Risk Management 

A QRM Discussion of Microbial Contamination of Non-sterile Drug Prod-ucts, Using FDA and EMA Warning Letters Recorded between 2008 and 2016
Santos AMC, Doria MS, Meirinhos-Soares L, et al. (2018). PDA J Pharm Sci and Tech, vol. 72, pp. 62-72.

Microbial quality control of non-sterile drug products has been a concern to regulatory agencies and the pharmaceutical industry since the 1960s. Despite being an old challenge to companies, microbial contamination still affects a high number of manufacturers of non-sterile products. Consequences go well beyond the obvious direct costs related to batch rejections or product recalls, as human lives and a company’s reputation are significantly impacted if such events occur. To better manage risk and establish effective mitigation strategies, it is necessary to understand the microbial hazards involved in non-sterile drug products manufacturing, be able to evaluate their potential impact on final product quality, and apply mitigation actions. Herein we discuss the most likely root causes involved in micro-bial contaminations referenced in warning letters issued by US health authorities and non-compliance reports issued by European health authorities over a period of several years. The quality risk manage-ment tools proposed were applied to the data gathered from those databases, and a generic risk ranking was provided based on a panel of non-sterile drug product manufacturers that was assembled and giv-en the opportunity to perform the risk assessments. That panel identified gaps and defined potential mitigation actions, based on their own experience of potential risks expected for their processes. Major findings clearly indicate that the manufacturers affected by the warning letters should focus their atten-tion on process improvements and microbial control strategies, especially those related to microbial analysis and raw material quality control. Additionally, the WLs considered frequently referred to failures in quality-related issues, which indicates that the quality commitment should be reinforced at most companies to avoid microbiological contaminations.

Die mikrobielle Kontrollstrategie in der biopharmazeutischen Low-Bioburden-Wirkstoffproduktion
Haas C, Krenn B, PharmInd, (2017). vol. 79(10), pp. 1444-1450.

Microbial Control Strategy in the Biopharmaceutical Low Bioburden Drug Substance Production Microorganisms are essential for our wellbeing, but may also cause serious illness if they appear at the wrong time and place. Primarily depending on the dosage form, drug products have legally binding limits specifying their bioburden. The bioburden of the drug product in turn dictates whether the pro-cesses for manufacturing have to be run non-sterile, low bioburden or sterile (aseptic). Biophar-maceuticals, like monoclonal antibodies or other proteins for parenteral applications, have a mixed process regime. The drug substance is typically produced in a low bioburden regime, then formulated and sterile filtered in order to yield a sterile drug product. Low bioburden processes for drug substance production are legally in an intermediate position between aseptic and nonsterile regulatory require-ments, and there is a lack of dedicated clear legal guidance. This article covers the EU and US regula-tory landscape for low bioburden processes and outlines the required microbial control strategy.

The Impact of Cleanroom Behaviour on Contamination Control
Agricola K, (2017). PharmInd, vol. 79(1), pp. 112-116.

Cleanrooms are used to prevent unwanted contamination of products. People are the major source of particles and a fraction of these particles carry micro-organisms. Cleanroom behavior consists of 2 aspects. First, the various procedures that are in place to minimze the impact of people and second, the correct behavior of personnel that are executing these procedures. Contamination control starts with a risk assessment followed by a design of the contamination control solutions. After the contamination control solutions are established the effectiveness of the contamination control solution during opera-tion should be demonstrated by a monitoring program. In this paper, both aspects of cleanroom beha-vior will be addressed.

Quantitative Microbial Risk Assessment of Pharmaceutical Products
Eissa ME, (2017). PDA J Pharm Sci and Tech, vol. 71, pp. 245-251.

Monitoring of microbiological quality in the pharmaceutical industry is an important criterion that is required to justify safe product release to the drug market. Good manufacturing practice and efficient control on bioburden level of product components are critical parameters that influence the microbio-logical cleanliness of medicinal products. However, because microbial dispersion through the samples follows Poisson distribution, the rate of detection of microbiologically defective samples lambda (_) decreases when the number of defective units per batch decreases. When integrating a dose-response model of infection (Pinf) of a specific objectionable microbe with a contamination module, the overall probability of infection from a single batch of pharmaceutical product can be estimated. The combina-tion of Pinf with detectability chance of the test (Pdet) will yield a value that could be used as a quan-titative measure of the possibility of passing contaminated batch units of product with a certain load of a specific pathogen and infecting the final consumer without being detected in the firm. The simula-tion study can be used to assess the risk of contamination and infection from objectionable microor-ganisms for sterile and non-sterile products.

Microbial Risk in Pharmaceutical Manufacturing and ICH Q9
Guilfoyle DE, Friedman RL, Hughes PF, et al. (2013). PDA J Pharm Sci and Tech, vol. 67, pp. 79-80.

Pharmaceutical manufacturing generally comprises a complex, multi-step processing system in which significant risks from microbial contamination are presented by diverse sources including raw materi-als, personnel, equipment, the facility, the environment, and container-closures. A comprehensive and rigorous approach to process design, operational control, and maintenance minimizes contamination risk to the product. A robust program should be in place to identify potential sources of microbiologi-cal contamination and to mitigate such risks. The risk management program should incorporate new information as knowledge and understanding regarding potential sources of risk expands. Indeed, as has often been found, subtle changes or anomalies that develop throughout the process lifecycle may introduce significant new microbial hazards that should be identified, evaluated, and appropriately addressed.