SC V F. Aseptic Preparation of Unlicensed Medicines

This section provides general guidance on the Aseptic Preparation of Unlicensed Medicines. It includes guiding principles that should be followed for all aseptically prepared unlicensed medicines and specific information relating to Parenteral Nutrition Solutions.

1. GENERAL GUIDANCE

Introduction

It is now an accepted principle that the aseptic preparation of medicines that are intended for parenteral administration should be undertaken in specialised aseptic preparation units, under the supervision of a pharmacist, and not in clinical areas. The Breckenridge report, published in 1976, recommended centralisation of IV additive services in hospital pharmacy units and the British National Formulary (BNF) supports this advice. There is now a wide range of diverse product types prepared in aseptic units. These can be parenteral nutrition solutions (PN), cytotoxic preparations, radiopharmaceutical injections and additives for parenteral administration. As aseptic preparation services have developed, the benefits of preparing these products in specialised, dedicated facilities has been quickly recognised and the demand for these products has increased. This has led to some standardisation of treatments, enabling batch preparation processes, and as a consequence commercial units operating under Manufacturer’s (‘Specials’) Licences have been developed to meet this demand. Home parenteral nutrition services that supply PN therapy direct to the patients’ homes, together with other homecare aseptic therapy services, are a feature of this service development.

The benefits that result from the preparation of these products in specialised facilities are well recognised: dose calculations can be automated or checked and confirmed; products are labelled correctly; documentation allows a treatment audit trail; sterility assurance is increased. There are, however, risks associated with centralisation of aseptic preparation services. Process failures, particularly those that result in product contamination can impact on a wider population compared with individually prepared medicines when a single individual patient is at risk. Furthermore, centralisation of aseptic activities into a small number of specialist facilities can significantly affect capacity and supply. All aseptic units have a finite capacity and increasing supply beyond this capacity, in response to increasing demand, may impact upon product quality and compromise patient safety. It is accepted, however, that the benefits of aseptic preparation in specialised units outweigh the risks and so it is now routine practice.

Aseptic preparation of unlicensed medicines is exempt from the licensing requirements of the Human Medicines Regulations 2012. This includes preparation for individual patients and the preparation of stocks from which to dispense to patients in accordance with a prescription. Nonetheless, it is expected that aseptic preparation activities for stocks are undertaken in units that possess a Manufacturer’s (‘Specials’) Licence that covers their activities. Aseptic preparation units that are dispensing preparations for individual patients are exempt from these requirements but should be operating in accordance with good practice and appropriate guidance (for example, the NHS guidelines on Quality Assurance of Aseptic Preparation Services¹⁾.The guidance provided in this Chapter applies to all products prepared aseptically for administration to patients. PN, cytotoxic injections, radiopharmaceuticals and additives for parenteral administration are the most common examples but other dosage forms e.g. irrigations, eye drops, are also applicable.

Patient safety is of paramount importance for aseptic preparation units. Incorrect dosage, inappropriate administration, product degradation, product contamination or lack of sterility can and has caused serious adverse reactions in patients and in some cases has been fatal. Published standards are needed for these high risk products. This should include advice on their safe preparation and the application of current guidelines including, where appropriate, compliance with any general monographs that define analytical requirements.

Standards for Aseptic Preparation Services

The following are the principles that should be followed in order to ensure a comprehensive quality management system (QMS) is implemented for aseptic preparation services that is fit for purpose. There is an abundance of guidance documents that should be referred to for the detail that the QMS should include. These general principles will be the basis for the QMS.

1. Facilities

All aseptic manipulations should be performed in a workstation with a controlled workspace environment conforming to EC grade A. This should be sited in facilities that protect and maintain the grade A environment during use and when transferring materials into and out of the workstation. Ideally, clean air devices should run continuously. All rooms and equipment used for aseptic preparation should be cleaned and disinfected regularly. Equipment should have written operating instructions and be part of a planned preventative maintenance programme. The facilities should be commissioned when installed and monitored at regular intervals.

2. Formulation and Stability

The range of formulations encountered in aseptic preparation units is very wide and can range from simple two component systems to complex mixtures with in excess of 50 constituents. For a substantial number of these, product stability data is limited or not available. However, an assessment of stability is needed to ensure the quality of the product is suitable for the patient at the time of administration. This assessment should include the chemical and physical stability of the product’s components, together with potential incompatibilities with containers and materials used during preparation. Where no assessment of stability can be made, the decision to prepare the product should be made in the context of the clinical needs of the patient, and the shortest possible shelf life that is compatible with the administration procedure and supply logistics should be assigned.

