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Pharmaceutical QC & QA Elective Course By Ayalew DesyeAbegaz (B.Pharm) Pharmaceutical Chemistry Course & Research Unit Department of Pharmacy College of Medicine & H ealth Sciences Wollo Universit y Dessie , Ethio pia 1

Pharmaceutical Qual ity Assurance . Outline – Introduction and definitions – Quality assurance of medicines – Elements of quality assurance for phar maceuticals – QC & operational task of QC – Quality assurance of drug procurement 2

Rationale for this Modu le . Quality medicines are safe, effective and efficient tools for treatment of d isease . Poor quality ( sub - standard ) medicines may not produce desired effects , may cause harm . Errors in production can lead to sub - standard medicines . Quality Ass urance principles can be used to: – detect errors or problems in production – ensure suppliers conform to standards and expec tations 3

Pharmaceutical Analysis . To ensure the safety , efficacy and quality of pha rmaceutical products – It is important to gain the information about the qualitative and quantitative composition of substa nces . i.e. to fin d out what a substance is composed of and exactly how much. . Quantitative test – measures the amoun t of a substance present . Qualitative test – determines whether the substance being tested for is present or absent . Video 4

. What to test ? th e drug product . Why to test ? ensures the safet y, efficacy and quality of pharmaceutical products . How to test ? compendial and non - compendial met hods presented in regula tory documents . A nalytical method used to achieve Qualitative and quantitative analysis Pharmaceu tical analysis … 5

Determinants of Medicine Qualit y . Identity : Active ingredient . Purity : Not contaminated with potenti ally harmful substances . Potency : Usually 90– 110% of the labeled amount . Uniformity : Consistency of color , shape , size . Bioavailability : Interchangeable products ? . Stability: Ensuring medicine activity for stated period 6

Quality is ….. Invisible when GOOD Impossible to ign ore when BAD 7

What is Quality? . Quality: – The totality of features & c haracteristics of a medicinal product and its ability to satisfy the stated &/or implied needs – Meeting requirements of specific cu stomer needs – Compliance wi th specifications . Quality can be achieved by three managerial processes which include: – Quality pla nning (QP): . The initial activity of the plan is to ide ntify the customers and their need . Then develop product and process d esign to respond to the need of the customers 8

Quality … – Quality control ( QC ): . A regulatory process which measures the qualit y performance of the products . The activities of QC involve laboratory proc edures – Quality improvement ( QI ): . Facilitates in improving deficiencies through the feedback from customers or regul atory bodies . The only way to achieve qual ity is to manufacture the product correctly . Quality cannot be achieved merely by checking , ex amination and testing . . “ There should not be any compromise for qual ity” 9

. In popular practice , the quality of medicines or pharma ceutical products is assured through qua lity control . . Quality assurance department must adop t “ good laboratory practice ” – to ensure reliability and accuracy of results given out by them . . Consequently the manufac ture and the control of drugs are very responsible task and they need substantial knowledge of the science . . Quality control is a concept , whic h strive – to produce a perfect product by series of measures designe d to prevent and eliminate e rrors at different stages of production . Quality … 10

Terminolo gy . Quality Assurance ( QA ) – It is the sum of all activities and responsibilities intended to ensure the products meet all the applicable quality specificat ions in the final dosage form . – “ a planned system of activities designed to ensure effective quality control . ” – Efficient QA program: – To monitor and evaluate effectiveness of polici es and procedures of quality control 11

Terminology … . Good manufacturing p ractice (GMP) – The part of the QA that products are c onsistently produced and controlled to the quality standard appropriate to their intended use . 12

Terminology … . Quality control ( QC ) – The part of GMP concerned with sampling, specification and testing and organ ization , do cumentation and release o f procedure to ensure the quality of the drug . – “ a planned coherent syst em of activities designed to provide quality product . ” – involve in - process , post - process & finished goods cont rol including stability testing – TQC ( Total Quali ty Control) 13

QA GMP QC/ GLP Quality Relationship Quality Management Quality Assurance Quality Cont rol GMP 14

Pharmaceutica l manufacturing Quality product 15

> The customersits at the centre of the quality system activities > The customer , meaning the patient in terms of pharmace uticals, is served by three bodies ( speci al product , services and science ) 16

Quality Assurance . QA : – Covers all maters that individually or collectively influence the quality of the product – Is not the duty of one organization unit in the company alone . The responsibility of all staff members who can in fluence product quality – Must be independent of financial pressur e – Must ensure the quality policies are followed All Staff 17

DRUG PRODUCT QUALITY TRANSPORT DISTRIBUTION DISPENSING & USE MANUFACURING PROCESSES & PROCEDURES HUMAN RESOURCES- PROFESSIONALS LABELLING & PRODUCT INFROMATION IMPORT & EXPORT CONTROL LEGISLATIVE FRAMEWORK REGULATIONS RAW MATERIALS- ACTIVE & INACTIVE FACTORS IN DRUG QUALITY ASSUR ANCE QC & ANALYSIS PACKAGING STORAGE 18

Components of Quality Assur ance . Internal Quality control : IQC – Nature : Concur rent – Performed by : lab staff – Objective: Reliable results on a daily basis . External qu ality assessment: EQA – Nature : Retrospecti ve to evaluate IQC – Performed b y: Independent agency – Objective : Ensure in ter-laboratory comparability 19

Quality sys tems Objectives - To prevent risks - To detect deviati ons - To correct error s - To improve effici ency - To reduce cos ts 20

Pre analytical Analytical Post analyt ical Right specim en Laboratory professionals Recording Right collection Reagents Interpretation Right labeling Equipment Turnaround tim e Right quantity Selection of test - SOP Report to r ight user Right transport Records Right storage Bio-Safety Factors influencing quality 21

The Quality As surance Cycle Record Keepi ng Quality Control Testing •Data and Lab Management •Safety •Customer Service Personnel Compet ency Test Evaluations Patient / Client P rep Sample Collection Sample Receipt and Accessioning Sample Tra nsport Reporting 22

Principal Acti vities of QA 1 . QA ensures that pr oducts are formulated and developed in accordance with QA principles - Product quality begins with development process - All of the development work sho uld be undertaken with a commitmen t to QA - Enable easier adherence to QA principle in other area of manufacturing 23

GxP Regulation Along the D rug Life GCP GMP GMP = process based GCP = clinical based GLP = study based NO GMP/GLP!!! GLP 24

Principal Activities of QA … 2 . QA identify al l management responsibilities , with written job description and organization diagram . - Assist in ensuring that there are suff icient qualified & experienced people available to carry out their responsibi lities . 3 . QA provides SOPs for all manufactur ing and testing methods . - State what should be done and ho w ? 25

Principal Activities of QA … 4 . QA ensures that ther e are up-to-date written procedures for supply and use of starting and pa ckaging material . - Includes all the procedures relating to purc hasing, reception , sampling and t esting materials . 26

Principal Activities of QA … 5 . QA ensures that there are up - to - date , written procedures to control all starting mate rials, intermediate and bulk produ cts – Proper management of all the handlin g & storage of materials is essential . Apply to all mater ials whether incoming, intermediate or finished goods for s ale . 27

Principal Activities of QA … 6 . QA system must also ensure that there are w ritten, up-to - date SOPs de scribing how the product is to be processed and checked . 7 . QA ensures that no product is released for distri bution before it has been checked by the authorized person - Product has b een produced and controlled in accordance with the established SOPs an d requirements of the market ing authorizations . 28

Principal Activities of QA … 8 . QA ensures that appropriate c onditions are provided for all storage & distributions - During product develop ment - Stability testing indicates condition under which product mu st be stored - Arrangement should be in place throu ghout the storage and distribution chain t o ensure that the product will not be exposed to conditions that could adversely affect it. 29

Principal Activities of QA … 9 . A QA system must ensure that there is a self i nspection process available and implemented , leadi ng to program of critical self evaluation and continuous improvements . - There should be an internal audit function with in department ( self - inspection ) - Is back up by quality audit , charged with looki ng at all department & assessing the application of the quality system within a com pany. 30

Compositio n of QA program 1. Appropriate up - to - date methodology – Analytical meth odologies are dynamic . Old methods g et either replaced by new ones or modified b/c of the advantages of sensitivity and selectiv ity – Procedures that should be fu lfilled with regard to methodology A. Analytical measurements should be performed using » Standard official method ( USP , BP , EP ) » Procedures developed & certified by the manufacturers » Procedures v alid through peer reviewed in literature 31

. Approach – Evaluating in the presence of acc eptable comparative method – Evaluating in the absen ce of documented methods (linearity, precision , accuracy ) B. Methods modified / adopt ed should be always evaluated by a written protocol pr ior to use. C. Written guideline for SO Ps Compositio n of QA program … 32

– An authorized writte n procedure giving instructions for performing operations . not necessarily specific to a given pr ocess, product or material – describe in a detailed form the activities p erformed in the laboratory – Provide unifo rmity, consistency and reliability in each of the activities p erformed in the laboratory – Reduce systematic error s – Provide training & guid ance for new staff Standard Operating Procedures ( SOP s) . SOP 33

– Written by the perso n performing the procedure or who knows the procedure well . – Supervisor reviewe d for completeness and content . – QA or QC staff ap proved  how a test or procedur e is to be performed  How a piece of equipment is operated , maintained and calibrated . SOPs … . SOPs shoul d be – written instru ctions that specify: 34

