Manufacturing: GMP

Following good manufacturing practices (GMP) is crucial for stability testing. The analytical data generated from stability studies is a pivotal part of a regulatory dossier submission to substantiate the shelf life claimed for the drug product or drug substance and further support that shelf-life post-approval. All aspects of the stability study must be executed to the highest level of quality to ensure they are resilient to the regulatory scrutiny expected of any medicinal product

Paul Barr at Broughton

Stability studies are a vital part of pharmaceutical development and supporting documentation for regulatory submissions. They must be bespoke, while adhering to requirements as outlined by the International Council for the Harmonisation of Technical Requirements for Pharmaceuticals in Human Use (ICH), and adopted by agencies such as the US Food and Drug Administration (FDA), and UK Medicines and Healthcare Products Regulatory Association (MHRA). Following EU Good Manufacturing Practice (GMP) during a stability study supports compliance of the pharmaceutical product with the standards defined by these authorities.

Stability studies involve placing samples (within their container closure system and any other packaging) into environmentally controlled chambers to determine how the product or substance will change over time when subjected to specific environmental conditions. During the study, samples will be periodically assessed through physicochemical and microbiological tests, according to the study protocol. For example, notable changes to pH, degradation, dissolution, assay, microbial activity and moisture content can be identified. Stability studies are generally conducted at the late-stage process of drug development, often starting at the preclinical stage, and continuing during clinical trials. To streamline route-to-market, there is a trend toward pharmaceutical businesses adopting stability studies earlier into their development process.

Several design factors must be considered before initiating a stability study. Stability study designs may be straightforward with a single formulation and strength, but this is rarely the case.

Firstly, for formal registration stability studies required to support the regulatory submission for a medicinal product, it is a regulatory requirement that these studies be performed on multiple batches of the manufactured drug product to assess the potential batch-to-batch variability of the product’s shelf life. Stability studies for a drug product may consist of multiple strengths, formulations, packaging types, storage orientations and container closure systems – numerous stock-keeping units (SKUs).

Another consideration is the impact of the product’s packaging on stability. Generally, the impact will depend on the study, and packaging assessments may not be required for all stability studies. For example, in-use stability tests assess product quality after any packaging has been opened. However, stability studies of the drug substance and product must simulate its expected storage conditions to establish shelf life.

Manufacturers may also want to consider the impact of the surface area contact ratio of the drug product to the container closure system. For drug products, shelf-life stability studies should be performed in the primary container closure system proposed for marketing. However, if the secondary packaging has protective properties, and the labelling states that the product is to be stored in the primary and secondary packaging, then this must also be assessed in the stability study.

Finally, when designing a stability study, the sample quantities set down at the start of the study are critical. Insufficient quantities can have a huge impact on cost and timelines, as stability studies may need to be repeated. Having adequate sample quantities is crucial to cover all testing specified in the stability study protocol, and to account for potential repeat testing, investigation of atypical results, and subsequent confirmation of data. Also, to provide flexibility, a sample quantity overage can allow for additional ad hoc testing that may be required at unspecified stability time points.

GMP standards describe the minimum criteria that pharmaceutical manufacturers must meet throughout the manufacture and distribution of the drug substance or drug product. In Europe, for example, any medicines manufactured that are intended for use on the continent must be manufactured in line with GMP. Manufacturing to GMP standards requires the manufacturer to comply with all relevant standards, including those from the International Organization for Standarization (ISO) or The Orange Guide.

If these standards are adhered to, and the product is made to GMP Standards and verified through an audit, the regulatory authority will then grant a manufacturing licence.

These licences are granted for specific activities: some may be granted for quality control (QC) testing only, and others may have a manufacturing licence for manufacturing and testing.

Not adhering to this guidance, either internally or by not partnering with a certified contract research organisation (CRO), closes off an entire market to a manufacturer from the outset. GMP requires that medicines are of constant high quality, appropriate for intended use and meet the requirements of the marketing authorisation or clinical trial authorisation.1 As stability studies cover batch-to-batch variability, simulated storage conditions and the impact of contact with packaging, these areas are all pivotal to testing the drug product’s quality.

With parts of the ICH standard due to change, with guidance to be released for public comment in 2024, alterations to practices recognised as GMP are expected.2 The revisions are aimed to harmonise standards and align stability testing further with GMP practices.3 The stability guidelines were last updated in 2003, with some standards in the guidance not updated since the 1990s. Guidance for testing new dosage forms and photostability testing of new drug substances and products were last finalised in 1996.

The aim is to consolidate standards Q1A-F into a cohesive document that will address core stability principles in the hope of making it more applicable across different product types such as advanced therapies and biologics. Updates will include the integration of modern risk management principles and the adoption of new technologies that support predictive modelling and enhanced stability strategies, while also clarifying ambiguities in the current guidelines.

Pharmaceutical businesses may wish to outsource stability studies for several reasons, including a lack of space, facilities or resources. In addition, stability testing and analysis is a specialist field, and with the updated guidance to come, it’s important to work with a trusted partner with regulatory expertise. If a company does not have in-house experts for method development and validation, particularly when working with a complex drug product, outsourcing may be a good solution.

Stability experts typically work with a manufacturer’s in-house scientists to consult on study design and create forward-looking testing strategies. With experience in similar studies, the partner should have a broad understanding of product types and their possible stress points and use this to suggest appropriate ways of monitoring them proactively.

Some CROs will have broader scientific subject matter experts available, such as analytical chemists and toxicologists, who can help provide a complete analysis of test data, understand deviations and troubleshoot problems. If the partner is also an expert in extractables and leachables (E&L), studies can be run in parallel, streamlining the route-to-market. Finally, a partner with an in-house regulatory team can help prepare everything needed for submission to the regulatory body.

With stability studies practices likely to change in the near future, it’s important to be on top of the latest regulations and guidance when it comes to GMP. Working with a specialist testing and regulatory consultancy can be beneficial to companies that require more expertise, to address any uncertainty. With stability studies forming an important part of a regulatory submission, certainty over documentation and trust in your compliance documents is paramount.

References

1. Visit: ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice
2. Visit: raps.org/News-and-Articles/News-Articles/2023/3/Pharma-official-Expect-substantial-revision-of-ICH
3. Visit: link.springer.com/article/10.1208/s12248-021-00641-6