Packaging of parenteral drugs – Evolution of pre fillable systems

Murli Sundrani Business Director – BD Medical –  Pharmaceutical Systems

Parenteral routes of drug administration such as intramuscular (IM), subcutaneous, intra venous (IV) and intra dermal (ID) are a means of introducing a drug into the body through injection, for quicker absorption by the body and these routes have the highest bioavailability and are not subject to first-pass metabolism or harsh gastrointestinal environments. Parenteral administration is also used for treatment of unconscious patients and under circumstances where a rapid onset of action is required. Parenteral administration provides the most control over the actual dose of drug delivered to the body.

Santosh Das Manager, Customer Quality Assurance & Technical Services, BD Medical

When we talk about packaging of parenteral drugs, the responsibility is many fold. The objective of the packaging systems is to protect the formulation from external environment and vice versa, protect and retain the efficacy with maximum possible shelf life, maintain the sterility with adequate packaging integrity, help administering the right dose accurately with safe disposal after usage. Historically, packaging and drug delivery devices were different but now the trend is that both are integrated. For example, the use of vials is common but provides challenges to the user. Like, the health care professional needs a syringe to prepare the injection and deliver the required dose. In an integrated system such as a pre fill syringe, it not only contains and protects the drug product but also act as a delivery device.

Using syringe/ vial for injection involves 10-12 steps whereas pre fill involves two to three steps. So it minimises response time during emergency and increases patient compliance and reduces chances of administration errors

In the traditional method the overfill volume need to be given in vial/ ampule and then again for syringe. In pre fill delivery system there is only syringe dead space. Apparently as compared to vial (over fill volume is 20 per cent – 25 per cent), pre fillable system requires much lesser overfill volume (2-5 per cent). When this is for expensive biotech products and vaccines, it can save substantial amount of money and valuable drug which can be used for many more patients.

Less preparation steps, less delivery steps, fewer materials, easier storage and disposal reduces overall cost of healthcare.

Prefill delivery systems enhance safety with less particulate matter , reduced risk of bacteriological contamination, reduced risk of medication error, reduced risk of misidentification and improper dosage delivery, reduced risk of injury and exposure to drug.

the world wide pre fillable market is foreseen to grow at CAGR 7.8 per cent from 2010-2016 and then 5.5 per cent from 2017-2022 (source visiongain in 2012).

Way back in 1954, BD produced the first single use glass pre fillable syringe, BD Hypak in the immunisation campaign against polio by Dr Jonas Salk. Since then the pre fill drug delivery systems have evolved significantly and is enriched with experience and expertise of many years. There is ever increasing demand, stringent regulatory requirement, more sensitive drug in pipeline and need for increased patient compliance, which will drive growth for pre fillable syringes

Significant development has happened to make the injection experience as comfortable as possible. One of the critical aspects of user experience is pain perception. Three main combined factors drive lower perception of pain and needle penetration force:

a) Gauge of the needle: Moving to a thinner needle :

• 25 Gauge to 27 gauge for IM injection (vaccines)
• 27 Gauge to 29 Gauge for SC injection ( biotech)

  Thinner needles also provide better internal diameter so that the drug flow is not compromised.

b) Needle point design and point quality

• Moving to a sharper needle : 3 bevels to 5 bevels

c) Needle shield material

• Moving to a less abrasive NS material: rubber to TPE

Considering the above factors BD has developed a prefill syringe BD Physiolis to make the injection experience more comfortable (less pain and less penetration force). This range of prefillable syringes are popular where multiple injections are required over a period of time such as multiple sclerosis.

New biologics drugs are increasingly complex (protein based) and interactions with primary container (tungsten, silicone oil) is a key issue.

Some emerging key expectations

Patients are becoming more empowered, demanding safe, convenient, and easy-to-use drug delivery with injection convenience (strong preference for auto-injectors) and injection comfort (reduced pain, short injection time);

Regulatory agencies have significantly increased their expectations and emphasising more on human factors requirement to asses when integrating drug product with a container and device apart from providing data regarding drug/container compatibility.

It requires substantial amount of investment in research to come up with advance product fulfilling these requirements.

