2006 jones qa in bio analytical

8/8/2019 2006 Jones QA in Bio Analytical

http://slidepdf.com/reader/full/2006-jones-qa-in-bio-analytical 1/6DOI: 10.1002/qaj.372

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.

Copyrightr 2006 John Wiley & Sons, Ltd. Qual Assur J 2006; 10, 101–106.


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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

102 AB Jones




‘ 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




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




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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