Drug contamination

In the summer of 2018, valsartan attracted great media attention worldwide when it became known that the carcinogenic compound NDMA (N-nitrosodimethylamine) had been found in this antihypertensive drug. And in the autumn of 2019, the health inspectorate ordered pharmacists to retrieve drugs with the antacid drug ranitidine back from 150 000 people, because of the same contaminant. In late 2019, a third case of NDMA contamination emerged. Several countries withdrew batches of metformin, a drug used by diabetics. The autumn of 2020 saw renewed commotion about contaminants found in drugs.^1,2,3,4,5 In none of these publications, however, was the true problem clearly defined. The problem here involves the quality of the active ingredient included in the drugs, which was contaminated with impurities that had arisen in the production process of the active ingredient.

Formulation

Drugs are manufactured by combining a pharmacologically active ingredient with the necessary additives in a formulation. Such formulations are subject to quality requirements. For instance, the formulation must contain the correct amount of active ingredient per unit, and in the case of an oral formulation, it must be able to optimise the uptake of the active ingredient  in the stomach and/or intestine.

Active ingredient 

The basis for manufacturing the formulation is the active ingredient. This active ingredient is often produced by another manufacturer than the one which incorporates it in the formulation. In recent decades, a large part of the production of both active ingredients and the final drugs has been shifted to countries outside the European Union (EU), such as China and India.⁶

Production of the active ingredient 

The production of active ingredient usually involves a number of successive chemical reactions. The final active ingredient is produced via a number of preparation steps (chemical or synthesis steps). In each step, the reaction may generate not only the intended intermediate product but also by-products, some of which may be undesirable. The intended intermediate product must therefore be purified of these unwanted by-products. The final active ingredient must be of high quality and must contain the lowest possible amounts of unwanted by-products.

Quality control

The manufacturer is obliged to check the purity of the active ingredient. There are international requirements for the quality of active ingredients, which have been laid down in the European Pharmacopoeia.⁷ This European Pharmacopoeia has legal status in the EU. This standard work states for each active ingredient the minimum concentration required and the types and quantities of by-products (contaminants) that are admissible. The Pharmacopoeia also specifies the methods and analysis instructions used to check these requirements. The requirements and analytical methods for by-products are based on the contaminants that can be expected to arise from the known preparation steps for the active ingredient. Hence, any changes to the production process must be controlled and reported by the manufacturer of the active ingredient.

Changes in the production process

Any changes made to the production process of an active ingredient may affect the nature and quantities of the by-products. This may mean that the requirements and the analysis methods, as established for the original production process, are no longer appropriate. This was what happened in the case of valsartan and the other sartans. The Chinese manufacturer had changed the production process of this drug in order to increase its yield.⁸ This led to the formation of impurities like N-nitrosodimethylamine (NDMA). The manufacturer’s quality control system did not take this impurity into account, so that it went unnoticed. In the end, the EU authorities put the producer under increased supervision.⁹

Quality by design

Manufacturers are primarily responsible for the quality of the active ingredient they produce, and they monitor this by means of their quality control systems. A possible tool for this purpose is ‘quality by design’.¹⁰ The essence of quality by design is that quality must, as it were, be ‘built into the product’, while taking account of the nature of, and the risks involved in, the production process. The supervising authorities also carry out quality control, but only in the form of random checks.

Certificate of suitability

Manufacturers that only produce the final formulations, and therefore make use of active ingredients produced by other manufacturers, are responsible for the quality of the active ingredients they procure. These procured active ingredients must meet the quality requirements, and the procuring manufacturers must also check this. To facilitate this, the European Medicines Agency (EMA) has developed a ‘certificate of suitability’ for active ingredients. Such a certificate guarantees that the quality of an active ingredient can be adequately controlled using the instructions in the European Pharmacopoeia. If necessary, these can be supplemented by certain tests indicated in the certificate. These certificates can be awarded to manufacturers of active ingredients after inspection and approval by the EMA.

Tighter requirements 

The European Pharmacopoeia now contains tighter and expanded requirements for the types and quantities of impurities in active ingredients. In addition, the Dutch Health and Youth Care Inspectorate (IGJ) has put additional information on its website. This information is specifically intended for drug preparation by pharmacists.¹¹

Changes in the valsartan production process

The production process of valsartan was changed to increase the yield in the formation of the so-called tetrazole ring in valsartan. Tributyltin-azide was replaced by sodium azide, using dimethylformamide as the solvent. Sodium nitrite was used to neutralise the excess sodium azide. In an acidic environment, hydrogen nitrite is formed from the sodium nitrite added. Hydrogen nitrite can react with dimethylamine, which is present in the dimethylformamide, finally resulting in the formation of NDMA.⁸

Preparation in (hospital or community) pharmacies

If authorised drugs are available in insufficient quantities for prescribers to meet the needs of their patients, pharmacists are allowed to produce a drug themselves. These may be so-called resupplied preparations, which means that they are prepared in specialised pharmacies and are then delivered to the pharmacies that provide them to patients. The number of drugs prepared and stocked in these specialised pharmacies and delivered by community pharmacies is considerable: 6.4 million preparations for over 2 million patients in the Netherlands in 2019.¹² In addition, pharmacies (hospital or community) also prepare patient-tailored drugs.

All these preparations involve the use of an active ingredient in a formulation. The active ingredient is always procured. The pharmacist (hospital or community) must always ascertain that the active ingredients they procure meet the quality requirements.