Lecture 2 Assessing Manufacturer’s Compliance to Product Quality Flashcards
What is the 1st phase of quality prior to 1880?
Quality by appearance based on Compounding Skills of Apothecary (Pharmacist)
- Rounder Pills
- Clearer/Tastier Elixirs
- Smoother/Whiter Creams
What is the 2nd phase of quality from 1880 to 1960?
Quality by Testing
- Product tested at the end of batch manufacturing process
- If product passes test(s), it was deemed to be of good quality
What are the limitations of conventional product testing?
- Only a representative size is tested (due to destructive nature of tests)
- Need to know analyte and the respective test method to test
- Can only test if test method is specific, accurate and reliable , i.e. if it is validated
What is the lesson learnt from the melamine milk scandal?
Test methods need to be specific, accurate and reliable to test for impurity
What is the 3rd phase of quality post 1960?
Quality by design
What does quality by design include? (QA of product moved upstream includes)
- Product Design/Formulation of Dosage Form
- Control of Starting Materials (APIs, Excipients and Containers)
- GMP Compliance by Manufacturers
- Contamination Control, Process Validation and Stability Testing
- Use of Process Analytical Technology (PAT) and Parametric Release
What is Parametric Release?
Parametric Release is the release of a batch of injectable product which has been terminally sterilized, without the need to conduct batch sterility testing
What led to the development of Parametric Release?
Limitations of the Batch sterility testing
- There is a high (statistical) probability of passing Sterility Test, even when contamination level is relatively high
- Sterility testing is not cheap
- 2 weeks of incubation period required for sterility testing
- Sterilized product cannot be released in real time
What is the expected sterilization assurance level for parametric release? (NOT TESTED)
<= 10^-6
What are the critical process parameters (CPP) for parametric release for injectables?
- Temperature
- Pressure
- Sterilization time/cycle
- Bioburden of pre-sterilized parenteral product
What is Quality Risk Management (QRM)?
QRM is a systematic framework to manage quality risk in a stepwise approach comprising risk identification, analysis, reduction and communication.
What is the objective of Quality Risk Management (QRM)?
To assess risks to product quality/patient, and then manage these risks to an acceptable level
What are the steps for Quality Risk Management (QRM)?
- Risk identification
- Risk Analysis
- Risk reduction
- Risk communication
Are clinicians able to assess quality of medicines?
No
Is the distributor and advertiser involved in quality?
Yes
How is quality defined?
Fit for purpose (for any product)
Fit for medicinal purpose (for a medicinal product)
fitness for use for treating patients (who are sick)
SUMMARY
What does quality of a medicinal product include?
- Identity and Potency of ingredients
- Purity (absence of contaminants, including impurities)
- Pharmaceutical Quality Attributes of finished dosage form: stability and homogeneity of finished product
What are the Pharmaceutical quality attributes of finished dosage forms?
- Viscosity, Sterility, Endo-toxin Levels
- pH, Clarity, Color Index, Microbial Limits, Sedimentation Rate
- Hardness, Friability, Particle Size, Dissolution Profile
- Stability, Homogeneity
I think critical quality attributes would be: purity, stability, homogeneity
How is purity assessed?
Absence of impurities/contaminants from product
What are contaminants introduced during manufacturing also known as?
Cross-contaminants
SUMMARY
How are contaminants classified?
Intrinsic Contaminants, often SPECIFIC in nature (aka impurities)
Extrinsic Contaminants, often NON-SPECIFIC in nature (aka cross-contaminants)
What are the types of impurities in APIs? (intrinsic contaminants)
- Process-related (at the end of synthesis reactions)
- Drug related (degradation, after API formed)
- Polymorphs
- Stereoisomers
- Impurities from Container-Closure System (primary containers, the polymer or coating materials) and Labels - impurities may seep through containers and contaminate product
How can intrinsic contaminants (impurities) be controlled?
- QC testing by manufacturer
- Assessments of impurity profile by HSA product reviewers
- GMP compliance by manufacturers
- Periodic GMP audits by HSA inspectors
How can extrinsic contaminants (cross contamination) be introduced?
