UNIVERSITY OF WASHINGTON

Audit and Restructure of

Gastroenterology Cancer

Resource Biorepository

BRAMS Final Report

Tanadinata, Amanda

7/15/2016

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Contents Introduction .................................................................................................................................................. 2

Regulatory Context .................................................................................................................................... 3

Project Description ..................................................................................................................................... 6

Environment ............................................................................................................................................ 6

Activities ................................................................................................................................................... 6

Work Product Description ....................................................................................................................... 19

Outlook ....................................................................................................................................................... 23

Learning Objectives and Outcome ........................................................................................................ 24

References ................................................................................................................................................ 25

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Introduction The University of Washington Medical Center (UWMC) has been providing specialized medical

care for patients in the Pacific Northwest for decades and is ranked as the best hospital in

Washington State.1,2 The Division of Gastroenterology (DGI) operates within UWMC under the

Department of Medicine and has been serving society by improving public health.3 Many

patients have received diagnoses leading to treatments for their gastroenterology (GI)

symptoms and diseases via DGI pathology services.4 Aside from providing services, DGI

studies and develops methods for diagnosing and treating GI diseases.5 Area of studies include:

colon, esophageal, and gastric cancer, inflammatory bowel disease, and new diagnostic

methods.5

In order to support these studies, the University of Washington’s DGI established a

Gastroenterology Cancer Resource (GICaRes) biorepository in 2008. The GICaRes

biorepository is a biobank, a library of biological samples that have been collected from patients

and are preserved for current and future research purposes.6 The GICaRes biorepository

contains samples from patients with diagnosed disorders of the GI tract (either GI cancer or

other disease) and disease-free individuals. The samples from disease-free individuals serve as

reference controls. Both diseased and healthy samples are collected from patients who are

scheduled for endoscopic procedures such as a colonoscopy or esophagogastroduodenoscopy

at the University of Washington. Samples collected from these patients are blood, colon and

esophageal tissues, buccal cells, and esophageal brushings. All these samples are kept at the

University of Washington until they are requested by an investigator for use in a research

project.

Even though the creation of the GICaRes biorepository was approved by the UW Institutional

Review Board (IRB) in 2008, the biorepository was in operational disarray at the beginning of

this project. In order to generate high-quality, consistent biospecimens, a biorepository must use

a quality management system (QMS).7 Unfortunately, the GICaRes biorepository did not have

one at the time of initiation. Additionally, many of the standard operating procedures (SOPs)

essential for the biorepository operations were either not implemented or had not been updated

since 2008. The biospecimen workflow, collection, preservation, and storage was disorganized

because of an ineffective communication that lead to misunderstanding among personnel

involved in the workflow. The biorepository’s data management software was being

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underutilized and the specimen labeling system was not properly established, creating

inefficiencies in the biorepository operation.

There were also no established preanalytical variables for the samples. The National Cancer

Institute (NCI) describes preanalytical variables as the most important variables that determine

the quality of a given biospecimen.8 Preanalytical variables, such as a patient’s physical

condition and specimen handling, may influence the biospecimen quality before testing are

important to know so that researchers can weigh these factors in their analysis.8 For example, if

the analytical result differs from expectation, it could be due to the patient taking medication

prior to biospecimen collection or the samples being left too long at room temperature. Thus, a

complete overhaul of the GICaRes biorepository practices was necessary to restore its proper

function as a valuable research resource.

The endpoint intended for this project was to formalize the biorepository operations according to

the International Society for Biological and Environmental Repositories (ISBER) and NCI

biorepository guidelines. To achieve this, I performed an audit of the GICaRes operation and

facilities and implemented the ISBER and NCI guidelines in restructuring the biorepository

operation. The GICaRes biorepository team and I assessed from the audit result whether the

operation before restructuring met those guidelines. After assessment, I formalized the

biorepository operation by documenting policies and procedures that have served well in the

biorepository according to existing best practices, and suggested changes to other policies that

weren't in compliance. A formalized set of operational policies and procedures were compiled

into the GICaRes biorepository operational handbook, and a set of SOPs regarding how to carry

out procedures was also developed. Although most topics within the ISBER and NCI best

practices are covered in the GICaRes operational handbook and recommendations from each

topic were followed for the SOPs, not all practices are in line with the ISBER and NCI best

practices. There remain some biorepository policies and procedures that have not yet been

completely developed, so the work to bring the GICaRes biorepository in line with best practices

is still ongoing.

Regulatory Context Currently there are no specific government regulations regarding biorepository operations.

However, there are best practice documents established by several organizations to achieve

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high-quality biospecimens. Two sets of best practices that I used for my project were

established by the ISBER and the Biorepositories and Biospecimen Research Branch (BBRB)

of the NCI. ISBER developed its standards based on the most effective practices from the

collective experience of its members and repository officials.9 The NCI established the BBRB to

develop its standardized policies and procedures for handling biospecimens.10 By following

these standards, the researchers expect to gather more reliable data. These best practices

provide guidelines on the functions, operations, and standards of a good biorepository.

