Risk-Based Approach for Defining Retest Dates for Active Pharmaceutical Ingredients and Excipients

Introduction

The ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) Q1A guidance document and the WHO (World Health Organization) expert committee report defines the retest period as follows: “The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be retested for compliance with the specification and then used immediately. A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a retest period. The same may be true for certain antibiotics” [1,2]. The guidelines place emphasis on immediate use after a retest and compliance with the specifications. However, “used immediately” is left for interpretation. To define “used immediately”, the WHO expert group has offered some guidance; for example, it stated that the API (active pharmaceutical ingredient) may be utilized within a month of retesting and complying with the specifications [2]. However, the WHO report does not allow the material to be given an additional period (next retest date) equal to the duration set for the retest (first retest date). However, it does allow for repeated retests of the material and its continuing use (as long as specifications are followed).

Similarly, the ICH Q1E guideline allows for data extrapolation to extend the retest period or shelf life beyond what is covered by the long-term data. However, any retest period or shelf life determined based on extrapolation must be verified with additional long-term stability data as soon as possible [3]. Whether or not stability data should be extrapolated depends on how well the change pattern is understood, how well any mathematical model fits the data, and whether or not there is adequate supporting data. Extrapolation should be conducted such that the extended retest period or shelf life is valid for a future batch released with test results that are near to the release acceptance requirements. The guideline offers an illustration of how to assess stability data. It recommends examining quantitative attributes like assay and related substances to find the earliest period when the 95% confidence limit for the mean intersects with the proposed acceptance criterion. The retest period or the shelf-life estimation depends on whether significant change takes place at accelerated conditions or intermediate conditions. For instance, if there is no significant change at accelerated conditions within 6 months and accelerated and long-term data show little or no change over time and little or no variability, statistical analysis is not required and a retest period or shelf life of 2 × period covered by long-term data (not exceeding the period covered by long-term data + 12 months) can be assigned for products stored at room temperature [3].

The importance of handling and storing raw materials in a way that prevents degradation, contamination, and cross-contamination cannot be overstated. Moreover, the storage conditions should prevent any physical changes to the material. The principal causes of product degradation and loss of effectiveness are temperature and humidity exposure. The accumulation of static charges in materials held at less than 45% relative humidity might cause the items to dry out, crumble, or stick together, causing issues during tablet pressing and packing [4,5]. Similarly, high-humidity storage environments can compromise potency and effectiveness, leading to material degradation and microbial proliferation. Materials held in fiber drums, bags, or boxes should be kept off the floor and spaced appropriately to allow for cleaning and inspection. The storage conditions and the storage period should be such that they do not negatively impact the quality. There should be sufficient control mechanisms in place to enable FIFO (first in, first out).

According to ICH Q7, materials should be reevaluated as needed to determine whether they are suitable for their intended application, especially after prolonged storage or exposure to heat or humidity. Initial API expiry or retest dates can be determined using pilot-scale batches as long as they are manufactured using the same procedure as commercial batches and have the same API quality [6]. In this article, we will look at the many steps that must be taken to establish the retest date. These are depicted in Figure 1. Considering their physicochemical characteristics and the role they play in pharmaceutical formulation, we address these steps independently for APIs and excipients. Furthermore, we propose a risk-based method for determining retest dates.

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3. Excipients

3.1. Classification of Excipients
The first step involves categorizing excipients based on the existing stability data or by evaluating their physical and chemical properties. Based on the stability of the excipients in their commercial package, IPEC (International Pharmaceutical Excipients Council) categorizes excipients into the following general categories: very stable, stable, and limited-stability excipients [68].

3.1.1. Very Stable
These excipients have a documented track record of stability in the specified packaging for at least five years. An assessment of their known characteristics can be used to forecast their stability. Furthermore, their manufacturing processes are robust and validated and any modifications in their manufacturing process are unlikely to affect the stability of these excipients. Ongoing stability studies are unnecessary if quality attributes remain stable for ≥60 months, as demonstrated by relevant literature and/or stability studies.

