Inadequate Sampling Plans lead to FDA 483 Inspection Report

Sampling of materials is one of the most important processes in pharmaceutical companies. Testing these materials is one of the main tasks of the quality control units. The quality of the substance has to be assured without compromise. It must be ensured that the necessary tests are conducted on the incoming goods and that the starting materials are released only after their quality was judged as satisfactory. Regulatory agencies require a sampling plan that utilizes basic elements of statistical analysis or provide a scientific rationale for taking a representative sample according to the lot size.

The Indian company Aurobindo Pharma Limited received a so-called 483 FDA report as a result of an inspection carried out in August 2021. The United States Food and Drug Administration (FDA) criticises, among various other points, inadequate sampling plans for raw materials and intermediates. Furthermore, components used in manufacturing were not tested and released prior to use.

FDA Requirements

The FDA requires in the Code of Federal Regulations (21 CFR Part 211.84) that sampling should be done upon statistical criteria and that lots are released prior to use:

Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures.
(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.
(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by § 211.170.

Inadequate Sampling Plans for Raw Materials and Intermediates

The company failed to provide scientific justification demonstrating that the sampling plans are representative. According to the FDA, the "sampling plans are not scientifically sound and appropriate to ensure that [...] raw materials and intermediates conform to established standards of quality and purity."

The following examples are given in this respect:

• A key starting material is received in a drum. A certain number of drums are sampled, but Aurobindo Pharma Limited could not provide scientific data demonstrating that sampling these drums is adequate to determine batch homogeneity.
• Another key starting material is received in bags. The FDA has doubts that the samples tested are representative batch samples.
• The current sampling process fails to ensure that a representative sample is obtained for water and residual solvent analysis. 

Components used in Manufacturing are not Tested and Released prior to Use

According to the FDA, it was not ensured that materials were appropriately tested for impurities prior to manufacturing. Examples are given where materials were used in manufacturing prior to complete testing. The Quality Unit could not provide a rational justification for conducting testing after manufacturing had already begun.

The complete 483 FDA report to Aurobindo Pharma Limited was published by the FDA on its website in the section "Frequently requested or proactively posted compliance records".