- Possible chemical incompatibility between the drugs At -first manufacture On -aging
- Assay of multiple but similar components in a manner that is accurate, precise and specific

In the case of blister products that contain multiple products, control of manufacturing procedures must ensure that packs contain exactly what is intended and that there are no mix-ups. There is precedent for this type of product in sequential oral contraceptives for which a single blister can contain up to four different types of tablet. Multiple containers in a single carton exist for triple combination therapy of gastric ulcers.

Chemical compatibility of drugs with excipients and with each other

Some interactions are predictable given a good knowledge of organic chemistry, whilst others are not as obvious. If the nature of any interaction is known, conditions of manufacture can be adjusted to as to minimise its occurrence.

Some known interactions in the group of drugs of interest at this meeting include:

- Acid/base interactions. Sulphonamides are mildly acidic and can form salts with bases. An interaction between sulfamethoxazole and trimethoprim is known and has caused manufacturing problems for combinations of these drugs. Stability problems could also result in the form of altered dissolution rate on aging if a reaction occurs slowly. Other such interactions could occur under certain conditions, for example between sulfadoxine and pyrimethamine.

- Schiff's base formation occurs between primary amines and carbonyl-containing molecules. Flavouring agents commonly contain aldehydes and ketones that can potentially react with primary amines such as lamivudine, primoquine, trimethoprim and pyrimethamine.

- When the primary amine component of a hydrazine reacts with a carbonyl group, the resulting compound is called a hydrazone. This reaction is the basis of the reduced bioavailability of isoniazid in the presence of food.

Consequently carbonyl-containing excipients (such as reducing sugars and many flavouring agents) are best avoided in the formulation of drugs that contain primary amine and hydrazine moieties, including isoniazid, lamivudine, primoquine, trimethoprim and pyrimethamine.

- The Maillard reaction and Amadori rearrangement have been proposed in relation to pharmaceuticals, including fluoxetine³⁴ but, at least in that case, was not in practice a problem.