Q: What was the most “surprising when viewed with the wisdom of hindisght” MDI manufacturing practice you saw prior to the HFA changeover?
A: Manufacturing practices were often particularly ad hoc in developing countries. I visited one tropical MDI manufacturer whose CFC MDI manufacturing facility was located in one long building. At one end of the building, operators mixed salbutamol (albuterol) sulfate suspended in CFC 11 in an open vessel inside a closed, hot room. They were working at considerable risk to themselves as CFC 11 has anaesthetic properties at high concentrations.
The suspension then passed to a small automatic filling machine in the next room that carried out standard CFC-based two-stage filling. The unlabelled aerosols then went to a line down the middle of a really long room. Young women sat on either side of the room, pulling aerosols off the line and sticking labels on from loose heaps on their desks. The same process continued with the carton and instructions. Finally, the finished aerosol cartons reached the far end, where another young woman hand packed them into cardboard boxes.
As a finale, the boxes were then taken out into reception and stacked there throughout the day, so that by end of office hours, the receptionist was completely hidden, sitting in a canyon of cardboard. These cartons were then collected overnight for delivery to the city pharmacies!
Q: How universal are the new improvements in manufacturing standards?
A: In many ways, the developing world respiratory sector is a little schizophrenic. On the one hand, we have export-led companies working to standards that are fast approaching – and occasionally meeting or even surpassing – those found in the developed world. On the other hand, we have the more inward-facing companies where cost is king and where a sometimes Nelsonian blind eye has to be turned to inconvenient truths to get the cost right. Often, both types of company can be found side by side in the same developing market.
In developing world countries, medication is often unaffordable or very hard to afford, for large sections of the population, and a significant increase in price of a medicine actually means a substantial section of patients who had been taking it will no longer be able to afford to do so. There is a grinding necessity to produce these goods for a given – often government imposed – price, which takes little account of changes in manufacturing circumstances.
As the HFA aerosol replaces the CFC propelled one, costs have tended to rise. Valves in particular are more costly, and propellants themselves tend to be as well. Both of these MDI components are made to far higher and stricter standards than the equivalent items in the days of CFC MDIs, and this comes at an unavoidable cost.
As a result, one occasionally encounters a “Don’t ask, don’t tell” quality ethos in some less reputable companies and countries, as they wrestle with this problem. Manufacturers may be tempted to use impure technical grades of propellant, valves with substandard tolerances, and elastomers and excipients with unpleasant off-tastes, to mention but three of many possibilities.
This is not only restricted to the world of the MDI, by the way. Dry powder inhalers (DPIs) have similar, or worse, problems in the developing world. Manufacturers may be tempted to use cheaper tableting grade lactose as a carrier instead of the more expensive specialty, very carefully ground, sieved, blended, and treated grades that are suitable for respiratory devices. Of course, there is a huge difference in cost — and in efficacy.
Q: Is more regulation or inspection of these facilities necessary?
A: The need for truly economical medications in sections of these markets does force one to confront some very uncomfortable truths when dealing with minor failures or quality infringements in components or excipients. Is it right to cling to the highest standards of cGMP if in the process supply into some of these cash-starved markets becomes sclerotic in consequence, resulting in real product shortages in the markets and putting lives at risk, over what is often a near academic GMP point? There are some tough soul-searching calls to be made on occasion.
