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QUALITY!MANAGEMENT!IN!THE!DRUG!INDUSTRY!

Pharmaceutical, and, cosmetic, manufacturing, is, recognized, as, a, major, industry, which, requires, a, clearly, defined,
organization.,Each,segment,of,this,organization,is,expected,to,fineAtune,its,functions,and,responsibilities.,An,effective,
coordination,is,called,for,among,its,personnel,,equipment,,building,and,inventory,of,materials.,All,these,activities,are,
performed,towards,the,production,of,a,drug,or,cosmetic,of,the,highest,standard,and,at,the,lowest,cost.,,

In, the, drug, industry, at, large,, quality( management, is, usually, defined, as, the, aspect, of, management, function, that,
determines,and,implements,the,“quality,policy”,,i.e.,the,overall,intention,and,direction,of,an,organization,regarding,
quality,,as,formally,expressed,and,authorized,by,top,management.,The,basic,elements,of,quality,management,are:,
, , —,,an,appropriate,infrastructure,or,“quality,system”,,encompassing,the,organizational,structure,,procedures,,
processes,and,resources;,,
, , —,,systematic,actions,necessary,to,ensure,adequate,confidence,that,a,product,(or,service),will,satisfy,given,
requirements,for,quality.,The,totality,of,these,actions,is,termed,“quality,assurance”.,,
,
Within, an, organization,, quality, assurance, serves, as, a, management, tool., In, contractual, situations,, quality, assurance,
also, serves, to, generate, confidence, in, the, supplier., The, concepts, of, quality, assurance,, GMP, and, quality, control, are,
interrelated,aspects,of,quality,management.,
,
Quality( assurance, (QA), is, the, overall, organizational, body, designed, to, assure, product, quality., It, is, a, wideAranging,
concept,covering,all,matters,that,individually,or,collectively,influence,the,quality,of,a,product.,It,is,the,totality,of,the,
arrangements, made, with, the, object, of, ensuring, that, pharmaceutical, products, are, of, the, quality, required, for, their,
intended, use., Quality, assurance, therefore, incorporates, GMP, and, other, factors,, including, product, design, and,
development.,,

The,manufacturer,must,assume,responsibility,for,the,quality,of,the,pharmaceutical,products,to,ensure,that,they,are,
fit,for,their,intended,use,,comply,with,the,requirements,of,the,marketing,authorization,and,do,not,place,patients,at,
risk,due,to,inadequate,safety,,quality,or,efficacy.,The,attainment,of,this,quality,objective,is,the,responsibility,of,senior,
management,and,requires,the,participation,and,commitment,of,staff,in,many,different,departments,and,at,all,levels,
within, the, company,, the, company’s, suppliers,, and, the, distributors., To, achieve, the, quality, objective, reliably, there,
must,be,a,comprehensively,designed,and,correctly,implemented,system,of,quality,assurance,incorporating,GMP,and,
quality, control., It, should, be, fully, documented, and, its, effectiveness, monitored., All, parts, of, the, quality, assurance,
system, should, be, adequately, staffed, with, competent, personnel,, and, should, have, suitable, and, sufficient, premises,,
equipment,,and,facilities.,
,
Good( manufacturing( practice( (GMP), is, that, part, of, quality, assurance, which, ensures, that, products, are, consistently,
produced,and,controlled,to,the,quality,standards,appropriate,to,their,intended,use,and,as,required,by,the,marketing,
authorization., GMP, are, aimed, primarily, at, diminishing, the, risks, inherent, in, any, pharmaceutical, production., Such,
risks, are, essentially, of, two, types:, crossAcontamination, (in, particular, of, unexpected, contaminants), and, mixAups,
(confusion),caused,by,,for,example,,false,labels,being,put,on,containers.,
!
Quality(control((QC),refers,to,the,sum,of,all,procedures,undertaken,to,ensure,the,identity,and,purity,of,a,particular,
pharmaceutical.,It,is,a,tool,which,gives,the,assurance,that,a,product,conforms,to,standards,and,specifications,through,
a, system, of, inspection,, analysis,, and, action., Such, procedures, may, range, from, the, performance, of, simple, chemical,
experiments, which, determine, the, identity, and, screening, for, the, presence, of, particular, pharmaceutical, substance,
(thin, layer, chromatography,, infrared, spectroscopy,, etc.),, to, more, complicated, requirements, of, pharmacopoeial,
monographs., Activities, extend, to, the, area, of, quality, control, laboratories, (good, laboratory, management, practices,,
models,, e.g., for, certificate, of, analysis, and, lists, of, laboratory, equipment,, and, an, external, assessment, scheme, (WHO,
website).,
,
,
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Quality, control, is, defined, in, the, European, Union, guidelines, as, that, part, of, GMP, that, is, concerned, with, sampling,,
specifications,, testing, and, with, the, organization,, documentation, and, release, procedures, which, ensure, that, the,
necessary,and,relevant,tests,are,actually,carried,out,and,that,materials,are,not,released,for,use,,nor,products,released,
for, sale, or, supply,, until, their, quality, has, been, judged, to, be, satisfactory., Quality, control, can, have, no, effect, on, the,
quality,of,the,product.,It,is,merely,a,measuring,process.,
,
The,relationship,between,quality,management,,QA,,GMP,and,QC,can,be,viewed,as,a,type,of,cascade,arrangement,as,
shown,in,Figure,1.,,
,
Quality,
Management,