SOP … • QA is impos sible without written guidelines of SOP containing pre-analytic, analytic, and post analytic instructions to perfor m a test . • A particular S OP should have: i. A title ( concise & descriptive ) ii . Test name , test procedure , reagent used includin g the limitation of the procedure a nd calculation explanation 35

SOP … III . Principle of the test ( type o f rxn, sample or test organism involved, reason for performing the test, formula to determine the final result) iv . Sample storage preservative con dition v. Report handling procedure ( reporting range , test & critical v alue) vi . Chemical handl ing technique vii . Reference material s pertinent to specific procedure 36

Composition of QA program … 2 . Laboratory material & supplies - uninterrupted supply of high quality reagents and chemicals and other labor atory materials 3 . Laboratory facilities and i nstruments - Purchasing the equipment , instrument and other laboratory that meet the objective of the laboratory & desi gned method . - Instrument calibration for proper fu nction of the instrument 37

Composition of QA program … 4 . Quality assurance personnel mana gement - Training of staffs and peri odic performance evaluation complements the Lab ’ s quality assessment progra m . 38

A Guiding Philosophy for Quality Assurance in the Pharmaceutic al Industry Poor Quality Medicines: – Are a health hazard – Waste money for governments and consume rs – May contain toxic substances that have unpredictable, unintended consequences – Will not have a desired therapeutic effect – Does not save anyone any money in the long ter m – Hurt everyone - patients , health care workers , policy makers , regulators , manufacturer s . Good quality is a sale able commodity 39

Consequences of Q A breaches • Poor Treatment Outcomes • High Health Bills • Treatment Failures & Deaths • Loss of Confidence in the Health Services • Enormous Economic Losses • National S ecurity Issue 40

Causes of Proliferation of Poor Qualit y Drugs • Poor health systems in developi ng countries • Lack of legis lation • Weak or absent drug regulat ory • Weak law enforcement and penal sanctions • High drug demands with short supplies • Illegal trade in the borders & informal mar kets • Corruption & conflict of interest • High cost of drug - lucrative business ( business with gr eat deal of profit ) 41

. How to minim ize the flow of poor-quality medicines? – Inspection – Port - of - entry control – Document verificati on – Registrat ion . Quiz 1 42

INTRODUCTION What is good ma nufacturing practice (GMP)? Part of QA which ensures that products are consistently produced & controlled to the quality standards appropr iate to their use GMP covers ALL aspect s o f production; from the starting materials, premises and equipment to the training and personal hygiene of staff Concept of Good Manufacturing Practi ce ( GMP ) 43

Good Manufacturing Practice ( GMP ) … The regulation developed FDA for pharmaceutical industry minimum requirements in the manufac turing processing A basic principle of GMP is that qualit y cannot be tested into a batch of product but must be built into each batch of product during all stages of the manufacturing proce ss It is designed to minimize t he risks involved in any pharmaceutical production that cannot be eliminated through testin g the final product Quality sh ould also be maintained during production stage 44

GMP Implementation by Countr ies Different country may use different GMP Guidel ines: WHO Guidelin es Country specific Guidelines (e.g . FDA) How do GMPs of different countries compared? At a high level, GMPs of various nations are very similar; most require : Equipment & facilities being properly designed, maintained, & cleaned SOPs be wri tten & approved An independent Quality unit ( like QC and/or QA) Well trained personnel & manag ement 45

What is c - GMP ? GMP is also some times referred to as "cGMP" Usually see “ cGMP ” where c = current , to emphasize that the expectations are dynami c C refers to current rules & regul ations that serve strictly follow the guidelines and manufacturing procedures that are current & most up to date . 46

What is c - GMP ? Manufacturers w ho agree to follow the cGMP guidelines but still use 20-25 year old machinery and equipment to produce healthcare products GMP forced many manufacturers to give up on old practices an d switch over to latest production processes Helped in avoiding contamination , errors and mix ups while at the same time helping in pro duction of highest quality healthcare and pharmaceutic al products 47

Advantages of GMP a. Prevent errors that cannot be eliminat ed through quality control of finished products unexpected cont amination of products incorrect labels on containers , which could mean that patients receive the wrong medicine . insufficient or too much active ingredient , resulting in i neffective treatment or adverse effects . b. Grantees credibility A drug that contains little or none of the c laimed ingredient w ill not have the intended therapeutic effect Poor Quality medicine l eads to loss for: Manufacturers, Healthy care workers, Governments , end users 48

Advantage of GMP … c. Ensure all units of a medicine are of the same quality (with in a specified parameters) d. GMPhelps boost pharmaceutical export opp ortunities Most countries will only accept import and sale of medicines that have been manufactured to i nternationally recognized GM P Governments seeking to promote their countries export of pharmaceuti cals can do so by o making GMP mandatory for all pharmaceutical prod uction, & o training their inspe ctorsin GMP requirements 49

Basic Requir ements for GMP 1. Appropriate resource : Qualified and trained personnel; Adequate premises and space; Suitable equipment Correct materials , containers and labels; Approved procedures and instruc tions; Suitable storage and transpor t; to produce a quality product 50

Basic Requirements for GMP … 2 . Validated critical steps of production process Due to variab i lity in quality of materials & performance o f equipments , there is a need to check whether the process works with all variability that can arise Process of checking and documenti ng variability is known as validation It carryout controlled experiments to ensure that whatever varia bles do occur , they can still produce products meet ing specifications . Validation is req uired if there is a change in any part of the process ( material or equ ipment used) 51

Basic Requ irements for GMP … 3. Clearly written manufacturing procedure 口 Including batch manufacturing and testing instructions and the SOPs needed for every department 4. Proper storage and distribution of the products 口 When a product is devel oped, stability testing is under taken in order to dete rmine the storage condition and its shelf life 口 Proper storage and distribu tion of the product minimize t he risk to their quality 52

Basic Requirements fo r GMP … 5 . Complete document of manufac turing process appropriate investigation s are carried out if quality problem come up . It must also have records that sho w what is actually done each time it makes an d tests those products The records are very important in the future as they show what was done by whom and whether the work confirmed to standards 53

Basic Requirements fo r GMP … 6. A recall system , in case quality problems are detected after release of produc ts If a product in th e market is found to be defective, there need of ge tting that the product off the market . ( recall ) Recall can be done in d / t way and with d / t degree s of severity , depending up on the reason for recall 54

Basic Elements of GMP … 1. Personnel 2. Premises 3 . Equipment 4.Documentation 5 . Production Control 6 . Quality Control 7 . Complaint and Product Re call 55

Personnel The establishment and maintena nce of a satisfactory system of QA and the correct manufacture of quality products rel ies upon people Personnel requir ements: Adequate number of pers ons With necessary qualifications With practical experien ce Individual respon sibilities should be clearly understood by the individuals All personnel should be aware of GMP : Must receiv e training in GMP: initial trai ning, continuing training including hygiene standards All responsible staf f should have specific duties recorded in individual written job descriptions Prevent unauthorized access to Production areas , Storage are as , Quality control 56

Personnel … Training, in accordance with a written, approved programme Personnel in the production areas; In the control labora tories; & Those whose activiti es could affect the quality of the product Training programmes should be available , approved by either the head of Production or the head of Quality Control Key Personnel Key personnel ( which norma lly should be full-time) positions include: Authorized person Head of Product ion Head of Quality Control Heads of Producti on and Quality Contr ol should be independent o f each other 57

Personnel … Key Personn el … 1. Should possess appropriate qualifications Scientific education such as : pharmaceutic al sciences and technology Chemistry microbiology chemical engineering 58

Personnel … Key Personnel … 2 . Should posses appropriate experience Practical experience Manufacture and quality assurance Preparatory period under professional guidance sometimes needed Education and experience should enable personnel to take difficult decisions in an independent , professional and scient ific way To resolve the problems encountered in manufacturing and QC 59

Personnel ... Head of Production: Responsibilities Approval and implementation of production instructions , in - process QC and ensure strict impl ementation Ensures that production records are evaluated and signed by designated per son Checks maintenance of production department, premises and equipme nt Ensures process va lidation and equipment calibration Ensures initial and continuous trai ning of production personnel 60

Personnel … Head of Quality Control : Responsib ilities Approval or rejection of materials ,e.g . packing materials , intermediates , bulk and finished products , i n accordance with specifications Ensures carry ing out of necessary testing Approval of qual ity control procedures,e.g . sampling and testing; specifications Checks maintenance of quality department , premise s and equipmen t Ensures validation ( including ana lytical procedure validation) Ensures initial and continuous training of QC personnel 61

Personnel … The Quality assura nce head : Responsibilities Ensuring Compliance with regulatory requirements and international standards Approval of the release of finished product for sale Establishment and implem entation of quality system Review of all QC testing results, production do cuments, results of in - process control , & overall compliance to the specification for the finished produ ct prior to releas e 62

Personnel … Visitors or Untrained Personnel Preferable not to enter production and control areas If this is unavoidable, then they must be given information in advance, particularly about personal hygiene protective clothing r equirements Must be accompanied and closely supervi sed at all times 63

Hygiene A high level of hygiene should b e practiced in every aspect of the manufacture of pharm aceutical products The scope of sanitation covers personnel premises equipment and apparat us production mat erials and containers products for cleaning and disinfecti on, and anything that could b ecome a source of contamination to the prod uct 64

