PREPARED BY: HELI N KARNAVAT GUIDED BY:

M.PHARM SEM-1 Ms.KRUPA THULA

ROLL NO:3 Assistant Professor

PMRA M.Pharm

LJ INSTITUTE OF PHARMACY

AHMEDABAD 1

CONTENTS INTRODUCTION

RESPONSIBILITIES OF PERSONNELS

ROUTINE CONTROL INSTRUMENTS

REAGENTS

SAMPLING PLANS

STANDARD TEST PROCEDURES

PROTOCOL

DATA GENERATION AND STORAGE

QUALITY CONTROL DOCUMENTS

RETENTION SAMPLE

RECORDS

AUDITS OF QUALITY CONTROL FACILITIES

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HISTORY OF QC LAB: GLP is a formal regulation that was created by the FDA (United

states food and drug administration) in 1978.

Although GLP originated in the United States , it had a worldwide impact.

Non-US companies that wanted to do business with the Unitedstates or register their pharmacies in the United States had tocomply with the United States GLP regulations.

They eventually started making GLP regulations in their homecountries.

In 1981 an organization named OECD (organization foreconomic co-operation and development ) produced GLPprinciples that are international standard.

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Quality Control Area.-(as per schedule M)

Quality Control Laboratories shall be independent of theproduction areas.

Separate areas shall be provided each for physico-chemical,biological, microbiological or radio-isotope analysis.Separate instrument room with adequate area shall beprovided for sensitive and sophisticated instrumentsemployed for analysis.

Quality Control Laboratories shall be designedappropriately for the operations to be carried out in them.Adequate space shall be provided to avoid mix-ups andcross-contamination. Sufficient and suitable storage spaceshall be provided for test samples, retained samples,reference standards, reagents and records.

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The design of the laboratory shall take into account thesuitability of construction materials and ventilation.Separate air handling units and other requirements shall beprovided for biological, microbiological and radioisotopestesting areas. The laboratory shall be provided with regularsupply of water of appropriate quality for cleaning andtesting purpose.

Quality Control Laboratory shall be divided into separatesections i.e. for chemical, microbiological and whereverrequired, biological testing. These shall have adequate areafor basis installation and for ancillary purposes. Themicrobiology section shall have arrangements such asairlocks and laminar air flow work station, whereverconsidered necessary.

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INTRODUCTION QUALITY CONTROL:

Quality control deals with the system which accepts or rejectsany activities or

parameters which affects the quality of product and thusprevent quality deficiency.

Q.C. is not confined to only laboratory operation but must beinvolved in all decisions,

concerning with the quality of the product”

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AS PER WHODEFINITION:

Q.C. is the part of GMP concerned with sampling,specification, and testing and with the organization,documentation and release procedure which ensure that thenecessary and relevant tests are actually carried out and thosematerials are not released for use, nor product released forsale or supply, until their quality has bee satisfactory.

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WHO guidelines for Q.C laboratory: Should be separated from production areas.

Areas where biological, microbiological orradioisotope test methods are employed should beseparated from each other.

Control laboratory should be designed to suite theoperations to be carried out in them.

There should be adequate suitable storage spacefor samples, reference standards and records.

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QUALITY CONTROL LABORATORY

ABOVE SHOWN IS THE OVERVIEW OF A QUALITY CONTROL LABORATORY OF A REPUTED PHARMACEUTICAL COMPANY.

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Figure:1.1- Quality Control Laboratory

RESPONSIBILITIES OF PERSONNELS

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LABORATORY DIRECTOR Responsible for overall operation and administration of the

laboratory, including employment of competent qualifiedpersonnels.

To ensure that laboratory develops and uses a qualitysystem approach to laboratory testing that providesaccurate and reliable patient test results.

Ongoing monitoring of each testing process used inlaboratory to identify potential problems that could resultin errors.

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Continued…

Take corrective action.

Evaluate the corrective actions taken, to make sure thatthey were effective and will not occur again.

To ensure that testing systems in laboratory providesquality services in all aspects of test performance.

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Lab technicians To operate laboratory equipment and computers and

performs other assigned work, in accordance todocumented laboratory procedures.

To perform chemical analysis.

