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Accred Qual Assur

DOI 10.1007/s00769-008-0379-5

PRACTITIONER’S REPORT

Built-in quality systems in regulated contract research


organizations (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 now Introduction


familiar with GXPs and have become more popular for
conducting bioequivalence studies, it is very important that Assurance of generic product quality dictates that the overall
the sponsor has the assurance that the study has been design of a bioequivalence study is based on knowledge of
conducted not only to the highest standard of science but the pharmacokinetics, pharmacodynamics, and therapeutics
also in compliance with regulatory requirements. The of the active drug substance. Furthermore, control over
dynamic role of quality personnel requires alert knowl- adherence of the followed procedures to protocol require-
edgeable people to recognise all the issues which arise and ments, standard operating procedures (SOPs), and
take the proper actions—experienced persons can detect international good practice rules, during conduct of the study
and rectify these. On the basis of equality, for quality will ensure good standing regarding regulatory compliance.
system personnel and scientists a firm grasp of regulatory The regulatory backbone for bioequivalence studies has
science is needed to succeed. It must be remembered its origins in the principles of GLP and GCP. Bioequivalence
that compliance is monitored by adherence to regulatory studies, pharmacokinetics studies, and/or pharmacodynam-
standards, whereas the regulatory bodies review the ics studies are non-therapeutic studies [1]. The essence of a
appropriately implemented regulatory science principles. quality system is that the quality has to be delivered by
workers, and the quality personnel should have the role of
Keywords Bioequivalence study (BES)  assuring through an umbrella of functions. The activities of
Generic product  Contract research organizations (CROs)  bioequivalence studies are either general (related to facility
Good practices (GXP) or system) or study-related, pointing to the need for a quality
control (QC) and quality assurance (QA) dichotomy. Com-
prehensively, bioequivalence studies require a hyphenated
Electronic supplementary material The online version of this quality system furnishing a network proceeding along two
article (doi:10.1007/s00769-008-0379-5) contains supplementary tracks, simultaneously—the regulatory track and the scien-
material, which is available to authorized users. tific track—wiring a rationally designed regulatory science
frame. Our aim here is to present some first-hand experiences
R. Tayyem (&)  J. Tamimi  M. Shihabeddin
BioCenter for Bioequivalence and Pharmaceutical Studies, we have confronted and overcome to achieve scientifically
Arab Company for Drug Industry and Medical Appliances sound and regulatory accepted bioequivalence studies.
(ACDIMA), P.O. Box: 17700, 11195 Amman, Jordan
e-mail: rabab01@gmail.com; rababt@acdima.com

R. Tayyem Analysis of general requirements


Faculty of Allied Health Sciences, The Hashemite University,
Zarqa, Jordan Regulatory requirements
N. Najib
International Pharmaceutical Research Centre (IPRC), The regulatory track covers a broad spectrum of good
Amman, Jordan practice rules. Information about manufacturing procedures

