QUALITY

QUALITY CONTROL
CONTROL
AND
AND
ASSURANCE
ASSURANCE
 CONCEPT OF QUALITY
CONTROL
• Refers to the process of striving to produce a
perfect product
• Requires a series of measures requiring an
organized effort
• Prevent or eliminate errors at every stage in the
production
 When?
• Quality must be built in to product during
– Process and product design
• Influenced by
– Physical plant design
– Space,ventilation
– cleanliness and sanitation
• Begins at R&D
• Includes
– Preformulation
– Physical,chemical ,therapeutic and toxicologic considerations
 Steps
• Material q.c
• Inprocess q.c
• Product q.c
• Specifications and tests for
– active ingredients
– Excipients
– Product itself
– Stability procedures
– Freedom from microbial contamination
– Storage and labelling
– Containers
• Provision for cross referecing
 Quality assurance

• Assuring the quality of the product

• Manufacturing unit – prime
responsibility
• Quality assurance essential from the
start up to the finished
pharmaceutical.
Sources of quality variation
• Raw materials
• In-process
• Packaging material
• labeling
• Finished product variables
 Control of quality
variation
• Can be done by
– Raw material control
– In-process items control
– Packaging materials control
– Label control
– Finished product control
 Raw material control
• Raw material specifications must be
– Complete
– Provide specific details of test methods
– Type of instruments
– Manner of sampling
– Properly identified.
 Raw material QA
monograph
• Raw material (name)
– Structural formula,MW
– Chemical names
– Item number
– Date of issue
– Date of superseeded , if any new material
– Signature of writer
– Signature of approval
 Raw material QA
monograph
• Samples
– Safety requirement
– Sample plan and procedure
– Sample size and container to be used
– Preservation sample required
• Retest program
– Retesting schedule
– Reanalysis to be performed to assure identity,
strength ,quality and purity
 Raw material QA
monograph
• Specifications (whereever applicable)
– Description
– Solubility
– Identity
• Specific chemical tests such as related
alkaloids,organic nitrogen bases etc.
• Infrared absorption
• UV absorption
• Melting range
• Congealing point
• Boiling point or range
• TLC,Paper,liquid chromatography
 Raw material QA
monograph
• Purity and quality
– General completeness of solutions,pH,SR,non
volatile residue,ash ,acid soluble ash etc.
– Special quality tests ,particle size,crystallinity
characteristics and polymorphic forms.
– Special purity tests in ferric and ferrous
salts,peroxides and aldehydes in ether and
related degradation products
• Assay calculated either on hydrous or
anhydrous basis
• Microbial limits especially for raw
materials of natural origin
 Raw material QA
monograph
• Test procedures
– Compendial,USP or NF references
– Non compendial if any
• Approved suppliers
– List of prime suppliers and other
approved alternate suppliers if any
 RAW MATERIALS
• Classified in general into
– Active or therapeutic
• Antibiotics
• Other active materials
– Inactive or inert
• Flavors
• Colorants
• Sweetening agents etc.
 ANTIBIOTICS
• Analytical methods appear in CFR 21
Parts 436-436.517 and 442-455
• Specifications for all the antibiotics
• Chemically, microbiologically or
biologically
• Sampling in dry ,dust free
,contaminant free environment.
 ANTIBIOTICS
• Minimal time of sampling
• Two separate weighings on each of
three different days(six different
assays using six different weighings)
 Other active materials
• USP and NF contains monograph on most
therapeutically active substances
• Degree of purity of each raw material
• 97% according to compendium
 Other active materials
• Specifications normally include
– Solubility
– Identification
– Melting range
– Loss on drying
– Residue on ignition
– Special metal testing
– Specific impurities
 Other active materials
• Analytical methods
– Spectrophotometry
– Potentiometric titrimetry
– GLC,HPLC,polarography,X-ray
diffraction ,radio tracer techniques
– Microbiological assay
– Pharmacologic assay
– Safety testing
 Inactive or inert
materials
• Major portion of the dosage form
• Color,odor and foreign matter
• Chemical purity
• Particle size
• Heavy metal content – arsenic, selenium
• Water limit
• Microbial limit
• Residue on ignition
 Colorants
• FDA approved
• Identity tests
• tests of volatile materials
• Heavy metals
• Water insoluble matter
• Synthetic impurities
• Arsenic,lead
• Total color
 F,D&C LAKES
• Additional tests for
– Chloride
– Sulfate
– Organic matter
 Flavors