- Personnel
- Premises
- Equipment
How can extrinsic contaminants (cross contamination) be controlled?
- Manufacturer compliance to GMP
- Periodic audits by GMP inspectors to verify compliance is impt
How should the Premises be controlled to minimize cross contamination?
- controlled environment
- effective partitioning (“closed system” with positive air pressurization)
How should the Personnel be controlled to minimize cross contamination?
- Proper Gowning by Personnel Collecting Samples of Starting Materials
- Observance of Personal Hygiene by Operator
How should the Equipment be controlled to minimize cross contamination?
- Use of Clean Stainless Steel Sampling Rod to Collect Samples
SUMMARY
What is the general rule of thumb for assessing cross contamination risk?
Increased operations within a facility/piece of equipment = increased risk for contamination
single product –> product groups –> multiple products (sharing multi-purpose env, in manufacturing env lacking contamination control)
Pay greatest attention to generic drug manufacturers
SUMMARY
Are contaminated products only found in manufacturers of developing countries?
No, it is a problem with both developing and developed manufacturers
What are the Product quality documents submitted to regulators for market authorization?
- Control of Drug Substances
- Control of Excipients
- Control of Container-Closure System
- Control of Finished Product
- Control of Manufacturing Processes
- Product Development
- Stability Testing
- Process Validation
What are some of the product related factors that can affect stability of a medicinal product?
- Formulation
- Physico-chemical properties of API/excipients
- Type of container and packaging material
What are some of the environmental factors that can affect stability of a medicinal product?
- Temperature
- Moisture
- Light
- Oxygen
- Physical stress during transportation
- In-use contamination during consumption
How can a stability testing program be conducted?
- real time studies
- accelerated studies
- continual stability studies
What is the purpose of a stability testing program?
to establish shelf-life of product when stored, distributed under recommended temperature, pH and other environmental conditions
What is the name of a study conducted under intended market conditions for 6months?
Real-time study
A study was conducted using NaOH, 90% humidity, 45 degrees Celsius. What is the study type?
Accelerated study under elevated/stressed conditions
A study spanning 2 years was conducted for a batch of product that claimed 1 year shelf life after market authorization was granted. What is the study type?
Continual stability study
What is the effect of elevated temperature during storage?
- loss of potency via degradation
- loss of vehicle via evaporation
- hardening of tablet via loss of moisture
What is the effect of elevated humidity/moisture during storage?
- formation of toxic degradation products via hydrolysis
- loss of package integrity and label clarity
- loss of adhesion for transdermal patch
What is the effect of agitation and vibration during transportation?
ingress of microbe/MO into product –>
- poor container-closure integrity/ hair-line cracks
- drop in microbiological quality of product
- unsafe product (if it is intended to be sterile)
What does process validation mean?
Process valdiation is the means of ensuring and providing documentary evidence that the manufacturing processes are capable of consistently producing a finished product of required quality.
- carried out on at least 3 consecutive full scale batches
What are the major steps involved in process validation?
- Establish Tablet Quality Specifications
- Identify Critical Processes: blending, milling, compression
- Design sampling plan
- blending: 10 samples
- milling: 1 representative sample
- compression: ~6x20 tablets - Design Testing plan
blend uniformity
compression - Set acceptance Criteria
- Perform statistical analysis (inter and intra batch) for 3 batches
How can the Process Capability (Cp) be calculated for intra-batch analysis?
Cp = (USL - LSL)/6SD
- USL = upper specification limit
- LSL = lower specification limit
- SD = standard deivation
What is the required Coefficient of Variation (CV aka SD) for inter-batch analysis?
CV (or RSD) among 3 validation batches and pilot batch <= 5%
How is the required Process Capability (Cp) for intra-batch analysis?
Cp >= 1.3 (outliers <= 63ppm)
What is the purpose of intra-batch analysis (part of statistical analysis)?
To demonstrate consistency within each of the 3 validation batches
- performed on blend content uniformity tests results
What is the purpose of inter-batch analysis (part of statistical analysis)?
