QUALITY CONTROL QUALITY CONTROL AND AND ASSURANCE ASSURANCE

QUALITY CONTROL QUALITY 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 upi. Raw materials processingii. Compoundingiii. Packaging materials controliv. Labels controlv. 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.