Guidelines from ISBER and the NCI provided strategies and recommendations that helped me

create the audit checklist, operational handbook, and set of SOPs in my project.

ISBER recommends that all repositories audit their SOPs and inventories regularly.7 The

GICaRes biorepository has never been audited. Therefore, performing an audit was necessary

to assess what needed to be changed for proper operation.

Although biorepository operations are not government regulated, biorepository activities

involving human subjects are regulated. According to 45 CFR Part 46 Subpart A, the

biorepository study needs to be approved by an IRB.11 The biorepository also needs to retain

informed consent from all subjects participating in the study using the appropriate version of the

consent form that has been approved by the IRB.11 Biorepository researchers must make sure

that every subject understands the study aims, requirements of participation, and potential risks

and consequences of participation before participating as a donor in the GICaRes

biorepository.11 These actions are mandated by the Office of Human Research Protection to

protect the rights of human subjects involved in research.12

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) privacy rules protect

private health information about patients, such that an institution that is subject to the act cannot

release any individual’s personal or health information unless the individual agrees to the

release.13 The GICaRes biorepository is an entity that is covered under the HIPAA privacy rule.

The HIPAA regulations are found at 45 CFR Parts 160, 162, and 164.14 Therefore, in addition to

agreeing to sign the consent form, participating subjects also need to sign the HIPAA

authorization form to give permission to the research team to obtain and use their health

information. Each specimen collected for the project is labeled with a unique barcode as well as

with the patient’s research study code number, not with patient names. A file linking code

numbers with patient names is maintained, but only a limited number of GICaRes biorepository

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staff, such as the study’s principal investigator and research coordinators, have access.

Performing an audit was helpful to identify whether the GICaRes biorepository is in compliance

with these regulations.

From ISBER and NCI’s quality management section, having a QMS that covers quality

assurance and quality control policies for all biorepository operations is important, because the

goal is to have the highest quality of biospecimens.7,8 The GICaRes QMS is developed to

oversee all activities and tasks needed to maintain the desired level of excellence, which is to

achieve the highest quality of biospecimen. If the biorepository activities and production can be

done consistently, the output would be increased satisfaction to customers (both those

individuals donating specimens and researchers utilizing these specimens to conduct research

on the GI system).15

ISO 9001, an internationally-recognized quality management standard,16 and FDA’s 21 CFR

820: Quality System Regulation17 both establish criteria which are essential to an effective

QMS. Among them are a quality system and quality manual, documentation control,

management responsibility, design and development, monitoring, and auditing.

According to NCI best practices, every biorepository needs to have SOPs for every activity

related to the biorepository operations.8 Each SOP should describe the policy and procedure of

that process in detail, undergo periodic review, and be available for easy access to all

personnel.8 NCI and ISBER have guidelines on developing SOPs, such as critical topics that

should be covered in an SOP manual. On top of that, both best practices also provide

guidelines for essential components of an SOP, such as title, number, date, version, and

purpose. The GICaRes had some existing SOPs that were outdated and not written according

to either NCI or ISBER best practices, but many of the procedures did not have SOPs at all.

Information was handed down ad hoc, person-to-person during training, and there was no

specific documentation on training of incoming and existing personnel. This method of training

was not consistent with the ISBER and NCI recommendations. Thus, new SOPs were required

and needed to be developed based on NCI and ISBER best practices to replace outdated SOPs

and to cover procedures which lacked an SOP.

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Project Description

Environment The project was done at UWMC. The GICaRes team was developed along with the start of this

project and has been providing me with advice and assistance. The team consists of personnel

with different responsibilities within the GI division. Below is the list of the GICaRes team:

● William Grady is the principal investigator (PI) and director of the GICaRes biorepository

who oversees the operation of the biorepository; he is my preceptor.

● Greg Cruikshank is the research manager who manages GICaRes operation; he is also

my preceptor.

● Evelynne Bautista is the program operation manager who manages the scheduling for

technicians to process samples. She reviews any workflow or SOP changes that involve

processing along with approval from the PI and research manager.

● Kimberly Anderson is the research coordinator who screens potential subjects, obtains

informed consent from subjects, and collects biospecimens. She reviews any workflow

or SOP changes that involve either biospecimen collection or obtaining patient’s

informed consent.

● Megan Maass is the IRB contact for GICaRes.

● Wynn Burke is the research consultant who is in charge of the web-based sample

management system in GICaRes. Proposed changes to the sample management

system are discussed with Wynn to determine whether they are possible to do with this

system.

I communicated with my preceptors via email and in person at bi-weekly team meetings. The

meeting’s purpose was to give updates about improvement in GICaRes operation, and for me to

receive feedback about my project.

Activities My practicum project was divided into three parts: creation of the audit checklist, performance of

the audit, and development of the operational handbook and set of SOPs. The QMS is included

in the operational handbook.

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Step 1: Audit checklist.

