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Formulation & Processing Flashcards

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1
Q

Typical Autoclave Cycles for :-
a) Steam
b) Dry Heat

A

a) 121’C 15 mins or 134’C for 3.5mins
b) 160’C 2hrs or 170’C 30mins

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2
Q

How do we ensure reliability of autoclaves?

A

Daily - Bowie Dick

Weekly - Leak Testing

Annually- Re-qualification- leak rate, air detector, Bowie dick, Automatic Process Control Testing, Load Testing (Min / Max), BI testing

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3
Q

What are the considerations for autoclave validation?

A

Define Process - Cycle temperature and duration (121’C 15mins), F0 cycle min SAL 10-6, what is the formulation?, Load Configuration (Max / Min)

Equipment- Validation/Qualification,
URS / FAT / SAT
IQ:
Calibration- air detector, pressure gauges, leak test rate, steam quality, utilities connections and materials of construction
OQ:
Safety features , Interlocking doors,
Empty Chamber Studied (Hot /Cold) spots, Leak Test, Bowie Dick
PQ
Load Patterns (Max / Min), Thermometric Testing, Equilibration Testing, BI Study - Geobacillus Sterothermophilus

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4
Q

What are the different types of Leak testing for sterile products?

A

Camera Systems
Vacuum Decay
Helium Leak Test
Dye Ingress Test
Bubble Test
High Voltage Application

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5
Q

What is the minimum batch size for PST’s?

A

5000

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6
Q

Give examples of activities carried out in:-
Grade A
Grade B
Grade C
Grade D

A

A - Aseptic Processing / High risk filling Operations
B - Background to filling in Aseptic preparations.
C - Preparation of solutions to be filtered and some preparations for terminally sterilised products.
D - Handling of components after washing, preparation of solutions for terminal sterilisation.

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7
Q

What testing would you do to qualify a clean room?

A

Particulate Counts
Airflow Volume & Velocity
Differential Pressures
Filter Integrity Testing
Airflow Visualisation
Recovery Testing
EM Monitoring
Containment leakage

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8
Q

How do we validate filters?

A

Bacterial Challenge Testing
- Bravundimonas diminuta
- Concentration of 107 organisms per cm2
-Direct inoculation of your product is preferred (not always possible)
- Worst Case conditions - eg max pressure time and temp.

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9
Q

Routine test for inhalation products?

A

Appearance
Weight of Container
Leak Rate
Spray Pattern
Water Content
Valve Delivery
Related Substances
Dose content uniformity
Particulates
Micro

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10
Q

What is the temperature for disintegration of tablets?

A

35-40 degrees Celsius (body temp)

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11
Q

Common Problems with tablets:-

A

Capping - air trapped in mix during compression , poor flow - uneven distribution of material

Lamination- over compression , air trapped,

Cracking- large granules or granules to dry

Hardness variation- unusual size or distribution of granules

Sticking - excessive moisture or improper lubrication , tooling issues, inadequate dwell time during compression

Mottling - improper mixing or coating issue , insufficient drying so moisture trapped

Flashing - unwanted edge around tablets caused by excess material in due cavity, upper and lower punches are misaligned

Chipping - lack of hardness, high friability, poor tablet design, excessive pressure

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12
Q

What are the components of a tablet and what do they do?

A

Binding Agent - (Starch) - holds or draws material together

Disintigrant- (croscarmellous sodium) facilitates disintegration after administration

Diluent- (Sorbitol) improves cohesion and compression

Lubricant (Mg Sterate) stops tablet sticking in dies

Glidant- improves powder flow during tablet manufacture

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13
Q

Typical Tablet Specification

A

Appearance
Average Weight
Friability
Hardness
Assay
Uniformity of Dose
Related Substances
Disintegration
Dissolution
TVAC Yeasts/Moulds

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14
Q

What are the constituents of Nolvadex?

A

Active - Tamoxifen
Diluent - Lactose Monohydrate
Binder - Maize Starch / Gelatin
Disintigrant - Crosscarmellous Sodium
Lubricant - Mg Sterate
Purified Water - Granulation Fluid

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15
Q

Outline a typical tablet manufacturing process:-

A

Dispensing > Mixing (API / Excipients Dry) > Granulation (Fluid Addition) > Drying > Sieving/Milling > Blending > Compression > Coating

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16
Q

Typical Manufacturing process for ATMPs?

A

Cell Collection (Leukapherisis)
Cell isolation / Activation
Genetic Modification
Expansion
Harvesting
Purification
Formulation with Buffer
Administration to patient

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17
Q

What are the two types of ATMPs ?

