Quality of medicines questions and answers: Part 2

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 1-3 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 (4-6Fr), 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 4.2 Posology and method of administration

• A reference to Section 6.6 for further information on administration through enteral tubes should be included.

SmPC Section 6.6 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 strength product 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 (2013/C 223/01) 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 B.II.a.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 B.II.a.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.

No. The mixing of active substances that can exist and are produced on their own should be considered as the first step of the manufacture of the finished product.

It should be noted that the definition of active substance given in part II of the European Union (EU) good-manufacturing-practice (GMP) guide (active substances) states that an active substance is a substance or a ‘mixture of substances’, but this definition takes into account cases when active substances are not single chemically defined substances (e.g. herbal extracts) and it is not meant to allow a mixture of chemically defined active substances to be considered as a single active substance.

As a consequence of what is stated above, the mixing of active substances is subject to compliance with part I of the EU GMP Guide (finished products) and it is not possible to present a single active substance master file for the mixture.

Batch-to-batch consistency of the finished product and compliance with the ±5% limit on active substance content specified by Directive 2001/82/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 fails.The 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.

2. 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.

3. 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 1.3, 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/4359/03) should be laid down.

Update January 2019: 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 Use guideline 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 5.1.1: 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.

Update January 2019: 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.

Terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation of the packaging materials takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity¹.

When GMP certification is not available, certification that the sterilisation has been conducted and validated in accordance with the following ISO standards would be considered to provide an acceptable level of sterility assurance for the empty primary container:

1. I.S. EN ISO 20857:2013 Sterilization of Health Care Products - dry Heat - Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 20857:2010);
2. I.S. EN ISO 11135:2014 Sterilization of Health-care Products - Ethylene Oxide - Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11135:2014);
3. I.S. EN ISO 17665-1:2006 Sterilization of Health Care Products - Moist Heat - Part 1: Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS 17665-2:2009 Sterilization of health care products -- Moist heat -- Part 2: Guidance on the application of ISO 17665-1;
4. I.S. EN ISO 11137-1:2015 Sterilization of Health Care Products - Radiation - Part 1: Requirements for Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11137-1:2006, Including 1:2013);
5. I.S. EN ISO 11137-2:2015 Sterilization of Health Care Products - Radiation - Part 2: Establishing the Sterilization Dose (ISO 11137-2:2013);
6. I.S. EN ISO 11137-3:2006 Sterilization of Health Care Products - Radiation - Part 3: Guidance on Dosimetric Aspects.

It is the responsibility of the user of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of packaging materials. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This should be checked during inspections.The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

Dossier requirements

The following details regarding the sterilisation of the packaging components should be included in the dossier:

1. The sterilisation method and sterilisation cycle;
2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;
3. The name and address of the site of sterilisation and, where available details of GMP certification of the site. Where the component is a CE-marked Class Is sterile device (e.g. sterile syringe), confirmation from the manufacturer that the component is a Class Is sterile device, together with a copy of the declaration of conformity from the Notified Body will suffice.

In the absence of GMP certification or confirmation that the component is a CE-marked Class Is medical device, certification that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.

¹Sites located in the EU which perform sterilisation of primary packaging components only are not required to hold a Manufacturer’s/Importer’s Authorisation (MIA). Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a MIA in relation to these activities.

No, in principle it is not acceptable to compensate for insufficient quality of raw materials (glass containers, rubber stoppers) or insufficient product development (which results in, for example, the formation of glass particles or the introduction of rubber in the finished product) by a user instruction to apply a specific filter prior to administering the product to a patient (or animal).

It is the responsibility of the applicant to develop a product of adequate quality and this includes the container-closure system. In certain cases a modification of the original formulation might be required to assure optimal compatibility with the primary packaging material. This responsibility cannot be partially transferred to the user/patient by an avoidable instruction. The use of a specific filtration step for this purpose may only be considered acceptable by the competent authorities in specific circumstances, for example, temporarily during redevelopment of a product with a high medical need.

The use of a specific filtration step for other purposes is not within the scope of this Q

Where relevant, the issue of glass delamination should be addressed in sections 3.2.P.2 and 3.2.P.7 (or veterinary equivalent) of the Marketing Authorisation dossier. It is noted that available scientific data indicate that glass delamination is commonly related to insufficient quality and consistency of glass vial manufacturing, and that data suggest that intra-batch consistency of a batch of vials may not always be guaranteed. In addition, certain formulations (especially those containing citrate, phosphate, or acetate or having a high ionic strength) seem to introduce an inherent risk.

Introduction

This Q&A provides points to consider for the requirements of multidose containers for preservative-free eye drops designed to prevent microbial contamination of the sterile contents and to minimise microbial growth on the internal and external wet surfaces of the dropper nozzle throughout the in-use shelf life.

For other aspects of eye drop container quality and safety e.g. usability, extractables and leachables, see other guidance, including QWP Q&A “What information on the functional qualities of plastic containers for eye drops should be included in the MAA dossier?”

1.1.1. An explanation should be provided how the container throughout the in-use shelf life:

• prevents microbial contamination of the sterile contents
• minimises microbial growth on the internal and external wet surfaces of the dropper nozzle

Specifically, the delivery mechanism and functions of the container, and if applicable the inclusion of antimicrobial substances (e.g. silver), should be described.

1.1.2. For containers relying on a physical barrier feature, such as valve and pump systems, the flow path of the product out of the container and air intake into the container should be clearly delineated. The mechanism for ensuring sterility of air entering the container (venting) should be described.

Video models of air and liquid flow may also be used to provide information in an easy, understandable manner.

Appropriately scaled cross-sectional drawings should be provided.

1.2.1 A failure mode and effects analysis, or equivalent, should be performed with respect to the container consistently delivering eye drops of appropriate microbiological quality, throughout the in-use shelf-life, including consideration of inappropriate use and storage or damaged product (e.g. drop test and testing in a range of appropriate orientations of the container).

1.2.2   The design and functions of the container, including physical and microbial integrity, should be regularly tested throughout storage during shelf life.

Containers should be stored in various orientations during stability to determine the effect of orientation.

1.2.3. If an antimicrobial substance is present as a container design feature, then the amount in dispensed eye drops should be toxicologically qualified. If necessary, patient safety warnings should be included in the product information.

1.2.4. It should be shown that the sterilisation of the container components does not affect the container design features and functions.

Microbiological stress testing consists of challenging with a high inoculum of suitable micro-organisms.

The range of test organisms should be according to EP 5.1.3, supplemented by other strains or species that may represent likely contaminants to the eye preparations. Each microbial challenge study should include appropriate positive and negative controls to demonstrate effectiveness of the challenge protocol and detection methodology

Validation studies to demonstrate the suitability of the tests employed, microbial recovery and limits of detection should be reported, discussed and justified.

Microbiological stress testing should be conducted throughout the in-use shelf-life.

The following should be considered:

(a) Microbiological stress testing of each element of the container’s design and functions, for example the microbial barrier functions, venting function.

(b) Microbiological stress testing to demonstrate the antimicrobial efficacy of container components with an antimicrobial substance design feature.

(c) Microbiological stress testing of the whole product to show that the container:

• prevents microbial contamination of the contents
• minimises microbial growth on the internal and external wet surfaces of the dropper nozzle.

(d) Following microbiological stress testing, the internal and external wet surfaces of the dropper nozzle should be examined for biofilm formation.

For container components necessary for each design feature and function:

(a)The name, description (including part number if necessary) and composition should be provided.

The combination of individual components to form a part-assembly should be stated, where applicable.

(b)The critical quality attributes of each component and part-assembly should be identified and specifications provided and justified.

1.5.1. To minimise the risk of microbial contamination and growth, the in-use shelf-life should be in accordance with product posology, acute or chronic use and pack size. The in-use shelf life should not exceed 28 days, unless otherwise justified and authorised.

1.5.2. The product literature (SmPC and PL) should refer to patient training, if required for the safe and appropriate use of the product.

