November 30, 2018 PAO-M11-18-CL-001
Hard-shell capsules offer unique benefits compared with other solid oral dosage forms (SODFs). In addition to simplifying the development and manufacturing of SODFs, they are highly flexible in terms of dosage concentration and delivery method, and, when sealed with a band, they increase the barriers to counterfeiting and tampering, which are two concerns of growing importance.1 They are a cost-effective approach to the formulation of sensitive and potent formulations and can facilitate dissolution of poorly soluble active pharmaceutical ingredients (APIs), particularly for liquid-filled hard-shell capsules.2 It is not surprising that the global empty capsules market is expanding at a compound annual growth rate of 9.1%, from just over $1.8 billion in 2017 to $3.7 billion by 2025.3
For SODFs formulated in hard-shell capsules, the quality and safety of the dosage forms correlate directly with the quality and safety of the hard capsules used to make them. To ensure successful production of SODFs in hard-shell capsules, it is therefore essential to partner with a capsule manufacturer that can ensure the supply of empty capsules that consistently meet or exceed customer requirements.
CapsCanada has implemented a holistic approach to raw material sourcing for the manufacture of gelatin and Hydroxypropyl methylcellulose (HPMC) capsules. It is essential to have comprehensive knowledge about the sources of the raw materials including traceability back through our suppliers into their supply chains; a significant portion of the raw gelatin supply to CapsCanada comes from its own manufacturing facilities.
As part of our supplier qualification process, all potential raw material suppliers must complete a comprehensive audit that, in addition to answering questions regarding product characteristics and processing technologies, covers the supplier’s own supply chain and quality management systems, registrations and certifications, regulatory history, GMP compliance record, packaging and shipping capabilities and any problems that have arisen in the past. A risk assessment is performed to determine the level of risk in raw material source and origin. On-site audits are conducted for suppliers of high-risk raw materials and key capsule ingredients, such as gelatin and HPMC.
The raw material qualification process includes a review of supplier documentation, identity and confirmatory testing of samples to verify conformance to CapsCanada’s quality and safety specifications, which are established according to regulatory requirements in different markets. In addition, the qualification process for key capsule ingredients also includes testing of multiple lots to confirm that they have the required physiochemical properties to ensure capsule functionality and stability. The suppliers of these ingredients must also be able to demonstrate that its production processes are robust and consistently yield materials of high-quality. For approved suppliers, monitoring of raw material performance and evaluation for manufacturing changes through periodic re-audits, ensures ongoing compliance.
The raw materials used in the manufacture of capsules include food additives, color additives, and ingredients that are generally recognized as safe. While there are significant overlaps among the regulations in most countries (U.S., UK, EU, Japan, and Canada, for instance) with regard to the use of these ingredients in food supplements and drug products, there are some differences. Staying abreast of these differing and constantly evolving regulations is a key aspect of CapsCanada’s quality assurance program.
The above approach to sourcing of raw materials enables CapsCanada to minimize lot–to–lot variability resulting in high-quality capsules with desirable properties and thereby assuring the performance of the capsules on filling machines and bioavailability of the encapsulated products.
Hard-shell capsules manufactured by CapsCanada are produced for use in dietary supplements and drug products. CapsCanada is an ISO certified company and all capsules are produced according to current good manufacturing practices for food (21 CFR Part 117). CapsCanada has adopted NSF/IPEC/ANSI 363-2016 GMPs for excipients which are based on the principles of ISO 9001 to produce capsules for use in drug products. Regardless of their end use, all capsules are monitored extensively during manufacturing to ensure that their color, weights, dimensions and moisture remain consistent and within specifications.
Our efforts also go beyond GMP compliance to include consideration of regulatory requirements in possible destination markets for our customers’ products. While pharmaceutical and supplement manufacturers are responsible for ensuring the regulatory compliance of their products, as part of our approach to capsule manufacturing at CapsCanada, we are committed to conducting due diligence in this area and help support their international product registration efforts.
Release testing for organoleptic, physical, chemical, microbiological parameters and AQL for defects is performed on all empty capsule lots both internally and at qualified, third-party laboratories, to ensure that all capsules produced in our facilities meet the level of quality designed for them. In addition to providing the data for the certificate of analyses, release testing data provides the assurance for a smooth encapsulation process that leads to the production of filled capsules without defects.
CapsCanada also performs dissolution studies with capsules filled with active ingredients representatives of different biopharmaceutical classes initially and when significant changes are made to ensure the filled capsules meet compendial dissolution specifications.
Traceability of raw materials throughout the capsule manufacturing process is essential to ensuring the safety of hard-shell capsules used in SODF products. CapsCanada has a system in place that enables the identification of raw materials used for the manufacture of a specific lot number of capsules. Similarly, given a specific lot number of a raw material, we can identify which capsules were produced using that material and who received those capsules within a few hours.
Production of empty capsules, whether composed of gelatin or HPMC, requires an understanding of customer requirements, raw material supplier capabilities and regulatory requirements in destination markets4. It also requires scientific understanding of the design, formulation, manufacturing process and process capabilities. Only capsule manufacturers with comprehensive quality assurance programs that address all activities from raw material sourcing to production to product release testing can ensure the reliable supply of robust, high-quality capsules.
When sourcing hard-shell capsules, therefore, pharmaceutical and supplement manufacturers should look to suppliers, such as CapsCanada, that use qualified suppliers and standardized processes in compliance with GMP requirements, maintain appropriate documentation and provide for clear traceability.
Bahirathan is Regulatory Affairs and Quality Manager for CapsCanada® Corporation, Ontario, Canada. He has over 18 years of experience in API, drug product, excipient, dietary supplement and food quality management and regulatory affairs. He holds a Ph.D. degree in Epidemiology and Community Health from Louisiana State University. Bahirathan is an ASQ certified Pharmaceutical GMP Professional, Quality Engineer and Six Sigma Green Belt and a Health Canada qualified external scientific expert. He represents CapsCanada at the Canadian Generic Pharmaceutical Association.
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