New product development: Consideration of the microbiological control factors

An important aspect of ‘Quality by Design’ is with ensuring that product development ensures the quality of the final product. This is only possible if the development process provides a detailed understanding of the factors affecting product quality. This includes the formulation of the finished product and the manufacturing process.

?

This article looks at Quality by Design, in terms of new product development, from the microbiological perspective.

?

Essential factors

?

The design considerations for a pharmaceutical product will have some points of commonality and some differences depending upon whether the product is a sterile product; a multidose product requiring a preservative; or a dry, solid oral dosage form. There will be different levels of risk, based on the product type and also with the intended patient population. Embarking on a proactive suitable quality risk management approach is essential (1).

?

In approaching the identification of focal points, the goal is to identify microbiological challenges.

?

The main factors to consider when considering microbiological quality include (2, 3):

?

• Bioburden levels of all ingredients (including what the expectation is and what the maximum value should be). This can extend to a consideration of any specific groups of organisms of concern.
• The microbial hazards present in the manufacturing process, in terms of contamination sources using risk assessment tools to consider both the severity of the hazard and the likelihood of contamination occurring.
• The use and effectiveness of preservatives (if appropriate for the product type).
• The effectiveness of cleaning processes.
• The effectiveness of disinfection or decontamination processes.
• The effectiveness of sterilization processes (if applicable).
• Design of equipment and utilities.
• Cleaning and disinfection of facilities.
• Suitability of microbiological test procedures in terms of contamination detection and the ability to detect failures at or above the acceptance criteria. It is useful to establish robust test methods early in the process of product development.

?

The above areas are considered in more detail next.

?

Formulation

?

When developing the formulation of a new drug, optimally the aim will be to keep this as simple as possible. Moreover, there is a need to justify the use and quantity of each ingredient as well as the interaction between each ingredient. From the microbiological perspective understanding how ingredients interact is as important as considering their individual bioburdens. For example, two ingredients coming together may create a pH that is suitable to sustain a larger variety of organisms compared with the two ingredients on their own.

?

Design space

?

The formulation process must define the design space. This includes considering aspects like whether preservative efficacy is affected by pH; the moisture content of the product (and the extent to which this is constant or variable); and process temperatures.

?

During manufacturing, hold times need to be understood, with sampling orientated towards the end of the hold time. Should a longer process interruption occur, the impact on the potential for microbial growth needs to be understood.

?

Certain aspects of the formulation may encourage and support or inhibit microbial growth. This extends to water activity (4).

Ingredients and suppliers

?

A specification needs to be in place for all products based around the formulation and processing steps. With each ingredient a microbiological specification is likely to be required. In instances where a specification is not required, this needs to be justified (for example, where an ingredient is inherently antimicrobial). Where ingredients require sampling for microbiological tests, the sampling procedures and environment should be designed to prevent contamination. Additional microbiological testing will be required in order to establish the material shelf-life (5).

?

Vendors of materials should be audited, and the audit process should include consideration of microbial contamination risks. This should extend to ensuring that materials arrive in suitable packaging, preventing the ingredients from moisture or other contamination ingress.

?

The bioburden for each ingredient must be proportional to the proportion of the ingredient that goes into the final product.

?

Process

?

Attention needs to be given to the manufacturing process in terms of microbial control and the process can often vary more than the formulation. Given the potential to influence microbial growth, attention should be paid to (6 – 8):

?

• Process temperatures.
• Heating and cooling times.
• Hold times.
• Mixing times.
• Mixing rates.
• Drying rates and times.
• Moisture content.
• Oxygen content.

?

Among other factors. Invariably water presents the biggest microbiological risk.

?

Contamination control measures also need to be factored in, such as the use of filtration; mechanical stressors; chromatography; pH adjustment; sterilization and so on (9). Microbial control measures cannot be considered in isolation as a given method may adversely affect the formulation leading to an alternative method being required (such as a particular filter leading to excessive absorption of an active pharmaceutical ingredient).

?

Understanding contamination sources and factors that can lead to an increase or decrease in contamination can assist with the design of the environmental monitoring program.

?

Technology transfer

?

To ensure success, the technology transfer process needs to be suitably defined. This is not only a matter for the formulation; in addition, the production facilities need to be assessed as suitable, including having cleanrooms of appropriate size and layout; the use of appropriate airflows and filters; ensuing equipment is suitable and that it can be effectively qualified and cleaned; and will personnel training.

?

Scale-up

?

The scale-up process needs to be validated and in defining critical process parameters and critical quality attributes there will be a number of microbiological measures to define (10).

