strengthening glp compliance through internal audits

Strengthening GLP ComplianceThrough Internal Audits

Henry Li*, Dominique Pifat, Gerald Klein and Steve Petteway

Talecris Biotherapeutics, Research Triangle Park, NC, USA

Summary

The Quality Assurance (QA) strategy for assessing Good Laboratory Practice (GLP)compliance at different testing facilities varies from focusing on study dataverification to taking a quality system approach. As a best practice and to ensureoverall compliance with GLP regulations, the Quality Assurance Unit (QAU) shouldperform three types of internal audits: study-specific, process-based, and systeminspection. These internal audits serve as a tool to ascertain whether a GLPcompliance program is functioning correctly. Information gathered from these auditscan also be used to provide assistance during the evolution of a new GLP complianceprogram. As the GLP compliance program matures, internal audits can be a usefulmechanism to help maintain compliance and promote continued improvement.Copyright # 2006 John Wiley & Sons, Ltd.

Key Words: internal audit; system audit; process-based audit; Good Laboratory Practice; GLP;Quality Assurance

Introduction

An effective Quality Assurance (QA) function

is an essential component of a Good Laboratory

Practice (GLP) compliance program. The

objective of a QA Unit (QAU) is to give

management and, eventually, regulatory agen-

cies confidence that safety studies and other

studies that are intended to be GLP compliant

meet regulatory requirements and have the

necessary quality and integrity. However, if a

QA group only focuses on verification of the

data at the end of a study, it may overlook the

quality system that supports the study and

affects data quality.

The responsibilities of a GLP QAU are out-

lined in 21 Code of Federal Regulations (CFR)

Part 58, ‘Good Laboratory Practice for Non-

clinical Laboratory Studies’. This document

states that the QAU ‘shall be responsible

for monitoring each study to assure manage-

ment that the facilities, equipment, personnel,

methods, practices, records, and controls are in

conformance with the regulations’ [1]. Specifi-

cally, the QAU shall: (1) maintain a copy of

master schedule sheet of all nonclinical labora-

tory studies conducted at the testing facility; (2)

maintain copies of all protocols pertaining to all

nonclinical laboratory studies for which the unit

is responsible; (3) inspect each nonclinical study

at adequate intervals to assure the integrity of

the study and maintain written and properly

signed records of each periodic inspection; (4)

periodically submit to management and the

*Correspondence to: Henry Li, Talecris Biotherapeutics,79 TW Alexander Drive, 4101 Research Commons,Research Triangle Park, NC 27709, USA. E-mail: henry.

Qual Assur J 2006; 10, 255–261.Published online in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/qaj.390Copyright r 2006 John Wiley & Sons, Ltd.

Study Director written status reports; and (5)

review the final study report to assure that such

report accurately describes the methods and

Standard Operating Procedures (SOPs), and that

reported results accurately reflect the raw data

of the nonclinical laboratory study [1].

The regulations emphasize two key QA

functions: (1) auditing to monitor studies, and

(2) reporting to communicate with Study Direc-

tors and management. Auditing is an important

tool for the QAU to ensure that a facility is in

compliance because it is during internal audits

that actual conditions are compared with the

requirements [2]. To be effective, the audit

results and findings should be reported in a

timely manner to the Study Director and facility

management. In this article, several types of

internal GLP audits are discussed. The effective,

strategic use of these internal audits to assist

with the development and continued improve-

ment of a GLP compliance program is also

reviewed.

Internal audit types

To completely fulfill regulatory requirements, a

QAU should conduct three types of internal

audits: study-specific, process-based, and sys-

tem-wide audits. The types of audits and their

roles in ensuring the quality and integrity of

study data are shown in Figures 1 and 2. Study-

specific audits, which typically include a study

protocol review, one or more critical phase

audits and a final report review, focus on the

integrity of study-related conduct and validity of

the data [1]. Process-based inspections are

conducted to assess areas such as routine testing,

methodological practices and procedures that

are typically beyond the scope of study-specific

audits. Facility or system-wide audits are com-

prehensive assessments of the level of compli-

ance of the testing facility.

