2006 jones qa in bio analytical
TRANSCRIPT
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Bioanalytical Quality Assurance:Concepts and Concerns
Anthony B. Jones*,y
SFBC Taylor, Princeton, NJ 08540, USA
Summary
The BioAnalytical Specialty Section (BASS) of the Society of Quality Assurance is agroup of Quality Assurance professionals who have an interest and expertise inassuring the quality of bioanalytical data. This paper presents an overview of theregulatory requirements for bioanalysis and some of the topics that have beendiscussed by the BASS group. This initial article will be followed by more specificarticles that we hope will contribute to better understanding and consistency in theconduct, audit and reporting of bioanalytical studies. Copyright# 2006 John Wiley &
Sons, Ltd.
Key Words: quality assurance; QA; FDA; bioanalytical; method validation; bioanalysis; audit
Introduction
Bioanalysis in this article refers to the quantita-
tive measurement of drugs or their metabolite(s)
in biological samples. This is performed in thecourse of pre-clinical and clinical drug develop-
ment for new chemical entities, as well as for
generic drugs, where the assessment of bioequi-
valence (BE) is the pivotal component of the
Abbreviated New Drug Application (ANDA).
Accurate, precise and reproducible bioanalytical
work is a critical part of drug development,
central to understanding efficacy and safety
through pharmacokinetic (PK) and pharmaco-
kinetic/pharmacodynamic analyses. To an ob-
server who has not been involved inbioanalytical assays, the area may seem straight-
forward relative to other development activities,
such as the logistical and data-handling chal-
lenges presented by large clinical trials. After all,
is it not just a matter of measuring how much
drug is present in the biological sample and
reporting the result? And didn’t the United
States (US) Food and Drug Administration
(FDA) release a comprehensive Guidance Docu-ment explaining what they required?
While the answer to both these questions is, in
theory, ‘ yes’, bioanalysis is far from being a clear
and well-defined discipline, especially from a
regulatory perspective. A role of the BioAnaly-
tical Specialty Section of the Society of Quality
Assurance is to identify and clarify the areas of
uncertainty in the regulatory framework of
bioanalytical work. This is being achieved
through discussion of the problems encountered
by the group’s members and review of regula-tory agency actions and advice. This paper is the
first of a series of short articles that aim to
disseminate the conclusions of the group and
highlight the open questions that bioanalytical
auditors are faced with on a regular basis. We
hope that these will be of use to those who are
directly involved with bioanalysis and of interest
to other readers who have a more peripheral
association with bioanalysis.
*Correspondence to: Anthony B. Jones, Director, Quality
Assurance, SFBC Taylor, 301 College Road East, Prince-
ton, NJ 08540, USA. E-mail: [email protected] behalf of the BioAnalytical Specialty Section,
Society of Quality Assurance.
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Relevant Regulations
The simple initial question to ask in an attempt
to understand the regulatory basis of bioanalysis
is ‘ which regulations apply?’. The answer is,
unfortunately, not so simple. While the majority
of bioanalytical laboratories base their proce-dures on the requirements of Good Laboratory
Practice (GLP) [1–3], many of these laboratories
do not meet the definition of ‘ test site,’ as per
FDA GLP. These laboratories are often analyz-
ing samples from studies that are not within the
scope of GLP, for example from clinical studies
and method validation studies. Furthermore,
GLP is written primarily to describe the princi-
ples that apply to the administration of test
drugs to animals, and translating these princi-
ples to apply to bioanalysis is sometimes
difficult. This difficulty in ‘ translation’ is often
at the heart of the uncertainties in the profes-
sion, as both laboratory and regulatory agency
personnel may have different opinions on how
the regulations apply. Nevertheless, the
‘ applicable parts’ of the GLP regulations are
commonly used as the basis for bioanalytical
operations.
A cornerstone for bioanalytical laboratories is
the FDA Guidance on Method Validation [4],
which was published by the FDA following
meetings between FDA and industry representa-
tives in 1991 and 2000 [5,6]. This Guidance
contains the FDA’s recommendations for meth-
od validation, the use of validated methods in
bioanalytical studies, and the associated doc-
umentation requirements. This was a big step
forward in clarifying regulatory expectations,
however questions persist, either because of the
document’s content or, conversely, because of
what was not included.