In 2005, BD first became aware that tungsten can cause protein aggregation. Tungsten in aqueous solution combines with a variety of chelating agent offering oxygen, sulfur, nitrogen as donor atoms. With tungsten as a central ion in a chelate ring the following systems have been reported:

O-W-O,O-W-S,O-W-N,S-W-S,S-W-N

Potentially all amino acids are donor atoms and especially cysteine and methionine if we consider sulfur. (Cysteine and methionine are both powerful antioxidants, and they both contain the health-promoting substance sulfur).

The source of tungsten is identified as the forming pin used to form the barrel tip of pre fill syringe. BD has developed expertise on the tungsten issue and developed process to offer low tungsten barrels. Combining this experience along with the other needs of biotech drugs, BD has developed Hypak for biotech.

Intra muscular and subcutaneous route of administration are more popular form of injection. Among the common vaccine delivery routes, notably for flu vaccine immunisation, intradermal injection (ID) has recently undergone clinical investigation and has reported an improved immune response resulting in decreased antigen dose requirements relative to standard IM immunisation. The challenge with delivery through intradermal route is injection technique and availability of an appropriate device to ensure the accuracy in terms of dose and site of injection.

BD Soluvia – Microinjection system is a proven, easy-to-use, intuitive and reliable method of intradermal delivery, which integrates a 1.5 mm length BD microneedle (in pic above). The tiny micro-needle penetrates 1.5mm into the skin from the outer skin surface to deliver a volume upto 250 µL. The ideal injection volume is drug dependent and would be determined by the pharma company. Intradermal route of administartion can save significant amount of active drug as compared to intramuscular route of administartion. The injection system has an integral mechanism that covers the needle after injection, protecting the user against inadvertent needle stick injury.

Another key feature of the BD Uniject is its auto disable feature or its difficulty to re-use.

This format of delivery system can be very good options for mass vaccination and injections in public health sector.

Safety

Safety is a major concern today for patients and healthcare workers. The protection against unsafe injection practices can lead to the transmission of blood borne pathogens from (i) patient to patient, (ii) patients to health personnel, (iii) patients to the community at large.

As per Occupational Safety and Health Administration (OSHA), hospital-based health care workers experience some 800,000 needle stick injuries each year in the US (Jagger, 1990). About 2 per cent or approximately 16,000 of these are likely to be contaminated by HIV (American Hospital Association, 1992). Needle stick injuries account for up to 80 per cent of all accidental exposures to blood. (Jagger, 1988).

Based on various studies, researchers have documented that needle stick injuries are under reported by healthcare workers and the number of exposures could potentially be much higher.

So regulatory requirements are becoming more stringent around the need for a safety integrated system which can prevent Needle Stick Injuries (NSI).

When a needle of choice has to be used along with the syringe, a safety needle is desirable to prevent needle stick injuries. The BD SafetyGlide is a sterile, detachable hypodermic needle that connects to any conventional or prefilled luer syringes. It can be activated by single finger stroke and helps prevent needlestick injuries by allowing easy and secure shielding of the needle tip immediately after injection.

The BD Eclipse shielding hypodermic needle is one of BD’s latest innovations, further expanding the broadest and most comprehensive array of safety-engineered medical devices in the industry.

Self injection system

Growing needs for injectable drug delivery and customised differentiated delivery systems are increasing the size of the self-injection market. Large aging populations with chronic diseases, healthcare cost pressures, and trend toward patient education and empowerment are increasing demand for self-injection systems. BD can offer a wide range of self injection systems to meet the needs of pharma companies, patients, healthcare professionals and other important healthcare stakeholders. Self injection systems can be syringe based or cartridge based. Also, it can be reusable or disposable and variable or fixed dose depending upon the requirement. The platform can range from a simple single dose disposable system to sophisticated systems with digital display and electronic controlled.

Auto injectors are used in therapeutic category like multiple sclerosis, rheumatoid arthritis, osteoporosis, anemia, neutropenia, CNS, hormones.

Disposable and reusable pens are used in therapeutic categories like diabetes, fertility, growth hormones, osteoporosis, other hormonal therapies, cancer management, Parkinson’s disease and sexual dysfunction.

Parenteral packaging and delivery systems are going through an exciting phase. As far as innovation in drug delivery is concerned, BD is always in the forefront to bring innovative and clinically proven product and solutions. With over 100 years of expertise in manufacturing and processing technology for parenteral drug delivery systems, BD has developed a strong understanding of how to help meet the pharma industry’s delivery requirements for injectable medications.

The authors can be reached at murli_sundrani@bd.com and santosh_das@bd.com