Personnel Hygi ene A high level of personal hygiene is required in pr oduction areas should be instructed to was h their hands before entering production areas Eating , drinking , chewing or smoking , in the produ ction and storage areas should be prohibited Direct contact should be avoided between the operat or's hands and the exposed product with any part of the eq uipment that comes into conta ct with the products Every person entering the manufacturing areas should wear protective garments 65

Premises Important aspects to be kept in mind to ensure the s uitability of the operations to be carried out in a given premises: Location Design Construction Maintenan ce must be located, designed , constructed , adapted and maintained to suit the operations to be car ried out should be situated in an environment which , presen ts minimal risk of causing cont amination of products 66

Premises … Location The land and buildings where the manufacturing operations are located must contribute towards the qual ity of the products Premises m ust be located to minimize r isks of cross-contamination permitting effective cleaning and maintenance minimizing the build - up of dirt a nd dust 67

Premises ... The design should aim to: Minimize risks of errors Permit effective cleaning and mainten ance Avoid cross - contam ination, build-up of dirt and dust Avoid any adverse effect on the quality of p roducts Prevent the entry of insects, birds and animals into the building Prevent the migration of extraneous mat erial from the outside into the building and from one area to another 68

Premises ... Construction Should be of Suit able materials To ensure proper cleaning , no cracks , a nd the building can withstand pressures, vibrations and other effects Electrical supply is re quired Suitable lighting ( especially for vi sual on-line checks) Temperature and relative humidity contr ol should be provided materials and products have to be stored or processed under controlled conditions . Appropriate and effective ventilation 69

Premises ... Maintenance Careful maintenance done Repairs and maintenance should not present any hazard to the quality of the products Maintenance works hops should be separated from production areas 70

Premises … Specific areas Ancillary area s Storage areas Production areas Quality control areas 71

Ancillary Areas Rest and refreshment rooms should be separated from production & QC laboratory areas Changing , washing and toilet areas should be availabl e and in appropriate number s Maintenance workshops separated fro m production AIR LOCK TOILETS CANTEEN CHANGE ROOM 72 FACTORY

Premises … Storage areas Storage areas of sufficien t capacity Separate and segregated areas for different materials are recommended starting mate rials packaging materia ls finished products quarantined , rel eased, rejected, returned and recalled products a nd materials Appropriate temperature and r elative humidity conditions within defined limit s 73

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Premises ... Production areas ... Designed to Minimize risk of cross-contamination: Separate facilities for other p roducts such as some antibiotics, hormones, cytotoxic substances Non-pharmaceuticals normally not produced in the same facility, e.g . pesticides , herbic ides Production areas should be effectively ventilated , with air contr ol facilities ( in cluding temperature and humidity) Should have adequate and appro priate spaces for: Personnel changing rooms, offices Equipments Documents and records Sample stor age Testing areas 75

Premises … Quality Control are as QC laboratories s hould be separated from production areas Suitable design with sufficient space to avoi d mix-ups and cross- contamination Suitable space for storage of samples , refere nce standards, solvents, reagents and records should be provided with effective ve ntilation and separate air supply from produc tion is recommended Separate room s for some instruments to protect them from interfere nce (e.g . electrical, vibration, moisture, etc. ) Balances and Dissolution apparatus (Vibration free) IR and KF (Moisture sensitive) 76

Equipment ... Equipment used in the manufacture and testing of pharmaceutical products must be Located, Designed, Constructed, & Maintained, to suit the operations to be carried out The equipment sh ould be located in areas of production or testing to supp ort the operator s in ensuring that the manufacturing process or testing procedure is followed correctly can prevent omissio n of steps in the process avoid possible cross -contamination 77

Equipment … Design can assist in easy cleaning and maintenance of equipment Equipment design must aim: to minimize cros s-contamination, dust to permit effective cleaning and maintenance To avoid any adverse effect on the quality of products Cross- contamination contaminati on in tablet compression and packaging machines is a common problem area use of compressed air is common for moving dust and dirt from inaccessible places on machines 78

Equipment … … … Construction material should suit the operation Should allow its use for the range of products (production or testing) Should not corrode or d eteriorate Should not influence the manufacturing or testing procedure Should not react with the product (very high quality stainless steel ) 79

Equipment … Maintenance Maintenance of equ ipment is important to ensure that the equipment will operate or perform i n accordance with its specifications There must exist maintenance schedules for major pieces of equipment Production equipment should be designed so that it can be easily and thoroughly cleane d Should not present any haz ard to the products Parts that come into contact with the p roduct must be non-reactive The equipment mus t be correctly labelled at all times (to show it is clean or dirty, and ready for use) Defective equipment removed, or clearly labelled ( status label ) ( to prevent it from being used wh en it is no longer capable of producing a good quality pr oduct) 80

Equipment … Quality Control Laboratory Equipm ents The general principles of GM P are applicable to production and QC e quipments Most requirements for Production Equipments ar e applicable for laborat ory equipment maintenance , calibration , records , etc . Defective equipment should be removed or l abelled to prevent analysts from using equipment for testing 81

Good Laboratory Practice ( GL P) is one of the co mponents of QA Concerned with the activ ities of QC laboratories carrying out tests & assay m ethods required to establish the compliance of the product with spec ification claimed for them . • Main goal is to help labora tories obtain results which are reliable , repeatable and recognized worl dwide & thus help to ensure : safety , efficacy & overall quality 82

Good Laboratory Practice ( GLP ) … The quality of th e product is achieved through GMP & monitored with GLP guidelin e The guideline pro vide guid ance to the laboratory control o f pharmaceutical products performe d either in: The manufacturing firm Regulatory lab oratories Research la boratories Objectives of G LP makes sure that the data submitted are a true reflection of the results that are obtained during th e study makes sure that data is trace able Promotes international acceptance of tests 83

Basic Elemen ts of GLP 1. Personnel Should have appropri ate qualification, experience and training in QC Availability of pr otective clothing and other safety facilities Availability of periodic training progra m for all personnel Sufficient p eople 2. Facilities Include laboratory building, furniture, etc The laboratory should have suitable size, construction & location to facilitate the proper condition of the test 84

Basic Elements o f GLP … Design & construction guid eline Locate in area free fr om noise, vibration, etc to prevent interference QC lab should be designed of sufficient spa ce: to suit the analytical operation to be performed to avoid mix - up and c ross contamination etc . QC lab should have adequate storage for sample to be analyzed Physico - chemical and mi crobiological laboratories etc . should be separated each other

Basic Elemen ts of GLP … Equipments Equipment design Equipments shall be appropriate design an d suitably located for operation, cleaning & maintenance Major instruments of a testing la boratory Analytical balance, IR , UV-Visible, GC, pH meter , dissolution & disintegration test apparatus , potentiometer , KFT , HPLC , flame photometer , AAS , HPTLC Equipment for micro biological laboratory Autoclave , microscope , in cubators, centrifuge with refrigerator, membrane filters 86

Basic Elemen ts of GLP … Maintenance & calibration Availability of qu alified & experienced personnel Detailed SOPs which describe: the instrument, calibration st andards & limits, calibration for each instruments , record keeping requiremen ts etc . Preventive mainten ance: Is very important for assuring that the instrument is in good operating condition

Basic Elemen ts of GLP … Testing operation SOPs Are written docume nts specifying the procedure that must be followed to carry out the oper ations Benefits: Prevents introduction of e rrors & variations by avoiding word of mouth communication o r reliance on memory Used to train pers onnel & thus help to prevent misunderstan ding Eliminate need to develop the procedure every time a n operation is performed et c 88

Basic Elements o f GLP … Chemical, reagent & solutions Storage should follow the storage co nditions recommended on the label Highly toxic chemicals should be stored in appropriate place Solution & reagents to be prepared in the laboratory sh ould follow the procedure in the pha rmacopeia & label properly Requiremen ts: Reagents and solutions shall be la beled Deteriora ted or outdated reagents and solutions shall not be used Include date ope ned Stored under ambient temperature Expiration date 89

Basic Elemen ts of GLP … Reference sta ndards The accuracy and pr ecision of test results and test methods is dependant on the reliability , authenticity and control over refer ence standards, reagents and stock sol utions Similarly the retrospective tes ting of materials and product is dependant on the protection and storage of rete ntion samples Primary Standa rds may be obtained from National reference l abs In House Secondary Sta ndards Standardized ag ainst primary standards using definitive methods 90

Basic Elemen ts of GLP … Test articles : Drug testin g laboratories receive d/t type of samples for test and control amo ng which are: finished pharmaceutical p roducts APIs Dressing, suturing materials Medical devices 91

Basic Elemen ts of GLP … Record & reports Records : Records regarding the d / t test applied & all readings an d calculation should be maintained in a bound laborato ry book Record of the prepa ration of solution & reagents, standardization o f solutions, raw data etc Type of docum ents Standard operating procedures , Protocols of tests , results & Reports 92

Basic Elemen ts of GLP … Laboratory records Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standard s Description and ident ification of sample received Description of method of testing Record of all data s ecured in the course of the test Record of test results and how they compare with standar ds of identity, strength and quality Record of all deviations and modification o f test Record of standardization of reference standard s Record of ca libration of equipments 93

Basic Element s of GLP … Reporting of results It is a GLP requirement that a final re port should be reported for each analytical work completed E.g. tablets & cap sule Name of the sample Date of receipt of the sample Analytical repor t No Batch / lot No Protocol of the test applied - description , identification , weight uniformity , disintegration time , resul t of assay Signature of analyst Opinion & signature of the approved analyst Signature of the laboratory h ead 94

