COMPREHENSIVE SAMPLE MANAGEMENT THE FOUNDATION OF DRUG DEVELOPMENT

COMPLIANCE & GxPs
COMPREHENSIVE SAMPLE MANAGEMENT
THE FOUNDATION OF DRUG DEVELOPMENT
Maximizing the potential of biospecimens for current and future drug
development by ensuring their long‑term integrity through best practices,
regulatory mandates and preparation techniques.
G
iven the significant role of biospecimens
in drug development, it has become
essential for pharmaceutical and
biotech companies to develop a
comprehensive strategy for the
preservation of collected biological samples. The value of
these materials (tissue, DNA, RNA, plasma and so on) is
rapidly increasing because of discoveries that can be made
from both prospective studies and retrospective analyses.
These invaluable and sometimes irreplaceable materials
represent assets that can bring significant long‑term
commercial and scientific value to an organization.
Companies are, therefore, collecting a growing amount of
patient samples during clinical research; in fact, there are
currently more than a billion samples stored in research
labs and biorepositories worldwide.1 These samples are
used to spearhead various initiatives, including a variety
of testing, auditing, validation and qualification processes
on collected specimens to:
• Detect new biomarkers.
• Identify biological and genetic factors responsible
for different drug responses across individuals or
populations.
• Reduce the time it takes to bring new drugs to market,
thus maintaining a competitive advantage.
• Expedite R&D processes for new pharmaceuticals and
therapeutics.
Because of the intrinsic value of these materials, preserving
clinical specimens to the highest of standards has become a
critical component of the drug development process.
Biospecimen Sample
Collection and Preparation
Pre-analytical variables introduced during clinical sample
collection and processing can significantly affect the
molecular integrity of specimens and bias the results of
assays and/or biomarker studies. An essential component
of any sample management strategy, therefore, requires
standardized protocols for sample collection and
preparation techniques.
Biospecimen collection involves three components:
collection of the sample, processing of the sample and
recording of information about the sample. Information
about the sample is of three types: its source (study
subject), its characteristics (skin tissue plug biopsy) and
its post‑collection processing and storage (for example,
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placement in freezer 10 min after collection).2 For
example, the time elapsed in each step from collection
through storage should be recorded and tracked to ensure
a consistent process and to possibly explain anomalies.
Unrecorded information could be unrecoverable, which
could exclude usage of a valuable time point, data point
and/or disease state. This omission could inhibit discovery,
as future uses of a sample often cannot be anticipated.
Sample preparation methods may also affect the results
or interpretation of biological studies. Inexact sample
preparation can lead to sample loss, reprocessing or
complicated data interpretation. This bottleneck can delay
studies, which ultimately delays a potential drug candidate
from going to market.
Logistical Challenges
in Specimen Management
With the globalization of clinical research, the safe,
punctual and compliant transport of biospecimens for
testing and analysis is ever increasing in complexity
and critical to the sample management process. The
strict temperature constraints placed on these materials
makes their timely distribution particularly important.
Cold chain management defines how specimens, such
as tissue, blood and DNA, are packaged and transported
throughout the research and development process.
Weakness or failure at any point in the chain of custody
can compromise product integrity, breach security,
delay shipments and ultimately result in financial loss
or liability. Common issues that can affect biospecimen
integrity during transport include:
• Prolonged delivery delays caused by transportation
glitches, security inspections or customs scrutiny.
• Temperature fluctuations whilst in transit inside
shipping vehicles.
• Seasonal or climatic differences between origination site
and destination.
To mitigate risk of material degradation and ensure
regulatory standards are upheld, personnel should
understand the intricacies involved in transporting
biospecimens on a global scale. The US Department
of Transportation and the International Air Transport
Association (IATA) require organizations and
individuals who ship or receive biological materials
to undergo formal training to meet their standards
in packaging, labeling, documentation, declaration,
September/October 2011
COMPLIANCE & GxPs
Section
Details
B4.000 — RECORD RETENTION
Unless otherwise specified by contract, corporate or government policy or other agreement,
each repository should establish a period of time during which all records are retained. A
policy should be in place for the destruction or return of records that no longer need to be
retained.
E2.000 — QUALITY ASSURANCE
PROGRAMME
Each repository should have a Quality Assurance Programme/Quality Management System
(QA/QMS) or adhere to the QA programme of the organization with which the repository is
associated. The programme should describe the repository’s commitment to its QA and QC
programmes and describe approaches for ensuring that the requirements of the QA and QC
programmes are met.
