August 5, 2013

In response to increasing demand for the processing of highly potent APIs, Haupt Pharma has — at its Münster, Germany, site — cultivated a centre of excellence for this application. Compression of tablets is, from a containment as well as a processing point of view, one of the most challenging unit operations in solid dose manufacturing.

The rapidly increasing demand in recent years for contract manufacturing, particularly in the solid dose sector, has meant that CMOs need to have an even greater ability to produce a huge variety of products at an economical speed, even when they consist of challenging formulations. Additionally, specific health and safety challenges arise when potent APIs are processed, requiring the use of equipment that combines very high flexibility with high productivity and an appropriate containment performance. GEA Courtoy’s MODUL rotary presses meet these criteria at Haupt Pharma’s Münster site.

Haupt Pharma and Haupt Pharma Münster  

With nine sites in Germany, Italy, France and Japan, Haupt Pharma is one of the largest European companies for pharmaceutical contract development and manufacturing. A full range of services — from pharmaceutical development, materials procurement and production and packaging to logistics and distribution, including the possibility of customised solutions — is offered for almost all dosage forms. In addition to the processing of conventional APIs, Haupt Pharma develops and produces various specialty products such as cytotoxics, hormones, beta-lactam antibiotics (penicillin/cephalosporin) and narcotics.

The Haupt Pharma Münster site specialises in the production of highly effective and low-dose preparations such as oral contraceptives, thyroid hormones and narcotics. Batches from 1 to 400 kg can be handled. Services range from development activities via scale up and clinical trial supplies to routine manufacturing. More than 2.5 billion single unit doses per year, including tablets, film-coated tablets and sugar-coated tablets, are produced. The facility meets the current FDA requirements applicable to medicinal products in the US market.

Containment concept at Haupt Pharma Münster  

As most of the APIs handled require special attention from a health and safety point of view, the entire site was designed according to EU Directive 89/391 EEC. Among other requirements, this implies that containment is assured purely by engineering methods, and personal protective equipment (PPE) is only used in the case of an emergency, as a last resort. This philosophy is seamlessly taken from dispensing all the way through to compression and coating.

The factory has been built to meet a design occupational exposure limit (DOEL) of 0.01 µg/m3. The DOEL was selected based on the mix of products to be processed. This includes sex hormones such as ethynyloestradiol (EE). All equipment was selected based on its containment performance according to standardised measurement of equipment particulate airborne concentration (SMEPAC) tests.

While most pieces of equipment performing the required unit operations such as granulation and drying or blending are tight enough by their design and operational principle, all transfer steps are a potential area of concern. Haupt Pharma opted for Müller drums in combination with GEA MC split butterfly valves. Due to its mechanical complexity, the tablet compression process demanded special attention, therefore Haupt Pharma decided on Courtoy MODUL presses.

MODUL press range  

The MODUL is Courtoy’s flagship product. It combines typical Courtoy features such as extended dwell time, which enables the compression of difficult formulations at reportedly unbeaten speeds, with the exchangeable compression module (ECM) concept. The ECM is completely isolated from the remainder of the machine, contains all product contact parts and can be easily removed from the press in a contained way to perform an off-line washing process. This means that the press itself remains powder-free and requires no cleaning. Benefits include the possibility of fast changeover, especially important when new products need to be processed, plus excellent containment performance.

Haupt Pharma Münster’s experience of MODUL presses  

The Haupt Pharma Münster site has assessed containment performance of its two MODUL S presses intensively by measuring particle load in the production environment under operating conditions. The two presses produce a huge number of tablets. When the turret of the single-sided press is equipped with BB tooling, it is able to produce up to one million tablets per hour, having been fitted for up to five-fold multi-tip tooling.

Additionally, the presses can be turned over in less than two hours to accommodate a change of product. For a product changeover, all product-contact parts are removed in a contained manner. Owing to the high containment performance, cleaning of the remainder of the press and room is not required. A second ECM and second set of peripheral equipment are brought to the compression area and allow production to resume in under two hours. The first set of parts is then cleaned off-line in a dedicated washing area, with no interference to manufacturing.

After a successful placebo-based site acceptance test (SAT), the presses were taken into verum production and air samplings were performed for an assessment of their containment capability. Sampling heads were placed close to the most critical areas that had been identified by a risk analysis. A series of tests has been performed, taking into consideration the full range of products. Seven series of tests were carried out, consisting of a total of 26 individual measurements. Out of these, 23 results were below detection limit, which is

0.001 µg/m3. In three cases, product was detected but the amounts found were well below the DOEL.

Haupt Pharma Münster GmbH, Dipl.-Ing. Heinz Schulte-Brochterbeck, +49 251 2855 446

heinz.schulte-brochterbeck@haupt-pharma.de, Günter Nykamp, Ph.D., +49 251 2855 201, guenter.nykamp@haupt-pharma.de, www.haupt-pharma.com.

GEA Pharma Systems, Harald Stahl, Ph.D., +49 6349 927 706, harald.stahl@gea.com,

www.gea-ps.com.

August 5, 2013

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