Ensuring Quality in Pharmaceutical Raw Materials

Gelatin is commonly used for drug encapsulation. Jean-Philippe Talmon, chief procurement officer at Capsugel spoke to Pharmaceutical Technology about the critical quality attributes of gelatin as an excipient in capsule production, as well as measures that can be taken to ensure an uninterrupted supply of quality raw materials.

Critical to quality

PharmTech: What are the most important ‘critical-to-quality’ attributes for gelatin, for encapsulation?

Talmon: In today’s increasingly interconnected and highly regulated global pharmaceutical market, adherence to ‘critical-to-quality’ attributes is required to deliver best-in-class products.

First, sourced gelatin must comply with the different pharmaceutical and food regulations in all the markets where the end product is sold. In global pharmacopeias, there are mandatory attributes to assure the quality, identity, and purity of the excipients used in the drug product. There are also non-mandatory attributes that provide information on control parameters for specific excipient use and include functionality-related characteristics. Various European Pharmacopoeia monographs, for example, have listed relevant parameters specific to the intended use of the excipient, which can form part of the regulatory filing process. Manufacturers are increasingly expected to understand the functionality of excipients and their potential impact on the final drug product.

Second, acquired gelatin must meet specific certification expectations and environment, health, and safety (EH&S) requirements. There are more than 15 regulatory references that form the basis of global gelatin purchasing specifications, including those from FDA, United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), Food Chemicals Codex (FCC), and World Organization for Animal Health (OIE).

For example, there are specific regulations on the sourcing of bovine raw materials for excipient use. While Bovine Spongiform Encephalopathy (BSE) is well under control as a disease, the OIE is leading a global movement to standardize BSE regulations and establish a common guidance on prevention, control, and eradication of the disease. Global regulators base their regulatory framework on OIE guidance. In Europe, manufacturers of bovine material must provide certificates of suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM) to be incorporated into marketing authorization dossiers for applicable medicinal products. This is just one example of the types of certifications required.

Third, sourced gelatin must maintain specified physical/chemical and microbiological requirements to provide appropriate encapsulation of individual APIs. These specifications cover a large number of criteria, including viscosity, pH level, loss on drying, and particle sizes, among others.

Through adherence to these three critical-to-quality attributes, companies with capsule and encapsulation capabilities can help to minimize the business continuation risks associated with gelatin raw materials and gelatin production. For example, in 2013, when heavy levels of chromium were detected in gelatin capsules made in China, the USP National Formulary (NF) monograph for pharmaceutical-grade gelatin was revised to include testing for heavy metals. Some companies scrambled to comply with the new requirements, which then had a negative impact on their customers. However, companies whose gelatin purchase specifications included chromium restrictions could maintain product supply without delaying delivery of their customers’ products to market.

Animal-sourced materials

PharmTech: What issues are entailed with the use of animal-sourced materials, as compared with synthetic or non-animal-derived materials?

Talmon: Animal- and non-animal sourced materials are used as excipients in pharmaceutical products. Each of these forms offers its own unique characteristics, specifications, opportunities, and challenges at various points in the development process. The positives and negatives associated with both forms must be well understood to ensure that any potential associated risks are identified in advance and controlled.

Gelatin, which is made from the hydrolysis of collagen of bovine, porcine, or fish origin, is well-suited for the encapsulation of pharmaceutical ingredients because of its excellent gelling and film-forming characteristics that support the manufacturing process. These characteristics are the result of the unique property of the gelatin polymer, which exhibits a reversible temperature-based gelification, turning into liquid when heating and hardening in the cooling process.

Hydroxypropyl methylcellulose (HPMC), which is made from plant/cellulose-based material, is an alternative to gelatin for drug encapsulation. Recent in-vivo and dissolution test results investigated the clinical performance of second-generation HPMC capsules compared to that of gelatin capsules, and found that the second-generation HPMC capsule performance was equivalent to that of gelatin capsules (1).

The choice between gelatin and HPMC materials is based on numerous factors including, for instance, the targeted product profile, characteristics of the fill, and consumer lifestyle considerations (i.e., dietary restrictions based on religious practices, such as halal and kosher requirements, or on vegan or vegetarian diets). For example, while gelatin sets the benchmark for pH- and ionic strength-independent disintegration and product dissolution profiles, HPMC capsules maintain lower moisture absorption, more flexibility, resistance to chemical crosslinking, and a higher thermal stability than gelatin capsules, providing greater benefit for hygroscopic and moisture-sensitive ingredients.

