Abstract
Robotic laboratory equipment malfunctions may affect the performance of integrated laboratory instruments. Thus, the qualification of robotics is necessary to ensure adequate performance of complete integrated systems. In this JALA Tutorial, we adapt the methods used in production processes to laboratory robotics and propose guidelines for performing the various steps required for qualification (i.e., installation, operational, and performance qualification), while emphasizing specific aspects of laboratory robotics. We think that the application of such guidelines will help in standardizing the acceptance of robotic equipment, facilitate their operation and performance evaluation, and improve traceability with quality assurance documentation.
Keywords
Introduction
In recent years, the use of robotic automation has grown rapidly in clinical laboratories to decrease tedious and manual tasks such as sample handling, aliquot processing, and associated errors, 1 and in the pharmaceutical industry to increase rates of drug discovery. A robot is an electromechanical device that has multiple degrees of freedom (i.e., it can move along or around multiple axes).
Robotic equipment is governed by the same regulations as other laboratory equipment, as eventual errors from robotics can affect the performance of linked laboratory instruments. Thus, qualification of robotic laboratory equipment is necessary to ensure adequate performance of integrated laboratory systems (robotics and instruments) that are equivalent to the qualifications required for the installation and performance of stand-alone laboratory instruments.
The goal of Qualification is to determine if robotic equipment is able to perform a given process consistently well. Qualification results in documentation that proves the critical functions of a robotic process are under control. Qualification is mandatory in pharmaceutical industry production processes. It is described in many national and international regulatory or professional documents, 2 and in many articles. Qualification is required for adherence to Good Manufacturing Practices (GMP), 3 Good Laboratory Practices (GLP), 4 and ISO 5 standards. However, there are no guidelines for qualification of robotic laboratory equipment.
This paper proposes guidelines to help users qualify robotic laboratory equipment. To prepare these guidelines, we followed the method of the Société Française des Sciences et Techniques Pharmaceutiques (SFSTP), 6 and documents are formatted as per ISO quality requirements.
Preliminary Steps of Qualification
Qualification Committee
To prepare for Qualification, it is necessary to set up a multidisciplinary group that will plan, execute, and check the qualification program. This group should include the laboratory personnel that use the equipment, specialists in laboratory engineering to check technical and metrological aspects, and a member of the quality assurance department. This first discussion emphasizes critical points and the assays to be performed. Then, the roles and responsibilities of each member of the group are defined. They can be summarized as follows: (1) a coordinator who checks the coherence between the various assays; (2) a person in charge of the validation of the assays; (3) experts in the fields of robotics, quality assurance, and others; and (4) several end users who perform the qualification assays.
The group may contract engineers from the company that manufactured its robots, and external consultants to assist in the management of the qualification process. In fact, the entire qualification may be performed by an external company. In this case, user requirements and goals must be detailed in the contract, and the external company should manage the assays. Final validation of the qualification, however, should be the responsibility of the Qualification Committee.
Qualification Program
Qualification must produce documented proof of several items. These steps must be performed successively (i.e., one qualification must be finished before starting the next qualification). (1) Verification that the equipment was designed and manufactured following good manufacturing practices (GMP) Standards. This can be determined by examining equipment documentation provided by the manufacturer. The group should check if the equipment is compatible with the regulations under which the laboratory is governed, and if user training was done correctly. (2) The equipment meets specified requirements and is appropriately placed and installed for use in the laboratory. This is called Installation Qualification (IQ). (3) The equipment is evaluated to ensure that it is capable of operating within established limits and tolerances, as well as throughout all anticipated operating ranges. This is called Operation Qualification (OQ). (4) The performance of the equipment during actual use in the laboratory fits with the specifications of the manufacturer. This is called Performance Qualification (PQ).