Quality,
Assurance,

GMP,

Quality,
Control,,
,
Figure,1.,The,relationship,between,quality,management,,QA,,GMP,and,QC.,
,
Quality,management,,with,the,overall,policy,of,the,organization,towards,quality,,comes,above,everything,else.,Next,
comes,quality,assurance,,which,is,the,unit,that,ensures,the,policy,is,achieved.,GMP,is,a,part,of,quality,assurance;,it,
deals,with,risks,that,cannot,be,tested,and,builds,quality,into,the,product.,Quality,control,is,a,part,of,GMP:,the,part,
that, is, focused, on, testing, of, the, environment, and, facilities,, as, well, as, testing, of, the, materials,, components, and,
product,in,accordance,with,the,standard.,
(
Quality! is! the, suitability, of, either, a, drug, substance, or, drug, product, for, its, intended, use., This, is, the, combination, of,
attributes, or, characteristics, (i.e.,, identity,, strength,, and, purity), of, a, product, which,, when, compared, to, a, standard,,
serves,as,a,basis,for,measuring,the,uniformity,of,the,product,and,determines,its,degree,of,acceptability.,The,quality,of,
drug, substances, and, drug, products, is, determined, by, their, design,, development,, inAprocess, controls,, GMP, controls,,
and,process,validation,,and,by,specifications,applied,to,them,throughout,development,and,manufacture.,,
,
In,enforcing,current,GMP,to,achieve,the,desired,goal,of,delivering,a,safe,,pure,and,effective,product,at,the,lowest,cost,
to,the,consumer,,a,specific,group,must,be,organized,to,be,the,core,of,the,company’s,quality,audit,program.,Thus,,the,
quality,control,department,is,organized,to,maintain,the,quality,of,products,to,a,prescribed,level.,The,most,effective,
organization,establishes,direct,reporting,from,quality,control,department,to,top,management.,The,structure,in,Figure,
2,is,recommended,to,avoid,conflict,of,interest,in,a,manufacturing,firm.,
,
The,overarching,philosophy,articulated,in,both,the,current,GMP,regulations,and(in,robust,modern,quality,systems,is:,
Quality(should(be(built(into(the(product,(and(testing(alone(cannot(be(relied(on(to(ensure(product(quality.,
,
With,this,responsibility,,a,quality,control,system,is,established,at,the,conception,of,a,new,product,,during,production,
of,the,batch,,and,during,distribution,of,the,commercial,package.,This,system,is,a,combination,of,those,administrative,
and, technical, procedures, which, must, be, used, to, produce, and, deliver, a, safe,, pure,, and, effective, product, to, the, end,
user.,,
,
The,potential,benefits,derived,from,a,quality,control,system,are,as,follows.,
1. The,system,minimizes,or,eliminates,the,risk,of,marketing,unsafe,products.,
2. It,guarantees,conformance,to,regulatory,requirements.,
3. It,guarantees,product,efficacy.,
4. It,reduces,operating,costs.,
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 5. It,reduces,operating,losses.,
6. It,produces,higher,employee,morale.,
7. It,motivates,the,pharmaceutical/medical,professions,to,sell,or,prescribe,the,product.,
,

