When you’re entering the world of pharmaceutical manufacturing, or any allied industry or role, it is critical for you to understand the basic terms involved in the production process. You don’t want to be frantically Googling pharmaceutical jargon when your colleagues or clients are discussing a new process or product launch. When someone says heat exchanger, clean room, AMC or small volume parenteral, it would be ideal to know what exactly is going on from the get-go.
In this article, our focus is on parenterals – small volume parenterals, specifically. It covers the definition, specifications, standards and risks involved in small volume parenterals and their production. So that the next time an injectable, ophthalmic drop or other parenteral preparation is being discussed, you already know all the essential details and more.
What are parenterals?
Parenterals are a category of pharmaceutical preparations which are designed and produced to be administered any way other than orally. Like eye drops, they may be applied topically to external tissue. Like most vaccinations, they may be administered intramuscularly. As in the case of insulin delivery, there are also subcutaneously-administered parenterals. Other than these, parenterals may also be delivered intravenously or directly into specialised tissue like the spinal cord.
In all of these cases, the pharmaceutical product bypasses the alimentary canal; it is not subject to the chemicals which break down substances in the digestive system. It has a much shorter route into the bloodstream or body tissue, and is therefore usually faster-acting that oral solid dosages. For these reasons, parenterals must always be pyrogen-free. Further, other than in the case of biologics or other products which are not heat stable, they must undergo terminal sterilisation to achieve sufficient sterility levels. In situations where terminal sterilization is not possible, the product must be aseptically produced and packaged.
Parenterals are of two kinds – small volume parenterals, or SVPs and large volume parenterals, or LVPs. The names of the two varieties give away the main difference between them: that of volume. Large volume parenterals are ordinarily packed in containers greater than 100 ml and less than 1000 ml in volume. Generally packed as a single dose, they are often intended for intravenous administration. We will discuss small volume parenterals in more detail below, but before that, it is also important to note that LVPs and SVPs also differ in terms of number of doses in a single package as well as delivery method.
What is a small volume parenteral?
A small volume parenteral is any sterile pharmaceutical preparation packed in a volume of 100 ml or less. You are likely to find a small volume parenteral contained in a vial, ampoule, pre-filled syringe, or a squeezable container. A single dose usually rangse from 1 ml to 30 ml, so a single SVP container may contain more than one dose. Small volume parenteral applications range from otic and oral drops to vaccinations and local anaesthetics.
A small volume parenteral may be in either dry powder form or liquid form; it all depends on the stability and characteristics of the active substance. Depending on the form of the SVP, it may be composed of any of the following elements: solutes, active pharmaceutical ingredients (APIs), water for injection, antimicrobial agents, antioxidants, and some more.
Manufacturing a small volume parenteral
In specialised equipment, the selected combination of these elements is brought together under controlled conditions of temperature, pressure and pH. But the compounding of the product is just one part of the process; storage, transfer and filling processes are also designed to maintain the integrity of the small volume parenteral.
For starters, the compounding or manufacturing vessels used are operated in specific Grade c areas under laminar air flow, or LAF. This creates a particle-free working environment, reducing the risk of contamination. These vessels are usually charged with water for injection, or WFI. APIs, antimicrobials and other components are added to make up the volume of the SVP, followed by nitrogen sparging, sampling and quality analysis.
From here, the product is moved to a storage or holding vessel which is placed in a Grade B area, under positive nitrogen pressure. Pre-sterilisation with steam ensures that the vessel doesn’t introduce any contaminants into the small volume parenteral. And then, the product finally passes through a sterile filter to make its way to the filling line. This whole process should ideally be customisable in terms of moveability of skid system, insulation, level sensing, radar, CIP and SIPintegrations, and load cells to make sure that your installed system is perfectly suited to your requirements.
What are the risks and standards involved in small volume parenteral manufacturing?
In the pharma industry, safety and quality are of utmost importance. Manufacturing a small volume parenteral, specifically, has extremely high standards given that the risk they pose can also be very high. Since SVPs enter directly into our organs, tissues or blood, their fast action has the potential to cause widespread damage. So there is absolutely no room for error at all.
Quality standards: In pharma production, international standards for products and processes are outlined in some prominent pharmacopoeia like the US Pharmacopoeia, the European Pharmacopoeia and the Japanese Pharmacopoeia. Following the prescriptions of these global standards ensures that your small volume parenteral is acceptable in markets around the world. These documents provide guidance on good manufacturing practices, permissible levels of endotoxins, standards for particulate and microbial presence, and recommended methods to achieve different purity levels. Essentially, they provide a guide, a recipe, for you to reference as your company embarks on the small volume parenteral manufacturing journey.
Sterilisation: If the final product is heat stable, the entire production process need not be aseptic, though sanitary standards would still be fairly high. In the case that terminal sterilisation is not being carried out, each part of the process must be aseptic. In both cases, the vessels, equipment, piping and other containers which come in contact with the small volume parenterals should be sterilised separately. This includes vials, ampoules, closures, filtration equipment and more. Moist heat, dry heat, special gases or radiation may be employed to achieve desired levels of sterility.
Quality testing: When it comes to sterile products like small volume parenterals, testing is effectively a destructive process. If a sample is drawn for testing, that particular unit cannot be used because its sterility has been compromised by the test. This is why when it comes to sterile products, sterile standards are built into the process.
The above mentioned sterilisation standards are an important part of the process; but they are only one part of the process. For both drug and liquid injection manufacturing, sections of the plant need to be separated as per the process occurring there. Further, warehousing, washing, sterilisation, compounding, storage, packaging and labelling also all deserve separate sections to prevent cross-contamination.
Even after ensuring sanitary standards during production, product testing is a must at different stages of production and packaging. Since the process is destructive, a few samples are chosen from each lot to be tested. They undergo tests to measure sterility, pyrogens, bacterial endotoxins and other potential contaminants. The leaker’s test checks that ampoules are properly sealed; the clarity test checks for particulate contamination.
All of these processes must be accompanied by documentation. Without record-keeping, there is no way for you or for regulators to look back on the temperature, humidity, pressure and microbial presence under which your product was made. There is no way to prove the quality of your product in the future. This is why environmental monitoring data, simulation trail records as well as validation documentation must remain updated and secure with you.This case study and this project for a major Indian cosmetics company display TSA’s expertise in solving a range of high purity and process challenges. Not only does our range of products and services meet the highest industry standards, but each piece of equipment is customisable to your specific needs. Check out TSA’s small volume parenteral manufacturing range and reach out to us for a chat about how we can solve for you.