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Accred Qual Assur

and data from quality-control release tests should indicate the USFDA guidance on method validation, applicable
that the products under investigation (biobatch test prod- parts of the GLP regulations are used as a common
uct) are of suitable quality and have been manufactured basis for bioanalytical operations to perform the pre-
under good manufacturing practice (GMP) conditions. As study and within-study validation [3]. When accidental
in-vivo bioequivalence studies are considered clinical events are encountered, concurrent and /or retrospec-
trials, it is generally required that recommendations of tive validation may suffice to guarantee the integrity of
good clinical practice (GCP) are implemented in all bio- results. Regulatory guidance has established clear
equivalence studies. Ironically, although good laboratory criteria for acceptance and rejection of the analytical
practice (GLP) guidelines apply to non-clinical safety runs. All these faced counterbalances need to be
studies, general principles of GLP are to be followed in the cautiously handled by the quality system by setting a
bioanalytical work of bioequivalence studies. Regulatory clear and valid bioanalysis plan which obviates
requirements enforce the proper use of statistics to evaluate deliberate QC use among clinical samples and cali-
the drug product under investigation for its effectiveness bration curve standards.
and safety. Having QC of each activity to check the result 3. Pharmacokinetic parameters obtained from drug con-
of the process and QA for the process itself means the QC centrations, are the surrogate parameters used for
role is incorporated into each activity in traceable and bioequivalence assessment. The area under the con-
verifiable documents (active role) whereas the QA has a centration–time curve calculated using the trapezoid
synchronized reactive inspection role and a proactive method, from time zero to the time (t) of last measured
quality improvement role, in a fairly harmonized quality concentration (AUC0-t), the area under the concentra-
system. tion–time curve calculated from time zero to infinity
(AUC0-?), and the peak of maximum concentration
(Cmax) occurring at peak time (Tmax) obtained directly
Scientific requirements
from the concentration time curve are considered to be
the primary parameters that are most relevant for
Needless to say, conclusion of bioequivalence is based on
assessing bioequivalence. AUC0-t should be equal to
the overall scientific assessment of the pharmacokinetic
or greater than 80% of the AUC0-?, except when the
study, and not only on meeting the acceptance criteria. To
truncated AUC is being used. The apparent volume of
set the scene, the quality system is required to assure that
distribution (Vd), mean residence time (MRT), and the
valid and correct conclusions are drawn from appropriately
elimination half-life (T1/2) should also be determined,
designed and well executed studies. In principle, the role of
although they are not needed to be statistically treated
a quality system should reveal the ‘‘science behind’’ and
or bioequivalence evaluation. When urine samples are
not hide ‘‘behind regulations’’ [2].
used, cumulative urinary recovery (Ae) and maximum
1. A two-period, two-sequence, single-dose, cross-over, urinary excretion rate are employed instead of AUC
open label randomized design is the first choice for and Cmax ratios. Statistical analysis of the bioequiva-
pharmacokinetic bioequivalence studies. Periods of the lence study should demonstrate that a clinically
study are separated by adequate wash-out interval significant difference in bioavailability is unlikely.
which is usually five to ten times the half-life of the The statistical method for testing pharmacokinetic
parent and/or the metabolic moieties. The number of bioequivalence is based on determination of the 90%
subjects to be evaluated in bioequivalence studies confidence interval around the ratio of the log-trans-
should be determined from data available from the formed population means (generic/comparator) for the
literature or from previous pilot and pivotal studies, pharmacokinetic parameters (AUC0-t, AUC0-? and
based on coefficient of variation (intrasubject CV%), Cmax) under consideration and by carrying out two
significant level (5%), power level (not less than 80%), one-sided-tests (TOST) at the 5% level of significance.
expected mean deviation from the reference product, The 90% confidence intervals (CI) for the AUC ratio
and the 90% confidence intervals of the geometric and Cmax ratio of relative bioavailability should lie
means. Also sufficient number of subjects should be within a bioequivalence range of 0.80–1.25%, for a
recruited to achieve the pre-stated statistical power and broad range of drug products. However, the Cmax-ratio
to allow for possible dropouts. is inherently more variable than the AUC ratio, and in
2. The plausibility of the bioanalytical method used to certain justifiable cases a wider acceptance range (e.g.
quantitate the moieties to be measured must be 0.75–1.33% or 0.70–1.43%) may be acceptable,
established before commencing the study, because depending on the regulatory authority to which the
storage conditions and the stability of clinical samples study is submitted. The USFDA allows only confi-
are to be defined in the protocol in advance. Besides dence intervals of 0.80–1.25% for both AUC ratio and

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Accred Qual Assur

Cmax ratio whereas the European regulatory authorities subject compliance with protocol requirements. For
may accept justified cases of widened confidence some studies, the predose sample can be assayed
limits for Cmax ratio. before the next drug administration to screen for any
significant carryover concentrations, based on which
the next period can be conducted.
(b) To reach the proposed adequate statistical power the
Discussion of the appropriate regulatory science basis add-on design is to be considered, whereas recruiting
for specific bioequivalence study issues ‘‘extra’’ subjects into the study seems most appropri-
ate if dropouts are to be replaced. Both cases should
Generally speaking, the standards of GLP, GMP, and GCP be indicated in the protocol. Additionally, analysis of
are required by regulatory authorities around the world, samples from ‘‘extra’’ should be clarified when not
with rigorous attention to employee training, detailed and required for statistical analysis.
authorized documentation, equipment validation, careful (c) Sampling times are scheduled to enable characteriza-
tracking of changes, and routine auditing of compliance. tion of Cmax and AUC taking into consideration the
Material violation of GLP, GMP, or GCP guidelines could inter-subject differences in absorption and elimination
result in additional regulatory sanctions and, in severe rate. So, sampling should continue long enough to
cases, could also result in complete disqualification if the ensure that not less than 80% of AUC ratios are
regulatory authorities issued warning letters directed accrued. But, generally, sampling after 72 h may not
towards the poor performance of the study. Initially, quality be necessary when the truncated AUC approach is
personnel shall use the internal audit findings as training employed and the sampling frequency is more
material, to train staff members who are in charge of exe- devoted to characterization of Cmax. During sampling
cution of the study, in order to avoid recurrence in future procedures the interval between samples should be
studies. On regulatory inspection, non-compliance consid- maintained constant, otherwise actual sampling times
ered as a Major Deficiency (examples are provided in the should be used in pharmacokinetics calculations.
ESM list) might mean rejection of the study or the entire (d) An acceptable number of missing samples should be
submission. When violations, deviations, or deficiencies defined which justifies the adequacy of sample points
infringe compliance, scientifically based corrective and pertinent to a subject to be included in the bioequiv-
preventive actions (CAPAs) will help bridge the gaps and alence evaluation.
bring the organization into a good position in its regulatory (e) For bioequivalence assessment, no simple generaliza-
compliance standing. tion can be made to conclude whether the parent drug
The following is rationalization for some challenges that or the active metabolite(s) is (are) to be measured.
were faced and treated during the conduct of different Stating a priori in the protocol which moiety is to be
bioequivalence studies, regulated studies, submitted to measured keeps the consumer risk (type I error) at the
different legislative bodies. 5% level. If more than one analyte is evaluated
retrospectively, consumer and producer risks will
Regulatory science rationale in study design change. [4–8]. Therefore, it is recommend that cases
requirements: are examined individually to decide which moiety is
to be evaluated and decision making should rely on
(a) The washout interval between study periods should the parent drug whenever possible.
be adequate enough in crossover design. When one
moiety (even if not the measurable one) has a longer
elimination half life, or when variations are reported Regulatory science rationale in bioanalytical
due to different metabolic genotypes, the wash-out challenges:
period should be extended to account for this moiety
until totally eliminated to avoid carryover effects. The quality system role becomes more challenging when
Alternatively, if the moiety is not the intended anecdotal issues are introduced into the bioanalytical work.
measurable one, bioanalytical method selectivity can The following illustrates some instances of current bioan-
be established so as to shorten the washout interval alytical evolving matters of concern:
according to the intended measurable moieties. (a) Carryover of analyte during the analytical process,
Although 5% of Cmax values can be accepted in either from the extraction procedure or during chro-
predose samples, the washout period should, never- matographic analysis, has recently become a major
theless, not be extended beyond one month to help problem because of the introduction and reliance on

