Michael Lehtinen, EP Scientific, part of Thermo Fisher Scientific, looks at how custom cleaning services can meet the strict regulatory needs of drug manufacturing and save on costs
The contamination problems that can face the pharmaceutical industry have been played out over the past few years in newspaper headlines and plummeting share prices. These have brought the importance of maintaining a clean working environment sharply into focus. Parenteral pharmaceuticals, for example, often entail volatile drugs and high-risk routes of administration, so regardless of what filling method is used, pharma companies must be extremely alert for potential contamination.
Contamination control is, therefore, a requirement that affects practically every area of pharmaceutical production, and the implementation of cleanroom technology is essential. Companies need to ensure that all equipment used in the critical working environment is fully validated and certified clean. This is the case for both the upstream R&D laboratory and the downstream manufacturing facility, where depyrogenation and sterilisation are of paramount importance to production quality.
Maintaining a clean environment and using certified clean sample containers are crucial factors in the provision of chemically and microbiologically safe products.
As well as potential negative effects on patient safety, the recent problems besetting the industry have had massive cost implications in terms of time, materials, production and reputation for the pharmaceutical companies concerned.
Commercial success and, in some instances, survival, will largely be decided by initiatives such as cleanroom implementation. To gain assurance that the complex regulations associated with cleaning are consistently met, and that the containers for critical environment applications are processed and certified to exacting specifications, companies are increasingly outsourcing this task.
Critical cleaning expertise
The key driver of outsourcing for larger pharmaceutical companies can be economic: to move fixed costs to variable costs, and to reduce the asset base to improve return on investment; whereas the key driver for mid-size pharma and biotech companies and start-ups is more technical – to find specialist expertise that is absent or insufficient in-house.
Cleaning newly manufactured drug product containers to appropriate specifications is a costly process, in terms of time, resource and in-house expertise. Since outsourcing companies have the expertise to ensure that all containers are compliant with various regulations, such as those from the FDA, as well as the European and US Pharmacopeias (Ph. Eur. and USP, respectively), in-house expertise is no longer a burden. Costs can, therefore, be saved on training and valuable laboratory researchers are freed up to focus on product development.
Customised critical cleaning can offer proven methods to guarantee essential GMP quality assurance and traceability. In addition, such companies also provide knowledge of the essential appropriate safety and regulatory requirements – not only of current regulations, but also how they may alter in the future.
The pharmaceutical industry demands a wide selection of chemicals and processes to achieve better contamination control at lower costs. Health and environmental concerns can result, however, in restrictions on the use of certain chemicals and processes. An understanding of how the approaches of regulatory agencies may change over time is advantageous in order to anticipate future trends.
The ability to outsource the supply of flexible quantities is invaluable. The journey from drug development can take 10–15 years and cost hundreds of millions, if not billions, of dollars. During this period, a new drug still in the discovery stages or clinical development may require only a few dozen containers to package the product under development.
Even though such experiments are being performed only on a small scale in the laboratory, to ensure that results are not compromised by laboratory grade containers the protocols adopted should be similar to those used in final production. Scaling up to pilot plant levels can increase this need; however, these volumes are still very small when compared with the facilities needed to process the final product.
Custom cleaning has the flexibility to meet all cleaning requirements, whether for high volumes or smaller quantities. An in-depth appreciation of the applications for which the containers will be used is necessary to ensure that the best cleaning process is implemented, while keeping costs to a minimum.
The USP sets limits and methods of analysis for a variety of contaminants. The key regulations relating to the cleaning of containers are:
• USP 71 regarding sterility testing; USP 85 relating to acceptable levels of bacterial endotoxins
• USP 643 regulating Total Organic Carbon (TOC) as an indirect measure of organic molecules
• USP 788 for particulate matter in injections
An expert custom cleaning service can ensure that all critical cleaning require-ments are met, or even exceeded, cost effectively.
In addition to endotoxin and sterility testing, various analytical parameters are necessary to enable certification and validation of every batch of containers following cleaning. Depending on the potential application, these include: GC, GC/MS, ICP/MS, AA and GF-AA.
