Jennifer Medlar is a consultant for Advanced Biomedical Consulting, LLC

Jennifer Medlar 

addressed the value of incorporating prerequisites into process validation using entering the Boston Marathon as an analogy. For Part 2, the focus will shift to equipment qualification and the benefits of incorporating prerequisites into qualification protocols. As was discussed in Part 1, entering the Boston Marathon involves a lot more than putting on a pair of running shoes and showing up saying "I'm ready to run." There are predetermined qualifying standards that every applicant must meet based on his or her age, sex, and disability status. In addition to having standards that must be met, the Boston Marathon distinguishes itself by including a verification of an applicant's ability to meet their qualifying standard. For the marathon, setting and verifying qualifying standards is important to evaluate the preparedness of the applicants for a safe and successful race, which helps to ensure that the event will run smoothly. 

The philosophy that is used to ensure a safe and smooth race also applies to a pharmaceutical or biopharmaceutical company preparing for an equipment qualification. Qualifying standards, or prerequisites, can be used to evaluate the readiness of a specific piece of equipment for qualification. Verifying prerequisites prior to the qualification ensures a safe and smooth qualification process. For pharmaceutical or biopharmaceutical companies, this translates into less time and money spent on avoidable delays. Because the requirements for a piece of equipment can vary widely from company to company, and even between pieces of the same type of equipment, it is important to devise a universal set of prerequisites that will address all the potential trouble areas. The following sections describe how prerequisites fit into an equipment qualification, discuss what should be verified during prerequisite verifications in an equipment qualification, and outline a universal set of prerequisites as well as address in detail the pertinent points for each category. 

How prerequisites fit in an equipment qualification protocol

The process of setting up equipment in a pharmaceutical or biopharmaceutical facility includes ensuring that the equipment will safely and consistently work as intended. To do this, it is necessary to verify that (1) the equipment is installed according to the manufacturer's instructions, (2) the equipment is operated properly and consistently, and (3) the equipment performs within the requirements determined by the facility. To cover all of the necessary criteria, equipment qualifications are typically organized by separating the protocol into three sections, installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). 

Since the IQ, OQ, and PQ are performed separately, each should have its own set of prerequisite verifications. A prerequisite in an equipment qualification is a documented verification that is intended to demonstrate that everything is in order prior to initiating the execution of the qualification section. Because the equipment requirements at each of the qualification stages are different, the prerequisite requirements at each of the qualification stages should be different as well. To explain this concept, picture three different race applicants as the three sections of the qualification. If each applicant is in a different age/sex category, then the qualifying standard that each would need to meet would vary depending upon which age/sex category they belonged to. Because the race's start times are varied according to the age/sex category, the qualifying standards for a 60-yearold woman do not require the same speed as the qualifying standard for a 20-year-old man. Likewise, it doesn't make sense for a piece of equipment to be required to be at the same level of preparedness for the PQ as it is for the IQ. 

What should be verified during prerequisite testing?

The general goal for prerequisite testing is to ensure that any items that commonly cause execution to be delayed or repeated are in order prior to starting the qualification. Because of the variations between equipment and the differences between how facilities operate, using the same prerequisite verifications may not always be the best approach. In order for prerequisites to significantly help streamline the qualification process, they have to be tailored to fit the specifics of both the equipment and the facility. Because it is easy to overlook potentially important prerequisites, it is often helpful to separate them into categories and address them one at a time. With a good understanding of the categories, the process of tailoring the verifications to suit a specific piece of equipment at a specific facility will be much smoother. Although it is nearly impossible to cover all possible prerequisite verifications, some of the most common prerequisite categories are presented and explained in the following paragraphs.  

Procedure verification includes any procedure that is required for operation or maintenance of the equipment as well as any sampling or testing procedures required to obtain and analyze the protocol samples. For each of these procedures, the status of the procedure, the title and the document number are typical items that are verified. The specifications vary depending on the section of the protocol the verification is being written for (i.e., IQ, OQ, or PQ). For example, during the IQ, it might be acceptable for the procedures to be in draft form, but by the time the PQ section is going to be executed, it is necessary for the procedures to be approved documents. 

