Best Practices For Designing Microbiology Experiments

Qualifying microbiological methods is not easy, compared with analytical ones. This partly rests with the relatively high variation inherent in many methods, especially the culture-based ones. While it is unlikely that microbiological methods will meet the more exacting demands of their chemical counterparts, a sound scientific approach can be taken for running experiments and “qualification” of microbiological methods.

This article looks at factors to consider in drawing up assessment criteria for a microbiological test, including the limit of detection (for example, what is the lowest level of microorganisms that can be detected?), specificity (for example, what range of different microorganisms can be detected?), and quantification (for example, the counting accuracy). These types of questions should form the basis of a microbiological method’s validation strategy.

Tim Sandle has writen a new article, the reference is:  

Sandle, T. (2021) Best Practices For Designing Microbiology Experiments, Pharmaceutical Online, at: https://www.pharmaceuticalonline.com/doc/best-practices-for-designing-microbiology-experiments-0001

To access the aricle, see:  Outsourced Pharma

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Three Times And We’re Alright? Replicates In Validation

Numbers are essential to validation, just as numbers are critical to much of human activity. Numbers represent the continuous variables that we use to describe the world. Numbers can be something directly observable, or they can be theoretical constructs, used as parameters within a model. While both play a part in ‘validation’, it is with the former that this article toys with. The issue at hand is with how much validation is required at the performance qualification stage for a given validation stage? This may be a cleaning cycle on a vessel or an autoclave load.

How many times should such validation exercises be conducted in order to show that the results are reliable? While the number of runs should rest with the outcome of a risk assessment, it is generally the rule that the number of runs is seldom less than three. This begs two questions: why is three considered acceptable?, and is three enough? Before entering this debate it is interesting to consider what is so special about the number 3. After this, this article looks at the issue from the process validation perspective and the analytical assay perspective, concluding that three runs or assays is rarely enough. Moreover, with process validation greater weight should be put onto the lifecycle approach for trending and hence understanding process performance.

 

To view see: ResearchGate

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Cleaning validation Q&A

Recently Pharmig ran a session on cleaning validation. Here are some of the questions posed, together with the answers.

How can irregular shaped objects (such as pipes) be swabbed to an exact figure e.g. 25cm². Is the surface area calculated and a depth decided upon to swab?

This is obviously not easy. If the surface area is smaller, then the count is still assessed as if it was 25cm² (to indicate what a ‘norm’ is and to allow a comparison to be made). With other areas, all you can do is gain an approximate assessment in terms of the number and length of strokes. It is generally accepted that where a template cannot be used, the swabbing is approximate.

How can a swab template be used for the irregular surfaces? If not, what justification may be used?

A swab template cannot be used on an irregular surface, all you can do is gain an approximate assessment in terms of the number and length of strokes. It is generally accepted that where a template cannot be used, the swabbing is approximate.

Where you can, it is best to use a contact plate – it gives a better recovery and if there are cleaning residues present, the agar can contain an appropriate neutralisers.

Are there any regulations or guidelines for swabbing in this manner?

Not for microbiological swabbing. There are a number of good guidance texts, although these are not ‘standards’. The microbiological aspects are invariably overlooked, which was the reason for putting the webinar together.

I’d recommend the work of Andrew Walsh, for example: https://pbe-expert.com/wp-content/uploads/2018/04/CleaningValidationforthe21stCentury-AcceptanceLimitsforCleaningAgents.pdf

How can training be provided for personnel to encompass this irregular swabbing?

Pharmig have run too training courses run by Gordon Farquharson in relation to this.

The best way is to use old items of equipment and allow personnel to practice on the lab bench, assessing their technique e.g. number of swab strokes, twisting the swab head etc.

Also when swabbing a surface do companies use cut out templates to get an accurate surface area? Or do companies just go on samplers judgement of surface area- between different samplers this could introduce a lot of variability?

Some companies use templates, which are sterilised. These will only work on relatively flat, regular shaped surfaces.

