Production and Aseptic Services
Stepping Hill Hospital
I know what some of you may be thinking … how can anyone be remotely interested in compounding drugs? It is not at all sexy, and yet how many pharmacists can say that the clinical needs of their patients can always met by licensed (or unlicensed) medicinal products?
While many pharmacists’ involvement in compounding has diminished over the years, it still presents all specialties within the practice of pharmacy with challenges. Sometimes these challenges are simple and are easily resolved, for example, the aqueous suspension of solid dosage forms; on other occasions there are complex and slightly unnerving concepts such as interactions between active pharmaceutical ingredients (APIs), pH constraints,
antioxidants and preservatives to be considered.
There is a late, but nevertheless welcome realisation that perhaps we have been deskilling pharmacists both academically and in practice over many years. Traditional compounding skills are no longer deemed to be required, and yet in nearly all product presentations we are asked for advice and resolution on topics such as:
- Admixture of intravenous injections.
- Concentrations of electrolytes and trace elements in compounded total parenteral nutrition (TPN) bags.
- Liquid oral mixtures of solid dose forms.
- Steroid cream concentrations in dermatological bases.
- Rectal administration for the nil by mouth patient.
- Clinicians involved in clinical trials.
In all these cases there is a continuing requirement for us to seek the advice of the compounding pharmacist.
A definition of compounding is: the formulation (or reformulation) of one or more active pharmaceutical ingredients into a form which is ready to use for the special needs of the patient(s).
Improvements in the pharmaceutical treatment of patients continues to advance. Formulations and presentations are now available that could only have been dreamt of a few decades ago (implants, prodrugs, gene therapy and biological mediators). But for some groups of people, especially neonates and children, patients with rare disease states or patients sensitive to certain chemicals, medication care pathways can be exceedingly complex. Sometimes commercial products fall short of satisfying these needs.
The term “compounding” can cover a wide range of activities in drug formulation. It can be as wide as the simple dilution of creams in the dispensary to large scale production in cGMP cleanrooms. The scale of the demand will influence where the solution may be found and who will supply the product. Requests to the compounding pharmacist will arise from various sources:
- Pharmacists and technicians working with patients on the wards or in the clinics will almost daily encounter a patient with special pharmaceutical needs.
- Medicines information pharmacists are often contacted by practitioners to enquire about the availability of medicines not licensed in the UK.
- Technical pharmacists may be asked to scale-up production of an extemporaneous preparation, or to formulate a different dosage form of an existing product.
All these different types of request draw on the skill and knowledge of the compounding pharmacist.
In the UK the regulatory authorities and current legislation differ slightly from the rest of Europe.
A pharmacist in the UK may:
- Extemporaneously dispense a drug against a prescription.
- Prepare limited quantities of certain drugs (under the supervision of the pharmacist) Section 10 exception, Medicines Act 1968.
- Prepare under a Manufacturing Licence (Specials), batches of product which are often reformulations of common actives or licensed products.
Therefore compounding can be either high or low output volumes and prepared either in designated areas of dispensaries or cGMP cleanrooms.
How my day starts
I arrive at work just before 08.00 and the first thing I do is check my emails for information I have requested previously. The Compounding Interest Group’s (CIG) website is a rich source of information including everyone’s “chatter” about the latest hot topic. The electronic superhighway has revolutionised the way we can research, share, discuss, agree (or disagree) our compounding problems.
Being at the ML (Specials) licensed end of activity and a subregional provider of noncommercially available medicines, we regularly have up to four or five different preparations to compound. Repeat requests of previously documented products as in certain hospital formularies, are quickly resolved. “Novel” drug forms require product development.
The stages of a typical compounding development are:
- Receive request – is it bona fide?
- Define and clarify problem – not always what it first seems!!
- Initial research – using textbooks, journals and electronic information.
- Discussion groups/development teams. Ideally clinical and technical pharmacists, quality assurance/ formulation scientist and interaction with the clinician(s) is essential.
- Documentation designed, approved and product made.
