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Built-In Quality Systems in Regulated Contract Research Organizations (CRO) Conducting Bioequivalence Studies

Built-In Quality Systems in Regulated Contract Research Organizations (CRO) Conducting Bioequivalence Studies

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Built-in quality systems in regulated contract research organizations (CRO) conducting bioequivalence studies: a regulatory science perspective.
As contract research organizations are now familiar with GXPs and have become more popular for conducting bioequivalence studies, it is very important that the sponsor has the assurance that the study has been conducted not only to the highest standard of science but also in compliance with regulatory requirements. The dynamic role of quality personnel requires alert knowledgeable people to recognise all the issues which arise and take the proper actions—experienced persons can detect and rectify these. On the basis of equality, for quality system personnel and scientists a firm grasp of regulatory science is needed to succeed. It must be remembered that compliance is monitored by adherence to regulatory standards, whereas the regulatory bodies review the appropriately implemented regulatory science principles.
Built-in quality systems in regulated contract research organizations (CRO) conducting bioequivalence studies: a regulatory science perspective.
As contract research organizations are now familiar with GXPs and have become more popular for conducting bioequivalence studies, it is very important that the sponsor has the assurance that the study has been conducted not only to the highest standard of science but also in compliance with regulatory requirements. The dynamic role of quality personnel requires alert knowledgeable people to recognise all the issues which arise and take the proper actions—experienced persons can detect and rectify these. On the basis of equality, for quality system personnel and scientists a firm grasp of regulatory science is needed to succeed. It must be remembered that compliance is monitored by adherence to regulatory standards, whereas the regulatory bodies review the appropriately implemented regulatory science principles.

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Published by: Ahmad Abdullah Najjar on Jul 28, 2008
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05/09/2014

 
PRACTITIONER’S REPORT
Built-in quality systems in regulated contract researchorganizations (CRO) conducting bioequivalence studies:a regulatory science perspective
Rabab Tayyem
Æ
Reema Tayyem
Æ
Naji Najib
Æ
Jaafar Tamimi
Æ
Mukhtar Shihabeddin
Received: 10 June 2007/Accepted: 8 February 2008
Ó
Springer-Verlag 2008
Abstract
As contract research organizations are nowfamiliar with GXPs and have become more popular forconducting bioequivalence studies, it is very important thatthe sponsor has the assurance that the study has beenconducted not only to the highest standard of science butalso in compliance with regulatory requirements. Thedynamic role of quality personnel requires alert knowl-edgeable people to recognise all the issues which arise andtake the proper actions—experienced persons can detectand rectify these. On the basis of equality, for qualitysystem personnel and scientists a firm grasp of regulatoryscience is needed to succeed. It must be rememberedthat compliance is monitored by adherence to regulatorystandards, whereas the regulatory bodies review theappropriately implemented regulatory science principles.
Keywords
Bioequivalence study (BES)
Á
Generic product
Á
Contract research organizations (CROs)
Á
Good practices (GXP)
Introduction
Assuranceofgenericproductqualitydictatesthattheoveralldesign of a bioequivalence study is based on knowledge of the pharmacokinetics, pharmacodynamics, and therapeuticsof the active drug substance. Furthermore, control overadherence of the followed procedures to protocol require-ments, standard operating procedures (SOPs), andinternationalgoodpracticerules,duringconductofthestudywill ensure good standing regarding regulatory compliance.The regulatory backbone for bioequivalence studies hasitsoriginsintheprinciplesofGLPandGCP.Bioequivalencestudies, pharmacokinetics studies, and/or pharmacodynam-ics studies are non-therapeutic studies [1]. The essence of aquality system is that the quality has to be delivered byworkers, and the quality personnel should have the role of assuring through an umbrella of functions. The activities of bioequivalence studies are either general (related to facilityorsystem)orstudy-related,pointingtothe needforaqualitycontrol (QC) and quality assurance (QA) dichotomy. Com-prehensively, bioequivalence studies require a hyphenatedquality system furnishing a network proceeding along twotracks, simultaneously—the regulatory track and the scien-tific track—wiring a rationally designed regulatory scienceframe.Ouraimhereistopresentsomefirst-handexperienceswe have confronted and overcome to achieve scientificallysound and regulatory accepted bioequivalence studies.
Analysis of general requirements
Regulatory requirementsThe regulatory track covers a broad spectrum of goodpractice rules. Information about manufacturing procedures
Electronic supplementary material
The online version of thisarticle (doi:10.1007/s00769-008-0379-5) contains supplementarymaterial, which is available to authorized users.R. Tayyem (
&
)
Á
J. Tamimi
Á
M. ShihabeddinBioCenter for Bioequivalence and Pharmaceutical Studies,Arab Company for Drug Industry and Medical Appliances(ACDIMA), P.O. Box: 17700, 11195 Amman, Jordane-mail: rabab01@gmail.com; rababt@acdima.comR. TayyemFaculty of Allied Health Sciences, The Hashemite University,Zarqa, JordanN. NajibInternational Pharmaceutical Research Centre (IPRC),Amman, Jordan
 123
Accred Qual AssurDOI 10.1007/s00769-008-0379-5
 