Others use judgement, and this has to be applied to irregular shaped surfaces. This can be supported by training.

As cannot contaminate equipment with organisms like can with chemicals. What does he think to the suggestion of supplementing cleaning validation study with lab based studies on samples of surfaces representative of the equipment? E.g. samples of SS 316L in lab – could contaminate with organism(s) representative of those found in facility and demonstrate effectiveness of cleaning regime/agents etc. is possible.  Overkill & unnecessary or good to do if have the time & resource?

This is useful if there is sufficient resource. The method outlined is similar to disinfectant efficacy testing in terms of phase 2 surface evaluation. However, it is not (as yet) a regulatory requirement. The standard approach is to evaluate ‘cleanliness’ through direct (swabbing) and indirect (rinse) samples.

The reference to facility isolates is interesting, although these are difficult to standardise.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

WHO revises non-sterile process validation

The World Health Organization (WHO) is revising its guidance on non-sterile processing validation. The guidance is titled “Revision of the Supplementary Guidelines on Good manufacturing Practice: Non-sterile process validation.”

The process of updating began in 2013. In August 2014 a new draft was circulated for comments. The final version is expected early in 2015.

Process validation data should be generated for all products to demonstrate the adequacy of the manufacturing process. The validation should be carried out in accordance with GMP and data should be held at the manufacturing location whenever possible and be available for inspection.

Central to the guidance is risk assessment, as the guidance states: “risk-based approach in validation is recommended. The use of in-line, online and/or at-line controls and monitoring are recommended to ensure that a process is in a state of control during manufacture.”

The current draft can be viewed here: WHO

Posted by Tim Sandle

EU GMP Annex 15 Revisions: Improving Qualification and Validation

Validation and qualification form an important part of the quality system in the pharmaceutical sector and can be defined in different ways. Tim Sandle, Head of Microbiology, BPL, UK discusses some standard definitions from a Good Manufacturing Practice (GMP) perspective.

The article can be viewed on the CleanroomTechnology website here.

Posted by Tim Sandle

EU GMP Annex 15 Revisions: Improving Qualification and Validation

Annex 15 of the EU GMP guide is concerned with the ‘Qualification and Validation’ of pharmaceutical facilities, addressing requirements for equipment, utilities and processes that are used for the manufacture of medicinal products. The broad requirement of Annex 15 is that a pharma manufacturer needs to identify what qualification and validation work is required; next, the manufacturer must prove that critical aspects of work are controlled; and finally, the key elements of qualification and validation need to be defined and documented.

Validation and qualification form an important part of the quality system in the pharmaceutical sector and can be defined in different ways. Tim Sandle, Head of Microbiology, BPL, UK discusses some standard definitions from a Good Manufacturing Practice (GMP) perspective.

The article has been published in the current edition of Cleanroom Technology.

The reference is:

Sandle, T. (2014) EU GMP Annex 15 Revisions: Improving Qualification and Validation, Cleanroom Technology, April 2014, pp14-16

If you are interested in reading the article, please contact Tim Sandle

Posted by Tim Sandle

New Process Validation Guideline (EMA)

The European Medicines Agency has published the following concept paper ‘Guideline on process validation for finished products -information and data to be provided in regulatory submissions’.

Process validation can be defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. Continuous process verification has been introduced to cover an alternative approach to process validation based on a continuous monitoring of manufacturing performance. These concepts form the basis of the new guideline.

The guideline is brought into line with ICH Q8, Q9 and Q10 documents and the possibility to use continuous process verification in addition to, or instead of, traditional process validation described in the previous guideline has been added and is encouraged. This guideline does not introduce new requirements on medicinal products already authorised and on the market, but clarifies how companies can take advantage of the new possibilities given when applying enhanced process understanding coupled with risk management tools under an efficient quality system as described by ICH Q8, Q9 and Q10.

The EMA paper can be accessed here.

Posted by Tim Sandle