Assessing Manufacturer's Compliance to Product Quality: Purity, Stability and Homogeneity Flashcards
What is a (Good) Quality Medicinal Product?
Quality = Fit for Purpose (for any product) / Fit for Medicinal Purpose (for a medicinal product)/ Fitness for Use for Treating Patients (who are Sick)
Quality of a Medicinal Product includes:
- Identity (of starting materials)
- Potency (of starting materials, especially active ingredients)
- Purity (absence of Contaminants/Undesirable Foreign Matters)
- Pharmaceutical Quality Attributes [of Finished Dosage Form]
» Hardness, Friability, Particle Size, Dissolution Profile
» pH, Clarity, Colour Index, Microbial Limits, Sedimentation Rate
» Viscosity, Sterility, Endotoxin Levels
» Stability, Homogeneity
- Cross Contamination Control is critical in QA of product.
What is a contaminated medicinal product?
- Contaminated medicinal product is defined as a product that contains undesirable foreign matters
» Of chemical or microbiological nature (or non-specific in nature)
» May be present in a starting material, intermediate, bulk product
» Introduced during the manufacturing process (e.g. procurement, sampling, processing, packaging, re-packaging, storage or transportation)
How can contaminants be classified?
- Intrinsic contaminants
- Present inherently in APIs, excipients (including water) and packaging materials used in formulating product.
- Not removed completely from starting and packaging materials during their manufacturing processes.
- Referred to as impurities – often specific in nature. - Extrinsic contaminants
- Originate externally from:
» Production personnel
» Processing equipment
» Packaging equipment
» Manufacturing Premises (Environment)
- Often non-specific in nature
Why is there a need to control impurities?
- Overall therapeutic effect of a product is not just dependent on its safety, efficacy and quality, but also on toxicity of impurities present.
- Need to control impurities to get marketing approval.
What are some impurities in APIs (Drug Substances)?
- Process-related impurities
- Drug-related impurities
- Polymorphs (e.g. ampicillin, carbamazepine, cimetidine, mefenamic acid)
- Stereo-isomers (e.g. dopamine, propranolol)
- Impurities from Container Closure System and Labels
a. Impurities from Primary Containers
» Residual Polymers / Monomers (polyethylene, polypropylene, PVC)
» Plasticizers, antioxidants, lubricants and stabilizers
» Coating materials (resinous and polymeric)
b. Impurities from Labels
» Adhesives
» Printing ink
How are intrinsic contaminants controlled?
- Through QC testing of materials and finished product by manufacturer
- Through assessments of impurity profile by HSA product reviewers
- Through GMP compliance by manufacturer
- Through periodic GMP audits by HSA inspectors
How are extrinsic contaminants (non-specific) controlled?
Extrinsic contaminants are controlled via GMP compliance (e.g. during sampling of starting materials for QC Testing)
- Premises (ENV) Control
Room for Sampling Materials:
- Has Controlled Environment
- With Effective Partitioning to Prevent Cross-Contamination - Personnel Control
- Proper Gowning by Personnel Collecting Samples of Starting Materials
- Observance of Personal Hygiene by Operator - Equipment Control
- Use of Clean Stainless Steel Sampling Rod to Collect Samples
What is the simple rule of thumb for the general assessment of contamination risk?
- Increased operations within a given facility / piece of equipment = increased risks for contamination.
- In ascending order of risk of potential contamination:
- Manufacturers of certain APIs - Penicillins, cephalosporins
» have dedicated and self-contained facility/building (single product) - Manufacturers of Hormones, Steroids
»have dedicated and self-contained areas/rooms (product groups) - Many generic drug manufacturers
» non-dedicated facility (multiple products)
What are the factors influencing stability of a medicinal product?
Product-related factors:
- formulation of the product
- physiochemical properties of drug substances/excipients
- type of primary container and packaging materials used
Environmental factors:
- temperature
- moisture
- light
- oxygen
- physical stress during transportation
- in-use contamination during consumption
How do you test for product stability?
- Demonstrated through Stability Testing Program
- Stability testing program takes into consideration both product-related and environmental factors, which includes:
» Real time studies
» Accelerated studies (under elevated/stressed conditions)
» Continual stability studies
With a view to establish shelf-life of product.
Why is proper storage, distribution and handling of product important?
(1) Elevated Temperature during Storage
(a). Loss of potency (through degradation)
- Loss in efficacy
- Patient’s Life at Stake (esp. if products are of low therapeutic indices)
(b). Loss of vehicle (through evaporation)
- Increase in Concentration of API to»_space; 110% of labelled amount
- Toxic/Harmful Product
©. Hardening of tablet (through loss of moisture content)
- Change in dissolution profile
- Alteration in bioavailability
- Change in rate and extent of systemic absorption
- Loss in efficacy or therapeutic failure
(2) Elevated RH/Moisture Content during Storage
(a). Formation of Toxic Degradation Products (through hydrolysis)
(b). Loss of Package Integrity & Label Clarity (reduction in label quality, critical if essential info is obliterated)
©. Loss of Adhesion of Transdermal Patch (patch may drop off – no medication administered).
(3) Increased Agitation and Vibration during Transportation
- Ingress of Micro-organisms into Product
» Poor container closure integrity / hair-line cracks
» Drop in microbiological quality of product
» Unsafe product (if it is intended to be sterile)
(4) Poor Handling of Product during In-Use
- Contamination of Product
» Drop in microbiological quality of product
» Unsafe product
What is process validation?
- Process validation 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.
Major steps involved in process validation
- Establish tablet quality specifications (blend homogeneity, hardness, thickness, friability, particle size, dissolution profile)
- Identify critical processes (blending, milling, compression)
- Design sampling plan, e.g.
» For Blending: 10 samples each taken from the top, middle and bottom of blender
» For Milling: 1 representative sample (~100g) drawn from mill
» For Compression: 6 x 20 tablets collected at 4 equal intervals from tablet compression machines; 3 compression speeds covered (low, target and high speeds) - Design Testing Plan
» For blend uniformity: assay content of blended samples
» For compression: test for hardness, friability, thickness, potency, disintegration, dissolution profile of tablet samples - Set acceptance criteria (e.g. within 90% to 110% of labelled amounts)
- Perform statistical analysis (intra-and inter batch)
a). Intra-batch analysis: process capability index (Cp)
» Demonstrate consistency of all 3 validation batches.
» Performed on Blend Content Uniformity tests results
» Cp = USL – LSL / 6SD
b). Inter-batch analysis: variance analysis – coefficient of variance (CV)
» Demonstrate equivalency across all 3 validation batches and pilot batch (used for clinical trial studies).
» Performed on Dissolution Test results.
» CV among 3 Validation Batches and Pilot batch should be statistically similar.
» CV (or RSD) <= 5%
What are the essential elements for 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 for validation report?
- Validation test results
- Data analysis
- Statistical Analysis (SPC & Cp, ANOVA)
- Recommendations and Conclusions
- Attachments
» Batch Records
» Manufacturing Flow Chart
» Statistical Control Charts
» Tables and Graphs