Study-specific audit

The essential task of a QAU is to monitor each

study to ensure compliance with GLP regula-

tions, the protocol, and applicable SOPs. These

study-specific audits are conducted at different

stages of a study, progressing from protocol

preparation to finalization of the study report

(Figure 1).

* Study protocol review

Although it is not required by US Food and

Drug Administration (FDA) regulations,

study protocol review by the QAU is currently

typical industry practice [3,4]. Protocols are

audited for internal consistency, compliance

with company SOPs and the Principles of GLP

regulations. This is good business practice

Typical work audit

Audit of activitieswithin a specific

timeframe

Audit of group-specificactivities

Critical phase audit

Protocol review

Study-specific audit

Final report audit

INTERNAL AUDITS

Process-based audit System-wide audit

All quality system elements

Figure 1. Internal audit types

256 H. Li et al.

Copyright r 2006 John Wiley & Sons, Ltd. Qual Assur J 2006; 10, 255–261.DOI: 10.1002/qaj

because it demonstrates that the facility is

taking a proactive approach to compliance.

A scientifically sound, compliant protocol

lays a solid foundation for the study. The

Organisation for Economic Co-operation and

Development (OECD) Principles of GLP

require a QAU ‘to monitor compliance of

the study plan with GLP’ and ‘to assess the

clarity and consistency of the study plan’ [5].

In today’s collaborative research environment,

a study can be conducted in different testing

facilities, sometimes even in different coun-

tries. OECD GLP No.13 [6] states that the

roles of the QAU at each test site should be

carefully planned. Often, the responsibilities

of each test site QAU are stipulated in the

study plan/protocol. For these reasons, it is

important that the QAU take a proactive role

in developing a plan with respect to their

responsibilities at each site.

* Critical phase or in-life audits

These audits are conducted to observe specific

tasks within the actual conduct of the studies

in order to verify whether experiments are

executed according to the protocol and

appropriate SOPs. For example, test article

preparation and dosing of test system are

often monitored for compliance with the

protocol. Critical pieces of equipment used

are often verified for proper calibration for

the intended use in the study. In addition, it is

imperative to verify that deviations are

appropriately documented and communi-

cated. The number and frequency of in-life

audits will vary depending on the length and

nature of the study. Usually critical phases are

jointly identified by the QAU and the Study

Director. If the QAU has sufficient experience

and scientific expertise, it can sometimes

determine which phases of a study are most

critical to audit.

* Final study report audits

The data generated in a study are intended for

inclusion in submissions to regulatory agencies,

such as the US FDA, in support of Investiga-

tional New Drug (IND) applications and/or

product licensure. The task of the QAU is to

ensure that ‘methods are accurately described

and that the results accurately reflect the raw

data’ [1]. OECD GLP Principles provide

detailed requirements for a final report audit [5].

In practice, the QAU is often required to

review large portions of the data in a

relatively short period of time. It should be

emphasized that in addition to a solid under-

standing of GLP regulations, the QAU audi-

tors should have a thorough understanding of

the science underlying each study in order to

be effective. In many cases there are regula-

tory guidelines and other documents that

provide important scientific and technical

information regarding how specific studies

should be conducted [4,7]. The QAU auditors

should have a working knowledge of these

requirements in order to perform truly value-

added audits, rather than focusing on minor

discrepancies in documentation.

Process-based audit

‘A process audit is verification by evaluation

of an operation or method against pre-determined

instructions or standards, to measure confor-

mance to these standards and the

effectiveness of the instructions’ [2]. It appears

that the process-based audit concept originates

System-wide audit Study-specific audit Process-based audit

Figure 2. Schematic diagram of relationships between internal audits

Strengthening GLP compliance Through Internal Audits 257


from manufacture-based quality systems [2].

