RABS?

  • at a safety cabinet operator is closer & in direct contact to working area, whereas in RABS interventions are made via gloves (barrier closed system) -> less safety of product & personnel in safety cabinet

  • RABS enables higher level of sterility (due to enclosed barrier system, no room air & air moves from A to B), whereas safety cabinet is not enclosed (room air gets inside & filtered from B to A)

• Open RABS= vents in the barrier allow air to move from Grade A zone to Grade B area


(b) Which RABS type is most comparable to an isolator?

= closed (active) RABS = closed barrier between operator & critical zone, similar to isolator; glove ports are used


(c) When is overpressure used within isolators?

= for aseptic purposes, protection of product -> infeed/ fillig & part of loading area


(d) How can it be tested whether an inert gas atmosphere is maintained in an isolator?

1) via Inertization test = test to verify that inert atmosphere is mantainted inside isolator is given by monitoring the concentration of oxygen (with oxygen sensor)

2) Gas Sampling = sampling of inert gas from different parts of isolator

3) monitoring of pressure inside isolator = const. pressure means isolator is sealed & inert gas environment is maintained




(19) Media fill (3 points)

(a) Media fill is also known as APS. What does APS stand for?

(b) How often must a media fill be performed as part of the introduction of a new product?

(c) An SOP for the aseptic formulation and filling of a liquid product specifies that two excipients and WFI should be added to the active ingredient while stirring gently. How do you take these specifications into account for a media fill?

(d) How long does incubation take after a media fill and how are the incubated containers subsequently analyzed?

(a) Media fill is also known as APS. What does APS stand for?

APS = aseptic process simulation


(b) How often must a media fill be performed as part of the introduction of a new product?

for new product = initial validation = 3x successful APS

& periodic revalidation 2x/year


(c) An SOP for the aseptic formulation and filling of a liquid product specifies that two excipients and WFI should be added to the active ingredient while stirring gently. How do you take these specifications into account for a media fill?

= instead of excepients is the nutrient medium is added

= all process should not have negative impact on microbial growth -> by adding WFI the nutrient medium might be diluted -> better to use pure medium

= media fill hast to be performed as a defined aseptic process according to manufacturing SOP & media fill plan


(d) How long does incubation take after a media fill and how are the incubated containers subsequently analyzed?

= incubation for 14 days

Evaluation = via visual inspection & turbidity


(11) Validation of sterilization processes (2.5 points)

(a) How do you call the release of terminally sterilized products without batch-related sterility testing, based solely on the measurement of physical process parameters?

(b) What must be considered in the PQ of a steam sterilization process with regard to loading - in addition to worst-case considerations?

(c) Which third key specification of a bioindicator besides the z-value and D-value must be known for the validation of a steam sterilization process?

(d) What should not be included in the URS of a steam sterilizer? Mark with a cross


(a) How do you call the release of terminally sterilized products without batch-related sterility testing, based solely on the measurement of physical process parameters?


(b) What must be considered in the PQ of a steam sterilization process with regard to loading - in addition to worst-case considerations?

= test load must contain a product that is routinely handled (loading patterns must be defined)

& the load must represent product families with the greatest difficulty for the sterilisation (worst-case consideration)


(c) Which third key specification of a bioindicator besides the z-value and D-value must be known for the validation of a steam sterilization process?

= bioburden N0


(d) What should not be included in the URS of a steam sterilizer? Mark with a cross.

URS = user requirements specifications & functional specification document

= a planning document that specifies what a system needs to do => part of DQ (Design Qualification)

  • NOT included: = WFI-monitoring because use of steam


(17) Fill and Finish (4.5 points + 0.5 bonus points for part h)


(c) How are glass ampoules sealed after the product has been filled?

(d) Which test must be carried out on all glass ampoules as a 100% check after sealing, regardless of whether the product is classified as a parenteral product or not?


(e) You should plan a crimping process as part of a filling and closure line. Specify two aspects in addition to the supply of sterile caps that must be taken into account for the crimping process.




(c) How are glass ampoules sealed after the product has been filled?

= closure by fusion with flame or laser -> top of the ampoules froms by gravity


d) Which test must be carried out on all glass ampoules as a 100% check after sealing, regardless of whether the product is classified as a parenteral product or not?

= 100% integrity testing -> the integrity of the container closure system = include several tests (CCIT = container closure integrity testing)

• Validation of container closure integrity is important = prove with tests that sterility of product is maintained during storage


(e) You should plan a crimping process as part of a filling and closure line. Specify two aspects in addition to the supply of sterile caps that must be taken into account for the crimping process.

  • Crimping of the cap should be performed as soon as possible after stopper insertion

  • • while crimping vials a lot of metal particles get generated = non-viable particle

    -> therefore, important that crimping is separated from filling area (physical separation)

    -> measures to prevent particle contamination & good air extraction are required


(1) Sterility testing (2.5 points)

(a) Why can sterility testing alone not guarantee the sterility of a batch?


(b) What is examined in the product-specific suitability test?


(c) A liquid vaccine is to be tested for sterility according to Ph. Eur. 2.6.1. The filling volume per container is 1.2 ml. What is the minimum volume per container that must be tested for sterility?


a) Why can sterility testing alone not guarantee the sterility of a batch?

  • sterility means = absence of viable microorganisms

= because its not possible to test every container without damaging the product/ batch

= in reality only small sample (max. 20 sample size) get taken for testing -> there is always a statistical probability that the test might miss a contaminated unit if the contamination level is low

=> exponential killing (e^-x) of microorgamisms never reaches zero = never 100 % sterility possible -> D-value never zero

-> sterility has to be assured by the application of a suitably validated production process (geeignetes validiertes Produktionsverfahren)



b) product-specific suitability test

= to prove that the product doesn’t inhibit the growth of the 6 test microorganisms

=> product shouldn’t kill organisms that might me brought in a container during process (e.g. aseptic filling) to detect a contamination

2 Techniques of sterility testing = membrane filtration & direct inoculation


c) minimum volume per container - liquid vaccine 1.2ml

=> liquids 1-40ml = half the contents of each container but not less than 1mL -> half the contents 1.2/2 = 0.6ml

=> 1 ml per container must be testes



(5) (a) A requirement for pure steam is the “correlation with dry saturated steam”. Why does pure steam have to be dry and saturated?