1.5.3. It is recommended that eye infections are monitored in the PSUR.  Misuse, medication error and device failure arising from product quality issues might also be monitored in the PSUR if the potential for these safety concerns is sufficiently substantiated for specific products.

Although some parameters should always be tested on receipt by the finished product manufacturer e.g. diethylene glycol in glycerol, what is actually tested on receipt is fully covered under good manufacturing practice and should be justified based upon risk assessments, based on historical data backed by supplier audit. Consequently, the relevant registered specifications in the marketing-authorisation application should not include any reference at all to reduced testing on receipt by the finished product manufacturer.

Commission Regulation (EU) 2022/63 of 14 January 2022 amending Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council as regards the food additive titanium dioxide (the Regulation) entered into force following its publication in the Official Journal of the European Union on 18 January 2022.

On 6 May 2021, EFSA published a scientific opinion on the safety assessment of titanium dioxide (TiO₂) as a food additive, which concluded that based on all evidence available, a concern for genotoxicity could not be ruled out.  

The Regulation foresees that TiO₂ remains for the time being on the list of authorised additives to allow its use in medicinal products as a colourant. One of the reasons for that decision is to avoid shortages of medicinal products containing TiO₂ as this could impact public health and animal health and welfare. The replacement of TiO₂ requires investigation and testing of suitable alternatives to ensure that quality, safety and efficacy of medicines are not negatively affected.

The function of TiO₂  is typically described as a ‘colourant’ although TiO₂ exhibits multiple functionalities from a pharmaceutics perspective (e.g. opacity, enhancing contrast, inertness, protection from UV light and the finish/smoothness of the resulting product) .

The Regulation is applicable to all medicinal products containing TiO₂ independent of its pharmaceutical form.

The Regulation also foresees a review clause after three years, meaning that the Commission will re-evaluate the situation within 3 years of the date of entering into force of the Regulation, on the basis of an updated assessment by the EMA which is to be provided by April 2024. It further calls on the pharmaceutical industry to make all possible efforts to accelerate the research and development of alternatives and to replace TiO₂ in both new and already authorised products.

In case an applicant has applied for a marketing authorisation or an application is close to submission and development work has already started, for the time being the proposed composition can include TiO2. Nevertheless, applicants are reminded to make all possible efforts to accelerate the research and development of alternatives and to replace TiO2. However, if applicants decide to replace or remove TiO2, this should either be done prior to applying for marketing authorisation or via a variation procedure (i.e. after marketing authorisation is granted), but not during an on-going marketing authorisation procedure.

Changes in the composition of medicines to replace/remove TiO₂ will require new formulations to be developed. The data requirements when replacing an excipient are elaborated in the Note for Guidance on development pharmaceutics (CPMP/QWP/155/96) and in the Note for Guidance on Development pharmaceutics for veterinary medicinal products (EMEA/CVMP/315/98). These guidelines state that the choice and characteristics of an excipient should be justified with respect to its purpose in the medicine and that the quality of the excipient should be guided by its role in the formulation and the proposed manufacturing process. In cases where a novel excipient is used (i.e. an excipient used for the first time in a finished product, or via a new route of administration in the EU), full details of the manufacture, characterisation and relevant safety data should be provided¹.

¹ Section 4.6. of the guideline on excipients in the dossier for application for marketing authorisation of a medicinal product, EMEA/CHMP/QWP/396951/2006. Commission Delegated Regulation (EU) 2021/805 amending Annex II to Regulation (EU) 2019/6 EUR-Lex - 32021R0805 - EN - EUR-Lex (europa.eu)

MAHs are reminded to make all possible efforts to accelerate the research and development of alternatives and to replace TiO₂ in their authorised products.

In this respect, it is essential that manufacturers collaborate with each other regarding research and development of alternatives for replacement, especially when it comes to replacing TiO₂ for similar products.

Regarding the scientific data required to support the change once an alternative has been found, see response on Question 4.

The development aspects outlined under Question 2 should be considered.

The removal or replacement of TiO₂ may go beyond a simple change and constitute a product/process re-development to a greater or lesser extent. 

It is also important to note that these product development steps are product specific.

As mentioned in Question 2, in cases where a novel excipient is used (i.e. an excipient used for the first time in a finished product, or via a new route of administration in the EU), full details of the manufacture, characterisation and relevant safety data should be provided.

Scientific data requirements to support a change in excipient(s) to remove or replace TiO₂ vary between products and depend on the function of TiO₂ in the individual medicine. Each medicinal product will need an individual review and assessment, which will require investigation of alternatives, reformulation, generation of new quality data (e.g. related to manufacture, dissolution, stability etc.) and potentially new clinical data (e.g. generation of bioequivalence studies).

In cases where TiO₂ is incorporated only to improve overall appearance of the medicinal product, the omission of TiO₂ with minor adjustment of the quantitative composition of the finished product where relevant, may be an acceptable option. The relevant supporting data in this case are:

• Amendment of the relevant section(s) of the dossier and revised product information as appropriate.
• Comparative dissolution profile data of at least two pilot scale batches of the finished product in the new and old composition where relevant.
• Stability studies under ICH/VICH conditions and relevant stability parameters in accordance with the relevant variation category data requirements.

In other cases, the MAH/applicant may need to find alternative excipient(s) to replace TiO₂ in the product composition, and in addition to the requirements detailed above, the inclusion of excipient(s) should be supported by the relevant data as detailed below:

• Appropriate pharmaceutical development. A suitable alternative would have to:
  • Be compatible with the other components of the pharmaceutical product.
  • Have an acceptable safety profile.
• Studies to demonstrate the compatibility of the new excipient with the active substance(s) and any other excipients in the formulation.
• In the case of colourants, confirmation of compliance of the new excipient(s) with Regulation (EC) No 1333/2008 and Commission Regulation (EU) No 231/2012 for colours for use in foodstuffs.
• For veterinary medicinal products authorised for use in food producing species, confirmation –where appropriate- of compliance of the new excipient(s) with Regulation (EC) No 470/2009 on the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin.
• An evaluation of whether the change(s) in composition has/have any impact on the finished product quality and manufacturability. Manufacturing process re-evaluation vis-à-vis the introduced formulation changes and the necessary technology transfer and relevant supporting data, including process validation.
• Where bioavailability may be affected, a bioequivalence study comparing the old and the new formulation.
• Data to demonstrate that the new excipient does not interfere with the finished product specification test methods. If necessary, amended or new analytical methods and (re)validation data demonstrating their suitability for use with the new product composition.
• Where the medicinal product is sensitive to light and TiO₂ protects the photosensitive active substance(s) from degradation due to exposure to UV/visible light, the container-closure system may need to be replaced to guarantee sufficient protection against UV/light. Additional restrictions in storage conditions or even shortening of the approved shelf-life period may be needed. For photo-sensitive products not packed in light impermeable containers additional photo-stability testing may need to be performed to demonstrate that current measures are already sufficient to guarantee good quality and sufficient stability of the product. If a change in container closure system is applied, it should be demonstrated that the packaging materials chosen provide better light protective properties compared to the approved materials.
• Where applicable, demonstration that the change in medicinal product composition does not affect the differentiation between strengths and does not have a negative impact on taste acceptability for paediatric and relevant veterinary formulations.

For human medicinal products

From the regulatory point of view, the EC variation classification guideline includes a classification for such a change (B.II.a.3)¹. The conditions and documentation to be supplied differ depending on the type of change, type of product, and the potential impact of the proposed change to the quality/safety/efficacy of the product.

In addition to the main variation change required, i.e. B.II.a.3. change in the composition (excipients) of the finished product, for coated tablets and capsules, it is likely that variation B.II.a.4 “Change in coating weight of oral dosage forms or change in weight of capsule shells” may also be required. This change may be a type IA, IB or II, depending on the type of product and fulfilment of the guideline conditions.

