L2 Flashcards
What are the three phases of Pharmaceutical Product Quality? (Hint: Quality by _____)
1st Phase (before 1880): Quality by Appearance (QbA) 2nd Phase (1880-1960): Quality by Testing (QbT) 3rd Phase (post 1960): Quality by Design (QbD)
What are the 3 limitations of conventional product testing?
- You test only on a “representative” sample size
- You can test only if you know the analyte and you have the test method
- You can test only if the test method is specific, accurate & reliable, ie it is validated
What are the 3 limitations of (conventional) batch sterility testing?
Then, how do we overcome the limitations of conventional batch sterility testing?
Three limitations of Batch Sterility Test:
- There is a high probability of passing the sterility test, even when contamination level is relatively high.
- Sterility test is not cheap.
- Two weeks incubation period is needed. Sterilised product cannot be released in real time and take up expensive storage space during quarantine.
Hence, due to these limitations, Parametric Release of Autoclaved/Terminally Sterilised LVPs is useful, where the release of a batch of injectables based on Critical Process Parameters of sterilisation process which has been rigorously validated
Parametric Release: Release is based on key parameters of a validated sterilisation process, instead of the results of batch sterility test
- Key Parameters: Temperature, Pressure, Sterilisation Time/Cycle, Bioburden of Pre-sterilized parenteral product (e.g. SAL or Sterility Assurance Level of < 10^ -6)
What is the solution that tackles the limitations of conventional batch sterility testing?
Parametric release
- Release of a batch of product based on key / critical process parameters (CCPs) of a validated sterilization process, instead of results of batch sterility test.
CCPs may include:
- Temperature
- Pressure
- Sterilisation Cycle/Time
- Bioburden of the presterilised product
Parametric release is release based on ___(A)___ of a ___(B)___ sterilization process, instead of results of ___(C)___
(A) Critical Process Parameters (CCP) / Key parameters
(B) validated (SAL <= 10^-6)
(C) Batch Sterility Test
What are the Critical Process Parameters of a sterilization process assessed for parametric release of a parenteral product? (Hint: there are 4)
- Temperature
- Pressure
- Sterilization time / cycle
- Bioburden of pre-sterilised parenteral product
Quality Risk Management (QRM) is a systematic framework to manage quality risk in a stepwise approach. It comprises: 1. 2. 3. 4.
- Risk identification (4M+1P)
- Risk analysis
- Risk reduction
- Risk communication
Who should assure quality medicine?
- The manufacturer (including distributor, advertiser, R&D, QC)
- The regulator (HSA)
How is “Quality” defined?
Fit for purpose
What are intrinsic contaminants? What’s another name for this?
Contaminants present inherently in APIs, excipients & packaging materials used. They are not removed completely.
AKA impurities.
What are Extrinsic contaminants? What’s another name for this?
Contaminants that originates externally.
AKA cross contaminants.
Why do we need to control impurities? (2 reasons)
- Overall therapeutic effect of a medicinal product is not only dependent on its pharmacological properties of API, but also on the toxicity of impurities present.
- Control of impurities is needed for marketing approval.
How are Intrinsic Contaminants controlled?
- Through QC testing of materials and finished product by the manufacturer
(Manufacturer check on quality and purity of APIs) - Through assessment of impurity profile by HSA product reviewers
- Through GMP compliance by the manufacturer
- Through periodic GMP audits by HSA inspectors
How are Extrinsic Contaminants controlled?
- GMP compliance is critical. It is difficult to control via QC testing and HSA assessment!
- Examples of Control through GMP compliance includes:
=> Premises (Environmental) Control
=> Personnnel Control (Proper PPE/Gowning, Personal Hygiene)
=> Equipment control (e.g. Use of clean stainless steel sampling rod, etc.) - Periodic GMP audits by HSA inspectors
What type of manufacturers face increased risk of contamination?
Generic drug manufacturers
Increased operations within a given facility/equipment = increased risk of contamination!
(They often produce a lot of different generic compounds, not just one - in a single facility)
How is product stability demonstrated?
Through Stability Testing Program. (3 types) 1. Real time studies 2. Accelerated studies 3. Continued Stability Studies
What are the 3 types of Stability Testing Programs?
- Real time studies (E.g. For a period of 6 months under controlled storage conditions)
- Accelerated studies (under elevated/stressed conditions)
- Continual stability studies (after granting Manufacturing Approval, MA or Product License, PL)
What are the 4-5 attributes that determine a product’s quality? (Hint: Consider the starting materials & the finished product)
- IDENTITY of starting material
- POTENCY of starting material
- PURITY of finished product
- Critical Quality Attributes (CQA) of finished dosage form, e.g.
- STABILITY
- HOMOGENEITY
Process validation is the means of ensuring and providing ________________ that the manufacturing processes are capable of _______ producing a finished product of required _______.
documentary evidence;
consistently;
quality
What are the 6 major steps involved in Process Validation?
Process Validation: The act of providing documentary evidence that the manufacturing process is capable of consistently producing a finished product of the required quality.