In a manufacturing facility, a manufacturing

process can be easily defined, for example,

a plastics part molding step. For nonclinical

studies conducted at a testing facility,

processes may not be as clearly defined as in

the manufacturing arena. However, process-

based audit approaches can be effectively

adapted for use in non-clinical laboratory

studies and can serve as an effective tool for

QAU auditors to assess the GLP compliance

level of a testing facility.

In general, process-based inspections are often

conducted by a GLP QAU to assess the areas

that are usually beyond the scope of study-

specific audits. Study-specific audits tend to

focus on data and are often not sufficiently

comprehensive to monitor other activities

that support data collection, due to time

constraints. If a process that supports a GLP

study is not in compliance, it may affect or

introduce doubt about the quality of study data.

During a process-based audit, QAU auditors can

concentrate on a specific area or a particular

quality system [5,8]. The scope of a process-

based audit can be flexible and the audit

relatively less time-consuming than a study-

specific audit. If one process or group is

identified as a weak area, the QAU can

strategically target that area. However, because

of this flexibility, it is not always easy to clearly

identify the group responsible for the weakness.

If several groups contribute to a defined process,

the auditors may have to deal with the

responsible heads of several groups and assign

appropriate responsibility for corrective actions

to each group.

Process-based audits can be classified based

on the type and scope of the audits:

* Typical work audit

Routine work, such as animal husbandry,

sample handling, routine testing, etc., may not

be within the scope of study-specific audits

because it supports multiple studies. A typical

work audit is therefore conducted to assess

compliance level of routine work. To facilitate

the establishment of a process-based audit

program, a test facility can analyze all routine

work conducted at the facility, including

testing, procedures and practices. The pro-

cess-based audit program should be designed

in such a way that all routine processes are

rotated for evaluation for a fixed duration, for

example, every year.

* Audit of group-specific activities

Another way to define a process-based audit is

to focus on operational units, such as Metrol-

ogy, Assay Support, and Formulation, etc.

The QAU can assess one group at a time for

GLP compliance. This is an easy approach to

designing a process-based GLP audit pro-

gram. The head of the group to be audited is

thus accountable for GLP compliance of the

activities conducted by his or her group.

* Audit of activities within a specific time frame

During these audits, auditors can assess study-

specific and/or support activities during a

specific time frame, for example, a day [9].

The advantage of this type of audit is that it is

flexible and relatively easy to schedule.

Several areas can be sampled during one

audit. However, it requires auditors to be

familiar with the facility operations and the

studies to be covered. The QAU auditors

should carefully plan this type of audit and

familiarize themselves with procedures and

study protocols to be audited.

System-wide audit

GLP is in essence a Quality Management System

(QMS) for drug research and development. To

assess the overall level of compliance of a testing

facility, auditors must take a systematic ap-

proach to evaluate the QMS. All quality

elements can be reviewed during one audit.

Consequently, the auditors can obtain a whole

picture of the quality system of the facility.

Because of this, system-wide audits are often

performed to prepare the test facility for possible

regulatory inspection. However, due to the

resources required and potential impact on

studies and operations, system-wide audits

are not frequently conducted. System-wide

audits are usually conducted annually or even

258 H. Li et al.


semi-annually, depending on compliance needs

and the development stage of a GLP compliance

program. The areas or quality system elements

audited should cover all quality elements out-

lined in 21 CFR Part 58 [1]. System-wide audits

should include, but not be limited to, the

following areas:

* Organization and Personnel* Facilities* Equipment/Computerized Systems* Test and Control Articles* Protocol and Study Conduct* SOPs* Methods* Controls* Reports* Storage and Retrieval of Records

Use of audits during development of anew GLP compliance program

Internal audits serve as an essential tool for a

QAU to verify GLP compliance of a facility. It is

suggested that for a new QMS, the stage

between the initial implementation and maturity

tends to be a difficult time for an organization to

establish procedures and policies [10]. Thus, it is

important for a QAU to analyze and summarize

internal audit results and to apply them to

facilitate the growth of a new GLP compliance

program.