Furthermore, it can also be envisaged that other variations may be warranted for individual products as a direct consequence of implementing the excipient change. For example:

• changes in the shape or dimensions of the pharmaceutical form (B.II.a.2)
• changes in analytical methods for the finished product (B.II.d.2)
• changes in the finished product specification (B.II.d.1)
• changes to processes (B.II.b.3) and in-process controls (B.II.b.5)
• changes in the packaging of the finished product (B.II.e.1)
• changes in product shelf life and storage conditions (B.II.f.1).

It is recommended that all variations that are a consequence of the deletion or replacement of TiO₂ are submitted together as a grouped variations.

Work-sharing and collaboration among marketing authorisation holders and national competent authorities should be explored.

For veterinary medicinal products

Removal or replacement of TiO₂ from an already authorised veterinary medicinal product should be carried out in accordance with Regulation (EU) 2019/6 for veterinary medicinal products.

In the simplest cases, removal of TiO₂ could be achieved via a variation not requiring assessment² (“VNRA”) category B.3.i – deletion of a component or components of the flavouring or colouring system.

In most cases, the main variation category would be ‘Change(s) in the composition (excipients) of the finished product’ which depending on the pharmaceutical form would be a VNRA (category B.18 c)) for non-sterile dosage forms or a VRA (category F.II.a.3) for sterile dosage forms or non‑sterile dosage forms that do not fulfil the conditions of VNRA B.18 c). Within category F.II.a.3 the sub-category applicable to the specific change should be selected including, if appropriate, the ‘z’ sub-category.

It can also be envisaged that other VRAs/VNRAs may be warranted for individual products as a direct consequence of implementing the excipient change. For example:

• change in the shape or dimensions of the pharmaceutical form (B.17 – VNRA; F.II.a.2 - VRA)
• change in test procedure for the finished product (B.3.e – VNRA; F.II.d.2 - VRA)
• change in the finished product specification (B.3.n/B.30.c – VNRA; F.II.d.1 - VRA)
• change in the manufacturing process of the finished product (F.II.b.3 - VRA)
• change to in-process controls (B.3.k/B.27.b – VNRA; F.II.b.5 - VRA),
• changes in the packaging of the finished product (B.34/B.35 – VNRA; F.II.e.1 - VRA)
• changes in product shelf life and storage conditions (F.II.f.1 - VRA)

The specific type of variations, the conditions to be fulfilled and documentation to be supplied differ depending on the type of product, the type of change and the potential impact of the proposed change on the quality/safety/efficacy of the product.

It is recommended that all VRAs that are a consequence of the deletion or replacement of TiO₂ are submitted together as a grouped VRA. MAHs are reminded that VNRAs cannot be included in grouped VRA submissions and where the replacement of TiO₂ requires a mix of VRAs and VNRAs, it is advisable that the recording of VNRA (s) in the Union Product Database is coordinated with the submission of the VRA(s).

In accordance with Article 65 of Regulation EU 2019/6 "Work-sharing procedure" where one or more VRA identically apply to one or several marketing authorisations which are held by the same marketing authorisation holder and which have been granted by different competent authorities or by the Commission, an identical application shall be submitted to the competent authorities in all relevant Member States and, where a variation to a centrally authorised veterinary medicinal product is included, to the Agency.

¹ B.II.a.3. Change in the composition (excipients) of the finished product of the Guideline on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures .

² See Commission Implementing Regulation (EU) 2021/17 establishing a list of variations not requiring assessment; EMA Guidance on variations not requiring assessment (veterinary medicines); and CMDv Best Practice Guide for variations not requiring assessment BPG VNRA

Individual impurities:

• the limits for individual impurities can be set by applying the VICH GL11 identification/qualification threshold of 1.0% (for impurities for which there are no specific safety concerns) irrespective of batch data results. Lower limits for individual impurities (e.g., 0.4%) are however also acceptable if proposed by the applicant and supported by batch data. It should be noted however, that individual impurities observed at levels greater than 0.3% should be reported, in accordance with VICH GL11.

Total impurities:

• the limits for total impurities should be based on batch results, nevertheless where limits of 1.0% have been accepted for individual impurities, a limit for total impurities of less than 1.0% should not be requested by competent authorities, irrespective of the batch data results.

Dropping of the device should be investigated as part of the robustness study defined in the guideline on the pharmaceutical quality of inhalation and nasal products (section 4.2.18).

The product performance should be investigated under conditions to simulate use by patients.

The delivery device should be carried between use and actuated at the frequency indicated in the instructions for use. Simulation of dropping the delivery device and the robustness of any lockout mechanism should be investigated. The dropping simulation should be performed towards the end of the life of the product (e.g. at dose 180 for a 200-dose product) in order to assess the effect of drug accumulated on the mouthpiece, or any other part of the device, during the lifetime of the device being dislodged. If the device is designed to have the mouthpiece removed for periodical cleaning, testing should be performed both with the mouthpiece removed and cleaned in accordance with instructions for use during the test, and, as a worst case, without removal and cleaning. Significant variations in the delivered dose and/or fine particle mass should be fully discussed in terms of the safety and efficacy of the product. Appropriate handling instructions to the patients should be established, based on the results obtained.

For inhalation powders in hard capsules the capsule shell is considered as an excipient and the components should be stated in section 6.1. of the SmPC under a separate subheading “Capsule shell”.

What are the requirements for the graduation of measuring devices for medicinal products for human use that are administered to patients as liquid preparations, in particular in relation to the suitability of the graduation of the measuring device regarding dosing accuracy and precision, and the suitability of the measuring device for its intended use? H

November 2018 question reworded and response supplemented with guidance on the measurement of small volumes

The points discussed below are applicable to new Marketing Authorisation (MA-)applications or fully reformulated existing medicinal products. These points should be considered when referring to the graduation of a measuring device for a liquid preparation for human use in the Common Technical Document section 3.2.P.2: pharmaceutical development. They should form part of the justification of the suitability of the graduation of the measuring device for dosing the preparation under application. The measuring device shall comply as well with the relevant parts of the Essential Requirements given in Annex I of the Medical Device Directive 93/42/EEC,  or with the General Safety and Performance Requirements given in Annex I of the Medical Device Regulation (EU) 2017/745, as and when applicable, and with International Organization for Standardization (ISO) standards.

Measuring devices may be required to deliver a variety of liquid preparations to patients through different routes of administration, e.g. oral, parenteral, nasal, vaginal and rectal. The related medicinal products may already be a liquid upon marketing (e.g. ready to use solutions, suspensions, emulsions) or the products may be marketed as a solid or a concentrate where the liquid preparation needs to be prepared prior to use. The measuring device can be marketed together with the medicinal product (e.g. syringes without needles to administer oral liquid preparations, measuring cups, spoons or beakers, pipette applicators) or can be incorporated as integral part of the medicinal product (e.g. prefilled syringes).

In general, the minimum volume of a liquid measured with any measuring device should not be lower than 10% of the maximum capacity (e.g. 0.10 ml for a 1 ml syringe). However, this percentage may not be acceptable in situations where dosing accuracy and precision are considered to be critical, e.g. for active substances with a small therapeutic range. When the minimum volume that is measured increases up to 25% of the maximum capacity (e.g. 0.25 ml for a 1 ml syringe), usually no issues with regards to accuracy and precision are expected. This should be confirmed during pharmaceutical development.

The recommendation of the minimum volume of a liquid to be measured (in milliliters) is not applicable to devices that measure insulin as they are graduated in insulin units.

Manner of graduation
The graduation should be applied to the measuring device in such a manner that accurate and precise dosing is guaranteed. The graduation can be embossed or debossed on the measuring device, or printed on it.

This precision and accuracy of dosing should be guaranteed from release throughout storage until the end of shelf life, and also during the use of the particular measuring device under the conditions recommended in the Summary of Product Characteristics and Package Leaflet (SmPC/PL). Attention should be paid to the possibility of the printing ink fading. Gluing of a label with a printed graduation to the measuring device is not generally favoured, because of the potential for dislocation of the glued label during storage and use. If a glued label is used, the effectiveness of the adhesive / label system under normal conditions of storage and use should be demonstrated.

