All 'Barr' None
Whoever does the investigation, it is always clear that the OOS result must be taken seriously, and acted on. Testing into
compliance is both unscientific and objectionable. The guidance notes make it clear that when there are no laboratory or calculation
errors identified and there is no scientific basis for invalidating the initial OOS results in favor of acceptable retest
results, then, "all test results, both passing and suspect, should be reported."
It goes on to say, "It is critical that the laboratory provides all individual results for evaluation" as "averaging the result(s)
of the original test that promoted the investigation and additional retest or resample results obtained during the OOS investigation
is not appropriate." This practice "hides variability," according to the guidance and which goes on to say that, "relying
on averages of such data can be particularly misleading when some of the results are OOS and others are within specification."
Anyone familiar with the USA versus Barr Laboratories case of 1993 will recognize the importance of not ignoring OOS results,
and why testing into compliance is unacceptable.2
Whether out of specification, or more usually, in specification, one of the most important pieces of communication between
the CAL and client is the actual result of any analysis. Modern LIMS allow for the production of secure, electronic copies
of certificates of analysis (CoA), which permit the CoA to be e-mailed directly to the client's inbox, rather than relying
on the slower postal service. In some cases, the laboratory may be able to grant the contract-giver access to secure parts
of its IT infrastructure or LIMS for live results. The client can view the progress of the analysis from sample receipt through
to the final result.
If this is the case, and if appropriate, then the requirements of 21 CFR Part 11 should be obeyed, with the appropriate use of automatic password ageing, unique identifiers, limiting access, and
audit trials. The complexities of 21 CFR Part 11 are such that no further detail can be entered in here.
The raw data, copies of the CoA, and all associated correspondence can now be archived for the period agreed in the technical
Throughout all processes, each party could have informal questions, so requests for information should be quickly answered.
CALs often have a dedicated customer- service team, or customer managers who should be the first point of contact for all
queries. The customer service team should be the customer's advocate with the laboratory should additional support be needed.
There are other potential sources of discussion between a CAL and its customers. These might include, for example, requests
from the customer for an audit, a laboratory tour, or debarment statements. One would hope that there was never a need to
register a complaint about the CAL's service, but it might be useful to know in advance what systems the CAL has in place
for dealing with and responding to complaints. On a more positive note, the CAL may want to conduct a customer-satisfaction
survey, and the cooperation of clients in completing such surveys is likely to be beneficial to both parties.
Communication between the CAL and client is an essential part of the working relationship. Although it might be tempting to
make a choice of partner laboratory on initial considerations of price, the long-term consequence of this decision should
always be kept in mind. Communication is particularly important when out-of-specification results arise. It is always to the
manufacturer's advantage if the CAL has the resources, back-up, and communication channels available to provide an assured
service when things are working well, and perhaps more importantly, the investigative resources to respond promptly and expertly
when results are OOS.
Adrian Kirk is a quality manager at RSSL Pharma, Reading Science Centre, Berkshire, UK, +44(0)1189868541, firstname.lastname@example.org
1. US Food and Administration. Guidance for Industry. Investigating out-of-specification (OOS) test results for pharmaceutical
production. Rockville, MD; 2006 Oct. Available from:
2. United States v. Barr Laboratories, Inc., 812 F. Supp. 458 (DNJ 1993).