A certified class 100/10 cleanroom is also essential for cleaning services and packaging. Finally, all raw data and benchwork must be retained to meet traceability requirements, and samples from every lot tested should ideally be archived for 10 years.
The development of novel, or even standard, applications may result in the need for new solutions, particularly due to the growing necessity for higher standards of purity demanded by today’s ultra-sensitive analytical instruments. Frequently, pharma and biotech customers require expertise in resolving the difficult challenge of sourcing containers as clean as the facilities in which they will be used.
Assessing a customer’s individual specification requirements involves determining: whether they will send their own materials or require them to be supplied; the cleaning processes needed; what packaging configuration is required, e.g. cleanroom bag, autoclave bag, foil wrap etc.; type of application and therefore what the certification requirements are, e.g. certificates of analysis, processing and sterility. Table 1 provides a breakdown of the types of cleaning options available for differing applications.
Containers used in applications such as stability studies, the preparation of injectable or parenteral drugs and lyophilisation, as well as final packaging prior to drug delivery, all require the destruction and removal of endotoxins by depyrogenation. Endotoxin content must be reduced by at least 99.9% or 3 logs. In addition, cleaning and packaging must be performed in a Class 100 cleanroom.
Silanisation treatment neutralises active sites in glassware, allowing materials to remain stable, and prevents them from reacting with the glass surface. It also prevents the components of the glass from leaching into the samples. As a result, silanised vials, culture tubes and autosampler inserts save valuable time and minimise costs when performing assays of blood serum, pharmacological assays of therapeutic drugs, or storing proteins or materials prone to adhering to glass and extraction glassware.
Similarly, siliconised containers are physically coated with a medical-grade silicone emulsion to prevent sample material from reacting with the glass.
TOC analysis is mandatory for validation of water systems, equipment validations, cleaning validations, and monitoring low levels of organic contaminates in numerous applications. Vials should be cleaned and certified to contain fewer than 10ppb TOC as background. In addition, all cleanroom applications in the pharma, biotech and medical industries require particulate cleaning to conform to USP 788. High purity, low particle water is heated and used for cleaning processes. Scientific vials and containers are available which are certified to contain fewer than 5 particles per ml larger than 0.5µm. This exceeds the USP 788 specifications for particle content of containers.
Cleaning and packaging is performed in a Class 100 cleanroom. Class 100, double-bagged glass bottles are assembled with low-shedding, polypropylene caps with chemically inert PTFE faced liners that do not contain adhesives.
Lyophilisation
For applications involving injectable or parental drugs, lyophilisation, final packaging prior to drug delivery and stability studies, the required sterility assurance level (SAL) for containers is 106. A number of sterilisation services are available that effectively destroy all viable forms of life; these include gamma irradiation, dry-heat, autoclave or e-beam.
In addition, customers should look for a service that uses a water purification system that exceeds the USP specifications for TOC, conductivity, bacterial and endotoxin levels to provide a final product that meets all regulatory requirements.
Effective cleanroom operation is vital to the pharma and biotech industries. Outsourcing to a reputable critical environ-ment products and services company can provide cost efficiencies at critical stages of the pharmaceutical manufacturing process, as well as significantly decrease the amount of in-house compliance work that needs to be undertaken.
Flexibility to meet all cleaning requirements, whether high or low volume, is also advantageous. Confidence in the quality of containers supplied for use within critical areas is key, along with the ability to understand, advise on and meet very specific needs.
If the outsourced company can offer the reassurance of traceability, this ensures that any regulatory queries can always be answered promptly. In addition, ensuring that products are handled in Class 100/10 environments can only further secure product quality.
| Irradiation | Sterile | Steam | Depyrogenation | Siliconisation | ||
|---|---|---|---|---|---|---|
| foil-wrap | sterilisation | Silanisation | ||||
| Injectable or parenteral drugs | ||||||
| Injectable or parenteral drugs | ||||||
| Final packaging prior to drug delivery | ||||||
| Stability studies | ||||||
| Clinical trials | ||||||
| Proteins | ||||||
| Assays of blood serum | ||||||
| Pharmacological assays of therapeutic drugs | ||||||