Graduated scale
The graduated scale should correspond with the way the dose or product strength is declared in the SmPC/PL. Generally, graduation in ‘ml’ is preferred as commonly available measuring devices are most often graduated in units of volume and as in many regions, health care professionals are more familiar with this type of graduation. This applies in principle to all measuring devices. For example, attention should be paid to the following:

• The possibility of the measuring device to deliver the minimum and maximum dose per single administration (nominal capacity);
• The suitability of the scale intervals of the measuring device in relation to the posology of the medicinal product or to the dose range when the posology is stated per kilogram bodyweight or square meter body surface;
• The ease of interpretation of the graduated scale: readability of the graduation numbers and the graduation lines, and distinction between the intervals of the scale.

European or international standards (European Committee for Standardization or ISO) may be available, e.g. for syringes recommendations are given on tolerances, graduated capacity, and graduated scale in ISO standards. These recommendations can be applied without further justification.

Suitability of a measuring device for a liquid preparation derived from/of a medicinal product: The suitability of the measuring device should be addressed. Attention should be paid to the following:

• The dosing accuracy and precision in relation to the therapeutic window of the active substance;
• The risk of overdosing in relation to the measuring device. If possible, overdosing should be prevented. If the risk of overdosing cannot be avoided, appropriate measures should be taken to prevent overdosing, e.g. the use of a device with a different scale interval;
• The physical characteristics of the liquid preparation in relation to the measuring device, such that accurate and precise dosing is assured. For example, considerations should be given to the needle diameter and the particle size of suspensions in injectables, the homogeneity (re-suspendability) of suspensions and emulsions prior to use and during the application of the measuring device, or residual amounts of liquid preparation in the measuring device after administration of the dose to the patient.

Furthermore, the suitability of the measuring device and its graduation for the intended patient population should also be taken into account.

Acceptance criteria
The graduation of the measuring device should be suitable to meet the acceptance criteria of the dose of the liquid preparation derived from/of the medicinal product under application, as measured with the measuring device under application. These acceptance criteria should be in line with European Pharmacopoeia (Ph. Eur.) requirements, if applicable (for example Ph. Eur. 2.9.27: uniformity of mass of delivered doses from multi-dose containers), or other accepted pharmacopoeias. For single-dose containers where only a portion of the content needs to be administered to the patient, the same requirements can be applied as for multi-dose containers.

Measuring small volumes
Liquid preparations are intended to be administered with a measuring device that is commonly available in the European Union. If this is not the case, a measuring device should be supplied with the product by the MA-holder.

In order to ensure accurate dosing, the maximum capacity (size) of a measuring device should be appropriate for the volume to be dosed. For example, the smallest size of syringes that are graduated in ml and that are commonly available in hospitals and pharmacies throughout the European Union are 1 ml syringes with 0.01 ml dosing increments. Where commonly available 1 ml syringes are not considered suitable for dosing a liquid preparation with sufficient accuracy and precision, the company should develop an alternative administration strategy that would enable the use of a 1 ml syringe, e.g. a lower strength product. Where this approach is not an option, it is expected that (a) suitable dedicated measuring device(s) will be co-packed with the product and that the company will demonstrate acceptable accuracy and precision with such (a) device(s).

If the volume is too small to be measured accurately, (serial) dilution may be considered. However, this practice is prone to error. If dilution is considered necessary, this must be justified in the development pharmaceutics. In addition, and to avoid error, the dilution steps should be described in the SmPC/PL.

In the absence of clinical data, the results of in vitro observations with alcohol (ethanol) may be considered, as a minimum, evidence of a possible physicochemical incompatibility with alcoholic drinks. The possibility of such an incompatibility with alcoholic drinks should be considered for all modified release products.

The general methods of in vitro release testing are considered capable of providing sufficient evidence of alcohol incompatibility. In the case where in vitro alcohol incompatibility of the drug product is demonstrated, then appropriate warnings should be included in the summary of product characteristics, in line with current guidelines.

The interaction with alcohol observed in vitro should be considered as a physicochemical incompatibility of the drug product. In line with current regulatory practice, reference to this incompatibility, albeit dietary rather than medicinal, has been included in the product literature to supplement the current pharmacological warning to avoid alcohol.

In vitro studies investigating the effect of alcohol / ethanol on dissolution / release are recommended for all opioid modified-release products where applicants consider the potential for incompatibility with alcohol exists.

To minimise the risk, it is recommended that the product design, if possible and practical, should be such that a physicochemical incompatibility with alcohol is avoided. This advice is especially important for drug substances with a narrow therapeutic index.

Where there are scientific grounds that the defined-release characteristics of the oral drug may be adversely affected by the presence of alcohol, then alcohol physicochemical incompatibility should be considered by the applicant. This would apply to all oral prolonged- (and delayed- and modified-) release products.

At this point in time, it is not possible to provide authoritative methodological requirements.

In vitro studies are considered sufficient to show evidence of alcohol incompatibility, with a consequential effect on the quality of the drug product, with respect to release performance.

It is noted that in vitro release testing primarily relates to the quality control of drug products, with limits set to be in line with those batches used for clinical studies for which satisfactory safety and efficacy has been established.

Taking this into account, if the presence of alcohol in the dissolution medium of the in vitro release test produces out of specification results, then this may be considered sufficient evidence of an incompatibility with alcohol, i.e. that alcohol adversely affects the quality of the drug product.

In the first instance, the applicant should consider the possibility of physicochemical incompatibility with alcohol. This should include a discussion of the solubility of the release controlling excipients in alcohol and the impact this may have on the in vitro release performance of the drug product. Where solubility or other information cannot exclude the possibility of physicochemical incompatibility with alcohol, then in vitro release data should also be provided to assess the extent of interaction.

The dissolution medium should be the same as that proposed for routine testing, but with a justified range of alcohol added. The range of alcohol in the medium should mimic levels that are likely to be reached in the fluid of the stomach and proximal gastrointestinal tract following alcohol consumption e.g. 5%, 10% and 20%.

The applicant should discuss the significance of any out of specification results, particularly at the early time points, together with consideration of the risks of dose dumping and accelerated release. Appropriate warnings in the summary of product characteristics should be proposed and justified.

It should be acknowledged that the clinical relevance of physicochemical incompatibility with co-administered alcohol is debatable, at the present time. The published literature is limited.

Where incompatibility with alcohol is evident, it is currently sufficient to address safety or other concerns by the inclusion of appropriate warnings in the product literature unless serious concerns are raised with respect to efficacy and safety.

Needle stick injuries commonly occur in the following cases: (1) before administration, when the cap is vigorously removed using two hands (holding the syringe/pen injector with one hand and removing the cap with the other); (2) during or after administration, when the patient or healthcare professional are distressed; (3) when an attempt is made to recap the needle after administration; (4) when sharps containers are overfilled and not disposed of in time.

The potential consequences of needle stick injury vary greatly from minor (e.g. pain or swelling around the stick site) to very serious (e.g. transmission of infectious disease such as HIV). The risks ensuing from needle stick injury are dependent upon a large number of factors such as: the nature of the active ingredient and excipients (e.g. cytotoxic substances), the indication (e.g. anti-retroviral medicines), the method of administration (self-administration by the patient vs. administration by a caregiver vs. administration by a healthcare professional), the target patient group (e.g. high-risk patient groups such as patients with infectious disease), and the setting where the medicine is administered (e.g. administration in emergencies).

No. Directive 2010/32/EU implements a framework agreement on the prevention from sharps injuries in the hospital and healthcare sectors signed by the European Hospital and Healthcare Employers’ Association (HOSPEEM) and the European Public Services Union (EPSU). It applies to employers whose primary activity is to organise, manage and provide healthcare, including where care is provided in the patients’ own homes.

Yes. The overall benefit-to-risk evaluation of a medicinal product includes assessment of the suitability of its medical device component(s).

