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Clean Solutions

Maxime Laugier at MP5/CREAPHARM discusses the importance of avoiding cross-contamination in the pharmaceutical manufacturing process, and highlights both current and future solutions

Increasing progress in medical research combined with the development of molecular synthesis and biosynthesis technologies is enabling drug companies to increase the effectiveness of molecules at low doses. The molecules considered to be highly active represent an undeniable interest for patients and physicians, but constitute a huge challenge for the pharmaceutical manufacturer.

Oncology and the treatment of metabolic disorders are rapidly growing markets compared with the overall pharmaceutical market as a whole. A growth of 12 per cent per year is expected in the field of anti-cancer, whereas the overall development of the pharmaceutical market stands at only three to six per cent. Thirty per cent of the molecules currently under development are intended in the long term for cancer treatment projects. Similarly, the parenteral pharmaceutical market increases continuously by 11 per cent year on year.

Facing this new paradigm, pharmaceutical sub-contractors must adapt particularly those involved in the pharmaceutical and clinical development of these new active compounds. Not only must they consider the implementation of highly technological medicinal products in the face of increasingly rigorous regulatory standards, but they must also face the requirements relating to the handling of these products by their collaborators, while also being aware of the increased risk of cross-contamination within their manufacturing units.

This combination of constraints means that the success of clinical manufacturing does not depend on infrastructure and technology alone, but also on an organisation that is reliant on the experience gained by their manufacturing team over several years in this field of activity. When it comes to the clinical production of injectable products, the implementation of products considered highly potent, or chemical and biological entities with incomplete toxicology data, is progressing considerably.

These molecules are usually recombinant proteins (especially activators of the apoptosis), monoclonal antibodies (sometimes combined with small, highly potent molecules), enzymatic inhibitors, cytotoxic or cytostatic products (platinum derivatives and alkylants), hormones, prostaglandins or even toxins.

It is commonly accepted that products are considered as potent when they present therapeutic doses lower or equal to 10 to 15 milligrams or 150 micrograms per kilogram of body weight. Moreover, in the field of environmental contamination, these products present an occupational exposure limit (OEL) lower than 10μg/m3 of breathed air per eight-hour working period. A product is considered as highly potent when this value of OEL is lower or equal to one microgram per cubic metre.

The Good Manufacturing Practices and their appendices relating to the manufacture of sterile products (Appendix 1) and products for clinical investigation (Appendix 13) stipulate that specific measures must be taken for the manufacture of these products with regard to the organisation of the facilities measures either to do with procedures or the training of staff involved in the handling of the product. It is generally accepted that not all therapeutic and toxicological data are always available. In this case, special attention must be paid to the management of crosscontamination and to the cleaning of equipment and facilities.

Thus, in order to implement such compounds for the manufacture of products for clinical trials, it is necessary to consider the safety of the product, the target patients and the collaborators involved, as well as environmental protection. A molecule which offers a considerable benefit to the patient can expose the collaborator who handles it to severe risk.

USE OF RANKING SYSTEMS

Turning to the safety of operators, it is important during the feasibility study of a new clinical project to study the toxicity of the handled active ingredient and to classify it in line with a rank of hazards, therefore making it possible to establish what protective measures should be taken and to create the most suitable working arrangement. This type of approach has been followed for several decades in the chemical industry. Classification performance-based exposure control limits (PB-ECL) are a commonly used reference point. More recently, the Safebridge Company proposed its own classification. These approaches fix the level of risk associated with the manufacture of a medicinal product by calculating the OEL.

Calculation of OEL 
OEL = ((N(L)OAEL) x BW) / (SF x α x V)

OEL: Occupational exposure limit    

N(L)OAEL: No (lowest) observed adverse effect limit
BW: Body weight (70kg)
SF: Safety factor which considers uncertainties data (animal to human variability in response, interindividual variability, and so on)
α: Degree of absorption (100 per cent in the absence of data)
V: Volume of air inhaled during an eight-hour working day

To establish this calculation, it is advisable to know the nature of the pharmacological and toxicological data product, the physicochemical properties of its components, its manufacturing process, its mechanisms of pharmacological action, toxicity data resulting from cellular tests or animal studies and of course the established clinical protocol. As a result, a simple material safety data sheet and a lethal dose of 50 are no longer enough.

Through use of these classifications, it is possible to categorise the product in question and to check if the conditions required for its implementation are available.

The simplified banding systems of Merck & Co and Safebridge are presented in Tables 1 and 2.