H2.000 — LABELS
Each specimen container should receive a computer‑printed label that tightly adheres under
all projected storage conditions. Information encoded on labels should be resistant to all
common laboratory solvents. Labels should include readable indications as to what is stored
in the container.
I3.200 — VERIFICATION OF PACKAGING
Packaging should be tested prior to use with specimens. Tests should include measuring
all parameters that could influence specimen integrity (that is, temperature, humidity, light
sensitivity, structural quality and spill containment).
J4.100 — FREEZE/THAW CYCLES
Freeze/thaw cycles can be deleterious to the macromolecules intended for analysis.
Therefore, it is important to select aliquot sizes that are appropriate for the intended uses
for the specimens to minimize the number of times a sample is thawed and frozen before
it is used.
J9.200 — SPECIMEN RETRIEVAL
Specimens should be located and pulled from storage as documented on specimen requisition
forms. If specimens are frozen, speed is necessary during the retrieval process. Such speed
may require that at least two individuals carry out the retrieval process. If possible, specimens
being retrieved should be maintained at the storage temperature throughout the process (for
example, specimens stored at −80 °C should be kept on dry ice during the retrieval process).
K2.200 — INFORMED CONSENT
Consent may be obtained for a specific research project, such that the details of the
project can be specifically outlined; alternatively consent may be obtained for unspecified
future research, in which case general information about the possible future research
uses is provided, in accordance with applicable national or local regulations and policies.
Mechanisms should be in place to assure that future research uses of identifiable
specimens are consistent with the original consent (e.g., through an IRB, ethics committee
review or other mechanisms consistent with applicable regulations and guidelines).
K2.600 — TERMINATION OF SPECIMEN RESOURCES
Specimen resources should develop plans at the time of their establishment for the
disposition of specimens and/or data should the resource be terminated for any reason.
The disposition, including any transfer of specimens and/or data to third parties, should be
consistent with the informed consent under which specimens and/or data were obtained.
A.200 — SPECIMEN ACQUISITION, ACCESS AND CULLING
Policies should be established for the acquisition of new specimens, access to specimens
for research purposes, for culling of collections when specimen resources have fulfilled their
original purpose or are no longer suitable for their intended purpose, or if participants request
the withdrawal of their specimens.
Table I: ISBER best practices for
the collection, storage, retrieval
and distribution of biological
materials for research.
Source: 2008 Best Practices for Repositories: Collection, Storage, Retrieval and Distribution of Biological Materials for Research
hazard assessment and emergency response. Aside
from the regulations, improper packaging and handling
are common causes of temperature deviations. Proper
training and qualification of all cold chain partners
minimizes such problems.
Regulations and Customs Agencies
The US Department of Transportation Hazardous
Materials Regulations (HMR) and IATA Dangerous Goods
Regulations (DGR), along with other country‑specific
regulations, specify requirements for the safe transportation
of hazardous materials by railway carriage, aircraft,
shipping vessel and motor vehicles.3,4 These regulations
dictate specifications for classification, packaging, hazard
communication, shipping papers, incident reporting,
September/October 2011 handling, loading, unloading, segregation and movement
of hazardous materials. Fines and shipping delays often
result from lack of compliance with these regulations.
Customs regulations in emerging regions are also complex
and strictly followed by informed local Customs agents.
Any issues with the shipment itself, or the accompanying
paperwork, can result in material being held by various
government authorities for prolonged periods. With the
current growth in temperature‑sensitive products and
time‑sensitive shipments, developing a strategy, including
contingency plans, to avoid these issues is essential. For
example, when materials face possible delays during the
clearance process at Customs, consigning shipments with
a courier who is capable of replenishing refrigerant, such as
dry ice, whilst awaiting clearance may be difficult.
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39
COMPLIANCE & GxPs
Rigorous demands from authorities and industry
associations worldwide necessitate that standard operating
procedures (SOPs) be set in place not only for shipping,
but also for labeling and documentation. Any controlled
transport storage conditions, as well as warning statements
or content identification, should be clearly stated on the label
applied to shipping containers. Labeling and packaging
must comply with IATA guidelines, be securely attached
and clearly state that materials are to be transferred to a
specified storage temperature upon receipt.
Specimen Storage:
Good Storage Practices
Lori Ball
Chief Operating Officer
BioStorage Technologies, Inc.