Quality Co ntrol (QC) . Each holder of a manufacturing authorizati on should have a quality contr ol department – QC department should be independent from other departments. . The QC department must have adequate resource . – Adequate laboratory facilitie s or access to them . e.g . government or contract laboratories – Appropriately qualified , trained & experienced personnel – Approved wr itten procedures 95

The operational task of the quali ty control department • Sampling • Inspecting • Analytica l testing • Monitoring of all materials & environmental conditions in the factory • Releasing or rejecting material for production use & finished product s 96

The targets of thes e activities are: • Starting materi als • Packaging materia ls • Intermediates • Bulk product s • Finished products • Environmental conditions 97

- It must be carried out in suc h a way that it is representative of the b atch & in accordance with an SOP - QC personnel must have acces s to the production area to undertake samplin g when necessary. 1 . Sampling should be undertaken by m ethods and personnel approved by the QC department Basic require ments for quality control 98

. The validation of test methods include verification of : – Accuracy – Precision – Linearity – Repeatabil ity – Robustness – Specificity . Test methods should be challenged to be able to demonstra te that the tests are able to giv e an accurate result on repeatable bases . 2. Validated test metho ds should be applied. Basic requirements for quality contr ol … 99

Basic requirements for qual ity control … - The method must be capable of being app lied with precision - The results obtained must be linear over a range of acceptable response - Finally the result must be repeatable over a number of identical tests . 3. Records for sampling , inspecting , te sting of materials, intermediates and bulk an d finished products need to be kept - This means that there will be traceability on what happened . 100

- This review need to cover all quality aspects - Ensures manufacturing documentations & the QA documentation are in harmony. - it is important that all deviation from the norm al procedure are recorded or docume nted . - Any impact on product quality must be assessed . 4 . The QC department should review and evaluate relevant production 5 . The QC department should generate or review records for deviations & failure Basic requirements for quality control … documentation investigations manufacturing 101

6. QC ensures that ingredients used comply with the qualitativ e and quantitative composition of the finished product as ap proved in market authorization . 7. QCensures that proper container s are used 8. QCensures corr ect labeling of finished products 9. QC ensures batches are released by appropriate authorization . Basic requirements for quality control … 102

Basic requirements for quality control … 10 . Sample of s tarting materials & products are retained . - Sufficient retention samples of the starting materials and the finished products in its final pack should be k ept for one year - This is to allow for an evaluation of the product after it has been distributed should t here be a need . - It will also allow ongoing stability trial to be done past the expiry date . 103

- RS are among th e most critical materials that QC has to handle - The result of much te sting rely upon comparison with analytical RS . - IfRS has not bee n looked after properly then all the test results maybe incorrect . 1. Establishing , validating and implementing all QC proce dures 2.Evaluating, maintaining & storing reference standards QC department has other duties to carryout , includi ng: 104

- It is nearly impossible for o perator to see that an error has occurred . - System must be in operation a s the main safeguard . - If equipmen t such as bar code readers are in operation it must be regularly checked for effectiveness . 3 . Ensuring correct labelin g of containers of materials and QC department has ot her duties … products 105

- A stability testing program should be developed for all produc ts, described in the form o f an SOP. - Stability of active pharmaceutical ingredients should be monitored - Active ingredients should be regularly tested within their shelf life to confirm sui tability for continued use . - QC should ensure that samples are taken for stability testing program and that analysis is undertaken at the right time 4 . Stability testing of active ingredients and finished products QC department has other du ties … 106

- With regard to products , the environment refers to that which can immediately affect product quality. - E.g . swab testing and s ettle plates in a sterile are a, testing o f temperature and h umidity control . - Complaints offer an opportunity f or the company to learn from mistakes or product design fa ilures . - In this way a ctions can betaken to prevent reoccurrence . 6 . Participating in environment al monitoring . 5 . Participatin g in complaint investigation . QC department has other duties … . 107

- Including the producti on condition - The results of in - process testing - The manufact uring (including packaging) documentation - Compliance with the specification for the finished product, and - An examinat ion of the finished pack Assessment of finished produc ts should embrace all relevant factors 108

QC personnel must have access to pro duction areas . For example sampling & inspection . This must be balanced because it may not be appropriate – QC staff enter asep tic filling suites, or – Areas where there is highly po tent dangerous material such as onc ology/ cytotoxic materials . 109

Head of QC r esponsibilities . Approval or rejection of materials : – Starting & packaging materials , inte rmediate, bulk and finished products . Evaluation of batch records . Carrying out nec essary testing . Approval of necessary QC procedures : – Sampling instru ction, Specifications, Test methods and other QC procedures . . Maintenance of quality department , premises and equipment . Validatio n ( inclu ding analytical procedure and calibration o f equipments) . Initial and continuous training of QC p ersonnel 110

. Specification consists o f test methods and their associated acceptance crite ria . Criteria applicable to all drug products: – Identity – Strength – Purity – Testing methods . Physicochemical a nalysis . Microbiological an alysis Testing references : Pharmaco peial standards (USP, EP, BP, etc) 111

– Tablet & capsul es . Suspension and solut ions – pH of solution – Particle size of suspending drug – Clarity of solution ( tu rbidity) – Color of soluti on – Viscosity – Volume of fill – Preservative t esting – Microbial limits – Stereo isomeric purity Additional specificatio ns – Residual solvents – Moisture ( water ) – Disintegration – Dissolution 112

– Product selection – Supplier qualification for medicine selection – Product certif ication – Contract specification Storage co ndition, expiry date 113 Quality Assur ance for drug supply management Import Local manufact urer GMP – appropriate sto rage, transport, dispensing & u se procedure – Product moni toring system . Critical Elements in QA for Procuremen t – Inspection of shipmen t – laboratory t esting Distribution Management system Procurement Selection Rational use Use

Storage/handling QA Product Specifications. Prequalification Tender cont ract Monitoring of su pplier performance GMP , inspection and licensing Evaluation of pro duct dossier Product Selecti on Inspections / licen sing Storage / dis tribution Procuremen t Use 114

Goals of Medicine QA Programs . To make certain that each me dicine reaching a patient is safe , effective , and of stand ard quality . Obtaining quality product s that are safe and effective through structured selection and procurem ent methods . Maintaining quality produ cts through the appropriate storage , distribution , moni toring, and use by prescr ibers, dispensers, and consumers 115

Characteristics of a Co mprehensive QA Program - 1 . Medicines are selected on the basis o f safety and efficacy , in an appropriate d osage form with the longest shelf life . Suppliers wi th acceptable quality standards are selected . Medicines receiv ed from suppliers and donors are monitored to meet qual ity standards . Medicine packaging meets contract specificat ions 116

Characteristics of a Comprehensive QA Program - 2 . Repackaging act ivities and dispensing practices maintain quality . Adequate storage conditions in all pharmaceutical areas are maintained . Transportation conditions are a dequate . Product quality concerns are reported & monitored 117

Pharmaceutical QA  Pharmaceutical pr oduct QA  Pharmaceut ical service QA - Quality of raw materials , intermediate & finished products - Maintaining quality products through the appropriate storage , distribution , monitor ing, & use by prescribers, dispensers, & consumers - Drug use review - Clinical p harmacy services - Other pharma cy services 118

• The following areas (GxP Quality Guidelines) are monitored under P harmaceutical QA > GMP - Good Manufacturing Practice > GLP - Good Laboratory Practice > GDP - Good Distribution Practic e includes all procurement & transportation pro cesses > GSP - Good Storage Practice > GPP - Good Prescribing Practice > GDP - Good Dispensing Practice > GRP - Good Review Practice , … 119

Pharmaceutical Quality Assurance Framewor k • Five critical elements to achieve the expected treatment outcome: 1. Active pharmaceutical ingredients ( API ) has b een shown to be safe & effect ive for the treatment 2. Product is of suitable quality to provide an effective outcome 3. Prescriber has accurately identified the need for the treatment 4. Prescriber or disp enser has properly instructed the patient on how to use the p roduct 5. Patient complian ce with the prescribed regimen correctly 120

Pharmaceu tical Quality Assurance Framework … • The first 2 items are pro duct-specific issues , which are the most easily addressed technically , whe reas • Items 3 & 4 are prescriber - specific & depends on the prescribers ‟ education , knowledge , & skills as well as the rigorous enforcement of performance standards • Item 5 is patient - specific issue that depends on the patient ‟ s knowledge & commitment & the patient ‟s access to serv ices 121

122

 Death  Toxic and adverse reaction  Waste of limited financial resources  Loss of credibility . Manufacturing process . Packaging . Transportation . Storage condition  Lack of therapeutic effect :  Prolonged illness Impacts of Low - Quality Medicines ? MEDICIN E QUALITY 123

How Is Quality Asses sed? . INSPECTION of products on arrival . Visual inspection . Product specification review ( including expiratio n dates) . LABORATORY TESTING for compliance with pharmacopoeial standards . International Pharmacopoeia . European Pharmac opoeia . U.S . Pharmacope ia . British Pharmacopoeia . National Pharmacopo eia . BIOAVAILABILITY D ATA COA 124