Higher,
Management,

Manufacturing,
Scientieic,V.P., V.P.,

R,&,D, QC, Purchasing, Production,

Warehouse, Maintenance,

, ,
,,,,,,,,,,Figure,2.,Reporting,responsibilities,in,a,manufacturing,firm.,
,
,
In,a,manufacturing,environment,,variety,of,people,will,have,apparently,different,goals,–,from,increasing,pressures,on,
costs,, to, increasing, technical, and, validation, requirements,, and, finally, to, quickly, release, the, products, to, the,
marketplace., , In, this, position,, the, pharmaceutical, manufacturing, personnel, are, faced, with, an, apparently,
irreconcilable,set,of,objectives,to,achieve.,The,cost,of,quality,will,help,to,achieve,all,the,objectives,in,one,go.,
,
Cost( of( quality, is, a, tool, that, has, been, used, in, many, industries,, usually, within, a, total, quality, management, or,
performance,improvement,programme.,There,are,three,main,types,of,quality,costs:,
1. Failure(costs,(costs,of,nonAquality),are,those,associated,with,getting,things,wrong.,They,can,be,tangible,costs,,
such,as,the,cost,of,rejects,or,“reworks”,,or,they,can,be,intangible,costs,,such,as,lost,sales,,damage,to,image,or,
problems,with,the,regulatory,authorities.,
2. Appraisal(costs,are,those,associated,with,checking,that,things,were,done,correctly.,It,should,be,emphasized,
that, this, is, not, valueAadding, activity, of, itself;, it, is, merely, an, historical, measurement, of, what, has, already,
happened.,
3. Prevention( costs, are, the, costs, associated, with, making, sure, that, things, will, be, done, right., This, is, the, one,
activity,of,the,three,that,can,be,considered,to,be,value,adding,
,
All, the, activities, related, to, quality, are, measured, and, categorized, as, failure,, appraisal, or, prevention, costs., By,
highlighting, the, various, costs, in, this, way,, it, makes, it, easy, to, decide, where, to, focus, efforts, in, order, to, improve,
performance,and,also,reduce,costs.,
,
,
STANDARDS,AND,SPECIFICATIONS,
,
A, specification, is, defined, as, a, list, of, tests,, references, to, analytical, procedures,, and, appropriate, acceptance, criteria,,
which,are,numerical,limits,,ranges,,or,other,criteria,for,the,tests,described.,It,establishes,the,set,of,criteria,to,which,a,
drug, substance, or, drug, product, should, conform, to, be, considered, acceptable, for, its, intended, use., "Conformance, to,
specifications",means,that,the,drug,substance,and,/,or,drug,product,,when,tested,according,to,the,listed,analytical,
procedures,,will,meet,the,listed,acceptance,criteria.,Specifications,are,critical,quality,standards,that,are,proposed,and,
justified,by,the,manufacturer,and,approved,by,regulatory,authorities,as,conditions,of,approval.,
,
Specifications, are, one, part, of, a, total, control, strategy, for, the, drug, substance, and, drug, product, designed, to, ensure,
product, quality, and, consistency., Other, parts, of, this, strategy, include, thorough, product, characterization, during,
development,, upon, which, specifications, are, based,, and, adherence, to, Good, Manufacturing, Practices;, e.g.,, suitable,
facilities,, a, validated, manufacturing, process,, validated, test, procedure,, raw, material, testing,, inAprocess, testing,,
stability,testing,,etc.,
,
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Specifications,are,chosen,to,confirm,the,quality,of,the,drug,substance,and,drug,product,rather,than,to,establish,full,
characterization,,and,should,focus,on,those,characteristics,found,to,be,useful,in,ensuring,the,safety,and,efficacy,of,the,
drug,substance,and,drug,product.,
In,a,product,,specifications,must,cover,the,following,points:,
,
1. Formula:(This, is, concise, and, precise, statement, of, the, ingredients, that, comprise, the, product,, together, with,
the,percentage,and/or,weight,of,each.(
2. Raw(material(specification:(This,should,enumerate,the,characteristics,of,all,materials,that,go,into,the,product,
and,the,permissible,range,of,purity,of,each,ingredient.,Deviation,beyond,this,range,may,be,expected,to,cause,
failure,of,the,product,to,function,as,planned,,or,,at,least,,result,in,an,undesirable,lack,of,uniformity.,Standard,
compendia,like,the,USP,,NF,,BP,,Merck,Index,,etc.,,provide,this,valuable,information.(
3. Standard(operating(procedure:, This, is, a, step, by, step, method, on, how, to, go, about, a, job., It, must, spell, out, all,
information,and,instructions,that,assure,that,variations,in,production,from,day,to,day,and,week,to,week,will,
be,held,to,within,acceptable,established,ranges.(
4. Finished(product(specification:,This,should,cover,all,characteristics,that,affect,the,proper,performance,,purity,,
safety,,and,stability,of,the,product.,Tolerances,may,be,minimum,,maximum,,or,both,,depending,on,the,nature,
of,the,situation.(
5. Packaging( material( standard:( This, should, be, set, for, everything, that, goes, around, the, product,, i.e.,, bottles,,
cans,, aluminum, foil,, cellophane,, jars,, caps,, cap, liners,, labels,, printed, inserts,, cartons,, wrapping, papers,, and,
shipping,cases.,Packaging,must,be,considered,with,the,following,points,in,mind:,
a. The,units,may,have,to,run,on,a,highAspeed,line.(
b. They,may,involve,a,complicated,assembly.(
c. The,package,may,be,functional.(
d. The,package,must,be,completely,compatible,with,the,product.(
e. The,package,must,protect,the,product,and,assure,its,stability,(
f. The,package,must,ship,well.(
6. Testing( methods:( These, are, indispensible, in, assuring, conformity, to, standards., Since, they, play, such, a, vital,
role,,testing,procedures,must,be,standardized,so,that,they,yield,results,of,comparable,precision,and,accuracy,
in, the, hands, of, different, operators, and, laboratories., The, tests, must, be, validated, to, ensure, precision, and,
accuracy,on,application.(
,
A, standard, is, a, document, that, provides, requirements,, specifications,, guidelines, or, characteristics, that, can, be, used,
consistently, to, ensure, that, materials,, products,, processes, and, services, are, fit, for, their, purpose, (ISO)., ISO,
International,Standards,ensure,that,products,and,services,are,safe,,reliable,and,of,good,quality.,The,ISO,9000,family,
addresses, various, aspects, of, quality, management, and, contains, some, of, ISO’s, best, known, standards., The, standards,
provide, guidance, and, tools, for, companies, and, organizations, who, want, to, ensure, that, their, products, and, services,
consistently, meet, customer’s, requirements,, that, quality, is, consistently, improved, and, that, the, system, is, being,
operated,effectively.,
,
Standards,in,the,ISO,9000,family,include:,
ISO,9001:2008,A,sets,out,the,requirements,of,a,quality,management,system,(QMS),
ISO,9000:2005,A,covers,the,basic,concepts,and,language,
ISO,9004:2009,A,focuses,on,how,to,make,a,quality,management,system,more,efficient,and,effective,
ISO,9011:2011,A,sets,out,guidance,on,internal,and,external,audits,of,quality,management,systems.,
,
ISO,9001,
The, organization, shall, establish,, document,, implement, and, maintain, a, quality, management, system, and,continually,
improve,its,effectiveness,in,accordance,with,the,requirements,of,this,International,Standard.,
