Purity Stability & Homogeneity Flashcards
What are the three phases of pharmaceutical product quality?
- 1st Phase: Quality by Appearance
- 2nd Phase: Quality by Testing
- 3rd Phase: Quality by design
Name some limitations of Conventional Product Testing
- Test only a “representative” sample
- Can only test if you know the analyte and you have a test method to do so (i.e. can only test for specific impurities)
- You can test only if test method is validated (Specific, accurate, reliable)
Main difference between 3rd phase and 2nd phase of Quality assurance?
In 3rd phase, the Quality assurance of product moved upstream (E.g. control starting materials and the processes)
Name some Disadvantages and limitations of sterility testing?
- High statistical probability of passing sterility test even when contamination level is high
- Expensive
- Requires time (2 weeks) to culture microorganisms (Bacteria/fungi)
- Sterilised product cannot be released in real time (e.g. take up storage space in warehouse as deadweight)
To overcome the limitations of sterility testing, how are sterilised products validated?
Based on Critical Process Parameters in the process of sterilisation, such as:
- Temperature
- Pressure
- Sterilisation Time/Cycle
- Bioburden of starting materials
Annex 20: Quality Risk Management (QRM) comprises of?
- Risk Identification
- Risk Analysis
- Risk Reduction
- Risk Communication
Name some soft skills required of a regulator/inspector, and why are they important
- Confidence
- Assertiveness
- Integrity and impartiality
- Perseverance (Probing Nature)
- Tact & Diplomacy
- Oral Communication & Negotiation Skills
- Report WRiting &Written Communication Skills
- Willing to travel Overseas
The 3 definitions of Quality according to the International Organisation for Standardisation (ISO)?
- Fit for Purpose (for any product)
- Fit for Medicinal Purpose (for a medicinal product)
- Fit for using to treat patients
What does the Quality of a Medicinal Product includes?
- Identity (of starting materials)
- Potency (of starting materials especially API)
- Purity (absence of undesirable matters)
- Pharmaceutical Quality Attributes a.k.a Critical Quality Attributes (CQA) (E.g. viscosity, sterility)
What is a contaminated medicinal product?
Product that contains Undesirable Foreign matters (aka comtaminants), which can be chemical or microbiological.
It may be present in any materials used, and can be introduced at any processes involved to make the product
State the 2 classification of contaminants, and give some examples for each
- Intrinsic contaminant (present inherently) , referred to as impurities, and are often SPECIFIC (e.g. excipients like water)
- Extrinsic contaminants: Anything else that is not intrinsic, and is NON-SPECIFIC (e.g. dust from premises, saliva of production personnel)
Why do we control impurities?
Overall therapeutic effect is also affected by toxicity of impurities present (on top of the pharmacological properties of API)
Name the 5 types of intrinsic impurities that may be present in medicinal products?
- Process-related impurities
- Drug-related impurities
- Polymorphs
- Stereo-isomers
- Impurities from Container-Closure system & labels
Name a few examples and their sources of process-related impurities in API
- Heavy metals from reactor vessels
- Un-reacted API from starting materials
- Residual Solvents
- By-products from chemical reaction
- Residual Reagents and Catalysts from reaction
What are drug-related impurities in API?
Degradation Products (after API has been formed)
Name some examples of impurities from Primary Containers
- From primary containers: e.g. polyethylene, Polyvinyl chloride
- Plasticisers, antioxidants, lubricants (E.g. plastic cap)
- Coating materials (Resinous and polymeric)
How can medicinal product labels act as impurities?
- Adhesive (adhere to product itself)
- Printing ink
- Both may seep through containers and contaminate products
How are Intrinsic contaminants controlled?
- QC testing of materials and finished product by manufacturers
- Impurity Profile by HSA Product Reviewers
- GMP Compliance by Manufacturers
- Periodic GMP Audits by HSA Inspectors
What is the best way to control EXTRINSIC contaminants?
- Manufacturer’s Comply to GMP
- Periodic Audits by GMP inspectors to Verify the Compliance
(difficult to control via QC testing due to UNKNOWN contaminants)
Name some sources of extrinsic contaminants, and name some examples of contaminants from each source
- Personnel: Micro-organisms, hair, saliva
- Equipment: Rust, lubricants, leached chemicals, product residues
- Premises: Pests, rodents, insects, cross-contaminants with adjacent Premises, pollutants and extraneous matter
How do we control each source of extrinsic contaminants?
