• 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

• Quality must be built in to product during – Process and product design • Influenced by • Begins at R&D • Includes
– Physical plant design – Space,ventilation – cleanliness and sanitation

– Preformulation – Physical,chemical ,therapeutic and toxicologic considerations

• • • •

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


• 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 .

strength .quality and purity .• 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.

organic nitrogen bases etc.Paper.Raw material QA monograph • Specifications (whereever applicable) – Description – Solubility – Identity • Specific chemical tests such as related alkaloids.liquid chromatography . • Infrared absorption • UV absorption • Melting range • Congealing point • Boiling point or range • TLC.

ash .non volatile residue.• 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.SR.pH.acid soluble ash etc. – Special purity tests in ferric and ferrous salts.crystallinity characteristics and polymorphic forms.particle size.peroxides and aldehydes in ether and related degradation products . – Special quality tests .

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. .

contaminant free environment.517 and 442-455 • Specifications for all the antibiotics • Chemically.dust free .ANTIBIOTICS • Analytical methods appear in CFR 21 Parts 436-436. . microbiologically or biologically • Sampling in dry .

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.radio tracer techniques – Microbiological assay – Pharmacologic assay – Safety testing .X-ray diffraction .

selenium Water limit Microbial limit Residue on ignition Inactive or inert materials .odor and foreign matter Chemical purity Particle size Heavy metal content – arsenic.• • • • • • • • Major portion of the dosage form Color.

Colorants • • • • • • • • FDA approved Identity tests tests of volatile materials Heavy metals Water insoluble matter Synthetic impurities Arsenic.lead Total color .

D&C LAKES • Additional tests for – Chloride – Sulfate – Organic matter .F.

Flavors • • • • • Refractive index Specific gravity Solubility Alcohol content GLC can be used .

residue on ignition.heavy metals.Sweetening agents • Furfuraldehyde in lactose • Reducing sugars in mannitol • Water content. 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 .

ceilings resistant to external forces – Adequate ventilation – Temperature – Humidity – Air quality monitoring .walls .QA before start up – Environmental and microbiologic control and sanitation – Sanitation program at all facilities – Control insects and rodents – Personal sanitation – Floors.

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 .

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 • Working formula procedures for each batch before.

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

addition of ingredient.Raw materials control • Only labelled enterin processing • QA-should maintain temperature & humidity within area of specified limits. • -should check in process procedure with SOP.mixing & drying time meshsize of sieves used in screening. . • Verify & document the proper equipment.

Cont. • Samples to be taken at certain points for potency assay& batch purity & uniformity. ..

.Compounding • Check labelled r.lot no.disintegration..out all stages of manufacturing • If deviation-corrective action by resampling.etc) • -documentation to maintained thro.manufacturing equipment..m staged in compounding staging area(for cleanliness.) • QA-manufacturing process performed acc.item no. . to SOP • -Checks tests to product(thickness.

Packaging materials control Container closure system Properties – 1.properties of container tightness 2.toxicity & phy/chem characteristics of materials needed in container constructions • • • • .moisture & vapor tightness regardless of container construction • 3.

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. • 4.Cont.

.quantity to be packed • 1. .copy to supervisor of label control • 2. no.packaging dept.lot no..packaging inserts & material operations..Labels control • Production control issues a packaging form that carries-(name.item no. of labels.

of labels • >identified & kept in separate container • >sent to packaging dept>(accounts to be maintained if excess destroyed) . Supervisor of label control • Counts required no..Cont..

cartons.ship cases)are supplied & operation done.cap.insert & packaging material.seal. Packaging dept • Product & its components (labels.Cont. ..stopper .

.identified -all materials of previous packaging • operation removed.Cont… • QA-all materials are clean.

• Results to statistical analysis • Product specifications -> additional production experience .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.

chem. economical and acc to pharmacopeia • Analytical procedure -> not required until quality of the product is equal to – compendia requirement .Bulk product testing • Each lot tested for -> ensuring identity. laboratory testing. purity. specific. • Accurate. quality. • QA -> further processing based on actual phy. bio. potency.

QA audit indicates that manufacturing operations are satisfactory.QA during packing • QA. QC confirm product ->sent to packing dept -> QA observes for product & labeling SOPs visual -> automated testing high speed equipment & visual. QA personnel periodically inspects packing lines and should check filled and labeled containers for compliance and written specification. . The bulk product is released to packing dept and production control notified • 2. • 1.

• 4.Contd… • 3. QA personnel should also select an appropriate size sample of FF package product and send to analytical control lab for final testing. . QA should perform independent inspection and select finished preservation samples at random from each lot.

• QA should evolutes batch records for in process controls and of all tests of final product to determine whether they conform to specifications .Auditing • GMP compliance documented.

Batch production • 3.Contd… • Areas of record keeping: • 1. taking in to account allowable loss limits. r. • 2. Individual components. Reconciliation of materials supplied and amts of tabs produced.m and packaging materials MWF and procedures. Proper signing and dating -> by at least 2 individuals independently for each operations in proper spaces. . • 5. Lab in process and finished control testing • 4.

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