Ensuring the Safety of Excipients
Read on to learn how Cognis implemented a wide range of good manufacturing practices for excipient manufacturing.
By Jochen Seifert
Global Product Line Manager Pharmaceuticals and Healthcare
Cognis Deutschland GmbH Co. KG
There can be no doubt that standardized and secure manufacturing processes are key when a product is going to come into direct contact with people—and this is especially true of pharmaceuticals. To safeguard consumers’ health, the safety standards that have to be observed by pharmaceutical manufacturers and their suppliers are very strict.
Specialty chemicals company Cognis has therefore implemented a wide range of good manufacturing practice (GMP) regulations relating to the manufacturing process for its pharmaceutical excipients, putting its whole supply chain under the microscope. The company, headquartered in Germany, has received a declaration by DQS (Deutsche Gesellschaft zur Zertifizierung von Managementsystemen) that its pharmaceutical excipient manufacturing process conforms to the IPEC-PQG GMP Guideline.
The quality of excipients is critical to the safety, quality and efficacy of medicines. Excipients have a wide range of applications and form an essential part of drug product formulations. They are used in topical, oral, parenteral and other pharmaceutical formulations, as tableting aids, solubilizers, consistency factors, emulsifiers, emollients, cream bases, and suppository masses for solid, semi-solid and liquid pharmaceutical dosage forms.
As excipients are used in so many applications, the advantages of implementing good manufacturing practice (GMP) are obvious. However, in contrast to finished dosage forms and active pharmaceutical ingredients (APIs), there are no specific GMP regulations for excipients. The sheer variety of excipients available and the large number of applications for them also make it difficult to develop binding and uniform GMP guidelines. However, there is a general expectation that these substances should be manufactured to recognized GMP guidelines.
Cognis developed its GMP guidelines for the manufacturing of oleochemical-derived pharma-grade exipients on the basis of regulations published by the International Pharmaceutical Excipients Council (IPEC) and the Pharmaceutical Quality Group (PQG). Cognis’ Düsseldorf site was reviewed with respect to the PharmaLine product range to be in conformity to the good manufacturing practice assembled in the 2006 IPEQ-PQG Guideline. The PharmaLine product range is manufactured by the company’s Nutrition & Health Strategic Business Unit and includes specialty esters, ethoxylates, stearic acids, fatty alcohols, castor oil derivatives and related products.
Objectives of an IPEC-PQG GMP Production Process
The emphasis in the IPEC-PQG GMP guideline for excipients is on ensuring product integrity, avoiding product contamination and ensuring processes are comprehensively documented. Hence the ultimate aim for an excipients manufacturer is to produce a consistent quality standard across all company locations worldwide. IPEC-PQG GMP regulations ensure transparency in manufacturing processes, adherence to strict guidelines in the area of hygiene, and comprehensive documentation of production processes. In 2001, Cognis was one of the first chemical company to achieve worldwide ISO 9001 (quality management) certification. This provided a useful framework for the implementation of the IPEC-PQG GMP standards, a process which Cognis started in 2003 by systematically rolling these out to all sites where pharmaceutical basestocks were being produced. The ISO certification also has the added benefit of reassuring customers that the excipient manufacturer’s quality management system has been independently verified.
Challenges in Following the IPEC-PQG GMP Guideline
Of course, the company had to face new challenges when it decided to produce its excipients according to the IPEC-PQG GMP standards. These standards set even higher benchmarks in the areas of training and hygiene, pest control, cleaning production equipment, documenting individual process steps, ensuring traceability of intermediate products and raw materials, auditing suppliers and communicating changes regarding products and processes, both internally and externally.
Even companies that take as rigorous an approach to quality management as Cognis still frequently manufacture pharmaceutical basestocks using the same equipment as they do for cosmetic ingredients and technical products. As a result, adequate precautions for avoiding cross-contamination are essential. The cleaning of production plants, filling units, transport vessels and storage areas is carried out according to detailed internal procedural guidelines, and is closely monitored. Batches of pharmaceutical basestock are always produced on the same production line as their cosmetic or technical equivalents, to avoid any risk of contamination by foreign chemicals. The quality of raw materials is also actively managed, with regular spot checks carried out on- and off-line at every stage in the production, storage and transportation process.
Steps taken to minimize the risk of contamination include the following:
• Maintenance guidelines are applied both to the equipment which comes into direct contact with the product (piping, reactor vessels, heat exchangers, pumps, filters, storage tanks, etc.) and to the facility as a whole. For instance, a strict policy is in place to prevent any glass particles getting into the final product, as these can be very difficult to isolate.
• Monitoring equipment in production, filling, storage and laboratory areas is recalibrated on a regular basis.
• All auxiliaries used, such as lubricants for stirrers and pumps, comply with the standards used in the food industry, as do packaging materials for the final goods. Suppliers provide health certifications.
