Jonathan M. Lewis

The Boston Marathon is one of the world's most prestigious racing events. It has distinguished itself from other races in many ways, one of which is the method of entry. Not only must each applicant meet a defined set of prerequisites in order to qualify as an entrant and compete in the race, but each entrant's qualifications are subject to verification prior to the race date. This qualification process coupled with the runner's own preparations for the race help to ensure that only experienced, capable, and well-trained athletes are competing on the streets of Boston on race day. 

Just as the race entrant must meet a well defined set of race prerequisites, train adequately, and have the right equipment ready prior to the race, so too must a pharmaceutical or biopharmaceutical company meet a predefined set of prerequisites before embarking on the course towards process validation. This Part I article will focus on the value of incorporating prerequisites into a process validation protocol. 

The quality systems approach to process validation

Developing a drug product is a lengthy process. Prior to commercial distribution, the US Food and Drug Administration requires that the manufacturing process for the product be validated. Process validation is defined as the accumulation of documented evidence that demonstrates with a high degree of assurance that a process can consistently meet its predetermined specifications and quality attributes. Not only does process validation satisfy regulatory requirements, it is good business practice to have the confidence that a manufacturing process is repeatable and will yield a quality product on a consistent basis.  

Most companies understand the requirement for process validation. However, the way companies go about process validation oftentimes lacks the business-related benefits that may result from truly challenging the entire process. 

Simply repeating the normal manufacturing process a series of times, collecting routine samples, and analyzing the samples for in-process and finished-product specifications is not sufficient to demonstrate that a process is validated. Performing validation in this manner only shows that at that particular date and time the technical aspects of the manufacturing process may or may not have been successful. In order to demonstrate repeatability, ensure a robust process after the process validation report is approved, and hence obtain a business-related benefit from the process validation activity, the quality systems contributing to the technical aspects of the process must be in a state of control. If these manufacturing support systems are not in control and sufficiently thorough, these so-called quality systems cannot be counted on to ensure the same process results. This is where the value of incorporating prerequisites comes into play.  

Just as the marathon applicant must prove he or she meets the technical requirements to compete at the high standards the Boston Marathon requires, if accepted, the runner still makes sure to have eaten the right foods prior to the race and that his or her gear is in top condition and ready to go prior to starting the race. The same situation applies to the pharmaceutical or biopharmaceutical manufacturer during process validation. The company should prove that they have addressed and controlled all supporting process-related variables prior to starting the process validation production runs. 

What are prerequsities? A prerequisite is defined within the context of this article as a documented verification in a process validation protocol, which, when met satisfactorily, is intended to demonstrate readiness for execution of a manufacturing run. A process that is not performed the same way every time cannot be considered validated. This is the core concept behind using prerequisite verifications during process validation. Any area that could lead to variation in a manufacturing process or in the analysis of the manufacturing process should be included in the prerequisite verifications section of the process validation protocol. The following is a brief description of the most common areas that should be verified, as these areas often lead to variation in the process. 

Using the example of the Boston Marathon runner, if the map has changed prior to the race and without notice, the runner may very well need a change of strategy and may even get to the intended destination without a considerable loss in valuable race time. The MBR is a road map for the manufacturing process. In this prerequisite, the effective version of the master batch record (MBR) is verified as the latest, approved version of the document and agrees with the version listed in the approved protocol. 

If the effective version generated during protocol generation is the same as what is being used on the production floor, then it is safe to initiate the process validation production runs. If not, there is a high probability that the protocol may be inaccurate (possibly resulting in numerous "failures") or that the process itself is not ready for process validation or even worse, commercial production.  

For example, during a recent process validation activity at a liquid dosage pharmaceutical plant, modifications were made to the MBR less than a day before the already approved protocol was to be executed. Certain processes were modified without the knowledge and consent of the validation team. As a result, there were numerous deviations (i.e., investigations) that needed to be documented and addressed during the execution of the process validation production runs. This was due to the approved protocol not stating the correct directions to follow, which resulted in a big waste of time and money-let alone questioning compliance (i.e., the ability of the quality system to catch issues prior to and during production). If the MBR status was verified as a prerequisite, this issue would have been caught prior to executing the runs. 

Operator and test personnel training verification.

 In manufacturing as well as in the analytical laboratory, many standard operating procedures (SOPs) and analytical test procedures are used. As the purpose of process validation is to provide assurance of the repeatability of a process, operators and analysts must be trained on all procedures that may affect the manufacturing and testing of the process. This prerequisite checks the training records of the operators and laboratory testing analysts to ensure that they have documented training on the procedures that they will be performing during the process validation activity. Again, not only is this a compliance risk, but it is also good business practice as failures due purely to untrained operator or analyst errors result in additional consecutive process validation production runs (i.e., avoidable wastes of time and money).  