I created the audit checklist by combining topics from ISBER and NCI. ISBER’s list of topics was

utilized as the checklist core topics because it has more comprehensive materials and has

better structure. For example, ISBER has its sections divided into thirteen sections while NCI

had three main sections and many subsections. It was harder to compile a checklist from a big

section with multiple subsections. I also incorporated NCI’s contents within the same area of

focus. Sections mentioned by NCI that were not mentioned in the ISBER’s list were added. For

example, ISBER doesn’t specify examples of essential topics for creating a quality manual but

NCI does. I added NCI’s list for a quality manual section in the quality management checklist.

Points that were mentioned in NCI and ISBER that were not relevant with the GICaRes

operation were removed. For example, ISBER has guidelines for dealing with urine samples.

The GICaRes biorepository does not collect urine samples so that section was not included in

the audit checklist.

From ISBER’s recommended thirteen topics, I divided the first topic, which is the repository

planning consideration into two topics. The two topics are “biorepository development and

operations” and “organization & management”. I believe biorepository development and

operation should be a topic of its own because it covers how the GICaRes established as an

entity, while the organization and management section covers the GICaRes organization

structure and staff responsibilities.

Below are the 14 topics covered in the audit checklist:

1. Biorepository development and operation. This section covers the type of activities

carried out by the GICaRes repository (banking services) and documentation of the

biorepository, including its goals, vision, and mission.

2. Organization and Management. This section covers personnel responsibility, authority,

and interrelation within personnel involved in the organization. 3. Facilities. This section has lists for important elements to make a good biorepository

facility. This is based on ISBER's list of criteria for biorepository spaces. 4. Biospecimen collection, processing, storage, retrieval, and dissemination. This

section is a combination of ISBER’s section #11, “specimen collection, processing, and

retrieval” with NCI’s section, “biospecimen collection, processing, storage, retrieval, and

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dissemination.” NCI has better detailed information regarding this topic than ISBER, so I

incorporated more of NCI’s information. 5. Storage equipment and environments. This section covers biospecimen storage, such

as storage container or storing method, as well as maintaining good environments for a

biorepository. This includes good monitoring of temperature, equipment calibration,

maintenance, and repair. 6. Quality management. This section is developed from ISBER’s list of topic combined with

NCI’s information. It covers essential components for SOP, staff responsibilities, audits,

and validation of sample processing methods. I incorporated more of NCI’s information

for this section because it offers more detailed explanation for quality management

problems. 7. Safety. This section covers safety topics that should be considered within a

biorepository, and training for potential hazards. 8. Training. This section covers training infrastructure, programs, and documentation. 9. Records management. This section has covers documentations management and

storage, forms and documents tracking, as well as security system for documents. 10. Cost management. This section covers cost and budgeting analysis for the

biorepository. 11. Biological material tracking. This section covers inventory systems, security, labels,

and biospecimen tracking. 12. Packaging and shipping. This section covers tracking, temperature, humidity, and

timing requirements for shipping specimens. 13. Legal and ethical issues for biospecimens. This section covers legal and ethical

issues regarding biospecimens. Compared to ISBER, NCI has more detailed discussions

regarding this issue such as IRB approval, federal regulations for obtaining informed

consent, and confidentiality protection. I incorporated various materials, primarily from

NCI, but also those of ISBER into this section. 14. Specimen access, utilization, and destruction. This section covers recommendations

for protecting specimens related to their access and utilization. This audit checklist took about two months to develop. The first month involved creating the

draft of the checklist, which was reviewed by the GICaRes team. Suggestions for improvement

were discussed during the GICaRes biweekly meetings. Once feedback was collected, I revised

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the checklist. After my revision, the checklist was reviewed again by the GICaRes team, then

was approved by my preceptors.

Step 2: Audit.

I carried out the audit by comparing the checklist I created to the GICaRes biorepository

operation. The audit activities and findings are described below:

1. Biorepository development and operations.

• I evaluated whether the biorepository was developed based on existing local or

national models (e.g., procurement service, banking service, population-based

collections, and virtual repositories). Based on my observation on how the GICaRes

collects, processes, and stores biospecimens for future needs, I concluded that the

GICaRes biorepository adopted the banking service model. GICaRes biorepository

receives its specimens through agreements with the hospital (UWMC), has specific

procedures for each sample type, and stores samples for current and future research

use; this fits ISBER’s definition of a banking system.7

• I also evaluated the GICaRes documentation for its goal, mission, and vision. Based

on my evaluation, the GICaRes has successfully stated its goal, mission, and vision in

its study protocol, which has been updated and approved by the IRB.

2. Organization and management. The GICaRes biorepository lacked documentation that specifies personnel responsibility,

authority, and relationship within personnel involved in the organization. There was an

organizational chart established by the Department of Pathology and Department of

Medicine that describes the GICaRes biorepository’s relation within the departments.

However, there was no structure for the biorepository itself, nor a list of current personnel

who work in the biorepository. 3. Facilities.

ISBER has list of criteria for expected spaces needed for biorepository operation, and the

GICaRes met all the checklist requirements. Although the GICaRes biorepository fulfilled all

the recommendations for a well-functioning facility, there was no formalized documentation

describing the facility information.

