Understanding the effect of API changes in pharmaceutical processing

There is, of course, the natural curiosity of the scientist to understand what they are working with, and how the molecule’s journey influences its performance. The regulators who control medicines for the benefit of the patients who take them also require an understanding of what is happening to the drug molecules and particles. These two interests combine in Quality by Design (QbD) initiatives, where scientists and regulators come together to provide a thorough understanding of the manufacturing process of a dosage form, to ensure that it is effective and fit for purpose.

Over the past few years there have been significant scientific advances in understanding how a molecule joins, and is incorporated into, the crystal that is its home until it reaches the gastric intestinal (GI) tract. Despite the fact that the instant of nucleation remains a moment of magic or mystery, the growth of a crystal can be followed, understood and modelled and the process of isolating and drying formed crystals has been closely studied.

The milling process has opened itself to greater understanding in recent years, such that the mechanism and extent of crystal fracture can be followed, and the properties of the resultant particles predicted with greater accuracy. We can characterise the end material, with its single particles, agglomerates or aggregates by size, shape and surface area, and examine them in detail using microscopy techniques. At the end of the particles’ journey to the dosage form we can follow the disintegration of the dosage form and the dissolution of the particles in a range of model media. This data can be combined with other observations to develop models of how drugs will reach the bloodstream and eventually be eliminated.

Characterisation challenges

The use of chemical imaging to investigate the distribution of single components with a formulated sample have previously been reported2. However, due to limitations in the optical resolution of such systems, the individual particle sizes cannot be directly measured; pixels often contain more than one of the constituents. Pixels are instead colour coded to indicate the relative concentration of each constituent, thus enabling identification of ‘domains’ (areas of high component concentration). The relationship between domain size and particle size can be affected by multiple factors such as homogeneity, aggregation and morphology.

The challenge of characterising the primary particle characteristics of single components within multi-component systems has recently been addressed through the application of image-based particle characterisation with integrated Raman capability. This approach enables the characterisation of particles in terms of both size and shape. Utilising the Raman probe, the components within a blended sample can be sub-classified in terms of their chemistry, thus enabling the actual particle size distribution of individual components to be determined rather than the domain size.

Examples of this approach have recently been reported; Gamble3 demonstrated the process-induced attrition of a formulated API. It was demonstrated that blending and cone milling process steps had little impact on the primary particle size of the API, whilst a powder feed system, associated to a roller compactor, was observed to significantly reduce particle size. Such attrition could impact the processability of the material, both positively and negatively. This work highlighted that the powder feeding step, a hitherto overlooked sub-process, has a significant impact on the API/blend properties, and therefore requires consideration when selecting sources of process variation.

In addition to size, changes to the particle shape were also investigated. The combination of the two datasets provides insight into the attrition mechanisms within the unit processes. For the milling process, minor shifts in both size and shape could suggest a surface abrasion mechanism where the elongated particles undergo ‘chipping’. For the powder feed system, however, more significant shifts in both size and shape were proposed to suggest a bulk fracture mechanism where the particles undergo more complete fracture.

The work not only demonstrates that the input API size was impacted by the process, but that by characterising the API particle characteristics one could understand the mechanism of the change. This improved understanding of the intermediate API/blend characteristics could be applied to subsequent processing steps, removing the requirement to rely on the input particle characterisation data.

Subsequent work4 utilised the measured API attrition to determine the location of attrition events within the feed system. These efforts applied the understanding of the process/API interaction in order to develop a better elucidation of the unit process and to investigate the impact of varying process conditions on the extent of attrition. The study demonstrated how changes in the feed screw speed could alter the extent of attrition; increased feed rates resulted in increased levels of attrition. This raises an interesting issue; for such unit processes the feed system is often utilised as part of the automated feedback control to maintain the intermediate product characteristics, but if by changing the feed system we alter the blend characteristics, the tool used to control process variation could be a significant source of said variation.

Active pharmaceutical ingredients (APIs) refer to vital chemicals that are responsible for making the drug work. Depending on type, biotech/biological API, synthetic chemical API, high-potency API, plant extracts API, and classical fermentation API are some of the products available in the active pharmaceutical ingredients (API) market.

Analysts at TMR emphasize that the global active pharmaceutical ingredients (API) market will show promising growth on the back of increase in number of abbreviated new drug applications (ANDA. This aside, the market will gain advantage of growing focus on government bodies toward biomedical innovation.

Key Findings of Active Pharmaceutical Ingredients (API) Market Report

The global active pharmaceutical ingredients (API) market was pegged at approximately US$ 169.1 Bn in 2018.

Analysts at TMR highlight that the market will develop at a promising CAGR of 5.4% during 2019–2027.

On regional front, Asia Pacific is one of the prominent regions for the market growth due to presence of major important players.

The nature of active pharmaceutical ingredients (API) market is highly fragmented.

Active Pharmaceutical Ingredients (API) Market: Key Driving Factors and Promising Avenues

The global active pharmaceutical ingredients (API) market is estimated to experience prominent expansion opportunities during the forecast period of 2019 to 2027.This growth is attributed to growth in abbreviated new drug applications (ANDA) in the recent few years.

Similarly, the market for active pharmaceutical ingredients (API) will gain promising avenues for development on the back of rising focus of government authorities toward biomedical innovation.

The rising number of patients living with various critical health conditions such as cardiovascular diseases, cancer, and diabetes is stimulating noteworthy demand avenues in the global the active pharmaceutical ingredients (API) market.

This aside, the market for active pharmaceutical ingredients (API) is expected to gain prominent sales opportunities in all worldwide location on the back of increasing older population and sedentary lifestyles of major populace all across the globe.

In recent years, the active pharmaceutical ingredients (API) market is experiencing remarkable growth in demand for cost-effective drug substitutes. Several vendors engaged in the pharmaceutical drug manufacturing do not have adequate in-house capacity to fulfill this stupendous growth in demand. This situation has resulted in increased number of active pharmaceutical ingredients (API) producers. This scenario shows that the active pharmaceutical ingredients (API) market will grow at rapid pace in the upcoming years.

DEFINITION OF ACTIVE PHARMACEUTICAL INGREDIENT (API)

Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when used so, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body (WHO Technical Report Series No.970,2012).

CLASSIFICATION OF ACTIVE PHARMACEUTICAL INGREDIENT (API)

API classification can be divided into:

i. Inorganic substances;
ii. Organic substances (isolated from materials of animal or human origin); and
iii. Organic substances (synthetic or semi-synthetic or isolated from herbal sources or micro-organisms).

SCOPE

i.The guideline encompasses the APIs of new products for registration and current / existing registered products. This is applicable to all pharmaceutical products (excluding traditional products, veterinary products, and health supplement products) both locally manufactured and imported.
ii. Biological active substances and immunological active substances are excluded from the scope of this guideline. Please refer to relevant guidelines available for Biologics.
iii. APIs used in products for export only (FEO) are exempted from the requirement for submission of the Drug Master File (DMF) and Certification of Suitability (CEP) in the product application.
iv. The API information required as in this guideline is only applicable for final APIs and not intermediate API

v. Separate registration of the APIs is not a requirement for the purpose of product registration. However, the required technical documentation pertaining to each API should be submitted with the new product registration application.
vi. Assessment of an API will be performed once submission of a new product registration application has been done.
vii. Assessment of an API will also be performed for a registered product prior to a product renewal application.