A

Autologous- cells from same person
Allogenic - cells from different person

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18
Q

Key Considerations ATMPs

A

Control of Raw Materials is Critical

Can release OOS product

Can use expired materials if re-tested

Can use testing in 3rd Countries

Release testing may not be complete prior to administration

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19
Q

Outline high level biological process

A

Master Cell Bank
Working Cell Bank

Upstream Processing
- Vial Thaw
- Inocculation in to Cell Culture Media
- Seed Bioreactor
- Production Bioreactor

Downstream Processing
- Harvesting
- Purification ( Filtration / Chromatography / Virus Inactivation) - media and cell debris removed
- Freeze of bulk (API)
- Formulation (Add Buffer)
- Sterile Filtration
- Freeze

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20
Q

What is a master seed bank and how do you make a working seed bank?

A

Master seed bank is the original carefully characterised cell line , virus or microorganism used in manufacturing.

Working cell bank is made by taking an aliquot from the master and proliferating under controlled validated conditions to produce a larger quantity.

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21
Q

Key tests for biological?

A

ICHQ6 and BP / EP

  • Sterility
  • Particulate Free
  • Endotoxin Free
  • Mycoplasma
  • ID
  • Assay (Potency)
  • Impurities
  • Adventitious Agents
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22
Q

As per Chapter 3 of Eudralex Volume 4 what are the 3 reasons you would require dedicated facilities?

A
  • Risk can’t be controlled by organisational and technical measures
  • Scientific data from toxicology evaluation does not support risk
  • Residue limits can’t be determined by validated method
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23
Q

Describe dry granulation process for tablets

A

Dispensing
Mixing
Compaction (Slugging/Roller)
Milling
Blending
Compression
Coating

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24
Q

Describe capsule manufacturing process

A

Dispensing
Mixing
Milling / Sieving
Capsule Filling
Capsule Closure
Polishing/ De-dusting
Inspection/ sorting

