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

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


Pharmaceutical Technology


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.


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