Table 1: Merck & Co classification        
Band 3+ 
OEB (mg/m3 10-1  1-0.1  0.1-0.01  0.01-0.001  <0.001 

<0.001 

Acute effects  Low  Low/moderate  Moderate  Moderate/high  High  Extreme
Requirements  GMP conditions  GMP conditions   Ventilated enclosures Containment systems   Closed systems Robotic systems 

Table 2: Safebridge classification     
Band
OEB (mg/m3 0.5  0.5-0.01  0.01-0.00001  <0.00001 
Acute effects  Low  Moderate  Highly potent  Extremely potent 
Requirements  GMP conditions  GMP + stringent conditions  Containment  Containment + robotic

Let us consider a recent example. A CMO was asked to manufacture a product for the treatment of cancer pain. This product was already the subject of clinical studies, in line with single- and multi-dose protocol. The dosage without observed effect was estimated to be 7mg over a 12-hour period. Taking into account the variations produced by different methods of absorption (parenteral versus inhaled), along with inter-individual differences, a certain number of safety factors were considered. Consequently the OEL for this product was evaluated at 4.9μg/m3 of air. From there, after taking into account the toxicological and clinical data available and its classification according to the Merck & Co or Safebridge banding systems, this product was deemed to be highly potent but acceptable considering the confined organisation of the manufacturing platform and the isolator performance. The formulation and filtration were carried out at grade C within isolators under depression, and the liquid filling was carried out at grade A within isolators which were running over overpressure.

If the assessment of a product determines that it is compatible with the technical capabilities of the pharmaceutical company, procedures adapted for the handling and elimination of the product are implemented. These procedures must be developed and followed in the manufacturing facilities and the quality control lab. A specific training programme is then established. The technical organisation necessary for the handling of the product throughout its manufacturing process is evaluated and improved if necessary (for example, by acquiring devices for a safe transfer or reassessing equipment performance). The environmental impact will also be looked at for the management of waste and effluents.

CROSS-CONTAMINATION CONCERNS

Turning to the safety of the target patients, it is necessary to manage cross-contamination throughout the manufacturing stage of the clinical products. Indeed, due to the variety and the specificity of the products managed by pharmaceutical contractors, and considering the highly active potential of the products at a very low dose and the transitory aspects of the clinical campaigns (few batches per clinical phase), it is essential to treat this approach as pivotal to the quality of the manufactured product, the safety of the patients and obviously to the relevance of the results of the clinical trial.

The most important aspect of the management of this stage in the process is related to the cleaning and control of the residual quantities of active ingredient on the manufacturing equipment. Because of factors such as the design of the equipment, surface qualities and physicochemical properties of the active ingredients, perfect cleaning does not exist. Thus it is necessary to validate the cleaning of the equipment in order to manufacture two different products using the same equipment and in the same suites without any risk of finding one-thousandth or even one tenthousandth of the daily therapeutic dose of the previous product within one unit of the new one.

To tackle this issue, pharmaceutical companies must establish cleaning procedures and cleaning validation programmes based on an approach specific to all the products being manufactured or by using an approach based on a worst case validation (the more toxic the product, the more difficult it is to clean). This approach is perfectly appropriate for routine production. On the other hand, when it comes to clinical manufacturing (a type that often involves only one batch), it is not always possible to make use of such a process of validation. Systematic and specific checking can be a solution, which could be treated as exhaustive. Nonspecific checking, by measurement of total organic carbon, is an interesting alternative, but requires perfect control of the carbon rate generated by the environment of work.

LIMITS OF TECHNOLOGY

Taking these constraints into account, pharmaceutical companies are currently operating single-use equipment, instead of trying to manage the cleaning and checking of equipment performance. Even though an increasing number of solutions are now available, technological limits remain and the manufacture of a clinical product on a totally disposable line is still not available. How do you guarantee that the balance which was used to weigh an electrostatically active ingredient will not contaminate another product? By cleaning the scale and by checking that the residual traces do not exceed an acceptable limit, by dedicating one scale per active ingredient, or by simply disposing of it altogether.

Furthermore, how do you make sure that during the freeze-drying of a product, there are no stains on the shelves within the condenser, and then avoid a risk of contamination of the following batch, if no method of elimination of the product is considered? By guaranteeing, amongst other things, that the speed of sublimation is under control but this is often far from being the case in the first developmental stages and during the manufacture of the batches for a Phase I or II clinical study. Alternatively, clean the equipment and check that there is no remaining active ingredient.

Currently, the entirely disposable production line is within the realm of fiction; indeed, we should applaud the inventiveness of the equipment supplier who eventually makes it a reality. When it comes to confined sterile manufacture, it is sometimes necessary to combine the two approaches; both the implementation of single-use devices and systematic checking of the cleaning of surfaces involved in the manufacturing process. A company should make a rule of eliminating any risk of crosscontamination and should guarantee the quality of injected products to its customers.

CONCLUSION

Today, clients evaluate their pharmaceutical contractors against financial, technological and quality criteria. Considering the characteristics of the products developed at clinical stage, an additional parameter must now be taken into account: the capacity to manage the inherent risks that come with the implementation of the active ingredient throughout the manufacturing process. This approach is leading more and more companies to adopt a process of evaluation of the risks beforehand first commercial and then technical in order to not find itself confronted with a product that it cannot manage or one that requires excessive investment (both material and human), so that the project is ultimately too slow.


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Maxime Laugier joined MP5/CREAPHARM in early 2007 as the Pharmaceutical Development and Projects Director. He has over 14 years of experience in pharmaceutical development, investigational medicinal products manufacturing and industrial up-scaling, with European contract manufacturing organisations. Maxime is an alumnus of the Clermont-Ferrand School of Pharmacy and has a degree in Pharmaceutical Development and Production from the Institute of Industrial Pharmacy in Bordeaux, France.
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Maxime Laugier
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