Responsible for operation of GC, Spectrophotometers,balances, computers, etc. Responsible to be cross trained toperform special laboratory functions.

Carry out sampling, testing, measuring, recording andanalysing .

provide all the required technical support to enable thelaboratory to function effectively whilst adhering to correctprocedures and health and safety guidelines.

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Continued…

performing laboratory tests in order to producereliable and precise data to support scientificinvestigations;

carrying out routine tasks accurately and followingstrict methodologies to carry out analyses;

preparing specimens and samples;

constructing, maintaining and operating standardlaboratory equipment, for example centrifuges,titrators, pipetting machines and pH meters;

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ensuring the laboratory is well-stocked and resourced;

recording and sometimes interpreting results to present to senior colleagues

keeping up to date with technical developments, especially those which can save time and improve reliability.

following and ensuring strict safety procedures and safety checks.

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ROUTINECONTROLINSTRUMENTS

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Normally practiced routine control includes:

The lab and instruments should be cleaned daily.

All the instruments should be validated and checked and theresults should be recorded.

The samples arrived in the lab should be noted in incomingregister.

Humidity and temperature of the lab should be recorded daily.

Log books should be filled correctly for every instrument used.

The results of the tests should be recorded appropriately.

Any fault in the instruments should be immediately reported tothe Q.C manager.

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INSTRUMENT RELATED TERMSo VERIFICATION: a quality control process used to

evaluate whether a product, service or system complieswith the regulations, specifications or conditions impliedby the standard.

o VALIDATION: is a quality assurance process ofestablishing evidence that provides high degree ofassurance that the product meets its intended standards.

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Continued…

o CALIBRATION: the set of operations that establishes therelationship between values indicated by an instrument orsystem and the corresponding known values of referencestandard.

o EQUIPMENT QUALIFICATION: the action of provingthat any equipment works properly and actually givesaccurate and reliable results.

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Reagents Reagent quality control records must be retained for 5

years.

Reagents shall be used and controlled according tomanufacturer’s recommendations.

All reagents and chemicals, including solvents andmaterials used in tests and assays, should be ofappropriate quality.

Reagent should be purchased from reputable,approved suppliers and should be accompanied by thecertificate of analysis, and the material safety datasheet.

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Preparation of reagents in laboratory

responsibility for this task should be clearly specifiedin the job description of the person assigned to carry itout

prescribed procedures should be used which are inaccordance with published pharmacopoeial or otherstandards where available. Records should be kept ofthe preparation and standardization of volumetricsolutions.

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The labels of all reagents should clearly specify:

Name;

content;

manufacturer;

date received and date of opening of container;

concentration;

storage condition;

expiry date or retest date

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23FIGURE 1.2 REAGENT LABELS

The labels for volumetric solutions prepared in the laboratory should clearly specify:

Name;

Molarity(concentration);

Date of preparation and initials of technician/analyst;

Date of standardization and initials of technician/analyst;

Standardization factor.

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Transportation and subdivision of reagents:

Whenever possible they should be transported in theoriginal containers;

When subdivision is necessary, clean containersshould be used and appropriately labelled.

All reagent containers should be visually inspectedto ensure that the seals are intact, both when theyare delivered to the store and when they aredistributed to the units.

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Continued...

Reagents that appear to have been tampered with shouldbe rejected; however, this requirement may exceptionallybe waived if the identity and purity of the reagentconcerned can be confirmed by testing.

Water should be considered as a reagent. The appropriategrade for a specific test should be used as described in thepharmacopoeias or in an approved test when available.

Precautions should be taken to avoid contamination duringits supply, storage and distribution.

The quality of the water should be verified regularly toensure that the various grades of water meet theappropriate specifications.

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Continued…

Stocks of reagents should be maintained in a store underthe appropriate storage conditions (ambient temperature,under refrigeration or frozen).

The store should contain a supply of clean bottles, vials,spoons, funnels and labels, as required, for dispensingreagents from larger to smaller containers.

Special equipment may be needed for the transfer of largervolumes of corrosive liquids.

The person in charge of the store is responsible for lookingafter the storage facilities and their inventory and fornoting the expiry date of chemicals and reagents.

Training may be needed in handling chemicals safely andwith the necessary care.