and data from quality-control release tests should indicatethat the products under investigation (biobatch test prod-uct) are of suitable quality and have been manufacturedunder good manufacturing practice (GMP) conditions. Asin-vivo bioequivalence studies are considered clinicaltrials, it is generally required that recommendations of good clinical practice (GCP) are implemented in all bio-equivalence studies. Ironically, although good laboratorypractice (GLP) guidelines apply to non-clinical safetystudies, general principles of GLP are to be followed in thebioanalytical work of bioequivalence studies. Regulatoryrequirements enforce the proper use of statistics to evaluatethe drug product under investigation for its effectivenessand safety. Having QC of each activity to check the resultof the process and QA for the process itself means the QCrole is incorporated into each activity in traceable andverifiable documents (active role) whereas the QA has asynchronized reactive inspection role and a proactivequality improvement role, in a fairly harmonized qualitysystem.Scientific requirementsNeedless to say, conclusion of bioequivalence is based onthe overall scientific assessment of the pharmacokineticstudy, and not only on meeting the acceptance criteria. Toset the scene, the quality system is required to assure thatvalid and correct conclusions are drawn from appropriatelydesigned and well executed studies. In principle, the role of a quality system should reveal the ‘‘science behind’’ andnot hide ‘‘behind regulations’’ [2].1. A two-period, two-sequence, single-dose, cross-over,open label randomized design is the first choice forpharmacokinetic bioequivalence studies. Periods of thestudy are separated by adequate wash-out intervalwhich is usually five to ten times the half-life of theparent and/or the metabolic moieties. The number of subjects to be evaluated in bioequivalence studiesshould be determined from data available from theliterature or from previous pilot and pivotal studies,based on coefficient of variation (intrasubject CV%),significant level (5%), power level (not less than 80%),expected mean deviation from the reference product,and the 90% confidence intervals of the geometricmeans. Also sufficient number of subjects should berecruited to achieve the pre-stated statistical power andto allow for possible dropouts.2. The plausibility of the bioanalytical method used toquantitate the moieties to be measured must beestablished before commencing the study, becausestorage conditions and the stability of clinical samplesare to be defined in the protocol in advance. Besidesthe USFDA guidance on method validation, applicableparts of the GLP regulations are used as a commonbasis for bioanalytical operations to perform the pre-study and within-study validation [3]. When accidentalevents are encountered, concurrent and /or retrospec-tive validation may suffice to guarantee the integrity of results. Regulatory guidance has established clearcriteria for acceptance and rejection of the analyticalruns. All these faced counterbalances need to becautiously handled by the quality system by setting aclear and valid bioanalysis plan which obviatesdeliberate QC use among clinical samples and cali-bration curve standards.3. Pharmacokinetic parameters obtained from drug con-centrations, are the surrogate parameters used forbioequivalence assessment. The area under the con-centration–time curve calculated using the trapezoidmethod, from time zero to the time (
) of last measuredconcentration (AUC
0
-
), the area under the concentra-tion–time curve calculated from time zero to infinity(AUC
0
-
?
), and the peak of maximum concentration(
max
) occurring at peak time (
max
) obtained directlyfrom the concentration time curve are considered to bethe primary parameters that are most relevant forassessing bioequivalence. AUC
0
-
t
should be equal toor greater than 80% of the AUC
0
-
?
, except when thetruncated AUC is being used. The apparent volume of distribution (Vd), mean residence time (MRT), and theelimination half-life (
1/2
) should also be determined,although they are not needed to be statistically treatedor bioequivalence evaluation. When urine samples areused, cumulative urinary recovery (Ae) and maximumurinary excretion rate are employed instead of AUCand
max
ratios. Statistical analysis of the bioequiva-lence study should demonstrate that a clinicallysignificant difference in bioavailability is unlikely.The statistical method for testing pharmacokineticbioequivalence is based on determination of the 90%confidence interval around the ratio of the log-trans-formed population means (generic/comparator) for thepharmacokinetic parameters (AUC
0
-
, AUC
0
-
?
and
max
) under consideration and by carrying out twoone-sided-tests (TOST) at the 5% level of significance.The 90% confidence intervals (CI) for the AUC ratioand
max
ratio of relative bioavailability should liewithin a bioequivalence range of 0.80–1.25%, for abroad range of drug products. However, the
max
-ratiois inherently more variable than the AUC ratio, and incertain justifiable cases a wider acceptance range (e.g.0.75–1.33% or 0.70–1.43%) may be acceptable,depending on the regulatory authority to which thestudy is submitted. The USFDA allows only confi-dence intervals of 0.80–1.25% for both AUC ratio and
Accred Qual Assur
 123
 
