Stability by Design - Guidelines for Assessing & Controlling Physical Stability

Recommendation

5-7 November 2024
Hamburg, Germany

GMP meets Development
GMP and FDA Compliance in Pharmaceutical Development and IMP Manufacturing

The United States Pharmacopeia (USP) Physical Stability Joint Subcommittee (which includes members of USP´s General Chapters Expert Committees for Physical Analysis, Dosage Forms, and Packaging and Distribution) has published a Stimuli article regarding Guidelines For Assessing and Controlling the Physical Stability of Pharmaceutical Raw Materials, Intermediates, and Dosage Forms in Pharmacopeial Forum (PF) 44(6) [Nov-Dec 2018]. 

The authors of this Stimuli article define physical stability to be as follows: “Physical stability is the ability of a material to remain physically unchanged over time under stated or reasonably-expected conditions for manufacturing, storage and use”.

According to the article, the physical stability of excipients, active ingredients, intermediates, and Drug Products (DPs) has received an increased level of attention because physical changes in these materials are more easily detected with modern instrumentation. In addition, such physical changes have been the cause of some high-profile product recalls. These recalls have included, for example, the withdrawal of ritonavir oral capsules from the US marketplace due to the unexpected appearance of a more stable and less soluble crystal form of ritonavir. According to the article, there are several factors contributing to this trend:

• In the past, the screening of Drug Substances (DSs) for polymorphism and the ability to form salts / co-crystals and hydrates / solvates (“pseudopolymorphs”) was not routine. Hence, there was limited awareness of the risks of physical transformations occurring during the manufacture, storage, and use of pharmaceutical dosage forms.
• During the last ten years, there has been a significant increase in the use of amorphous DS and intermediates, increasing the probability of physical instability occurring because of re-crystallization.
• There has been an increased understanding of the risks of developing salt forms of weak bases, where the physical stability of common salt forms of these compounds can be compromised.

Existing Guidance

Regulatory agencies have provided guidances globally that highlight the importance of physical stability in pharmaceutical development and its role in the stability of drug products over their shelf-life. Physical instability can impact the quality, safety, and efficacy (bioperformance) of the DP and its subsequent lifecycle. A systematic investigation including the selection of suitable forms of DS and formulation ingredients is therefore recommended early in the drug development process to create a mechanistic understanding of the process involved in the instability.

Even small changes in the critical physical attributes of an excipient, DS, intermediate, or DP over time can impact the shelf life of a material and any product manufactured from it. Several health authorities have therefore discussed this topic in guidance documents (e.g. ICH Q Guidelines 1A, 1B, 6A, 8, 11; FDA, EMA, and WHO Guidelines). In addition, several national pharmacopeias have mentioned physical stability testing and control topics in their monographs and chapters (e.g. USP, Ph.Eur., JP).

Certain health authorities and official compendia consider physical properties to be potential critical quality attributes (CQAs) for excipients, DSs, DPs, and intermediates for some dosage forms. As a result, demonstration of

• manufacturing processes capable of producing DSs and DPs of consistent physical quality at release, and  
• the physical stability of these materials during storage

is required for successful regulatory filing and approval of marketing applications.

BUILDING AN APPROPRIATE CONTROL STRATEGY

A risk-based scientific approach is recommended to ensure product quality throughout development and commercialization. Strategies such as Quality by Design (QbD) can be applied to understand and ensure the compatibility of all materials and processes throughout the entire manufacturing process of a finished product. The deep understanding gained through a QbD approach will assist in identifying risks and vulnerabilities associated with DP manufacturing, storage, and use, which will facilitate implementation of a control strategy. The understanding will also contribute to informed decisions regarding the selection of storage conditions and appropriate packaging materials, as well as possible need for validated test methods. The authors state that "in many cases detailed development studies can support the elimination of routine testing or the use of simpler “QC techniques” to ensure the quality of the commercial product".

For more information please see the stimuli article on Guidelines For Assessing and Controlling the Physical Stability of Pharmaceutical Raw Materials, Intermediates, and Dosage Forms on the Pharmacopeial Forum Website. The authors request feedback and comments from stakeholders regarding the proposal to develop an informational USP general chapter on physical stability.