QUALITY CONTROL AND 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

• • • •

Material q.c Inprocess q.c Product q.c Specifications and tests for
– – – – – – –

Steps

• Provision for cross referecing

active ingredients Excipients Product itself Stability procedures Freedom from microbial contamination Storage and labelling Containers

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

• Samples
– – – –

Raw material QA monograph

• Retest program

Safety requirement Sample plan and procedure Sample size and container to be used Preservation sample required

– 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

• Purity and quality

Raw material QA monograph

• Assay calculated either on hydrous or anhydrous basis • Microbial limits especially for raw materials of natural origin

– 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

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 – Inactive or inert
• Antibiotics • Other active materials • 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

• • • • • • • •

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

Inactive or inert materials

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. ii. iii. iv. v. Raw materials processing Compounding Packaging materials control Labels control 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.