Expiry periods given to products must be evaluated in accordance with local conditions. Data obtained from the literature or from the manufacturer of the products used for the preparation should be carefully assessed to ensure its applicability and validity. As a general principle, the shortest expiry date consistent with the usage pattern of the product should be used.

Microbiological integrity must also form a part of the shelf life assessment.

3. Documentation

A comprehensive documentation system should be prepared and approved. These documents should be clear and detailed. They should include standard operating procedures (SOPs) for all the critical activities and functions that will affect the quality of the product. A list of SOPs that should be available can be found in the various guidance documents.

All products that are prepared in the unit should have their own worksheet and labels that ensure product traceability from preparation to administration and identify the person(s) responsible for its preparation and release. Within any one unit, worksheets and labels should have a standardised style and presentation. Batch worksheets should be reproduced from an approved master document. The batch documentation should be sufficiently detailed to allow traceability of starting materials and components to establish an audit trail for the product. Completed worksheets should be retained for a sufficient period to satisfy regulatory requirements. For example worksheets for paediatric medicines should be retained for 30 years.

Operation, cleaning, maintenance and fault logs should be maintained. All Planned Preventative Maintenance (PPM) and breakdown maintenance should be recorded. A permit to work system should be used.

4. Personnel and Training

An aseptic preparation service must be managed by a person who has up-to-date practical and theoretical experience in aseptic preparation. In unlicensed units this must be a pharmacist. In NHS units the responsible pharmacist is designated as the Accountable Pharmacist. He/she should have practical experience in Good Manufacturing Practice (GMP), formulation of aseptic preparations, validation of aseptic processes and QMS.

All staff working in an aseptic preparation unit should have the knowledge and skills required to perform their duties. A documented training programme should record and confirm the competencies of all staff working in the unit. Staff should not work in the unit until training (or retraining) has been satisfactorily completed. There should be a system of accreditation linked to specific activities for all staff involved in aseptic preparation services.

Media fill trials should be used to validate and confirm the competence of the operators in different aseptic activities.

5. Monitoring

Regular monitoring of the environment, processes and finished products is an essential and fundamental part of the QMS. Standards and guidelines are available for many of the physical and microbiological aspects. Where definitive standards do not exist it is important to set in-house standards and action limits based on meaningful results and monitoring trends.

Senior personnel within the aseptic preparation unit must have an understanding of clean room technology, together with a thorough knowledge of the design and operation of their department e.g. ventilation systems, position and grade of HEPA filters, work stations, etc. A documented programme of monitoring should be in place and should be adhered to. This will include test limits for environmental monitoring both at rest and in use.

When the unit is in use, the critical zone of the controlled workspace should be monitored continuously.

There should be a planned programme of physical, chemical and microbiological monitoring of finished products to further validate the aseptic processes. Samples may be obtained from unused products, additional samples that are specially prepared, or in process samples taken at the end of the compounding procedure. Sampling of the final container after completion of preparation and prior to issue may be a threat to product integrity and is therefore not recommended.

Media fill trials should be used to validate the process initially and subsequently on a regular basis. These should mirror the batch sizes in the unit and cover the number and types of manipulations performed on the actual batch.

6. Cleaning and Disinfection

All areas of an aseptic preparation unit should be regularly cleaned and, where necessary disinfected, according to written approved procedures and a log kept. Workstations should be cleaned and disinfected before and after each work session and appropriate measures put in place to prevent chemical cross-contamination. The effectiveness of cleaning and disinfection should be routinely demonstrated by microbiological monitoring. The surfaces of all items that are to be used in the grade A workstation should be disinfected by means of swabbing, spraying or immersion prior to their introduction. A sporicidal agent should be used for the transfer process. Gaseous sterilisation of enclosed isolator workstations is also possible.

7. Starting Materials, Components and Consumables

Where available, starting materials should be licensed products. Where unlicensed products are used, it is the responsibility of the pharmacist to ensure that the product is of an appropriate quality by means of Certificates of Analysis, analytical testing, or a combination of both, in accordance with appropriate Royal Pharmaceutical and GPhC Specials guidance. Unlicensed materials should be obtained from a supplier with a Manufacturer’s (‘Specials’) Licence. Imported products that are licensed in the country of origin may also be used, subject to appropriate import controls.