An example of how performing a procedure verification could make a costly difference to a company is evident in the events during an HVAC qualification at a sterile drug facility. Additional personnel were brought in to perform the time-consuming task of collecting microbial samples for the qualification and when the samples arrived at the laboratory, they realized that the testing procedure for the samples was still in development. None of the samples taken were usable, and the entire collection process had to be repeated once the testing procedure was approved. The expense of the wasted man-hours and supplies and the delay to the qualification could have easily been avoided by implementing a procedure-verification prerequisite. 

The importance of verifying the training of operators and test personnel is a universal prerequisite throughout the various types of validations and qualifications. For equipment qualification, verifying training is like making sure a runner has the experience they need to successfully finish the marathon. With equipment, it's important to verify that the personnel who will be operating the equipment, in addition to the personnel executing the protocol, have the training required to successfully perform the necessary tasks according to the currently acceptable method. 

Picture an operator executing a performance qualification of an autoclave if that person doesn't know how to control the equipment—the importance of verifying operator training becomes clear. What may not seem as clear is why it is important to verify the training of the qualification test personnel. A biopharmaceutical manufacturer learned the importance of test personnel training during the qualification of a freezer. The freezer qualification included a 72-hour temperature mapping, which required monitoring and recording the temperature in different quadrants of the freezer at specified time intervals for a 72-hour period. During an audit, it was discovered that the data was not collected for the full 72 hours. An investigation was conducted and the error was determined to be due to the fact that the test personnel who set up the mapping were trained on an earlier revision of the protocol and didn't realize the time interval had been changed. When compared to the time spent on tasks that have to be repeated due to avoidable mistakes, spending the time to perform prerequisite verifications becomes time well spent. 

Though not actually a part of the equipment, utilities are essential to their operation since the equipment cannot run without them (e.g., electricity, compressed air, gas, water, etc.). Utilities that should be verified include any utility that is required to execute the protocol and has the possibility of not being available or not being available at the required level. 

An example of the benefit of performing utility verifications was seen during the qualification of a packaging line of a drug manufacturer. For the packaging line to operate as required, the air compressor needed to maintain a specific pressure. During one of the qualification runs, failures were observed in both the desiccant and the cotton insertion stations. Investigation led to the discovery that the capacity of the compressed air system was not adequate to operate all of the stations of the line simultaneously. Although the problem was identified, the time needed to correct the problem and re-run the test was costly and could have been avoided had the capacity of the compressed air system been verified using the utility qualification of the compressed air system prior to starting the testing. 

Test-instrument verification is a simple way to eliminate costly delays and misunderstandings. The items that should be verified in this section include any instrument or piece of equipment that is required during the execution of the protocol. Some examples of instruments or equipment that are typically verified in a test-instrument verification include voltage meters, particle counters, and scales. Because testing and sampling instruments and equipment are often used by many people and are often required to be calibrated, typical items that are good to verify include the availability and/or location of the instrument and equipment and the calibration status for the expected duration of the qualification execution. Just imagine the headache if, when it came time to start a qualification, you realize that your scale is out of calibration or the particle counter you ordered a month ago never arrived. Making arrangements for calibrations or tracking down an order often involves time-consuming activities (i.e., getting approvals, contacting customer service representatives, and tedious paperwork). These tasks are time consuming in general so why add to the burden by waiting to do them until it's too late to resolve the issue without holding up the qualification? Performing prerequisites allows you to address the items before they start causing delays. 

