Aarti Drugs USFDA 483 Flags Unique Challenges of Generic Pharma Companies

Release of Rework batches / OOS batches for other markets.

The FDA 483 observes that out-of-specification (OOS) batches were reworked (not reprocessed). The reworked batches which were failing USP specifications for unknown impurity were shipped to local and export markets after testing against alternate specifications (Observation 1A). The reworked batches were shipped without stability data (Observation 5E).

• While there is technically no restriction on releasing a batch to another market if it meets the specifications for that market, at the least the following aspects should be taken care of:
• The OOS shall not be for a parameter which present risk to patients. For example, an OOS for an unknown impurity, a new impurity or a genotoxic impurity, could have safety concerns for patients. Where as an OOS is for a parameter such as assay, dissolution, or inorganic impurities typically do not pose the same risk to patients
• The root cause for the OOS must be identified, with corrective and preventive actions (CAPA) implemented to prevent recurrence. Also, it should be evaluated whether the root cause exposes other unknown risks. For instance, does an OOS for assay indicate impurities that were not detected by regular methods, or could factors like higher water content or acidity lead to future OOS issues?
• The root cause should not point to systemic issues questioning the process capability. One cannot have an approach like if a batch complies with a stringent regulated market specification or USP specification it will be released for US, otherwise it will be released for local market or less regulated markets
• When a batch is reprocessed / reworked stability should be evaluated. In the case of a reprocessed batch, the batch may be loaded for stability and yet released. But in the case of a reworked batch sufficient stability data must be obtained and evaluated before releasing the batch

All these aspects must be carefully evaluated, documented, and justified to demonstrate that the Quality Management System (QMS) is in control of potential risks while taking the batch release decision.

Number of retests for invalidating an OOS.

An out of specification (OOS) batch was invalidated with a single retest after hypothesis testing in Phase 1B investigation with sample preparation as assignable cause.

• If the OOS result is due to an obvious error established during Phase 1A investigation (such as sample spillage, instrument malfunction, or breakdown etc.), a single retest after rectifying the error may be sufficient to invalidate the OOS result.
• When the error is not obvious and only probable root causes are hypothesized in Phase 1B investigation (e.g., potential sample preparation issues), retesting should carry a higher statistical significance than the initial test for invalidating the same. Two scenarios should be considered for retesting:

1. 1. The test is repeated after removing all identified potential errors (e.g., air bubbles, sample preparation issues). This can be performed by the same analyst or a second analyst. If the analysis result complies, perform confirmatory testing by the other analyst and conclude the OOS.
   2. Hypothesis test simulating induced errors (for example, moisture ingress, acidity to verify observation of extra peaks). After confirming the hypothesis, there shall be a retest by first analyst (or a second analyst). If this result complies perform confirmatory testing by the other analyst and conclude

• The hypothesis testing and retesting should be documented in a retest plan prior to taking up the analysis and retests shall not extend beyond the predefined plan.
• Also refer to the MHRA guidance on out-of-specification investigations.

Power failure / UPS failure disrupting analysis and impact evaluation

A power failure due to an uninterruptible power supply (UPS) failure disrupted the start of an analysis sequence for Related Substances (RS) and Assay testing. Despite the UPS being connected to other critical systems in Quality Control (QC) and Production, such as stability chambers, incubators, Plant PLC, HMI, and SCADA systems, the incident report recorded no impact (Observation 1D).

The issue raises two concerns and both of which must be addressed in the investigation:

1. When a system failure disrupts an equipment, investigation and impact analysis should cover all other equipment connected to the affected system. If other incident evaluations logged for the failure, ensure to cross refer the same in the investigation. This is obvious requirement.
2. There is one more issue to be evaluated in cases like a power failure or UPS failure disrupting an HPLC (or other analysis) run. The investigation should evaluate whether any abnormal observations like unusual impurity peaks or other failures in the chromatograms run occurred during the analysis, and these findings should be thoroughly documented. If such issues are overlooked, they have the potential to escalate into data integrity concerns

Test methods not stability indicating / No degradations achieved in forced degradation studies

FDA 483 observed that test methods for drug product analysis are not stability indicating; In several forced degradation studies there was no degradation achieved, yet methods were concluded to be stability indicating. (Observation 3).