3.1.2. Stable
These excipients have a minimum retest/re-evaluation interval of at least 24 months but less than 60 months. Their stability can be determined by analyzing stability-indicating attributes such as assay and impurities; hence, data must be generated to substantiate the retest/re-evaluation interval and expiration date. The stability of these excipients is supported by sufficient literature citations and/or stability studies. Nevertheless, compared to excipients categorized as extremely stable, their stability is more susceptible to modifications in the manufacturing process or product packaging.

3.1.3. Limited Stability
They have a retest/re-evaluation interval or expiration date of less than 2 years. Like stable excipients, their primary stability-indicating parameters, including assay and impurities, help to assess their stability characteristics. Quite often, only a limited amount of stability data is available to support the expiration date or the retest or re-evaluation of these excipients. This category of excipients is distinguished by stability characteristics that render them more susceptible to changes in the manufacturing process or product packaging, necessitating specific packaging and storage conditions. These excipients may contain functional groups that are prone to hydrolysis and oxidation. Additionally, these excipients may also be susceptible to moisture absorption, heat or light deterioration, and viscosity change; hence, their compliance with specifications is compromised by unfavorable environmental conditions. Therefore, an on-going stability program (accelerated and real time) is recommended to be conducted in the packaging in which they are to be commercialized. Any changes in the packaging (container-closure system) or the manufacturing process that could impact excipients’ stability would require that a new stability study be performed. However, if moisture vapor penetration or oxygen permeation studies demonstrate that the new package is similar to or superior to the packaging system used for the stability studies, a new stability study may not be necessary to determine the impact on excipient stability. The finished product manufacturer should have access to a summary stability report providing information on the stability conditions, attributes monitored, packaging, and the stability study’s findings. An excipient can be categorized into more than one class depending on how much protection the product packaging offers [68].

3.2. Identification of Critical Material Attributes and Risk Assessment
Critical material attributes of excipients must be identified as they have the potential to change during storage or have an impact on the CQAs of the finished products [15]. While performing risk assessment, the impact of the storage condition on material attributes, as well as on product CQAs, should be considered.
An example of a stable and very stable excipient is provided below for ease of comprehension.

3.2.1. Polyplasdone XL-10 (Crospovidone): Example of Stable Excipient
Crospovidone is a white-to-creamy-white, free-flowing, fine hygroscopic powder. It is a water insoluble cross-linked homopolymer of N-vinyl-2-pyrrolidinone [69]. It is commonly used as a tablet and capsule disintegrant at a concentration of 2–5%. It exhibits high capillary activity and hydration capacity. The particle size of crospovidone may impact the disintegration property of the finished product, with larger particles providing faster disintegration in comparison to smaller particles [15]. The harmonized specifications of crospovidone are presented in Table 3. The Polyplasdone™ XL-10 is a crospovidone brand manufactured by Ashland (Wilmington, DE, USA) [69]. The manufacturer assigns a retest date of 24 months for its brand in specific packaging. Crospovidone has a remarkable impact on the disintegration time and dissolution of the solid dosage forms. Moreover, it is known to contain peroxides, which can trigger the degradation of oxidation-sensitive drug candidates [70]. The dissolution tests are an essential part of the battery of tests for finished-product specifications and can detect any impact that storage conditions may have on the disintegration properties of crospovidone. Drug–excipient compatibility performed during product development can detect any impact on impurity profile characteristics arising from peroxides present in crospovidone [71]. Further, related substances are an important component of the finished-product specifications. Therefore, description, impurity A, loss on drying, peroxides, microbial test, and particle size can be recommended to be performed at retest (Table 3). The excipient manufacturer must also confirm, through stability studies on a reasonable number of batches, that nitrosamine impurities in the raw material are under control [72].

Table 3. Specifications of crospovidone and risk-assessment-based retesting.

