PQRI Case Study (2): Functional Equivalence for Equipment Replacements

Pharmaceutical manufacturers have an obligation to ensure that their manufacturing equipment is properly designed, installed, tested, operated, and maintained throughout their service lifetimes. During these service lifetimes, manufacturing equipment will likely require both preventive and corrective maintenance activities that may involve the replacement of parts within the systems. Parts replacements must be performed under the appropriate change controls to ensure that manufacturing equipment remains in a validated state with respect to installation, operation, and performance. Change-control considerations are greatly facilitated when replacement parts are exactly identical to the original parts. However, it is not uncommon for pharmaceutical manufacturers to resort to procuring and installing replacement parts that are not identical to the original parts due to changes affected by parts suppliers (e.g., product redesigns, discontinuations). In these instances, a risk-management approach may be used to systematically assess whether replacement parts are functionally equivalent (i.e., like-for-like) with original parts to ensure proper change control while also preventing unnecessary revalidation activities.

This case study on functional equivalence for equipment replacements is the second of eight in a series put together by the Product Quality Research Institute Manufacturing Technical Committee (PQRI–MTC) risk-management working group. The series is meant to advance the understanding and application of the International Conference on Harmonization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-management assessments used by the bio/pharmceutical industry. The introductory article explaining the history and structure of the series, as well as the first case study, on defining design space, appeared in the July 2011 issue of Pharmaceutical Technology (1).

In this case study, a risk-management approach was taken by the firm to identify the following:

• Risks associated with equipment-parts changes that might adversely impact the validated state of manufacturing equipment

• Risks associated with the process of determining whether original and replacement parts are functionally equivalent

• Proper roles and responsibilities of the functional areas involved in the process of determining whether original and replacement parts are functionally equivalent.

The outputs of the risk-management approach used by the firm included a generic, robust, and repeatable process for performing functional-equivalence assessments as well as defining organizational roles and responsibilities supporting the process.

Risk question and risk-assessment method

The risk question developed for the subject case study was: What process and associated functional area roles and responsibilities are required in order to assess whether replacement parts are functionally equivalent with original parts in order to ensure proper manufacturing-equipment change control while also preventing unnecessary revalidation activities?

The firm elected to craft one risk assessment for the overall (generic) functional-equivalence assessment process to achieve two objectives:

• Identify potential gaps, inconsistencies, and redundancies within the process that had historically been used for replacement-parts functional equivalence determinations

• Identify new or improved activities that would lead to robust, efficient, and consistent functional-equivalence assessments moving forward.

To support selection of a risk-assessment method, the team examined the above risk question and identified the core activities supporting the historical functional-equivalence assessment process. Core activities examined included the equipment change-control process and the maintenance-systems inventory process-control flow. The team noted the following observations:

• The functional-equivalence assessment process was historically dependent upon human judgment, expertise, and experience

• Process risks (e.g., potential breakdowns of the process) were qualitative in nature and difficult to quantify with specificity.

Given these observations, the risk-assessment team selected Fault Tree Analysis (FTA) as its risk-assessment method because it is well suited for analysis of qualitative fault conditions that may be related to human performance factors.

Risk identification, analysis, and evaluation

The risk-assessment process began with a review and analysis of the change control system to determine how equipment parts replacements could potentially cause an unwanted or undetected change to the equipment's validated state. The analysis was organized into the fault-tree structure (see Figure 1). This fault tree illustrates the potential means by which equipment changes, such as parts replacements, could pose risk to the validated state of the equipment. The team concluded that many of the potential fault pathways were already being appropriately mitigated by robust quality systems (e.g., training, validation, and change control) that were performing as intended and that were being routinely audited. However, significant gaps and improvement opportunities were noted around the process used for the functional-equivalence assessments (see Figure 1, yellow pathway).

Figure 1: Fault-tree analysis (FTA) of equipment changes and associated validation impact. (ALL FIGURES ARE COURTESY OF THE AUTHORS)

To further explore the risks associated with the functional-equivalence assessment process for equipment replacement parts, the risk-assessment team continued development of the fault tree as shown in Figure 2. The team focused on two key areas of risk: functional-equivalence assessments performed by parts vendors, and functional-equivalence assessments performed internally by the firm's functional areas.

Figure 2: Fault-tree analysis (FTA) of functional equivalent assessments.

The detailed FTA executed by the risk-assessment team revealed two areas of significant risk where improvement was required:

• The Initiator (i.e., petitioner and preliminary data collector) for functional-equivalence evaluations should be a subject matter expert (SME) who is appropriately trained and qualified to craft accurate initial assessments (see Figure 2, green triangles).

• Specific roles and responsibilities for each functional area participating in functional-equivalence assessments should be clearly defined (see Figure 2, beige triangles).

Risk control

For each of the two areas of significant risk identified in the FTAs and summarized above, associated risk-control plans were established, as follows:

Training curricula were created to define the training and qualification criteria for personnel initiating functional-equivalence assessments. These controls were designed to ensure that Initiators would be able to identify, compile, and/or generate the data and rationale required to support thorough and accurate functional-equivalence assessments.

Roles and responsibilities for each functional area participating in functional-equivalence assessments were delineated in the form of executable checklists designed to ensure that every functional-equivalence assessment will be performed in a thorough and reproducible fashion. Each organization identified in Figure 2 (Engineering, Technical Services, Quality Assurance, and Regulatory) created a checklist tailored to their specific roles and responsibilities that the team had collectively defined.

This approach minimized both gaps and redundancies in the assessment efforts while also providing a common assessment record format to facilitate overall review of the assessment package. Each functional area checklist details unique areas of consideration for the assessment and provides spaces for the assessment conclusions and the signatures of the assessor(s). An example checklist from the Engineering functional area is shown in Table I.

Table I: Checklist template for determining engineering functional equivalence.

Risk documentation and communication

The outputs of this risk-management effort comprise the documented justification for controlled revisions to:

• Training and qualification curricula for personnel initiating change controls where functional-equivalence will be assessed

• Equipment change control standard operating procedures that direct the functional-equivalence assessment process for parts replacements

• Maintenance-systems inventory process-control flow.

Training is required to be performed on these updated documents and training records are periodically audited for compliance.

Risk review

As part of the firm's standard practice for the ongoing maintenance of quality systems, routine audits and document reviews are performed throughout each of the quality systems impacted by this risk assessment (i.e., training, change control, and equipment maintenance). Adverse findings or trends identified during these reviews would provide indication whether the risk assessment needs to be revised.

Ted Frank is with Merck & Co; Stephen Brooks, Kristin Murray,* and Steve Reich are with Pfizer; Ed Sanchez is with Johnson & Johnson; Brian Hasselbalch is with the FDA Center for Drug Evaluation and Research; Kwame Obeng is with Bristol Myers Squibb; and Richard Creekmore is with AstraZeneca.

Risk trainers. NOTE: In assembling this collection of case studies, the authors recognized the benefit of providing industry with additional background on core risk methodologies. Training tools for the application of risk ranking and filtering, FMEA, FTA, and HAZOP are available online with the web version of this article at PharmTech.com/PQRIstudies. These tools are meant to facilitate greater familiarity with the risk methodology used in each corresponding case study.

*To whom all correspondence should be addressed, at kristin.murray@pfizer.com.

Reference

1. T. Frank et al., Pharm. Technol. 35 (7), pp. 72–79.