• The goal of a forced degradation study is not to demonstrate the stability of the molecule but to confirm that the method is capable of detecting impurities if degradation occurs. The test method should be sensitive enough to identify any degradation products that form under stress conditions
• Typically, samples are exposed to degradation conditions for 1-3 days, with some studies extending to 5-7 days to ensure that sufficient level of degradation is achieved, to be able to show that the method is detecting degradation peaks. But some drugs may exhibit high resilience to specific degradation conditions, remaining stable even after exposure to harsher conditions for 5-7 days.
• If degradation is not observed under specific conditions (e.g., acidic pH, oxidative stress), the forced degradation study report should document all efforts made to achieve degradation and provide a scientific rationale for the molecule’s resistance. For instance, the chemistry of the functional groups and their stabilization effects, supported by literature data, can explain why degradation does not occur. The discussion should demonstrate that under these conditions, degradation is not a risk, and thus there is no risk of the test method failing to identify degradants.
• Literature on metabolites and known degradation pathways of the drug can also provide reference points in assessing whether impurities might form under specific conditions, such as gastric pH, to further justify the robustness of the test method

Sample traceability and Chain of custody of sample between different labs within QC

The FDA 483 highlighted that after the receipt of samples in Quality Control (QC), the movement of these samples between different labs for various tests could not be traced (Observation 5C).

Issue of Chain of Custody of sample is picked by FDA in more than one audit (e.g. Jubilant 483 /Jan 2024). Different procedures may be worked out to avoid this issue

• If a lab distributes samples to different labs from a master sample, this distribution can be documented directly in the sample inward log.
• For each sample logged, a sample usage sheet may be opened which moves along with sample to different labs to record activity on the sample as well as the time it was returned to the sample storage area.
• After completion of analysis, the sample usage sheet can be archived along with analytical records, which shall be reviewed along with test reports before approving the sample results.

Unannounced Internal Audits

The FDA investigators observed that internal audits at the facility were ineffective as all Internal audits were preannounced, based on predefined checklists, and conducted by auditors who were not adequately qualified, except for general internal audit training (Observation 6).

• This is a very pertinent issue. If internal audits are effective, they should identify lapses before they are flagged during regulatory inspections and Companies can take CAPAs well in time. allowing companies to implement corrective and preventive actions (CAPAs) in a timely manner. However, it is often the case that the lapses found by FDA audits are not picked up in self-inspections.
• Typically, internal auditors are selected from departments other than the one being audited to ensure independence. However, this can result in auditors lacking the necessary expertise in the specific area they are auditing. Additionally, the surprise element is lost when audits are pre-scheduled due to auditors’ regular day jobs and familiarity between personnel
• Larger organizations with multiple manufacturing sites are addressing this issue by setting up Corporate Compliance & Audit teams with experts from various functional areas. These teams conduct unannounced audits to ensure a more objective and effective assessment.
• For smaller firms, this can be more challenging. One solution is to engage expert third-party auditors to perform unannounced inspections on a semi-annual or annual basis, providing a more impartial and thorough evaluation.

Training Effectiveness – Despite repeated trainings mistakes are repeated.

Another issue the FDA 483 pick up is the effectiveness of Training as a corrective action for repeat incidents. The 483 sites the case of repeat errors of employees in updating electronic note books despite repeat training (Observation 5D).

• This is a dilemma most companies face. Employees often repeat errors and mistakes, for example, while updating records, following sequence of activities, software entries etc., and the only action taken is repeat “Training” in SOPs or cGMPs. But how many times?
• An important point to note is that training itself is not a Corrective and Preventive Action (CAPA). The employee wouldn’t have been placed in the job if he / she was already not trained.
• What is required is to identify underlying reasons for the frequent errors even when at the outset it is an employee manual error or oversight – Is it system inadequacy, software issues, employee multitasking, lack of skill? A Human Error Checklist is a useful tool which can help to identify the underlying reasons. And address the root causes – address software issues, provide for double checks or confirmatory prompts when updating records and so on.
• Another effective tool is creating a Ready Reckoner of Common Mistakes made by personnel. Frequent group reading of Ready Reckoner of Common Mistakes can help raise awareness of recurring errors, sensitizing employees to these mistakes while they perform tasks. Over time, this practice can significantly reduce or even eliminate these errors
• And of course provide training too, not as a CAPA for a deviation, but as an ongoing awareness-building program aimed at reinforcing correct practices and preventing errors from recurring.