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4. Biospecimen collection, processing, storage, retrieval, and dissemination. For this section, I examined the questionnaires given to patients and the GICaRes

biorepository’s electronic records. I assessed whether the subject’s medical condition was

successfully recorded.

• I evaluated GICaRes sample collection forms to see whether important information

such as time and size or volume of biospecimens were recorded during collection,

processing, and storage. Based on my observations, GICaRes biorepository

adequately recorded time of collection, processing, and storage, but not the

size/volume of specimen.

• I also evaluated the GICaRes biospecimen labels and found some discrepancies. For

example, stored DNA tubes were labeled as DNA plasma. According to the GICaRes

sample collection form and the DNA extraction procedure followed from the QIAGEN

kit, DNA was obtained from whole blood and not plasma. This constituted mislabelling.

5. Storage equipment and environments.

• I reviewed GICaRes equipment for biospecimen storage, including items such as a

liquid nitrogen tank, and -70°C freezer. Serum, plasma, buffy coat, and buccal cells

were stored in the -70°C freezer, while tissue and esophageal brushing cells were

kept in liquid nitrogen. These storage methods were appropriate according to ISBER

and NCI practices.

• I also evaluated the type of storage container used for biospecimens, and found that

the storage container used to store these biospecimens was not appropriate. NCI

recommends using screw-cap cryovials for long-term, long-temperature storage, and

the GICaRes biorepository had been using microcentrifuge snap-cap tubes. Based on

the audit result, GICaRes biorepository needs to change its storage container to

screw-cap cryovials.

6. Quality management.

• I found some SOPs in old biorepository computer files. They were written in casual

language, written by multiple people, and have not been updated since 2008.

• The GICaRes biorepository workflow was also not efficient. The research coordinator

had to print aliquotted biospecimen labels in addition to screening and collecting

samples and the laboratory personnel also had to call the research coordinator to get

more labels if needed. These actions created jam in the workflow.

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• I also found little documentation about inventory supplies. I found information about

the brand for pre-filled formalin bottles used to collect biopsies in the computer’s

inventory folder.

7. Safety.

• The biorepository had a safety manual that was printed from the UW Environmental

Health and Safety website, but it was not tailored specifically to the GICaRes

operation. For example, the UW chemical hygiene plan has information for every

chemical. It would be more efficient to list only the contents of the chemical hygiene

plan that are specific to the GICaRes biorepository.

• Biohazard signs were posted in every biospecimen cooler as a warning for potentially

biohazardous specimens contained inside the coolers.

8. Training. Even though all personnel who collect and process samples had been trained, training was

not done systematically. There was no written documentation indicating when the training

was done, who performed the training, or any assessment regarding whether the trained

personnel understood the materials.

9. Records management. I looked for the following documentation to review: training documents, protocols, SOPs,

informed consent documentation, procurement documentation, processing records, testing,

equipment maintenance records, audit/review documents, specimen storage location

information, sample distribution, and quality control activities. From all the documents listed

above, only the procurement, processing, and storage documentation were organized.

Other available records, such as SOPs or equipment maintenance schedule, were scattered

and/or incomplete. Some information was located in scattered folders in the computer drive,

only had paper copy, or was missing data.

10. Cost management. There wasn’t a lot to discuss for this section because the GICaRes

biorepository budget comes from the department budget and we do not have control of it. In

the future, this is something the GICaRes can revisit. 11. Biological material tracking. For this section, I evaluated the Lab Matrix (GICaRes web-

based electronic data management) for its biomaterials tracking method using barcodes.

The GICaRes biorepository had not been utilizing it properly because the software was not

tailored to its operation. For example, there was no section in the software that indicates the

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time of biospecimen collection, process, and storage. This information was manually typed

in the notes section. As a result, this information was inefficient for QC activity, because the

data input within the notes section cannot be analyzed by the software. 12. Packaging and shipping. For this section, I checked whether there was a specific

procedure for packing and shipping of biospecimens, and determined that the GICaRes

biorepository lacked one. I then checked shipping documentation, and GICaRes has

successfully recorded time, date, place, and recipient. 13. Legal and ethical issues for biospecimen.

• For this section I evaluated GICaRes records for consent form, HIPAA authorization

form, and study protocol. I checked every consent form collected from patients to see

whether everything was collected using the appropriate consent form version that has

been approved by the IRB, and that no deviation or violation existed. From my

evaluation, the GICaRes biorepository successfully utilized the appropriate version of

the consent form that reflected the study at the time and had been approved by the

IRB to obtain informed consent. However, there was one minor violation regarding

inappropriate documentation of informed consent. The previous research coordinator,

who has since left the institution, dated the consent form instead of the subject doing

so. This incident was reported to the IRB as a small deviation.

• The appropriate version of HIPAA authorization form was also successfully used.

• The study protocol reviewed during the audit was the one from 2008. A revised

version of the study protocol to change the inclusion exclusion criteria was submitted

to the IRB after the audit. 14. Specimen access, utilization, and destruction.

