Compliance, Curiosity & Consequences
Galenisys Newsletter : March 2026
Table of Contents
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TALES FROM FARAWAY PHARMA
It seemed perfect, until it wasn’t ……
by Steve Biddulph -
IT MUST HAVE BEEN THE SUGAR, …., YEAH, ……… (I THINK).
The 25mcg strength puzzle
By Bill Torpey -
DODGY DOCUMENTS IN THE LAND OF PAPER DRAGONS
But where is the factory?
By Richard van Duyse -
OUCH! - “EVERYONE WOULD HAVE SAID YOU WERE MAD”
Doubling but not quitting.
By Tony Dunford
TALES FROM FARAWAY PHARMA
by Steve Biddulph
Fellow of Royal Society of Biology. Board level pharma experience. QSM and Aseptic Manufacturing & Control Expertise. Galenisys Managing Director.
IT SEEMED PERFECT ...UNTIL IT WASN’T
In my roving brief as Head of Quality, I was asked to review the aseptic processes in a vaccine manufacturing plant. Soon after arriving at the site, I was “treated” to a presentation which included:
- the Site Organisation,
- Quality & Compliance and, of course,
- the preparation and Training of personnel for aseptic activities.
These aspects were very well presented, although I had time to muse on why I’d been invited to assess things.
Next, I sat down with the Quality Team, and they showed how they managed and controlled the manufacture, filling and finishing of all the various aseptically filled and inspected vaccines.
Obviously, I needed to observe the resulting reality as well, so after gowning up (compliantly), I visited the manufacturing area for formulation and filling which was physically impressive.
The latest facilities and equipment were very well designed, layouts were logical as were personnel, material and product flows. Utility systems were well designed and maintained but I felt the site was uneasy about something.
My next port of call was to watch people in the filling areas. I saw an operator preparing a filling machine. The equipment was inside a Restricted Access Barrier System (“RABS”) to provide an ISO Class 5 environment, and the operator was using the glove ports to set up the line.
And then it all went wrong
Visibly he was having difficulty in attaching the filling lines to the filling needles. This is where things started to go wrong. He opened a door on the side of the RABs and placed a flask of clear liquid on the filling line. He then went further into the RABS and dipped the filling lines into the flask of clear liquid and attached them to the filling needles. With a quick spray he exited the RABS and left the area. There were so many of his activities that compromised sterility and the integrity of the RABS (if a RABS actually can have integrity) that I waited for him to come out of the changing rooms. (The separate entry and exit changing rooms were another good design feature).
I asked the operator about his behaviour in the area and pointed out to him that he had compromised the integrity and sterility of the RABS.
I then asked him about the clear liquid, pointing out that he could not use silicone of isopropyl alcohol to “wet” the filling lines. Oh, don’t worry, he replied, it was saliva!!
My follow up review revealed major weaknesses in operator training and poor appreciation of microbiological issues at supervisor & management levels. Batch reviews exhibited questionable rationale (for example batches handled by an operator whose right gloved hand dabs revealed Staph Epidermidis, were released because it was argued the man was left handed).
“GO COMPARE”
You might like to make your own checklist (CAPAs) of the various points which this Manufacturing Site needed to correct in view of my findings. and you can contact Galenisys to discuss your results with us, & use of the Audit Triangle.
Steve Biddulph
IT MUST HAVE BEEN THE SUGAR, …, YEAH, … (I THINK).
The 25mcg strength puzzle
By Bill Torpey
B.Sc in Applied Biology. 40 years’ experience in pharma & healthcare as production manager working across all the dosage forms. Recently he spent 8 years working with Q A on validation
Production Management in the Pharmaceutical industry throws up some interesting challenges; and a particular potent puzzle for me was the manufacture of Thyroxine uncoated tablets 25mcg strength. During this time, I was responsible for the transfer of all high potent products (HRT’s and Thyroxine) to the new processing area on site.
As this is a high potency product (approx. 25gms in a 100kgs batch), staff needed to be in air suit PPE’s, with well controlled Local Air Extraction, in spec Clean Room air velocities, direction and pressures.
Thyroxine is also a relatively unstable hormone being sensitive in particular to light and moisture. It is common practise therefore for all batches to be blister packed within the target time set from the start of granulation to the and end of packing to prevent loss of potency (to help compensate most formulations contain an overage of 3% - 5% of the API). All tablet batches were tested for Content Uniformity of course.
Following Qualification of new “Potents Facility”, and after successful trial batches; process validation was carried on 3 full scale batches. Samples were tested from the final blend; and at start, middle, and end of compression, to check for correct potency and provide assurance of homogeneity. (Sampling as per AQL BS6001 (ISO2859-1) with a sample size of 1,250 Level 1 Accept 21 Reject 22).
All samples passed, apart from a fail for high potency in one tablet from the compression stage in the third batch. Damn! So, after the relevant risk assessment meeting the following actions were agreed and completed before the validation study was resumed.
• Staff briefing and training, were repeated regarding the particular challenges of 25mcg thyroxine manufacture.
• Local extraction points were checked for correct location and velocity to prevent loss.
• It was stressed that manual interventions, and any recycling of residues, were strictly forbidden.
• Accordingly, the target net yield was reduced to 93% since it was agreed that loss of material was less important than tablet content uniformity.