How Is Medicine Quality Assured? (1) . Productsele ction . Long shelf - life ; Accepta ble stability . Acceptable bioavai lability . Selection of appropriat e suppliers . Supplier pre-qualification; Request samples from new suppliers . Request specific reports and data for certain medici nes (e.g., bioavailability and stability studies) . Collect and maintain information on s upplier performance . Product certifi cation . GMP certific ate of manufacturer . Product / batch certi fication (COA) . Random local testing 125

How Is Medicine Quality Assured? (2) . Contract and procurement specifications . Pharmacopeia re ference standard . Local language for product label . Standards for packaging to mee t specific storage and transport conditions 126

How Is Medicine Quality Assured? (3) . Appropriate sto rage, transport, dispensing, and use procedure s . Pharmaceutical distribution & inventory con trol procedures . Provision for appropriate storage & transport including adequate T 。 control , security , and cleanliness . Explicit en forcement of cold chain procedures . Appropriate dispensing : containers , labeli ng, counseling . Avoidance of repacking unless q uality control in place 127

How Is Medicine Quality Assured? (4) . Product mon itoring system . Problem reporting : who , h ow, where, and to whom; what additional measures; what follow- up informati on . Product recalls : hospital or cou ntry level 128

Who Ensures Med icine Quality? . Drug regulatory authority . Drug and Therapeutics Committee . Hospital procurement office . Physicians and other prescribers . Pharmacy ( and dispensers ) Medicine Quality . Patients 129

Implications of Pharmaceutical QA for the DTC . Providing technical advice on procurement of pharmaceutical s . Defining produc t specifications . Generic medicin es . Bioavailability issues . Stability issues . Defining minimum laborator y testing 130

Implications of Pharmaceutical QA for the DTC … . Providing technical a dvice to hospital departments . Medicine transportation and storage . Dispensing . Analyzing pr oduct problem reports . Quality complaints . Medicine recall system 131

Quality assurance in drug supply ma nagement . Targets: – Product selection and specif ication – Suppliers selection – Product certification – Contract specificati on – Inspection of shipment – Targeted la boratory testing – Maintaining drug quality during storage , distribn & u se 132

SN QA QC 1 Helps us to build pro cesses Helps us to i mplement the built processes 2 Is duty of the c omplete team Is only the duty o f the testing team 3 Comes under the categ ory of verificati on Comes under the categor y of validatio n 4 Is considered process oriented exercise Is considered product oriented exercise 5 Prevents the occurren ce of issues , bugs , or defect s in the application Always detects , correc ts & reports the bugs or defects in the application 6 Doesn ‟ t involve ex ecuting the program or code Always invo lves executing the program or code 133 Difference between QA & QC

SN QA QC 7 Is done before quality contr ol Is done only after QA activity is completed 8 Can catch errors & mistakes QC cannot catch, that is why it is considered low level a ctivity Can catch errors QA cannot catch, that is why it is considered high level activity 9 Is human - based checking of documents or files Is computer - ba sed execution of program or code 10 Planning done for doing a process Means action has been take n on the process by executing it Difference between QA & QC ... 134

SN QA QC 11 Mainly focuses on preventing defects or bugs in the system Mainly focuses on iden tifying defects or bug s in the system 12 Is not consid ered a time consuming activity Is always cons idered a time consuming activity 13 Makes sure that you are doing the ri ght things rightly, that is why it always comes under the category of verification a ctivity Makes sure that whatever we‟ve done is as per the requirement, means it is as p er what we‟ve expected, that is why it comes under the category of validation activity 14 Is pro-active means it identifies w eaknesses in the processes Is reactive means it identifies th e defects & also corre cts the defects or bugs Difference between QA & QC ... 135

In - process Quality Control (IPQC) 136

“TESTING” IN PROCESS QUALITY CONTROL ( IPQC ) 137

IPQC ... • Definition : " It is a planned system in which samples are taken and tested a t various critical steps during the manufacturing in ac cordance with the written directions " . It monitors all the feat ures of the product that may affect its quality and prevent er rors during processing . Areas controll ed by IPQC Manufacturing area Packaging area 138

PURPOSE To control the procedure involved i n manufacturing To monitor all features which affect the quality To detect significant human errors To ensure quality of final pr oduct To monitor and , if necessary , to adjust the p rocess to ensure that the product conforms to its specification s It sometimes identifies a defective produ ct batch that can be corrected by re work 139

Various Instruments Used in IPQC Dep’t Disintegr ation apparatus Dissolution apparatus Analytical balanc e Friability testing apparatus pH meter Tablet hardness tester Chromatographic meth ods U. V Spectroscopy Karl fisher Titrimeter 140

Conditions for Designing of IPQC Tes t Identify the types o f formulation (tab, liquids, ointments) Identify the critical steps involved in manufacturing of the product Identify the specification of parameters whi ch conform the parameters are within control Define the frequency of che cking for each parameter 141

Tablets a) Content uniformity b) Dissolution test c) Assay of active in gredients d) Weight variation e) Hardness test f) Disintegration tes t g) Friability IPQC Tests for Various Do sage Forms 142

IPQC Tests for Various Dosage Forms … Syrups & Suspension a) Content uniformity b) Assay of active ingredients c) pH = affects the stability of the product d) Appearance - color , odor , taste Product is checked for un iform distribution of color absence of air bubbles e) Clarity test 143

IPQC Tests for Various Dosage Forms … INJECTABLE S a) Content uniformity b) Clarity test c) pH d) Pyrogen test e) Stability test f) Leakage test g) Sterility test 144

IPQC Tests for Various Dosage Forms … Capsules Wt variation Assays Content unif ormity Dissolution test Disintegra tion time Moisture content 145

IPQC Tests for Various Dosag e Forms … PACKAGING Line clearance must b e given before starting packaging operation Print details on labels must be cer tified Leakage testing bottles , a mpoules, vials must be performed Objectives of Line c learance To assure that notra ces of previous product To assure that correct materials brought f or processing/ packing 146

Packaging Materials Testi ng 147

Packaging M aterials Testing Pharmaceutical packagin g is the means of providing protection, presentation, identification , info rmation, convenience and stability of the product pharmaceuticals sh ould retain their therapeutic effectiveness fro m the time of packaging till they are consumed 148

Packaging Materials Testing … Functions of packaging Product Id entification Product Pro tection Protects the contents of a product from spoilage, breakage, leakage Facilitating the use of product Packaging should be convenience to open, handle and use for the consumers Product Promotio n used for promotional and attr acting the attention of the people while purchasing 149

Packaging Materials Testing … There are two types of packaging materia ls 1. Primary : e.g. vials , plastic bottles , blister packs 2. Secondary : e.g., boxes , cartons , labels , leaflets 150

Packaging Materials Testing …  The choice of p ackaging material will depend upon: The degree of protection required Compatibility with the dosage form Customer convenie nce e.g . size, weight of dosage form cost  Composition of package A. Container B. Closure C. Carton  Container ’s one in which the product is placed a device that holds the drugs and may be in direct contact with the preparation 151

Packaging Mat erials Testing … QUALITY CONTROL OF PACKAGING MATE RIALS The testing of packaging mater ials is requirement for any pharmaceutical i ndustry There are various tests for determi nation of quality of packaging materia ls They should pass the specifications of tests before it reached the local markets 152

Packaging Materials Testing … Materials used for Making of Container s a. Glass b. Plastic c. Metal 153

Tests on Glass c ontainer 1. LEAKAGE TEST : Drug filled container is placed in a container filled with coloured solution ( due to the addition of dye) which is at high pressure compared to the press ure inside the glass container The coloured solution enters the conta iner if any cracks or any breakage is present 154

TYPES OF PLASTICS They are made up of polymers such as polyethylene ( PE ), polypropylene (PP), polyvinyl chloride ( PVC ), & pol ystyrene (PS) Evaluation of Plastic Leakage test Collapsibility test Transpare ncy test 155

Tests on Plastic Container 1 . Leakage Tes t Fill ten conta iner with water Fit with intended closures and keep tem inverted at room temperature for 24 hour There are no signs of leakage from any contai ner 2. Collapsibility Test applicable to containers which are to be sque ezed in order to remove the contents carried out by squeezing the container to remove the c ontents which should yiel d the 90% of the contents at the required rate o f flow at room temperature Then it indicates the passes the test 156

Tests on Closures Closure is the component which is used to close the diff erent types of containers Purpose It prevents loss of material by spilling or volatilization It avoids contami nation of the product from dirt, micro-organism or insects It prevents deterioration of the product from th e effect of the environment Materials used for making of Closure s a. Glass b. Plastic c. Rubber 157

Evaluation of c losures 1. Penetrability measured to check the force required to make a hypodermic needle penetrate eas ily through the closure It is measured by using th e piercing machine The piercing force must not exceed a s tated value If it exceeds th at stated value, the hypodermic needle can be damaged a s a result of undesirable hardness of the closures 158

Documenta tion 159

Documentation A GMP document is any written record associated with the manufacture , control and distr ibution of the pharmaceutical product Documentation is a method of preparing a w ritten material , which describes the process in ter ms of specifications, instructions etc Good document ation is an essential part of the QA system Should exist for all as pects of GMP 160

Documentation ... Purpose Defines specifications and procedures for all mate rials and methods of manufacture and cont rol Ensures all personnel know what to do and when to d o it Ensure tha t authorized persons have all information necessary for release of product It provides the wor king details necessary for manufacturing, packaging , q uality control Help in decr easing the batch to batch variation To ensure the existence of documented evidence, traceability “ If it hasn ' t been d ocumented, then it hasn't been done!” 161

