Tablets Flashcards
(32 cards)
Talk us through a typical tablet formulation and manufacture? What are the CQAs and Critical/Key Parameters in this process?
Dispensing - Tolerance on weighing
Wet or dry granulation - wet or dry - Agitator speed, mesh size, liquid addition rate, CQA - Uniformity of content
Fluid bed dryer / Microwave drying - Drying temperature, mesh size and drying time, CQA - moisture
Blending - Rotation speed and time, CQA - Moisture
Compression - Fill volume, dwell time, compression force, ejection force and tooling, CQA - Tablet hardness and thickness, weight variation, friability, disintegration and appearance
Coating - Spray rate and pattern, drum speed, inlet air temperature and airflow across the tablet bed, CQA - Appearance (AQL 1250)
List the components of a tablet and give examples of each
Diluent - act as a fillers to increase weight and improve content uniformity. Common diluents starch and lactose
Glider - act by filling in the gaps on the surface to improve flow. Examples are colloidal silicon dioxide, magnesium stearate, and silica
Lubricant - reduce the friction between the tablet and the die metal surface to improve ejection from the die. Common lubricant is magnesium stearate
Binder - to facilitate bonding of powder particles during granulation. Examples are gelatine, water and starch
Disintegrant - aids mechanical break up of a compressed tablet into small granules upon ingestion
What would be the impact of over lubrication? What is typically used as a lubricant?
Magnesium stearate is a common lubricant. Over lubrication can lead to over coating of the granules with a lipid layer which will protect the tablet from breaking up as required within the body, which in turn will have an impact on bioavailability
Why are broken tablets a problem?
Impact to dissolution / bioavailability and delivery system e.g. if enteric coated - broken tablet would be more susceptible to disintegration in the stomach which may not be the target area
A company want to change the IPC limits for the moisture content of a granulate; what are the implications for the QP?
Is the IPC registered if so this will require a variation
What are the issues around controlling the end point in high shear and low shear granulators.
Granulation endpoint can be defined as the time when the granules reach the desired properties such as granule size distribution, flowability or bulk density, as stipulated by the formulator.
High shear, or very forceful, mixing processes uses high-speed impellers, and low shear mixing processes use flow, turbulence, and rotational force to combined miscible goods.
A high shear mixer has the following disadvantages:
It may cause degradation of powder, especially for fragile or thermolabile powders.
Over wetting may cause the production of large lumps.
Produces less compressible granules.
A narrow range of operation conditions.
The main disadvantages low shear granulation are the open nature of the equipment, the manual transfer of the materials being processed and the long drying times.
How could you control the endpoint in a fluidised bed drier?
The conclusion should be made based on drying temperature, air velocity and drying time. A IPC moisture sample can be taken at endpoint to confirm dryness.
What are the issues in a fluidised bed drier?
While fluid bed dryers are generally more gentle on the product, in some cases the material may experience some attrition and dust generation during fluidization, which could require additional measures in dust and air quality control. It may also make the fluid bed an unsuitable choice in some settings.
Disadvantages of Fluid Bed Dryer. A Possibility of Product Loss. Chances of Electrostatic Build Up May be High. Drying Sticky Material is Quite Difficult.
Poor drying performance: If the fluid bed dryers (FBD) is not drying the material properly, it may be due to insufficient air flow or an incorrect temperature profile. Check that the air flow rate is within the recommended range and that the temperature profile is appropriate for the material being dried.
What factors affect the bioavailability of active from solid dosage form?
Correct composition, homogenous mix, blending time, Coating, broken tablets
Describe the manufacture of a wet granulated tablet.
Dispensing, binder make up and addition, granulation, screening, drying, lubricant addition and blending, compression, coating, bulk packing
What is “capping” and what causes it?
The term tablet capping is used when either the upper or lower part of the tablet separates horizontally either partially away from the main body or completely to form a cap when ejected from the press or during the handling process.
Excessive turret speeds, rapid decompression, and elevated pressure force can cause it.
Name a source of information on tablet ingredients
Patient information leaflet
What is the greatest risk of (bacterial) contamination in a tablet?
Water content, raw materials e.g. maize starch, binder solutions, hold times
In terms of a dry compaction process for making tablets – what tests would you typically do as in process controls?
Hardness, thickness, weight, friability, disintegration
What grade of water would you use in wet granulation?
