PQRI Case Study (4): Process Deviation and Empty Product Capsules

This risk-management case study focuses on assessing empty capsules.

The following case study on an empty-capsule product deviation is the fourth 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/pharmaceutical 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). The second study addressed functional equivalence for equipment replacement, and the third addressed facility biocontainment and inactivation; they appeared in the August and September 2011 issues, respectively (2, 3).

The deviation

A drug product site produces pain-free capsules, which are indicated as an anti-epileptic and for treatment of neuropathic pain. Multiple customer complaints of empty capsules were received. Lot ABC was fully distributed in the United States and no product remains within company control. There is no evidence of tampering.

Batch record review indicated that during processing, a loose dosator was replaced on the encapsulation equipment. Following replacement—and prior to resuming encapsulation, acceptance testing of capsules produced required by standard operating procedure was performed and product met requirements.

Further investigation revealed that the loose dosator caused empty capsules to be produced. The encapsulation system used a vacuum system to remove empty capsules. This empty capsule removal system includes a reservoir for holding empty capsules rejected during the manufacturing process. As a result of the loose dosator, an atypically high number of reject empty/low fill capsules were produced during the encapsulation operation, causing the reservoir to be filled and eventually overflow. The reservoir was physically located over the acceptable capsule flow. Therefore, it was determined during the investigation that, if the empty capsule chamber overflowed, there was potential for rejected capsules to fall back into the acceptable capsule exit chute and to be reintroduced to the lot.

Sealed bottles were obtained from remaining inventory of the lot. Of 30,661 capsules examined, 151 empty and 5 low-fill weight capsules were found. During the inventory evaluation, one to five empty capsules were found in 46% of the bottles evaluated.

In the this case study, the manufacturer decides to use quality risk management to evaluate the potential impact of the deviation.

Risk question and risk-assessment method

The risk question developed for the subject case study is: Do a small number of potential low fill or empty capsules in a single batch of pain-free capsules pose an unacceptable risk to patients, and secondarily, to the company?

In this case study, the risk factors are more qualitative than quantitative. Failure-mode effects analysis (FMEA) is specifically designed to systematically study processes for possible failure modes and then to develop actions to mitigate these failure modes. An element that requires consideration in this case study is detectability of the defect. Is it possible for the pharmacist or the patient to readily detect empty capsules? The FMEA technique is an optimal tool for this application as the standard methodology includes all three risk components (i.e., probability, severity, and detectability). Therefore, the risk methodology selected for the subject case study is: FMEA.

Risk identification, analysis, and evaluation

The FMEA process used intends to identify potential risks that could result from empty capsules in the market and the possible consequences of each risk. It is understood that sufficient data may not always be available to reach conclusions, and identification of risks should be based on best available data, scientific knowledge, and historical experience. The rationale used to identify risks should be documented.

Examples of potential risks include the following: patients may receive empty capsules, patients may not have availability of medically necessary product, the company could receive an audit observation from an internal auditor or external regulatory agency, and so forth.Numerical ratings for the FEMA analysis are based on the following criteria:

  • Severity of the failure
  • Frequency of the failure
  • Ability to detect the parameter.


Table I: Failure-mode effects analysis risk-score ranking.
A numerical ranking of 1–3 is applied to each evaluated hazard, as demonstrated in the example FMEA risk-score ranking table using a three-point ranking scale (see Table I).

In the FMEA analysis executed for this case study, the firm determined that, if there was potential for greater than a moderate risk-evaluation score, appropriate risk mitigating actions would be required to lower the risk to an acceptable level. Therefore, If the score for an evaluated hazard exceeds 9, corrective measures to the reduce risk of failure will be taken. If after attempting risk mitigation, the score could not be lowered below 9, the resulting risk would not be accepted. For those items with a score below the defined threshold, risks will be accepted. Conclusions are documented.


Table II: Sample worksheet for calculating a risk-evaluation score.
An example worksheet for calculating the Risk Evaluation Score for this analysis is presented in Table II.