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Sampling plan:

Sampling is an activity which is of crucial significance to thequality control in Pharmaceutical and Healthcare industrywhere necessary to take the samples.

Sampling at the end of a manufacturing process provides acheck on the adequacy of the quality control procedures ofthe manufacturing department.

Sampling plan is detailed outline of which measurementwill be taken at what times,on which material,in whatmanner,and by whom.

In quality control activity “sampling” is one of the majoractivity

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In QC laboratory;

Procedure available for receiving, storage and handling ofsamples for analysis.

Sample receiving procedure should be documented and keepit.

Each sample having distinct identification number andinformation for its storage with handling and labeling.

Storage condition facilities in laboratory like refrigerator andabsence of light.

Detailed description of sub sampling of samples for analysis. Reserve samples should be retained for additional testing if

quantity is adequate.

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Continued… Sampling may be required for different purposes for example;

Acceptance of batches

Clearance of batches

In process controls

Stability studies

Complaints

The control that applied to the samples may be;

Checking the identity of materials

Performing complete Pharmacopoeia or testing

Performing the special test

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Sampling kit

The QC person may require the tools and equipment for collecting the

samples (Sampling kit).

The tools are knives, pliers, saws, hammers, wrenches etc. to open

packages, barrels and containers.

Not used the complicated tools for sampling of samples.

Pipette with suction bulb use for liquid of low viscosity.

Glass rod can be used for highly viscous liquid

Spatulas and scoops used for granules.

When it is necessary to take sample of materials at three different

strata (Top, Middle, Bottom) sampling stick used.

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Continued…

All tools and implements should be kept

scrupulously clean before use, washed it

thoroughly with water or suitable solvents and

then dried.

It will be better if more than one set of sampling

kits are available in clean and dry condition.

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Types of sampling:

Single sampling.

Double sampling.

Continuous Sampling.

Sequential Sampling

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Single sampling: A single sampling plan is defined by sample size, n, and the

acceptance number c. Say there are N total items in a lot. Choosen of the items at random. If at least c of the items areunacceptable, reject the lot.

N=LOT NUMBER

For a single sampling plan, one sample of items is selected atrandom from a lot and the disposition of the lot is determinedfrom the resulting information. These plans are also denoted as(n,c) plans since there are n observations and the lot is rejected ifthere are more than c defectives.

Single sample plans are the most common and easiest plans touse. However, they are not the most efficient in terms of theaverage number of samples needed.

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Inspect n

pieces in a

sample

If the number defective found in sample

Accept the

lot

Equals or

exceeds r

Does not

exceed c

Do not

accept lot

n= sample size,

c= allowable no. of defect in the sample,

r= rejection no.

Fig:1.3 SINGLE SAMPLING CHART.

DOULE SAMPLING Double and multiple sampling plans were invented to give a

questionable lot another chance. For example, if in double samplingthe results of the first sample are not conclusive with regard toaccepting or rejecting, a second sample is taken. Application of doublesampling requires that a first sample of size n1 is taken at random fromthe (large) lot. The number of defectives is then counted and comparedto the first sample's acceptance number a1 and rejection number r1.

Denote the number of defectives in sample 1 by d1 and in sample 2 byd2, then:

If d1≤a1, the lot is accepted.

If d1≥r1, the lot is rejected.

If a1<d1<r1, a second sample is taken.

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Continued…

If a second sample of size n2 is taken, the number ofdefectives, d2, is counted. The total number ofdefectives is D2=d1+d2. Now this is compared to theacceptance number a2 and the rejection number r2 ofsample 2. In double sampling, r2=a2+1 to ensure adecision on the sample.

If D2≤a2, the lot is accepted.

If D2≥r2, the lot is rejected.

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Inspect first sample,n1 pieces

Does not exceed , c1

Do not accept lotEquals or

exceed r2Does not

exceed c2Accept lot

Inspect asecond sample ,

n2 pieces

Equals or exceeds , r1

If the no. of defectives in the first sample

Exceeds c1 but does not exceed r1

If the no. of defectives in combined sample

Fig:1.4 DOUBLE SMAPLIN CHART

CONTINUOUS SAMPLING Continuous sampling is used where product flow is

continuous and not easily grouped in lots. Twoparameters exist for continuous sampling. One is thefrequency (f) and the second is the clearing number(i).