(b) Why is there also a limit value for bacterial endotoxins in pure steam?

(1.5 points)

a) Why does pure steam have to be dry and saturated?

Pure steam = pharmazeutischer Reinstdampf

  = steam with special purity, for direct exposure to group II sterilization goods

-> condensed pure steam has quality of water for injection (highest water quality)

  • saturated steam (100% dry) = contains 100% of the latent heat available at that pressure

  • Saturated water = has no latent heat & 0% dryness, contains low heat.

= has to be dry & satured for effective sterilization:

1) Optimal heat transfer = dry satureated steam has highes amount of energy and can transfer this energy more effectively (weat has lower energy transfer is & takes too long)

2) can condensate immediately -> because saturated team has boiling point of water ensuring a concitent temperature (better effectiveness)

3) with dry saturated steam germs are exposed to the max. thermal energy leading to more reliable sterilization (as with via wet steam, droplets)


(b) Why is there also a limit value for bacterial endotoxins in pure steam?

  = pure steam can get in direct contact with pharmaceutical products

(e. g. primary packaging, solutions for production of aseptic medicinal products, parts in contact with medicals)

-> limit value to ensure that product is not cntaminated -> to ensure patient safety, product integrity, quality & positive (desired) clinical effect of the drug

(16) Barrier systems (3 points)

(a) What is the difference between a passive and active RABS?

(b) Which cleanroom class must be used as the background environment for a RABS?

(c) What are the characteristics of an isolator called "open aseptic"?

(d) How do you perform the leak test of an isolator glove (in addition to the visual inspection)?

(a) What is the difference between a passive and active RABS?

• Active RABS = integral HEPA-filtered air supply (HEPA inside)

• Passive RABS = air supply by sealing mounted HEPA-filters (outside)


Open, active RABS = HEPA filter is inside, independent air supply unit


Open, passive RABS = air flows aout of the system, not for toxic products


(b) Which cleanroom class must be used as the background environment for a RABS?

• Surrounding room classification should be ISO 7 minimum in operation -> surrounding area of RABS = class B

Isolator surrounding = for open isolator class C & for closed isolator class D


(c) What are the characteristics of an isolator called "open aseptic"?

Product protection isolators = “Aseptic isolator”


II) Open isolator systems = allows continuous material flow, hermetic seal for decontamination, with unidirectional air flow

 = designed for continuous or semi-continuous ingress and/or egress of materials (Ein-/ Austritt) during operations through one or more openings -> mouse holes

 = Openings must be engineered (e.g. using continuous overpressure) that no external air/ contaminant get into the isolator

-> has tiny openings (“mouse holes”) with inside overpressure to ensure that no particles get inside

-> min. grade C surrounding (because of holes)


(d) How do you perform the leak test of an isolator glove (in addition to the visual inspection)?


2) Leak testing:

 2.1) Pressure decay test = gloves get blowed up with pressure

 2.2) airflow test at constant pressure = air gets inside of gloves & measurement of volume that is needed to keep pressure constant => if tight, no additional air needed


(14) In preparation for aseptic filling of a medicinal product, the formulated product is usually first subjected to germ-reducing filtration and then finally to sterile filtration in class A.

(a) Why does the formulation of the product have to be carried out at least in clean room class C, when subsequently two filtration steps are carried out to achieve sterility?

(b) What must be checked on each filter before and after use?

(1.5 points)

(a) Why does the formulation of the product have to be carried out at least in clean room class C, when subsequently two filtration steps are carried out to achieve sterility?

= to ensure a low & controlled bioburden before getting to the filtration

-> according to EMA-guidline = Frequent bioburden limit: ≤ 10 CFU / 100 ml -> to fulfill this clean room conditions necessary

= the lower the bioburden, the slower cake formation during filtration (during dead-end filtration)


(b) What must be checked on each filter before and after use?

= Filter integrity testing– GMP Guidline

= The integrity of the filter must be checked before & after use

-> after usage = easy to perform -> filter can get taken out for a quality control in lab or in production area

-> before usage = is critical because it must be assured that filter doesn’t get contaminated -> 2 possibilities to keep filter sterile:

1) sterilization in autoclave after filter testing -> validation important

2) filter gets installed in production area & gets sterilized in place -> filter testing can be done in place


(18) Preparation of equipment and primary packaging material

(2 points + 0.5 bonus points for part d)

(a) Why is primary packaging material considered more critical then secondary packaging material?

(b) Name one way in which two silicone tubes can be connected aseptically.

(c) Why are cartridges siliconized on the inside?

(d) At which point in the process does siliconization take place?

(a) Why is primary packaging material considered more critical then secondary packaging material?

= its the first layer of packaging that is in direct contact with pharmaceutical product (e.g. vials/ ampoules/ syringes/ stoppers/ caps)

-> shouldn’t cause recontamination or have negative impact on product -> must be sterile (depyrogenation) / inert/ abrasive proof etc.

-> Sterilization tunnel (continuous sterilization) = used for sterilization & depyrogenation of primary packaging materials (glass containers) -> not for plastic because high °C!


(b) Name one way in which two silicone tubes can be connected aseptically.



(c) Why are cartridges siliconized on the inside?


  • without siliconization stopper doesn’t move at all due to high friction or stopper suddenly moves & stops -> syringe doesn’t work well, no correct dosage (insulin) -> dangerous for patient

break loose force = force that is needed to start movement of a stoper

gliding force = force that is needed to keep stopper moving


(d) At which point in the process does siliconization take place?