Documentation
Documentation is built according to the well-known pyramidal process design, with top-down organization. All of these documents should be written, validated, and filed to facilitate eventual audits or inspections: (1) At the top, the Qualification plan presents an overview of the robotic equipment, including operation capabilities and procedures, precautionary measures during use, the laboratory plan, laboratory personnel training, and the maintenance program. The Qualification Committee and the Qualification program should also be included in this document. (2) A general procedure describes the rules of the qualification: the critical points to check, how the validations will be performed, the terminology that will be used, the documents used as references, the schedule (flowchart), and a list of the associated operating procedures and records. (3) Three operating procedures define the three steps of the Qualification: IQ, OQ, and PQ. Each operating procedure should include the goal, the points to qualify, step-by-step instructions for how to perform the assay, and data collection. (4) Three records (qualification sheets) are associated with each of the previous operating procedures. (5) The Qualification Report is the final record. This document records the qualification process, the remarks and proposals of the Qualification Committee, and the final decision.
Prospective Qualification
Qualification is conducted prior to using the equipment for laboratory production, or after a technical operation on the robot, or after modification of the environment in which the robot functions. It is also necessary when calibrating external measurement systems used to control the robot. In these cases, a limited qualification may be performed with focus on critical points that may be directly affected by “Retrospective Qualification” In some cases, qualification can be conducted for equipment that is already in use by a laboratory. This qualification would be based on accumulated production, testing and control data.
Implementation
As mentioned, the three steps of Qualification, IQ, OQ, and PQ, are performed successively as shown on the ANSI symbols flowchart (Fig. 1). If one of the steps is not validated, it becomes necessary to find, decide, and implement corrective action to achieve validation before starting the next step. During a step, the process may be detailed in a generic way as shown in Figure 2. We will emphasize the specific aspects of each step.
General flowchart of an equipment qualification process.
Flowchart of one qualification step for robotic equipment.
Installation Qualification (IQ)
This step requires a qualified operator in robotics and equipment design. The documentation includes the manufacturer's guidelines, the map of the installation, operating manuals and technical instructions, specifications, and the Qualification plan. The operator describes the different parts of the robot and its functions and details the different steps of a complete work cycle for the robot.
The operating procedure of IQ must include the following controls: (1) Site: Compliance of the laboratory with GLP, fire safety, protection against electrical power variations (Uninterruptible Power Supply (UPS)), air conditioning requirements, stability of the robot, and conformity of the connections; and (2) Robot: Were all parts assembled as described in the manufacturer's instructions? Is the installed equipment in accordance with the technical documents provided by the manufacturer? Has a list of the embedded safety systems been established (start, pause, emergency stop, various alarms and dialog boxes), and is access available to the main parts of the robot? If the robot performs measurements, the calibration of the metrological parts can be controlled.
To perform IQ. After the equipment and location have been completely identified, the operators check the equipment visually, and compare what they see with the reference documents (specifications and regulations). They interview the different users and the responsible person, and they check the level of their knowledge resulting from the manufacturer's training.
All data is reported on the IQ record, and compared to the established criteria. Qualification operators may write comments or improvement proposals. In the case of new equipment, a technical report of receipt, startup, and maintenance of the robotic equipment should be written by the engineering team, the manufacturer, and the users. This “home” user manual should detail starting instructions, how to replace used parts, and a maintenance schedule of key parts of the robot (e.g., electronics, pneumatics, and mechanics).
Validation. If a critical problem is noted, the Qualification Committee must require that corrective action be implemented and verified before validation. If everything is correct, the IQ is validated. If slight defects are detected, they can be noted and proposals for corrections can be made. The committee may validate the IQ with some reservations. Validation of IQ allows the initiation of OQ.
Operational Qualification (OQ)
OQ does not require an operator with specific know-how other than an understanding of the IQ report and documents. Referencing the different steps outlined for a complete work cycle, the operator can determine how to test the equipment while it is operating under typical circumstances, and to detect the critical points of the cycle that will be used to test the reactivity of the robot to an abnormal event. These tests will be written in the operating procedure of the OQ. The OQ record sheet will be designed to receive the data and the conclusions of the committee.
Testing the equipment during normal use reveals if the various tasks described in the user's specifications are being performed by the robot properly, corresponding to the operator request. If the instrument performs a measurement (e.g., delivers a given amount of liquid to a tube), the operators must perform the assays to collect adequate relevant data. If the robot is integrated with other analytical or transport systems, compatibility must be checked.