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Continued…

Carrying out a continuous sampling plan is simple andcan be carried out in 3 steps.

1. Inspect all i data.

2. If no defects are found, randomly sample fraction fof data and check again for defects.

3. Whenever a defect is found, correct the flaw andrepeat step 1.

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SEQUENTIAL SAMPLING Sequential sampling is different from single, double or

multiple sampling. Here one takes a sequence ofsamples from a lot. How many total samples looked atis a function of the results of the sampling process.

The sequence can be one sample at a time, and thenthe sampling process is usually called item-by-itemsequential sampling. One can also select sample sizesgreater than one, in which case the process is referredto as group sequential sampling.

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STANDARD TEST PROCEDURE

An authorized written procedure giving instructionsfor performing operations not necessarily specific toa given product or material but of a more generalnature (e.g. equipment operation, maintenance andcleaning; validation; cleaning of premises andenvironmental control; sampling and inspection).Certain SOPs may be used to supplement product-specific master batch production documentation.

Sampling: -

There shall be written Standard OperatingProcedures for sampling which include theperson(s) authorized to take the samples.

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Continued… The sampling instruction shall include:

(a) The method of sampling and the sampling plan,

(b) The equipment to be used,

(c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality,

(d) The quantity of samples to be taken,

(e) instructions for any required sub-division or poling of the samples,

(f) The types of sample containers to be used,

(g) any specific precautions to be observed, especially in regard to sampling of sterile and hazardous materials.

Testing:

There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded.

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Physical

Analysis

:

Description :

Diameter :Measure the diameter of approximately 6 tablet using Vernier

calipers.

Thickness : Measure the diameter of approximately 6 tablet using Vernier

calipers.

Hardness :Check the hardness of approximately 6 tablet using hardness

tester .

Friability :Note the accurate weight of 20 tablet. Keep it into drum of

friability apparatus and allow to rotate for 100 revolution at 25

RPM.

Disintegration :Place one tablet in each tube of basket rack assembly of

disintegration apparatus and observe the time period for

complete disintegration.

Identification : Identification Test by HPLC. The retention time of the major peak in the chromatogram

of sample preparation should correspond to that of in thechromatogram of working std preparation in the assay.

Assay: Mobile Phase: Take 45volume of water in 55 volume of

Acetonitrile and add 0.1 volume of triethylamine. AdjustpH 3.5 using phosphoric acid and filter it.

Standard Preparation : Dilute 69.3mg amlodipine besilate (50mg amlodipine)+

54.39 mg Lisinopril (equal to Lisinopril Anhydrous ) working standard in

mobile phase to obtain 50ml Further dilute 5 ml in 25 ml inmobile phase to get final concentration amlodipine 200ppm / ml and Lisinopril Anhydrous 200 ppm/ml

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Test Preparation : Accurately weight of fine tablet powder equvalent to 10 mg Amlodipine +10 mg Lisinopril Anhydrous and dissolve in 50 ml to mobile phase to

get final concentration amlodipine 200 ppm / ml and LisinoprilAnhydrous 200 ppm/ml.

Column: C18 Flow rate: 1.0 ml / min. Wavelength : 215 nm Run Time : 15 min. Procedure: Inject 20 l of standard preparation and test preparation separately.

And calculate the %assay for each tablet individually. Calculation: % Assay = Area of Sample X Std. Dilution X Potency Area of Std Sample Dilution 100

Limit : 90 % to 110 %

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PROTOCOL

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DEFINITION

Protocol is a system of rule about the correct way to actin formal situation .

Each study shall have an approved written protocolthat clearly indicates the objective and all methods forthe conduct of study.

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WHAT SHOULD A PROTOCOL CONTAIN??? Every protocol needs to focus specifically on one type of

experiment to be performed.

Title and statement of the purpose of the study

Identification of the test and control articles by names,chemical number or code number.

The name of the sponsor and the name and address of thetesting facility at which the study is being conducted.

The procedure for identification of the system

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Type and frequency of test, analysis andmeasurements to be made.

Records to be maintained.

The date of approval of the protocol by the sponsorand the dated signature of the study director.