An incident during a qualification of an HPLC at a contract-testing laboratory shows how test instrument verification can make a difference in a timeline. Arrangements were made for the manufacturer of the HPLC to come onsite to perform the qualification. Due to the schedule limitations of the HPLC manufacturer, the first available time the qualification could be completed was two weeks away. When the technician arrived, he quickly discovered that all of the scales in the laboratory that were suitable for his requirements were due for calibration. The calibrations were scheduled and performed but the delay left the technician with insufficient time to complete the qualification before his next assignment. A second visit had to be scheduled with the technician for the qualification to be completed. The hassle of additional scheduling and the delays incurred could have been eliminated had the contract-testing laboratory performed a test-instrument verification prior to the arrival of the technician. 

The purpose of equipment-status verification is to ensure that the equipment being qualified is installed and ready for qualification. Like with procedure verification, different requirements, or specifications, are typically desired for different sections of the qualification. For example, while it might be necessary for the equipment to be set up, calibrated and ready to run during a PQ, for the IQ, it's only necessary for the equipment to be installed. Another possible inclusion in equipment status verification is the availability of the equipment for use. Unlike process validation, which cannot be started until a process has been developed, equipment qualification protocols are sometimes written before the equipment is even received. As a result, a protocol can be ready for execution long before the equipment has arrived and been installed. 

Recently, the qualification of a building management system at a biopharmaceutical facility was scheduled to begin and consultants were hired to execute the protocol. When the consultants arrived at the facility to begin the qualification, they found out that an ancillary electrical panel had not been installed because it was on back order. If the equipment status had been verified prior to the qualification, the cost and time of the additional onsite visit by the consultants in order to reassemble the team could have been avoided. 

Now that some of the ways prerequisites can be beneficial during the execution of an equipment qualification have been identified, it should be mentioned that prerequisites offer benefits to other areas as well. Documenting the prerequisites creates a system that proactively assists in tracking future problem areas rather than tracking only problems that have already occurred. When combined with the existing methods of identifying trouble areas of the quality system, prerequisites provide a little extra help in meeting the overall goal of preventing problems rather than just reacting to them. 

Last, but certainly not least, in the list of benefits to adding prerequisites to a validation/qualification program, is how they will help before an audit. By performing these simultaneous "spot checks" or verifications of the quality system, it will be possible to generate trends of where problems tend to arise in the quality system. The additional method of locating these holes and inconsistencies will help a company know where they need to focus their efforts prior to an audit instead of after an auditor has found the issues. 

Just as a person entering the Boston Marathon can not just arrive and say that they are ready to run without providing the proof that they have the necessary components and training and are up to race standards, an equipment qualification should not be started without having some proof that the equipment is ready for qualification. By incorporating prerequisites into an equipment qualification, you are creating a system for ensuring that the equipment is ready to run consistently and reliably and can pass the testing outlined in the protocol with fewer failures, investigations and retesting. 

Of the many benefits to using prerequisites, the most sought after is the potential to save time and money. Having a clear understanding of the benefits and being able to apply them to your facility can ensure smooth, cost-effective qualification efforts. 

Jennifer Medlar is a consultant and Nancy Cafmeyer* is a project manager for Advanced Biomedical Consulting, LLC, PO Box 76405, St. Petersburg, FL 33734, tel. 888.614.7177, fax 727.897.9522, 

ncafmeyer@advancedbiomedicalconsulting.com

*To whom all correspondence should be addressed. 

1. N. Cafmeyer and J.M. Lewis, "Running a Marathon in Flip-Flops – Part 1: The Value of Incorporating Prerequisites into Process Validation", 

pharmtech.findpharma.com/pharmtech/manufacturing/home/article/detail/505375

2. FDA, "Guideline on General Principles of Process Validation," (Rockville, MD, May 1987). http://

3. "Current Good Manufacturing Practice for Finished Pharmaceuticals," Code of Federal Regulations, Title 21, Food and Drugs (General Services Administration, Washington, DC, Rev. April 2006) Part 211. http://

www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211

Articles

Equipment qualification is a critical step in ensuring that a product or service is provided accurately and consistently with regards to manufacturing and testing. The time-saving attribute of adding prerequisites to a qualification program, along with the benefit of gaining the ability to track and trend problem areas, make the addition both worthwhile and cost-effective.