Components, including reconstitution devices, syringes and needles, and the product contact parts of filling systems, transfer tubing and final containers, should be purchased sterile from the manufacturer or sterilised prior to use. All such products should be CE marked. Components should be packaged in such a way that they can be transferred into the grade A workstation environment without risk of contamination to the product or the environment

8. Storage and Distribution

A close examination should be made of all stages between product approval and product use to ensure that the quality of the product is not compromised before its expiry. Distribution should be controlled and validated as rigorously as storage. Where necessary, the security of the cold chain should be assessed and assured. Staff involved in storage and distribution should be aware of their responsibilities and trained appropriately. Distribution records of all products should be kept to ensure that effective recall can take place if necessary.

Management Principles for Aseptic Preparation Units

Aseptic preparation departments must ensure that the products they supply are fit for their intended use and do not place patients at risk. Achieving this objective is the responsibility of senior managers and pharmacy managers and requires the commitment, understanding, and participation of all staff who are involved in the ordering, preparation, storage and supply of aseptic products. Some units may not have the facilities, equipment or competencies to do certain tasks and some products or processes may present too high a risk for the resources available. Appropriate controls are needed to manage this. There must be a comprehensive and correctly implemented QMS. It should be fully documented and its effectiveness monitored. It is the responsibility of the management of the aseptic unit to ensure that standards within the unit are maintained and that any faults or deficiencies, once identified, are rectified.

Senior managers should be aware of current Legislative and Regulatory requirements for aseptic preparation services and ensure that the unit(s) comply with these requirements.

Management of aseptic preparation services should be the responsibility of a named Accountable Pharmacist. Management of day-to-day functions can be delegated but all line-management responsibilities should be defined in the QMS. Senior pharmacy managers and senior managers in the organisation with management accountability for the aseptic preparation service should be familiar with the QMS and support the delivery of safe and effective aseptic products.

The prescribing physician must also understand his/her responsibility for the clinical decision to prescribe an unlicensed medicine and the liability for the efficacy of the product.

1. Quality Management System

The QMS should fully document the procedures whereby the standards for aseptic preparation outlined above will be applied and achieved. All staff involved in the preparation and supply of aseptically prepared products should have a knowledge and understanding of the QMS and be able to apply it to their areas of work. Evidence of staff competencies in their fields of work should be documented and continuously reviewed. The QMS should be continuously reviewed and the outcome of the review documented and implemented.

All departments undertaking aseptic preparation activities should have a documented organisational structure which indicates clearly the responsibilities and accountability of each member of staff. All staff should be clear about their level of responsibility.

2. Product Approval

A formal recorded decision of approval should be made by a person authorised to do so before a preparation can be released for use. The person who authorises the approval for use, or his/her deputy, should be suitably trained and have the appropriate knowledge to fulfil this role.

There should be a written procedure for dealing with preparations that fail to comply with the required standard. The investigation should be documented and senior managers informed.

3. Capacity Planning

Managers must know and document the maximum capacity at which their aseptic preparation units can operate. This will vary depending upon staff resources, the size and design of the unit and storage facilities, but managers need to understand these variables and plan accordingly. No unit should operate at more than 80% capacity for a sustained period. There needs to be sufficient flexibility to accommodate unplanned critical demand. Increasing output beyond capacity represents a critical risk to the integrity of the product. These decisions to operate at over-capacity are normally taken to minimise costs or increase profits but neither of these reasons are justified at the risk of patient safety. The QMS should define the capacity of the unit and should be constantly updated to reflect changes in staff numbers, staff competencies and facilities.

There should be a contingency plan in place to manage situations when the risk assessment of an over capacity concludes that the risk to product quality, product integrity and patient safety is unacceptable. This should include measures to maintain the supply chain until the capacity of the facilities is restored. The plan should be documented and approved through appropriate management structures and developed with the agreement of pharmacy, medical and nursing staff.

Diversity of supply is also an important aspect of capacity management. Aseptic preparation covers a wide range of product types as evidenced by Section 2 of this chapter. These different product types have different requirements regarding facilities design, equipment, preparation procedures, storage and operator competencies. Activities are not necessarily transferable between units. The capacity for each type of activity should be individually defined in the quality system.