The Guidance states that ‘ the analytical
laboratory conducting pharmacology/toxicology
and other preclinical studies for regulatory
submissions should adhere to FDA’s Good
Laboratory Practices’ and that ‘ the bioanalytical
method for human BA, BE, PK and drug
interaction studies must meet the criteria in 21
CFR 320.29’. The latter reference is to the FDA
regulations governing bioavailability (BA) and
bioequivalence studies [7], where a very general
statement is made that an analytical method
‘ shall be demonstrated to be accurate and of
sufficient sensitivity to measure, with appropri-
ate precision, the actual concentration of the
active drug ingredient or therapeutic moiety, or
its active metabolite(s), achieved in the body’.This regulation is cited by FDA Investigators
who review bioavailability and bioequivalence
studies at bioanalytical laboratories and, by its
non-specific nature, is another cause of
uncertainty in bioanalysis. A useful reference
to help discern the FDA requirements in this
field is the Compliance Program Guidance
Manual [8] which describes what FDA Investi-
gators will review and their expectations in each
area.
Since BASS is composed of primarily United
States members, the BASS discussions have been
‘ FDA-centric’; however, there are numerous
international guidelines and regulations that, to
a greater or lesser extent, address bioanalysis. To
mention a few of these: Canada’s Health
Products and Food Branch have issued compre-
hensive guidance documents for bioavailability
and bioequivalence studies, including guidance
on bioanalytical methods [9,10]. The ICH S3A
Guideline ‘ Toxicokinetics: The Assessment of
Systemic Exposure in Toxicity Studies’ briefly
mentions bioanalysis, stating that analytical
methods should be specific and of adequate
accuracy and precision, have an appropriate
limit of quantitation, and be suitably validated
[11].
In Europe, the EMEA Committee for Proprie-
tary Medicinal Products (CPMP) adopted a
revised Note for Guidance on bioavailability
and bioequivalence that came into effect in 2002
[12]. This guidance stated that the bioanalytical
part of bioequivalence trials should be con-
ducted according to the applicable principles of
GLP. Following this, the United Kingdom GLP
Monitoring Authority issued a clarifying note to
explain that this did not mean that laboratories
needed to be included in their country’s national
GLP programs [13]; just that they should adopt
‘ the applicable references from the GLP
principles.’ The ambiguity of the term
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‘ applicable’ contributes to the confusion sur-
rounding regulatory expectations.
Recognizing the difficulties concerning the
regulatory status of analysis of samples from
clinical trials, the British Association of
Research Quality Assurance (BARQA) pub-
lished a document on ‘ Good Clinical LaboratoryPractice’ in 2003 [14]. This document proposes
a framework for the management and docu-
mentation of clinical bioanalysis, based on GLP
principles.
One common question is whether bioanaly-
tical laboratories need to comply with require-
ments for diagnostic clinical testing laboratories
when analyzing human samples for clinical
trials. In the United States the Clinical Labora-
tory Improvement Amendments (CLIA ‘ 88)
requires certification of laboratories involved
with patient samples [15]. This act defines a
laboratory as ‘ a facility for the biological,
microbiological, serological, chemical, immuno-
hematological, hematological, biophysical,
cytological, pathological, or other examination
of materials derived from the human body for
the purpose of providing information for the
diagnosis, prevention, or treatment of any
disease or impairment of, or the assessment of
the health of, human beings’. The applicability
of this act to the measurement of drugs in
humans during clinical trials is uncertain when
the bioanalytical results are used to guide the
treatment of clinical trial subjects. Bioanalysis
for some clinical trial samples is successfully
performed in CLIA-certified laboratories.
Finally, lest we forget, the regulations and
guidance related to electronic records and
electronic signatures [16–18] apply to bioanaly-
tical work; of course, this is a highly automated,
data-based environment where electronic
records abound.
Concerns and Questions
Despite all the guidelines and regulations, there
are real problem areas in bioanalysis which
cause inconsistency, uncertainty, regulatory
citations and re-work. The principal causes of
these problems may be one, or a combination of
the following:
* Technical areas not covered in the guidances
or regulations.* ‘ Translation’ and application of the GLP
regulations to the bioanalytical environment.* Regulatory citations for deficiencies in areas
not clearly defined in guidances or regula-
tions.
Future articles will address these topics in more
depth, but for the purposes of this introduction
we will provide a ‘ taster’, an hors d’oeuvre of
some the meatier issues in bioanalysis.