References
1. w
ww.labmanager.
com/?articles.view/
articleNo/3455/
2. http://firstclinical.com/
journal/2011/1101_
Biostorage.pdf
3. w
ww.phmsa.dot.gov/
staticfiles/PHMSA/
DownloadableFiles/Files/
Overview%20of%20
HMR.pdf
4. w
ww.iata.org/Site
CollectionDocuments/
51NoticeUN3373Dec09.pdf
5. w
ww.isber.org/bp/
BestPractices2008.pdf
6. www.biomedcentral.
com/1471-2407/9/409
For more
information
Lori Ball
Chief Operating Officer
BioStorage Technologies, Inc.
Tel. +1 866 697 2675
+49 6155 898 1011
www.biostorage.com
40
The specifics of a sample management strategy may
vary, depending on the nature and intended use of the
biospecimen, as well as the size and complexity of the
collection. To ensure biospecimens are properly handled,
transported and stored, companies should be aware of
and follow Good Storage Practices (GSPs) guidelines.
While GSP is not a regulatory mandated requirement,
specific good storage practice guidelines have been
established by the International Society of Biological and
Environmental Repositories (ISBER) and governmental
organizations like the US National Cancer Institute (NCI).
In 2008, ISBER drafted guidance of best practices for the
collection, storage, retrieval and distribution of biological
materials for research (Table I). Industry experts expect
these guidelines to evolve into regulations such as those
that exist in other GxP environments (for example, GTP,
GCP, GLP, and GMP). Today, the guiding principles of
GSP mandates the standardization of sample handling
and management processes to ensure samples are
prepared and stored in consistent conditions.5
Because it may take years before specimen samples
are needed for future research, testing, or audits, samples
must be stored in highly specialized and consistent
conditions, often for decades. To maintain sample
integrity for such long periods of time, standardized,
secure and compliant storage is crucial. A sample that
has maintained the appropriate storage temperature will
yield better results than a sample that has undergone
fluctuations in temperature because of poor handling or
storage practices.6 In addition, proof of sample conditions,
temperature history and chain of custody must be proven
if samples are to be viable for inclusion. Examples of the
various components of GSP include
• Secure facilities and robust quality assurance measures
to ensure specimens are stored in compliant conditions
at all times.
• Qualified staff that has been trained and certified in global
sample transportation procedures, including regulatory
and customs issues.
• Temperature monitoring and recording of samples around
the clock with a comprehensive, uneditable audit trail and
automatic notification system.
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• Business continuity plans, back‑up power and redundant
systems to protect sample integrity during emergencies.
Information Systems
for Specimen Management
Although proper storage and transportation are critical,
specimens are useless unless they can be located with
their associated data, in a timely fashion. In the past,
researchers applied ad hoc tracking systems, such as
spreadsheets, to track and plot information associated
with biospecimens. Today, the complexity of clinical
trial research has rendered these outdated and archaic
systems inefficient to handle expanding biospecimen
inventories. The ideal system should offer tracking and
reporting processes through all stages of a sample’s
shipping, handling and storage life cycle.
Often, critical information about a sample is
“missing” or “inaccurate,” which can lead to costly
study‑specific errors. To this end, a solid informatics
approach includes integration of sample preregistration,
cataloging of qualitative and quantitative information
at the time of accessioning, as well as defined SOPs
regarding sample discrepancies.
Because pharmaceutical and biotech labs typically
implement a wide range of information systems,
specimen management systems should seamlessly
interface with other systems, provide global data
integration and access and be highly configurable to easily
integrate with a variety of laboratory workflow models.
Recent innovations have even expanded information
management systems to include mobile and web‑based
solutions. The integration of sample storage, consent
authorization and clinical result data is another area of
expansion occurring as a result of the advent of new
technology systems. Connecting information on sample
storage location, temperature and pretesting evaluation
with the resulting data from a clinical study can enable
researchers to improve their selection of samples for
biomarker testing and shorten personalized medicine
research timelines.
Conclusion
Whether samples are outsourced and stored offsite at a
global biorepository or managed onsite by an insourced
service provider, a robust infrastructure for biospecimen
tracking and distribution will be required to support a
successful comprehensive sample management strategy.
This combination of GSP and innovative technology
streamlines the process of sample management; ensuring
samples and information are readily available for today
and tomorrow’s research initiatives. Now is the time for
organizations to establish a comprehensive management
strategy that incorporates and dictates how samples are
handled, stored, transported and documented throughout
their entire life cycle.
September/October 2011