99 Bottles 1.0 serial key or number

The Q&A applies to patients of any age. It elaborates on the issue raised in the Guideline on pharmaceutical development of medicines for paediatric use.

When the feasibility of administering a particular medicinal product through an enteral feeding tube is to be investigated, feasibility studies should address the following:

Ease of administration

• Administration of a medicinal product via a syringe and enteral tube should be feasible using finger pressure on the syringe plunger. If it is not possible to administer the product through the tube with reasonable effort, modification should be considered.

Product modification

• Product modification may be required for feasible administration and prevention of tube blockage. Preferably, solid dosage forms should be completely dissolved, or finely dispersed to minimise risks of tube blockage. The effect of modification on bioavailability should be considered.
• Where enteral tube administration presents unacceptable risks (e.g. tube blockage), changing factors such as the dispersion medium or viscosity, or particle size may reduce the risk of sediment build-up in the tube.

Tube blocking

• Where necessary, repeat-use in vitro feasibility studies, mimicking intended clinical practice, should be performed. If performed, tube blockage and the build-up of residues should be studied. The length of the study should be justified with respect to the likely life span of the tube and the posology of the product.

Dose recovery & flush volumes

• Flushing of tubes is normally performed with water.  The use of other flushing media may be needed for products targeting specific patient populations such as preterm newborn infants and should be justified.

• Flush volumes to achieve an acceptable dose recovery should be determined, taking into account the dose volume and size of tube lumen. Dose recoveries above 90% are usually considered acceptable. Small dose volumes and large lumen tubes are generally worst case for dose recovery.
• The flush volume should be appropriate to the patient population. Information on minimum or smaller flush volumes appropriate in the management of fluid-restricted patients and patients prescribed many medicinal products (polypharmacy) should be provided. For neonatal patients, flush volumes of mL are often required and may need to be restricted to the lowest volume necessary.
• Since enteral tubes can vary with regard to length and internal diameter, tube size should be considered and justified to be appropriate for the intended use (e.g. fine-bore tubes for neonates (Fr), small to medium tubes for the feeding of children and adults (8Fr–12Fr) and large (up to 24Fr) for ostomy tubes (e.g. PEGs)).   

Physicochemical compatibility

• Medicinal products are often administered via tubes as bolus doses, and as such are in transient contact with the tubing. Satisfactory dose recovery, using tubes made of commonly used materials (e.g. polyvinylchloride (PVC), polyurethane (PUR) and silicone), is normally sufficient to demonstrate physicochemical compatibility.
• Leachable and extractable studies are not usually necessary because of the transient contact between medicinal products and tubing. A risk-based approach could be accepted and should consider tube types/materials and all components of the medicinal product. There is little published evidence that medicinal products cause damage to enteral tubes.

General considerations for feasibility studies

It is not necessary to include all combinations of tube type (commonly used tubes are sufficient), dose and flush volumes; an appropriate design of experiments, with justified bracketing and/or worst-case approach, could be acceptable. For example, a worst-case approach to study ease of administration and tube blocking might consider a large dose of the medicinal product administered via a small lumen tube, with a closed end and holes at the side (a common design of enteral tube). 

Where feasibility studies have been performed with enteral tubes, the following should be included in the product information:

SmPC Section Posology and method of administration

• A reference to Section for further information on administration through enteral tubes should be included.

SmPC Section Special precautions for disposal and other handling

• Information for the following should be considered for inclusion:
• Enteral tube sizes and dimensions through which administration of the medicinal product is feasible. 
• If necessary, a description of the modification of the medicinal product.
• If necessary, guidance on strategies to avoid tube blockage.
• Flush volumes appropriate for the indicated patient populations, including, where relevant, minimum/smaller flush volumes for fluid restricted patients.
• If necessary, details of tube types/materials/diluents that are not compatible with the medicinal product.
• Special precautions for caregivers and healthcare professionals regarding occupational exposure to toxic substances.

Patient Information Leaflet (PL) Section 3 (How to take [name of the medicinal product])

The PL should provide relevant information for patients/caregivers on administration of the medicinal product through an enteral feeding tube.

