Regulatory Considerations for Sampling in Drug Manufacturing

Explore the regulatory framework for sampling in this technical article.

Regulatory Guidance Related to Sampling

Table 1 provides an overview of key regulatory recommendations and guidance related to sampling that apply in most geographies. Additional guidance specific to local regions or countries should be considered to design the appropriate sampling strategy for any drug manufacturing process. General recommendations on eliminating operator bias and assuring the representativeness of samples are described in WHO Annex 4 FDA GMP and the International Council for Harmonization’s (ICH) ICH Q7.^3-5

Sampling Methods & Sample Volumes

Annex 4 of the WHO guidelines states that all sampling tools and implements should be made of inert materials that do not interact, or react, with the sample itself, thereby affecting the analytical results. It also states that the use of disposable, or single use, sampling materials has distinct advantages.³

FDA cGMP guidelines for Phase I drugs recommends the use of closed systems to minimize the risk of contamination and that sufficient sample is collected to perform additional testing if required. ⁴

The volume of samples to collect is dependent on type of sampling and stage of development. Sometimes the stability of the sample or the post-process lot verification is out of specification, and testing retained samples may be necessary. Typically, twice the quantity to perform all tests should be collected and retained for two years after the expiration date of the lot or completion of the trial.

Aseptic Process Sample Risk Mitigation

Bioburden control during the manufacturing of pharma and biopharmaceuticals is an ongoing challenge for manufacturers and extensive sampling to monitor bioburden levels is performed throughout drug manufacturing. Read our technical article on Sterile Sampling and Bioburden Control to explore this topic in depth.

EU GMP Annex 1 advocates that manufacturers implement comprehensive contamination control strategies (CCS) to identify “all critical control points and assess the effectiveness of all controls […] and monitoring measures employed to manage risks associated with contamination” from microbial and particulate sources.¹ This guidance advocates for terminal sterilization where possible, and where not possible, terminal bioburden reduction steps such as heat treatment combined with aseptic processing should be considered.

For products that can’t be sterilized in their final container, such as many biopharmaceuticals, EU GMP Annex 1 and other guidance documents recommend liquids should be sterilized by filtration through a sterilizing-grade filter of nominal pore size of 0.22 µm or less. In these circumstances, it is also recommended to implement bioburden reduction filters throughout the manufacturing process to maintain low bioburden levels in the process fluid before it reaches the sterilizing grade filter. Bioburden should be continually monitored and there should be working limits on bioburden levels, which are related to the efficacy of the sterilization method to be used.² This ensures that the bioburden requirements are met before sterilization in terms of verifying a sterility assurance level and a final bioburden level.

• For terminally sterilized products, where overkill sterilization parameters are set, bioburden might only be monitored at scheduled intervals.
• For aseptic processing, bioburden must be monitored before sterilization on every batch: samples should be collected from the bulk product and immediately prior to the final sterile filtration.

Sampling for Process Monitoring

The concept of process analytical technology (PAT) originated in a regulatory framework published by the United States Food and Drug Administration (FDA) in 2007.⁶ The goal of this framework is to encourage the use of more efficient strategies for development, manufacturing, and quality assurance with a focus on building quality into products. This science-driven, risk-based, proactive approach introduces the concept of Quality by Design (QbD) and is endorsed by the ICH draft guidance “Considerations for Complying With 21 CFR 211.110 Guidance for Industry”. It discusses quality considerations for drug products manufactured using advanced manufacturing methodologies that include process monitoring and modelling into manufacturing control strategies. ^{6- 13}

When integrated into development and manufacturing workflows, PAT improves process understanding and enables optimization of product quality. It supports a more dynamic manufacturing environment through real-time monitoring, accelerated control through feedback loops, real-time quality assurance, and real-time release. Appropriate sampling strategies, such as automated aseptic sampling, facilitate process monitoring using PAT. High sampling frequency, reduced turnaround times, and easy implementation into the process are key considerations especially relevant for this application.

For additional information on sampling solutions, please visit Bioprocess Sampling Systems: Find the Right Sampling Approach for Your Needs.