To demonstrate equivalency among the 3 validation batches + pilot batch (used for clinical studies)
- performed on dissolution test results
What are the essential elements of the validation protocol?
- objectives
- scope
- persons responsible
- critical processes (with manufacturing flow chart)
- list of raw materials and equipment used
- sampling plan
- testing plan
- frequency of sampling/testing
What are the essential elements of the validation report?
- validation test results
- data analysis
- statistical analysis (SPC and Cp, ANOVA)
- recommendations and conclusions
- attachments (batch records, manufacturing flow chart, statistical control graphs, tables and graphs)
SPC - statistical process control
Cp - process capability
ANOVA - analysis of variance
What is the new approach to process validation (adopting quality by design)?
- Extensive Process design and process qualification
- identify critical quality attributes (CQA)
- monitoring of critical process parameters (CPP)
- continued process verification beyond 3 production batches
- assures processes remain continually in a state of control and products manufactured are consistently of good quality
Why is Purity an important quality attribute?
Contaminants and impurities in trace amounts can be highly toxic, rendering a product unsafe and harmful
Why is Stability an important quality attribute?
A stable product maintains its quality, safety and efficacy throughout its shelf life
Why is Homogeneity an important quality attribute?
A homogeneous product means that each and every unit of dosage form meets quality specification.
How can Homogenity (consistency) be demonstrated?
Homogeneity is demonstrated through process validation.
Whose business is it to assure quality medicines?
- manufacturer: product and manufacturer’s licence holder; distributor and advertiser
- the regulator (HSA): Product quality reviewers; GMP inspectors
What are the hard skills and knowledge required for manufacturers/regulators in assessing quality of products?
- pharmacology/ pharmacotherapy
- medicinal chem
- pharmaceutics
- pharmaceutics microbiology
- pharmaceutical laws
- GMP and quality standards
- Statistics
What are the soft skills required of a regulator/ inspector?
- confidence, assertiveness, integrity and impartiality, perserverance, tact and diplomacy, oral communication and negotiation skills, report wiritng and written communication skills; willing to travel overseas regularly
What is a contaminated medicinal product?
Product that contains undesirable foreign matters
- of chemical/microbiological nature (non-specific in nature)
- may present in starting material, intermediate, bulk product
- introduced during manufacturing
What are intrinsic contaminants?
present inherently in APIs, Excipients (incl water) and packaging materials used in formulating product
not removed completely from starting and packaging materials during their manufacturing processes
What are extrinsic contaminants?
Originate externally from
- production personnel
- processing equipment
- packaging equipment
- manufacturing premises (environment)
Why is there a need to control impurities (intrinsic)?
- overall therapeutic effect of medicinal product is dependent not only on its pharmacological properties of API (safety, efficacy and quality), but also on toxicity of impurities present
- for MARKETING approval
What are some polymorphs to take note of?
ampicillin, carbamazepine, cimetidine, mefenamic acid
What are some stereo-isomers to take note of?
dopamine and propanolol
What are some starting materials that could be an impurity?
- closure: types of rubber, plastics
- container: types of glass, plastics
- active pharm ingredient
- excipients
What is the effect of poor handling of product during in-use?
contamination of product; drop in microbiological quality of product; unsafe product
Under product stability, which of the following falls under ‘proper storage’?
- elevated temp during storage
- elevated RH/moisture content during storage
Under product stability, which of the following falls under ‘distribution’?
- inc agitation and vibration during transportation
- poor handling of product during in-use
SUMMARY
what is purity?
contaminants and impurities in small or trace amts can be highly toxic, rendering a product unsafe and harmful
SUMMARY
what is stability?
a stable product maintains its quality, safety and efficacy throughout its shelf ife. Hence, a product needs to be properly formulated, stored, distributed and handled
SUMMARY
what is homogeneity?
a homogeneous product means that each and every unit of dosage form meets quality specification. Homogeneity (consistency) is demonstrated through process validation
SUMMARY
what are the 3 impt quality attributes of a medicinal product?
Purity, Stability, Homogeneity