Device components incorporating a needle are expected to comply with the requirements of Annex I (known as “The Essential Requirements”) to Directive 93/42/EEC (the Medical Devices Directive). Sections 1, 2, 8.1 and 13 thereof state that: (1) the design of the device should not compromise the safety of the patient, user (patient, caregiver, healthcare professional) and other persons; (2) risks (including the risk of infection) should be eliminated as far as possible and (3) state-of-the-art technology should be considered. Therefore, the decision on the suitability of the device component will be product-specific and risk-based, and will reflect current state-of-the-art technologies.

No. Regulatory authorities may grant a marketing authorisation for a medicinal product that does not contain a needle safety system. However, the development and use of needle safety systems is encouraged and highly recommended.

Needle safety information is expected in case of new marketing authorisation applications, and where appropriate relevant variation applications, concerning medicinal products incorporating a safety feature. The development of the needle safety system and any risk assessments performed should be included in Module 3.2.P.2 Pharmaceutical Development. The technical details should be submitted in Module 3.2.P.7 Container Closure System. Information regarding the needle safety of the product should be communicated to users in the Summary of Product Characteristics (SmPC) and Packaging Leaflet (PL).

In cases where the medicinal product incorporates a needle without a safety feature, the company would be expected to justify why this approach is acceptable for the intended use of the medicinal product in the intended setting and patient group. The justification, along with the company’s product-specific risk assessment should be submitted in Module 3.2.P.2 Pharmaceutical Development. Overall, the same principles are applied to the assessment of needle safety systems (or their absence) as to the assessment of other device components in medicinal products.

For already approved medicinal products with a needle safety system, the information on the needle safety feature may not yet be included in the SmPC/PL. It is recommended that the missing reference is added with the next variation affecting the SmPC/PL to align the dossier with the current regulatory standards.

In line with the current regulatory standards, separate EU numbers will be required where the product is provided with and without a needle safety system.

The needle safety system should be listed in:

• Section 6.5 “Nature and contents of the container” of the SmPC
• Section 4 “Pharmaceutical form and contents” of the labelling (on the outer packaging, and if applicable, on the immediate packaging)
• Section 6 “Contents of the pack and other information” of the package leaflet.

Furthermore, handling instructions related to the needle safety system should be described in:

• Section 6.6 “Special precautions for disposal and other handling” of the SmPC
• Section 3 “How to X” of the package leaflet, or at the end of the package leaflet as part of the information intended for healthcare professionals.

The FPD and other relevant aerodynamic particle size distribution (APSD) ranges are critical quality parameters as they represent the fraction(s) of the dose with a larger probability to reach the lungs (unless partially eliminated by mucocilliary clearance), absorbed systematically from the lungs and exert a local effect. According to the guideline on the pharmaceutical quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005 Corr), the specification limit of FPD should be based on the batches used in clinical studies (pivotal clinical and/or comparative studies). The proposed specification range(s) should always be discussed and justified in the dossier. Normally, it is considered that a specification range of up to ±25% is adequate for quality control of most inhalation products, based on the manufacturing process and the variability of the analytic methods. Ranges wider than ±25% should be sufficiently justified by in vitro or in vivo data. The proposed specification limits should take into account the shelf-life performance of the FPD/APSD of the product. If the application is covering several strengths, the specification range(s) for each of the strengths should normally not be overlapping.

The batch(es) of the comparator used in clinical studies should be representative of the commercial batches available on the market, including consideration for different ages or shelf-life of the product. The test product has to be representative of future batches and therefore the specification limits are critical to ensure similar characteristics even at the end of the shelf-life.

How the representative batch(es) is chosen should be fully discussed and justified in the dossier, preferably in Module 3. For some inhalers the FPD/APSD may decrease over time and in these cases ageing of the product should be considered. Characterisation of several batches of the comparator from different markets should be performed. A minimum of 5 to 6 batches may be sufficient if suitably justified. However, if the comparator shows great variability and/or degradation, a larger number of batches are needed. The FPD/APSD of the reference batch(es) chosen for clinical studies should be as close as possible to the median of the observed values. A deviation within ±15% is reasonable.

According to the OIP guideline  CPMP/EWP/4151/00 Rev. 1 , dose proportionality should be demonstrated to establish therapeutic equivalence clinically with only one strength. In vitro proportionality should be demonstrated for the whole APSD although groups of stages could be used if a pooling strategy is justified from a clinical perspective. The different strengths should be compared with a ±15% acceptance range in each stage. If the different strengths of the test and the comparator are not shown to be proportional in vitro in the range of relevant flow-rates, in vivo equivalence should be demonstrated with a bracketing approach. Bracketing should include the strengths most similar and most different from an in vitro perspective.

Healthy adult volunteers are easier to recruit and less variable than patients. In addition, patients may be less discriminatory since lung depositions are mostly central due to bronchoconstriction. PK studies in healthy volunteers to investigate systemic exposure and lung deposition may be acceptable if the test and the comparators have shown a) no flow-rate dependency or b) similar flow-rate dependency in vitro determined through evaluation of FPD and APSD for both test and comparator. The flow-rate interval to be studied should be justified based on e.g. resistance of the device or the trigger threshold of the device and the flow-rate observed in the healthy adult volunteers and patients populations. Normally, a flow-rate interval of 30-90 L/min is acceptable.

Reference to relevant paragraphs of the guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004) is given for each question.

Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches).

Compliance with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) requirements is not required, if proper justification is provided.

Where specifications are set for potential genotoxic impurities, the guidance given in questions and answers on the guideline on limits of genotoxic impurities (EMEA/CHMP/SWP/431994/2007) should be taken into consideration (question 6: staged threshold-of-toxicological-concern approach).

Reference to relevant paragraphs of the guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004) is given for each question.

The table in the guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.

For non-substantial amendments documentation should not be proactively submitted, but the relevant internal and study documentation supporting the change should be recorded within the company and if appropriate, at the investigator site.  At the time of an overall investigational medicinal product dossier update or submission of a substantial amendment the non-substantial changes can be incorporated into the updated documentation. There is no need to use the notification of amendment form for these changes.

Reference to relevant paragraphs of the guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004) is given for each question.

The criteria based on which it is intended to extend shelf life during an ongoing study should be given. The information should include extension protocol limiting the maximum time period for extrapolation. In the case of any significant negative trend for stability data observed during long-term and accelerated testing, the sponsor should commit to notify any shelf-life extension as a substantial amendment.

Reference to relevant paragraphs of the guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004) is given for each question.

No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the investigational medicinal product dossier. Results for batches controlled according to previous, wider specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.

Reference to relevant paragraphs of the guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004) is given for each question.

Data from representative batches should be provided. This implies that data should be provided for each proposed site. However, where one legal entity has multiple sites (in the same country), then batch data from one site only would be sufficient.

For non-substantial amendments documentation should not be proactively submitted, but the relevant internal and study documentation supporting the change should be recorded within the company and if appropriate, at the investigator site. At the time of an overall investigational medicinal product dossier update or submission of a substantial amendment the non-substantial changes can be incorporated into the updated documentation.  There is no need to use the notification of amendment form for these changes.

The functional aspects of plastic containers for eye drops products should be qualified as part of development pharmaceutics, incorporating the usability engineering design principles (Annex I Medical Devices Directive 2007/47/EC; BS EN 62366: 2008 Medical Devices – Application of usability engineering to medical devices).

These functional aspects should include usability, dose delivery performance, the controls for quality of the container and rationale for choice and optimisation of the design, including size and shape of the container closure system. It is known that the size and shape of the container can affect ease of handling and dispensing of drops by patients, especially those with impaired dexterity such as the elderly.

Usability, i.e. that the container can be used safely to deliver the required dose by the target patient population or representative subject group, should be discussed for all eye drop medicinal products.

It is recommended that a formal usability study is undertaken, in accordance with a valid protocol to systematically observe and evaluate the usability of the eye drop medicinal product, particularly for novel containers and containers that are required to be used in a specific (non-intuitive) way. The usability study may be integrated into clinical or therapeutic equivalence studies. In the absence of such study data, evidence of usability should be supported by published or other data, if available, and risk assessment.