Steps involved in Process Validation:
- Establish Critical Quality Attributes (CQA) of the product
- Identify Critical Processes Parameters (CPP)
- Design Sampling Plan
- Design Testing Plan
- Set Acceptance Criteria
- Perform Statistical Analysis (Intra- & Inter-batch)
- Documentation
Intra-batch analysis is performed to demonstrate _______ of 3 validation batches.
consistency
Inter-batch analysis is performed to demonstrate _______ among the 3 validation batches and pilot batch.
equivalency
A __________ is needed and should be kept by manufacturers to demonstrate that they have conducted process validation.
Validation Protocol
Manufacturers should be getting a Process Capability Index (Cp) of
Cp >=1.3
less than or equal to 63 defects/million tablets
New Approach to Process Validation
Quality by Design (QbD) :
- Identifies Critical Quality Attributes (Identifies what is important for product)
- Extensive process design and qualification (Design the process around whats important)
- Monitoring of critical process parameters (CPP) which can affect CQA
(e. g. temperature, tablet compression speeds) - Continued process verification beyond 3 production batches
Define the Traditional (old) Process Validation
Compare it against the new, modern Process Validation
Traditional (old) process validation consists of achieving:
- 3 Consecutive successful batches
- Revalidation of any changes to critical processes, equipment and materials
vs QbD based newer process validation processes which:
- Continued validation beyond 3 consecutive batches (continuously)
- Identifying the CQA (Critical Quality Attributes) of a product
- Designing Critical Process Parameters (Processes) around the CQA of the product
- Monitoring of the CPPs (e.g. Mixing and Drying Time, Temperature, Tablet Compression Speeds)
What are the three most important quality attributes of a medicinal product?
- Purity
- Stability
- Homogeneity
State some examples of intrinsic contaminants (Impurities) - There are 5
- Process Related
- Drug Related
- Polymorphs
- Stereoisomers
- Impurities from container closure systems and labels
What are the differences between extrinsic and intrinsic contamination?
Extrinsic contaminations are introduced externally, and may
be non-specific (random, unpredictable), while intrinsic contaminations are introduced endogenously within APIs, and may be specific (e.g. Expected Stereoisomers, Polymorphs, Drug-related, impurities from Container Closure systems/labels etc.)
Intrinsic contaminants can be well controlled through
- QC testing of materials by manufacturer
- Assessments of impurity profile by HSA product reviewers
- GMP compliance by Manufacturer
- HSA periodic audits of GMP Compliance by manufacturer
Extrinsic Contaminants are harder to control via QC TESTING and via HSA product review. Therefore, Manufacturer’s compliance to GMP is more crucial for Extrinsic Contaminants. Periodic GMP compliance by inspectors is also important.
Name AND define the 3 most important characteristics of a good quality product (Hint: P,S,H)
Purity : Products must be free from contaminants, impurities which even in small/trace amounts, can be highly toxic
Stability: maintains quality, safety and efficacy THROUGHOUT shelf life. Need to be properly formulated, stored, distributed and handled
Homogeneity (consistency) : Each and every unit of dosage form meets quality specification. This is demonstrated through process validation
- Process validation: The act of providing documentary evidence that the manufacturing process is able to consistency produce a finished product of required quality.
What are the Product Quality Documents submitted to regulators for Manufacturing Approval (MA)?
- Stability Testing Form (Stability)
- Process Validation Form (Homogeneity/Consistency)
(Note: Purity, Stability and Homogeneity is defined as one of the most important attributes in terms of quality for a product)
Name the factors influencing Stability
- Product Related (Formulation, Physicochemical properties, Type of container/packaging materials)
- Environmental (Temperature, moisture, light, physical stress during transportation, IN USE CONTAMINATION)
Define Stability of a pharmaceutical product
Stability is defined as maintaining the quality, safety and efficacy throughout its shelf life, ONLY WHEN IT IS PROPERLY FORMULATED, STORED, DISTRIBUTED AND HANDLED according to its specified conditions.
Quality by Design is the third phase of Product Quality since what year?
Post 1960 and beyond
Designing the sampling plan is one of the steps under Process Validation
Describe how many sample are taken for Blending, milling and Compression Respectively (e.g in the case of tablet production)
Blending: 10 samples taken from top, middle and bottom of blender
Milling: 1 representative sample from the mill
Compression: 6 x 20 tablets collected at 4 equal intervals from compression machines (Total: 120 x 4 = 480 tablets in total)
The dissolution test and results obtained is done for
Inter-batch analysis. Inter-batch analysis is done to demonstrate equivalency among 3 validation batches AND pilot batch
(Explanation: You need to compare EQUIVALENCY)
Note: pilot batch for Clinical Trial Studies
Blend Content Uniformity Test Results is done for
INTRA-batch analysis.
Intra-batch analysis is done to demonstrate consistency of all 3 validation batches within the same batch. Manufacturers should be aiming for a process capability index (Cp) of more than or equal to 1.3 (Cp >= 1.3, or 63 outliers/million)
Note: A ‘batch’ is defined as a specific quantity of product with uniform quality and characteristics within specified limits, produced within one manufacturing order of the same manufacturing cycle
Under Design Testing Plan for Process Validation, what is done?
For Blend Uniformity: Assay content of blended sample
For Compression: test for Hardness, Friability, Thickness, Potency, Disintegration, Dissolution Profile of Tablet Sample