The tolerance to variations in the manufacture of consumables should be assessed, if applicable. If the specifications do not recommend specific brands for consumables (e.g., microplates), tests should be performed with material from different sources to ensure compatibility and reproducibility of performance.
Behavior of the robot, in the event of abnormal occurrences, also must be tested. For example, are the safety systems efficient (emergency stop, pause, etc.)? Do the robot's sensors (cf., manufacturer's specifications) detect operator errors (e.g., no bar code, no tube, etc.)? Is the robot able to detect these defects? Do its alarms work? Are the messages given by the user interface clear and informative? If there is a failure of only one part of the robotic equipment, do the other parts function properly?
Performing the OQ. The purpose is to measure performance during instrument operation, without any associated devices, samples, or reagents. If the robotic equipment functions properly (as defined by the specifications), its successful operation should be verified. These operational tests should be performed on the installed and connected equipment in normal, abnormal, and even critical circumstances. For each test, acceptance criteria must have been previously defined by the Qualification Committee. The operators monitor the robot's reactions to those situations detailed in the operating procedure to assess compliance with expected results. The results of some tests may suggest required adjustments. Data are collected on the recording OQ sheet, and eventually proposals may be added.
Validation. If an important defect is found in the automatic operation, the Qualification Committee should require that corrective action be implemented and verified before validation. If everything is correct, the IQ can be validated. If slight defects are detected, they can be noted and proposals can be made for correcting them. The committee may validate the OQ with some reservations. The validation of the OQ allows the start of the PQ.
Performance Qualification (PQ)
This step must be performed by the end-users of the robotic equipment. Requirements include the specifications, the local user manual written at the end of the IQ, and the qualification plan, where the work cycle is described. The goal of the operating procedure of the PQ is to evaluate the consistency of robotic equipment performance over a long period of use. Operators study its ability to perform as expected after completion of many work cycles with other devices, samples, or reagents. These tests should simulate conditions that will be encountered during actual use, in the range allowed, including upper and lower limits.
Data should be analyzed to determine the standard deviation of the replicates done by the robot (i.e., how reproducible is the performance of the robot, and what is the normal range of variation for the throughput). Furthermore, data should be analyzed to identify any variation due to controllable causes such as temperature, humidity, vibrations, light, and variations in electrical supply. These results may be compared to those obtained when a human performs the same task. Data will be recorded on the PQ sheet, and compared to the previously defined criteria. Comments or proposals may be added.
Validation. If an important defect is identified during performance, the Qualification Committee must require that corrective action be implemented and verified before validation. If everything is correct, the PQ can be validated. If slight defects are detected, as controllable causes of variations, they can be noted and proposals can be made for correcting them. The committee may validate the PQ with some reservations.
Final Decision of the Qualification Committee
The committee meets to ensure that all the points listed in the Qualification Plan were tested, and that no critical defects or errors were detected in the design, operation or performance of the robotic equipment. The committee may share some recommendations and proposals for improvement. The committee discusses the global results of the Qualification and makes a decision to validate the Qualification of the robotic equipment if all the steps (IQ, OQ, PQ) were validated without major changes.
Change control. Some modifications may be recommended. In this case, they should be documented, justified, and accepted. A risk analysis should be performed to assess the impact of these changes on the operation of the robot. In case of new equipment, a logbook should be created and attached to the equipment. The logbook should include information such as description, identification number, dated events, operators, etc.
Conclusion
Qualification is a common activity in manufacturing drugs and medical devices. In this paper, we transferred this activity to the robotic equipment of a laboratory where the scientific culture, based on the production of assays, is different. Scientists are used to evaluating analytical instruments, but not robotic equipment. Increased use without qualification increases the risk of assay result degradation from a lack of process control. We think the application of these Qualification concepts will help in standardizing the acceptance of robotic equipment, facilitate operation and performance evaluation, and improve traceability with quality assurance documentation.