4. Inspection and Audit

Internal and external audits should be carried out routinely. Audits should cover all areas where aseptic products are prepared, stored or distributed. They should include examination of documentation, preparation and quality control methods, validation, training and complaints and recall procedures. The Accountable Pharmacist for the unit should take responsibility for all remedial actions.

Internal audits are part of the QMS and should be carried out at regular intervals. An external audit, performed by a suitably trained and qualified person should be undertaken at least every two years.

In the UK, NHS hospitals collaborate in an independent audit programme for aseptic preparation units, which was initiated in 1997. This programme continues and the NHS guidelines for aseptic preparation services provide the standards against which the audits are performed.

2. TYPES OF FORMULATION

Parenteral Nutrition Solutions

Parenteral nutrition solutions are one of the most widely prescribed, and one of the most frequently prepared, unlicensed medicines. Currently, due to the complexity of the formulations, there is only limited routine testing performed on these products and there are no published standards for their pharmaceutical quality.

The demand for end-product testing is increasing, notwithstanding the challenges that sampling of PN solutions presents. A pharmacopoeia General Monograph would provide a suitable standard for such testing.

Parenteral nutrition solutions provide essential nutrition requirements in the form of protein (amino acids), carbohydrate (glucose), and fat (lipids), together with essential elements, trace elements and vitamins. The composition of PN solutions varies according to the needs of the individual patient with regard to calorific requirements, metabolic status, fluid and electrolyte balance, acid-base status, as well as other specific PN requirements. As a consequence, many are formulated uniquely to the patient’s requirements. PN solutions will typically contain the following components:

The composition of PN solutions will vary significantly depending upon individual patient needs. Requirements for adult PN differ significantly from those for neo-natal and paediatric populations. Therapeutic ranges and established dosage regimens will limit the ranges for the various components, but defining limits is not always possible or practical. The upper range limits of some constituents may be controlled by other factors, such as stability. For example, interaction between phosphate and calcium will cause precipitation above a certain concentration.

Standards for Preparation

Starting Materials

All starting materials used in the preparation of parenteral nutrition solutions should comply with relevant pharmacopoeial standards (including the monographs for Substances for Pharmaceutical Use and Pharmaceutical Preparations). Licensed preparations should be used, where available. Any unlicensed preparations should have been manufactured in a licensed Specials manufacturing unit in compliance with the conditions of the licence.

Manual Preparation

Due to the complexity of the formulation, and the preparation process, PN should be prepared or manufactured in aseptic preparation facilities. No preparation should be performed in uncontrolled environments and all processes should be automated or semi-automated. Manual preparation carries the greatest risk of error and should only be undertaken in emergency situations.

Automated Systems

Automated compounding devices are routinely used for the preparation of PN solutions. A number of containers can be attached to such devices using specific, single-use tubing. The system IT technology can control the identity of products and components (bar codes), pump flow rates and addition sequence. The systems also incorporate an audit record to facilitate quality checks.

Automation of the preparation process for PN solutions reduces the risk of microbiological contamination since the numbers of manual manipulations are reduced, but increases the risks of reconstitution or mixing errors because when these occur they can affect a wider population. Such errors can arise from:

Fatalities due to the use of incorrect concentrations of glucose and electrolytes have been reported.

These risks apply equally to manual preparation but are multiplied in automated systems.

Validation of automated filling apparatus should be part of the QMS and should be repeated at appropriate intervals. Process checks should confirm the products and containers are connected correctly.

Incompatibilities

Monovalent cations do not cause physical incompatibility of PN solutions unless they are in high concentrations. Positively charged divalent and trivalent ions neutralise the zeta potential of lipid droplets leading to aggregation, coalescence and phase separation.

Admixture of calcium and phosphate ions in PN solutions may result in the precipitation of calcium phosphate, similarly with magnesium and phosphate. The precipitate will not normally be detected by visual examination in lipid-containing solutions and needs to be prevented by the sequence and rate the ions are added to the solution, the phosphate salt used, the phosphate concentration and the volume of the PN solution. Organic complexes of calcium and phosphate can reduce the risk of precipitation and may be preferred.