- Personnel: PPE, personal hygiene
- Premises: Controlled environment, partitioned to prevent cross-contamination (such as positive air pressurisation)
- Equipment: Materials of equipment like using clean stainless steel sampling rod to collect samples
The rule of thumb for general assessment of contamination risk
Increased operations within a given facility/piece of equipment = increased risks for contamination
Manufacturers of what kind of drugs pose the highest risk for extrinsic contamination?
Generic Drug manufacturers (due to non-dedicated facilities, and multiple products, which may cross-contaminate)
The 2 main factors that can influence stability of a medicinal product?
- Product-related factors
2. Environmental factors
Name some examples, or some ways in which product-related factors can affect the stability of a medicinal product?
- Formulation of the product
- Physio-chemical properties of drug substances
- Type of container and packaging materials
These can interact with the API, hence affecting its stability
Name some environmental factors that can affect the stability of a medicinal product?
- Temperature
- Moisture
- Light
- Oxygen
- Physical Stress during transportation
- In-use Contamination during Consumption (E.g. enzymes from saliva)
The three types of studies required to test product stability?
- Real time studies (minimally 6 months under appropriate storage conditions) (E.g. Singapore –> Store at 30ºC
- Accelerated studies: subject the product to elevated/stressed condition, such as increasing storage temperature
- Continual stability studies
Reasons for proper storage, distribution and handling of:
- Any medicinal product
- Liquid dosage forms
- Tablets
- Loss of efficacy due to product degradation
- Loss of vehicle (e.g. by evaporation), which can increase API concentration, making doses toxic
- Tablet hardening due to loss of moisture, which changes drug’s physiochemical properties, hence changes in PK
Briefly describe how elevated moisture or relative humidity can contribute to instability?
- Formation of toxic degradation products mainly through hydrolysis (E.g. acetic acid from aspirin)
- Loss of package integrity and label clarity = loss of critical essential info
- Transdermal patches: Loss of adhesion. Patch may drop off = no medication administered
Briefly describe how increased agitation and vibration during transportation can contribute to instability?
Ingress of micro-organisms into product due to hair-line cracks, poor container-closure etc. which may make product unsafe (especially sterile products)
Briefly describe how poor handling of product during use can contribute to instability?
Contamination of product, such as eye-drop, causes drop in micro-biological quality of product, making it unsafe
How is product homogeneity demonstrated?
Process Validation
What is Process Validation?
Ensuring and providing documentary evidence that manufacturing processes are capable of CONSISTENTLY producing a finished product of required quality (usually consecutive three batches of product)
List the Major steps involved in Process Validation
- Establish quality specifications
- Identify critical processes
- Design Sampling Plan
- Design Testing Plan
- Set Acceptance Criteria
- Perform Statistical Analysis
What are some examples of tablet quality specifications?
Blend homogeneity, hardness, thickeness, friability, particle size, dissolution profile
What are some Critical processes and their respective sampling plan?
- Blending: 10 samples taken from top, mid and bottom of blender
- Milling: 1 representative sample drawn from mill (≈100g)
- Compression: 6x20 tabs collected at 4 equal intervals from tablet compression machines, for each of the compression speeds (low, target, high)
Describe the 2 types of statistical analysis
- Intra-Batch analysis: consistency of all 3 validation batches, usually by blend content uniformity test results
- Inter-batch analysis: show equivalency among the 3 validation batches AND the pilot batch (which is used for clinical trial studies), usually by dissolution
Two types of documentation made for Process Validation Studies?
- Validation Protocol (E.g. objectives, scope, personnel responsible) i.e. info about the tests
- Validation Report, i.e. results, with recommendations and conclusions
What is the new approach to process validation?
Quality by Design (QbD), which includes:
- Identifying CQA
- Extensive process design and qualification
- Monitoring CPPs
- Verification beyond 3 production batches (to ensure continuity)
What was the traditional approach to Process Validation?
- Process Validation, and stop after 3 consecutive successful production abtches
- Then Revalidation, only if there were changes to critical processes, equipment and materials
