Graphic representation of the human upper body with a focus on the lungs, which are highlighted in bright red-orange.

Active pharmaceutical ingredients (API)

from development to production

The particle size is an important parameter in the development and manufacture of pharmaceutical products. Micronisation serves to significantly improve the dissolution rate of active pharmaceutical ingredients (API). In the case of inhalers (DPI – dry powder inhalers), the particle size of the active ingredients and carriers is a decisive, quality-determining property in the formulation of the dry powder. The optimal particle size ensures the transport of the medicine into the lungs and also its effectiveness.

Flexibility is required with respect to the different fineness values and products. Furthermore, varying batch sizes often call for different handling concepts.

The process transfer is a special challenge: whether it be from development to production scale regardless of the location, or to a toll manufacturer.

The quality is always paramount in the manufacture of pharmaceuticals, achieved through reliable, reproducible and well-documented processes.

Whether continuous production or batch mode, the construction materials, surfaces, the automation and documentation of production systems for pharmaceuticals are all prepared according to cGMP design criteria.

A solution for manifold challenges

Quality begins as early as the planning and project phase. An individual system concept is prepared to match the user requirement specification (URS). A wide range of different technologies from preliminary crushing to fine grinding and micronisation can be chosen from.

The aim is to achieve an optimum grinding process.
Typical quality-determining features are:

Product- and process-gas-contact parts in AISI 316L
Surface roughness standard Ra < 0.8 µm (dependent on the product Ra < 0.4 or Ra < 0.25 with/without eletropolishing)
Seals and filter materials are food- and drug-grade quality as defined in FDA 21CFR177.2600
The pharma bearing concept includes a clear separation between drive and process, thus the end product contains neither particles nor oil
Encapsulated, permanently lubricated bearing or the use of USDA-H1 grease
Fully CIP/SIP-capable machines thanks to the patented Pharmaplex® bearing concept
Largely monobloc components with a minimum of welds and seals
Design free from dead spaces
Drainage and venting points for complete emptying with CIP/SIP-capable systems
Controls as defined in GAMP 5 and 21 CFR Part 11

Increasingly important is to ensure the flexibility and thus to make the systems obsolescence-proof. The multi-mill system concept is a tried-and-tested approach in order to produce different products, fineness values and batch sizes.

Design free from dead spaces
Easy to dismantle and clean
High production quality
Modern automation concepts
Manufacture in monobloc design
Validation documents

Table of practical examples

Typical examples of ground active ingredients (API).
Product	End-product fineness	Throughput kg/h	Machine size
Acemetacin	99 % < 32 µm; 50 % < 8	190	200 ZPS
Acyclovir	97 % < 28 µm	20	140 AFG
Amoxicillin	99 % < 18 µm; 50 % < 6	9	50 ZPS
Bisphenol A	99 % < 63 µm	370	40 ACM
Carbamazepine	86 % < 8 µm	2	100 AFG
Cholestyramine	99 % < 7.5 µm	0,3	100 AFG
Celecoxib	90 % < 23 µm	33	200 AS
Cilostazol	99 % < 10 µm	4	100 AFG
Cimetidine	99 % < 32 µm	11	100 AFG
Dextromethorphan	97 % < 5 µm	0,5	50 AS
Flutrimazole	97 % < 38 µm; 50 % < 4,4	5	50 ZPS
Lactose	97 % < 25 µm; 50 % < 8	20 - 25	50 ZPS
Lactose	99 % < 30 µm	137	10 ACM
Lactose	97 % > 8.9 mm	16	200 AS
Lactose	99 % < 5 µm	1	100 AS
Lactose	95 % < 6 µm	39	200 AFG
Lactose	98 % < 10 µm	100	400 AFG
Metformin	99 % < 150 µm	480	400 AFG
Naftidrofuryl	90 % < 19.6 µm; 50 % < 7.4	45	100 ZPS
Nifedipine	97 % < 45 µm; 50 % < 17.9	125	200 ZPS
Nifedipine	90 % < 2.4 µm	32	500 AS
Nifedipine	97 % < 3.8 µm	2,7	100 AS
Nifedipine	98 % < 96 µm	23	100 AFG
Omeprazole	97 % < 4.1 µm	0,8	100 AS
Omeprazole	98 % < 7.5 µm	10	200 AFG
Oxytetracycline	99 % < 25 µm	50	140 AFG
Pharma polymer	90 % < 50 µm	2	100 AFG
Piroxicam	99 % < 61 µm	30	50 ZPS
Piroxicam	99,9 % < 15 µm	3,2	50 ZPS
Progesterones	99 % < 14 µm	20	200 AS
Salbutamol	97 % < 5.2 µm	4	100 AS
Salbutamol sulphate	97 % < 9 µm	4	100 AFG
Simvastatin	90 % < 10 µm	3	100 AFG
Sodium ascorbate	99 % < 130 µm; 50 % < 19	140	100 ZPS
Sodium chloride	99 % < 4 µm	10	200 AFG
Sorbitol	99 % < 300 µm	230	10 ACM
Tartaric acid	99 % < 100 µm	100	10 ACM
Theophylline	99 % < 87 µm	170	300 ZPS
Ticlopidine	99 % < 30 µm	13	100 AFG
Vitamin B2	99 % < 50 µm	25	200 AS
Vitamin B2	99 % < 5 µm	12	200 AFG
Zaltoprofen	90 % < 9 mm	4	100 AS