For this section, I examined the Lab Matrix to determine whether every patient’s Protected

Health Information (PHI) is masked, and only certain personnel such as PI, research

manager, and coordinator have access to patient’s PHI. Based on my evaluation, GICaRes

successfully fulfilled the two criteria above. I also examined whether there was a policy that

describes how samples should be treated after the patients drop out. Based on my

evaluation, the GICaRes mentioned in its consent form that samples would be destroyed if

patient drops out. However, there was no SOP available that explains the appropriate way

to do it.

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After the audit was completed, I reported my findings to the GICaRes team, including my

preceptor(s), in a formal audit report. The audit report was made as a formal letter indicating

audit results with suggestions addressed to the responsible manager of the GICaRes

biorepository.

Step 3: Restructuring.

At the beginning of the audit report, I gave recommendations for what should be done to

address any deficiencies found during the audit. These recommendations include revision of

workflow and study protocols, and development of training manual, safety manual, operational

handbook, and a set of SOPs. I used ISBER and NCI recommendations as my guidelines.

I found that when the research coordinator printed labels, it caused workflow jams. Therefore, I

suggested for the lab to create and print labels as needed in regards to how much biospecimen

the research coordinator collects. My suggestion was welcomed and we did a test of

performance on this new workflow for a week to see whether the new workflow increased the

efficiency of research coordinators and lab personnel. It created a smoother workflow between

the research coordinator and laboratory personnel, and created better control in biospecimen

tracking. This revised workflow was approved and implemented (documented in the GICaRes

operational handbook).

I made recommendations to create a training manual and modify the safety manual. However,

these actions were not done during my practicum. This is because there was not enough time,

and developing the operational handbook and set of SOPs were considered more important for

the GICaRes biorepository operation.

GICaRes operational handbook

I modeled the operational handbook based on the ISO 9001 and 21 CFR 820 elements for

QMS, with incorporation of the ISBER and NCI best practices topics. For example, both ISO

9001 and 21 CFR 820 mentioned how management responsibility and personnel descriptions

are essential elements of a quality system. ISBER and NCI have recommendations related to

the director’s responsibility, organization structure, and personnel descriptions and roles.

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The GICaRes operational handbook serves as a quality manual that provides guidelines for

accomplishing the quality system for the project. The operational handbook has a quality

statement for how to satisfy QA/QC objectives, description for roles and responsibilities of all

personnel, and their connection within the biorepository operation.

The operational handbook consists of eight main sections that were constructed based on the

audit checklist, with some topics incorporated into individual sections.

1. Biorepository development and operation. This section has three subsections:

model, scope, and objective and goals. The model content was constructed based on

the result of the audit under the same section. GICaRes adapted the banking model

because its development was initiated by the need for various samples for current and

future gastrointestinal cancer or other gastrointestinal disease studies. The scope or

area included in this study, objective and goals section were explained using the

GICaRes study protocol text with minor revision. 2. Organization and management. This section was developed to cover organization

structure and personnel responsibility in the GICaRes biorepository that were lacking

based on the audit result. This section describes the structure of the biorepository within

the departments, using a tree diagram that explains the hierarchical structure of the

biorepository personnel, including their responsibilities.

3. Facilities. This section was developed based on the audit result. The GICaRes

successfully fulfilled the facility requirements listed by the ISBER and this section serves

as a formalized documentation about the facility which it previously lacked. This

document contains facility information, hours of operation, responsible personnel, and

activities performed related to biorepository. This information was obtained by consulting

with the biorepository manager and the biopsy laboratory manager. 4. Biospecimen collection, processing, storage, retrieval, and dissemination. This

section is divided into seven subsections: type of specimen to collect, preanalytic

variables to consider, methods, workflow, storage conditions, retrieval, and shipping.

Information for each type of biospecimen to collect and methods of processing were

defined using the text from study protocol with minor revision. I also included a table

(Table 1) with figure (Fig. 2) as a descriptive summary for the collection so it is easy to

follow. Example is below:

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Collection type Biospecimen Amount

Red-top tube (no additive) Whole blood Up to 10 mL

Purple-top tube (foiled) 1 (K2EDTA additive) Whole blood Up to 10 mL

Purple-top tube (foiled) 2 (K2EDTA additive) Whole blood Up to 10 mL

Green-top tube (lithium heparin additive) Whole blood Up to 10 mL

Mouthwash in 50 mL tube Buccal cell 10 ml mouthwash

Freezing medium x3 Tissue biopsy Up to 3

10% NBF x2 Tissue biopsy Up to 2

Esophageal brushing Esophageal cell Up to 2

Table 1

Fig. 2

Policies regarding preanalytic variables and analytic variables were developed based on

recommendations from NCI and discussion with the PI and research manager.

Documentation of preanalytic variables are completed using Standard PREanalytical Coding

(SPREC) from ISBER.20 It will be used as a base calculation for specimen’s quality control.