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Each study shall have an approved written

protocol that clearly indicates the objectives and all

methods for the conduct of the study. The protocol

shall contain, as applicable, the following

information:

The requirement to indicate “all methods for the

conduct of the study” does not mean that all

laboratory SOPs must be reiterated in the protocol;

it is sufficient if the protocol indicates “what” will be

done and “when” it will be done. Laboratory SOPs

describe “how” each study activity is to be

performed.

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The description shall include specifications foracceptable levels of contaminants that are reasonablyexpected to be present in the materials and are knownto be capable of interfering with the purpose orconduct of the study if present at levels greater thanestablished by the specifications.

Each dosage level, expressed in milligram perkilogram of body weight or other appropriate units, ofthe test or control article to be administered and themethod and frequency of administration.

The type and frequency of tests, analyses, andmeasurements to be made.

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DATA GENERATIONAND

STORAGE RECORDS

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Storage facility for records should reflect the need topreserve confidentially, integrity and logical retrieval.

Thought should be given to the susceptibility of therecords to damage from fire (heat), flood (humidity),electric or magnetic fields, dust, solvents etc.

It is the responsibility of laboratory staff to ensure allrelevant documentation is kept for the specifiedtimeframes and to archive large quantities ofdocumentation that is to be kept long term but notnecessarily looked at on a regular basis.

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PURPOSE The purpose of this procedure is to describe the

requirements for the retention of laboratorydocumentation under GMP and the disposal of suchdocumentation.

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RETENTION SAMPLES

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DEFINITION

A sample from every batch of product made and thechemicals and components that make up a finishedgood are kept for a set period of time for use asreference material should be a problem with a specificproduct or batch.

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CONDITIONS TO BE MET The sample shall consist of at least twice the quantity

necessary for all tests required to determine its compliancewith specification.

The sample shall be stored in controlled room temperatureexpect where the product labeling or specification statesotherwise.

The sample shall be stored in the same primary containerenclosure system in which the product is marked or shipped,or in one that has essentially the same characteristic.

The sample shall be securely stored in accordance with theirlabels requirements and segregated from other material.

The conditions in the store area must be supervised andrecorded.

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DOCUMENTATION

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Documentation is an essential part of the qualitymanagement System.

The laboratory should establish and maintainprocedures to control and review all documents (bothinternally generated and from external sources) thatform part of the quality documentation.

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THE PROCEDURES SHOULD ENSURE Each document, whether a technical or a quality

document, has a unique identifier, version numberand date of implementation;

Appropriate, authorized SOPs are available at therelevant locations, e.g. near instruments;

Documents are kept up to date and reviewed asrequired;

Any invalid document is removed and replaced withthe authorized, revised document with immediateeffect.

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A revised document includes references to theprevious documents.

Old, invalid documents are retained in the archives toensure traceability of the evolution of the procedures;any copies are destroyed.

All relevant staff are trained for the new and revisedSOPs

Quality documentation, including records, is retainedfor a minimum of five years.

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RECORDS

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DEFINITION Any production, control, or distribution record that is

required to be maintained in compliance with this partand is specifically associated with a batch of a drugproduct shall be retained for at least 1 year after theexpiration date of the batch.

Quality management records should include reportsfrom internal (and external if performed) audits andmanagement reviews, as well as records of allcomplaints and their investigations, including recordsof possible corrective and preventive actions

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CLOSURE AND LABELLING RECORDS The identity and quantity of each shipment of each lot

of components,

Drug product containers, closures, and labeling;

The name of the supplier;

The supplier’s lot number(s) if known;

The receiving code and the date of receipt.

The name and location of the prime manufacturer, ifdifferent from the supplier, shall be listed if known.

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MASTER PRODUCTION AND CONTROL RECORDS The master manufacturing records should clearly

identify:

Name of product,

Product type,

Strength Ingredients to be added,

Name, alphanumeric code,

Amounts or dosage unit or percentage Amount ofeach ingredient for a batch

Sequence of adding ingredients

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Equipment to be utilized designated by name and,where appropriate, by number processing steps withdetails of conditions such as time, temperature, speed

Special precautions and hazardous conditions whichexist and the necessary safety equipment to be used

Theoretical yields and actual yields (action levels)

Space for signature and date of operator/supervisorperforming or checking each significant step.

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THANK YOU

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