Carryover and Contamination
The FDA’s Division of Scientific Investigation’s
(DSI) scrutiny of bioanalytical analysis in sup-
port of bioequivalence studies has generated a
number of current issues. For example, contam-
ination and carryover has gained much attention
following FDA untitled letters in 2004 [19, 20].
The basis of the problem is the unwanted
presence of analyte introduced during the
analytical process, either from the extraction
procedure or during the chromatographic ana-
lyses. The FDA untitled letters demonstrate that
this can lead to possible invalidation of studies,
widespread investigations of facilities and
reconsideration of a product’s therapeutic
equivalence rating. Assessment of carryover
and contamination are not, however, treated in
any detail in regulatory guidelines, leading to a
number of different approaches to detecting and
addressing this problem.
Investigations
Many laboratories are handling the incidence of
contamination, or other problems that poten-
tially affect data integrity, by performing a
formal investigation into the problem. This is
becoming an expectation in the industry, yet
regulations concerning investigation of out-
of-specification results reside in the Good
Bioanalytical Quality Assurance 103
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Manufacturing Practice arena [21]. Further, it is
not clear when such investigations should be
conducted. Recent discussion seems to indicate
that FDA and industry opinions can differ on
this.
Reference Standards
Another topic being debated is the characteriza-
tion and documentation of the materials used as
reference standards for bioanalytical assays.
There is still confusion about whether these
substances are ‘ test article’ as defined by GLP
(and therefore subject to the characterization
requirements of the regulations). Consensus
opinion is that they are not test articles, but
‘ reference standards’ as defined by the FDA
Bioanalytical Method Validation Guidance [4].
Even so, there are still complications here, one
being the level of characterization and docu-
mentation needed when metabolites are being
quantitated.
Quality Control Sample Concentrations
A wave of FDA Form 483 observations relating
to the placement of Quality Control (QC)
samples in the assay calibration range has
recently swept over bioanalytical laboratories
conducting assays in support of bioequivalence
studies. When at least two QC samples are not
within the range of concentrations observed in
study subject samples, FDA 483 observations
have been received for ‘ inappropriate selection
of QC levels in relation to the actual subject
plasma concentrations’. In these instances, the
laboratories involved addressed this by adding a
fourth level of QC within the range of study
sample concentrations. The concentration of
QC samples in relation to the concentrations
observed in subject samples is not addressed
per se in the aforementioned regulatory docu-
ments and the difficulties in estimating concen-
trations of all analytes (including metabolites) a
priori has presented challenges for sponsors and
contract research organizations.
Other Bioequivalence Issues
Other current issues in bioequivalence include
stability assessment, re-integration of chromato-
grams, repeat analysis of results suspected to be
pharmacokinetic outliers and adequacy of meth-
od validations. In many instances an FDAinspection of a bioequivalence study may occur
up to two years after the bioanalytical work has
been completed. If a practice in place at the time
of the bioanalysis is cited on the 483, there is a
good chance that practice is still in place or has
not changed enough to avoid agency scrutiny. As
the BASS group continues to grow and mature,
the sharing of recent 483 ‘ hot topics’ has
increased, helping members of the group to be
more proactive in addressing recent FDA trends
in a more timely manner.
Conclusion
In the light of these (and many other) bioana-
lytical concerns, industry groups and FDA are
meeting at various events, including a major
workshop in May 2006 in Arlington, VA, USA
[22], to understand the details of the technical
issues and to attempt to resolve remaining
questions. The BioAnalytical Specialty Section
of the Society of Quality Assurance provides a
forum for Quality Assurance personnel to re-
view developments, debate questions and help
clarify problem areas through meetings and
publications. Through the continued effort of
all stakeholders in bioanalysis we believe that
consistency of practices and understanding
between the FDA and industry will improve,
benefiting the overall drug development process
in which bioanalysis plays a central role.
Acknowledgements
The author wishes to thank Margaret Beamer,
Kevin Boschert, Helen Lysy, Gregory Maisel,
Pollyann Nee and Carol Reber for their editorial
review of the article. The author acknowledges
all of the members of the BASS group who have
104 AB Jones
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contributed to teleconferences and meetings.
This article has been written based on the ideas
and input of these members and their discussion
within the group; however, the opinions pre-
sented in this paper do not necessarily represent
the views of the Society of Quality Assurance or
the employers of the individuals participating inthe BioAnalytical Specialty Section.
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