It is not appropriate to make further additions to PN solutions. The complexity of the formulation makes assessment of interactions and incompatibilities very difficult. There are reports confirming the use of some additives; these include heparin, insulin, ranitidine and iron, but, in general, all additions should be avoided.

PN solutions are packaged in plastic containers and so container compatibility for PN solutions needs to be considered. Interactions of PN solutions with the surfaces of containers and administration devices can occur. PN solution components can be adsorbed or absorbed to plastics, for example vitamin A is absorbed by PVC bags and tubing. Components of the plastic material can leach into the solution. There are a variety of specialised container-closure systems for use with PN. The most appropriate should be selected for the application concerned. Ethyl-vinyl-acetate (EVA) bags are a better option than PVC, but multilayer bags are now the preferred choice. These provide a barrier to oxygen and therefore have the potential to improve stability.

Stability

The large number of components (>50) and the metastable lipid emulsion present significant challenges to the stability of PN solutions. Physicochemical reactions that will impact on the stability include:

Storage

PN solutions should be stored in a refrigerator and protected from light.

Safety Considerations

Aluminium in Parenteral Nutrition Solutions

Aluminium is a polyvalent cation and is found in its ionic form in almost every animal and plant tissue. The general population is exposed to aluminium from a variety of sources including food, water, beverages, canned products, containers and cooking utensils. Exposure to aluminium can also occur through medication such as antacids, buffered analgesics and through parenteral nutrition (PN).

The body has a natural protective barrier to prevent systemic absorption of aluminium. Both skin and lungs are effective in limiting aluminium exposure as is the GI tract. However, these protective mechanisms are bypassed when aluminium is administered parenterally. In adults, 40% of aluminium that is infused intravenously is retained; in neonates, this figure increases to 75%². Aluminium becomes bound to transferrin and albumin and is eliminated via the kidneys. It follows, therefore, that patients with reduced or impaired renal function are at the greatest risk of aluminium toxicity. Premature and neonatal babies who have immature renal function are especially prone to aluminium toxicity. No current UK or EU guidelines are available on the daily limit for aluminium exposure or aluminium content in parenterals. However, in the US, to limit patients’ exposure to aluminium, the Food and Drug Administration (FDA) has restricted the aluminium content of large-volume parenterals for PN to 25 μg/L (but no limit currently exists for small-volume parenterals, although labelling of the aluminium content is required)³. Other publications refer to aluminium toxicity following parenteral nutrition, particularly in neonates^4,5. Aluminium toxicity is more likely to occur in patients with impaired kidney function, including premature infants, who receive parenteral levels of aluminium at greater than 4 to 5 μg/kg/day⁵.

The risk of aluminium exposure can increase substantially due to abnormally high levels of aluminium in some parenteral preparations. Calcium Gluconate Injection in glass ampoules is one such product. Calcium Gluconate Injection is routinely used as a source of calcium ions for PN preparations. In September 2010, the MHRA published a Public Assessment Report entitled “Calcium gluconate injection 10% in 10 mL glass containers: risk of aluminium exposure”. It reported that, when the aluminium content of Calcium Gluconate Injection 10%, packed in 10 mL (type 1) glass ampoules, was compared to those packed in 10 mL plastic ampoules, there was around 200 times more aluminium in Calcium Gluconate Injection packed in glass ampoules than in that packed in plastic ampoules. Type 1 glass ampoules contain a significant amount of aluminium which may be leached into Calcium Gluconate Injection during autoclaving and storage. As a result of these data, the report made the following recommendations:

High aluminium levels may also be found in other parenteral products used as additives in PN solutions including preparations containing magnesium or containing inorganic phosphates.

Bibliography

¹ Quality Assurance of Aseptic Preparation Services: Standards Handbook, Fifth Edition, Royal Pharmaceutical Society & NHS Pharmaceutical Quality Assurance Committee, 2016.

²Klein GL. Aluminium in parenteral solutions revisited – again. Am. J. Clin. Nutr. 1995; 61: 449-456.

³Aluminium in large and small volume parenterals used in total parenteral nutrition. Code of Federal Regulations 2009; 21CFR201.323.

⁴Fewtrell MS et al. Aluminium exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up. Paediatrics 2009; 124 (5): 13729.

⁵Bishop NJ et al. Aluminium neurotoxicity in preterm infants receiving intravenous-feeding solutions. N Engl J Med 1997; 336: 1557–1561.