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QUALITY CONTROLQUALITY CONTROLANDAND

ASSURANCEASSURANCE

QUALITY CONTROLQUALITY CONTROLANDAND

ASSURANCEASSURANCE

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CONCEPT OF QUALITY

CONTROL Refers to the process of striving to

produce a perfect product

Requires a series of measures requiringan organized effort

Prevent or eliminate errors at every

stage in the production

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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

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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

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Quality assurance

Assuring the quality of the product

Manufacturing unit prime

responsibility Quality assurance essential from the

start up to the finished

pharmaceutical.

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Sources of quality variation

Raw materials

In-process

Packaging material

labeling

Finished product variables

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Control of quality

variation Can be done by

Raw material control

In-process items control

Packaging materials control

Label control

Finished product control

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Raw material control

Raw material specifications must be Complete

Provide specific details of test methods

Type of instruments Manner of sampling

Properly identified.

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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

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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

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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

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Raw material QA

monograph Purity and quality

General completeness of solutions,pH,SR,nonvolatile residue,ash ,acid soluble ash etc.

Special quality tests ,particle size,crystallinitycharacteristics and polymorphic forms.

Special purity tests in ferric and ferroussalts,peroxides and aldehydes in ether andrelated degradation products

Assay calculated either on hydrous oranhydrous basis

Microbial limits especially for raw materialsof natural origin

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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

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RAWMATERIALS Classified in general into

Active or therapeutic

Antibiotics Other active materials

Inactive or inert

Flavors

Colorants Sweetening agents etc.

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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.

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ANTIBIOTICS Minimal time of sampling

Two separate weighings on each of

three different days(six different assaysusing six different weighings)

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Other active materials USP and NF contains monograph on

most therapeutically active substances

Degree of purity of each raw material

97% according to compendium

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Other active materials Specifications normally include

Solubility

Identification Melting range

Loss on drying

Residue on ignition

Special metal testing Specific impurities

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Other active materials Analytical methods

Spectrophotometry

Potentiometric titrimetry

GLC,HPLC,polarography,X-ray diffraction

,radio tracer techniques

Microbiological assay Pharmacologic assay

Safety testing

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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

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Colorants

FDA approved Identity tests

tests of volatile materials

Heavy metalsWater insoluble matter

Synthetic impurities

Arsenic,lead Total color

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F,D&C LAKES Additional tests for

Chloride

Sulfate

Organic matter

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Flavors

Refractive index

Specific gravity

Solubility

Alcohol content

GLC can be used

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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

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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

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In-process items control Quality assurance before start up

Quality assurance at start up

Packaging material contol

Labels control

Finished product control

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QA before start up

Environmental and microbiologic control andsanitation

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

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QA REVIEWS Sanitation

Cleaning of building and equipment

Ventilation

water

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Master working formula

procedures (MWFP) Documentation of component

materials

Processing stepsWith production operation

specifications

Equipment to be used

Prepared for each batch

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QA REVIEWS

Working formula procedures for eachbatch before,during and afterproduction 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

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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.

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QA REVIEWS Proper labeling of released components

and equipment

Product name Strength

Lot number

Item number

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QA at start upi. Raw materials processing

ii. Compounding

iii. Packaging materials control

iv. Labels control

v. Finished product control.

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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 properequipment,addition of ingredient,mixing &drying time meshsize of sieves used inscreening.

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Cont.. Samples to be taken at certain points

for potency assay& batch purity &

uniformity.

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Compounding Check labelled r.m staged in compounding

staging area(for cleanliness,manufacturingequipment,item no.,lot no.,)

QA-manufacturing process performed acc.,to SOP

-Checks tests toproduct(thickness,disintegration,etc)

-documentation to maintained thro;out allstages of manufacturing

If deviation-corrective action by resampling.

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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

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Cont.. 4.Phy /chem chages of container upon

prolonged contact with product

5.compatibility b/w container & product

Packaging material should not interactphy/chem with ff

Specifications & test methods for lightresistance,tightly & well closed,

Submit stability data of ff in same containerclosure system.

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Labels control Production control issues a packaging

form that carries-(name,item no.,lot

no., no., of labels,packaging inserts &material operations,quantity to bepacked

1.copy to supervisor of label control

2.packaging dept.

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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)

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Cont.. Packaging dept Product & its components

(labels,cartons,insert & packaging

material,stopper ,cap,seal,shipcases)are supplied & operation done.

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Cont QA-all materials are clean,identified

-all materials of previous packaging

operation removed.

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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 productionexperience

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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

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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 operationsare satisfactory. The bulk product is released topacking dept and production control notified

2. QA personnel periodically inspects packing linesand should check filled and labeled containers for

compliance and written specification.

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Contd 3. QA should perform independent inspection and

select finished preservation samples at random from

each lot.

4. QA personnel should also select an appropriatesize sample of FF package product and send to

analytical control lab for final testing.

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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

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Contd Areas of record keeping:

1. Individual components, r.m and packagingmaterials MWF and procedures.

2. Batch production 3. Lab in process and finished control testing

4. Proper signing and dating -> by at least 2individuals independently for each operations inproper spaces,

5. Reconciliation of materials supplied and amts oftabs produced, taking in to account allowable losslimits.