max
ratio whereas the European regulatory authoritiesmay accept justified cases of widened confidencelimits for
max
ratio.
Discussion of the appropriate regulatory science basisfor specific bioequivalence study issues
Generally speaking, the standards of GLP, GMP, and GCPare required by regulatory authorities around the world,with rigorous attention to employee training, detailed andauthorized documentation, equipment validation, carefultracking of changes, and routine auditing of compliance.Material violation of GLP, GMP, or GCP guidelines couldresult in additional regulatory sanctions and, in severecases, could also result in complete disqualification if theregulatory authorities issued warning letters directedtowards the poor performance of the study. Initially, qualitypersonnel shall use the internal audit findings as trainingmaterial, to train staff members who are in charge of exe-cution of the study, in order to avoid recurrence in futurestudies. On regulatory inspection, non-compliance consid-ered as a
Major Deficiency
(examples are provided in theESM list) might mean rejection of the study or the entiresubmission. When violations, deviations, or deficienciesinfringe compliance, scientifically based corrective andpreventive actions (CAPAs) will help bridge the gaps andbring the organization into a good position in its regulatorycompliance standing.The following is rationalization for some challenges thatwere faced and treated during the conduct of differentbioequivalence studies, regulated studies, submitted todifferent legislative bodies.Regulatory science rationale in study designrequirements:(a) The washout interval between study periods shouldbe adequate enough in crossover design. When onemoiety (even if not the measurable one) has a longerelimination half life, or when variations are reporteddue to different metabolic genotypes, the wash-outperiod should be extended to account for this moietyuntil totally eliminated to avoid carryover effects.Alternatively, if the moiety is not the intendedmeasurable one, bioanalytical method selectivity canbe established so as to shorten the washout intervalaccording to the intended measurable moieties.Although 5% of 
max
values can be accepted inpredose samples, the washout period should, never-theless, not be extended beyond one month to helpsubject compliance with protocol requirements. Forsome studies, the predose sample can be assayedbefore the next drug administration to screen for anysignificant carryover concentrations, based on whichthe next period can be conducted.(b) To reach the proposed adequate statistical power theadd-on design is to be considered, whereas recruiting‘‘extra’’ subjects into the study seems most appropri-ate if dropouts are to be replaced. Both cases shouldbe indicated in the protocol. Additionally, analysis of samples from ‘‘extra’should be clarified when notrequired for statistical analysis.(c) Sampling times are scheduled to enable characteriza-tion of 
max
and AUC taking into consideration theinter-subject differences in absorption and eliminationrate. So, sampling should continue long enough toensure that not less than 80% of AUC ratios areaccrued. But, generally, sampling after 72 h may notbe necessary when the truncated AUC approach isemployed and the sampling frequency is moredevoted to characterization of 
max
. During samplingprocedures the interval between samples should bemaintained constant, otherwise actual sampling timesshould be used in pharmacokinetics calculations.(d) An acceptable number of missing samples should bedefined which justifies the adequacy of sample pointspertinent to a subject to be included in the bioequiv-alence evaluation.(e) For bioequivalence assessment, no simple generaliza-tion can be made to conclude whether the parent drugor the active metabolite(s) is (are) to be measured.Stating a priori in the protocol which moiety is to bemeasured keeps the consumer risk (type I error) at the5% level. If more than one analyte is evaluatedretrospectively, consumer and producer risks willchange. [48]. Therefore, it is recommend that cases are examined individually to decide which moiety isto be evaluated and decision making should rely onthe parent drug whenever possible.Regulatory science rationale in bioanalyticalchallenges:The quality system role becomes more challenging whenanecdotal issues are introduced into the bioanalytical work.The following illustrates some instances of current bioan-alytical evolving matters of concern:(a) Carryover of analyte during the analytical process,either from the extraction procedure or during chro-matographic analysis, has recently become a majorproblem because of the introduction and reliance on
Accred Qual Assur
 123

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