• Label management systems are used in filling units to keep track of how many labels are printed, used and left over. This information is checked for discrepancies compared with the amount of product produced and shipped, providing a reliable way of preventing labeling errors.
Guaranteed Standards of Hygiene
Hygiene is a vital element of the IPEC-PQG GMP requirements. To ensure that excipients are protected from contamination, personnel receive adequate ongoing hygiene training. Cognis has also established guidelines on industrial hygiene, ensuring that the company’s plants all around the world follow standardized procedures to avoid microbiological contamination, and the presence of undesirable substances. Proper pest control is in place in all manufacturing and storage areas. Another important aspect is the water used in the manufacture of excipients, which must of course be of suitable quality for its intended use. The water used in processes at Cognis for aqueous products is based on potable water and is regularly monitored to ensure that the microbiological contamination is below 1 CFU/ml. This specification is 100 times stricter than specified in the European Pharmacopoeia. Before new products are approved, they must first undergo a product- and process-related risk assessment to determine their susceptibility to germs. Because preservatives are undesirable in pharmaceutical basestocks and microbes can easily proliferate in them, Cognis takes the view that even one germ is one too many.
Comprehensive Documentation
IPEC-PQG GMP requires full and comprehensive documentation of the entire supply chain, and that a system be in place to manage relevant documents and data. This must include procedures for the identification, collection, indexing, filing, storage, maintenance and disposal of documents. If any problems are discovered, it is vital that products are fully traceable, so that recalls can be carried out quickly and efficiently. Thorough documentation also ensures that even the smallest errors can be immediately identified, rectified and avoided in future. Capturing the relevant data needed for the documentation requires that proper monitoring procedures be in place, each of which must be adapted to the specific conditions at each site. Also, any changes in raw materials, test methods or manufacturing equipment, must be evaluated and documented. Finally, samples of the final goods are retained by the manufacturer for a sufficiently long period of time.
Infrastructure and Production Facilities
The audit procedure carried out at the Cognis site also required the DQS to carry out a thorough inspection of the company’s production facilities and laboratories. They checked whether the infrastructure was being managed, operated, cleaned and maintained in accordance with IPEC-PQG GMP principles. For example, manufacturing processes associated with the production of highly sensitizing or toxic products (i.e., herbicides or pesticides) should be located in dedicated facilities or use equipment separate from that used for excipient manufacture. Also, where the excipient is exposed during manufacture, it should be in an appropriate environment to minimize contamination; the manufacturer must also apply suitable controls to maintain this environment.
Quality Assurance Throughout the Production Process
From purchasing the raw materials to manufacturing the finished excipient, Cognis has adapted every stage of the production process to the strict IPEC-PQG GMP quality guidelines. Suppliers of raw materials need to undergo an evaluation of their quality management system and, if necessary, periodic audits of their manufacturing facilities. Raw materials and intermediates must be stored under appropriate temperature, humidity and light conditions to preserve their quality and purity. In-process inspection and testing is performed, including both monitoring of the process and actual sample analysis at specified locations and times. And each finished batch is tested to ensure that the excipient conforms to documented specifications. Each batch of monograph-listed products is analyzed according to methods laid down in the European Pharmacopoeia, USP or JP. Extensive trace analyses for substances such as PAH and heavy metals complete the product impurity profiles. These analyses are all included with the final product release, together with a complete batch record review, to ensure that even the slightest deviations in the manufacturing process, including those which may not be detectable in analyses of the end product, are discovered.
Changing Operators’ Attitudes
The working habits of operators in the chemical industry are generally quite different from those of people who work in pharmaceutical environments. However, it is vital that these operators have a thorough understanding of what IPEC-PQG GMP guidelines are. Appropriate systems must be put in place to communicate IPEC-PQG GMP and regulatory requirements, quality policies, quality objectives and applicable procedures throughout the organization. In light of this, Cognis employees receive regular training in:
• Process control;
• Preventing contamination;
• Packaging and labeling; and
• Hygiene.
Competitive Advantage for Customers
The fact that Cognis follows the IPEC-PQG GMP guideline shows the commitment to its customers to offer pharmaceutical excipients with the highest degree of quality and regulatory requirements. Proper quality management processes also help customers to manage the process of licensing new products with the relevant authorities, by ensuring all the necessary documentation is already in place. Nowadays, customers rightly expect outstanding performance, and want the best possible ingredients for their products. Providing customers with data from external and internal audits carried out to international standards is all part of good customer service, and can make an important contribution to success in their markets. In accordance with the IPEC-PQG GMP, Cognis also notifies customers of significant deviations from established production and process control procedures that may affect excipient quality.
IPEC-PQG GMP has proven to be an ideal mechanism for aligning basestock suppliers more closely with the needs of their customers, as well as helping suppliers to improve their own quality management. This makes it an essential element for the future viability of any pharmaceutical and health care business.