1. The,quality,management,system,documentation,shall,include:,
a. Documented,statements,of,a,quality,policy,and,quality,objectives,,
b. A,quality,manual,,
c. Documented,procedures,required,by,this,International,Standard,,
d. Documents,needed,by,the,organization,to,ensure,the,effective,planning,,operation,and,control,of,its,
processes,,and,
e. Records,required,by,this,International,Standard,
,
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 2. The,organization,shall,conduct,internal,audits,at,planned,intervals,whether,the,quality,management,system,
a. Conforms,to,the,planned,arrangements,to,the,requirements,of,this,International,Standard,and,to,the,
quality,management,system,requirements,established,by,the,organization,,and,
b. Is,effectively,implemented,and,maintained.,
3. The,organization,shall,continually,improve,the,effectiveness,of,the,QMS,through,the,use,of,the,quality,policy,,
quality,objectives,,audit,results,,analysis,of,data,,corrective,and,preventive,actions,and,management,review.,
a. The, organization, shall, take, action, to, eliminate, the, cause, of, nonconformities, in, order, to, prevent,
recurrence.,Corrective(actions,shall,be,appropriate,to,the,effects,of,the,nonconformities,encountered.,
b. The,organization,shall,determine,action,to,eliminate,the,causes,of,potential,nonconformities,in,order,
to, prevent, their, occurrence., Preventive( actions, shall, be, appropriate, to, the, effects, of, the, potential,
problems.,
,
,
QUALITY,VARIATION,
,
Quality, characteristics, are, subject, to, variation., Quality, variation, which, is, not, confined, within, the, specific, range,,
tolerance,or,limit,,will,grow,to,uncontrolled,magnitude,and,will,encourage,the,proliferation,of,errors;,thus,producing,
a,defective,product.,In,a,broad,sense,,a,defect,is,an,undesirable,characteristic,of,a,product.,It,is,defined,as,a,failure,to,
conform,to,specifications.,A,unit,of,a,product,,which,contains,one,or,more,defects,,is,called,a,defective.,Defects,can,be,
classified,as,follows:,
,,
1. According,to,measurability:,
a. Variable( defect, –, a, defect, which, can, be, measured, directly, by, instruments, giving, dimensions, of,
length,,weight,,height,,thickness,,concentration,,volume,,viscosity,,pH,or,size,particles.,
b. Attribute(defect, –, a, defect, which, cannot, be, measured, directly, by, instruments., It, shows, mainly, the,
conformance, or, nonconformance, of, the, material, to, specifications., This, applies, to, many, things, that,
can,be,judged,only,by,odor,or,visual,examination,like,color,,clarity,,sheen,,cleanliness,,smoothness,,
taste,and,presence,or,absence,of,a,characteristic.,
2. According,to,seriousness,or,gravity:,
a. Critical( defect, –, a, defect, which, may, endanger, life, or, property, and, may, render, the, product, nonA
functional.,Absence,or,warning,in,a,label,for,a,potent,drug,or,disintegration,time,of,one,hour,for,an,
analgesic,are,considered,critical,defects.,
b. Major( defect, –, a, defect, which, may, affect, the, function, of, the, object, and, therefore,, may, render, the,
product,useless.,The,presence,of,a,crack,in,a,bottle,is,a,major,defect.,
c. Minor(defect,–,a,defect,which,does,not,endanger,life,nor,will,it,affect,the,function,but,nevertheless,
remains,a,defect,since,it,is,outside,the,prescribed,limits.,An,example,of,a,minor,defect,is,the,slight,
deviation,of,the,color,of,the,label,from,the,color,standards.,
3. According,to,nature:,
a. Ocular(defect,–,a,defect,that,is,visible,,e.g.,,foreign,particulate,contamination.,
b. Internal(defect,–,a,defect,which,is,not,seen,although,present,,e.g.,,a,subpotent,drug,product.,
c. Performance(defect,–,a,defect,in,function,,e.g.,,a,suppository,that,does,not,melt,at,body,temperature.,
,
The, manufacture, of, a, cosmetic, or, drug, product, frequently, involves, a, series, of, simple, to, complex, steps., The, risk, of,
errors,increases,as,the,number,of,materials,used,in,the,formulation,becomes,larger,,and,the,manufacturing,processes,
become,more,complex.,Errors,may,be,due,to,chance,or,assignable,causes,such,as:,materials,,machines,,methods,and,
men.,
,
, Sources,of,variation:,
1. Materials,
a. Variation,between,suppliers,of,same,substance.,
b. Variation,between,batches,from,same,supplier.,
c. Variation,within,a,batch.,
2. Machines,
a. Variation,of,equipment,for,the,same,process.,
b. Difference,in,adjustment,of,equipment.,
c. Aging,and,improper,care.,
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 3. Methods,
a. Inexact,procedures.,
b. Inadequate,procedures.,
c. Negligence,by,chance.,
4. Men,
a. Improper,working,conditions.,
b. Inadequate,training,,and,understanding.,
c. Dishonesty,,fatigue,and,carelessness.,
,
,
ORGANIZATION,OF,QUALITY,CONTROL,
,
Each,pharmaceutical,or,cosmetic,company,has,an,organizational,structure,which,differ,somewhat,from,those,if,other,
companies,in,scope,and,responsibilities.,Figure,3,shows,a,typical,organization,within,the,quality,control,department.,
,
,
,
, Quality,Control,
, Material,
,
,
, Materials, Biological, Specieications, Quality,
, Inspection, Analytical, Testing, &,Analytical, Coordinating,
, Laboratory,
Section, Laboratory, Development, Ofeice,
,
Figure,3.,A,quality,control,organizational,chart.,
,
,
Materials(Inspection(Section,
, ,
Inspectors, are, alert, individuals, who, had, experience, and, who, are, familiar, with, the, physical, characteristics, of, the,
materials,they,sample,and,are,well,versed,in,sampling,techniques.,The,functions,of,this,section,are:,
1. To,sample,and,examine,all,raw,materials,received.,
2. To,sample,and,conduct,physical,tests,on:,
a. All,shipments,of,packaging,materials,
b. All,manufacturing,,filling,and,packaging,operations,
3. To,maintain,periodic,examination,on,the,quality,of,inventories,throughout,all,phases,of,storage,,shipping,and,
distribution.,
4. To,perform,an,audit,which,is,independent,of,the,work,done,by,production,personnel.,
,
Inspection,stations,are,placed,in,the,area,of,operation,,viz.,,warehouse,,manufacturing,and,packaging,areas.,
,
Analytical(Laboratory(
The, analytical, laboratory, should, be, in, an, accessible, area, and, protected, from, noise, and, vibration, common, to,
manufacturing,operations.,
,
In,order,to,perform,physical,and,chemical,analysis,,the,analysts,should,know,the,usual, gravimetric,and,volumetric,
analysis.,Furthermore,,they,should,be,skillful,in,handling,instruments,for,ultraviolet,and,infrared,spectrophotometry,,
nonAaqueous, titrimetry,, autoanalysis,, polarography,, xAray, diffraction,, xAray, fluorescence,, spectrophotofluorimetry,,
radioactive, tracer, techniques, and, chromatography,, viz.:, column,, gas,, paper,, thin, layer, and, high, performance, liquid,
chromatography.,
,
Biological(Testing(Laboratory,
The, staff, in, a, biological, testing, laboratory, should, be, well, trained, and, experienced, in, both, simple, and, complex,
microbiological, procedures, and, biological, interactions., They, should, possess, a, high, degree, of, skill, and, judgment, in,
order, to, perform, the, job., A, veterinarian, is, recommended, to, supervise, the, care, and, maintenance, of, the, various,
species,of,animals,used,in,the,tests.,The,functions,of,this,laboratory,are:,

