Sneak Peak Into Aseptic Manufacturing Unit (Cytotoxic Drug and TPN Production)

Licensed Medication. Unlicensed Medication. Specials. Each can be written on a prescription for a patient to take to their local Pharmacy, however Specials are truly 'special' in their own right. Not only are they not confined to the requirement for pods - the new system of patients having to order their own medication over the phone, but they are ordered to be made specifically for that patient based on the list of ingredients given on the recipe - the prescription. Although the manufacture of medications is closely associated with pharmaceutical companies such as GSK and AstraZeneca, some hospitals over the UK have a MHRA certificate to manufacture licensed and unlicensed medication.

Cheltenham General Hospital is one of the few Hospitals in the UK with this Certificate and is where I undertook a placement, allowing me to look around their Aseptic manufacturing Unit to observe the manufacture of cytotoxic drugs and TPN (Total Parenteral Nutrition). Not many people are privy to the location of the site within the Hospital and not many people know about it's existence, however the contribution the unit makes to improving the quality of life of a patient it extraordinary.

The Unit receives prescriptions for many different cytotoxic drugs for patients within the Cheltenham and Gloucestershire Hospital for patients suffering from Cancer, together with prescriptions for TPN (Total Parenteral Nutrition) with the exact electrolytes the nutritionists have agreed are required to improve their health. The Unit produces over 1000 products alone each month.

Importance of A Manufacturing Unit Within A hospital:

Within this placement I partook in experiential learning, allowing me to further understand and consolidate my lecture 'Asepsis and Antisepsis', by observing isolators and drug manufacture in person. I observed the entire process, from receiving the prescription for manufacture of medication, selecting the correct worksheet, labelling, clinical and accuracy checking, spraying before placing in isolator room hatch, manufacture, checking product with a light box, adding labels and warnings to products, and the final check before dispensing to the wards. During my observations of the process, I really enjoyed talking to the staff about what they were doing, their training and how they ended up where they are today, and as a result I have discovered so much more about the training of a Pharmacy technician and the ginormous role that they take within Pharmacy. The experience gave me a newfound appreciation of Aseptic Manufacturing Units, as it is the only part of the Hospital which is completely run and organised by the Pharmacy Department and really embodies what Pharmacy stands for: providing patients with the best quality of care by providing high quality non-contaminated medication. I really admire the time spent by the Pharmacy team to precisely and correctly calculate, produce and check medications as it is a physical representation of how passionate and dedicated the Pharmacy team is about their patients and their position within the multidisciplinary healthcare team.

A break-down of how the Unit Works:

Prescriptions Received:

Prescriptions have already been checked by the dispensing team upstairs before being sent down electronically to the Aseptic Manufacturing Unit. Someone reviews prescriptions to see if the Unit has the products / if they need to be ordered in, and works out a schedule for when the medicines should be produced based on their expiry and when the patient needs to receive the dose. This is important as some products have an expiry date of 4 hours to 24 hours, and it has to be made in consideration of their appointment time.

Worksheets:

There is a worksheet for each 'special' medication that the Hospital makes, with a colour coded system dependent on route and high risk (through the spine = yellow sheet at high risk). The technician will start to transfer the patient details from the prescription to the worksheet e.g. Ward, Hospital Number, Medication and dose, before starting the calculations. Apparently, the Hospital Aseptic Unit creates around 1000 products per month, 80% of these are cytotoxic drugs for cancer patients and the others are TPN and each product is assigned a Hospital 'batch number' specifically for that product using an excel spreadsheet. TPN stands for Total Parenteral Nutrition: ("supplies all daily nutritional requirements. TPN can be used in the hospital or at home." via a central line and may contain water (30 to 40 mL/kg/day), energy (30 to 45 kcal/kg/day, depending on energy expenditure), amino acids (1.0 to 2.0 g/kg/day, depending on the degree of catabolism), essential fatty acids, vitamins, and minerals http://www.merckmanuals.com/professional/nutritional-disorders/nutritional-support/total-parenteral-nutrition-tpn.) The Batch Number includes a letter from the alphabet referring to the month (J for October), 17 (for the year), and the product number e.g. 0636 (number dispensed that month so far.) The excel spreadsheet will include the product, expiry and patient name. Recalls are made by HPR 'Healthcare Professionals' Responsibilities', as a result of bad side effects and there are different recall grades, with 1 being the worst and 2/3 being a result of too much histamine/ plastic present, which requires for the patient to be monitored to ensure no other medication is being prescribed that would interact/ worsen the side effects. I have found more information on page 11 here: https://www.uhb.nhs.uk/Downloads/pdf/QcwmDefectiveMedicine.pdf. Boots describes the grades as follows:

"Class 1: Requires immediate recall because the product poses a serious or life-threatening risk to health

Class 2: Specifies a recall within 48 hours because the defect could harm the patient but is not life-threatening

Class3: Requires action to be taken within five days because the defect is unlikely to harm the patients and is being carried out for reasons other than patient safety

Class 4: Advises caution to be exercised when using the product but indicates the product poses no threat to patient safety " https://www.webmd.boots.com/medications/guide/drug-recalls-what-are-they.)

