Purity, Stability, Homogeneity Flashcards
What is good quality medicinal product
- identity & potency of ingredients
- overall purity
- pharmaceutical attributes of its dosage form, including stability and homogeneity
QbA is
Judge Quality of a medicine by its APPEARANCE
what is QbT
test quality into a pdt: pdt tested at the end of batch manufacturing process. If pdt passes test(s), it’s deemed to be of good quality
problem with conventional product testing?
- test only a representative sample
- can test only if we know the analyte & we have the test method for it
- can only use the test if the test method is specific, accurate & reliable; only use when its validated
in QbD, quality assurance (QA) is moved upstream. what are some QA done?
- product {design}
- control of {starting materials}
- {GMP compliance} by Manufacturers of API & finished dosage forms
- {contamination control, process validation & stability testing}
- use tech e.g. process analytical tech (PAT) & parametric release
What is the definition of parametric release?
- release of a batch of injectable pdt which has been terminally sterilised, without the need to conduct batch sterility testing
- in annex 17
Limitations of (batch) sterility Testing?
- high probability of passing sterility tests, even when contamination level is relatively high
- sterility testing is EXPENSIVE
- two weeks of incubation period needed for sterility test
- Thus sterilised pdt cannot be released in real time (test not out yet; expensive to store, esp the large volume parenterals)
to overcome the limitations of sterility testing, what method was developed?
- Parametric release of Terminally-sterilised LVPs
- Annex 17
(LVPs: large volume parenterals)
Why Parametric release of Terminally-sterilised LVPs is better than the sterility testing method?
- the release of LVPs are based on parameters of a validated sterilisation process
Parameters are:
- Temp
- Pressure
- Sterilisation time/cycle
- bioburden of pre-sterilised parenteral pdt
what is quality risk management (QRM)
QRM framework seen in annex 20
Objective: assess risk to pdt quality/patient, and then manage these risks to an acceptable level
What are the 4 steps for QRM?
- Risk identification
- quality of starting Material
- pdt & packaging process (Methods)
- premises & equipment (Machine)
- human errors (Manpower)
- warehouse & pest control (Premises)
4M, 1P
- Risk analysis
- failure mode & effects analysis (FMEA)
- fault tree analysis (FTA)
- hazard analysis & critical control points (HACCP) - Risk reduction
- Risk communication
Who are the TWO groups of people who should be concern of quality of pdts and why?
- Manufacturer
- license holder
- distributor & advertiser - Regulator (HSA)
- Quality reviewers
- GMP inspectors
What skills do these 2 groups of people need to ensure quality of pdts?
Hard and soft skills
What are the hard skills
- pharmacology
- med chem
- pharmaceutics
- microbiology
- Pharm Law
- GMP & quality standards
- statistics
What are the soft skills
- assertiveness
- perseverance (probing nature)
- tact & diplomacy
- oral skills
- writing skills
- willing to travel overseas
What is good quality medicinal product
- identity (of starting material)
- potency (of starting materials, esp API)
- purity (absence of contaminants)
- Pharmaceutical Quality Attributes (CQA) of finished dosage form
- -> stability, homogeneity
- cross-contamination control
What affects the purity of medicinal product
contamination & impurities in small or trace amounts can be toxic, making pdt unsafe & harmful
What is a contaminated Medicinal product?
- pdt that contains undesirable foreign matter
- could be chemical, microbiological or non-specific in nature
- may be present in starting materials, intermediate, bulk pdt
How does a medicinal product get contaminated
- introduced during MANUFACTURING –> procurement, sampling, processing, packaging, re-packaging, storage, transportation
What are the TWO classification of contaminants
intrinsic and extrinsic
What are intrinsic contaminants?
- present INHERENTLY in API, excipients (incl water) & packaging materials
- not removed COMPLETELY from starting & packaging materials during manufacturing
- impurities SPECIFIC in nature
What are extrinsic contaminants?
- externally from
- -> production personnel
- -> processing equipment
- ->packaging equipment
- -> premise
(cross-contamination)
- impurities NON-SPECIFIC in nature
Why do we need to control impurities?