Improving SOPs

Audit results can be used to fine tune SOPs [10].

When SOPs are first developed, they might not

capture all critical steps or be consistent with

actual experimental procedures. Verifying actual

conduct with the SOPs helps ensure that the

SOPs are compliant with GLP and provide clear

instructions. The same approach can be applied

to improve standard forms, for example, an

equipment routine maintenance form, and tem-

plates, such as those for the protocol and final

report.

Identifying best practices

The QAU auditor(s) have the advantage of

evaluating practices of different groups or depart-

ments during internal audits. This unique position

allows the auditors to compare and identify best

practices. Those practices can then be recom-

mended for implementation within the testing

facility. When a GLP compliance program ex-

pands and new groups are brought into the

program, it is often necessary to establish new

procedures or modify existing procedures to

accommodate the new groups. The QAU auditors

are again in a unique position to advise the groups

as to the appropriate practices and procedures.

Enhancing a mature GLP complianceprogram

It is important for the QAU to understand that

GLP compliance is a continuous process. As a

QMS, a GLP compliance program is dynamic.

For example, new regulations, guidelines, stu-

dies, procedures, and industry practices relevant

to GLP compliance are continually being intro-

duced. When new employees join the company,

they may have a different perspective toward

GLP compliance. Within a facility, ‘habitual’

deficiencies may exist. In mature GLP compli-

ance programs, analyzing patterns of noncom-

pliance, taking a risk-based approach to

auditing, and following regulatory develop-

ments are all useful mechanisms that can help

maintain compliance levels and facilitate con-

tinual improvement.

Pattern and trend analysis

Analyzing and trending patterns of noncompli-

ance is a key quality system approach [2] to

maintain continued improvement of a quality

system. This approach facilitates: (1) identifica-

tion of the system-wide issues, specifically the

‘habitual’ deficiencies; (2) investigation of the

root causes of noncompliance; and (3) develop-

ment and verification of effective corrective and

preventive action plans.



Taking a risk-based approach

Effective use of internal audits can strengthen

drug development compliance risk management.

A risk-based approach toward auditing should

be applied during internal audits.

The QAU should prioritize audits based

on the potential risk of noncompliance to

product development and concentrate efforts

on areas in which noncompliance would have

a significant impact on product development.

When audits are completed, the auditors

should focus on the correction of critical

findings. Furthermore, auditors with a strong

knowledge of the regulations and broad

familiarity with the operations and scientific

studies, for example, can identify and help

eliminate or reduce documentation redundancy,

which could result in improved operating

efficiency.

Following regulatory development

In addition, it is very beneficial for auditors to

remain abreast of new regulatory audit trends

and apply that knowledge in designing audit

strategies. This helps ensure that the GLP

compliance program remains up to date and

current regarding new regulatory requirements.

There are many ways to obtain regulatory

information. For instance, the US FDA website

provides a wealth of information. At this site,

one can easily access the latest guidance docu-

ments, warning letters and other compliance

information. Quality Assurance professional

society meetings also are a good place to learn

new regulatory developments and current in-

dustry practices. Last, but not least, quality-

related articles and publications are traditional

sources for quality- and compliance-related

information and ideas.

Conclusion

To meet regulatory requirements, a QAU should

establish an effective internal audit program

consisting of study-specific, process-based, and

system-wide audits. These audits should be

designed and conducted to assess the level of

GLP compliance within a particular facility or

study from multiple angles, and at different

levels. This will allow the QAU to obtain

sufficient information to ‘assure management

that the facilities, equipment, personnel, meth-

ods, practices, records, and controls are in

conformance with the regulations’ [1]. Informa-

tion gathered from internal audits can be further

used to assist in the development of a new GLP

compliance program and to facilitate the con-

tinued improvement of a mature GLP compli-

ance program.

References

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