The QWP considers that two different tablet appearances (tablet shape, dimensions or colour) of the same product (same name, same packaging details, same marketing authorisation number) may confuse patients (or users of veterinary medicinal products). Such confusion is considered to have a negative effect on therapeutic adherence and therefore considered as a risk to public and/or animal health. Acceptance of such different tablet appearances in the specification of a single strengthproduct would formally also allow the company to dispense these two appearances in the same container/blister, which may even cause greater confusion. In addition, it is not clear to which extent such different appearances would have an effect on patient / user acceptability.

Moreover, the introduction to the variation classification guidelines (/C /01) includes the following statement: "References in this Annex to changes to the marketing authorisation dossier mean addition, replacement or deletion, unless specifically indicated." For the purpose of illustration and comparison, change code cromwellpsi.coma.1 (Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking.) includes specific reference to addition, which means that tablet markings can be added if not currently present. However, change code cromwellpsi.coma.2 (Change in the shape or dimensions of the pharmaceutical form) does not include any reference to addition. Therefore, in view of this specific absence and taking into account the highlighted introductory text, this could be interpreted as meaning that any change to the shape or dimensions of the pharmaceutical form cannot include the addition of an additional/alternative shape but only replacement. This is also true for A.2 (Change in the (invented) name of the medicinal product) where only a change is referred to and where only replacement is possible.

In the case of applications for more than one tablet strength, the different tablet strengths should be distinguishable at a level sufficient to avoid mistakes between the different strengths by the final user. Distinguishing tablet strengths by colour / shape and marking / embossing is preferable.

Batch-to-batch consistency of the finished product and compliance with the ±5% limit on active substance content specified by Directive /82/EC should be ensured unless otherwise justified. When the active substance has a range of greater than ± 5 % permitted in the active substance specification or situations when the assay method is a microbiological one and it is not possible to correlate activity to weight the inclusion of excipient(s) is strongly recommended to address the issue. This will ensure that the active substance content is in line with the Directive requirements and therefore ensure the correct dosage of the veterinary medicinal product.

Data on the in-use stability of such products should be generated through a dedicated in-use stability study under long-term conditions when there is an indication from stability and/or stress studies that the drug product may be susceptible to deterioration. If there are no such indications, in-use stability studies do not need to be undertaken.

The length of the in-use stability studies will be dependent on the intended use of the drug product. An in-use shelf life should only be set if necessary, i.e. when significant changes as defined in ICH Q1A (R2), or veterinary VICH GL3 as relevant, are observed.

• If only one multi-dose container will be needed for the treatment, the in-use studies should cover at least the length of the treatment. The study should cover the worst case scenario in respect of the container closure system size. If more than one container is needed, one of the two bullet points below should be used for guidance.
• If the treatment is of definite length and the content of one multi-dose container will not suffice, or if the treatment is continuous without a defined end, the studies should cover at least the time necessary to consume the content of two containers to accommodate a situation where the patient takes doses from two containers in parallel.
• If the treatment is intermittent with the dosing instruction “when needed”, the in-use studies should be designed with the aim of finding the time-point where the in-use stability cromwellpsi.com study could be designed with a less than daily opening of the container.
• If no relevant change is observed in the in-use study after 6 months for a product in its immediate packaging, the study does not need to be continued and no in-use shelf life should be set. A relevant change in this context is an observed change to a quality attribute that is trending toward an out of specification result.

Yes. Storage without the protection of the immediate container is considered as a worst case scenario, and can in some instances be used to assess the need for an in-use shelf life. Such studies are relevant as, in clinical practice, oral solid dosage forms may need to be stored in multi-compartment compliance aids or multi-dose dispensing packages to ensure adequate drug adherence, avoid medication errors and/or ease medication management. If no relevant change is observed after 3 months of open dish storage, no in-use shelf life is necessary. If there are relevant changes, normal in-use studies with repeated opening and closing of the container as outlined above are required to establish an in-use shelf life. The conditions of the open dish studies should be controlled in order for the results to be comparable. Open-dish studies at 25 °C/60% RH are considered to be acceptable without further justification as constant exposure to humidity can be regarded as a worst-case scenario.

