Stability:- Basic Concepts And Objectives

Stability:Basic Concepts and ObjectivesESSENTIAL DEFINITIONS ACCORDING TO ICHSTABILITYSTABILITY is officially defined as the time lapse(period) during which drug substance (API) ordrug product (FPP) to retains the same properties and characteristics(i.e. Physical,Chemical, Microbiological, Therapeutic and Toxicological specifications to maintain itsidentity, strength, quality, and purity ) that it possessed at the time of manufacture.ACCELERATED STABILITY TESTINGThese are the studies designed to increase the rate of chemical degradation and physicalchange of a drug by using exaggerated storage conditions as part of the formal stabilitytesting programmes. The data thus obtained, in addition to those derived from real – timestability studies, may be used to assess longer – term chemical effects under nonaccelerated conditions and to evaluate the impact of short-term excursions outside the labelstorage conditions, as might occur during shipping. The results of accelerated testing studiesare not always predictive of physical changes.LONG-TERM STABILITY STUDIESExperiments on the physical, chemical, biological, biopharmaceutical and microbiologicalcharacteristics of an API or FPP, during and beyond the expected shelf-life and storageperiods of samples under the storage conditions expected in the intended market. Theresults are used to establish the re-test period or the shelf-life, to confirm the projected retest period and shelf-life, and to recommend storage conditions.ONGOING STABILITY STUDYThe study carried out by the manufacturer on production batches according to apredetermined schedule in order to monitor, confirm and extend the projected re-testperiod (or shelf-life) of the API, or confirm or extend the shelf-life of the FPP.STRESS TESTING–FORCED DEGRADATION (API)Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of thedevelopment strategy and is normally carried out under more severe conditions than thoseused for accelerated testing.To identify potential degradants (degradation pathways) of the API and assess if they canbe formed during mfg. or storage of the FPP (Finished Pharmaceutical Product )STRESS TESTING–FORCED DEGRADATION (FPP)Studies undertaken to assess the effect of severe conditions on the FPP. Such studiesinclude photo stability testing (see ICH Q1B) and compatibility testing on APIs with eachother in FDCs and API(s) with excipients during formulation development.MEAN KINETIC TEMPERATURE (MKT):MKT, as defined by the USP, is a “single calculated temperature at which the total amountof degradation over a particular period is equal to the sum of the individual degradationsthat would occur at various temperatures”

RE-TEST PERIODThe period of time during which the API should be examined to ensure that the material isstill in compliance with the specification and, thus suitable for use in the manufacture of agiven FPP,when stored under the defined conditions.SHELF LIFE ( Expiration dating period, conformance period):The time period during which an API or a FPP is expected to remain within the approvedshelf-life specification, if stored under recommended conditions.SPECIFICATION - RELEASEThe combination of physical, chemical, biological, and microbiological tests and acceptancecriteria that determine the suitability of a drug product at the time of its release.SPECIFICATION - SHELF LIFEThe combination of physical, chemical, biological, and microbiological tests and acceptancecriteria that determine the suitability of an API throughout its re-test period, or that an FPPshould meet throughout its shelf life.PRIMARY BATCH (called also exhibit batch)A batch of an API or FPP used in a formal stability study, from which stability data aresubmitted in a registration application for the purpose of establishing a re-test period orshelf life, respectively. A primary batch of an API should be at least a pilot scale batch. For aFPP, two of the three batches should be at least pilot scale batch, and the third batch aproduction batch.PRODUCTION (SCALE) BATCHA batch of an API or FPP manufactured at production scale by using production equipmentin a production facility as specified in the application.SUPPORTING DATAData, other than those from formal stability studies, that support the analytical procedures,the proposed re-test period or shelf life, and the label storage statements. Such data include(1) stability data on early synthetic route batches of API, small-scale batches of materials,investigational formulations not proposed for marketing, related formulations, and productpresented in containers and closures other than those proposed for marketing; (2)information regarding test results on containers; and (3) other scientific rationales. TYPES OF STABILITY Mainly Five types of Stability are generally recognizedType ofCondition Maintained throughout the shelf life of drug productStabilityEach active ingredient retains its chemical integrity and labeled potencyChemicalwithin the specified limitThe original Physical properties including appearance palatability,Physicaluniformity, dissolution and suspendability are retained.Sterility or resistance to microbial growth is retained according toMicrobiologicalspecified requirement.TherapeuticTherapeutic effect remains unchangedToxicologicalNo significant increase in toxicity occurs