1) siliconisation of packaging (syringe/ cartridge) usually before sterilisation (after washing & drying) -> often applied backed on siliconization which has formation of silicon layer during (hot air) sterilization


2) siliconisation of syringe & cartridge stoppers = optionally after sterilization -> stoppers must move to achieve equal distribution of silicone


(19) Fill and finish - Dosing systems

(a) What dosing system is shown in the picture?

(b) Explain the principle of time-pressure dosing.

(c) Why does Annex 1 specify that crimping must be separated from filling and stoppering?

(d) Which test must be carried out on glass ampoules after fusion as a 100% check in addition to the visual inspection?

(e) What is the main advantage of using nested ready-to-fill syringes in tubs compared to using bulk syringes?

(f) How do you call the process for manufacturing infusion or parenteral nutrition bags?

(g) What is used to blow up the containers during the blow fill seal process?



a) (Dual) peristaltic pump

= single-use silicone tube -> tube get sandwiched between rollers (Dialyse-pumpe)

= benefits: single use/ high precision/ quick product change possible

(b) Explain the principle of time-pressure dosing.

Time-pressure system = gravity & viscosity dependent system

- benefit: ultra-high output/ CIP-SIP compartible

- not for: viscous products & products that are sensitive to silicone tubes

Principle:

- pressure inside vessel must stay constant -> precise monitoring of pressure

 - pinched valves are opened & then after defined dosed product valves get closed

 - temperature very important (high impact on viscosity) -> influences flow through


(c) Why does Annex 1 specify that crimping must be separated from filling and stoppering?

Crimping = aluminium cap gets placed on the stopper

• while crimping vials a lot of metal particles get generated -> non-viable particle => therefore, important that crimping is separated from filling area (physical separation)

=> to prevent particle contamination & good air extraction are required


(d) Which test must be carried out on glass ampoules after fusion as a 100% check in addition to the visual inspection?

-> closure by fusion, e.g. glass or plastic ampoules should be subject to 100% integrity testing.


(e) What is the main advantage of using nested ready-to-fill syringes in tubs compared to using bulk syringes?

bulk syringes = Washing, drying, siliconisation, sterilization necessary before filling

nested ready-to-fill syringes = just opening & filling & closure (ready to use) -> no washing & sterilization etc.


(f) How do you call the process for manufacturing infusion or parenteral nutrition bags? = form- fill- seal production


(g) What is used to blow up the containers during the blow fill seal process?

Blow/ fill/ seal system = purpose-built machine in which, in one continuous operation, containers are formed from a thermoplastics granulate, filled & sealed, all in one production line

Blow mould closes, bottom is welded -> blowing with sterilized compressed air


(6) Sterility testing

(a) Explain the effect of air pockets within the sterilization load during steam sterilization.


(b) How is the pressure in an autoclave related to the amount of non-condensable gases in the autoclave chamber?


(c) How is venting / air elimination performed in a steam sterilization process that uses the gravity or flow principle?


(a) Explain the effect of air pockets within the sterilization load during steam sterilization.

Steam sterilization (= autoclaving) relies on the presence of saturated steam to transfer heat efficiently to all parts of the load.

-> when saturated steam is coming into an autoclave = it reaches a cold product surface & gets condensate because the steam cools quickly down & transfers all its saved energy to the product -> so product heats up

-> condensation = very fast & powerful energy transfer process


Effects of air pockets:

1) incomplete sterilization: - Air pockets act as barriers to the penetration of steam -> due to air pocket area may not reach the required temperature for effective sterilization -> creation of cold spots -> higher risk of surviving germs -> air prevents steam for reaching the product -> bad sterilization

2) longer sterilization time: - Steam provides higher efficient heat transfer than air -> areas with air pockets require longer exposure times to reach the required temperature -> extention of overall cycle time


b) How is the pressure in an autoclave related to the amount of noncondensable gases in the autoclave chamber?

limit < 40ml/kg non-condensable gases (NCGs)

3) Pressure increase: In a closed system the pressure rises up (because of high energy & steam needs more space) so the vaporization curve reaching 212°C and it becomes a saturated steam

= if pressure rises to high, then there is a lot if air left causing overpressure (p1+p2= Ptotal)

Effects of Noncondensable Gases on Sterilization

  1. Interference with Steam Penetration: NCGs can form pockets or layers that disturb the distribution of steam, leading to uneven heating & insufficient sterilization.

  2. Lower Effective Sterilization Temperature: The presence of NCGs can lower the effective sterilization temperature. For example, if the chamber pressure is read as 121.1 °C (1 atm of steam pressure), but part of this pressure is due to NCGs, the actual steam temperature will be lower than 121.1 °C. -> reduced SAL & uneffective strilization


(c) How is venting / air elimination performed in a steam sterilization process that uses the gravity or flow principle?


(8) Dry heat sterilization (3 points)

(a) What is meant by compensation time in (dry) heat sterilization processes?

(b) In a pharmaceutical plant, a hot air sterilization tunnel is used to sterilize glass cartridges.

In addition to sterilization and depyrogenation, what third purpose is met by the treatment in the hot air sterilization tunnel?

(c) The z value for heat resistant endotoxins is about 46 °C. What does this mean when you compare the required process times at 280 °C and 326 °C?

(d) Why is it important to cool glass containers slowly after hot air treatment?

a) What is meant by compensation time in (dry) heat sterilization processes?




b) In addition to sterilization and depyrogenation, what third purpose is met by the treatment in the hot air sterilization tunnel?

