Running a Marathon in Flip-Flops – Part 1: The Value of Incorporating Prerequisites into Process Validation3

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.
Raw material status verification. 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.
Product quality attributes verification.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.
ConclusionIn 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.
Nancy Cafmeyer, 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.
Jonathan M. Lewis, 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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