What happens due to Instability ?1) Increase in the concentration of API :For some products, loss of vehicle can result in an increase in the concentration of activedrug.For example, some lidocaine gels exhibit this behaviour, perfusion bags sometimes allowsolvent to escape and evaporate so that the product within the bags show an increase inthe concentration.2) Loss of content uniformity :Suspensions are the drug delivery system most likely to show a loss of content uniformityas a function of time. For such systems, determination of ease of redispersion orsedimentation volume may be included in a stability protocol.3) Decline of microbiological status :The microbiological status of a pharmaceutical product can change significantly with time .First, micro – organisms present in the product at the time of manufacture may reproduceand thus increase the number of viable micro-organisms.Drug assayed for the bioburden at the time of manufacture, is within limits, and whentested after say 6 months storage, exceed the maximum permitted limits.4) Formation of toxic degradation products :If a drug degrades to a molecular species that is toxic, there must be a special attentiongiven to the quantity of such products. E.g. Conversion of p-amino salicylic acid to p-aminophenol (Toxic). OBJECTIVES OF STABILITY TESTING:(1) Our concerns for patients’ welfare: Obviously, our primary reason for stability testing should be our concern for the wellbeing of the patients who will use our products. Sometimes in the mad rush to complywith other requirements, this important fundamental may be discounted or forgotten.Indeed, sometimes one gains the impression that is some quarter’s stability is regardedas having clinical relevance. Certainly, if a product that does not degrade to toxic decomposition products and that ischaracterized by a narrow therapeutic ratio is present on the market at only 85% of labelclaim; one would not expect patients to be dropping dead in the streets because of thisdeficiency instability. However, this is not to say that stability problems can never have serious clinicalconsequences. For example, in the early 1980s a packaging stability problem withnitroglycerine tablets unfortunately resulted in some tablets have 10% of label claim.Since nitroglycerine is used for the emergency treatment of a most serious cardiacconditions, angina, there is unfortunately strong cause for concern that some patientsmay have died as a result of this stability problem.(2) To protect the reputation of the producer.We should be jealous for the reputation that the stability of our pharmaceutical products– compounded or manufactured – enjoys. Thus a most important reason for conducting astability testing program is to assure ourselves the our products will indeed retain fitnessfor the use with respect to all functionally relevant attributes for as long as they are onthe market.

(3) Requirements of regulatory agenciesIn many parts of the world, there are legal requirements that certain types of stabilitytests, as required by regulatory agencies, must be performed. Obviously, the law must beobeyed. However, it is wrong to abdicate from all scientific judgements and only conductthose stability tests that a regulatory agency is perceived as requiring. Indeed, there areoccasions when any manufacturer with a true dedication to quality will perform stabilitytests that are over and above those required by regulation.(4) To provide a database that may be of value in the formulation of other products.Data obtained in the stability evaluation of product X in 1999 may prove to be of valuewhen, in 2003, we start developing product Y. There may be occasions, although theyare probably rare, when it will worthwhile to continue stability testing on an R&Dformulation that we know will never be marketed just because we are interested in thestability of a new excipient that we have included in the formulation.(5) Shelf-life & storage condition and labeling specification:By carrying out stability testing we can find out the shelf –life and expiry date can becalculated. We ca have information about best storage condition at which drug willcontain its characteristic for long time. And if there is any specification that we can writeit on the label.(6) Adequate formulation & container closer systems.We can have idea about the formulation which will be more stable. And if during stabilitytesting we find any specification of container. e.g. Menadione injection is packed inamber color ampoule to protect from photo degradation.(7) How quality of drug substance or product varies with the time under thevarious factors.influence of(8) Degradation product & possible degradation pathway(9) Development & validation of stability indicating methodology(10) Prevent great loss by recalling the batch due to stability.If any difficulty is found during storage and in marketed product, than industry has torecall all the drugs of that batch which is not economical . But if stability studies arecarried out than we may over come those problems.(11) To verify that no changes have been introduced in the formulation or manufacturingprocess that can adversely affect the stability of the product(12) Providing evidence on how quality of drug substance or product varies with the timeunder the influence of various factors like temp, humidity and light.(13) Loss/increase in concentration of API(14) Modification of any attribute of functional relevance, e.g., aalteration of dissolutiontime/profile or bioavailability(15) Loss of pharmaceutical elegance and patient acceptability