QbD aims to establish a solid product and process understanding to increase the overall product quality and safety. Excipients are considered to be critical input parameter for potential variability. These variabilities need to be understood and eventually evaluated for their impact on the product and the process to achieve consistently the desired quality and performance. Excipients therefore must follow the same QbD principles during their own development and manufacturing. The application of QbD principles to the hard gelatin capsules as a component to a final drug product have been performed on a set of suggested CQA and within the recommended storage and processing conditions for the capsule of 15–25°C and 35–65% RH.
The dimensional and weight specifications are considered critical for the manufacturing of capsule products on the high-speed filling machines, which produce up to 250,000 capsules per hour. Dimensional variations can cause issue on the rectification, feeding, opening and closing of the capsules at high speed leading to machine stops and damaged capsules. Other pharmacopoeial capsule specifications like sulfur dioxide, sulfated ash, and lubricant content are less critical but might have an impact on the stability of a specific drug formulation in the hard capsule and should therefore be reproducible. As gelatin is derived from a natural source, there is a risk for microbiological contamination of the empty capsule. The capsule disintegration has been determined as a CQA for the in vivo release of the drug formulation. Hence, the above-defined parameters have been suggested as CQA of the empty capsule because they are considered as “critical” or “key” factors for the product quality attributes (4).
The results provide evidence that the CQA remained well within their specified ranges. Moreover, the data showed that the variability within and between batches on an average sample, as well as an individual sample basis, is represented well by the specification ranges. The data provided cover different capsule batches manufactured over a period of at least 24 months at different locations and therefore are considered representative for the routine manufacturing process of empty hard gelatin capsules.
The capsule weight is a critical parameter that can impact the dimensions, machinability and disintegration behavior. The data show that the capsule weight is well within the specified 71–81 mg (average 76 mg) for the average weight as well as for the individual capsule weight of the size 1 capsule. The specification limits represent the operating space of the capsule manufacturing, showing capsule weights at the upper and lower end within one batch and across batches.
The dimensional data for capsule body length and capsule cap length are within the specifications and no difference has been observed between transparent capsules and opaque capsules containing dyes. Within the physical data, the major source of the variability for a single capsule is down to within lots, i.e., noise in the process. There is a low probability that a batch will be produced with a mean out of specification, but this risk can be minimized by ensuring that the variability between lots is as low as possible, thereby maximizing process capability statistics.
The disintegration test is a pharmacopoeial procedure used for immediate release oral product performance. The disintegration test is described in the 7th edition of the Ph. Eur. under monograph 2.9.1 Disintegration of tablets & capsules, in the 15th edition of the JP under 6.09 Disintegration test and the USP 30 monograph <701> Disintegration test. A harmonized guideline has been published by the ICH in the Q4B Annex 5 guideline Disintegration Test General Chapter from June 2009. The endpoint of the disintegration test is determined by the operator as “… the state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the discs…”. For two-piece capsules, the endpoint of the disintegration means the complete dissolution of the shell and does not take into account the initial rupture of the capsule. The rupture is the time point when the shell wall breaks up and releases the formulation into the media to dissolve. Rupture times of the capsule appears much faster than the complete dissolution of the shell (7,8). Moreover, it has been demonstrated that the results of the disintegration test are sensitive to the chosen test conditions and might vary dependent on the formulation filled (1,3). The operator endpoint determination depends on the operators’ judgment by when the unit is disintegrated and the residues are considered fragments. With below 15 min (or 900 s) for both tablets and capsules, the disintegration time is quite unspecific and set as a fail or pass criteria. Operator-determined disintegration times of the capsules are ranging from 50 to 850 s (Fig. 5), with the majority being determined after 300 s and a distinct population being at 700 s. To overcome the operators’ subjective endpoint determination, a disintegration test system with automatic endpoint detection was investigated using 144 samples from different batches. Compared to the operators’ visual endpoint determination, the results from the automatic endpoint detection show significantly lower variability in the results centering around 110 s, with the lowest disintegration time at 70 s and the longest at 180 s (Fig. 6). These results are significantly different compared to the results from operators’ determined endpoints who suggested much longer disintegration times in general.
Some specific observations with capsule disintegration might be due to methodological settings. Gelatin capsules easily tend to stick to wet surfaces resulting in slowly dissolving gelatin plaques on the surface. Even in the disintegration test with automated endpoint detection gelatin residues sticking to the mesh or the disk have been observed to prevent signaling. The issue has been specifically observed when the capsules were exposed to wet disintegration baskets or disks resulting in longer disintegration times. The automatic endpoint detection system is a novel method and further studies will be performed to confirm the validity and consistency of the disintegration time using automatic endpoint detection systems in comparison to the traditional visual endpoint detection.