An in-use shelf-life should only be claimed when significant changes as defined in ICH Q1A (R2), or veterinary VICH GL3 as relevant, are observed.

Examples

1. The in-use stability studies show no relevant deterioration. The applicant proposes an in-use shelf-life of x months, as this is the time covered by the in-use stability study.
   
   To comply with this Q the in-use study should be performed according to Questions 2 or 3 at the applicant’s discretion. When no relevant deterioration is observed an in-use shelf-life is not necessary. No claims should be made in the SPC and questions on the introduction of an in-use shelf-life should not be raised by the Authorities.

1. The in-use stability studies show out of specification results after y months and support stability over x months. The SPC makes a claim for an in-use shelf-life of x months.
   
   In this example an in-use shelf-life of x months in the SPC would be warranted.

1. The in-use stability studies show a trend for deterioration, although the values are all within specification. The applicant proposes an in-use shelf-life of x months as this is the time covered by the in-use stability studies.
   
   An assessment should be made on a case-by-case taking into account the intended use of the medicinal product (see Question 2).The assessment should be based on the overall stability of the drug product and the rate of degradation observed in the in-use studies. An in-use shelf-life should be set if out of specification results are expected based on the observations made. Too short in-use studies, where the intended use of the medicinal product has not been taken into account, are not an acceptable justification for a short in-use shelf life.

No, this decision is not at the applicant’s discretion. Such limitations should be introduced only when strictly necessary, due to the possible implications of in-use shelf lives to patients and to the National Health Care Systems.

The chapters of the European Pharmacopoeia (Ph. Eur.) that describe materials and containers are not exhaustive with regard to all different types of plastic materials and additives. Reference to the specifications published in the Ph. Eur. is therefore not always possible. As outlined in the Ph. Eur. general notices , it is not obligatory that only materials complying with a given specification in a chapter of the Ph. Eur. can be used as immediate packaging materials. Materials with a different formulation, complying with a different specification may be used, if justified, and subject to agreement by the competent authority.

For solid oral dosage forms and solid active substances, it has been agreed by the Joint Committee for Medicinal Products for Human Use / Committee for Medicinal Products for Veterinary Use Quality Working Party that plastic materials compliant with the relevant European Union (EU) food legislation relating to plastic materials and articles intended to come into contact with foodstuffs are considered acceptable. A specification elaborated in accordance with the provisions described in the EU guideline on plastic immediate packaging materials (CPMP/QWP//03) should be laid down.

Update January This Q&A has been superseded by the Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container. Please refer to this guideline for further information.

Ensuring the sterility of medicinal products is the main issue when considering the packaging for sterile products, and therefore the method of choice for the production of any sterile products should be terminal sterilisation.

The European Medicines Agency / Committee for Medicinal Products for Veterinary Useguideline on development pharmaceutics for veterinary medicinal products and its annex decision trees for the selection of sterilisation methods currently state in the introduction to the annex that, “the use of an inappropriate heat-labile packaging material cannot in itself be the sole reason for adoption of aseptic processing. Manufacturers should choose the best sterilisation method achievable for a given formulation and select the packaging material for the product accordingly. However, it may be that the choice of a packaging material for a given product has to take into account factors other than the method of sterilisation. In such cases these other factors need to be clearly documented, explained and scientifically justified in the marketing authorisation dossier.”

Aseptic processing cannot be considered as a simple replacement for terminal sterilisation. The European Pharmacopoeia (Ph. Eur.) general text methods of preparation of sterile products states that, “wherever possible, a process in which the product is sterilised in its final container (terminal sterilisation) is chosen,” and that, “if terminal sterilisation is not possible, filtration through a bacteria-retentive filter or aseptic processing is used; wherever possible, appropriate additional treatment of the product (for example, heating of the product) in its final container is applied.” Such a combination of aseptic processing with non-standard lower temperature heat treatments, either before aseptic filling, or after aseptic filling, should be pursued where possible in line with the recommendations of the Ph. Eur.

The guideline therefore does not prevent the use of heat-labile packaging materials for sterile products, but there must be justified reasons for having such packaging for sterile products, and these must be supported by the overall benefit:risk balance of the product.