Problem sharing is vital for inputting sound judgements into the “elegance” of the compounded finished product. At 08.30 I have a regular review of progress with the production and compounding pharmacists. At the moment we have an ongoing problem with tobramycin oral solution 80mg/ml. This is essentially a potency of salt problem and conflicting pH requirement. This needs a further review meeting with our development scientist and so I arrange one at 10.00 to discuss the issue.
The CIG website reveals that colleagues are today concerned with:
- Vancomycin line locks (vancomycin and heparin). Is it stable at the concentrations required?
- Phosphate buffered sodium chloride 0.9% pH 5.5 injection – for use in nuclear medicine.
- Nonavailability of raw materials from an ever decreasing number of suppliers and the need to outsource raw materials from far and wide!
The enjoyment in being asked to make something, which is not commercially available is tangible. There can be a real sense of satisfaction in investigating, developing and producing these formulations. If the result is, a patient goes home tomorrow with a mixture that is stable, preserved, and of the correct strength and organoleptically acceptable then the task is rewarding. The “nil by mouth” patient, or the new clinical information/perceived wisdom that product X may be more useful than compound Y, presents opportunities for us to display our unique skills in making ready-to-use medicines for patients.
Continuing my rounds, I check in with the aseptic services pharmacist to review the orders, particularly those for TPN from the neonatal intensive care unit (NICU). This is the high-risk business of compounding all the electrolytes, trace elements, fats, amino acids, carbohydrates and final volumes necessary to give a tiny baby its nutritional requirements.
The outcome of the 10.00 development meeting is a new method of preparation and the decision to produce a test batch for analysis.
Around 11.00 the phone rings. The local community pharmacy requires amiloride 2.5mg as a nebuliser solution for a seriously ill patient with cystic fibrosis. My production pharmacist and I quickly meet to discuss the situation. Our first thoughts are that it needs to be sterilised which immediately raises question about temperature stability. Can it be terminally sterilised or does it require aseptic filtration? We divide up the research and agree to get back together after lunch with our investigation findings.
Another problem that has been focusing our minds for the past week is the development of arginine 2.5%/lycine 2.5% renal protective infusion for a patient awaiting radiotherapy.
This product will be for the named patient and I phone the clinicians and pharmacist at the requesting hospital to discuss:
- Raw material availability.
- QC specifications on raw materials and finished products.
- Customer is requesting osmolarity measurements.
- The formulation including product presentation.
- Route of administration.
- Presentation of finished product.
- Urgency of request.
- Cost of finished product (a financial trading account is in operation).
I get through finally by email and an agreement to proceed is reached by early afternoon. The first test batch is to be made tomorrow.
Straight after lunch I get on with other aspects of my “specials” production and aseptic preparation job but am interrupted by a call from a medicines information pharmacist about a patient’s known allergy to iodine – is there any trace in one of our injections? I ask my deputy to deal with this one.
Documentation development is a key part of compounding, particularly the specifications for raw materials and finished products. These, together with the worksheet or batch manufacturing record, are submitted to quality control for approval. Sometimes a product is required so urgently that there is very little development time allowed and decisions regarding the quality assurance of the product need to be weighed against its potential clinical benefit. Quality is never compromised but the degree of testing can be relevant.
A unit like ours, involved in sterile, nonsterile and aseptic products on a cross regional basis will always attract many and different types of requests. It also provides a training resource not only to NHS staff, but we also have links with universities and colleges, and tomorrow we will entertain some student technicians.
At the end of the day I switch off the computer and look forward to the next days’ requests.
The author would like to thank Sally Miller, Deputy Production Manager at Stockport Pharmaceuticals, and Martin Jones, Head of Research, Quality Control North West.
Stockport Pharmaceuticals is a supplier of “Specials” to the NHS and other private contractors.
Compounding Interest Group
Special interest group of the UK Guild of Healthcare Pharmacists. Provides a forum for pharmacists and technicians with an interest in pharmaceutical formulation and processing