= siliconization : silicon layer (anti-friction coating) is made up to minimize break loose & gliding forces

-> for cartridges & syringes = have stopper inside, it has to move while injection

-> silicone oil or emulsion is sprayed to the inner surface of syringe


(c) The z value for heat resistant endotoxins is about 46 °C. What does this mean when you compare the required process times at 280 °C and 326 °C?

t = 326-280°C/ 46°C = 1

=> 1* z-value (reduction of 10log)

= Process tima at 326°C will be reduced by factor of 10 compared to 280°C


d) Why is it important to cool glass containers slowly after hot air treatment?

= to prevent thermal stress and potential breakage

= to avoide class breakage (due to possible micro-cracks)

= to guarantee product safety (no contamination through glass crackes)

(10) Gamma irradiation

Gamma irradiation and gassing with ethylene oxide are often used for the sterilisation of entire pallets with consumables.


(a) What is the mechanism of action of gamma irradiation?



(b) Give a reason why gamma irradiation is preferred over electron irradiation for this application.



(c) Name one advantage and one disadvantage of gamma irradiation compared to sterilization with ethylene oxide.


(d) Give a reason why ethylene oxide is used for that application but not hydrogen peroxide.(2.5 points)

(a) What is the mechanism of action of gamma irradiation?

= use of high-energy gamma rays to disrupt the DNA or RNA of microorganisms, making them incapable of reproduction

  • mechanism of action:

    1) Generation of Ionizing Radiation: = cobalt-60 creates during radioactive decay high-energy gamma rays

    2) Penetration of Materials = Gamma rays have high energy and short wavelengths, allowing them to penetrate deeply into materials (sterilization)

    3) Ionization of Atoms & Molecules = As gamma rays pass through a material, causing ionization of atoms -> results formation of highly reactive ions & free radicals -> killing germs


(b) Give a reason why gamma irradiation is preferred over electron irradiation for this application.

electron irradiation = Limited penetration, but sterilization of products in final packaging possible -> may be not sufficient to penetrate whole pallet (bad sterilization)

Gamma irradiation = High penetration capability sterilization of products in final packaging -> higher assurance level (to penetrate whole pallet)


(c) Name one advantage and one disadvantage of gamma irradiation compared to sterilization with ethylene oxide.


Gamma Irradiation

  • High penetration capability sterilization of products in final packaging & no residuces

  • Problem of radio active waste

Advantages - ETO

1) Broad spectrum of activity

2) Alkylation of nucleic acids, proteins (requires H2O)

3) Excellent penetration capacity


Disadvantages - ETO

1) Carcinogenic

2) Extremely flammable, forms explosive mixtures with air

3) Leaves toxic residues -> not allowed in food sector


(d) Give a reason why ethylene oxide is used for that application but not hydrogen peroxide = sterilisation of entire pallets with consumables.

because: ETO has excellent penetration capacity & broad spetrum of activitity -> better for entire pallets with undefined consumables


hydrogen peroxide

= Very strong oxidizing agent

= Highly corrosive

= Penetration capacity limited






(12) Validation of sterilization processes (2.5 points)

(a) During the DQ you have to select a steam sterilization process for the sterilization of 2 m long silicone tubes used for aseptic filling. Which process do you choose? Give a justification for your choice.


(b) What is the name of the document in which the user demands on a sterilization system are recorded as part of the DQ?


(c) What is checked during thermoelectric testing with an empty sterilization chamber as part of the PQ of a steam sterilization process?

(a) During the DQ you have to select a steam sterilization process for the sterilization of 2 m long silicone tubes used for aseptic filling. Which process do you choose? Give a justification for your choice.

DQ = Design Qualification = Determination of requirements for the equipment ->(URS = user requirements specifications & functional specification document)


Justification:

  • with SIP is effectively sterilization of long tubing systems possible

  • tubes can remain in their installed positions within the system during sterilization, maintaining aseptic integrity

  • SIP systems are designed to ensure uniform distribution of steam, which is critical for sterilizing long silicone tubes uniformly. This prevents any cold spots or areas where steam might not reach effectively.


(b) What is the name of the document in which the user demands on a sterilization system are recorded as part of the DQ?

URS = user requirements specifications & functional specification document


(c) What is checked during thermoelectric testing with an empty sterilization chamber as part of the PQ of a steam sterilization process?

= uniformity of temeprature & pressure


(15) Validation of sterilization processes (1.5 points)

(a) List four different non-economic requirements that should be included in a user requirement specification (URS) for an autoclave.


(b) What must be considered in the PQ of a steam sterilization process with regard to loading - in addition to the loading schemes of routine production?

(a) List four different non-economic requirements that should be included in a user requirement specification (URS) for an autoclave

URS = user requirements specifications & functional specification document

= a planning document that specifies what a system needs to do => part of DQ (Design Qualification)


1) Location / Environment / Dimensioning

·   Place of installation/ Environment / zone requirements

·   Constructional conditions, e.g. available area, floor load


2) Process

·    Procedure / operating mode (e.g. FRVV)

·    Special requirements for the process (e.g. accelerated cooling)

·    Design / Type, (cylindrical/rectangular; horizontal/vertical)

·    Working range (pressure / temperature)/ Programms


3) Monitoring / Measurement technology

·    Sensors/ Accuracy/  Additional features


4) Materials and surfaces

·        Materials

·        Surface properties

·        Hygienic Design



(b) What must be considered in the PQ of a steam sterilization process with regard to loading - in addition to the loading schemes of routine production?


5) PQ = Performance Qualification = Verification of sterilization success based on relevant loads -> actual process validation

  • PQ of a steam sterilization process = involves demonstrating that the sterilizer operates effectively and consistently within the defined parameters to achieve the desired level of sterility.

1) load & packaging system should contain product & be identical to the packaging used for routine production

2) Worst-Case Loading & Conditions should be included (max/ min/ cold spots)

3) loading configuration/ amount/ distribution inside (spacing) must be defined


(12) Validation of sterilization processes (2.5 points)


(b) What should be considered when validating a steam sterilisation process with regard to loading?


