USFDA 483 / IPCA / June 2023 /Failure in Investigation of OOS, Deviations, Complaints

Observation 1:

Investigations are inadequate to determine root cause for failures of API and intermediates

A. In an assay analysis test with three batches in one sequence two batches were OOS, air bubble was determined to be the root cause, hypothesis testing performed on one batch and OOS invalidated. The root cause is not fully supported by the %RSD of initial and bracketing standard and hypothesis testing was performed only on one batch.

B. Two API batches were OOS for solubility. Manufacturing investigation stated no assignable root cause (but no information was available in report), Phase II laboratory investigation determined lower temperature as the reason for hazy solution, OOS invalidated; Root cause is not supported by the laboratory temperature and also the solvent is stored at room temperature.

Third party auditor flagged both these OOS, but no feedback whether the remediation plan is sufficient

C. In a deviation for equipment breakdown, a bolt was identified as the root cause for damage. Investigation confirmed a nut was missing (assumed to be drained along with water during partial cleaning); Investigation did not include a picture of the equipment to verify all parts are accounted for

D. In another deviation of equipment damage, a missing screw from the SOP display board was identified as root cause, no photographs of the SOP display board or surroundings were included to assess likelihood of screws falling in the material during unloading process

E. On a complaint of foreign substances including metallic particles in API powder, investigations did not identify any assignable root cause; equipment for preventing extraneous matter and metallic / magnetic substances are not qualified. There were multiple complaints of metallic contamination in API.

F. On a complaint on foreign substance like metallic particles in an API batch, the investigations did not evaluate whether the particles are metallic or non metallic; Investigations stated machines not a contributing factor for foreign particles, but investigations did not include all manufacturing equipment.

OOS

In OOS investigations, where a root cause is not clear and conclusive, all possible factors which can cause an OOS result should be evaluated and documented.

An assay OOS could have several possible factors – for e.g. (but not limited to) incomplete dissolution of sample in diluent, filter (if used in sample preparation) absorbing the API, peak broadening due to column issues, sample handling, weighing, transfer-dilution errors, other factors like inorganic impurities, water/ solvent content, or manufacturing related issues. All possible factors should be evaluated and documented. When root cause is not conclusively established. Phase II manufacturing investigation should be performed comprehensively considering all possible factors which can cause a lower assay for e.g. (but not limited to) – inorganics retention, filtration issues, deterioration, process deviations and so on and ruled out. If most probable cause zeroed down, for e.g. air bubble, is not well supported by the other indicators of the cause (e.g. %RSD of bracketing standard,  system pressure..), a scientific rationale should be presented how the identified cause can affect only specific batches. Then the proposed root cause has more credibility. Such an elaborate evaluation will help in getting to actual root cause and appropriate CAPAs. Or else the issue may recur, if only selected most convenient root causes are evaluated in the investigation and concluded. Also, in assay analysis by chromatography, it is a good practice to have duplicate sample preparation and sample injection. This can indicate effect of random issues like air bubble on specific sample chromatographic runs and help investigation of OOS and arriving at root cause.

Similarly in the case of OOS in solubility investigations should be comprehensive. There could be several reasons for e.g. (but not limited to) – inorganics in the batch, polymorphism issues, extraneous matter, particle size issues which should be evaluated and ruled out. If indeed the temperature of the test conditions / reagents are the reason, the CAPA should address the same in the test method. Often, non significant attributes like solubility in several solvents are captured in specification of APIs, just copying from Pharmacopeia or literature; without sufficiently being evaluated during development. In Pharmacopeia the statements on solubility are general in nature and not a monograph requirement for a substance unless quantitative solubility test is given in the individual monograph and designated by a test heading (Refer Description and Solubility in US Pharmacopeia). Solubility specifications should be defined in few select solvents only where it is quality indicating after evaluating the same in the different developmental baches.  Or else surprises can happen during commercial batches causing OOS results.

Deviations

In deviations involving equipment, missing bolt, screws etc. one concern is how comprehensively the issue is investigated, whether all possible areas and aspects covered, or issue is addressed only peripherally. Such investigations should address all equipment parts, accessories in operational areas. And as indicated in the OOS, attach photographs as evidence of investigation and evaluation for both the issue observed as well as where similar issue is ruled out.

Complaints

Investigation on Complaints of black particles, extraneous matter (Contamination) should be elaborate covering all possible sources – Manufacturing equipment, Manufacturing area and environment, Manufacturing process itself. Some times causes may be obvious, but often not so. A very deep comprehensive investigation involving a cross functional team from manufacturing, engineering, quality, R&D functions is necessary to identify potential causes. Sources could be several (for e.g. but not limited to) – process equipment (e.g. reactors, reactor seals, driers, centrifuges, filters and so on…), sampling and sampling tools, solvents, solvent lines, other input materials, process issues (like charring), process auxiliary materials like carbon, ventilation systems and ducts and so on. Each potential source should be evaluated and ruled out. Where possibility of contamination exists, appropriate control measures – for e.g. filters / screens, filtration steps in process, process control measures and so on should be implemented as CAPAs. In complaints and deviations involving extraneous particles / black particles, evaluation for metallic and magnetic particles should be performed and efforts should be made to characterize the nature of the particles. This also will help in identification of potential sources of contaminants and implement CAPAs. Document all investigations performed, and possible sources identified and CAPAs proposed. All equipment involved in GMP manufacturing including those meant for detection of metals (like metal detectors), prevention of contamination (like sifters, screens etc) should also be qualified to verify they perform as intended and periodically verified.

When a root cause is identified, there should also be an impact evaluation performed – looking at how many other batches and products could be impacted. All batches within expiry should be covered in the scope of assessment and based on the assessment initiate actions like customer intimation, market recall for the impacted batches.

Reviewing and learning from the observation in the USFDA 483, companies may well take up a review of their Quality events and systems for similar events and take appropriate CAPAs like:

1. Review all invalidated OOS where root cause is not conclusive. Perform an extensive evaluation of the OOS investigation and manufacturing investigations, if not already performed. If additional factors are identified, implement appropriate corrective and preventive actions (CAPAs).
2. Review quality events like OOS for solubility and also all APIs for solubility specifications. Evaluate whether the solubility specifications are relevant and quality indicating. If not consider revising the specifications.
3. In OOS / deviations involving equipment / facility ensure appropriate evidences like photographs, diagrams are provided in the investigation report. Make it a part of the investigation procedure and checklists.
4. Review all deviations and complaints for extraneous matter, black particles, metallic particles and assess whether the investigations have been comprehensive. If not perform extended assessment and identify all possible causes and CAPAs for them. Assess whether all equipment involved in GMP manufacturing are appropriately qualified and if there are gaps, address the same. For equipment like metal detectors implement periodic checks for performance verification of the equipment.
5. Perform a risk assessment of contamination control measures (if already performed, take up a review) of each manufacturing line. Identify additional measures where required to prevent contamination. 
6. Train the Quality and Operations team in handling investigations and documentation comprehensively.