Dose delivery performance should be qualified by evaluation of accuracy and reproducibility of dose delivery from the dropper in various orientations such as inverted or inclined. The force required to dispense a drop should be correlated with physical capabilities of the target patient population. Evaluation of dose delivery performance should be performed with containers manufactured by the same process and stored in same condition as proposed in the marketing authorisation; for example stored at 2-8 ˚C, if a cold storage product.

In addition to the general information to be provided on quality of containers (Ph Eur monograph 3.2.2 Plastic containers and closures for pharmaceutical use; ICH M4Q(R1): Quality; CHMP/CVMP guideline on plastic immediate packaging materials (CPMP/QWP/4359/03, EMEA/CVMP/205/04)), the specification of plastic containers for eye drops for human or for veterinary use should also include a qualitative test for surface defects such as excessive burrs and sharp edges around the dropper tips.

Plastic containers manufactured by blow-fill-seal process are particularly prone to surface defects and the specification should include tests for:

• Appearance;
• Wall thickness;
• Container opening characteristics including check for burrs and sharp edges after the container is opened; and
• Leak testing.

These tests should form part of in-process control checks of the blow-fill-seal process.

Appropriate acceptance criteria and standards for control of excessive burrs, sharp edges container opening characteristics should be established and outlined in the dossier, including photographs as necessary. The sample size should be adequate and justified.

Close-up photographs of intact and opened containers should be included in the dossier.

The product information texts (SmPC, Patient Information Leaflet, Labels) should include appropriate instructions based on the development data and studies undertaken.

Samples of the drug product should be provided to the Competent Authorities, on request, to enable independent assessment and reporting on the quality of the container.

The European Pharmacopeia (Ph. Eur.) general monograph “Substances for pharmaceutical use” and VICH guideline GL10 (impurities in new veterinary drug substances) both define the following thresholds for reporting, identification and qualification of impurities in substances used for veterinary medicinal products as follows:

• Substances for both human and veterinary use: the guideline refers to the ICH thresholds; and
• Substances for veterinary use only: the thresholds are Reporting 0.10 %, Identification 0.20 % and Qualification 0.50 %.

Active substances for pharmaceutical use have to comply with the Ph. Eur. general monograph “Substances for pharmaceutical use”. Pharmacopoeial active substances should also comply with their specific monograph.

The active substance can only be considered as “Veterinary use only” in the following cases:

• The active substance is described in a Ph. Eur. monograph, or the monograph of a pharmacopoeia of an EU member state, which explicitly states in its heading that the substance is for veterinary use (e.g. ‘Enrofloxacin for veterinary use’, ‘Xylazine Hydrochloride for veterinary use’); and
• The active substance is not described in any Ph. Eur. monograph, or the monograph of a pharmacopoeia of an EU member state, and the applicant can provide proof that the substance is not used in any human medicine authorised within the EU.

It is not considered acceptable to declare the active substance as “Veterinary use only” for example, purely on the basis of an active substance manufacturer declaration that they produce that substance only for veterinary use, or it is declared by the applicant that the active substance is used in a veterinary only dosage form.

Ideally, compendial grade excipients should be used in new veterinary medicinal products.

Premixes for medicated feeding stuffs should comply with the requirements of the European Pharmacopeia (Ph. Eur.) general chapter 5.1.4: microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use. It is expected that these products comply with the requirements for non-aqueous preparations for oral use.

If it is not possible to comply with these limits, premixes containing excipients of natural (animal, vegetal or mineral) origin should comply with the requirements of “Special Ph. Eur. provision for oral dosage forms containing raw materials of natural (animal, vegetal or mineral) origin for which antimicrobial pretreatment is not feasible and for which the competent authority accepts…….”.

However, if justification is provided that these limits cannot be met, then the requirements of the “Special Ph. Eur. provision for premixes for medicated feeding stuffs for veterinary use using excipients of plant origin for which antimicrobial treatment is not feasible.” are applicable.

In cases where an oral powder and a premix for medicated feedingstuffs have the identical composition, it would be expected that the same microbiological limits would be applied to both pharmaceutical forms. In this case the stricter limits are applicable (normally those for oral powders requested in chapter 5.1.4: non-aqueous preparations for oral use).

The guideline on quality aspects of pharmaceutical veterinary medicines for administration via drinking water (EMEA/CVMP/540/03-Rev.1) sets out how the solubility of a product in drinking water should be tested (soft water / low pH with a pH range from 5.0 to 7.0 and hard water / high pH with a pH range from 8.0 to 9.0).

In principle, a veterinary medicinal product can only be authorised if it fully dissolves (and remains in solution) without further aid in drinking water of the usual pH range (which is usually a pH range between 5.0 and 9.0). If a pH adjustment of the drinking water is necessary this should be done with excipients (acid, base or buffer) included as part of the authorised veterinary medicinal product. Exclusions are only acceptable if justified (e.g. it has been shown that other formulation principles have been excluded).

The use of unlicensed acids or alkalis for the pH adjustment of the drinking water before (or after) adding the veterinary medicinal product in order to achieve the necessary solubility is not acceptable unless justified.

Such an example would be considered to be two different pharmaceutical forms (and also in this specific problem case, routes of administration) and therefore to need two different marketing authorisation (sub)numbers, as well as two different summaries of product characteristics.

In the European Union, different marketing authorisations (sub)numbers are necessary for different pharmaceutical forms. See the guideline on the categorisation of new applications versus variation applications.

Another reason is that using multidose containers for both intramammary and parenteral use may result in an increased risk of microbial contamination of the product in its multidose container.

Rubber stoppers (bungs) used for vial closures for multidose veterinary injectables are often punctured many times during use. Therefore suitable criteria regarding fragmentation (and self-sealing) are required. Problems can mainly arise in large multidose injectables, which can be used for different target species and / or ages of animals, but particularly for smaller animals where dose volumes are small, and so the pack could be punctured many times (e.g. in extreme cases in excess of 100 punctures). Should the general chapter on rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders (3.2.9) be applied in these cases? Which criteria for the maximum number of rubber fragments are deemed acceptable for a test design which is a multiple of the number of punctures described by Ph. Eur. 3.2.9? Should a worst-case scenario be used? V

The general chapter on rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders (3.2.9) is not mandatory on its own. If suitable justification is provided, the requirement (maximum of five fragments) contained in this chapter does not necessarily need to be applied. It is noteworthy that the European Pharmacopoeia (Ph. Eur.) test is designed to demonstrate that a stopper fulfills the general minimum requirements that are expected for rubber stoppers for medicinal products, but this can of course not cover all their potential uses.

The pack concerned should be proven to meet the requirements of the Ph. Eur. test modified to use the maximum number of punctures expected in relation to the target species, dose and route of administration (using the appropriate needle size for that scenario). Note that the maximum number of fragments expected remains exactly as in the Ph. Eur. test.

The summary of product characteristics (SmPC) and other product information should then reflect the number of punctures for which the closure has been demonstrated to meet the requirements of the Ph. Eur. test. For example, if the closure has been shown capable of withstanding X punctures with fragmentation and self-sealing characteristics which meet the relevant Ph. Eur. requirements. That is, with no additional increase in fragments for the increased number of punctures.

Risk-management tools

Some examples of advice (if necessary in combination) which could be included in the SmPC (section 4.9) and other product literature to reduce potential damage to the stopper from excessive numbers of punctures:

• “The cap may be safely punctured up to X times.”
• “When treating groups of animals in one run, use a draw-off needle that has been placed in the vial stopper to avoid excess broaching of the stopper. The draw-off needle should be removed after treatment.”
• “Only the xx ml vial should be used to treat small piglets.”
• “As the vial should not be broached more than X times the user should select the most appropriate vial size according to the target species to be treated.”
• “When treating large groups of animals use only an automatic dosing device (with vented draw off apparatus when using the xx ml vial).”
• “For xxx pack sizes, use only automatic syringe equipment.” (Applicable for large collapsible packs where a large number of doses may be withdrawn from the vial and concern about the stopper integrity exist.)
• “For xxx pack sizes, use of a multiple dose syringe is recommended.” (Applicable for large non-collapsible packs where a large number of doses may be withdrawn from the vial and concern about the stopper integrity exist.)

