Manufacturing Flashcards
Packaging, Mixing, Comminution, Drying, Quality control, quality assurance (116 cards)
1
Q
Packaging definition?
A
Packaging is defined as the collection of different components (packs) which surround the pharmaceutical product from the time of production until its use.
2
Q
Pack definition?
A
The pack is necessary for:
- providing life-saving drugs i.e. guarantee stability of the drug
delivering medicines to patients in every imaginable dosage form
e.g. liquid, solid, suspension, drops
3
Q
Function of a pack?
A
Containment: the packaging should be designed considering the needs of the product, the manufacturing and the distribution;
Protection: the packaging must protect the product against all adverse external influences e.g. light, moisture, mechanical damage, biological contamination;
Presentation and information: the packaging is essential to show and inform the patient;
Identification, the packaging identity the product;
Convenience, the packaging facilitate the use or administration of the product.
4
Q
Pack requirements?
A
Easy to dispose, and preferably:
- -> Made from renewable resources;
- -> Be recycled, or reused;
- -> Reduce pollution (and waste products).
5
Q
Packaging and quality control considerations on the product side:
A
- Quality Control (QC) department tests product-pack during manufacturing;
- Quality Assurance (QA) provides all the documents and records related to the product, e.g. starting materials, production, stability.
6
Q
Packaging and quality control considerations on the sack side:
A
Package QC is not only performed on the final pack-product combination, BUT also on all the packs used for intermediate products.
7
Q
Who are the regulatory bodies for packaging and what do they guarantee?
A
- US, Food & Drug Administration (FDA)
- Europe, European Medicine agency (EMA)
- UK, Medicine & Healthcare Regulatory Agency (MHRA)
Regulatory bodies guarantee that a pack is:
- -> Safe
- -> Efficacious
- -> Perform to the guidelines
8
Q
Packaging materials requirements:
A
Inert –> the pack material in contact with the formulation MUST be chemically inactive. This is necessary to preserve the physical and chemical properties of the medicine.
Protect –> the packaging material should guarantee the physical protection and prevent mechanical damages to the medicine, e.g. fracture, cracks.
9
Q
How is glass produced?
A
Produced by heating silica, calcium carbonate and sodium carbonate
10
Q
Classification of different types of glass?
A
Type I: borosilicate neutral glass – best pharamceutical grade and most inert glass;
Type II: soda lime glass, sulfur dioxide treated surfaces to reduce glass components leaching to the pharmaceutical product;
Type III: soda lime glass, produced to contain large volumes (reduce the surface-to-volume ratio = minimise leaching);
11
Q
What is Oxygen Transmission Rate?
A
Plastic is a gas permeable material: level of oxygen influx can be calculated accordingly to the packaging polymer used.
12
Q
What are laminates?
A
A laminate is a composite material;
- Laminates are made by layers of different materials, such as paper, plastic and metal;
- Laminates combine different properties in a single packaging material.
- The main advantages of laminates combining aluminium and plastic are:
- -> Mechanical strength;
- -> Light protection;
- ->Moisture protection.
13
Q
Paper as a packaging material advantages and disadvantages?
A
Known as one of the oldest pharmaceutical packing, its use is mainly for the secondary pack, as in labels, leaflets, and cartons.
Advantages:
- Low cost and readily available;
- Non-toxic;
- Easily recicled;
- Easily printed.
Disadvantages:
- No barrier properties against moisture, gases and odours;
- Moisture sensitive;
- Poor transparency.
14
Q
There are different sub-sets of packaging embedded with electronic functionality, these are:
A
1) Smart packaging: Any packaging that serves a purpose other than containment and protection.
2) Active packaging: Packaging that actively improves the product or its potential use e.g. inhaler
3) Intelligent packaging: A packaging system that transmits or gathers data or information about the product.
15
Q
What are positive mixtures?
A
Components mix spontaneously and irreversibly by diffusion (almost perfect mix achieved) e.g. miscible liquids.
- -> No issues in manufacturing processes.
- -> No energy required IF unlimited mixing time.
- ->Input energy required to shorten the mixing time.
16
Q
What are negative mixtures?
A
Components that tend to separate and need a constant input energy to maintain the desired dispersion e.g. suspension of solid particles in low viscosity solution.