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 1. To, perform, and, evaluate, microbiological, and, pharmacological, assays,, sterility,, pyrogen, and, bacteriological,
tests,,irritation,,safety,or,acute,toxicity,tests.,
2. To,conduct,environmental,monitoring.,
,
Sterile,conditions,should,be,provided,for,areas,where,biological,tests,are,conducted.,Noise,should,be,precluded,from,
areas,where,animals,are,used.,An,animal,house,should,be,maintained,as,a,separate,unit,from,the,main,laboratory,,if,
necessary.,
,
, Microbiological,Tests,
1. Antimicrobial(Effectiveness(Testing,
This, test, is, to, demonstrate, the, effectiveness, of, antimicrobial, protection., Added, antimicrobial,
preservatives, must, be, declared, on, the, label., Antimicrobial, preservatives, are, substances, added, to,
nonsterile,dosage,forms,to,protect,them,from,microbiological,growth,or,from,microorganisms,that,
are, introduced, inadvertently, during, or, subsequent, to, the, manufacturing, process., In, the, case, of,
sterile, articles, packaged, in, multipleAdose, containers,, antimicrobial, preservatives, are, added, to,
inhibit, the, growth, of, microorganisms, that, may, be, introduced, from, repeatedly, withdrawing,
individual,doses.,
,
Test,organisms,include,Candida(albicans,(Aspergillus(niger,(Escherichia(coli,(Pseudomonas(aeruginosa,(
and,Staphylococcus(aureus.,All,media,used,in,the,test,must,be,tested,for,growth,promotion:,SoybeanA
Casein,Digest,Broth,or,Agar,for,E.(coli,(P.(aeruginosa,(and,S.(aureus,(and,Saboraud,Dextrose,Agar,or,
Broth,for,C.(albicans,and,A.(niger.(
(
2. Microbial(Limit(Test,
This, test, is, for, the, estimation, of, the, number, of, viable, aerobic, microorganisms, present, and, for,
freedom, from, designated, microbial, species, in, pharmaceutical, articles, of, all, kinds,, from, raw,
materials,to,the,finished,forms.,
,
Test,organisms,are,Staphylococcus(aureus,(Escherichia(coli,(Pseudomonas(aeruginosa,,and,Salmonella.,
Culture,media,that,can,be,used,are,pH,7.2,Phosphate,Buffer,,Fluid,Soybean–Casein,Digest,Medium,,
or,Fluid,Lactose,Medium,to,name,a,few.,
,
3. Sterility(Tests,
This,test,is,applied,to,substances,,preparations,,or,articles,which,,according,to,the,Pharmacopeia,,are,
required, to, be, sterile., However,, a, satisfactory, result, only, indicates, that, no, contaminating,
microorganism,has,been,found,in,the,sample,examined,under,the,conditions,of,the,test.,
,
This,test,may,be,carried,out,using,the,techniques,of,Membrane(Filtration,or,by,Direct(Inoculation(of(
the( Culture( Medium, with, the, product, to, be, examined., For, membrane, filtration, technique,, use,
membrane,filters,having,a,nominal,pore,size,not,greater,than,0.45,μm,,in,which,the,effectiveness,to,
retain,microorganisms,has,been,established.,Cellulose,nitrate,filters,are,used,for,aqueous,,oily,,and,
weakly, alcoholic, solutions;, and, cellulose, acetate, filters, are, used, for, strongly, alcoholic, solutions.,
Specially, adapted, filters, may, be, needed, for, certain, products., For, direct, inoculation, of, the, culture,
medium,technique,,the,preparation,to,be,examined,is,directly,inoculated,into,the,culture,medium,so,
that,the,volume,of,the,product,is,not,more,than,10%,of,the,volume,of,the,medium,,unless,otherwise,
prescribed., If, the, product, to, be, examined, has, antimicrobial, activity,, carry, out, the, test, after,
neutralizing,this,with,suitable,neutralizing,substance,or,by,dilution,in,a,sufficient,quantity,of,culture,
medium., Fluid, Thioglycollate, Medium, is, primarily, intended, for, the, culture, of, anaerobic, bacteria.,
However,, it, will, also, detect, aerobic, bacteria., SoybeanACasein, Digest, Medium, is, suitable, for, the,
culture,of,both,fungi,and,aerobic,bacteria.,
,
Biological,Tests,
1. AntibioticsSMicrobial(Assay,
The, activity, (potency), of, antibiotics, may, be, demonstrated, under, suitable, conditions, by, their,
inhibitory, effect, on, microorganisms., ,A, reduction, in, antimicrobial, activity, also, will, reveal, subtle,
changes,not,demonstrable,by,chemical,methods.,,
,