• Refractive index
• Specific gravity
• Solubility
• Alcohol content
• GLC can be used
 Sweetening agents
• Furfuraldehyde in lactose
• Reducing sugars in mannitol
• Water content,heavy metals,residue
on ignition, arsenic
• Specific rotation
• Melting range
• Selenium
• Readily carbonizable matter
In-process items control
• Identify critical steps in mfg process
• Controlling them within defined limits
• Batch to batch variation
• GMP emphasizes on good
environmental conditions
In-process items control
• Quality assurance before start up
• Quality assurance at start up
• Packaging material contol
• Labels control
• Finished product control
 QA before start up
– Environmental and microbiologic control and
sanitation
– Sanitation program at all facilities
– Control insects and rodents
– Personal sanitation
– Floors,walls ,ceilings resistant to external forces
– Adequate ventilation
– Temperature
– Humidity
– Air quality monitoring
 QA REVIEWS
• Sanitation
• Cleaning of building and equipment
• Ventilation
• water
 Master working formula
procedures (MWFP)
• Documentation of component
materials
• Processing steps
• With production operation
specifications
• Equipment to be used
• Prepared for each batch
 QA REVIEWS
• Working formula procedures for each
batch before,during and after
production for the following details
– Signature and date of issue given by a QA
employee
– Proper identification by name and dosage
form
– Item number
– Lot number
– Effective date of the document
 QA REVIEWS
– Reference version if any
– Amount
– Lot
– Code numbers of each raw material utilized
– Calculations of both active and inactive
material
– Start and finish times of each operation
– Equipment to be used and specificaation of its
setup.
 QA REVIEWS
• Proper labeling of released
components and equipment
– Product name
– Strength
– Lot number
– Item number
 QA at start up
i. Raw materials processing
ii. Compounding
iii. Packaging materials control
iv. Labels control
v. Finished product control.
 Raw materials control
• Only labelled enterin processing
• QA-should maintain temperature & humidity within
area of specified limits.
• -should check in process procedure with SOP.
• Verify & document the proper equipment,addition of
ingredient,mixing & drying time meshsize of sieves
used in screening.
 Cont..
• Samples to be taken at certain points
for potency assay& batch purity &
uniformity.
 Compounding
• Check labelled r.m staged in compounding staging
area(for cleanliness,manufacturing equipment,item
no.,lot no.,)
• QA-manufacturing process performed acc., to SOP
• -Checks tests to product(thickness,disintegration,etc)
• -documentation to maintained thro;out all stages of
manufacturing
• If deviation-corrective action by resampling.
 Packaging materials
control
• Container closure system
• Properties –
• 1.properties of container tightness
• 2.moisture & vapor tightness regardless of
container construction
• 3.toxicity & phy/chem characteristics of
materials needed in container constructions
 Cont..
• 4.Phy /chem chages of container upon
prolonged contact with product
• 5.compatibility b/w container & product
• Packaging material should not interact
phy/chem with ff
• Specifications & test methods for light
resistance,tightly & well closed,
• Submit stability data of ff in same container
closure system.
 Labels control
• Production control issues a packaging
form that carries-(name,item no.,lot
no., no., of labels,packaging inserts &
material operations,quantity to be
packed
• 1.copy to supervisor of label control
• 2.packaging dept.
Cont.. Supervisor of label
control
• Counts required no., of labels
• >identified & kept in separate
container
• >sent to packaging dept>(accounts to
be maintained if excess destroyed)
 Cont.. Packaging dept
• Product & its components
(labels,cartons,insert & packaging
material,stopper ,cap,seal,ship
cases)are supplied & operation done.
 Cont…
• QA-all materials are clean,identified
• -all materials of previous packaging
operation removed.
Finished product control
• Specification: Final testing in QC labs-Why?
To determine compliance with SOP prior to
packaging & distribution.
• + In process testing: Stable in ccs.
• Compare-label with product-> available for
complete absorption.
• Test (GMP) parameter done during product dev
-> no toxic foreign and substance detected.
• Results to statistical analysis
• Product specifications -> additional production
experience
 Bulk product testing
• Each lot tested for -> ensuring identity,
quality, potency, purity.
• QA -> further processing based on actual phy,
chem, bio, laboratory testing.
• Accurate, specific, economical and acc to
pharmacopeia
• Analytical procedure -> not required until
quality of the product is equal to – compendia
requirement
 QA during packing
• QA, QC confirm product ->sent to packing
dept -> QA observes for product & labeling
SOPs visual -> automated testing high speed
equipment & visual.
• 1. QA audit indicates that manufacturing
operations are satisfactory. The bulk product
is released to packing dept and production
control notified
• 2. QA personnel periodically inspects packing
lines and should check filled and labeled
containers for compliance and written
specification.
 Contd…
• 3. QA should perform independent inspection
and select finished preservation samples at
random from each lot.
• 4. QA personnel should also select an
appropriate size sample of FF package product
and send to analytical control lab for final
testing.
 Auditing
• GMP compliance documented.
• QA should evolutes batch records for in
process controls and of all tests of final
product to determine whether they conform to
specifications
 Contd…
• Areas of record keeping:
• 1. Individual components, r.m and packaging materials
MWF and procedures.
• 2. Batch production
• 3. Lab in process and finished control testing
• 4. Proper signing and dating -> by at least 2
individuals independently for each operations in proper
spaces,
• 5. Reconciliation of materials supplied and amts of
tabs produced, taking in to account allowable loss
limits.