3.2.2. Pearlitol® 200 SD (Mannitol): Example of Very Stable Excipient
Mannitol is a white, odorless, crystalline, free flowing powder or granules. Mannitol is used as a diluent in pharmaceutical preparations [73]. It is not hygroscopic and is thus used with moisture-sensitive drugs. It also possesses negative heat of solution, sweetness, and a good mouth feel due to which it is also used in chewable tablets. The USP (United States Pharmacopoeia), Ph.Eur. (European Pharmacopoeia), and JP (Japanese Pharmacopoeia) have harmonized mannitol monograph. The specifications are shown in Table 4. As it is used in considerably high quantities in the formulation, its particle size can play a significant role in flow, compressibility, and other characteristics [74]. Hence, in-house specifications are typically set by the finished product manufacturers for the particle size. Pearlitol® 200SD is a mannitol brand manufactured by Roquette Pharma (1347 Beaver Channel Parkway, Clinton, IA, USA). The manufacturer has assigned it an expiry date of 5 years [74]. The CQAs that are likely to be impacted due to mannitol include uniformity of dosage units and dissolution. It may also influence the compressibility of the powder blend. However, typical quality control tests for a finished product, such as uniformity of dosage units, disintegration time, and dissolution, would facilitate timely detection of any impact on these parameters. Moreover, since it is a very stable excipient, the occurrence of these events is very low. Therefore, description/appearance, loss on drying, assay, microbial test, related substances, reducing sugars, and particle size tests can be recommended to be performed at retest (Table 4).

Table 4. Specifications of mannitol and risk-assessment-based retesting.

3.2.3. Nitrosamine Risk Due to Excipients
The composition and impurity profile of excipients are often determined by their source (natural or synthesized). Nitrosating impurities (nitrites and nitrates) can be present in regularly used excipients, such as polyvinyl pyrrolidone (binding agent), pregelatinized starch (diluent and disintegrant), sodium starch glycolate (disintegrant), cross-polyvinyl pyrrolidone(disintegrant), lactose (diluent), and croscarmellose sodium (disintegrant); therefore, a risk factor in nitrosamine generation exists in pharmaceutical products containing amine containing components [72,75]. These impurities in excipients originate from processing water and manufacturing procedures, particularly those that involve acids and bleaching chemicals. One high-risk event that might lead to the generation of nitrosamines is oxidation during the drying process. Research on metformin tablets has demonstrated that the co-existence of two processing parameters, namely, heat and water, as well as the excipients’ nitrate and nitrite contents, are important factors in the formation of nitrosamine impurities. Various control strategies have been proposed to mitigate the risk of nitrosamine formation in pharmaceutical products, including the risk arising from the presence of nitrites and nitrate impurities in excipients [57,76].

3.3. Defining Retest Period
Upon receipt, the excipients undergo initial testing. The retest date will be determined by the finished product manufacturer’s policy, the stability of the excipients, and other available information. Manufacturers may choose to retest (first retest date), for example, one year later, at 50% of the excipient manufacturer’s designated retest or shelf life, or on the excipient manufacturer’s assigned retest date (whichever comes first). It is important to note that the excipient cannot be retested after the expiration date specified by the manufacturer. Within the boundaries of the retest date assigned by the excipient manufacturer, the finished product manufacturer may designate a second retest date either 1 year after the first retest date analysis or the excipient manufacturer’s retest date (whichever comes first), subject to the first retest date analytical data. Beyond the retest date designated by the excipient manufacturer, retest dates can be assigned depending on the stability characteristics of the excipients. For instance, 1 year may be assigned to very stable excipients, 6 months to stable excipients, and 3 months to limited-stability excipients (Table 5). Of course, this will be determined based on the analytical results of earlier retest analyses, as well as compliance to specifications.

Table 5. An illustration of defining retest period for excipients.

Charoo, N.A.; Akanji, O.; Rahman, Z.; Khan, A.A.; Badshah, A. Risk-Based Approach for Defining Retest Dates for Active Pharmaceutical Ingredients and Excipients. Pharmaceuticals 2024, 17, 903. https://doi.org/10.3390/ph17070903