For example, during a recent pre-approval inspection of a pharmaceutical manufacturer, an investigator was reviewing the executed process validation protocol for the product being assessed. The investigator asked to see the training records for two of the analysts who performed the release testing on the finished lot of product. When given those records, the company realized that the two analysts had not been trained on the test procedures. This situation called into question the validity of the test results and ended in the company repeating the costly and time consuming testing. This situation would have been easily avoided by verifying training prior to execution.  

Equipment and utility system qualification verification. 

Just as an individual marathon runner chooses a very specific pair of running shoes to compete in versus a pair of everyday flip flops, equipment and utility systems are two of the most critical areas affecting the outcome of a manufacturing process. It is important to verify that the commercial equipment and support utility systems have first been qualified and second have been qualified within the specified process ranges prior to executing the process validation manufacturing runs. 

Not only is the lack of equipment or utility system qualification a common gap discovered during inspections, and for which entire process validation efforts been disregarded, but many unforeseen commercial production issues may arise when these activities have not been completed prior to process validation production runs. This situation was clearly demonstrated when a coating process for a solid oral dosage pharmaceutical was developed and optimized at a specific spray rate using a process development pan coater. The pan coater used during the process validation runs, although similar in function to the process development pan coater, was not challenged during equipment qualification at a spray rate that bracketed the intended use. When the process went into validation, the difference in the spray nozzles caused the commercial pan coater to be unable to consistently obtain the specified MBR specifications for spray rate.  

In this case, the entire batch was lost because the problem was discovered after the coating process was already in progress. A prerequisite verification of equipment qualification would have avoided the loss of a potentially saleable batch as well as the requirement to run a new set of consecutive process validation batches. 

Manufacturing and inspection instrument calibration verification. 

Another important factor that should be assessed during prerequisites verification efforts (i.e., prior to manufacturing runs) is verifying and documenting that each instrument used in the manufacturing and testing process and that requires periodic calibration is within the current calibration interval and that each will remain within that interval throughout the process validation activity. For example, a validation engineer managed a shipping validation project for a biopharmaceutical product using numerous rented temperature and humidity monitors.  When the data was collected and reviewed, it was noted that several of the instruments had results just out of the specified ranges. Upon investigation, it was noted that numerous instruments used in the study went out of calibration during the process resulting in questionable results. All product shipped was then considered of questionable quality as was the study itself requiring a redo of the process and lost saleable product. 

Just as the manufacturing equipment and utilities needed to produce a product must be able to perform within predetermined criteria, the raw materials that go into the product must also meet their predetermined specifications. As dictated by the good manufacturing practices (GMP) regulations, a raw material must be tested and approved prior to use. The acceptance of the raw materials called for in a process validation should be verified prior to use. While this may seem to be a redundant task, spot-checking this aspect of the materials management quality system prior to a critical effort such as process validation again makes good business sense versus being a specific regulatory requirement.  

Consider the situation when a contract manufacturer received a purchase order to produce a liquid oral dosage pharmaceutical product for a new customer. Of course, this activity requires process validation for which the minimum of three consecutive batches for process validation was agreed to by both parties. The raw material lots were assigned for each of the raw materials to be used in the three process validation batches. As typically is the case with contract manufacturing, the time period for manufacturing each lot was dictated by the customer's order of the product. Due to an unanticipated lack in the customer's product sales, the third batch was manufactured more than a year after the first two validation batches were made. The shelf life of the active ingredient was only one year and it had therefore expired. However, no raw material status prerequisite check was performed prior to manufacture. Upon testing of the third lot, the quality control testing laboratory found the product samples to be subpotent.  

An extensive investigation was conducted which resulted in the batch failing and all three consecutive batches for process validation having to be redone at the manufacturer's cost. This situation could have been avoided with a simple verification of raw material status prior to manufacture of each process validation batch.  

Analytical test method status verification.

 This verification is one of the more controversial prerequisite verifications to incorporate into the process validation program due to the perception that the laboratory is seen as independent of the production process. Nonetheless, as stated previously, the results obtained by the laboratory for a specific process are a critical piece in the overall process of manufacturing and releasing a quality product as the laboratory produces results on which many of the validation conclusions rely. Therefore, it is of paramount importance to verify and document that all the test methods have been validated (nonpharmacopeial methods) or shown to be suitable (pharmacopeial methods).  

The purpose of performing this prerequisite verification is not to check the adequacy of the test method validation or suitability effort. Rather, it is a spot check to verify and document that method validation (if necessary) has been completed and closed out prior to moving forward with the costly and time consuming effort associated with process validation. As a recent example, a sterile pharmaceutical manufacturer undergoing a preapproval inspection was recently given a 483 observation when the agency investigator discovered that the finished product potency test for the drug product had not been validated prior to beginning the validation activity. The entire validation was called into question by the investigator and ultimately had to be repeated.   

