Seqens eBook - 16

CROs

Technical Audit

organization's situation (dosage form, types of drug products, types of

It is the scientific rigor and quality of an E&L study that dictates whether

require close and meaningful contact between the CRO's key staff

the efforts required to design, implement and report the study are well
spent and produce useful, credible outcomes. Although a CRO's technical
capabilities might be established as being adequate during the candidate
screening and selection stage, a more extensive and detail-driven
technical audit should be conducted in order to qualify a CRO. As the

plastics used, etc.). An appropriately detailed staff qualification would
members (especially those doing the actual work) and the contracting
organization's qualification team. This close and meaningful contact could
take a number of forms; for example, the contracting organization's team
could interview individual CRO staff members or the CRO staff could host
a "symposium," wherein the CRO's staff members present case studies,

primary tool used in an E&L study is analytical chemistry, this technical

theory and practice scenarios, methodological or technique details (such

audit considers the analytical capabilities and capacity of the CRO, and

as the development and validation of a leachables method) or high level

specifically includes three activities: a more detailed review of the CRO's

strategies to the contracting organization's assessors. A personnel audit

technical resources, a very detailed review of the methods and procedures

performed in this manner can rival the due diligence that the contracting

used by the CRO, and a thorough competency evaluation (Table 2).

organization might exercise if it was hiring the CRO's staff members for
their own organization.

Table 2. Technical Qualification of Partner CROs
(Part D of Step 3)

In addition to reviewing the analytical tools and personnel, the CRO
qualification process should include an assessment of the processes

A. Detailed review of technical inventory
1. Detailed instrumentation and facilities reviews; focus on extract generation and
extract testing

that are followed for performing the work, which may be documented
in specifications, procedures and manuals. At the screening level, the

2. Detailed personnel review (quality and quantity)

activities of procedure and process reviews were focused on the more

3. General review of relevant technical documents (e.g., method SOPs)

general aspects of business and laboratory procedures as part of the

B. Detailed review of methods and procedures

quality audit. For example, the initial screening investigations are focused

1. Detailed, line-by-line review of SOPs, looking for technical gaps and high level thinking
(e.g., use of system suitability)

on the "do you have?" level, manifested in questions such as, "do you
have a procedure for reporting and addressing results that are out of

2. "How do you handle this?" session
3. Generation and review of a mock proposal (an example protocol)

specifications?" or, "do your instruments have maintenance logs?" At the
qualification stage, the focus is on the contents of the documents and

C. Competency Evaluation
1. Intra-laboratory testing

whether those contents are sufficiently rigorous to ensure the quality of

2. Characterization of test mixture

the work that the documents are related to. Such an assessment could
require a line-by-line examination of the CRO's most critical Standard
Operating Procedures, (SOPs), where the choice of SOPs to examine would

The detailed and in-depth review of a CRO's technical inventory takes

be made by the contracting organization, not the CRO. For example, in

into account the physical inventory noted in the CRO screening stage

one's review of a procedure specification for a chromatographic method

and evaluates each technical asset in terms of its capability to perform

used to screen extracts for extractables, it might be necessary to look for

effectively in an E&L assessment. Individual instruments and instrument

required system suitability testing with the intent of establishing whether

systems for generating extracts and testing extracts are evaluated in terms

the system suitability test is meaningful (e.g., are the right method

of matching their performance specifications with the requirements for

parameters considered and are the acceptance criteria sufficiently

E&L testing. For example, it is no longer sufficient at this stage to note

rigorous such that poor method implementation would actually cause

that the CRO has LC/ MS capability; rather, it is necessary to take note of

a system suitability failure). If internal standard response factors are

which specific LC/MS systems the CRO has as well as the system's inherent

used to estimate the levels of extractables in extracts, then it could be a

capabilities. Consider TOC as a case in point. If a CRO has TOC capability

proper question for the contracting organization to ask the CRO, "where

because it frequently tests purified water, this TOC capability may not be

is the response factor database that was used to justify the choice of

adequate to test pH 9 extracts containing relatively large concentrations

your internal standard?". If the test method requires extensive sample

of multiple organic extractables. In terms of capabilities, both the

processing prior to instrumental analysis, then the SOP for performing the

manufacturer's specifications and user input into system performance

sample processing should be examined from the perspective of scientific

(for example, historical system suitability data) are examples of relevant

credibility, ease of implementation, and the presence of appropriate

considerations. An audit performed in this manner can be as extensive

means of revealing and resolving cases of unacceptable performance. In

as to the due diligence that the contracting organization would have to

the final analysis, the most rigorous assessment of a laboratory SOP may

exercise upon purchasing the equipment for its own laboratories.

be for a member of the contracting organization's qualification team to

In a similar vein, the actual technical qualifications of the CRO's staff

take the SOP and try to implement it as specified.

need to be examined more closely than the "number and degree" count

It is the nature of studies into extractables and leachables, especially

that may have occurred while screening potential candidate CROs.

at the extractables discovery and identification stages, that the path

At the qualification stage, the CRO's staff must be assessed in terms of

from initiation to completion is not always straight, and that the means

two important attributes: the breadth and depth of their experience

of getting from point "A" to point "B" cannot always be captured in

in E&L assessment and their specific experiences with the contracting

procedures and specifications. An experienced CRO will have encountered

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Seqens eBook

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