Purified water
What are the CPPs and CQAs for a typical tablet process?
CPPs Drying temp, Milling speed and screen size, Blending speed and time, tablet weight and hardness, press speed, coating air temp and flow rate.
CQAs content uniformity, granulate moisture content, particle size of milled dried granulation, blend uniformity, assay, dissolution, content uniformity, appearance
Typical tablet QC tests
Dose uniformity
Dissolution
Assay
Water content
Uniformity of content
average weight
active agent
Talk through a standard tabletting process and what IPC are required?
Dispensing, granulation, compression, coating, bulk packing
Weight (20 tablets)
Disintegration
Friability
Hardness
Thickness
What about tablet coatings?
CPPs
Solution viscosity
Spray width
Spray rate
Distance of gun from tablet bed
Atomising air pressure and volume
Exhaust temperature
Temperature, humidity and volume of drying air
IPCs:
Appearance
Weight gain (gross weight of 20 tablet – 2-3% 60% for sugar-coated)
What are the 3 most critical factors for drug absorption from a solid dosage form?
Tablet hardness, tablet coating, granule size. pH at site of dissolution
Your micro department informs you that they have discovered a trend of Micrococcus luteus
and Bacillus subtilis in the tablet compression room of your grade D facility. What are your
concerns?
What type of micro are these?
Are they pathogenic?
Where is guidance found on clean rooms?
Was originally above alert level, but now above action level Trend: therefore not above specs.
What action would you take?
Micrococcus most likely source humans, Bacillus can be equipment, materials and water, air or facility.
Both are non-pathogenic - incapable of causing disease
Where is guidance found on clean rooms? EU GMP Chapter 3 - premise and equipment, chapter 5 - production, ISO14644 validation of
Where is guidance found on micro for tablets? Pharmacopeia
How long has it been going on? When was it first identified? What else may have happened at that time (materials, process, people, micro lab analysis, was an OOT raised/investigated?)
Start OOT and investigate the above. Identify possible root causes to take corrective/preventive action. Check batches manufactured/being manufactured (extent), check historical data, assess impact on patient safety and product quality/reg status. Assess stability concerns of any affected batches (extrapolate, dry product, minimal risk for exceeding micro spec at end of shelf life, but needs to be considered).
What is Uniformity of Dosage Units and where is it applied?
PhEur 2.9.40
Degree of uniformity of the API in the dosage units
2 ways: Content Uniformity (CU) or Mass Variation (MV)
CU applies to all forms (excluded multi vitamin, single vitamin and trace element preparations)
MV applies when API ≥ 25mg AND ≥ 25% in the formulation
CU
Collect 30 dosage units
Assay 10 individually
Calculate the acceptance value, must be ≤ L1 (15)
MV
Assay active on a representative sample of batch (% label claim)
Collect 30 units
Weigh individually 10 units
Calculate active in each unit from assay above and weight determined
Calculate acceptance value must be ≤ L1 (= 15)
If there are deviations PhEur allows for L2 value (utilising all 30 units)
OSD formulation
Lubricant – lubricates granules, prevents sticking in press – magnesium stearate, HVO
Glidant – helps granules ‘glide’ & improves flow char. by preventing friction – silicon dioxide
Bulking agent/Diluent – adds bulk to the formulation, increases patient compliance – lactose, MCC, mannitol
Binding agent – binds the formulation together, adds mechanical strength – maize starch, povidone
Disintegrant - aids breakdown of the tablet, swell when wet – MCC, HPC, Starch
Surfactant/Wetting Agent – aids with solubility/assist dissolution – SLS, polysorbates
Others – Colours, Sweeteners, Coating, Printing Inks, WATER
Tablet coatings
Sugar – to disguise taste
Film – Cosmetic – to make tablets easier to swallow, taste masking, ID, easier handling in packaging
Functional:
Stabilising – protective coating, e.g. to protect against moisture/light
Modify release – to control the release of the product, usually over a longer time period or to target a specific area.
Patient compliance: get drug/plasma levels more constant.
Reduce dose frequency reduce side effects
Risk of dose dumping if anything in stomach reacts with coating & all drug is released (e.g. Alcohol).
EXTENDED/SUSTAINED/CONTROLLED/ DELAYED release
Delayed release - e.g. enteric coating, protects tablet from acid in stomach (for products which are easily hydrolysed).
