Certain types of quality control (QC) testing are often outsourced by pharmaceutical companies, regardless of an organization's size — typically because the company is either incapable of performing the assays in-house or does not wish to bring them into its facility. The decision to outsource may be based on

• the complexity of techniques involved

• special skills required for conducting the assays

• a need for biohazardous reagents such as radioisotopes

• limited testing frequency for the assays

• or (in biologics testing) because they require propagation and/or manipulation of potential biological contaminants, including positive controls, which present a risk to the purity and safety of biological products manufactured on site.

Examples of contracted testing include viral and mycoplasma safety studies with infectious positive control organisms, analytical testing using highly specialized equipment such as inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma atomic emission spectroscopy (ICP-OES), and radiolabeling studies for metabolism or biodistribution. Fortunately, a number of contract research and testing organizations can and will perform such types of testing.

The wrong way to manage a contract laboratory (Click to enlarge)

Much has been written about the rationales for and advantages of outsourcing manufacturing and/or testing services, selecting outsourcing partners, and optimizing sponsor/contractor relationships (1,2,3,4,5). In any such relationship, the contractee (contract giver) has responsibilities as well as the contractor (contract acceptor) — relating both to business and regulatory compliance. We will address the contractor's responsibilities in a future article (6). The business realities and regulatory expectations associated with a pharmaceutical company's use of a contract service organization must be considered in making a decision to outsource. The optimal and most defensible contract laboratory administration programs are those in which the practices described herein are formalized within internal quality systems, policies, and/or standard operating procedures (SOPs).

Contract Laboratory Selection

Selecting a contract test laboratory typically involves an assessment by the contractee of the laboratory's technical capabilities, its available capacity, its regulatory track record (compliance history), testing facilities, quality systems, and assay pricing. Before or during the course of that assessment process, a confidentiality agreement may be necessary to protect the proprietary interests of both organizations. Thorough evaluation of a contractor's quality systems will ensure that they meet a contractee's requirements. Once all the quality and pricing considerations described below have been addressed, the contract laboratory can be approved.

Methods and Capacities: During evaluation of a laboratory's technical capabilities and capacity, attention should be placed on the analytical methods themselves. Do the methods comply with relevant compendia or regulatory guidances? Are appropriate standards and/or controls used? Are assay invalid rates monitored — and if so, whatdo they look like? Are noncompendial methods validated? In evaluating capacity, the following also might be addressed:

• What is the normal lead time from sample submission to assay initiation?

• How long after assay completion are results reported?

• Can those times be minimized, and how much will that cost?

• Are appropriate instruments available, and are there redundancies in both the equipment used and trained operators for the assays?

• Are assay reagents, standards, and controls readily available and stocked at adequate levels? Are those inventories monitored to prevent unexpected delays in initiating and completing assays?

Compliance History: A contract laboratory supporting a sponsor's QC needs is acting as an extension of that company's QC group and is therefore subject to scrutiny by regulatory agencies during preapproval inspections. In addition, testing organizations are typically subject to routine inspection, depending on their geographical locations, by one or more regulatory agencies: e.g., the FDA in the United States, the EMEA in the European Union, the PMDA in Japan, and the COFEPRIS in Mexico. A sponsor may request an inspection history as well as redacted establishment inspection reports and responses from the contract laboratory either during on-site visits or through correspondence.

In a perfect world … (Click to enlarge)

Depending on the nature of the laboratory's business, it may be subject to inspection by other types of regulatory agencies. For example, if a lab performs animal testing, it could be inspected by the Animal and Plant Health Inspection Service (APHIS) of the USDA. Any testing laboratory can be inspected by the Environmental Protection Agency (EPA) or Occupational Safety and Health Administration (OSHA) in the United States. Although results of such inspections are not GMP related, the reports may be useful in due diligence because a contractor can be shut down or face sanction if it fails an audit by one of those organizations. And that can disrupt a contractee's business.

Information obtained can be combined with a contractee's own assessments of quality systems to form a clearer picture of the contract lab's potential to successfully stand up to regulatory inspection. This helps uphold the contractee's own high standards for QC testing.

Quality Systems: Evaluation of a contract testing organization's quality systems is a required part of the selection process (7,8). Ordinarily this is done during on-site audits, when a potential contractee is allowed full access to a contractor's quality manual, policy documents, and SOPs. Such documents are typically considered, along with procedural descriptions (e.g., protocols and method SOPs), to be proprietary and normally aren't allowed to leave a testing facility. Particular attention should be paid to the laboratory's procedures for data archiving, test sample login, change control, deviations/nonconformances, and investigation of unexpected and out-of-specification (OOS) results (7). The contractor's policies for use of subcontractors should also be evaluated.

Numerous tools and checklists from both US and EU perspectives are available to help evaluate contract laboratory quality systems. For example, company-specific questionnaires may be developed and used to evaluate analytical chemistry (9,10) and biosafety or microbiology laboratories (11,12,13,14). Quality systems at a contract testing laboratory should be compatible with the level of compliance the contractee requires for the work to be outsourced (e.g., research, GLP, or GMP).

Facilities and Equipment: An inspection of the contract laboratory's facilities conducted in an on-site visit can provide much information about its operation. GMP requirements associated with manufacturing facilities also apply to laboratory areas (15). It is important to evaluate access and security of the building; design, cleaning, and maintenance of the laboratory; computerized systems; utilities; and pest control. Particular attention should be paid to equipment and lab design:

• Is the equipment validated, and is it being calibrated according to schedule?

• Are reagents being used within their expiry and discarded if expired?

• Are laboratories clean, uncluttered, and of sufficient size?

Personnel Training: Documents addressing staff training should be examined too. Is there evidence that the staff have received appropriate compliance training (GLP, GMP)? Is frequency of retraining stated in SOPs, and does the company adhere to it? Are the operators who perform the analytical methods of interest sufficiently educated, trained, and experienced in those techniques? Are there sufficient numbers of trained operators to conduct the testing? If contractors are hired to perform GMP tasks (e.g., calibration, maintenance, and cleaning), then are they trained, and is their training documented?