?

Sampling and testing considerations

?

There are some necessary decisions to be made in relation to sampling and testing. This applies to incoming materials, intermediate manufacturing and with finished products and includes:

?

• Selecting a suitable sample size. During development, batches may be small therefore sampling and testing need to be scaled as appropriate. When taking a sample, the sample should be representative of the container (and here a multi-stage sampling tool may be required).
• Neutralization of antimicrobial activity (this is necessary with several materials).
• Understanding of the types of contamination likely to be present.

?

For new product development, it is useful to keep in mind that processes can change and therefore steps should be taken to ensure that results are comparable at different stages of the product development.

?

Sampling and testing should extend to the requirements of stability testing and with defining the key microbiological aspects that will require assessment over the shelf-life of the product (11).

?

Test methods

?

The types of microbiological test methods required will vary according to the product. The process formulation will require bioburden testing and with the finished product, depending on the product type, this may require bioburden testing, preservative efficacy testing, sterility testing and endotoxin testing.

Each test method needs to be demonstrated as suitable for the recovery of microorganisms. This can be challenging with some product types, especially those that are not in liquid form. Method suitability is the minimum requirement, to show recovery of a representative set of microorganisms. For non-compendial methods, method validation is required. This needs to account for the fact that different microorganisms will have differing growth requirement. The culture medium selected needs to be suitable for recovery, and specific media will be needed where the targeting of specific organisms is required.

?

Testing considerations will include an assessment of shelf-life.

?

Packaging

?

The design of the primary packaging should not be overlooked, especially as good packaging design is essential for preventing microbial contamination. Selecting packaging will need to take into account product quantities and the intended use of a product. ?

?

Summary

?

This week’s article has looked at some of the microbiological aspects necessary for new product development. Understanding the product profile and microbial contamination risks are important both for the development phase and for the scale-up.

?

Assessing these risks will be a combination of environmental controls and product-based specifications. When developing specifications, these should center of ensuring the suitability of the product; showing that the product is safe for use; and with demonstrating that GMP requirements have been consistently met. Specifications need to be set realistically and be supported by data.

?

References

?

1.????? Long, M, (2013) Risk management: regulatory expectations, risk perception and organizational integration’, in H Mollah, H Baseman, E Long (eds), Risk Management – Applications in Pharmaceutical and Biopharmaceutical, Wiley, Hoboken, NJ, pp. 49–73

2.????? Yu, L.X. (2008) Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control. Pharm Res 25, 781–791 (https://doi.org/10.1007/s11095-007-9511-1

3.????? Sandle, T. (2013) Risk management and risk assessment for pharmaceutical manufacturing – a contamination control perspective, Microbiol. Solutions, vol. 1, pp. 164

4.????? Cundell, AM (2009) Effects of water activity on microorganisms, in AM Cundell and AJ Fontana (eds), Water Activity Applications in the Pharmaceutical Industry, Davis Healthcare International Publishing, River Grove, IL , pp. 175–204

5.????? Cundell, AM (2005) Managing the microbiological quality of pharmaceutical excipients, PDA J. Pharm. Sci. Technol., 59 (6): 381–395

6.????? Izawa S, Inoue Y, Kimura A. (1995) Oxidative stress response in yeast: effect of glutathione on adaptation to hydrogen peroxide stress in Saccharomyces cerevisiae. FEBS Lett. 368(1):73–6

7.????? Cundell, T. (2016) The role of water activity in the microbial stability of non-sterile pharmaceutical drug products. European Pharmaceutical Review: https://www.europeanpharmaceuticalreview.com/29889/european-pharmaceutical-review-magazine/past-issues/issue-1-2015/the-role-of-water-activity-in-the-microbial-stability-of-non-sterile-pharmaceutical-drug-products/

8.????? Fu, N, Chen, XD (2006) Towards a maximal cell survival in convective thermal drying processes Food Res. Int. , 44: 1127–1149

9.????? Blair, TC, Buckton, G, Bloomfield, S (1991) On the mechanism of kill of microbial contaminants during tablet compression, Int. J. Pharm. , 7 (3): 111–115

10.? Ganzer, W., Materna, J., Mitchell, M., and L. K. Wall, L. (2005) Current thoughts on critical process parameters (CPP’s) and API Syntheses. Pharm Tech.

11.? Dao, H., Lakhani, P., Police, A. et al. (2018) Microbial Stability of Pharmaceutical and Cosmetic Products. AAPS PharmSciTech 19: 60–78 https://doi.org/10.1208/s12249-017-0875-1