(c) What is the general name of test strips with bacterial spores used to validate sterilization procedures?

b) What should be considered when validating a steam sterilisation process with regard to loading?

1. Loading Patterns

  • Standard and Worst-Case Loads: Validate using both routine (standard) and worst-case load configurations. Worst-case scenarios may include maximum and minimum load capacities, as well as challenging load items that are difficult to sterilize.

  • Uniformity & Spacing : Ensure that the load is uniformly distributed within the sterilizer chamber to allow for proper steam penetration and heat distribution. Maintain enough spacing between items and ensure proper orientation to facilitate steam access to all surfaces and areas of the load.

  • PQ = Performance Qualification = Verification of sterilization success based on relevant loads -> actual process validation

    • test load of the sterilizer contains products which are routinely handled -> loading patterns must be defined

    • load should represent product families which have the greatest difficulty for the sterilisation -> include worst case conditions

    • the loading configuration & amount of load must be defined Ò size and/or the mass of the sterilizer load

2. Material and Container Types

  • Diverse Materials: Include a variety of materials (e.g., metal, glass, plastic, textiles) that are commonly processed to ensure that the sterilization process is effective for all types.

  • Container Sizes and Types: Validate using different container sizes and types (e.g., vials, bottles, pouches, trays) to ensure steam penetration and effectiveness across all configurations.

3. Temperature and Pressure Monitoring

  • Sensor Placement: Strategically place temperature and pressure sensors (thermocouples) throughout the load and chamber, especially in hard-to-sterilize areas, to ensure uniform conditions.

  • Environmental Mapping: Conduct temperature and pressure mapping studies to identify potential cold spots or areas where steam penetration might be insufficient.

4. Biological and Chemical Indicators

  • Biological Indicators (BIs): Place BIs in the most challenging locations within the load to provide direct evidence of effective sterilization. BIs should contain highly resistant microorganisms (e.g., Geobacillus stearothermophilus) to validate the process.

  • Chemical Indicators (CIs): Use CIs as visual markers to confirm that sterilization parameters (e.g., temperature, steam penetration) have been met throughout the load.

5. Process Controls

  • Cycle Parameters: Validate all critical cycle parameters, including temperature, pressure, and exposure time, to ensure they consistently achieve the required conditions.

  • Steam Quality: Verify that the steam used meets the required quality specifications, including purity and dryness fraction, to ensure effective sterilization.

6. Repeatability and Reproducibility

  • Multiple Runs: Conduct multiple validation runs to demonstrate that the sterilization process is reproducible and consistently achieves the desired outcomes under varying load conditions.

  • Statistical Analysis: Analyze the data statistically to ensure consistency and reliability across all validation runs.

8. Regulatory and Compliance Requirements

  • Compliance Standards: Ensure the validation process meets relevant regulatory standards and guidelines, such as those provided by the FDA, EMA, ISO, and other pertinent bodies.

  • Documentation: Maintain thorough and accurate documentation of all validation activities, including protocols, test results, and analyses, to provide evidence of compliance and process control.

9. Load Configuration Specifics

  • Dense and Light Loads: Validate both densely packed and lightly packed loads to ensure steam can penetrate effectively regardless of load density.

  • Mixed Loads: Include mixed loads with different item types and materials to validate the versatility of the sterilization process.


c) What is the general name of test strips with bacterial spores used to validate sterilization procedures?

The general name for test strips with bacterial spores used to validate sterilization procedures is "biological indicators" or "biological indicator strips”

  • biological indicator (for validation) = filter paper strips with spores/ spore suspensions with colour indicator

These strips contain a known number of highly resistant bacterial spores, such as Bacillus subtilis or Geobacillus stearothermophilus. Biological indicators are employed to assess the efficacy of sterilization processes, for steam (autoclaving), ethylene oxide gas, hydrogen peroxide gas etc.


(4) F0 & D value

(a) How are the F-value and the D-value related?


(b) For a given z-value of 10 °C, how does the D-value change if steam sterilisation is carried out at 120 °C (increased pressure, e.g. pressure cooker) instead of 100 °C (atmospheric pressure)?


(c) For a steam sterilisation process, the F0 value is 30 min. How can this value be interpreted?

(3 points)

(a) How are the F-value and the D-value related?

F-value [mins] = holding time at a temperature T in minutes to reduce the existing population (N0) with the specific D value by the desired number of powers often/ log10 levels (n) to a final value (N)

D-value = duration of sterilization to kill 90% of germs (of N0)

F-value is directly proportional to D-value.

  • low F-value = short sterilization (holding time) => means low D-value = short duration of sterilisation to kill 90% of germs = steep curve

  • high F-value = long sterilization (holding time) => means huge D-value = long duration of sterilisation to kill 90% of germs = flat curve

  • The higher the F value, the … more extensive (better) is the killing of germs.

  • The lower the F value, the slower is the SAL value achieved (low assurance of sterility)

  • With increasing temperature the D-value [mins]… decreases -> high °C results faster killing & a less D-value


(b) For a given z-value of 10 °C, how does the D-value change if steam sterilisation is carried out at 120 °C (increased pressure, e.g. pressure cooker) instead of 100 °C (atmospheric pressure)?



= D-value decreases for factor 10^-2


(c) For a steam sterilisation process, the F0 value is 30 min. How can this value be interpreted?

F0 = 1 min means the lethality of a method that works for 1 minute at 121.1 °C (250 °F) and a z-value of 10 °C (18 °F) or an equivalent temperature-time combination


F0 value of 30min = means the same lethality of a method that works for 1 minute at 121.1°C


7) Sterility testing

(a) For which sterilization goods is the steam-air mixture process used?


(b) Why does the steam-air mixture process use a steam-air mixture and not pure saturated steam?

(1.5 points)

a) For which sterilization goods is the steam-air mixture process used?