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 Two, general, methods, are, employed,, the, cylinderAplate, or, ‘‘plate’’, assay, and, the, turbidimetric, or,
‘‘tube’’, assay., The, first, depends, upon, diffusion, of, the, antibiotic, from, a, vertical, cylinder, through, a,
solidified,agar,layer,in,a,petri,dish,or,plate,to,an,extent,such,that,growth,of,the,added,microorganism,
is, prevented, entirely, in, a, circular, area, or, ‘‘zone’’, around, the, cylinder, containing, a, solution, of, the,
antibiotic.,The,turbidimetric,method,depends,upon,the,inhibition,of,growth,of,a,microbial,culture,in,
a, uniform, solution, of, the, antibiotic, in, a, fluid, medium, that, is, favorable, to, its, rapid, growth, in, the,
absence,of,the,antibiotic.,
,
2. Bacterial(Endotoxins(Test,,
The, Bacterial, Endotoxins, Test, (BET), is, a, test, to, detect, or, quantify, endotoxins, from, GramAnegative,
bacteria, using, amoebocyte, lysate, from, the, horseshoe, crab, (Limulus, polyphemus( or, Tachypleus(
tridentatus).(
,
There,are,three,techniques,for,this,test:,the,gelAclot,technique,,which,is,based,on,gel,formation;,the,
turbidimetric, technique,, based, on, the, development, of, turbidity, after, cleavage, of, an, endogenous,
substrate;, and, the, chromogenic, technique,, based, on, the, development, of, color, after, cleavage, of, a,
synthetic, peptideAchromogen, complex., Proceed, by, any, of, the, three, techniques, for, the, test., In, the,
event, of, doubt, or, dispute,, the, final, decision, is, made, based, upon, the, gelAclot, limit, test, unless,
otherwise, indicated, in, the, monoA, graph, for, the, product, being, tested., The, test, is, carried, out, in, a,
manner,that,avoids,endotoxin,contamination.,
,
3. Biological(Reactivity(Tests,(In(Vitro,
These,tests,are,designed,to,determine,the,biological,reactivity,of,mammalian,cell,cultures,following,
contact, with, the, elastomeric, plastics, and, other, polymeric, materials, with, direct, or, indirect, patient,
contact,or,of,specific,extracts,prepared,from,the,materials,under,test.,
,
Three,tests,are,described,(i.e.,,the,Agar(Diffusion(Test,(the,Direct(Contact(Test,(and,the,Elution(Test).(
a. Agar,Diffusion,Test,
This,test,is,designed,for,elastomeric,closures,in,a,variety,of,shapes.,The,agar,layer,acts,as,a,
cushion, to, protect, the, cells, from, mechanical, damage, while, allowing, the, diffusion, of,
leachable,chemicals,from,the,polymeric,specimens.,
b. Direct,Contact,Test,
This, test, is, designed, for, materials, in, a, variety, of, shapes., The, procedure, allows, for,
simultaneous,extraction,and,testing,of,leachable,chemicals,from,the,specimen,with,a,serumA,
supplemented, medium., The, procedure, is, not, appropriate, for, very, lowA, or, highAdensity,
materials,that,could,cause,mechanical,damage,to,the,cells.,
c. Elution,Test,
This, test, is, designed, for, the, evaluation, of, extracts, of, polymeric, materials., The, procedure,
allows,for,extraction,of,the,specimens,at,physiological,or,nonphysiological,temperatures,for,
varying, time, intervals., It, is, appropriate, for, highAdensity, materials, and, for, doseAresponse,
evaluations.,
,
4. Biological(Reactivity(Tests,(In(Vivo(
The, following, tests, are, designed, to, determine, the, biological, response, of, animals, to, elastomerics,,
plastics,, and, other, polymeric, material, with, direct, or, indirect, patient, contact,, or, by, the, injection, of,
specific,extracts,prepared,from,the,material,under,test.,
,
Three, tests, are, described., The, Systemic( Injection( Test( and, the, Intracutaneous( Test( are, used, for,
elastomeric, materials,, especially, to, elastomeric, closures, for, which, the, appropriate, Biological(
Reactivity(Tests,(In(Vitro,have,indicated,significant,biological,reactivity.,These,two,tests,are,used,for,
plastics,and,other,polymers,in,addition,to,a,third,test,,the,Implantation(Test,,to,test,the,suitability,of,
these, materials, intended, for, use, in, fabricating, containers, and, accessories, thereto,, for, use, in,
parenteral,preparations,,and,for,use,in,medical,devices,,implants,,and,other,systems.,
,
The,systemic,injection,test,and,the,intracutaneous,test,are,designed,to,determine,the,systemic,and,
local,,respectively,,biological,responses,of,animals,to,plastics,and,other,polymers,by,the,singleAdose,
injection,of,specific,extracts,prepared,from,a,sample.,The,implantation,test,is,designed,to,evaluate,