17
Q
What are neutral mixtures?
A
The components have no tendency either to mix or to separate spontaneously.
It is possible to separate the mixture, but energy is required
18
Q
What is a random mixture?
A
the components are perfectly mixed, hence the probability of selecting o type of particle is the same in all the positions in the mixture
19
Q
What is ordered mixing?
A
- Components are not independent of each other, resulting in a “spontaneous” degree of order in the mix
- It is driven by interactions and cohesive/adhesive forces between components
20
Q
Why is mixing important?
A
- Ensure the quality of pharmaceutical products
- Provide even distribution of active component(s) and other ingredients
- Guarantee drug(s) release with the desired rate(s)
- Give even appearance to dosage forms:
- -> Mixture of solids: tablet, capsule, dry powder, etc.
- -> Mixture of liquids: emulsion, cream, etc.
- ->Dispersion of solid particles: paste, suspension
21
Q
What and how is the scale of scrutiny selected? (How to select testing samples/sample size)
A
The scale of scrutiny is the amount of material (in weight or in volume) used to test the QUALITY of a mixture.
The proportion of the active component in the dosage form and in the scale of scrutiny is an important factor to determine the quality of a formulation
- -> The lower concentration of active drug in the mixture
- -> The bigger Scale of scrutiny is used
22
Q
Importance of particle size in mixing:
A
Particle size of the drug (API) and other excipients (powder form) in the formulation influences:
- Physical performances of the medicine
- Pharmacological effects of the drug
Powders might possess variations in particle size distribution
23
Q
Segregation is mainly caused by particles differing in:
A
size, shape, density, and surface properties.
24
Q
How do size, shape and density exactly influence segregation?
A
Particle size effects:
- Smaller particles tend to fall through the voids between larger particles
Particle density effects:
- The denser particles tend to move downwards (gravity). IF particles are denser and smaller, the segregation is higher
Particle shape effects:
- Spherical particles are easier to mix, hence segregate more easily than non-spherical particles
- Non-spherical particles have greater surface area to weight ratio: increase cohesive effects
25
How does segregation occur between manufacturing processes?
Vibration, mechanical forces, gravity
26
How does segregation occur in an ordered mixture?
This happens when:
- Coarse particles differ in size
- Active sites on coarse particles surface compete with other materials than the fine particles
- Coarse particles are not sufficient to interact with the finer ones
- External mechanical forces (e.g. vibration) reduce the surface attraction energy
27
The 3 mechanisms of mixing powders?
Convection: macroscopic mixing, relatively quick (extended mixing time is necessary to achieve random mix)
Transfer of large group of particles through the powder bed
Shear: interface mixing
Flows of one ‘layer of material over another ‘layer’, resulting in moving layers at different speeds
Diffusion: allows the movement of individual particles to achieve a true random mix.
Powder bed forced to move: the movement generates space between particles
28
Tumbling mixers?
- Mix blending granules or free-flowing powders
- Have many different designs
- Might have intermediate containers e.g. feeder for a tablet machine
- Generally rotate about an axis with controlled speed
- Typical powder weight used range from 50g to 100kg
- For best performance, the powder mixture should occupy from ½ to ⅔ of the mixer volume
- Generally used in the blending of excipients prior tableting
- With a correct speed set, shear mixing will occur. With movement the powder dilates, allowing particles to move under gravitational force: diffusive mixing occurs
29
Mixing of liquids and suspensions:
The same applies to suspensions, with increasing viscosity the mixing:
- Is more “difficult” and take more time
- But, particle sedimentation rate is reduced, hence the suspension is more homogeneous
30
Methods of mixing liquids:
- Bulk transport: quick degree of mixing
Movement of large amount of material within the mix
- Turbulent mixing: highly effective mixing mechanism, volumes forced to move
Constant change in speed and direction; still part move together leaving unmixed volumes
- Molecular diffusion: slow diffusion across concentration gradients
31
Mixing of liquids and suspensions: What are propeller mixers?
Angle blades to promote fluid movement in both axial and radial direction
Formation of vortex (centrifugal forces) is suppressed by:
- Offset angle mounting (A)
- Vertical baffles (B)
32
Mixing of semi-solids: What are planetary mixers?
