Understanding 5 Batch Analysis for Technical Grade Active Substances: Ensuring Product Safety and Regulatory Compliance

Why do we need it?

Whether you are registering your Plant Protection Product (PPP) or Biocide Product (BP) you are required to verify the contents of the technical grade Active substance (TGAS) produced by the manufacturer.

The technical grade will be used to develop and formulate various PPPs or BPs, so it is important to know the composition and consider any potential effects additives or impurities might have on end-use products.

The 5 Batch process confirms the level of Active Ingredient (AI) in the product, as well as identifies and quantifies any impurities. Regulations require a minimum of 98% of the technical material to be quantified and include data on all components present as active ingredients, inactive and active isomers, impurities, and additives at levels of more than 0.1%.

This establishes the hazardous potential of the product by determining anything of toxicological concern to humans, animals, or the environment. 

All manufacturing processes vary and during the production of the AI, chemical reactions may take place that form impurities. Not all technical materials are 100% AI and therefore there will be some additives, or solvents used during the manufacturing process that also need to be quantified.

In some cases, especially with the rise of natural products, the material is made of lower purity. We have seen TGAS from 30% to 100% purity, so if your AI is only 30%, there are a lot of other components to identify that ensure the product meets regulatory requirements and will be safe for use on the market.

Significant vs Relevant Impurities

Relevant impurities are defined as impurities at any level that have toxicological effects on the environment. 

Significant impurities are those present above 0.1% of the AI content. They may not be hazardous but make up what is considered a significant portion of the composition.

Potential areas to consider when commissioning a 5-batch analysis:

• Moisture and Ash content

• Elements that may occur naturally or be introduced by the manufacturing process

• Solvents added during the manufacturing process

• Other additives where the AI is of a lower purity

• Isomers 

• Other Impurities that may form naturally or as part of the manufacturing process such as those affected by heating

How do we deliver these services efficiently?

The key is knowing the details of the manufacturing process and having multiple techniques available to screen the batches to determine composition as quickly as possible.

Techniques such as GC-MS and LC-MS/MS are usually fundamental in screening as they can identify a wide range of potential impurities at low levels.

We are also now seeing a larger push for elemental impurity identification so a technique such as ICP-OES with a heat map screening is useful. 

ICP-MS can be a great partner for anything elemental that needs to be quantified at even lower levels, or where certain territories specify extremely low limits of acceptance.

A 5 Batch can take anywhere from 2-6 months from screening through to GLP 5 Batch Report on average depending on the purity and details of the process that are available.

The higher the purity, and the higher clarity of the process, the quicker and simpler the process is.

What is technical equivalence?

This is required when there is a change to the manufacturing process, or source material used, to establish that the material is equivalent to the original registration. 

Below is a summary outlining the differences:

As you can see, there is not much difference in the process, but the key to delivery is knowing the changes. This reduces the techniques required, which then, of course, reduces the overall cost. 

If the screening can demonstrate the product equivalence, and methods are already validated, then no further validation is necessary and the entire process could be completed very quickly.

What are the steps to 5 Batch Analysis?

The steps were previously outlined, but for enhanced clarity and detail, they are now presented here.

1) Screening & confirmation of AI content

After a review of the manufacturing process, the AI content will be quantified, and screens performed to carry out an initial AI-based quantification of impurities likely to be present above 0.1%. 

Screening techniques will provide a picture of the product composition and aid in the qualification of expected impurities, as well as potential unknown impurities. 

The techniques selected initially will cover a wide range of parameters in order to provide a full profile.

A typical screening may look like this, and using GC-MS or LC-MS library searches various peaks can be identified. 

2) Method Development for Impurities

Once screening is completed, any impurities of relevance or significance then require further quantification. Preferably against reference material where this is available.

Conditions will be refined to quantify the impurity levels using the preferred techniques selected during the screening process.

3) Method Validation for AI, including relevant and significant impurities

All details by this point will be known and method validation studies will be designed to comply with the territories you intend to register the TGAS. 

Studies can be designed to meet global regulatory requirements for areas such as Europe, Brazil, USA and Australia. Including typical parameters such as:

Linearity – to show the calibrated range of the method, usually with a range ± 20% of the AI or impurity nominal content

Precision – to demonstrate the repeatability of the method using samples or standards, and if required intermediate precision on a separate day by a separate analyst, or on a separate instrument

Specificity and confirmation – to demonstrate no interferences coming from the reagents, blank or impurities and to confirm the species identity. 

Accuracy (Recovery) – spiking onto the sample to show the recovery of the method at nominal or low ranges as required.

Robustness – some authorities also require the method to be tested in terms of changing columns or other conditions to determine the extent that changes may impact the results.

LOQ – the limit of quantification of the method (the lowest standard)

4) 5 Batch Analysis

This is the final stage and requires the quantification of 5 selected batches of the AI and all relevant and significant impurities determined during the screening process, and validated. 

Other impurities may also be considered such as sulphated ash, moisture, unsaponifiable matter etc.

These do not require method validation as there are published methods available. These can be completed simply and quickly as part of the 5-batch analysis.

An example impurity 5 batch analysis composition

Many factors can be determined depending on your product. The important factor is that 98% is quantified and methods are validated for the purpose of analysis.

About Oxford Analytical Services Ltd

Oxford Analytical has been a GLP testing laboratory since its foundation in 1989 that specialises in providing analytical services to clients across a range of industries. OAS offers a wide range of services, including chemical analysis, stability testing, and product development support. They also provide consultancy services to help clients navigate regulatory compliance and ensure product safety.

OAS has state-of-the-art analytical facilities equipped with the latest technologies and instruments, staffed by highly trained staff with expertise in various analytical techniques. They use advanced analytical methods to identify, quantify, and characterise chemical substances, helping clients to make informed decisions about their products.

OAS serves a broad range of industries with a strong expertise in biocides, biostimulants and plant protection products. They are committed to providing high-quality analytical services with a focus on accuracy, reliability, and timely delivery. By partnering with OAS, clients can access the expertise and resources they need to support their research, development, and quality control efforts.

Whatever your requirements Oxford Analytical Services Ltd provides a comprehensive range of physical and chemical analytical services combined with the highest integrity and standards of service.

OAS support many industries specialising in registration support for the Plant Protection and Biocides industries, but also for many other industries with our wide range of equipment and skills.

Website: https://www.oxford-analytical.co.uk/

Contact person: Sherry White

Email:enquiries@oxford-analytical.co.uk

Tel: +44 1869 629821

This article was initially published in AgroPages' '2023 CRO & CRAO Manual' magazine.