Documentation … GMP guidelines specify certain documents to be maintained necessarily: 1 . Labels 2 . Specifications 3 . Records 4 . SOPs 162

Labels Labels are used for identification or status of containers, equipment and premises According to status of conta iner the following color labels are used Quarantine yellow Approved green Rejected red Different types of labels, e.g . cleaning status, production stage, status of materials 163

Labels ... Labels can indicate the status of materia ls such as " quarantine “ materials are under "quarantine “ and cannot be used until released by QC

Finished Product Label ... Label of all finishe d drug products contains the name of th e drug product a list of the active ingredients the amount of each i ngredient the batch number the expiry date precautions and wa rnings storage conditions & dire ctions for use the name and address of the manufacture r 165

Documentation ... 2. Specifications Lists of detailed requirements with which the products or materials used during manu facture have to conform important to ensure quality and compliance with a qualit y standard Materials including st arting materials, packaging materials, intermediates , bulk and f inished pharmaceutical products should have specifications Specifications includes tests for identity , content , purity and q uality Pharmacopoeias, reference standards and reference spectra should be available in the QC laborat ory 166

Documentation … Specifications for finished products sho uld include: the name of the produc t the formula a description of the dosage form and pa ckage details the qualitative and quantitative requirements acceptance li mits the storage conditions and precaution s 167

Records Documents maintained in p roduction department are: Raw material records Batch production record s Quality control records 168

Documentation ... Standard Operating Pr ocedures (SOPs): written documents specifying the procedures that must be followed to carryout operations " are written specifi cations for all aspects of manufacturing“ The purpose of a SOP is to provide detailed instructions on how to carryout task so that any employee c an carryout a task correctly everytime There should be written SOP for each operation a. equipments b. sampling c. testing d. process e. packaging 169

Purity 170

Definition & Aspects of Purity  Purity: the state of chemical compound when no impurity can be det ected by any experimental method . No other molecules differing in anyway can be present in a pure preparation of a chemica l substance . . In practice absolute puri ty is never achieved • B/ c there is no as such experimental me thod for recognizing or proving the ideal state of purity 171

> Official compendia are legi timate to ensure purification by monitoring > Undesired by - product s arose during synthesis or isolation, > Decomposition of dosages of pharmaceuticals und er normal condition of storage for stipulated period, etc . > Specify descriptive as well as informative det ails > All pharmaceutical substances, chemicals & dosage forms must rigidly conform to laid - out standar ds 172

 Some of the parameters include to e nsure purity in official compendia are: . Description of the d rug/finished products . Identification test . Physical test . Assay of active i ngredients . Limit test . Storage condition 173

 The purity of a produ ct cannot be ensured merely by inspection an d lab analysis  A control system h as to be built from the very beginning o f the manufacture of a drug through GMP, beside: . QC measures of raw mater ial . Process cont rol . Assessing the shelf - life & bioa vailability of a finished product . 174

Assay Method of Purity & Attainable Standards  The standards o f pharmaceutical chemicals and dosage forms should fulfill the criteria set by various official compendia . These includ e:  Broad based highest attainable standards for chemical purity : . It is always fixed though t here may be difference in method of manufacturing and ch anging pattern of stability e.g . Chloramphenicol : 98- 102% Aspirin : 99.5- 100.5%  Attaining the desired biological response : 175

 Attaining the desired biological response: . Includes retention of acceptable level of potency and free from toxic ity. . The fixed ( set in range ) standards of biologic al responses could ensure in order to: • Facilitate the production of reasonably reprodu cible products in d/ tmanufacturing companies • Minimize the difference inactive ingredients in various lots • Retain acceptable lev el of potency • Avoid toxi city during usage and storage 176

Biological Response Vs Chemical Puri ty I- Biological response a) Clinical efficiency of dr ugs : orally administered drugs efficiency depends on their Bioavailabi lity > Bioavailab ility absolutely determined in vivo test but is not suit able in terms of ethical consideration, biological differen ce, cost etc > Most of the time it is determined using in - vitro method 177

 Bioavailabi lity differen ce caused by a number o f formulation varia bles, namely: . Particle size . Crystalline s ize, . Binding or disintegration agents or . Other excipie nts that has role on the rele ase pattern o f the DF b) Drug adverse reaction 178

II-Chemical purity: • This can be ascertained through chem ical analysis such as:  Analytical techniques: . TLC , HPLC , IR , UV - Visible spectrophotometry , titr ation, MS etc  Determination of physical constant and chemical properties . MP , BP , RI , optica l rotation etc  Miscellaneous characteristics need to be m onitored . Sulphatedash value f or organic cpd . Loss on drying for hydrosc opiccpd . Clarity & color of solution . Heavy metal determination 179

Stability Indicating Studie s  Stability of a drug defined as : . The time from the date of manufacture until its chemical or biological activ ity is not less than a predetermined level o f labeled potency and its physical characteristics have not changed appreciably or deleteriously.  Stability testing : . The assessment of a pharmaceutical do sage form under stressful condition fo r a change in terms of physical or chemical properties or both to ensure the product desirable biological effect an d stability for the claimed shelf l ife (expiry date) . 180

 Stability test data is ve ry important for both manufacturers and regulatory bodies .  It is useful for : . Anticipating the rate of decomposition thereby ensure that no toxic substances are produced to signific ant amount . . Ensuring that there is no significant reduction in the potency of the drug . 181

Factors Contr ibuting to Instability of a Pharmaceutical Pr oduct a) Incompatibility :  Due to undesired reaction b / n two or more comp onents of a drug.  This may lead to : i . Physical i ncompatibility: . Leads to physical change that is recognizable by unusual odor change , col or change, gross precipit ate. ii. Chemical incompatibility: . This is a reaction in which a visible c hange may not occur and an experiment is required to identify the cause. iii . Therapeuti c incompatibility: 182

 Therapeuti c Incompatibility . This is an u ndesired pharmacological interaction between two or more ingredients which may l ead to: • Potentiation of t herapeutic effects, • Destruction of th e effectiveness of one or more of the ingredie nts or the occurrence of toxic manifestations . 183

b ) Oxidation & reduction reaction :  Many oxidat ive reactions are first order type .  When molecular oxygen is i nvolved, the reaction is known as auto oxidation (occurs spontaneously at room temp) .  N 2 or CO 2 are frequently used to displace the head space air in pharmaceu ticals in order to minimize deterioration by oxidation .  In many oxidat ion reaction, the reaction rate is dependent on : . The concentration of oxidizing species . Not on the concentration of oxygen present . 184

 The rate of oxidation i s influenced by: . Increase in temperature, . Radiation . The presence of catalysts • trace of heavy metals , hydro nium & hydroxyl ions  Oxidation can be inhibit ed by the use of antioxidants (negative catalysts) . . E.g . sodium bisulfite , sodium thiosulfate, ascorbic acid, ascorbyl palmitate , hydroquinone , etc . 185

c) Hydrolysis :  Drugs possessing an ester or an amide linkage are susceptible to hydrolysis . . E.g . physostgmine , procaine , benzyl pencill ine etc .  Rate of hydrolysis depends upon T & pH of the solution .  The reaction order for hydrolytic reaction follows zero & first types .  The rate of hydrolysis doubles for every 1 C rise in storage T . 186

 Many oxidative h ydrolytic reactions are catalyzed by both [H + ] or [OH - ], . The pH range of min imum decomposition or . Maximum stability depends upon • The ions having greatest effect on the reac tion  In general , [ OH -] has stronger catalytic eff ect & the maximum stability is often found between p H 3 & 4 .  Sometimes it is necessary to compromise b/n the optimum pH for stability & that of pharmacologic activity, . e.g . several local anesthetics are most st able at acidic pH where as the desired biological activity is possible at neutral or slightly alkaline conditions . 187

 The amount of wat er present in a given sample have also a profound effect on the rate of hydrolysis , . And when hy drolytic reactions take place fairly rapidly in water, other solvents should be used . 188

 Hydrolysis can be prevented by structural modification of the active substance like: . Adding constituents like alkyl , acyl chain of aliphatic & aromatic ester • Reduce the solubility of the compound there by prevent ing hydrolysis . Steric & polar complexation • e.g . caffeine complexes of local anesthetics such as procaine, benzocaine, etc , reduce hydrolytic r eactions . Addition of a surfactant to facilitate stabilization, • e.g . the ha lf life of benzocaine i s increased by 18 times by the addition o f sodium laury l sulfate . 189

d) Decarboxylation :  Protolytic solid state degradation through decarboxylation is less common . Due to high heat of activation requirement to favor the reaction (25-30 Kca l) .  However, first order reaction catalyzed by [H + ] at high temperature can take place for P - aminosalicyl ic acid to under go protolytic degradation to M-aminophenol & CO 2 . 190

e) Racemiaza tion:  The process of changing fr om an optically active compound into optically inactiv e (racemic) mixtures of corresponding dextro & levo forms .  It follows first order reaction that is dependent on temperature , solvent , catalysts and the pres ence of light .  It is a major factor of pharmaceutical stability, . e.g . l-epinephrine - 15 to 2 times more active than the d - form .  It depend up on a functional group . Bound to the asymmetric carbon atom, with the aromatic substituent group at the asymmetric carbon tending to ac celerate the process . 191

f) Photochemical :  Photolytic degrada tion is an important limiting factor in the stability of pharmaceuticals .  A drug can be chemi cally affected by the radiation of aparticula r wave length, . If it absorbs ra diation at that wave length and the energy absorbed exceeds the t hreshold limit . . UV-radiation has a large energy level hence it is the cause for many degradation reactio ns . 192