The functional aspects of plastic containers for eye drops products should be qualified as part of development pharmaceutics, incorporating the usability engineering design principles (Annex I Medical Devices Directive 2007/47/EC; BS EN 62366: 2008 Medical Devices – Application of usability engineering to medical devices).

These functional aspects should include usability, dose delivery performance, the controls for quality of the container and rationale for choice and optimisation of the design, including size and shape of the container closure system. It is known that the size and shape of the container can affect ease of handling and dispensing of drops by patients, especially those with impaired dexterity such as the elderly.

Usability, i.e. that the container can be used safely to deliver the required dose by the target patient population or representative subject group, should be discussed for all eye drop medicinal products.

It is recommended that a formal usability study is undertaken, in accordance with a valid protocol to systematically observe and evaluate the usability of the eye drop medicinal product, particularly for novel containers and containers that are required to be used in a specific (non-intuitive) way. The usability study may be integrated into clinical or therapeutic equivalence studies. In the absence of such study data, evidence of usability should be supported by published or other data, if available, and risk assessment.

Dose delivery performance should be qualified by evaluation of accuracy and reproducibility of dose delivery from the dropper in various orientations such as inverted or inclined. The force required to dispense a drop should be correlated with physical capabilities of the target patient population. Evaluation of dose delivery performance should be performed with containers manufactured by the same process and stored in same condition as proposed in the marketing authorisation; for example stored at 2-8 ˚C, if a cold storage product.

In addition to the general information to be provided on quality of containers (Ph Eur monograph 3.2.2 Plastic containers and closures for pharmaceutical use; ICH M4Q(R1): Quality; CHMP/CVMP guideline on plastic immediate packaging materials (CPMP/QWP/4359/03, EMEA/CVMP/205/04)), the specification of plastic containers for eye drops for human or for veterinary use should also include a qualitative test for surface defects such as excessive burrs and sharp edges around the dropper tips.

Plastic containers manufactured by blow-fill-seal process are particularly prone to surface defects and the specification should include tests for:

• Appearance;
• Wall thickness;
• Container opening characteristics including check for burrs and sharp edges after the container is opened; and
• Leak testing.

These tests should form part of in-process control checks of the blow-fill-seal process.

Appropriate acceptance criteria and standards for control of excessive burrs, sharp edges container opening characteristics should be established and outlined in the dossier, including photographs as necessary. The sample size should be adequate and justified.

Close-up photographs of intact and opened containers should be included in the dossier.

The product information texts (SmPC, Patient Information Leaflet, Labels) should include appropriate instructions based on the development data and studies undertaken.

Samples of the drug product should be provided to the Competent Authorities, on request, to enable independent assessment and reporting on the quality of the container.

It is not possible to have a product in both powdered and granulated forms under the same marketing authorisation. The two different pharmaceutical forms require different SPCs, labelling, etc, and have different marketing authorisation numbers.

(Note: If authorised via the centralised system the two different pharmaceutical forms would be authorised under the same marketing authorisation, but with different MA sub-numbers and different SPCs, labelling, etc.).

The reasons for this are:

• Powders and granules are two different pharmaceutical forms (see also the relevant monographs on dosage forms in the European Pharmacopoeia). A change from a powdered product to a granulated product needs an extension application, as it is a change of the pharmaceutical form (see Commission Regulation 1234/2008, Article 19 in connection with Annex I);
• For several of this type of active substances (for example, antibiotics) compaction is used to produce granules of the active substance for better handling. As compaction is a granulation step, the resultant dosage form should be described in the SPC (and other product information) as granules;
• It is not acceptable for these (100% active substance) products to be marketed under the same marketing authorisation in alternative dosage forms (different batches in powder form or in granulated form, e.g., depending on availability or commercial reasons);
• The principles described above are also applicable vice versa (if a granulated product is changed to a product in powder form);
• For such 100% active substance products, any granulation step can be regarded as active substance manufacture. A full description of the granulation process has to be provided in the marketing authorisation dossier, in part 2.C.1 (NtA format) or 3.2.S (CTD format);
• The submission of a certificate of suitability (CEP) which covers different grades of an active substance (e.g. powder and compacted product) does not exempt companies from complying with the above requirements.

Article 58 of Regulation (EC) 726/2004 widens the scope of the European Medicines Agency and the Committee for Medicinal Products for Human Use to include applications for certain medicinal products intended exclusively for markets outside the Community, e.g. for antiretroviral therapy:

“1. The Agency may give a scientific opinion, in the context of cooperation with the World Health Organization, for the evaluation of certain medicinal products for human use intended exclusively for markets outside the Community. For this purpose, an application shall be submitted to the Agency in accordance with the provisions of Article 65. The Committee for Medicinal Products for Human Use may, after consulting the World Health Organization, draw up a scientific opinion in accordance with Articles 6 to 9. The provisions of Article 10 shall not apply.”

For these applications, it is of great importance to apply standards that ensure the same adequate product quality as for products to be marketed in the European Union (EU). In this context, stability data need to be submitted by the applicant that demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries, i.e. countries in climatic zones III and IV. Merely applying the same requirements as for the use in the EU, i.e. countries in climatic zone I / II, could potentially lead to substandard products when marketed in climatic zones III and IV.

The guideline stability data package for registration in climatic zones III and IV (ICH Q1 F) was officially withdrawn by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) steering committee in June 2006 due to controversial discussions about the adequacy of storage conditions defined. The World Health Organization (WHO) expert committee on specifications for pharmaceutical preparations has decided to split climatic zone IV into zone IVa (hot and humid) with storage conditions of 30°C/65% relative humidity (RH) and zone IVb (hot and extremely humid) with storage conditions of 30°C/75% RH; the WHO stability guideline will be revised accordingly.

When evaluating applications under Article 58 of Regulation EC/726/2004, it has to be assumed that the respective medicinal product will be used in all sub-zones of climatic zones III and IV, unless otherwise confirmed by the applicant. Therefore, in order to safeguard product quality throughout its entire intended shelf-life, stability studies under the conditions defined for climatic zones IVb need to be performed, i.e. the shelf-life needs to be established based on long-term data at 30°C/75% RH, supported by SIX months of data at 40°C/75% RH. The principles of extrapolation described in the note for guidance on evaluation of stability data (CPMP/ICH/420/02) as well as reduced testing designs as described in the note for guidance on bracketing and matrixing designs for stability testing of drug substances and drug products (CPMP/ICH/4104/00) may be applied. In cases where these data demonstrate stability over the required period of time, no special storage conditions need to be labelled.

If an application under Article 58 of Regulation EC/726/2004 only contains data adequate for climatic zones I / II, the list of questions should request the respective data appropriate for climatic zones III and IV. If the data show stability problems at 30°C/75% RH with regard to humidity, the circulation and use of the product should preferably be restricted to those countries and regions that are covered by data, e.g. the product should only be used in countries within climatic zones III and IVa. As an alternative, storage conditions need to be labelled, including humidity, e.g. 'keep protected from ambient humidity' as, especially for climatic zone IVb, humidity may be the stability-limiting factor.

However, it has to be noted that due to the technical equipment and logistics available in some of the climatic zone-IV countries as well as the education and compliance of patients in the respective area, exposure of medicinal products to higher temperatures and humidity cannot be ruled out. This needs to be taken into account when defining shelf-life and storage conditions. For products to be stored at 'normal conditions', i.e. stable at 30°C, submission of accelerated data, i.e. 40°C/75% RH, can not be waived as they are needed to assess the impact of extreme temperature or humidity conditions that may occur in climatic zone IV, even though a product may not be stable for six months at these storage conditions.

Please note that for aqueous products in semipermeable containers to be marketed in climatic zone III, i.e. regions of extreme temperature, long-term testing should be performed at 30°C/35% RH. As an alternative, the calculation factors described in section 2.2.7.3 'drug products packaged in semi-permeable containers' of the note for guidance on stability testing of new drug substances and products (CPMP/ICH/2736/99) may be applied.