1) steam/air mixture process


(b) Why does the steam-air mixture process use a steam-air mixture and not pure saturated steam?

 = because to generate steam higher °C is needed, which raises the pressure: p = p1 + p2 -> container may burst

-> higher °C to create steam may have negativ impact on product


Reasons for using a steam-air mixture:

I) Temperature Control:

  • Reduced Temperature: Pure saturated steam provides uniform heating at fixed temperature corresponding to its pressure (e.g., 121.1°C at 1 atm). But for sterilization processes with lower or more precised temperatures stea,-air mixtures are necessary.

  • Mixture Adjustments: By mixing steam with air, the overall temperature can be adjusted below the saturation temperature of pure steam. This enables more controlled heating environment for delicate items or processes that cannot withstand higher temperatures.

II) Uniform Heating

  • The addition of air can help in distributing heat more uniformly

  • Avoiding Condensation Issues: Pure steam can condense on cooler surfaces, leading to uneven heating and potential cold spots. A steam-air mixture can reduce the rate of condensation, leading to a more uniform temperature profile within the chamber.

  • steam-air mixture allows better control over temperature. Pure saturated steam can have a high temperature & cause damage on products. By introducing air into the steam, the overall temperature can be moderated to prevent overheating



(14)

A silicone tubing shall be used for the aseptic filling of a drug. The preparation of the silicone tubing consists of the following steps:

[1] In class D it is placed in a double-door washing machine, washed therein, and then removed to class C.

[2] In class C the hoses are double-wrapped in tyvek bags and loaded into a pass-through autoclave.

[3] The removal of the sterilized hoses takes place in class B.

[4] The hoses are then transferred to a previously decontaminated RABS. During transfer, the door of the RABS is briefly opened and the outer tyvek bag is removed.

[5] Finally, with the doors closed, glove ports are used to open the inner tyvek bag and install the tubing.

How do you evaluate the process?

Are all steps (1 to 5) in compliance with the requirements of Annex 1 and a minimal contamination risk for the drug processed in class A?

Is there potential for optimization? If yes, which?

(3 points)

How do you evaluate the process?

= the process doesn’t fulfill the criteria of aseptic preparation

Are all steps (1 to 5) in compliance with the requirements of annex 1 and a minimal contamination risk for the drug processed in class A?

= No are not, high contamination risk due to wrong unpacking in wrong zone


Is there potential for optimization? If yes, which?

[1] ist right

[2] & [3] = tubs get unpacked/ opened (removal of second packaging tyvek bag) in class C -> surface sterilization from C to B is correct

[4] door of RABS shouldn't get opened -> high contamination risk (class A inside) & unpackaging of second packaging layer has to be in class C

[5] doors shouldn't open (transporttation via decontamiantion airlock or RTP better) - inner tyvek bag better to open in class B area & transfer sterile tub to class A for final filling/ processing


Main steps:

I) Class C/D: 1) tubs get mechanically unpacked/ opened -> HEPA filtered air

 2) tubs get introduced into E-beam tunnel -> through airlock doors

 3) tubs get transferred to irradiation zone -> surface sterilisation

II) Class B: 4) tubs get transported trough class B zone to class A

III) Class A: 5) filling zone -> presterilized syringes/ vials get filled

(19) Validation of sterilization processes

Preparation of equipment and primary packaging material (2 points)


(a) What is measured to monitor CIP processes?


(b) Sterile couplings are used for single-use systems. What is their purpose?


(c) In addition to the glass body, which parts of a finished syringe are also siliconized?

(a) What is measured to monitor CIP processes?

= is a Validated automatic cleaning without disassembly

-> Mobile or fixed systems with connection to SIP


Monitoring = measurement of Conductivity (possibly also pH / TOC = total org. carbon) in the effluent (Abwasser)

Conductivity = property of water to conduct electrical current. Is influenced by the concentration of ions in the water. => used as an indicator of overall water quality.

High conductivity = high concentration of dissolved ions in water

= may suggest the presence of contaminants or changes in the composition of water.




(b) Sterile couplings are used for single-use systems. What is their purpose?

Sterile connectors/ couplings = presterilized system with membraned (gets taken out) for product transfer

= for Hose connection with sterile couplings (under class A air) = disposable system for product transfer in class A to maintain sterility

- tiny hole in the wall between class C & class A (overpressure)

- tube can be fixed in this hole & get connected with sterile coupling

-> reduced risk of recontamination




(c) In addition to the glass body, which parts of a finished syringe are also siliconized?

= syringe stopper & needle (if present)


(18) Preparation of equipment and primary packaging material (2.5 points)

(a) In CIP processes, it is important that no spray shadows occur. What is meant by this?


(b) Stoppers that will later be used in syringes in an aseptic process are to be prepared. Outline the process steps of automatic stopper treatment (excluding transfer and storage processes).


(c) What process takes place for syringes after final rinsing and blow-out with compressed air before treatment in the hot air sterilization tunnel?

(a) In CIP processes, it is important that no spray shadows occur. What is meant by this?

"spray shadows" = areas or surfaces within a processing system that are not effectively reached or cleaned by the spray nozzles during the CIP cycle.


(b) Stoppers that will later be used in syringes in an aseptic process are to be prepared. Outline the process steps of automatic stopper treatment (excluding transfer and storage processes).

Automatic stopper treatment

1) Washing & cleaning = to remove any contaminants, particles, or residues.

2) Rinsing = After cleaning, the stoppers undergo rinsing to eliminate any remaining cleaning agents or impurities

3) Drying = to remove moisture

4) Sterilization = autoclaving, gamma irradiation

5) Siliconization = application of a thin layer of silicone oil to the stopper surfaces. This is done to facilitate the movement of the stoppers within the vial or syrange and reduce frction & enebale correct dosing

6) Inspection and Quality Control = to ensure that quality: visual inspection for defects, dimensional checks, and testing for sterility.