Class 1 recalls are unusual and rare. The Batch Number and Expiry should be present on the worksheet and and label. The expiry is calculated based on the time that the worksheet is being completed/ just before labelling e.g. if the product has a 24 hour expiry and the worksheet is being completed at 12:15 pm (afternoon) on Wednesday the expiry is 12:15pm on Thursday. The worksheet should also have a 'time made' given meaning that there is a lee-way produced in case someone forgets. When filling in the worksheet it should be stated about who is funding the product: NHS/ NICE/ CDF https://www.england.nhs.uk/cancer/cdf/: Cancer Drugs Fund is "a source of funding for cancer drugs in England which provides patients with faster access to more promising new cancer treatments; helps to ensure more value for money for taxpayers; offers pharmaceutical companies a new fast-track route to NHS funding". This is helpful as some cancer calculations require active ingredients that can cost around £1000 and can be very fragile. When working out calculations from the active ingredient: e.g. 25mg in 1mL and you want 200mg you need to work out the volume of active ingredient required which is in this case 8mL. Then the other volumes should be figured out - including solvents. If placing in an infusion bag you can use the data folder to find out how much it holds e.g. 50mL with a mean of 56mL and upper limit of around 80mL. From this we can figure out if we can add the amount of active ingredients and other substances e.g. water without is bursting or overfilling the upper limit bag capacity and we can remove some of the NaCl from the bag and make room for the other ingredients as it will still have the same amount of active ingredient. In the worksheet the number of syringes used and number of labels used should also be stated and then the labels are printed off, placed into a tray and taken to be checked.

This is then checked by an Accuracy Technician and Pharmacist.

After Checking:

All sheets placed into a bag and products to be placed into a bag before being cleaned down with wipes and then sprayed. This is left for 2 minutes while the spray evaporates whilst taking away the microbes, before being placed in the tray (which is also cleaned) and placed in a hutch to be collected by the manufacturing team.

Manufacturing:

Before starting the manufacturing process, you must first enter the side room where you are changed into a new overcoat, gloves and footwear before entering the isolation room. The isolators for cytotoxic drugs have negative flow as it is safer for the operator for air to be sucked away from the product, whilst TPN isolators have positive flow as the operator is not at risk of harm as much and therefore preventing contamination of products is more important. After changing, the manufacturing session starts - the person manufacturing has an assistant who assists in carrying out volume checks for syringes and placing ingredients and materials required in a hutch to the left of the isolator which can be accessed by the operator through foot peddles. The operator places their arms inside 'astronaut arms and gloves' before placing a resting agar open during the session, and starting the manufacturing process. The calculation list is placed at the top. When the product is formed it is placed onto the right hand side of the isolator, which the assistant removes, and places in the exit hutch. At the end of each session the operator does finger dabbing on an agar before removing to look at later and then clears the inside of the isolator.

1) Gloves sprayed

2) Clean inside of isolator - spray and then clean with wipes

3) Get new gloves

4) Take off first glove by tugging it inside and taking off the rubber ring band

5) Put glove on outermost ring

6) Use other hand to put the new glove on and put the rubber band on top

7) Now take the old glove through and dispose in a bin

8) Repeat with the other hand, ensuring the new glove does not touch the old glove

After manufacturing: next check:

The calculations and prescription are removed from the bag, and so do the products. The labels are positioned together with warning labels, and then checked against a lightbox - black side for clear liquids and white side for colours. The infusion bag is lightly tapped to look at the bubbles flowing up to check if there are any small pieces of plastic from syringes. If there is a small amount of plastic present, they would get the Pharmacist to check and state for it to be given to the patient through a filtered infusion. However if a larger/ black object e.g. from the lid, or protein aggregate is observed the product would have to be failed. Syringes have the volume checked against lightbox. The product is then placed within a suitable bag (yellow for normal and red for high risk) and sealed with appropriate labels on the bags and worksheet.

Next check:

Take product to final checking bench.

Background Behind Running The Unit

I was amazed about the amount of effort and consideration that the Quality Assurance branch and also the Admin staff had to complete to keep the Unit running: from admin scheduling timetables, Technician and Pharmacy Rotations within the Unit, Holidays, and adjusting requirements and SOPs dependent on new information received. The Quality Assurance alone has to ensure isolators get their monthly checks, cleaning and that the pressure is maintained, whilst ensuring all staff are trained; materials to go into medicines are checked; and to get the Unit ready for MHRA inspections. Whilst Quality Control is in charge of the final-product checks. So much effort has gone into keeping the Unit running and this is what makes the Aseptic Unit team a credit to the Hospital, as they have a team of people passionate about making that Hospital be one of the few Hospitals with a MHRA certificate to manufacture licensed and unlicensed medication. However, when I was shown around the Manufacturing Department, my fascination over the Manufacturing process grew, as I discovered the importance of keeping a 10pa difference between isolator, changing side and middle rooms, because if the pressure is too low contamination risks increase, whilst high pressure increases the likelihood of nose-bleeds. Other than the background requirements to keep the Unit running, I was impressed by the worksheets and method sheets for different medication production prescriptions, making it easier for staff to understand how to undertake their tasks and eliminating the risk of mistakes by standardising procedures.