Evaluation of capsule drug products

Evaluation of capsule drug products

Drug product testing is generally divided into three stages:

1. In-process testing, during the manufacture of the drug product. These batteries of tests are carried out at predefined intervals during the product manufacturing, by the manufacturing personnel, and their results recorded on the batch record. Adverse findings in these tests can be used as a guide to alter the manufacturing-process parameters.

2. Finished product testing, after the whole batch has been manufac-tured. These tests help identify whether the batch is acceptable for marketing or its intended usage.

3. Shelf-life testing, after the whole batch has been packaged. These tests are frequently carried out after defined periods of storage at prede-termined conditions. They help to assign and verify the shelf life and usability of the drug product.

In-process tests

Visual inspection of soft gelatin capsules is done to ensure absence of clearly malformed, damaged, or improperly filled capsules. During the encapsula-tion of soft gelatin capsules, the following parameters are usually closely monitored and controlled:

·           Gel ribbon thickness and uniformity across the ribbon

·           Seal thickness

·           Weight of the capsule fill and its variation from capsule-to-capsule

·           Weight of the capsule shell and its variation from capsule-to-capsule

·           Moisture level of the capsule shell before and after drying

Visual inspection, fill weight, and fill-weight uniformity are the key in-process tests used for hard gelatin capsules.

Finished product quality control tests

Permeability and sealing

Soft gelatin capsules are tested for physical integrity (absence of leakage) by visual inspection. Similarly, hard gelatin capsules are tested for any breach of physical integrity (breakage or opened cap and body).

Potency and impurity content

All capsules are tested for drug content (potency, as a percent of label claim). In addition, most drug products are tested for the related substances or impuri-ties. These must meet predefined specifications for a batch to be acceptable.

Average weight and weight variation

Ten hard gelatin capsules are usually weighed individually and the con-tents are removed. The emptied shells are individually weighed and the net weight of the contents is calculated by subtraction. The content of active ingredient in each capsule may be determined by calculation based on the percent drug content in the formulation for high drug load formulations.

For soft gelatin capsules, the gross weight of 10 gelatin capsules is deter-mined individually. Then each capsule is cut open, and the contents are removed by washing with a suitable solvent (that dissolves the fill but not the shell). The solvent is allowed to evaporate at room temperature, fol-lowed by weighing of the individual washed shells. The net contents are calculated by subtraction and the content of active ingredient in each of the capsules can be determined by calculation based on the percent drug content in the formulation.

Fill-weight variation of capsules is often a function of equipment setup and filling operation. An automated capsule sizing machine and/or weight checker is frequently used to discard over- or underfilled capsules.

Uniformity of content

Uniformity of content of the active ingredient can be determined by weight variation of the fill of hard or soft gelatin capsules for high drug load (API ≥25% w/w of the total fill weight), high fill-weight (250 mg/capsule) formu-lations. For low drug load and low fill-weight formulations, each capsule must be analyzed individually by the potency method for the content of the active ingredient. The uniformity of content is assured if predetermined criteria for the range and variation in the content of the active ingredient are met.

Disintegration

Disintegration of hard and soft gelatin capsules is evaluated to ensure that the drug substance is fully available for dissolution and absorption from the GI tract. The disintegration media varies depending on the type of capsules to be tested.

Dissolution

Drug absorption and physiological availability depend on the drug sub-stance being in the dissolved state at the site of drug absorption, viz. the GI fluids. The rate and extent of dissolution of the drug from the capsule dosage form is tested by a dissolution test. Dissolution test provides means of quality control in ensuring that (a) different batches of the drug prod-uct have similar drug release characteristics and (b) that a given batch has similar dissolution as the batch of capsules that was shown initially to be clinically effective.

Moisture content

Water content of the entire capsule or the capsule contents are determined by Karl Fisher titrimetry to enable the correlation of water content with the degradation profile or drug-release characteristics of capsules.

Microbial content

The capsules are tested to ensure lack of growth of bacteria and mold by microbiological tests. These tests are usually carried out by incubation of the capsule contents in a growth medium and counting the colonies formed after a predefined period of time. Selection of the growth medium and duration of the test, as well as maintenance of aseptic conditions during the testing, are critical to successful assessment of microbial contamination by this method.