Requirements For the Use of Alternative Empty Hard Gelatin Capsule Suppliers for the Manufacture of Pharmaceutical Products

Introduction

Two-piece empty hard gelatin capsules have long been a reliable oral drug delivery system. They are the preferred choice of many pharmaceutical products because they require fewer excipients than other drug formulations. In addition, they are manufactured to standards that allow for multiple sourcing and machinability on different types of filling equipment. Drug product manufacturers undertake alternative capsule source projects for a number of reasons, including but not limited to the following: cost savings, the addition of supplementary and alternative suppliers, an existing supplier may no longer be able to supply, and reduction of risk due to relying on a single source. A drug product manufacturer considering a change to the hard gelatin capsule source must ensure the regulatory requirements for reporting the change and other requirements including those for supplier qualification, dissolution, machinability, process capability, and visual and print quality described in this article are met.

Regulatory Requirements

For empty hard gelatin capsules used in drug products marketed in the United States of America (US), the addition of a new capsule supplier is an annual reportable change to the drug product manufacturer, provided there are no changes to capsule composition or appearance which includes changes to size, color or dye.¹ The following information should be provided for review in the annual report to the US Food and Drug Administration (FDA):

1. Full name and address of the new hard gelatin capsule shell supplier.
2. Certification from the new hard gelatin capsule shell supplier that the gelatin used conforms to USP/NF specifications.
3. Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathy (BSE/TSE) certification for gelatin from the new supplier, and
4. Specification of the hard gelatin capsule shell from the new supplier, which should be consistent with existing specifications.

It is important to note that any changes in capsule composition, appearance, or a change from gelatin to a non-gelatin alternative such as Hypromellose may be categorized as a prior approval supplement (PAS) requiring additional data for review and approval by the FDA before the change can be implemented. It may take up to six months for the review and approval of a standard PAS. Therefore, when sourcing capsules from new suppliers, drug product manufacturers would want to see that the addition of capsules from the new source is simply an annual reportable change so that they wouldn’t need to wait for FDA approval to market the drug product made with capsules from the new supplier.

Other Requirements

Supplier qualification

Once a prospective alternative supplier is identified, the drug product manufacturer begins the supplier qualification process with an assessment to determine the potential risks due to the source and origin of the capsule ingredients. Following this step, an audit is conducted to verify that the capsules are produced in a facility that follows Good Manufacturing Practices (GMPs) for pharmaceutical excipients. Though there are no legally binding GMP standards for the manufacture of hard gelatin capsules for pharmaceutical use, capsule manufacturers are expected to comply with NSF/IPEC/ANSI 363 GMPs² or an equivalent standard such as USP <1078>, GMPs for Bulk Pharmaceutical Excipients.³ Around this time, samples of capsules from representative empty capsule lots are tested by the drug product manufacturer to determine conformance to specifications.

Once compliance with GMPs and confirmation of specifications have been demonstrated, the drug product manufacturer will request and review the information and documentation required for regulatory submission for the addition of capsules from the new supplier. Drug product manufacturers also request documentation from the supplier to verify the safety of the capsules which includes BSE/TSE, residual solvent, and elemental impurity statements.

Dissolution

Though a comparison of dissolution profiles of a drug product made with the capsules from the new and the original supplier is not an FDA requirement when the change to the capsule is annually reportable, drug product manufacturers perform dissolution testing to ensure the dissolution profiles for the two products are similar and there is no risk of dissolution failure due to the change to the capsule source.

Machinability

Though empty hard gelatin capsules from different suppliers are expected to conform to the same standards for weights, cap and body lengths and cap and body external diameters, slight differences in these quality parameters, cap and body profiles, and encapsulation machine set-up and/or tooling dimensions may result in varying performance during capsule filling operations. Machinability issues can occur during the feeding, rectification, separation, filling, and closing stages of the encapsulation process and they may manifest as miss feeds, loose pieces, non-separation, improper seating of cap or body in segments, dents, tucks, splits, and pinholes leading to machine stoppages and loss of fill material and productivity.

Machinability issues may require making modifications to the capsules and/or the machine set-up or tooling and performing trials to ensure the changes to the capsule and or equipment or tooling are effective in resolving the issue. The following is an example of a machinability issue that was discovered during a capsule qualification trial and the actions taken to resolve it. When standard size 00 gelatin capsules from a new supplier were used to fill a highly granular material, they presented tuck and split defects. The issue was resolved by optimizing the cap diameters to facilitate closing without defects while maintaining a pre-lock that is tight enough to prevent the formation of loose pieces.

Five trials (each consisting of 1,000 capsules) were performed using two types of gelatin capsules (standard size 00 capsules and size 00 capsules optimized for cap diameters) on one filling machine using tooling dimension A. Another five trials (each consisting of 1,000 capsules) were performed on the same machine using the same two types of capsules with tooling dimension B (Table 1). Though the type of tooling can affect the performance of the capsule the results of this study show that tooling has negligible effect. The trials that used the standard capsules produced filled capsules with tucks, splits, and dents, whereas the trials that used capsules optimized for cap diameters produced filled capsules with none of these three defects. Two trials with capsules optimized for cap diameter showed non-separation in 1 in 1000 capsules indicating the need for a slight increase in vacuum pressure to eliminate this issue.