Ensuring supplier quality

PharmTech: How do you ensure supplier quality?

Talmon: First, stringent raw material purchasing specifications and quality agreements are required that cover a large number of criteria. Second, a robust supplier qualification program is needed to provide a sound framework to guarantee that hard capsules meet the highest standards for quality, traceability, and integrity. At Capsugel, our multi-phase program requires that our critical raw material suppliers undergo an intensive, year-long selection process that includes 150 critical parameters for evaluation to verify they meet the most stringent regulatory and industry standards, the most important being unique specifications related to dissolution profiles and impurities. The process includes the following:

• Step 1: Supplier screening and investigation. A review of the quality system of the vendor, the state of their manufacturing technology, the scope of their product and service offerings, and a detailed understanding of their performance metrics, regulatory compliance, and raw material traceability. For example, more than 15 regulatory agency regulations inform the basis of our purchasing specs.

• Step 2: Quality evaluation. A review of supplier material quality compliance with the company’s specifications.

• Step 3: Manufacturing suitability evaluation. An analysis of small-scale production trials and R&D pilot, when relevant. This analysis ensures compatibility of materials with manufacturing processes and protocols and confirms both finished capsule product quality and manufacturing efficiency performance levels.

• Step 4: On-site supplier audit. A thorough traceability analysis, from raw material delivery to finished goods release, including a detailed review of quality systems. This audit also confirms compliance of production equipment and compliance to current good manufacturing practice (cGMP) requirements.

• Step 5: Scale-up and final approval. This step involves a full-scale manufacturing run of capsules to confirm that material consistently meets specifications and is continuously suitable to our full-scale production. This also requires an evaluation of the supplier’s ability to control product integrity and proper documentation across the entire supply chain.

Third, it is important that long-term supplier partnerships are supported by a continuous supplier performance management program. This program includes an ongoing evaluation process designed to ensure supply-chain traceability and finished capsules that comply with the highest integrity standards. This program helps to maintain a global network of qualified suppliers with whom there are established long-term partnerships. Key components of this program are constant testing to the highest standards, updated with the most advanced instrumentation for contaminants tests, for example; regular in-depth onsite audits of suppliers; continuous monitoring at manufacturing facilities, including performing incoming quality control on each lot of raw material prior to its use; and follow up on supplier performance. Finally, a global sourcing strategy is needed to ensure consistent quality and security of supply.

PharmTech: How do you prepare for potential disruptions in the supply chain?

Talmon: The key to preventing supply-chain disruptions is to develop long-term partnerships with suppliers across multiple production sites to ensure that alternative resources can be ramped quickly and effectively in the event of an unexpected issue. Companies must always look one step ahead of their current needs and the requirements of the regulatory environment and business market. This process includes continuously screening potential new suppliers, monitoring industry and governmental standards and trends, building and maintaining an extensive knowledge base of international regulatory requirements, and participating in membership associations and working groups. All of these efforts are aimed at anticipating and rapidly implementing changes to safeguard the integrity of supply chain and products.

PharmTech: Which supplier criteria are crucial?

Talmon: Supplier selection is guided by several core principles, including the quality of the suppliers’ products and services as well as their product traceability and integrity framework. Additionally, suppliers’ quality systems, certifications and cGMP, regulatory compliance, and EH&S compliance are important. Finally, it is critical to look for suppliers to maintain responsible sourcing initiatives and have viable business continuity plans. All of these attributes are central to ensuring that suppliers can consistently and reliably deliver.

PharmTech: What are best practices for working with offshore suppliers?

Talmon: A robust framework is required to ensure that offshore suppliers meet the global expectations of companies and their customers. At Capsugel, we have a global production footprint, and our raw material sourcing efforts are globally coordinated and managed.

We maintain supplier evaluation programs to secure identification of potential sourcing risks and development of appropriate mitigation plans in close collaboration with our suppliers. Supplier audit results, for example, are used to dictate the frequency, as well as the depth and breadth of the follow-up supplier audits we conduct.

In parallel, we also maintain a thorough business continuity risk assessment program across our entire global supplier base. These assessments are conducted along six main dimensions, including supplier production capacity constraints; compliance to Capsugel quality expectations; compliance to regulatory requirements; single-sourcing risks; supplier financial health; and supplier intellectual property risk and third-party misappropriation.

Reference

1. A. Shanley, “Establishing a New Performance Standard for HPMC Capsules,” PharmTech.com, May 20, 2016,.