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 the,reaction,of,living,tissue,to,the,plastic,and,other,polymers,by,the,implantation,of,the,sample,itself,
into,animal,tissue.,
,
a. Systemic,Injection,Test,
This,test,is,designed,to,evaluate,systemic,responses,to,the,extracts,of,materials,under,test,
following,injection,into,mice.,
b. Intracutaneous,Test,
This, test, is, designed, to, evaluate, local, responses, to, the, extracts, of, materials, under, test,
following,intracutaneous,injection,into,rabbits.,
c. Implantation,Test,
This,test,is,designed,for,the,evaluation,of,plastic,materials,and,other,polymeric,materials,in,
direct,contact,with,living,tissue.,
,
5. Pyrogen(Test(
This,test,is,designed,to,limit,to,an,acceptable,level,the,risks,of,febrile,reaction,in,the,patient,to,the,
administration,, by, injection,, of, the, product, concerned., The, test, involves, measuring, the, rise, in,
temperature, of, rabbits, following, the, intravenous, injection, of, a, test, solution, and, is, designed, for,
products, that, can, be, tolerated, by, the, test, rabbit, in, a, dose, not, to, exceed, 10, mL, per, Kg, injected, IV,
within,a,period,of,not,more,than,10,minutes.,
,
If, no, rabbit, shows, an, individual, rise, in, temperature, of, 0.5o, or, more, above, its, respective, control,
temperature,,the,product,meets,the,requirements,for,the,absence,of,pyrogens.,If,any,rabbit,shows,an,
individual, temperature, rise, of, 0.5o, or, more,, continue, the, test, using, five, other, rabbits., If, not, more,
than,three,of,the,eight,rabbits,show,individual,rises,in,temperature,of,0.5o,or,more,and,if,the,sum,of,
the, eight, individual, maximum, temperature, rises, does, not, exceed, 3.3o,, the, material, under,
examination,meets,the,requirements,for,the,absence,of,pyrogens.,
,