. If the absorbing molecules react, the reaction is said to be photochemical . . If the absorbing molecule passes the energy to the other reacting molecule ( d o not participate directly), the absorbing substance is call ed photosensitizer . . Variables such as intensity and wave length of the light, size, shape , composition & c olor of the container containing the pharmaceutical ma y affect the reaction velocity. • Considerable protection from UV radiation and little form IR is required . 193

. The kinetics is very complex , in mo st cases zero & first order react ions are followed . . Colored glass containers are most commonly used to protect light s ensitive formulation s, • e.g . yellow - green glass give best protection in UV region while amber colored glass confer 194

g) Radiation used for sterilization  Ultrasonic energ y: . Consists of vibrations & wave with frequencie s greater than 20,000/ sec . . It is used for sterilizati on of pharmaceuticals . . It promote the formation of free radicals & alter drug molecules hence , aba ndoned as a means of sterilizing medicaments . . Degradation increas e linearly with increase i n power o f radiation . 195

 Ionizing radiatio n: . Ionizing radiatio n especially γ-rays was used for sterilization of products . . The usual sterilizing d ose 2 .5 mrad causes appreciable chemical degradation of drugs . . In general, in most formulations which are in the solid or frozen state are more resistant to degradation from ionizing radiation than those in liquid form . 196

Reaction kinet ics  The study of rate of chemical change and the wa y in which this rate is influenced by conditions of concen tration of reactants , products , other chemical sp ecies and factors such as solvents , pressure and te mperature . . It permits a rational a pproach for the stabiliza tion o f pharmaceuticals . . It facilities the prediction of shelf life an d optimum storage conditions . . It is useful for the elucidation of mechanisms by which chemical reactions proceeds a nd formulation of a model for the conversion of reactants to prod ucts . 197

Rate of reaction & order of reac tion  Rate of reaction is the velocity with which reactants under go chemical reaction towards a product . E.g . Hydrolysis of sucrose ; C 12 H 22 O 1 1 + H 2 O C 6 H 12 O 6 ( Glu ) + C 6 H 12 O 6 ( Fru ) . The rate at which conc of sucrose decr ease with time, ‘t‟ is proportional to the unhydrolyzed sucrose (C) . i.e. - dC / dt = K.C • Where , K is velocity or rate constant and - dC / dt is decrease in conc of sucrose wi th time.  Reaction order refers to the wa y in which the conc of a reactant influences the rate of chemical reaction . 198

Zero order of re action: • The rate of reaction is independent of the conc of reactants . • Mathematical expression for the general re action: A Product (P) in zero order is given by : - dC A / dt = K • Plot of Concentrati on Vs time will give straight line . 199

 The following examples demo nstrate zero order o f reaction . . Photochemical reaction i n which the rate determining factor is the light intensity rather than the c oncentration of reactants . . Decomposition through hydrolysis, weakly concentrated solutions tends to decompose at higher percentage ratio than the concentrated one if the reaction is zero o rder kinetics . 200

. If a compound for which decomposi tion in solution is first order is present in e xcess of its maximum solubility ( a su spension), • The concentration of the reactant in solution will be invariant (constant) as long as there is excess solid reactant present , such a reaction is c alled apparent zero order or pseudo zero order . i .e . the observ ed reaction rate will be : - dC / dt = KCo , where C o is constant . 201

First order of r eaction  When the rate of a reaction is proportional t o the first power of conc of a react ant . . Mathematical expres sion for the general reaction: A B In first order , - dC A / dt =K. C A . The above expression can be written as dC A / C A = - k dt  On integration : - ln C A = kt + constant  In common logarith m, log. C A = -kt / 2.303 + constant. 202

> If „a‟ is the initial conc of the reactant & „x‟ is the amount that has been rea cted at time t, then K = 2.303 / tx log (a / a-x ). > When the concentration at Co and elapsed time,t are known then , the conc C 1 at time t 1 and C 2 at l ater time t 2 are used to calculate „k‟ by the following equation, k = 2.303 /t 2 -t 1 x log C 1 /C 2 203

 A more useful expression of reaction rate in ter ms of half- life of a reaction (t 1/2 ), . Which is the time required for half of the reactant to under go reaction , and given by the expression t 1/2 = .693 / K .  This showed that t 1/2 value for the first order reaction is constant & which explains that , . The time interval required for the disappearanc e of any specified fraction of the reactant will be constant irrespective of the conc of the reactant .  Thus in studies of drug stability the time required for the loss of 10% of the original conc or time required for the 90% of the conc to remain is the commonly employ ed term to calculate shelf life . 204

 It is also appare nt that an infinite period of time would be required for all the substance to undergo reaction, . Hence it is impossible to measure first order reaction rate to completion and the log . Conc Vs time plot cannot be extrapolated to zero . . Plotting log C Vs time will give straight line & the rate constant, • k can be calculated fro m the slope of the line . . E.g . for fist order reaction that a re shown to occur at rates proportional to the conc of drug s: • The passive diffusion of drugs across biological membrane, distribution , metab olism and excretion . • Rate of growth of microorganisms and rate of killing or inact ivation of microorganisms by heat or chemical agents . 205

Second Order Reaction  The experimentally determined rate of reaction is found to be proportional to the conc of each of the two reactants or to the second power of the conc of one reactant . . Mathematical expression : For a general reaction, A + B C -dC A / dt = - d C B / dt = K C A C B • If „a‟ and „b‟ represent molar conc of „A‟ and „B‟ at t = & the number of moles of each reacted at time t = t considered as „x‟, then the number of molecules unreacted will be (a-x) and (b-x), then dx /dt = K (a-x) (b-x) dx/ (a-x) (b- x) = K dt • Integratio n and converting to logarithmic form will give the mathematical expression, K = 2 .303 / t(a-b) X logb (a-x) /a (b -x) . A plot of logb(a-x)/a(b-x) Vs t (when „ a‟ & „b‟ are not equal ) will give straight line 206

Note : > Zero , first & second order rate processes are by far the most common type of rate process encountered in consideration of drug s tability. > If a reaction is a higher order , it is often convenient to adjust the experimental conditions by keeping the conc of one of the react ant to remain constant through out t he experiment . > e.g . CH 3 COOC 2 H 5 + NaOH CH 3 COONa + C 2 H 5 OH , if the base is in gre at excess or if a buffer s ystem is employed then the observed reaction rate will depend on changing the conc of the ester , the reaction is then s aid to be apparent 1 st order or pseudo 1 st order. > In complex reacti ons it is often desirable to use this appro ach o f maintaining the conc of all but one o f the reactants constant in order to facilitate determination of the dependency of reaction rate on each of the reactants in turn . 207

Third order rate of re action  The experimentally determined rate of reaction is found to be proportional to : . The concentration of ea ch of the three reactants . . Or the conc of one of the reactant & the second power of the co nc of the other. . Or the third power of the conc of a single reactant . • Mathematical expressio n: For a general reaction, A+B+ C D at molar c onc of „a‟, „b‟ & „c‟ .  Rate equat ion, -dC A /dt = -dC B /dt = -dC C /dt = KC A C B C C dx / dt = K(a-x) (b-x ) (c-x), when a = b = cthen , dx /dt = K (a-x) 3 , on integration 1 / 2 (a-x) 2 = Kt + constant . Evaluating the constant by substituting zero for „x‟ at t = will giv e the expression K = 1 / 2t [1/ (a-x) 2 – 1 /a2 ] 208

Complex re actions  Many chemical reactions are not simple reaction like zero, first , second or third order often consists of a combination of two or more reaction . . The rate equations in such cases become a complicated function involving 1 st , 2 nd or 3 rd order intermediate steps . . A reaction order which is no t integral or fractional are considered to be complex . . The complex nature of a reaction is converted to in tegral reaction order by controlling the concentration of vario us reactants to permit simplified form of o rder of reaction . . Complex reactions are clas sified as simultaneous, consecutive and opposing r eactions . 209

Arrhenius equation & temperature effect on react ion rate • Temperature : I t increases the rate of chemical reaction because the nu mber of collision per unit time becomes higher. • Vant - Hoff ’ s rule : Reaction rate is increased 2 to 4 times when the temperature is increased by 10 C in the vicinity . • Hence , the importan ce of temperature on the chemical stability of a pharmaceutical produ ct cannot be over- emphasized because reaction rate doubles for every 10 C rise in temperature . 210

Arrhenius equation & temperature effect on re action rate … • Arrhneius equation : variation with temperature of rate constant of chemical reaction could be expressed by the equation , K = A e – Ea / RT • Where K = temperature rate constant , Ea = Arrhenius activatio n energy e - Ea / RT = Boltzmann factor R = is gas constant (1 .987 ca l/K) & T is absolute temperature (273 K) . A = frequency f actor 211

> Converting the equation to the logarithmic form will give, ln K = lnA - lne -Ea/RT , Log K = LogA - Ea /2 .303 RT > Integrating between limits K 1 and K 2 and T 1 and T 2 will give Log K 2 /K 1 = Ea / 2 .303 R x ( T 2 - T 1 / T 1 T 2 ) . > Plotting Log K Vs 1 / T yields straight line with intercept of LogA and Ea can be calculated f rom the slope of the line . > This plot is known as Arrhenius plot . 212