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25
What is critical to control in gelatine capsules?
BSE / TSE Temp Humidity
26
Give different coatings and why we use them
Sugar Coating - aesthetic / organoleptic purposes (Sucrose, gelatine and calcium carbonate, TiO2) Enteric - protect from stomach acid to dissolve in gut (polymer CC or TiO2) Sustained/ controlled release- prolong for steady plasma levels
27
What is magnesium sterate poisoning?
-Over lubrication of granules - Affects disintegration , dissolution, hardness and bioavailability. - Coats granules with hydrophobic coat preventing water penetration.
28
How can water ingress impact OSD products?
- API may undergo hydrolysis causing degradation and increased impurities - physical changes in hardness and thickness - result in lack of efficiency and impact to dissolution
29
How does a fluid dryer work?
Dryer is Loaded Heated air forced upwards lifting and suspending granules. Moisture migrates to granules surface and evaporates
30
What is the test for Friability?
Tumble Test NMT 1% weight loss
31
What is disintegration test?
Performed in water or simulated gastric fluid 37 degrees C +/- 2 degrees C No visible fragments
32
What properties are desirable for direct compression process?
Flowability Compressibility Lubricity Uniform particle size
33
Talk through the MDI manufacturing process
Two types of- single stage fill and two stage fill Single: Canister feed > Valve Insertion > Crimp > Pre-mixed drug and propellant through valve > actuator placement > capping > leak test Two Stage Canister Feed >drug concentrate filled into can > valve insertion > crimp > propellant filled through valve> actuator placement> capping> leak test
34
Advantages and disadvantages of MDIs vs DPIs
DPI - highly moisture sensitive - requires strong respiratory flow - better patient compliance - not harmful to the environment MDI - only slightly moisture sensitive - uses HFA - green house fade - low patient compliance requires coordination(Use of Spacers)
35
Constituents of an MDI and DPI?
MDI - Active Concentrate - Suspension - eg Ethanol - Popellant DPI - Active - Carrier (Lactose)
36
Typical tests for MDI / DPI
Identification Assay Impurities Micro Content uniformity Uniformity of Dose Aerodynamic Particle Size Distribution Moisture Content DPI Only: Spray Pattern Valve Function Leak Rate DPI - Particle Size Distribution Moisture
37
What is the difference between: a) Solution b) Suspension c) Emulsion
a) One continuous liquid phase b) A liquid phase and suspended solid phase which is dispersed on shaking c) Continuous liquid phase and emulsified liquid phase
38
Typical components of Cream / Ointment
Cream (50:50) Water : Oil Ointment (20:80) Water: Oil API Preservative Antioxidant Emulsifier Thickener Humectant
39
What are the components of a suspension?
Water, Suspending Agent, Wetting Agent, Flocculating Agents, Preservative, Flavours, Colorants
40
What are the advantages and disadvantages of suspensions?
Good alternative to tablets for paediatric formulations Can have good stability Patient compliance can be an issue Uneven distribution of API due to dose to dose variation.
41
What is in a typical liquid specification? What are the additional test for Suspensions?
Appearance identity Assay Impurities Preservative assay PH Viscosity Micro Content Uniformity Suspensions: Re-dispersibility Uniformity of Dose Sedimentation Rate
42
What differences are then in manufacturing liquid suspensions vs liquids?
- Raw materials include - suspending agents, wetting agents and flocculating agents - Particle size is critical for suspended solids ( typically milling / micronisation step) - order of additions is more critical to enable solids to disperse in continuous liquid phase. - Requires high shear mixers to avoid aggregation and sedimentation - Can’t filter suspension
43
Differences between RABs and Isolators?
Isolators - Complete physical Barrier - Open sealed system that has openings that allow continuous or semi continuous ingress or egress of materials while maintaining over pressure for sterility- minimum background grade C - Closed completely sealed minimum background is grade D - Typically use VHP Clean in place - Closed during interventions RABs - Minimum background Grade B - Typically manual cleaning - Open 1 for direct human intervention - Closed - interaction via glove ports - Can be opened for process interventions.
44
Key things for process simulation trials
- 0cfu - Twice annually or in the event of any changes - Cover all shifts and campaigns - Operators at least once annually - Minimum 5000 units - Use sterile nutrient instead of product - Worst case room occupancy, number of interventions, campaign length, hold times - For failure 3 PSTs prior to start up
45
What is F0 and FH?
F0 - is the time equivalent to the time at 121 degrees C an object is exposed to the desired temperature FH - is the time equivalent to 170 degrees C that an object is exposed to the desired temperature FH
46
What is D value?
The time required to get a 1 log reduction of microorganisms
47
What is a Z value?
Temperature required to get a ten fold reduction in temperature h D value
48
What are the test we do on steam quality? Acceptance Criteria
EN285 Condensable Gasses NMT 3.5% by volume Super Heat NMT 25Kelvin Steam Dryness 0.95 % dryness fraction
49
Why do we perform the following tests? - Leak Test - Automatic Process Control Test - Bowie Dick - Thermometric - Biological IndicatorTesting
- Ensure Chamber Integrity and prevent air ingress - Demonstrates autoclave is functioning correctly and instrument readings are accurate - Demonstrates efficient air removal and steam penetration - confirms heat penetration throughout chamber - Validate microbial kill effect
50
What is an equilibration test?
Ensures all points within autoclave reach the desired temperature at nearly the same time. NMT 60 seconds
51
What is the acceptance criteria for: Leak Testing Empty Chamber Studies Air Detection Bowie Dick
Leak Testing - NMT 13mbar over 10mins Empty Chamber NMT 2 degrees C difference Air Detection - temp in test pack NMT 2 degrees C from drain Bowie Dick - uniform colour change
52
Why do we not pulse on a fluid load autoclave cycle?
Liquid loads don’t trap air like porous loads Can cause flash boiling or risk damaging glass containers
53
What are the CPPs for a VHP system?