- Flowing issues compare to fluids
- High viscous fluids are mixed using the same mixers as semi-solids
- High risk of “dead spot” with non-mixed materials
- Mixers must produce high shear mixing: diffusion mixing cannot occur
33
How to estimate the variation of the content of a component with respect to the ideal proportion (p, calculated in the total mixture), knowing the sample size (n):
Two are parameters used to describe the variation:
- Standard deviation, SD
- Percentage coefficient of variation, %CV
34
What is the mixing index?
Compares the content standard deviation from a samples under investigation (SACT) with the one of a fully random mix sample (SR):
The simplest form is M=SR/SACT
35
Advantage of combining two manufacturing processes in one piece of equipment:(mix and granulate)
No need to transfer the product between processes (reducing segregation associated risks)
36
How to minimise segregation?
- Similar size of drug and excipients (better with narrow size distribution)
- Use size smaller than 30 um to reduce segregation (but it might cause aggregation)
- Control the shape
- Select components with similar densities
- Granulate the mixture
- Reduce mechanical stresses (e.g. vibration) during the transport between manufacturing processes
- Use equipment for multiple operations e.g. high-speed mixer/granulator for mixing and granulation
- Use of ordered mixtures
37
Definition of moisture content:
The amount of water contained in a material
%Moisture by volume (MV) is defined as the molecules of water per unit volume by the total number of molecules per unit volume
In case of air, it can be defined as kg of contained water per kg of dry air (water free)
38
Relative humidity definiton:
Humidity is referred as the amount of water vapour present in the air
--> Relative Humidity (RH), indicates the amount of moisture in the air as a percentage of the maximum amount of moisture that the air can hold (at a specified temperature)
39
The lower the temperature, the higher is the amount of water vapour that can be held. True or false?
False - the LOWER the temp the higher is the amount of water vapour that can be held
40
What is the drying process?
- It is (generally) the last and more critical operation in manufacturing pharmaceutical ingredients:
- Drying before packaging ensures quality performances in terms of material processing (intermediate materials, e.g. flowability) and product stability (final product)
- During manufacturing drying is essential to guarantee process performances e.g. granulation, compaction
41
During drying, moisture content AND temperature can vary due to:
- Evaporation of water from the material to the drying air
| - Cooling of drying air to reduce heat-exchange with the material
42
What is total moisture?
Total moisture is the total amount of water (or liquid phase) associated with a wet solid
TOTAL = FREE + EQUILIBRIUM
43
What is free moisture content?
the amount of water that can be easily removed e.g. evaporation (aka unbound water)
44
What is equilibrium moisture content?
The portion of water that is more difficult to be removed
Also known as bound water
Once unbound water is removed, the remaining moisture is in equilibrium with the moisture in the air
45
What is solute migration?
- Movement of solution in a wet system during drying
| - The solute is transported towards the surface, being left where the solvent evaporates
46
Within solute migration, what are Inter-granular and intragranular migration?
- Inter-granular migration: the solute moves between granules towards the surface
Differences in solute composition between granules
- Intra-granular migration: granules are separated during the process
Even distribution of solute within a granule
47
Inhomogeneity between granules impact on quality aspects. Which ones?
- Manufacturing
- Appearance
- Dose
48
Which factors can be considered to reduce solute migration phenomena?
- Initial moisture content
- Slow convective drying
- Drying with microwave radiation
- Dynamic drying methods
49
Factors to be considered with regards to the drying process?