- pdt’s therapeutic effect does not only depend on API (safety, efficacy, quality), it also depends on toxicity of impurities
- thus need to control impurities in starting material AND finished pdt for marketing approval
types of intrinsic impurities
- process-related impurities
- un-reacted API
- residual solvents, reagents, heavy metal
- by-product - drug-related impurities
- degradation pdt (after API is formed) -
Polymorphs (diff crystal form)
- drugs exhibiting polymorphism:
- -> Ampicillin
- -> carbamazepine
- -> cimetidine
- -> mefenamic acid - stereo-isomers (same mw but diff 3d structure)
- -> dopamine
- -> propanolol - impurities from container-closure system & labels
a. primary containers
- -> residual polyymer/monomer (PVC, VC, PP, PE)
b. plasticisers, lubricants, stabiliser
c. coating materials
d. adhesives and printing ink from label
(seep thru container & contaminate)
- excipients
how can we control the intrinsic impurities
- QC testing of starting materials & finished pdt by manufacturer
- impurity profile assessment by HSA
- GMP compliance by manufacturer
- periodic GMP audits by HSA inspector
what are the types of extrinsic contaminants (non-specific)
- personnel
- dirt, saliva, bacteria, hair - equipment
- rust, corroded
- grease
- leached chemicals - premises
- pest
- pollutants
- cross-contaminants
how can we control the extrinsic impurities
- difficult to control via QC testing and and difficult for HSA to assess via product review
- thus Manufacturers compliance to GMP is impt
- and period audits to verify compliance
- Premises control
- -> controlled env
- -> partitioning to prevent cross-contamination
- -> closed system w positive air pressurisation
- Personnel control
- ->gowning
- -> personal hygiene
- Equipment control
- clean stainless steel sampling rod to collect samples
when can we deduce that a manufacturer has an increased risk for contamination (simple rule of thumb)
the greater the operations in a facility, higher risk for contamination
manufacturer of certain APIs (Single pdt) –> manufacturer of hormones/steroids (Product groups) –> generic drug manufacturer (Multiple pdt/multi-purpose equipment) [HIGHEST risk of contamination]
What are the factors affecting stability of a medicinal pdt
- Product-related factors
- formulation of pdt
- physico-chemical properties of API/exicipients
- type of primary container and packaging materials used - environmental factors
- temp
- moisture
- light
- oxygen
- physical stress during transportation
- in-use contamination during consumption
What is a stability testing program and what studies are done? why are the studies done?
Stability testing takes into account product-related and env factors, doing studies like:
a. real-time studies (6 mths - storage conditions)
b. accelerated studies under elevated/stress condition
c. continual stability studies
- to establish shelf-life of pdt at recommended temp and other env conditions
Why is proper storage important for the stability of the product?
- Elevated temp during storage can cause:
a. loss of potency (through degradation)
- low therapeutic effect
b. loss of vehicle (through evaporation)
- harmful pdt as increase in conc of API
c. hardening of tablet (through loss of moisture content)
- bioavailability changes
- absorption profile changes
- Elevated RH/Moisture content during storage
a. formation of toxic degradation products (through hydrolysis)
b. loss of package integrity & label clarity
c. loss of adhesion of transdermal patch
Why is proper distribution important for the stability of the product?
- Increases Agitation & vibration during transportation
- cracks
- unsafe if intended to be sterile
Why is proper use important to ensure the stability of the product
- poor handling of product in-use
- e.g. eye drops
What is homogeneity and
How is homogeneity demonstrated through?
- each and every unit of dosage form meets quality specification
through process validation
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
- done on at least 3 consecutive full-scale batches
what are the major steps involved in process validation
I wrote this is important to know
- establish tablet quality specifications
- CQA - identify critical processes
- blending, milling - design sampling plan
a. for blending: 10 samples taken from top, middle, bottom of blender
b. for milling: 1 representative sample (100g) drawn from mill
c. for compression: 6 x 20 tablets collected at 4 equal intervals from tablet compression machines AND at 3 compression speed (low, target, high speed)
- -> 120 x 4 x 3 in total
- design testing plan
- blend uniformity: assay
- compression: test for hardness, friability, other CQA - set acceptance criteria
- perform statistical analysis
- intra-batch
- inter-batch
what is intra-batch analysis in statistical analysis
Process capability index (Cp)
to demo CONSISTENCY of all 3 validation batches (top, center, bottom)
–> analysis performed on blend content uniformity test results
~ Cp >= 1 (outliers =< 2700 ppm)
~ Cp >= 1.3 (outliers =< 63 ppm (acceptable)
~Cp >= 2 (outliers =< 0.002 ppm (acceptable)
what is inter-batch analysis in statistical analysis
coefficient of variance (CV)
to demo EQUIVALENCY of all 3 validation batches & pilot batch
–> analysis performed on dissolution test results
~ CV among 3 validation batches & pilot batch should be statistically similar (CV =<5%)
what is the rule of three in process validation
three successful run - scientific
three successful batch - there’s linearity/correlation and NOT due to luck
what needs to be documented for a process validation study
the validation protocol; which includes:
- objective
- person responsible
- critical processes
- raw material & material used
- sampling and testing plan
AND
the validation report; which includes:
- validation test results
- data analysis
- statistical analysis
- batch records
- manufacturing flow chart
What is the difference between the traditional approach of process validation (QbT) and the new approach to process validation (QbD)?
traditional approach:
- process validation of 3 consecutive successful production batches
- revalidation
new approach (QbD):
- identify critical quality attributes (CQA)
- extensive process design and process qualification
- monitoring the critical process parameters (CPP): e.g. mixing time, temp, compression speed
- continued process verification BEYOND 3 production batches; a state of control ensuring good quality
what is stability important
stable pdt maintains its quality, safety & efficacy throughout the shelf life, thus need to be properly formulated, stored, distributed and handled