The water content of hard gelatin capsules determined as LOD has been found within the specifications. The LOD level of the different batches showed a trend to be at the upper end of the specification defined as 13–16% water, which can be explained by the hysteresis properties of the gelatin polymer. It should be noted that the LOD is a dynamic property of hard gelatin capsules which depends on the environmental conditions of storage, capsule packaging, and handling. When exposed to higher or lower humidity, capsules will equilibrate to the respective equilibrium moisture level. Stored between 35–65%RH and 15–25°C, the LOD of hard gelatin capsules will remain within the optimal range of the gelatin capsules of 13–16% of moisture (2). When the moisture level of hard gelatin capsules drop below the LOD of 13%, the capsule shells gradually lose the flexibility and increasingly tend to break upon mechanical stress (brittleness). Figure 12 shows the sorption isotherm as a function of absorption and desorption of hard gelatin capsules exposed to different relative humidity conditions at 25°C.
In case of formulating capsule products which are sensitive to moisture, the LOD of the capsules when introduced into the process might be a critical quality attribute for product stability. In such a case, the LOD of the capsules can be adjusted to a certain range even below 13% by exposure to lower relative humidity during processing or storage. The respective design space defined for the capsule LOD will have to be evaluated in a set of Design of Experiments (DoE) with the finished product to investigate the impact of the lower LOD level on the mechanical resistance of the shell (brittleness), the product performance and the handling by the patient.
The sulfated ash residue is determined by the mineral content of the capsules, which arises from the combination of the gelatin and the colorants. Since the recommended maximum colorant level is 4%, the maximum sulfated ash content of the capsules should not exceed 7%. Levels of sulfated ash have not been found to be outside of the specification.
According to the specification, the sulfur dioxide concentration might reach 50 ppm as a residual component from the gelatin-manufacturing process. During the past 6 months, sulfur dioxide was not determined in hard gelatin batches and the maximum level over the past 5-year period reached a maximum of 20 ppm. For products sensitive to sulfur dioxide, it may be necessary to design specific experiments to evaluate product stability at a 50-ppm level to build the evidence that the specification reflects the design space of the product. In case that a higher sulfur dioxide concentration is critical for a given compound, the specification of the capsule can be lowered to a level at the upper end of the normal operating space.
The microbiological determination revealed the absence of CFU in the majority of batches and a contamination at the upper end of the capsule specification of ≤1,000 CFU in two batches. Gelatin is a natural material that can be contaminated during the manufacturing or during the preparation of the gelatin solution for the capsule manufacturing. In gelatin solution, the microorganisms can grow from single cells exponentially but can also decline over time when water is removed due to the changing microenvironment up to cell death (11). Water activity (a
w) has been found to be critical for the survival of the microorganisms with a very abrupt threshold level between growth and nongrowth (12). The minimum a
w required for the growth of Listeria innocua in gelatin has been determined to be between 0.935 and 0.946, with no growth observed at 0.911 and below (6) which was consistent with a
w minimum growth levels found in other media like NaCl, sucrose, and glycerol (10). The a
w of gelatin is dependent on the water content in the gelatin solution, which decreases from about 40% during the manufacturing down to the specified water content of 13–16% in the finished capsule. The respective a
w declines from 0.96 down to 0.4–0.6 in the finished capsule, which is significantly below the minimum threshold for growth and survival (6). This is in accordance with internal findings of the empty capsule stability program that the microbiological counts tend to decrease during the storage of the capsule.
The dipping pins are lubricated at the start of each cycle to enable the dry capsule to be stripped off the pins smoothly. The amount of lubricant is controlled as part of the production process and monitored on a nonbatch specific basis. The target is <0.5% w/w of capsules but typical levels are <0.1% w/w, which means that the normal operating range is at the very low end of the specification. Within the development program of a product, the likelihood of testing all the boundaries of the specification is low and leaves a potential gap between the control space defined by the specification and the knowledge space evaluated in the development of the product.
Selection and qualification of the raw materials for the empty capsule manufacturing is most important to achieve the desired capsule properties consistently. With a global qualification and supply program, as well as the harmonized manufacturing equipment and processes, product consistency was assumed for the empty capsules. The samples tested represented several batches manufactured over 24 months and were collected from different manufacturing sites. No differences between the tested CQAs were identified confirming that there are no seasonal or site-to-site differences present.
This study explores the variability of standard empty gelatin capsule within the recommended storage and processing conditions as an input parameter for product development and manufacturing. These data provide relevant information for the determination of a potential impact of the empty capsule on the product quality during the risk assessment. The impact of formulation and process parameters on the capsule performance (e.g., residual aldehydes, hygroscopicity) or the impact of the capsule characteristics on a specific formulation (e.g., capsule moisture) are beyond the scope of this study. Such product-specific CQAs need to be determined during the risk assessment and evaluated in product-specific DoE within the drug product and process development program. Based on these data provided on standard hard gelatin capsules, product-specific or customized specifications and variability of hard gelatin capsules can be defined.