- Heat sensitivity of materials used
- Materials physical characteristics
- Solvent/liquid to be removed e.g. boiling point
- Efficient mass transfer of evaporated liquid
- Efficient vapour removal from drying air
- Amount of material to be processed e.g. scale-up considerations
- Sterility
50
Convection as a drying process uses:
A fluidised bed dryer:
- Optimised contact between warm drying air and wet powders/particles
- Increase in air velocity will induce a pressure drop with powders/particles suspended in the air
Frictional drag equal to gravitational force (Stokes’ Law)
Further increase will cause particle free move
51
Such turbulence in a fluidised bed dryer induces:
- Particle mixing with good contact with air
- Maximised surface area of the powder bed
- Efficient heat and mass transfer
- -->Reduced drying time
- -->Good vapour removal
52
Advantages of using a fluidised bed dryer:
- Efficient heat transfer (minimise effects on thermo-sensitive materials)
- Homogeneous process:
- Free movement of particles reduces migration process and separation/aggregation phenomena
53
Disadvantages of using a fluidised bed dryer:
- Turbulence might damage granules
- Small particles might need specific attention to be removed from the fluidizing air
- Particle movement in turbulence and warm environment might cause charges of static electricity
(adequate electrical grounding is essential)
54
Vacuum oven as a method of drying a solid:
- Large area for heat conduction (direct contact between hot surface and material)
- Airtight seal to control the drying air
- --->Vacuum pump to bring operating pressure to 0.03-0.06 bar (low air content minimises risk of oxidation)
- ---->Temperature between 25-35°C are sufficient to boil water (convenient for thermo-sensitive materials)
- Generally used for small-scale processes e.g. development laboratories
55
Microwave radiation as a method of drying a solid:
- Microwave penetration in wet material generate uniform heat
- Better results are obtained with ‘small’ polar molecules
- --->Loss factor is defined as ratio of absorbed microwave energy to the provided energy: higher values return better performances for heat generation
- --->Different solvents have different loss factor, which is the result of their electronic molecular structure
56
Advantages of using microwave radiation drying technique:
- Rapid dry at controlled temperatures
- Energy absorbed in the wet material, not in the air
- Stationary conditions decreases small particles movement
- Uniform heating reduces solute migration effect
57
Disadvantages of using microwave radiation drying technique:
- Small batch size
| - Shielding from radiation is essential
58
What is a spray dryer?
- Fabrication of particles and drying in a single process
- Small droplets provide a larger surface area: beneficial for heat exchange and mass transfer
- Circulating air used to dry each individual particle
59
How is final particle size determined?
- By the initial droplet volume
60
Several atomizers have been developed to optimise:
--->droplet size (1-500 μm),
--->jet stream (uniformity),
--->solution feed rate (up to 100 L/hour),
etc.
61
Different types of atomisers:
- Solid-stream jet atomizer
- Solid-stream shaped orifice
- Rotary atomizer
- Two-fluid nozzle
Note - higher flow rate = smaller droplets
- Gas flow promotes the formation of smaller droplets.
62
What is freeze drying?
Low drying temperature making this process:
- -> Suitable for heat-sensitive materials
- ->Able to minimise chemical decomposition and enzymatic activity
- Obtained products are porous , with faster solubility due to larger surface area
- High-vacuum conditions minimise the contact with air, hence oxidation in reduced
63
Process steps of freeze drying:
- Freezing: Freezing temperature are well below the normal freezing point of water
- -->The presence of solute(s) shifts the phase diagram
- Vacuum: Pressure is reduced below the triple point
- Sublimation: Ice is transformed to vapour at the frozen surface
- ->Surface area and sublimation time should be evaluated to optimized the drying process
- ->Primary drying: Porous dry product with about 0.5% moisture
- ->(Secondary drying): happens at higher temperature (50-60°C)
- Packaging: necessary step to protect the product from air moisture
64
What is the dew point?
- Related to the quantity of moisture in the air
the temperature to which moisture condense and evaporate at the same rate (equivalent to 100%RH or saturated with water vapour)
- When the dew point is reached, and the temperature further cooled, the water vapour will condense (RH cannot exceed 100%!)
65
Particle size: definition
“The size of particulate solids is important in achieving optimum formulation and production of efficacious medicines.”
66
Importance of particle size?
Particle size of the drug (API) and other excipients (powder form) in the formulation influences:
- -> Physical performances of the medicine e.g. dissolution rate
- -> Pharmacological effects of the drug
- -> Accumulation of micro-particulates after parenteral administration
- --> Influences manufacturing steps
67
Particle size: dimensions
Equivalent sphere: reduce the three-dimensionality to a single number (simplify QC)
- Equivalent sphere diameter (or equivalent diameter
- Several methods can be used to determine the equivalent sphere diameter, based on:
--> Volume
--> Surface
-->Sieve aperture
-->Sedimentation characteristics
Etc.