7) insert stopper in syringe (with pipe or vacuum)


(c) What process takes place for syringes after final rinsing and blow-out with compressed air before treatment in the hot air sterilization tunnel?

= siliconization



(21) Preparation of equipment and primary packaging material (2.5 points)


(b) Which test is performed in the pharmaceutical sector for the validation of CIP processes?


(c) When in the course of the process does siliconization of glass syringes take place?


(d) Name one disadvantage that oily siliconization has compared to baked-on siliconization.


(e) For which pharmaceutical products is the final drying of the stoppers after automatic stopper treatment of particular importance?

(b) Which test is performed in the pharmaceutical sector for the validation of CIP processes?

Validation = Riboflavin test (at least 2 times): flush is fluorescence (green) substance & good water soluble

1) contamination of the inner surfaces with a riboflavin solution

2) drying

3) CIP verification of successful cleaning with UV lamp

-> no green fluorescence should be visible! otherwise dirt left


CIP = Cleaning in Place


(c) When in the course of the process does siliconization of glass syringes take place?

= before sterilization (glass syringes) -> baked-on siliconization preferred & to reduce friction while transport/ sterilization


d) Name one disadvantage that oily siliconization has compared to baked-on siliconization.

oily siliconization = thick layer -> may cause mechanicall problems e.g. in syringe due to limited space

-> backed-on silionization = due to treatment by heat (during sterilization) more robust silocon layer results, lower risk of silicone migration


e) For which pharmaceutical products is the final drying of the stoppers after automatic stopper treatment of particular importance?

Lyophilized (Freeze-Dried) Products = are highly sensitive to moisture (API)

= Dual-chamber technology - syringes

• Chamber 1 = lyophilized drug

• Chamber 2 = diluent for reconstitution

-> Used because: dilution of drug is easier, safer & higher dosage precision


(18) Aseptic filling (2.5 points)

(a) Name two dosing systems besides the peristaltic pump that are used for aseptic filling.


(b) What is the purpose of a stopper sorting bowl? Name two aspects.


(c) What needs to be considered when placing a lyophilization stopper following aseptic filling?

(a) Name two dosing systems besides the peristaltic pump that are used for aseptic filling.

1) Rotary piston pump = Drehkolbenpumpe: for temperature sensitive product

= used for: viscous products & for high precision filling (low volumes)

-> not for: metal sensitive products & quick product changes

 Principle:

- cylinder (no valve) & a piston that moves up/ down

- groove of upper part can rotate

- product get inside, groove rotates (180°C) & get filled to final container

 

2) Rolling diaphragm pump = multi-use or single use pumps

- intake port open & product gets inside, piston moves inside

- discharge port opens & product gets out, piston moves out

- diaphragm inside housing covers completely the piston,

no connection to outside (closed system)





(b) What is the purpose of a stopper sorting bowl? Name two aspects

Feeding of stoppers (Zufuhr von Stopfen) = Singularization (Vereinzelung) & correct stopper alignment with (vibratory) sorting bowl

- inside barrier system get transported to a vibratory sorting bowl (is rotation & vibrating)

- only stoppers that are located in right direct/ position are get transferred for capping


(c) What needs to be considered when placing a lyophilization stopper following aseptic filling?

Lyophilization = performed in free dryer under class A conditions

-> because: - vials have special lyophilization stopper (with opening), so the solvent/ vapor can get out

  - opening in stopper = risk of contamination -> class A surrounding & CIP/SIP capable (steam sterilization/ H2O2)

(21) Blow fill seal (1.5 points)

(a) Which step of the blow-fill-seal process is the most critical step for the integrity of the container? In addition, provide a brief justification.


(b) Name one advantage of the blow-fill-seal process over traditional filling in glass containers besides the exclusion of glass breakage

(a) Which step of the blow-fill-seal process is the most critical step for the integrity of the container? In addition, provide a brief justification.

Critical:

sealing step = not good sealed container has a high risk of contamination

  • The sealing step is crucial because it is the point at which the container is permanently closed. Any defect or contamination during sealing can compromise the sterility of product, leading to potential contamination

  • Proper sealing ensures that the container is leak-proof, which is essential for maintaining the integrity of the product throughout its shelf life.

  • The seal must be strong and durable to withstand handling, transport, and storage conditions. A weak or defective seal can lead to container failure, which can have negative impacts on the quality of product inside.



(b) Name one advantage of the blow-fill-seal process over traditional filling in glass containers besides the exclusion of glass breakage


Blow/ fill/ seal system = purpose-built machine in which, in one continuous operation, containers are formed from a thermoplastics granulate, filled & sealed, all in one production line

= is used for aseptic production

 

Advantage: BFS gives very high process & product safety (no transport routes, sterilization of vessels)




(23) Media fill (3 points)

(a) In which documents is the execution of a media fill specified?


(b) How often / with what frequency must a media fill be repeated after successful initial validation?


(c) An SOP for aseptic formulation and filling of a product requires that the product is freeze-dried and nitrogen is applied for inertisation before closing the stopper after freeze-drying. How do you take these process steps into account for a media fill?

(a) In which documents is the execution of a media fill specified?

= manufacturing SOPs & media fill plan (Plan for the media fill)



(b) How often / with what frequency must a media fill be repeated after successful initial validation?

Frequency - EU GMP Annex 1

-> APS should be performed as initial validation = including 3 successful APS that cover all working shifts when significant modification in process occurs = again initial validation is required

-> periodic re-validation = APS should be repeated twice a year (2x/ year) per shift & process

-> Every employee who is routinely involved in aseptic processes must participate in 1x successful APS min. 1x/ year with an appropriate job profile.


c) An SOP for aseptic formulation and filling of a product requires that the product is freeze-dried and nitrogen is applied for inertisation before closing the stopper after freeze-drying. How do you take these process steps into account for a media fill?