Workflow, storage, and retrieval sections were also described graphically with tables and

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descriptive illustrations. Policies within those sections and shipping were written based on

the ISBER and NCI recommendations that are modified to suit GICaRes biorepository

operation. For example, because ISBER recommends screw cap tubes for long-term, low-

temperature storage, GICaRes biorepository uses Nalgene® System 100TM Cryogenic

Tubes made from polypropylene, threaded with silicone gasket. These tubes are made by

Thermo Scientific and are CE-marked for storage of diagnostic samples in the EU as its

certification. Policy regarding GICaRes storage management is based on having two boxes

of storage per type of biospecimen. Box 1 serves as the primary source and box 2 serves as

a backup if box 1 is not available through damage or loss.

5. Quality management. Based on the ISO 9001 and 21 CFR 820, I created a QMS model

(with consultation and approval of my preceptor) to guide the biorepository operation. The

five elements we decided to base our QMS model on are a quality manual, training and

development, documentation control, production, and self-assessment. These five elements

are continuously maintained by monitoring activity to achieve consistent productivity and

customer satisfaction. This QMS model is described in a chart form (refer to Fig. 3).

The QA/QC section was created based on the NCI’s QA/QC outline that provided

recommendations for staff proficiency, facility infrastructure, biospecimen data collection and

management, record management, and auditing. For example, for record management,

GICaRes needs to maintain records (with specifications) of these following documents: ● Protocols → need to be reviewed and updated periodically

● SOPs → need to be reviewed and updated periodically

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● Informed consent documentation → needs to be reviewed and updated periodically

● Procurement documentation → receipts for LN/ dry ice delivery, purchase, etc.

● Processing records → biospecimen collection, processing, and tracking, with detailed

annotation of pre-analytical parameters

● Testing → testing for validation of new protocol, QC

● Chemical/ reagent records → item name, company from which the item was purchased,

date of purchase, expiration date, and all related Material Safety Data Sheets

● Equipment maintenance → calibration/ performance verification/ repair

6. Cost management. This section was written by the research manager as I have

minimal knowledge about the departmental budget. 7. Safety. Information for this section was obtained from ISBER and NCI

recommendations. This section discusses biological and chemical major safety

precautions that should be followed in biorepositories. This section also describes

personal protective wear for working in the laboratory. 8. Appendix. This section serves as a place to attach certain documents that are being

utilized for biorepository operation such as sample collection forms. 9. Reference. This section provides references used in the GICaRes operational

handbook. I consulted with my preceptors and the GICaRes team for every section I created for

confirmation and feedback for suitable policies that reflect the GICaRes operation.

Set of SOPs

I developed a standardized set of SOPs based on NCI and ISBER best practices to replace

outdated SOPs and to cover undeveloped SOPs. Important topics to have in an SOP manual

are informed consent, collection, processing, storage, labelling, and data management. While

operations such as auditing, shipping and handling were also important, these activities are not

currently performed and an SOP was not needed immediately. An in house laboratory testing

and training policy has not been developed; therefore an SOP could not be written.

For all SOPs, I included a title, reference number, effective date, revision, division/ staff

covered, purpose, protective wear, equipment and materials, and step-by-step guidance that

were described as essential elements to construct a good SOP. Protocol and consent form

policies and template were downloaded from the UW IRB website.21

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Below are descriptions of how I revised or developed these SOPs.

1. Quality Assurance and Quality Management. This section was revised from ISBER

and NCI section for QA/QC and also using a quality manual published by the Sheffield

Biorepository.22

2. Biospecimen Identification and Labeling Conventions for Sample Processing. This

SOP was developed based on the new workflow for labelling that was proven to be

effective (described on page 11). In this new workflow, the research coordinator no

longer needs to print aliquotted biospecimen labels to give to the lab personnel. The lab

personnel will print labels as needed in regard to how much biospecimen the research

coordinator collects.

3. Informed consent. This SOP was revised from existing one that was created by

previous coordinator. I compared the SOP made by the previous coordinator to the

required criteria in line with 45 CFR Part 46.116, General requirement of informed

consent while orally presented to the subject, and good documentation as stated in 45

CFR Part 46.117, documentation of informed consent. I then revised the document by

giving major correction with the format to match the other SOPs I created. I also added

fuller explanations of steps in acquiring the informed consent.

4. Blood collection

5. Buccal collection

6. Tissue collection

7. Brushing collection

8. Serum processing

9. Plasma processing

10. Buccal processing

11. Tissue with freezing medium processing

12. Tissue with 10% NBF processing

13. Brushing processing

SOPs #4 to #7 describe procedures of how sample are collected and #8 to #13

describes procedures of how samples are processed. Because the SOPs written by the

previous coordinator were hand-drawn pictures with a little bit of explanation with casual

language, I revised these SOPs by adding detailed step-by-step explanation about the

procedure, written in formal language. For serum and plasma sample processing SOPs,

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I use the SOP from Qiagen’s QIAamp DNA Blood Mini Kit, and adjust it with minor

revision to fit the GICaRes procedure. I discussed these SOPs with my preceptor to

make sure they are effective for implementation. I also discussed these SOPs with the

research coordinator and technicians, to make sure they understand the procedures and

whether these SOPs portray their activities clearly. Most of these SOPs have table and

pictures to help readers understand the procedure better.