68
Classification of pharmaceutical powders:
- Coarse powder >350 μm
- Medium/fine powder 100-350 μm
- Fine powder 50-100 μm
- Very fine powder 10-50 μm
- Micronised powder <10 μm
69
Particle size analysis methods?
- Sieve method
- Microscope method
- Sedimentation method
- Laser diffraction
70
Ideal particle size distribution?
- Ideal monodispersed particle population consists of spheres (or equivalent spheres) of the same diameter
- Most powders contain particles with a range of different equivalent diameters i.e. polydispersed or heterodispersed.
71
Importance of meal particle size:
- A single number cannot represent (or fully describe) the size distribution of a powder
BUT: to keep things simple, it is necessary to use one value to describe the powder sample
- Median or Mode can be used to represent the tendency of the sample/batch
- The mean diameter is more informative
72
What is communition?
Comminution is the reduction of solid materials from one mean particle size to a smaller mean particle size
The size reduction process break down particles in different size ranges, the process depends on properties (physical, mechanical) of the material
73
What do smaller particles influence?
- Mixing of different solid powders (solid dose forms)
| - Production of suspensions (liquid dose forms)
74
Size reduction: considerations:
When particle size is reduced to about 1-5 μm:
- Particle-to-particle forces predominates comminution stresses
- Particle agglomeration might happen with an increase of the average particle size
75
What does the cutting method involve?
- Series on knives/blades on a rotor
- Fracture of particles occurs during milling between knives/blades
- A screen acts to retain material larger than a specified size
- Coarse degree of size reduction in dried granules due to high shear rates
76
Roller mill compression method?
- The material is compressed by frictional forces as it pass between rollers
- ->One roll is mechanically driven, the other rotated by force transmission
- ->Series of rolls can be included to obtain smaller particles
77
Vibration mill method?
- Filled up to 80% total volume with porcelain or stainless steel balls (A) or 50-70% (B);
- The speed of rotation is an important factor (see video);
- Vibrating body of the mill (B): size reduction occurs by repeated impact and attrition;
- A screen at the base of the mill allows particles to exit;
The efficiency of vibratory milling (B) is greater than that for conventional ball milling (A).
78
Different methods of sieving?
- Agitation methods (A): oscillation, mechanical vibration, gyration (most efficient)
- Brushing methods (B): a brush orientate particles and prevent blocking of the sieve surface. It is fundamental that the brush does not force particles through the sieve.
- Centrifugal methods (C): a high speed rotor generate are flow that pushes bigger particles outwards, while fine powders are processed
79
How is size separation efficiency measured?
Separation efficiency is determined as a function of the effectiveness of a given process in separating particles into oversize (fO) and undersize (fU) fractions.
80
What does sieving do?
- Common method to analyse particle size;
- It sorts a large quantity of particles into different size ranges and determine the particle size distribution based on the mass collected in each range;
- Simpler and cost effective method than microscopy, but does not provide any particle shape information (classified as particle size analysis process);
- Offline analytical tool, and tends to be less accurate with non-spherical particles (due to their orientation during vibration).
81
Microscope method as a particle size analysis method?
- Perhaps the most obvious and accurate method for determining the particle size and shape characteristics of a small sample;
- Operator time required to analyse a sufficient number of particles to be representative is prohibitive;
- Offline method of particle characterisation with very limited throughput which may make it unsuitable for a number of applications.
82
Laser diffraction as a particle size analysis method?
- Fully automated and in-line method of measuring the particle size distribution;
- Size distribution of particles is calculated using angle of diffraction principle (light is inversely proportional to the particle size);
- Theoretically an extremely accurate method, however results are poorly reproducible between different detection systems;
- Only particle size can be measured (as for sieve analysis);
- Another limit resides to the models used to calculated particle size, which are based on the hypothesis that measured particles are perfect spheres.
83
Considerations about material properties: which are influencing the final size?
- Crack propagation
- Surface hardness
- Energy requirements
84
What is crack propagation?
- Localised stresses produce strains in the particles to cause rupture and crack propagation
- Not all the materials possess brittle behaviour e.g. plastic materials resist better to stresses
85
Name of scale that measures hardness? (qualitative)
Moh's scale (qualitative)
86
Name of scale that measures hardness? (quantitative)
Brinell or Vickers
87
Definition of quality?
