In-process controls and results

Generally speaking, there are several areas in the manufacturing section related to in-process controls and exhibit batch results that raise questions during the review of an ANDA. These areas can be broken down further into the following general categories: reconciliation, in-process tests, and the manufacturing process.

Reconciliation. An issue that is often unaddressed in the ANDAs is unjustified, low reconciliation of the exhibit lots. In the QbR–QOS, as well as, the body of data, a table for reconciliation should be provided. Yield should be cumulative and all losses accounted for with adequate rationale for the losses. Applicants are routinely asked to demonstrate how the low reconciliation observed in the exhibit batches will be corrected or mitigated for the commercial process. ANDA applicants are encouraged to include a reference to any applicable investigation of losses to avoid deficiencies cited on this topic.

Also, the frequency of testing during compression or other similar processes should be proposed and justified based on batch size and equipment used. Additionally, when changes are made to the release or regulatory/shelf-life specifications for the drug product, the applicant should assess the impact on the proposed in-process controls and revise them accordingly (e.g., disintegration, dissolution, residual solvents, etc.). In general the in-process controls should not be more relaxed than the drug product release criteria.

A frequently asked question for solid oral dosage forms is regarding adequate in-process control of the blend, based on the acceptance criteria for the assay of the drug product. This is especially common when the release assay criterion for the drug product is tighter than the commonly proposed range of 90.0–110.0% of the labeled amount. In these cases, a composite blend assay with proposed range comparable to that of assay of the drug product during routine release analysis is desirable.

For parenterals, deficiencies are often cited regarding adequate or excess fill volume. Usually, containers for parenterals are filled with volumes in slight excess of the labeled amount that is to be withdrawn. The excess volume is meant to be sufficient to permit withdrawal and administration of the labeled amount. It is recommended that the US Pharmacopeial Convention's USP <1> and <1151> should be followed for excess volume (5). However, excess volume may be justified at lower than recommended in USP <1151>. This may be justified based on data, on multiple containers, demonstrating that the intended volume can be extracted consistently or by inclusion of a routine extractable volume test. Large overfills, exceeding USP <1151>, should also be appropriately justified as this excess may pose a potential safety concern.

Manufacturing process. For manufacturing processes which involve dry blending, the ANDA applicant is frequently questioned regarding the possibility of powder segregation. It is well known that achieving and maintaining homogeneous blends of powders are critical for establishing the quality of the solid pharmaceutical dosage forms, especially in formulations involving small amounts of highly potent components. In most cases, the individual components of the blend are powders with differing physical characteristics such as particle size distribution, density, shape, and cohesiveness. These materials may demonstrate tendency to segregate and lead to lack of homogeneity of the final blend. Thus, it is desirable that the ANDA applicant demonstrate a thorough understanding of the blending process and possibility of powder segregation in the pharmaceutical development section, 3.2.P.2. Additional controls for a blend may include, but should not be limited to, particle size distribution of the various components of the blend, particle size distribution of the final blend, flow characteristics and density.

The justification of the proposed tablet compression controls (usually the hardness range) is often requested from the ANDA applicant. The proposed range of hardness during compression and during release or stability testing, should to be justified by demonstrating that the drug product meets the dissolution and the friability criteria at the lowest and the highest points of the proposed ranges. However, the ANDA applicant may refer to studies performed during pharmaceutical development as justification for the proposed range.

When an applicant uses a wet granulation process, it is preferred that a quantitative end point determination is proposed. As factors such a solvent addition and granulation time may be critical to producing consistent, high quality product process, adequate controls should be in place. In many cases, a deficiency is cited if no control or justification is provided by the applicant and the sole control proposed is a subjective, visual observation. For high shear processes, suitable controls may be related to the change in power consumption with respect to the granulation equipment (e.g. amperage). For fluid bed processes, moisture content can be a suitable control for end point of the desired granules. The applicant may also choose to justify the proposed processing ranges of solvent addition, granulation time, etc., during pharmaceutical development studies.

Other issues that arise during review of ANDA submissions, with respect to use of wet granulation processes, are controls for the granulation solvent used. If organic solvents are used in the granulation, appropriate controls should be proposed during the process and/or in the drug product release specification. The following of the recommendations found in USP <467> and OGD Q&A documents may ensure that the residual solvents are adequately identified controlled (5, 6). If water is used as the granulating solvent, it is recommended that a control for water content be proposed, with rationale for the proposed criterion as a function of impact on the stability and quality of the product. Studies to assess impact of water content on product stability and quality may be performed during pharmaceutical development.

Dosage forms comprising multi-unit beads (pellets) or multi-particulates in capsules are a growing area for ANDA applicants. These dosage forms are convenient as they have the capability of providing optimal release profiles (e.g. some varied combination of immediate, delayed and extended release) for single drugs or drug combinations. An added advantage of these dosage forms are as the possibility of alternative administration techniques for certain populations, such as sprinkling beads (pellets) onto soft food. Since many of the beads (pellets) are manufactured as coated, modified release products in order to retain their integrity during mastication, it has been proposed in a draft guidance from the FDA (7), that the bead size be limited to not more than 2.0 mm. Thus, it is recommended that in-process controls be incorporated which establish the final bead size for these dosage forms. In addition, if the dosage form is comprised of multiple controlled release delivery systems (i.e., immediate, delayed and/or extended release pellets), in-process controls need to put in place at the appropriate manufacturing stages for the beads, which establish and monitor the release profile of the beads.

Finally, deficiencies may be cited in the case of parenterals, and other liquid formulations, when justification is not provided regarding the compatibility of the listed manufacturing equipment process materials and the drug product solution. Again, compatibility of the dosage form with the process materials which come in direct contact with the dosage form during manufacturing is recommended to be a part of pharmaceutical development studies.

These comments only scratch the surface with regard to types of in-process controls and data that are provided in submitted applications. Deficiencies will be cited for these and other manufacturing processes if it is apparent the processes are not well understood; and it is imperative that adequate justification be provided so that the risk of problems occurring during commercialization be minimized.