Process Capability

Unlike the GMPs for active pharmaceutical ingredients and drug products, excipient GMPs do not require empty capsule manufacturers to perform process validation studies, however, equipment qualification and process capability data for empty capsules are required by the drug product manufacturers because they provide the assurance that the manufacturing process will produce capsules of consistent quality and machinability.

Process capability can be determined by calculating a process capability index (Cpk). For the estimated CpK to be meaningful, two requirements must be met; they are (1) the data must be normally distributed, and (2) the process must be in statistical control (stable mean and variation). Normal probability plots and control charts are used to verify the normality of the data and process control, respectively. Once the normality of the data and process control are verified CpK is determined using process mean and standard deviation (within) and the specification limits as shown here:

The capability index CpK increases when the process mean moves closer to the target and or the process variation is reduced; CpK is reduced when the process mean moves away from the target and or the process variation is increased.

The following example shows the determination of CpK for the % moisture content of empty gelatin capsules. The % moisture content of 20 empty gelatin capsule lots made in the last six months of 2021 was used to plot control charts which showed the process is in control. Figure 1 shows the distribution of % moisture content of these lots, the upper and the lower specification limits for moisture content (13.0 and 16.0%) and the mean (15.3%), and the within standard deviation (0.10%); all moisture measurements are within the specification limits and the CpK is 2.33. There is a degree of non-centering of moisture measurements, and this is because capsules have the highest moisture content immediately after production, and the moisture values used to generate Figure 1 were taken from in-process test data for the lots.

Visual and Print Quality

Incoming empty hard gelatin capsule lots from the supplier are inspected for visual and print quality defects by the drug product manufacturer. The supplier and the drug product manufacturer must have an agreement, that stipulates the Acceptable Quality Levels (AQLs) for visual and print quality defects, in place before the inspection begins. An acceptance sampling plan (defined by a sample size and an acceptance number) is used for the inspection of capsules and the drug product manufacturer is required to keep documentation to show statistical validity of the sampling plan.

Since the acceptance sampling bases its decision on a sample of the lot and not the entire lot there is always a chance of making an error. There are two types of errors (risks) associated with an acceptance sampling plan and they are called producer’s risk (risk of rejecting a good quality lot) and consumer’s risk (risk of accepting a bad quality lot). In an acceptance sampling plan used for inspection of empty capsules for visual quality and print defects, producer’s and consumer’s risks are usually kept at 5% and 10% levels, respectively; this means the sampling plan would accept lots with AQL quality 95% of the time and reject them 5% of the time and it would reject lots with Rejectable Quality Level (RQL, which is also known as the Lot Tolerance Percent Defective) 90% of the time and accept them 10% of the time.

Selecting a statistically valid acceptance sampling plan consists of two parts; they are (1) defining the objectives of the sampling plan and (2) generating documented evidence to show the sampling plan meets the objectives. Statistical validity of the acceptance sampling plan can be demonstrated and documented by constructing an operating characteristic (OC) curve. An OC curve shows the probability of accepting lots at various incoming quality levels and the procedure described below shows how an OC curve is used to show an acceptance sampling plan is statistically valid.

For example, for a drug product manufacturer requiring an acceptance sampling plan with an AQL of 1% and RQL of 4%, a sampling plan with a sample size of 198 and an acceptance number of 4 would satisfy these requirements. The OC curve for this sampling plan (Figure 2) shows when this plan is used, lots at AQL quality (1% defective) will be accepted 95% of the time and lots at RQL quality (4% defective) will be rejected 90% of the time. This acceptance sampling plan meets its objectives and therefore, it is statistically valid.

Conclusion

Regulatory change has provided pharmaceutical manufacturers with more flexibility in exploring new capsule suppliers. Pharmaceutical manufacturers contemplating a change to the hard gelatin capsule source must ensure the new supplier complies with good manufacturing practices, provides the required documentation for regulatory filing, and supplies capsules that consistently meet the quality and functionality requirements and are compatible with their filling machines. In addition, they should make sure the new supplier is reliable, has sufficient capacity, and has the appropriate technical personnel with extensive knowledge of filling machines and pharmaceutical operations.

References

1. Change in hard Gelatin capsule shell supplier, Manual of Policies and Procedures 5016.6 (2016). US Department of Health and Human Services, Food and Drug Administration, CDER.
2. NSF/IPEC/ANSI 363-2019, Good Manufacturing Practices (GMPs) for Pharmaceutical Excipients.
3. United States Pharmacopeia (2023). General Chapter, <1078>Good Manufacturing Practices for Bulk Pharmaceutical Excipients.

Author Details

Bahirathan Mahesan, Regulatory Affairs Manager -CapsCanada® Corporation

Bahirathan Mahesan, holds a PhD degree in Epidemiology and Community Health from Louisiana State University. He is an American Society for Quality Certified Quality Engineer, Six Sigma Green Belt, and Pharmaceutical GMP Professional with more than 20 years of experience in Active Pharmaceutical Ingredient, Drug Product, Medical Device, Excipients, Dietary Supplements, and Food Quality Management and Regulatory Compliance. Currently, Bahirathan is the Regulatory Affairs Manager at CapsCanada® Corporation; he represents CapsCanada® in the Canadian Generic Pharmaceutical Association.

Publication Details