Editorial | Open Access | Published 30th September 2022

GUEST EDITORIAL : Due Diligence

Author : Malcolm Holmes

I have been involved in the pharmaceutical industry for well over 50 years now, though in latter years I have mainly restricted this to being an active member of the PHSS Management Committee and producing the monthly Regulatory Update for them and the Quarterly Regulatory Review for this Journal.

It has almost always been intriguing, exciting, and exciting plus of course on occasions frustrating and occasionally disappointing. It gave me the opportunity to travel the world, firstly with senior site roles whilst on secondment for a total of 10 years in Iran, Spain and New Zealand, then in Global Quality roles and eventually as a consultant.

I have always had a real interest in seeing that ‘manufacture’ in its widest sense was done correctly and that Industry and its Regulators could both best function in the interest of patients by maintaining an open, honest dialogue with one another in order to develop a mutual respect and trust. It is a position that needs to be earned and rigorously maintained once achieved.

Our industry is going through a period of rapid change (e.g Annex1 finally published this month and the exciting moves towards cell based and personalized medicines. What a time in which to live and learn.

Over the years I have had many interesting, exciting, surprising and even threatening experiences whilst conducting my various roles. Below you will find an example of one which perhaps fits best into the surprising category.

Due Diligence

It was a long trip to Japan for a colleague and me to conduct a Due Diligence audit of an API manufacturer. If successful, the company we were representing would go through with its plans to purchase the API and then manufacture and market the finished product to supply many global markets.

We had only two days allocated in which to complete our work and my role was principally focused on the manufacture and QA of the API.

On day 1 I went initially through QC and data integrity issues then entered the manufacturing suites to review the manufacturing process itself. I had already reviewed engineering drawings for HVAC, water systems etc. and all seemed in order. The area itself was well laid out and dedicated to the one product so cross contamination / contamination did not seem an issue. Each piece of equipment was clearly labeled in Arabic script (V, RV, CF) followed by Japanese script. The process schematics and indeed the batch records were much more simple / straightforward than I was used to, so I proceeded to run through the process with the local team. They seemed very surprised that I could ‘read’ the manufacturing instructions despite me having said that I could neither read nor speak Japanese. But when you understand that V = holding vessel, RV = reaction vessel, CF = centrifuge and any addition of ingredients were written as chemical formulae or actual names in Arabic script then there was no mystery.

All seemed quite well until I noted that one stage of the process stopped at a point where liquid was transferred from a Reaction Vessel to a Holding Vessel and the next stage was then a centrifugation to isolate a solid material. I asked how this was possible without a chemical reaction /crystallization stage and heads were scratched. Back in the meeting room I confirmed that the schematic had been included in the draft NDA and other registration documents. So ended day 1 with the promise of “we will find out” from the host company.

Next morning came the surprise. A large team 20 plus people had been assembled and the most senior member of the host team announced “We have found another building”.

To cut a long story short liquid stage product was being transferred in a mobile vessel to an unsuitable (non GMP) facility elsewhere, where a precipitation operation took place in a different vessel before transfer back to the dedicated facility for centrifugation. I never got to the bottom of how this change occurred / was sanctioned but I did suspect it might have arisen via a Quality Circle (not subject to adequate change control) to avoid a bottleneck in the process.

Day 2 was then dedicated to how the issue could be resolved. The final outcome was satisfactory, but it resulted in significantly delayed submissions and repeat validation batches. (A very expensive error indeed).