Specified process parameters verification.

 If a product has been thoroughly developed, all of the critical manufacturing process parameters (i.e., processing ranges) that are specified in the MBR are based upon results obtained during the process development effort and verified during the confirmation run or technology transfer phase.  

However, many times one or more ranges specified in a MBR are not associated with any justification at all (i.e., where the range came from in the first place). While it may seem to be a worthy risk to simply run the process validation with specified yet unsubstantiated ranges (versus generating a development report retrospectively), it truly presents a significant risk. 

While never recommended, ranges that have not been challenged or assessed prior to process validation must be challenged during the process validation effort. This "dry run" approach during process validation has a significant cost factor if a "failure" occurs during execution of the runs. This is true even if the process is well-characterized and well-established. Without some sort of documentation supporting the range specified (e.g., a development report), a processing failure associated with a specified process parameter can only be assigned a defendable corrective and preventive action (CAPA) if it involves a thorough retrospective analysis of a statistically significant number of historical batches for which the specified process parameter data is obtainable. Of course, this would lead a savvy auditor to question the development of other parameters for other products as well. As you can see, this can be very costly on many fronts. The only way to avoid this situation prior to digging up the proverbial can of worms is to verify and document the origin of each specified process parameter present in the MBR prior to the execution of the process validation runs.    

The purpose of this final process validation prerequisite is to verify and document that the in-process and finished product quality attributes match those in product development reports or are the most currently approved specifications reported in the product regulatory submission.  

When a product has been approved in both the United States and countries outside the US this verification becomes even more important because product specifications for the same product can differ from country to country. For example, a solid dosage form manufacturer was undergoing a process (re)validation effort after making some process improvements. The product was approved for distribution in both the US and Canada. Prior to commencing the process validation runs, this prerequisite verification of the product quality attributes was conducted, at which time it was recognized that the impurity specification differed between the two countries for the same product. The Canadian specifications were tighter than the US specifications. However, only the U.S. values were listed in the validation protocol. If this prerequisite had not been verified prior to performing the production runs, the process validation effort may have resulted in problems meeting the more strict Canadian requirements.  

In order to compete in the Boston Marathon, runners must demonstrate to the race organizers that they are ready to compete, so the unqualified entrants are weeded out of this prestigious event. In addition, the qualified runners check their own gear before the event as they want to maximize their chances to succeed.  

The same concept applies to process validation. By using the process validation prerequisite approach, many of the potential pitfalls and hazards along the process validation route can be avoided before the costly production runs and laboratory testing. 

Not only does this approach make good economical sense, but using this approach can also demonstrate, during government and customer audits, that quality is built into the process, and the quality systems approach to regulated product manufacturing is alive and well in your facility.   

, a consultant at Advanced Biomedical Consulting (ABC), LLC, with over 28 years industry experience has consulted at numerous pharmaceutical, nutritional supplement, and medical device manufacturers and prior to working for ABC has held both hand-on and management positions at companies such as King Pharmaceutical, Geopharma, and Daniels Pharmaceuticals. 

, a principal at Advanced Biomedical Consulting (ABC), LLC, has consulted at over 50 different biopharmaceutical, pharmaceutical, and medical device manufacturers and prior to starting ABC has held both hand-on and management positions at companies such as Cardinal Health, KMI, and PAREXEL International. 

Advanced Biomedical Consulting (ABC), LLC, PO Box 76405, St. Petersburg, FL 33734, tel. 888.671.4292, fax 727.897.9522, 

1. I.R. Gerry and R.A. Nash, Eds. Pharmaceutical Process Validation, (Marcel Decker, Inc., New York, 2nd ed., 1993), pp. xiii-24. 

2. Code of Federal Regulations, Title 21, Food and Drugs, Part 211, (FDA, Department of Health and Human Services, Rockville, MD, April 1, 2006).  

3.  Guideline on General Principles of Process Validation, (FDA, Rockville, MD, May 1987). 

4.  Compliance Policy Guide Manual, Chapter 4, Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval, Document 7132c.08, (FDA, Rockville, MD, 2006). 

5.  Guidance for Industry, Q7A, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, (FDA, Rockville, MD, August 2001). 

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Articles

Undertaking process validation involves a major commitment in terms of personnel, resources, time, and money. Performing prerequisite verifications can reduce the risk of making costly mistakes. This Part 1 article explains the value of performing prerequisite verifications and presents case-study examples and real-world solutions to avoid costly process validation failures.