In the repeated validation batches, there was a tighter range of tablet potency, indicating the process was now more consistent and in control.
However, after over a year, a batch failed due to the presence of ONE tablet over the specified limit for thyroxine content!! And despite further improvements and increased sample testing etc., this random occurrence of an occasional above potency limit tablet occurred roughly every 10 batches.
The phenomenon only occurred for the 25mcg tablet; and the cause was never identified. Batches of 50 and 100mcg strengths made on the same processing equipment at the same batch size never produced a fail. Roughly 500,000 tablets of thyroxine 25mcg were tested over the 14 years. But strangely not a single one was below the potency limit!!
All sorts of statistical reviews took place without providing clues.
I suspect the use of granulated sugar in the formulation, (and possible humidity control lapses) was the cause. The branded formulation contained sodium citrate instead of granulated sugar, & had no potency issues! Keen to solve the problem (as production managers are), I suggested reformulating with sodium citrate instead of sugar, but of course Quality Assurance vetoed it.
“Answers on a postcard please…”
Bill Torpey
DODGY DOCUMENTS IN THE LAND OF PAPER DRAGONS
But where is the factory?
By Richard van Duyse
Experienced international vaccine industry consultant. Specialized in project & operational management, facility design, start-ups, & technology transfers. Bachelor of Applied Science (B.Sc.).
Over the years 2005 through 2008 I worked in Hangzhou, a major city in the Yangtze River delta of China, at a vaccine manufacturing facility.
During this time the inspection requirements of the European Medicines Agency (EMA) were modified to require auditing to be carried out at the manufacturing facility of raw materials, and not only at the (local) supplier/distributor in Europe.
So, the user has to satisfy the requirement that “Manufacturing authorisation holders shall ensure that they only use active substances that have been manufactured in accordance with GMP ’in their regulatory documentation”.
As I was in territory, our Dutch company, a buyer of Histamine DI-HCL, asked me to do an audit of the Chinese manufacturer. OK so off I went on a long paper chase:
- Initially a company in Hangzhou was mentioned in documents as “supplier”.
- Then the raw material questionnaire received back from the Dutch importer, and a GMP certificate received from China, indicated the product was manufactured in Suzhou, (near Hangzhou), where I contacted “Mr. Yu”.
- However, Suzhou’s raw material Questionnaire of Histamine DI-HCL, eventually received, was not signed off by “Ms. Xia” who had been identified as the QA Responsible Person. (“Ms. Xia” worked in logistics!)
- Also, careful scrutiny showed that Suzhou’s GMP Certificate list of manufactured products had been falsified by adding Histamine Dihydrochloride in the space where one of their other products had been erased.
- Finally, after discussions with the Hangzhou potential supplier, “Mr. Yu” my contact in Suzhou, confessed that the Suzhou company did not manufacturing Histamine, & the GMP certificate was false.
- The Hangzhou supplier then explained there are no suppliers with a GMP certified facility in China for Histamine (although “Mr. Yu” at Suzhou doubted this statement).
After the months of investigation my conclusions were that:
- The Hangzhou company was a trader (probably not a manufacturer) and had looked for a company with a GMP certification for the pharmaceutical industry. They abused Suzhou’s GMP certification by inserting the line about histamine on the certificate (thus embarrassing the Suzhou company).
- The GMP certificate was a copy, not a genuine one. Genuine certificates were yellow with a white border. The normal background with SFDA (Chinese FDA) logo was not on the copy or not visible.
- GMP certification for pharmaceutical grade Histamine probably doesn't didn’t exist in China at that time.
- In any case neither party wanted a plant visit / audit and the confusion caused served to just delay things.
Now, even without any Histamine, I’m very allergic to documentation I get from there!!
OUCH! - “EVERYONE WOULD HAVE SAID YOU WERE MAD”
Doubling but not quitting.
By Tony Dunford
If you’re booking your sunny summer holiday spare a thought for the Chikungunya virus which was first detected in 1952 in Tanzania and used to be confined to tropical regions, (where there are millions of infections a year). The disease causes severe and prolonged joint pain, which is extremely debilitating and can be fatal in young children and older adults.
Now a study by UK Centre for Ecology and Hydrology (UKCEH), notes that “The rate of global warming in Europe is approximately double the rate of global warming at global scale and warns of a growing trend in infections, as the Asian tiger mosquito (Aedes albopictus) moves northwards across Europe with the rising temperatures (it’s been detected in the UK but is not yet established). There are costly vaccines for chikungunya, but the best protection is to avoid being bitten.
A small number of cases had been reported in more than 10 European countries in recent years, but in 2025 large-scale outbreaks hit France and Italy. France previously had recorded 30-odd cases of chikungunya over a decade. Last year, they had over 800, apparently caused in part by travellers from French overseas territories in the tropics, including Réunion where there were outbreaks.
Dr Steven White, at UKCEH, said: “Twenty years ago, if you said we were going to have chikungunya and dengue in Europe, everybody would have said you were mad: these are tropical diseases. Now everything’s changed. This is down to the invasive mosquito and climate change – it really is as simple as that”.
And the global response is … not to quit warming the climate.
In 20 years time “Everybody will say you were mad”?
Tony Dunford