Execution of Media Fill: = done by following the manufacturing SOPs & media fill plan

  • instead of nitrogen (inert gas) must be replaced by replaced by sterile air toguarantee perfect growth condition for usually aerobic (need O2) germs

  • no freezing steps = only simulation of time without lowering the °C because it may affect the growth of germs



(21) Media Fill (2.5 points)

(a) What should be considered in a media fill with regard to personnel besides going for the maximum number of persons involved in the routine process? Name one additional point.


(b) An SOP for aseptic formulation and filling of a liquid product states that two excipients and WFI are added to the active ingredient for formulation, followed by stirring at 300 rpm for 30 min ± 10 min. How do you take these specifications into account for a media fill?


(c) Which number is missing in the following extract from Annex 1?

“Process simulation tests should be performed as initial validation with ____ consecutive satisfactory simulation tests”.

a) What should be considered in a media fill with regard to personnel besides going for the maximum number of persons involved in the routine process? Name one additional point.

APS = Aceptic process simulation

-> Every employee who is routinely involved in aseptic processes must participate in 1x successful APS min. 1x/ year with an appropriate job profile.


b) An SOP for aseptic formulation and filling of a liquid product states that two excipients and WFI are added to the active ingredient for formulation, followed by stirring at 300 rpm for 30 min ± 10 min. How do you take these specifications into account for a media fill?

1) Create a plan for the media fill

2) all excipients should get replaced with nutrient medium & WFI as well!

3) stirring of medium should be part of process simulation -> simulation of time without affecting the growth of germs is allowed


c) Which number is missing in the following extract from Annex 1?

“Process simulation tests should be performed as initial validation with _3___ consecutive satisfactory simulation tests”.


(20) Media fill (3 points)

(a) What should be considered during a media fill with regard to personnel? Name two points.


(b) An SOP for aseptic formulation and filling of a liquid product specifies stirring for three hours as part of the aseptic batch formulation and storing the product at -20°C after filling into syringes. How do you take these specifications into account for a media fill?


(a) What should be considered during a media fill with regard to personnel? Name two points.

• max. Number of personnel & their activities -> must do their normal work

• Shift changes, breaks, and gown changes (Kleiderwechsel) (when applicable)

-> Every employee who is routinely involved in aseptic processes must participate in 1x successful APS min. 1x/ year with an appropriate job profile


b) An SOP for aseptic formulation and filling of a liquid product specifies stirring for three hours as part of the aseptic batch formulation and storing the product at -20°C after filling into syringes. How do you take these specifications into account for a media fill?

= all aseptic operations of process must be included

= EVERYTHING is replaced by nutrient medium (all excipients)!

1) The stirring or recirculation should be part of the simulation: means that 3 hours of stirring under sterile conditions must be done (includes real process duration)

2) Media should not be frozen at any stage during simulation = syringes should not be frozen, and precautions should be taken that ensure that the medium remains in an aerobic state to avoid potentially inhibiting the growth of microorganisms.

  • Crystallisation of the medium should be prevented because it may reduce the likelihood of recovery of organisms.


(26) Media fill (3 points)

(a) List two worst-case situations that could be considered in a media fill of an aseptic filling.


(b) An SOP for aseptic formulation and filling of a liquid product specifies that for formulation two excipients are added to the active ingredient while stirring. The product is then sterile filtered and aseptically filled. After filling, the product is stored at -80°C. How do you take these process steps into account for a media fill?

(a) List two worst-case situations that could be considered in a media fill of an aseptic filling.

  • Stopping of a machine -> extended process duration -> vials stay open (high contamination risk)

  • maximum number of resonable interventions that my occure in a process

    -> Each intervention has a risk of contamination, process shooul stay sterile despite frequent disruptions.

(b) An SOP for aseptic formulation and filling of a liquid product specifies that for formulation two excipients are added to the active ingredient while stirring. The product is then sterile filtered and aseptically filled. After filling, the product is stored at -80°C. How do you take these process steps into account for a media fill?

1) all excipients & API should get replaced with nutrient medium

2) stirring process should get performed as real as possible (incl. duration)

3) Media fill (process simulation) includes the steps of sterile filtration -> medium should be capable of being filtered through the same filter as used in production.

4) aseptical filling must also be simulated according to reald process

5) storage at -80°C not allowed: Media should not be frozen at any stage during simulation = product should not be frozen, and precautions should be taken that ensure that the medium remains in an aerobic state to avoid potentially inhibiting the growth of microorganisms -> only simulation of storage time possible



(13) A buffer is required for the aseptic formulation of a medicinal product which is not finally sterile-filterable. The buffer is prepared in cleanroom class D and subjected to germ-reducing filtration. For aseptic formulation in cleanroom class A, the sterile active substance is added directly to this buffer. Which two points are incorrect here? (2 points)

A buffer is required for the aseptic formulation of a medicinal product which is not finally sterile-filterable.

The buffer is prepared in cleanroom class D and subjected to germ-reducing filtration. For aseptic formulation in cleanroom class A, the sterile active substance is added directly to this buffer.

Which two points are incorrect here?

1) not sterile filterable product = aseptic processing required

Preparation of buffer has to be done at least in class C (preparations of solutions to be filtered)

2) The buffer should be subjected to sterile filtration (through a 0.2 micron filter) rather than just germ-reducing filtration. This ensures that the buffer is sterile before it is used in the aseptic formulation process.

  • all product components need to be sterilized separately beforehand

  • and then bring/ fill everything in aseptic processing together under class A conditions

What to do if filtration is not possible? = all product components need to be sterilized separately beforehand & bring/ fill everything in aseptic processing together (Aseptic formulation: class A)

 

-> Aseptic processing has higher contamination risk because product gets filled into pre-sterilized open container systems



Author

Daria S.

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