Predicting the shelf life of a pharmaceutical product  A number of factors should be considered during stability studie s & accelerated testing procedures .  The most important ones are the following . a) Humidity (moisture ): Medicaments may absorb or adsorb humidity that facilitate chemi cal reaction at faster rate leading to decompose p roduct . . The saturation of the crystal structure of a solid with moisture follow zero or der. 213

Predicting the shelf life of a pharmaceutical pro duct … . Adsorption and desorption phe nomena varies with the type of crystal stru cture of the drug . • E.g . Phenobarbitone the phenomena give hysteresis loop (type of curve ) while for procaine adsorption / desorption pr ocess will not occur until certai n specific relative humidity. . A set of relative humidity i s used for accelerated testing of sample , these include 75% RH , 80% RH and 90% RH ( note ambient humidity without stress co ndition is 40 to 60% RH ) . 214

• The product is kept with or without its final container in a cabinet ( adjusted with different stressed R H) for specified period . • The samples are then analyzed for the set di fferent RH conditions . • A graphical plot of the % potency of the drug Vs % relative humidity is done for the stressed sample . • The plot will be subsequently used to determine the cri tical humidity ( the point beyond which the drug is u nstable) . • The critical humidity valu e is very important in giving information regardi ng the storage and protection needed for the sample . • The potency of the drug should be above 90% . 215

b) Light : It is one of th e factors that bring photochemical reaction since UV radient e nergy can enhance certain type of reaction . . Light enhance activation energy t here by increase reaction rate . . For specific kinetic study of a reaction, the λmax and intensity of the radiant energy should be kno wn because the type of energy responsi ble for the reaction can be identified . E.g .  oxidation: adrenaline;  auto oxidation : oil ranc idity, color fading . 216

. Type of radient e nergy that influence photochemical reaction: sunlight > day light >> artificial light or a combination of these . . Colored bottles are used for the protection of light reactions because they prevent the passage of certain wave length of the l ight . . Accelerated testi ng : a more intense source of radient energy is used for kinetic studies . • Fluorescent lamp is commonly used to produce decay of a product 217

c) Mechanical stress and gravity:  Stress ( vibration ) and pressu re brings breakage, abrasion and chipping of formulated product like tabs and suspensio ns .  Solid sample : the test performed are friability and hardness test . Friability test is associated with chipping a nd abrasion . . Hardness helps to anticipate the strength of tabs to withstand stress conditions during transportation , handling and us age .  Suspensions (liquids): The mechanical stress is due to gravity during storage conditions and physical stability. . The degree of physical stability of a suspension is determined by:  Shaking : proof for homogenous re - distribution with moderate shaking .  Pourability : proof for easy pourability during its shelf life . 218

 Brook field viscometer is used for quantitat ive determination . . It gives idea about the pa rticle size distribution in quantitative manner. • Emulsion ( oil / water or water / oil ): its instability is asso ciated with creaming ( due t o gravity) .  The particle size distribution can be determined by: • Microscopy : globule particles observed are cons idered as particles . • Coulter counter method : th e dimension and the No . of particles are determined, a n d a histogram is plotted (for frequency o f particles Vs dime nsion range ) to determine the homogeneity o f the particle size . 219

d) Temperature . It enhances the reaction ra te because the numbe r o f collision per unit time become hi gher. . The importance of tempe rature on the chemical stability of a pharmaceutical product cannot be over- emphasized because the rate of chem ical reaction doubles for eve ry 10 C rise in temperature . – E.g . Reconstituted syrup preparation like amoxicillin syrup are stable: 220

d) Temperature … • For 14 days if stored at room temperature . • 3 weeks to 1 month if stored in refrigerator. • The stability will be reduced to a week or less , if it stored in very hot and humid environme nt . • Stability testing at controlled laboratory conditions (usually for samples used in clinical study) is usually performed at room temperature (15 to 25 C) or 2 .8 C ( refrigeration condition ) and ambien t humidity (40-60 %RH) . 2 21

 The stability of a product can be predicted by t esting at higher temp ( accelerated testing ) .  This facilitates the prediction of an expi ry date by Arrhenius equation (K = Ae -E/ RT = log K = - Ea /2.3 03 R x 1/T + logA )  The test is pe rformed on at least three elevated temp conditions with identical relative humidity , i .e . 40 C (75% RH), 50 C (75% RH), 70 C (75% RH ), and higher tem p .  The value obtaine d at elevated temp is extrapolated to shelf life at room temp . . e.g . if the shelf life at 60 C is 30 days the shelf life at room temp (15-20 C) will be 8 to 9 months . . Taking log K = - Ea /2.303 Rx 1/T + log A and plotting log K Vs 1/ T a straight line plot with a negative slope . 222

 Plotting either: . Conc Vs time for zero order (equation C = -Kt + Constant) or . log Conc Vs time for first order (equation log. (a- x) = -Kt /2.303 + log. A) • Yield straight line with a negative slope in both case s • The t ½ for first order and second order given by t ½ = 0.693 / K and t ½ = 1 / Ka , respectively . 223

Prediction of shelf life using Arrhenius equation & graphical plots following accelera ted stability testing Illustration -1: Using the plots of zero , first order reactions and Arrheni us equation:  If given sample is kept un der stressed conditions at different temp (e.g . 35 , 50 , 60 & 70 C) .  The samples ( that were under stressed conditions) are removed and analyzed at a fixed interval of time .  A plot of conc Vs time (zero order) or log . Conc . Vs time ( first order ) is then made . . The value of „K‟ at ea ch temp can be obtained from both types of plots . . If log k Vs 1/ T plot is drawn from the above plot ( Arrhe nius plot) . The value for log K 25 can be obtained by extrapolation . 35 50 60 C or log C t 70 224

. Given the value of K 25 that was obtaine d by extrapolation , the t 10% ( shelf life ) for a sample that under go first order type of decomposition can be obtained from the equation . Let K 25 = . 17x10 -3 per days . i .e . t = 2 .303 / K xlog C / C t t10% = 2 .303/ . 17 x 10 -3 x log 100/90 = 619 days . * Hence the shelf life of the product w ill be about 20 months . 225

Guidelines or scheme for stabili ty studies: 1. Pre - formulation stability studies on active ingredient :  Include studies on the active ingredient at various stress conditions i . e . elevated temperature (the most important one ), high relative humidity , the effect of acidic and alkaline solution , oxygen and artificial light exposure . . The testing int erval is at most one month . It should give a good understanding of possi ble degradation route . If possible the degradation product should be isolated and characterized . . Compatibility of the active ingredient with the excip ients relevant for intended dosa ge from . 226

2. Accelerated stability studies on dosage form for clinical studies > This study is used to predict the expiry date of the specified dosage ( the stability of the acti ve ingredient is also studied at the sametime as a control) . > At least th ree elevated temperature with identical relative humidity i .e . 40 C (75% RH ), 50 C (7 5% RH ) and 60 C (75% RH ) are used for two batches . • The testing interval are zero, one, two , three and six months . • Studies are carried out in open glass containers ( tabs or caps) or in a clear glass ampoule or vials . 227

3. Stability studies on clinical supplies > This study is used to assess the stability of clini cal supplies that are stored in their primary pack at a controlled laboratory conditions i .e . 15-25 C and ambient relative humidity (40-60% RH ) or in a refrigerator (2 to 8 C) . • Testing interval : the samp les are routinely analyzed at zero time and then at half yearly or yearly interval up to a final expiry date of 5 years . 228

4. Long term stabili ty studies on the finished product and active ingredien t > The study is carried out both in the final packing and in open container ( for solid dosages / parentera ls) or final packing and glass container to demonstrate the compatibil ity of the chosen pack with its content . • The testing intervals are zero time , three , s ix, nine, 12, 18 , 24 months (optional t esting per iod depending on the type o f finished product are 30, 36 , 48 and 60 months) • The study is carried out in order to choose long term storage condition and to compare the stability of the final dosage for m with the dosage use d in clinical studies . • The accelerat ed testing conditions are 40 C (75% RH), 50 C (75% RH ) and 60 C (75% RH ) for three b atches . 229

5. Post - marketing ongoing stability studies > The stability of the first three production batc hes is performed after product is on the marke t . • The testing interval as of No . 4 6. Post - marketing stability surveillance studies > This study is carried out to co nfirm for the claimed shelf life with respect to the recommended storage co nditions . • The stabil ity of the registered product is tested by analyzing a cluster of batches of finishe d product for the claimed shelf life . • The approach is a product oriented instead of batch oriented . • The study may facilitate in i dentifying change in product specification at early stage . 230

Analytical methods in stability s tudies > The analytical methods used to assess the stability of active ingred ient or dosage forms should be stability indicating and valid ated according to the requirements of GLP in QA program . > A method is considered to be stability indic ating when it differentiates between the act ive ingredient and its possible by products, decomposition products and other compo nents . > The stability of active ingredient can be assessed by di fferent instrumental analytical technique . E.g . TLC, HPLC, GC, IR, NMR, measuring physical constants, etc . > The stability of a dosage form should be characterized by considering its physical , chemical , biological effects and in some cases microbiological chara cteristics 231

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