14. Storage 15. Retrieval 16. Biospecimen Data Collection and Management (Informatics) 17. Storage mapping

SOPs for biospecimen storage, retrieval, and storage mapping (#14 to #17) describe the

procedures of how to properly store biospecimen, locating them, and retrieving them. I

developed them based on my training, which was verbal only. After I consulted with my

managers whether the method and procedures for those categories were appropriate, I

documented the detailed step-by-step procedure and wrote them in a formal document

format for the SOP. I consulted with the technicians to make sure they understand the

procedure, and that the SOP represents the operation. Tables and figures were used in

the SOP to help the end user to understand them better.

18. Equipment Monitoring, Calibration, Maintenance, and Repair I revised minor descriptions and information from the GI Biopsy laboratory’s equipment

maintenance SOP about the procedure, while adding more equipment that needs to be

maintained. I used this SOP because the GI Biopsy laboratory has established SOPs

that have been accredited by the College of American Pathologists. I also used another

reference I found online from the University of Florida because I found that SOP to be

detailed and informative.23

Work Product Description Audit checklist

The checklist was presented as a table constructed of five columns. The first column is the

topic, while the second, third, and fourth columns will indicate whether the GICaRes would meet

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the checklist items mentioned in the topic section. The checklist items were answered using

“Yes,” “No,” or “N/A” options. The fifth column is for comments and recommended changes.

Table 2 is an example of what part of the audit checklist looked like.

Topic Yes No N/A Comments

Section A: Biorepository Development and Operations

1. Was the biorepository developed

based on existing local or national

models (e.g. Procurement Service,

Banking Service, Population-Based

Collections, Virtual Repositories)?

x GICaRes is developed as a banking service.

Banking stores samples for current and

future needs. ISBER stated, “Banked

specimens may be received into the

repository through agreements with

clinical sites, hospitals, or for non-human

banks, through agreements with

individuals who collect specimens routinely

from field sites.”7 For the GICaRes, the

agreement is with DDC.

Table 1

There were 14 sections covered in this audit checklist, and one section covers more than one

topic. For example, section A, Biorepository Development and Operation, covers not only the

development of the GICaRes biorepository, but also its operation.

Audit Report The audit report was written in a formal letter style directed to “GICaRes biorepository

management.” The report includes 14 sections:

1. Biorepository development and operations

2. Organizations and managements

3. Facilities

4. Biospecimen collection, processing, storage, retrieval, and dissemination

5. Storage equipment and environments

6. Quality management

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7. Safety

8. Training

9. Records management

10. Cost management

11. Biological material tracking

12. Packaging and shipping

13. Legal and ethical issues for biospecimen

14. Specimen access, utilization, and destruction

Overall, the GICaRes needs to document its policies and procedures. Many sections from the

audit checklist gave results that the GICaRes did not meet the expectations. For instance, while

the GICaRes met all the expectation for facilities section, it did not have any documentation that

showed it. Sections such as the biorepository development and operations, organizations and

management, and facilities just needed a formal documentation without any major changes. The

rest of the sections need to have major revisions, or undergo policy changes, because for

example in the storage equipment and environment sections, the GICaRes did not use the

appropriate type of tubes to store its biospecimens. That needs to be changed and documented.

GICaRes Operational Handbook

The GICaRes operational handbook consists of policies and procedures about GICaRes

operations. This handbook will be used as the mainframe of the GICaRes quality management

system. There are nine sections, with each section divided into multiple subsections. Below is

description of the GICaRes operational handbook.

1. The biorepository development and operation section discusses the type of

biorepository and the scopes of operation (sample types, participants, and storage

locations). The objective and goals describe why the GICaRes biorepository was

established, and what is the long term goal of the biorepository.

2. The organization and management section describes the role of GICaRes

biorepository within the Department of Medicine and Pathology, and defines how the

GICaRes biorepository supports the research and studies done by other organizations

using samples from the biorepository.

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3. The facilities section describes hours of operation, activities performed, and operating

personnel for locations of GICaRes operation. This includes specimen collection,

processing, and storage.

4. Biospecimen collection, processing, storage, retrieval, and dissemination section discusses the type of specimens GICaRes collects, factors that affect specimen quality

(pre-analytic and analytic variables), the workflow for GICaRes operation, and how

specimens are collected, processed, and stored.

5. The quality management section consists of procedures and activities needed to

maintain the desired level of excellence, which is to achieve the highest quality of

biospecimen.

6. The cost management section discusses how the GICaRes manages its funding. This

section was written by the research manager.

7. The safety section describes how activities should be done in a safe manner in the

GICaRes operation.

8. Appendix. This section contains all the sample collection forms used to collect various

biospecimens (blood, buccal cells, colon biopsies, esophagus biopsies, and esophageal

brushings)

9. References. This section provides references cited in the GICaRes operational

handbook.