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sensitive analytical instruments based on mass spec- each subject dataset is not acceptable for studies of
troscopy. Because assessment of carryover and relatively short duration (\72 h). However, other
contamination are not treated in any detail by regu- criteria can be considered for studies of longer
latory guidelines, appropriate approaches to detecting, duration ([72 h), to account for the missing samples
addressing, and rectifying this problem are needed. of uncommitted subjects.
Although GLP has not dealt with these issues, han-
dling the incidences that potentially affect data
integrity, by performing a formal investigation into Regulatory science rationale in unresolved issues for
the problem and out-of-trend results/adverse trends, bioequivalence evaluation
may represent a supportive manoeuvring tool that
helps the quality professional in root cause analysis, The used range of the 90% confidence interval for the
failure investigation reporting, and subsequent reso- bioequivalence pharmacokinetic determinants (AUC0-t,
lution of the problem. AUC0-?, and Cmax) must be defined prospectively and
(b) Another controversy is the placement and levels of should be justified, taking into account safety and efficacy
quality control (QC) samples that may result in considerations. We have developed a scheme (Fig. 1)
‘‘inappropriate selection of QC levels and place in enabling in-house decision of what to draw the conclusion
relation to the actual subject plasma concentrations’’. of bioequivalence based on the 90% confidence interval
Addition of a fourth level of QC within the range of approach and in accordance with the regulatory authority to
study sample concentrations may help manage this which the study is to be submitted. This decision becomes
problem [9]. Judicious placement of QC according to very critical when the 90% confidence of the AUC ratio
expected ascending and descending levels of the falls between 0.80–1.25% while for the Cmax ratio it is
profile seems fairly reasonable, when planned before outside this range. Before reaching a conclusion, the sim-
the start of analysis. ilarity factor between products in-vitro dissolution profiles
(c) Criteria for maximum allowable limits for missing and geometric means of the Cmax ratio should all be
samples should be set in the statistical analysis plan. examined thoroughly vis-à-vis the drug or drug product
For example, lack of more than10% of the values for variability characteristics (intrasubject CV) and the power
concentrations of a measured moiety (moieties) from of the study [5–7].

Fig. 1 Decision scheme


bioequivalence conclusion

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Accred Qual Assur

(a) When the 0.80–1.25% confidence limits are not met without an appreciation of the underlying concepts a great
by the calculated Cmax confidence limits, it can be opportunity is missed. On the other hand, it is easy for
widened to 0.75–1.33% provided that a powerful scientist to become immersed in details and overlook
study surrendered results for AUC ratio confidence something basic, and the more that quality personnel
limits falling between 0.80–1.25%, geometric means understand the governing scientific principles the more
of Cmax ratio and AUC ratio are between 0.90–1.11%, effectively such pitfalls can be avoided or rectified.
and in-vitro dissolution testing had indicated product Approaches of risk-based auditing and evidence-based
similarity (F1 factor \ 15 and F2 factor [ 50). decisions are developed by knowing which elements are
(b) When underpowered study is the case, add-on study the most critical in the study of integrity. Because bio-
may be conducted and the confidence limits for the equivalence studies may not involve a tremendous number
sum-up studies are calculated. If the new limits did not of scientists, due to their more classical and less sophisti-
meet the 0.80–1.25% confidence interval, and the cated design, the new trend is to have regulatory scientists
study indicated high drug or drug product variability as quality professionals; this makes the pace of regulatory
(intrasubject CV [ 30%), the confidence interval for approval processes within the drug-development tunnel
Cmax can be widened to 0.75–1.33% or 0.70–1.43%, faster, efficient, and successful.
depending on safety and efficacy issues, provided that
the AUC ratio confidence limits fall between 0.80–
1.25%, the geometric means of the Cmax ratio and AUC References
ratio are between 0.90–1.11%, and in-vitro compara-
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