Temperature Humidity Concentration Spray rotation speed Chamber Integrity Time
54
How do you validate VHP systems?
URS , FAT, SAT, IQ / OQ Utilities connections, Materials of Construction, Calibration, PQ: 3 x Cycles Geobacillus Sterathermophillus Chemical Inducators Enzymes
55
What actions would you take for a critical Grade A HEPA failure?
Raise Deviation - Anything greater than 0.01% is failure. - Use Portable Particle monitor to determine if Grade A non-viable monitoring is maintained (Typically done in worst case as in shut down) - Perform airflow visualisation studies to determine how this is impacted by failure. - Review previous EM data - Review previous building management data - Typically you would do a bracketing PST - this would be worst case. Perform Risk assessment as p art of deviation - what filter is prior to terminal HEPA? - F8 / F9 or two HEPAs - 80/90% recirculated air - Laminar airflow maintained - Location of failure vs critical activities - Damaged - how bad as this will still maintain some level of efficiency.
56
Draw HVAC system
See Image
57
What values would you expect for the following: a) Air Pressure Differentials between rooms b) Air Change rates d) Air flow Velocity e) HEPA efficiency
a) 10-15pa b) 20-60 changes an hour c) 0.45ms d) 99.99%
58
What test do we perform on a HVAC?
Face velocity HEPA efficiency- via DOP testing
59
What test are performed to qualify clean rooms?
Environmental Monitoring - Viable / Non-Viable Recovery Testing Air Pressure Differentials Airflow Visualisation Studies HEPA - FIT, DOP and Face velocity Air Change Rates Air Velocity Leak Containment
60
How do you perform recovery testing?
Ability of room to dilute airborne particulates Introduce particulate loaf and measure the time it takes to reduce limits outlined in Annex 1 20 air changes an hour should take NMT 15-20mins
61
What is Lyophilisation?
I lost know as freeze drying its removal of ice via sublimation (solid - gas) Products are frozen under pressure
62
Different types of leak testing for sterile products
Camera Systems Vacuum Decay Helium Leak Testing Dye ingress Bubble Test Hi Voltage Application
63
Different types of sterilisation and key considerations
Moist Heat- - Typical cycles 121 degrees C for 15mins or 134 degrees C for 3.5mins - Works by latent heat of condensation. Dry Heat - Typical cycles are 160 degrees C for 2 hours or 170 degrees C for 30mins - Works by convection - Removes Endotoxins Filter - 0.2micron Filter - Bacterial Challenge Testing to validate - PUPSIT Irradiation - 25 Killer Greys - Gamma or Beta - Batch or Continuous Ethylene Oxide - Last resort - TACT
64
Draw an Autoclave
See Image
65
What is PUPSIT?
Pre Use Post Sterilisation Integrity Testing Brought in as a requirement in new Annex 1
66
What organisms are used to validate the following - Steam - Filters - Dry Heat - Irradiation - VHP
-Geobacillus Stearothermophillus - Brevudimonas Diminuta - Bacillus Subtilus or Astrophaeus - Bacillus Pumilus - Geobacillus Stearothermophillus
67
What is the following media used for? - TSB - SDA - FTM - R2A - Mackonkey
- TSB - Bacteria, Yeasts and Moulds - SDA - Yeasts and Moulds - FTM - Anerobes (Sterility Testing) - Water Testing - Excursions with Gram -‘ve bacteria
68
Key Considerations for in house media manufacturing?
Think PEMME People - Trained Environment -Aseptic Conditions, Storage, Materials - Supplier Management of Raw Materials ( Pharmacopeial Grade), Sterility of Containers, Water Quality, Method- Growth Promotion Testing, Sterility testing, visual inspection, stability
69
What is in a contamination control strategy?
Annex 1 Cleaning / Disinfection Outsourced Activities and Vendor Approval Monitoring Systems Preventative mechanisms CAPA / Trending Personnel Risk Management / Process Validation Excipient Controls Sterilisation Scheduled Maintenance Container Closure Utilities Premises and Equipment
70
What are the EM Monitoring requirements in Grade A according to Annex 1?
Continuous Viable / Non- Viable monitoring during manufacturing Particulate Monitors Air Samplers and / or Settle Plates exposed Change Plates every 4 hours Air samplers minimum of 1m3 of air ( Run for approximately 45mins)
71
What would you find in a validation protocol?
- Process description - Summary of critical steps - Equipment/ Facilities - Finished Product Specifications and Methods - IPC criteria - Additional testing for validation - Sampling Plans - Acceptance criteria - Roles and responsibilities
72
What aspects of IMPs would you expect to be fully validated?
Equipment Analytical Methods Sterile / Biological Products
73
Talk through different validation stages and what you do at each
VMP - Overall strategy URS - What you want DQ - The suppliers proposal to meet URS FAT - basic functionality before delivery SAT - Impact of transit IQ - installed as per DQ, Correct Materials, Connections, Change Parts, Maintenance/ Calibration schedules, SOPs / Training OQ- operate as intended- controls speed, functionality PQ - Successfully process product
74
Advantages and disadvantages of oral liquids.
Advantages - Easily absorbed because API is already in solution - Easy to swallow- ideal for paediatric formulations - Solutions are homogeneous and show good dose uniformity Disadvantages - Microbial contamination risk - Reduced Stability - Imprecision dosing by patients eg 5ml spoon
75
Typical components of oral solution
API Water Preservative Flavour Colourant Anti oxidant Chelating Agent
76
Draw / Explain a water plant for producing WFI and PW
Portable Water Add Chlorine- kill bacteria Sand Filter - remove suspended solids Add Softener Carbon Filter- remove Chlorine / Organics Reverse Osmosis- removes Salt / Organics and Bacteria Electro Deionisation (EDI) - removes ions Purified Water Tank ( with spray ball) UV meter on distribution loop For WFI - Further Distillation step
77
Describe the coating process for tablets and critical process parameters
- Coating components pre-mixed - Tablets loaded into coater - Drum rotates and tablets are sprayed with coating - Warm Air enters coater to dry and fix film CPPs - Spray Pattern - Drum Speed - Temperature/ Humidity - Air Flow
78
Give an example of: - Suspending Agent - Wetting Agent - Flocculating Agent
- methyl cellulose - PEG polyethylene glycol - Aluminium Sulfate
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