Manufacturing: "Strict and consistent adherence to measurable and verifiable standards to achieve uniformity of output that satisfies specific customer or user requirements."
ISO: the totality of features and characteristics of a product or service that bears its ability to satisfy stated or implied needs
88
Definition of pharmaceutical quality?
“ The term quality control refers to the procedures undertaken to ensure the identity and purity of a particular pharmaceutical. Such procedures may range from simple chemical experiments e.g. screening for the presence of particular pharmaceutical substance, to more complicated requirements of pharmacopoeial monographs."
89
Quality assurance is:
a wide range concept covering all matters that influence the quality of a pharmaceutical product
90
Good manufacturing practice:
GMP ensures that pharmaceutical products are produced and controlled to meet appropriate quality standards
91
Quality control:
A process dedicated to sample, test and specify materials at each level of manufacturing.
It determines if materials/products met the requirements
92
Pharmaceutical products must meet the following specifications:
- Identity: existence of API(s) indicated on the label;
- Purity: no harmful contaminants, no cross-contamination;
- Strength or potency: API(s) content range [90-110], ensuring long shelf life;
- Uniformity of the dosage form in: consistency, colour, shape, size of tablets/capsules, etc.;
- Bioavailability: speed and completeness with which the pharmaceutical enter the bloodstream;
- Stability: the medicine should retain its properties until the expiration date.
93
Importance of quality control?
Ensures:
- Correct and correctly dosed ingredients
- Correct labels with: instructions, expiration date, ingredients,
- Number of items per pack
- Packaging requirements
94
Quality control department-->
- Raw materials have to meet the appropriate specifications;
- Partial/intermediate products are tested (in-line tests) and need to meet criteria
Feedback on manufacturing processes, e.g. adjust parameters;
- Finished pharmaceutical products are tested to determine if the requirements are met.
- Suitable packaging specifications are issued (pack-product requirements);
- Stability tests are performed to determine product’s shelf-life and storage conditions
95
Who is testing the products? (quality control)
- Quality is tested by the manufacturer’s Quality Control department,
- Quality of products must be checked also by other authorities e.g. British Pharmacopoeia
- Product specifications are assessed by the government regulatory agency
(Monographs can be used to provide information about the quality of the medicinal product.)
96
```
Analytical testing:
Definition of
--> Specificity
--> Sensitivity
--> accuracy
--> Repeatability:
--> Intermediate precision:
--> Reproducibility:
--> Acceptance criteria
```
- Specificity: the ability to register only the desired analyte, while all other components in the formulation do not influence the results.
- Sensitivity: the smallest absolute amount of change in analyse that can be detected by a measurement.
- Accuracy: the sense of trueness and precision.
- Repeatability:
-->Minimum of 9 determinations e.g. 3 concentrations x 3 replicates each
-->Minimum of 6 determinations at 100% of the test concentration
Intermediate precision:
Evaluate the effects of random events on the precision of the analytical method/procedure
- Reproducibility:
The same analytical method/procedure should be validated inter-laboratory
- Acceptance criteria
Numerical limits, ranges or other criteria defined for each test/instrument.
97
Acceptance criteria API?
In the case of API these values have a narrow range for acceptance:
- API content ±10% of target value, with accepted 5% standard deviation
- API content after stability tests 90-100% of target value
- Acceptance range varies with the method used
98
Detection limit=
lowest amount detected in analytical testing
99
Quantitation limit=
lowest amount quantitated in analytical testing
100
Documenting requirements for QC:
A document should be prepared for each batch of a substance or product and usually contains the following information:
- Registration number of the sample (batch number)
- Date of receipt
- Name and address of the laboratory testing the sample
- Name and address of the originator of the request for analysis
- Name, description, and batch number of the sample (where appropriate)
- Name and address of the original manufacturer
- Reference to the specification used for testing the sample
- Results of all tests performed (mean and standard deviation, if applicable) with the prescribed limits
- Conclusion as whether or not the sample was found to be within the limits of the specification
- Expiry date or retest date, if applicable
- Date on which the test(s) was (were) completed
- Signature of the head of laboratory or other authorised person
101
What are counterfeit medicines?