Specifications(and(Analytical(Development(
This,section,should,have,firm,background,not,only,in,the,principles,of,quality,control,and,analytical,procedures,but,
also,in,manufacturing,,research,,product,development,and,in,statistics,in,order,to,perform,the,following,functions:,
1. To, coordinate, with, research,, product, development,, production,, sales, and, management, towards,
improvement,of,a,product.,
2. To,establish,specifications,for,raw,and,packaging,materials.,
3. To,validate,existing,and,tentative,procedures,of,testing.,
4. To,develop,new,assay,methods,for,inAhouse,use.,
5. To,develop,and,improve,specifications,for,quality,characteristics,of,the,final,product,being,manufactured.,
,
Quality(Coordination(Office,
This, section, should, be, accessible, to, all, manufacturing, and, packaging, operations, since, documentation, is, its, main,
responsibility.,The,functions,of,this,section,are:,
1. To, maintain, and, store, records, that, represents, the, history, of, the, batch, from, start, to, finish., These, records,
include, the, batch, and, master, formula, records,, raw, material, analytical, records,, printed, and, packaging,
material,inspection,reports,and,retention,files.,
2. To,be,able,to,furnish,data,that,will,aid,in,analyzing,product,performance,in,the,market.,These,documents,are,
the,stability,studies,and,returned,goods,reports.,
3. To, investigate, customer, complaints, or, inquiries, on, product, quality, and, to, forward, the, results, of, the,
investigations,in,the,form,of,technical,reports,to,the,sales,organization.,
4. To,call,the,attention,of,the,appropriate,development,group,any,aspect,that,provides,a,basis,for,improvement,
of,a,product,for,consideration,and,action.,
5. To, provide, data, that, give, specific, and, legal, status,, i.e.,, data, generated, from, the, use, of, recognized, standard,
compendia.,This,is,essentially,a,function,of,the,distribution,section,or,warehouse.,
6. To,maintain,and,develop,SOP’s.,
,
,
,
,
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References:,
,
FDA, Guidance, for, Industry, on, Quality, Systems, Approach, to, Pharmaceutical, CGMP, Regulations., In:, Pharmaceutical(
CGMP(Regulations.,Office,of,Compliance,in,the,Center,for,Drug,Evaluation,and,Research,(CDER),in,cooperation,with,
the,Center,for,Biologics,Evaluation,and,Research,(CBER),,the,Center,for,Veterinary,Medicine,(CVM),,and,the,Office,of,
Regulatory,Affairs,(ORA),,2006.,
,
ICH, Harmonised, Tripartite, Guideline, on, Pharmaceutical, Quality, System, Q10., In:, International( Conference( On(
Harmonisation( Of( Technical( Requirements( For( Registration( Of( Pharmaceuticals( For( Human( Use.( Step( 4( version.( ICH,
Expert,Working,Group,,2008.,
,
ICH, Harmonised, Tripartite, Guideline, on, Specifications:, Test, Procedures, And, Acceptance, Criteria, For, New, Drug,
Substances, And, New, Drug, Products:, Chemical, Substances, Q6A., In:, International( Conference( On( Harmonisation( Of(
Technical( Requirements( For( Registration( Of( Pharmaceuticals( For( Human( Use.( Step( 4( version.( ICH, Expert, Working,
Group,,2005.,
,
Lerma,, Norma, V., and, Marina, O., Osi., Drug( and( Cosmetic( Quality( Control( with( Instrumentation,, 2nd, ed., Manila,,
Philippines:,UST,Publishing,House,,1996.,
,
McCormick,,Kate.,Quality.(Pharmaceutical,Engineering,Series.,Oxford,,2002.,
,
Philippine, National, Standard, ISO, 9001:2000, Quality, Management, Systems, –, , Requirements., In:, Bureau( of( Product(
Standards.,Philippines,,Department,of,Trade,and,Industry,,2000.,
,
United,States,Pharmacopeia–National,Formulary,(USP–NF),35/30.,The,United,States,Pharmacopeial,,
,Convention,,2012.,
,
WHO,guidelines,on,quality,assurance,of,pharmaceuticals,:,a,compendium,of,guidelines,and,related,materials.,Vol.,2,,
Good(manufacturing(practices(and(inspection.(–(2nd(ed.,Geneva,,World,Health,Organization,,2007.,,
,
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