Set of SOPs

Below is the table of contents of the set of SOPs. Each title in bold font represents one SOP that

was revised from existing SOPs. Each title in blue represents new developed SOPs. Points 1.2,

7, 8, 9, and 10 have not yet been developed; therefore, no SOP was written. Points 2.1 and

3.1.1 were previously made by the research coordinator and can only be revised by research

coordinator because it requires certain access to program that I did not have access to.

Therefore, I was not able to revise them.

1. Quality Assurance and Quality Management

1.1. Quality assurance/ management 1.2. Audit

2. Biospecimen Identification and Labeling Conventions

2.1. Biospecimen identification and labeling conventions for collection

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2.2. Biospecimen identification and labeling conventions for processing

3. Biospecimen Collection and Processing Methods

3.1. Collection

3.1.1. Screening

3.1.2. Informed consent 3.1.3. Blood

3.1.4. Buccal 3.1.5. Tissue

3.1.6. Brushing

3.2. Processing

3.2.1. Serum

3.2.2. Plasma

3.2.3. Buccal 3.2.4. Tissue with freezing medium

3.2.5. Tissue with 10% NBF

3.2.6. Brushing

4. Storage and Retrieval

4.1. Storage

4.2. Retrieval

5. Biospecimen Data Collection and Management (Informatics)

5.1. Biospecimen data collection and management 5.2. Storage mapping

6. Equipment Monitoring, Calibration, Maintenance, and Repair

7. Shipping and Receiving

8. Laboratory Tests Performed In-House Including Biospecimen Quality Control Testing

9. Training

10. Security

Outlook The GICaRes biorepository is expanding to Harborview Medical Center (HMC) and identical

samples will be collected, processed, and stored there. The SOPs for collection and processing

will be utilized at HMC as the procedures are identical. However, the GICaRes biorepository at

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HMC will have a different workflow and facility policies. The operational handbook will be used

as a model to create the HMC operational handbook. There are some SOPs that still need to be

written when the GICaRes establishes its policies and procedures (as described in the SOP

section). Training manuals and safety manuals will also be developed in the future.

Learning Objectives and Outcome Having completed this project, I am now able to

● Prepare a checklist and perform an internal audit for a biorepository laboratory.

● Develop an operational handbook and set of SOPs for a biorepository laboratory.

● Describe standards for biorepository operation.

What I gained from this experience met my initial learning expectations. As I was auditing, I

identified aspects of biorepository operations that failed to meet NCI and ISBER guidelines. I

suggested specific modifications to be implemented in the biorepository workflow, labelling,

storage management, and the type of long-term storage containers being used. These

suggestions have been implemented by the biorepository. I also created and updated

operational handbook and SOPs based on the accepted standards. This practicum made me

realize that I enjoy doing QA, and would like to pursue it as a career path. I will continue to

author the SOPs for the GICaRes at UWMC, and to also further develop the operation manual

and document procedures for GICaRes at HMC.

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References 1. UW Medicine. About the School of Medicine.

http://www.uwmedicine.org/education/about. Accessed March 15, 2016

2. UW Medicine. About UW Medical Center

http://www.uwmedicine.org/uw-medical-center/about. Accessed March 15, 2016

3. UW Medicine. About UW Medicine.

http://www.uwmedicine.org/about Accessed November 4, 2015.

4. UW Medicine Division of Gastroenterology. About our patient care program.

http://www.uwgi.org/Ptcare/Default.aspx Accessed April 24, 2015.

5. UW Medicine Division of Gastroenterology. UW Digestive Disease Research.

http://www.uwgi.org/Research/Default.aspx Accessed April 24, 2015.

6. National Cancer Institute. NCI Dictionary of Cancer Terms. Biorepository

http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=561323. Accessed

April 29, 2016.

7. International Society for Biological and Environmental Repositories. ISBER Best

Practices for Repository.

https://www.ucdmc.ucdavis.edu/biorepositories/pdfs/bestpractices/ISBER_Best-

practices-repositories_3rd-edition.pdf Accessed November 24, 2015.

8. NCI Best Practices for Biospecimen Resources.

http://biospecimens.cancer.gov/bestpractices/2011-NCIbestpractices.pdf Accessed April

26, 2015.

9. International Society for Biological and Environmental Repositories. ISBER Best

Practices for Repository.

http://www.isber.org/?page=BPR Accessed June 6, 2016.

10. Biorepositories and Biospecimen Research Branch (BBRB).

http://biospecimens.cancer.gov/default.asp Accessed November 24, 2015.

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11. 45 CFR Part 46 Subpart A, Protection of Human Subjects

http://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html

Accessed April 26, 2016.

12. U.S. Department of Health & Human Services. Office for Human Research Protection.

http://www.hhs.gov/ohrp/ Accessed April 26, 2016.

13. U.S. Department of Health & Human Services. Health Information Privacy. The HIPAA

Privacy Rules. http://www.hhs.gov/hipaa/for-professionals/privacy/ Accessed April 27,

2016.

14. 45 CFR Parts 160, 162, and 164. HIPAA Administrative Simplifications.

http://www.hhs.gov/sites/default/files/ocr/privacy/hipaa/administrative/combined/hipaa-

simplification-201303.pdf Accessed April 27, 2016.