Counterfeit medicine is fake medicine. It may be contaminated or contain the wrong or no active ingredient. They could have the right active ingredient but at the wrong dose. Counterfeit drugs are illegal and may be harmful to your health.
102
Quality control definition:
Quality Control is the part of the quality management that aims at DETECTING product defects, monitoring the manufacturing products
103
Quality Assurance definition:
is the part of the quality management that aims at PREVENTING product defects, monitoring the manufacturing process
104
What is Tableting and Quality Assurance?
It focuses on appearance of the tablet e.g. shape, dimensions, colour, engraving;
- Composition e.g. excipients, total mass, coating thickness;
- Properties of the tablet e.g. mechanical strength, disintegration, no capping/layering;
- Properties of the drug product e.g. package, label, leaflet.
105
Main purpose of quality assurance?
The main purpose of quality assurance (QA) in pharmaceutical industry is to ensure that the manufacturing process produces a safe, effective and of acceptable quality medicine.
106
The main aspects covered by GMP are:
- Buildings and Surrounding - Areas
- Equipment
- Cleanliness and Hygiene
- Production Procedures and documentation
- Quality Control
- Records
- Transportation
- Verification of Procedures
107
GMP requirements:
All manufacturing processes should be clearly defined;
All necessary facilities are provided including:
- appropriately trained personnel
- adequate premises and space
- suitable equipment and services
- correct materials, containers and labels
- approved process/procedures (including cleaning)
- suitable storage and transport;
- Procedures (Standard Operating Procedures, SOPs) are written in a clear unambiguous language and are specifically applicable to the provided facilities
- Records, retained in a legible and accessible form
108
What guide is used to regulate manufacturing and packaging operations in the pharmaceutical industry.
The Orange Guide:
- The Orange Guide collates European and UK guidance documents and information on legislation relating to the manufacture and distribution of medicines for human use in one convenient and authoritative source.
The 1998 Edition of the Orange Guide* includes 9 key elements of GMP
109
GMP: the ten principles?
1) Make sure you have the correct written instructions before any task is started.
2) Always follow instructions precisely. Do not cut corners. If in doubt, ask.
3) Ensure that the correct materials are being used.
4) Ensure that the correct equipment is being used, and check that it is clean.
5) Prevent contamination and mix-up.
6) Always be on your guard for labeling errors.
7) Work accurately and precisely: always check that the equipment and the materials are the ones stated in the procedure.
8) Keep everything clean and tidy (including yourself!).
9) Always be on the look out for mistakes, defects and unusual events. Report them immediately (“covering up” could cost lives!).
10) Make clear accurate records of what was done and the checks carried out
110
The four GMP components?
- Personal
- Permises/equipment
- Hygiene
- Validation
111
Good laboratory practice (GLP)
- Standards and protocols are intended to regulate toxicological studies, but they also include standards for controlling identity, purity, stability, strength and storage of products tested.
Records, documents, batch records of materials and animal used are also essential!
- GLP introduces regulation to cover non-clinical safety studies, promoting Quality and Validity of test data.
112
GLP helps scientists to obtain results which are:
Reliable;
Repeatable;
Auditable;
Recognised by scientists worldwide.
113
What are SOP's?
Protocols and Written standard operating procedures (SOPs) describing the main steps of research studies e.g. the study plan, protocol.
Laboratories need to standardise techniques/methods to facilitate comparison of results (note: written SOPs are an invaluable tool).
114
Drug development and Good clinical practice (GCP)?
GCP is defined as: “A standard for the design, conduct, performance monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.”
- GCP ensures the validity of clinical trial data
- GCP covers the design, conduct, recording and reporting of clinical trials.
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What is a clinical trial?
A clinical trial (CT) is a systematic investigation in human subjects for evaluating the safety and efficacy of any new drug.
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The different phases in a drug trial?
Phase 0: exploratory studies, micro dose administration
Phase I: safety, tolerability, pharmacokinetic/dynamics, dose/response
Phase II: dosing, efficacy
Phase III: efficacy compared to gold standard treatment
Phase IV: post-marketing surveillance, pharmacovigilance
