23 May 2024 | Bryan Abney, Kevin Swiss


In the rapidly evolving pharmaceutical industry, the quality and safety of drug substances and products hinge significantly on the integrity of raw materials used in their manufacture. A risk-based approach to raw material testing and specification setting has emerged as a pivotal strategy to ensure compliance with regulatory standards and safeguard patient health. This paper delves into the nuanced aspects of this approach, offering insights into its implementation through real-world examples and good industry practices.

Risk Assessment as a Foundation

The journey begins with a thorough risk assessment, categorizing raw materials based on their potential impact on drug quality and patient safety. For instance, a manufacturer might evaluate the risk more carefully associated with an excipient’s source variability by considering its role in the drug formulation. Using the principles, tools, and methodologies outlined in International Council for Harmonization (ICH) Q9 Quality Risk Management, the company assesses risks through a combination of historical data, scientific literature, and empirical testing, aiming to identify materials that necessitate more stringent control measures beyond compendial controls.
Current concerns have been focused on nitrosamines in drug products, the use of excipients (e.g., sodium starch glycolate) with higher nitrite and nitrates have been implicated for nitrosamine in drug products. At this time, the USP/NF does not require these tests in any excipient monograph. By judiciously analyzing batches of excipients for nitrites and nitrates would allow the reduction in the risk of nitrosamine formation.

Many drug substances have water mediated degradation pathways. The use of anhydrous excipients and processes (e.g, avoiding wet granulation) can ameliorate the water-borne degradation pathways. Anhydrous or low water grade excipients which can be tested and accepted as for water easily.

Case Study: Criticality of Attributes

A practical example involves a manufacturer of a drug, where the raw material’s impurity profile could significantly influence the product’s safety profile. Through risk assessment, the residual levels of certain impurities are classified as critical quality attributes (CQAs). The company then tailors its testing protocols to rigorously monitor these impurities during manufacturing.
An example would be the use of lower-grade excipients in dry powder inhalers causing potential safety concerns to the patients. In this case, the manufacturer would be relying on the additional testing during routine manufacturing to ensure excipient quality and patient safety.

Another example would be the use of ethanol in a process step which also includes water. Typically, ethanol would include water content as a quality attribute. However, in this case, the company may choose to not assess the water content of the incoming ethanol because it can be justified as not being critical due to its insignificance relative to the water added during the process step itself.

Navigating Regulatory Compliance

Compliance with regulatory requirements is mandatory. Different regions have defined specific requirements for raw material testing. For example, the European Medicines Agency (EMA) using the European Pharmacopeia (Ph. Eur.) might require detailed testing for certain materials compared to the United States Pharmacopeia (USP) or the Japanese Pharmacopeia (JP). By adhering to the strictest of these pharmacopeial standards, manufacturers can often meet or exceed global requirements, as seen in the harmonization efforts under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q4, Pharmacopeias. This approach enables global registration of the drug with little to no changes required to the raw material control strategy.

Vendor Qualification and Quality Agreements

Establishing robust quality agreements with suppliers is critical. A case in point is a pharmaceutical company that sources key active pharmaceutical ingredients (API) from multiple suppliers. By conducting audits and requiring comprehensive quality documentation, the company ensures that each batch of API meets predefined quality standards regardless of the supplier. This practice is complemented by quality agreements that outline the testing responsibilities of each party, ensuring transparency and mutual accountability.

Embracing Reduced Testing Strategies

Reduced testing strategies may be employed that can streamline operations without compromising quality. An example includes a manufacturer that, after receipt of multiple lots of consistent quality from a particular supplier, shifts to accepting certificates of analysis (CoA) for non-critical materials, reserving in-house testing for critical raw materials only. This approach, informed by a thorough risk analysis, demonstrates confidence in the supplier’s quality management system while optimizing resource allocation. Typically, to continue to monitor for consistent quality, a single lot is tested per the manufacturer’s receipt COA on a periodic basis, such as once per year or after a defined number of lots received.

Internal Quality Standards and Specification Justification

The creation of internal quality standards is managed by a combination of different regulatory requirements, industry best practices, and risk assessment outcomes. For instance, a company might develop stringent internal specifications for a solvent used in a process step, beyond what is mandated by pharmacopeias, to mitigate specific risks identified through risk assessment exercises, perhaps a tighter water specification, nitrite/nitrate or an acidic impurity which cannot be purged. At the same time, a company may reduce the testing requirements of other raw materials that are less critical to the quality of the final drug product or drug substance.

Conclusion

The risk-based approach to raw material testing and specification setting represents a dynamic and comprehensive strategy to enhance pharmaceutical product quality. Through detailed risk assessments, robust regulatory compliance, strategic vendor management, and innovative testing strategies, manufacturers can ensure the safety and efficacy of their products. This approach not only aligns with regulatory expectations but also fosters a culture of quality and continuous improvement within the pharmaceutical industry.

Syner-G Biopharma Group provides comprehensive Quality support across various stages of pharmaceutical development, ensuring regulatory compliance throughout your product’s life cycle. Our expertise encompasses:

Risk Management: We adopt a strategic approach to vendor management and specification setting.

Regulatory Sciences and Services Team: We assist with IND/NDA/MAA documentation, covering everything from regulatory strategy to writing, publishing, and submission.

 


 

Bryan Abney
Bryan Abney is an experienced pharmaceutical quality professional with 30 years of progressive experience directing quality control, analytical development and validation, product/process remediation, and quality assurance.

 

 

 

 

 

 

 

Kevin Swiss, Ph.D.
Kevin Swiss, Ph.D., is an experienced pharmaceutical quality professional with 30 years of progressive experience in CMC regulatory, CMC development, and technical operations including analytical development, drug substance, and drug product manufacturing.