Over the last twenty years or so, the paradigm behind setting specifications has undergone something of a transformation. Much can be attributed to the adoption of risk-based methodologies, such as Quality by Design (QbD), advancements in technology, and harmonization of world regulatory expectations.
The Art of Medicinal Science
Specification setting is – in some measure – an art. While regulatory guidelines delineate what specifications should entail to ensure patient safety (e.g., ICH Q6A specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances), applying specifications throughout pharmaceutical development requires interpretation and judgement applied by various scientific subject matter experts. Developing suitable specifications requires not only an understanding of process and analytical chemistry, but also a grasp of regulatory expectations combined with in-depth knowledge of the realities at commercial-scale versus bench to manage process variability.
What is Specification Setting?
Setting specifications is the practice of establishing conformance criteria for a drug substance, or API, to ensure a safe and effective product. The specifications describe the analytical procedures and limits an API must meet to conform to the specification. According to ICH Q6A:
“A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use. “Conformance to specifications” means that the drug substance and / or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.”
ICH addresses commercial product specifications and may not directly apply to early stages of development or upstream control points in the process (i.e. raw materials, intermediates, and in-process controls). Development chemists must keep their eyes on ICH limits to keep the end in mind and manage risks during clinical studies. As the relationship between product quality with raw materials and process parameters becomes better understood, specifications are applied to raw materials, isolated intermediates, and various checkpoints throughout the process. These raw material, intermediate and in-process controls ensure a capable process producing product of consistent quality.
Typical Test Methods
There are a number of common tests used in analytical chemistry when producing small molecules. These may include:
Challenges with Specification Setting
There are several key factors the pharma industry must consider when establishing drug substance specifications.
According to the ICH: “When a specification is first proposed, justification should be presented for each procedure and each acceptance criterion included. The justification should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long-term stability studies, as appropriate.”
Regis’ Approach to Setting Specifications
The pharmaceutical industry has historically approached analytical method development as a static set of tasks. Once specific methodologies were identified and defined, they were largely set in stone. This approach was common, as it resulted in lower costs and avoided any delays needed to qualify a new method (and requalify the drug substance).
The last few decades have seen vast changes in industry approaches to drug development throughout the product lifecycle imparting a mentality of ‘continuous improvement’. Advances in analytical technology have played a key role, as have risk-based approaches such as QbD, DoE, and other statistical tools. FDA’s risk-based approach to process changes allows, an improvement-focused mindset, in which advancements in methods emerge as more understanding of a molecule or its process is acquired. This can result in the avoidance or reduction of non-conformances.
At Regis, we use a collaborative partnership-based approach to specification setting involving multidisciplinary teams including Process Chemistry, Analytical, Engineering, Quality and the Client / Sponsor. This team strategizes over each critical quality attributes of the drug substance at Control Strategy Meetings. Regis conducts Control Strategy Meetings each aligned with development and scale-up milestones. This formal review examines the chemical process, development outputs, lot history, customer expectations, and product requirements (dose and route of administration) and arrives at an appropriate strategy for the process at each stage of the development process.
The output of these meetings is a living and breathing strategy that clearly describes the necessary effort, including justification, so all the stakeholders, internal and external to Regis, are aligned on what is necessary to deliver on-time, first time, and in full. The collaborative process functions as a feedback loop, resulting in an improved process and better-defined specifications:
Do you want to learn more about specification setting and how Regis can help solve your small molecule API development and commercialization challenges? Contact us today!