As foreseen by the note for guidance on declaration of storage conditions, when a product needs to be stored refrigerated, the wording 'store in a refrigerator' should be used in the labelling, and a reference to the temperature range, e.g. 2°C to 8°C, should be included in the summary of product characteristics (SmPC) and in the package leaflet.

According to the same note for guidance, when the need for refrigerated transport (cool chain), in addition to refrigerated storage, is envisaged, the following statement should be used: 'store and transport refrigerated'.

Guidance can be found in the note for guidance on the start of shelf-life of the finished product (CPMP/QWP/072/96 / EMEA/CVMP/453/01) and the Committees for Mutual Recognition and Decentralised Procedures and Quality Review of Documents product information templates. In summary, the expiry date should be calculated from the date of release or in case the period between the date of production and the date of release exceeds 30 days, from the date of production. The expiry date should be expressed as MM/YYYY. The product expires at the end of the specified month.

In the worst case, this method of calculation results in an extension of the expiry date of two months:

Table 1: Example of the calculation of the expiry date of a tablet with a shelf life of 24 months

*The bulk compressed tablets have been stored for six months. It is expected that a shelf life for the intermediate product is detailed in the dossier and stability data to support this are also presented in the dossier.

Particularly for products with a shelf-life of less than twelve months, this is not considered acceptable. The expiry date should therefore be calculated on a DD/MM/YYYY basis starting from the date of release, or if applicable from the date of production, and rounded up or down to MM/YYYY according to the following example: 14/01/2007 becomes 12/2006 and 15/01/2007 becomes 01/2007. See table 1 for recalculated expiry dates.

¹Note: This question and answer was first published in July 2008 with a mistake (the recalculated date for examples 3 and 4 were mixed-up). Later the mistake was identified by QWP and in March 2009 the present corrected version was published.

Endotoxin testing is not requested at the end of shelf life, taking into account the fact that it is not considered a stability-indicating parameter. The shelf-life specification should be completed with a footnote stating that endotoxins are not tested during stability studies.

Sterility is part of the shelf-life specification.

Sterility testing should be performed at least at the end of shelf life but it can be replaced by testing of the container closure integrity. Depending on the nature of the container, intermittent integrity testing might be envisaged, independent of whether the sterility testing is replaced or not.

In principle, each product will be assessed on its own merits and differences may exist. However, when the difference in in-use stability and/or compatibility potentially leads to detrimental medication errors in daily practice, such a difference cannot be accepted. Each difference will be assessed in relation to the products at issue and the context in which the products are used, in line with the CHMP position paper on potential medication errors in the context of benefit-risk balance and risk minimisation measures, EMA/CHMP/277591/2013. Although the CHMP position paper relates only to medicinal products for human use, the same principles can be applied if necessary to veterinary medicinal products when there is a known or demonstrated potential for medication errors.

In principle, each product will be assessed on its own merits and differences may exist. However, when the difference in storage temperature potentially leads to detrimental medication errors in daily practice, such a difference cannot be accepted. This will be assessed on a case by case basis in relation to the products at issue and the context in which the products are used, in line with the CHMP position paper on potential medication errors in the context of benefit-risk balance and risk minimisation measures, EMA/CHMP/277591/2013. Although the CHMP position paper relates only to medicinal products for human use, the same principles can be applied if necessary to veterinary medicinal products when there is a known or demonstrated potential for medication errors.

Yes, as long as the selected design is explained and justified.  The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline bracketing and matrixing designs for stability testing of drug substances and drug products (CPMP/ICH/4104/00), is applicable to new drug substances and products used in human medicine. However, veterinary companies may elect to follow this guideline. Where the guideline is followed, all aspects of the guideline should be followed.

Finished product stability guidance does not address storage of bulk product during the manufacturing process. The purpose of these questions and answers is to address the information to be provided in the marketing-authorisation dossier to support storage and / or transportation of bulk product during the manufacturing process.

Good-manufacturing-practice guidance indicates that bulk products should be stored under ‘appropriate conditions’ and therefore, the data provided in the dossier should be aimed to demonstrate the suitability of these conditions in relation to the intended storage and / or transportation arrangements of a bulk product and the effect of these on the quality of the given finished product over its declared shelf-life.

The objective is to increase the transparency of the supporting data required and not to introduce any new regulatory requirements.

The data required will depend on the type of product and the activities performed (i.e. prolonged storage or transportation) and a risk-based approach is encouraged in order to demonstrate the suitability of the data generated in each individual case.

The described framework is intended to cover all pharmaceutical bulk products. However, it is understood that the requirements for some specific types of products (e.g. biological products) may require additional data relevant to the type of product and this should be taken into consideration depending on the characteristics of that particular product.

The question most frequently arises in relation to solid oral dosage forms (particularly tablet cores before coating or packaging) but could be applicable at any stage in the manufacturing process of any pharmaceutical product where bulk is held in storage prior to further processing (e.g. bulk solution prior to filling, granulates, etc.).

In general, the level of information to be provided will be dependent on the nature of the bulk product. The qualitative and quantitative (if required) composition of the bulk container should be described in the dossier and its control specification stated (module 3.2.P.3.4 or part 2.B).

It should be stated whether the bulk product is to be stored (and if relevant, transported) under controlled or non-controlled storage conditions.

Where bulk product is transported between manufacturing sites, the transportation arrangements should be described in general terms (bulk container / storage and transportation conditions / monitoring arrangements) in the dossier (module 3.2.P.3.4 or part 2.B).

According to the guideline on good distribution practice, the following should be taken into consideration:

Principle:

• Quality should be maintained throughout the distribution network;
• Storage conditions should be observed at all times, including during transportation.

Storage:

• Temperature should be monitored and recorded periodically;
• Records should be reviewed regularly.

The maximum storage interval for the bulk product should be declared in the marketing-authorisation dossier, or alternatively, the maximum batch manufacturing time from start of product manufacture to completion of packaging in the final primary container for marketing.

When storage is prolonged (i.e. more than 30 days for solid oral dosage forms; more than 24 hours for sterile products), evidence of the suitability of the proposed container, storage interval or transportation arrangements should be included in the dossier. The data to be provided will be dependent on results of development studies that represent the conditions proposed.

In line with the principles described for finished products in the relevant International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) or International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH) guidelines, it is expected that data from pilot scale batches (minimum of two batches) stored under conditions that represent the storage conditions for the bulk product will be provided to support the storage of bulk products. Unless provided in the dossier, these data should be verified in post-approval stability commitments on commercial scale batches.

Where transportation of bulk between manufacturing sites is proposed, the impact of excursions outside of the original storage conditions should be discussed and, where necessary, supported by accelerated stability data.

Calculation of the product’s shelf-life should be in accordance with the Committee for Medicinal Products for Human Use / Committee for Medicinal Products for Veterinary Use note for guidance on the start of shelf-life of the finished dosage form (CPMP/QWP/072/96 / EMEA/CVMP/453/01). If other methods are proposed, these should be declared and justified through inclusion of batches that represent the full proposed holding intervals of the bulk product (intermediate) in the finished product stability programme.

It is not necessary to conduct stability studies on bulk according to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) or International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH) recommendations (temperature or humidity). Stability studies on bulk should reflect real storage conditions in the standard container foreseen at the manufacturing site.

In the event that more than one manufacturing site is involved, the stability studies should also cover any transportation (duration and conditions).

During product development, the effect of orientation should be investigated in the priming and repriming studies according to the guideline on the pharmaceutical quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005). If storage orientation has a significant effect on the delivered dose during these studies (i.e. different repriming periods / number of actuations are required for re-priming when stored in different orientations), a storage orientation recommendation should be added to the product information (summary of product characteristics, package leaflet and label). The preferred storage orientation should be detailed.

As it cannot be guaranteed that the product will always be stored in the preferred orientation, the repriming instructions in the product information should be based on the worst-case scenario (i.e. the orientation which requires the shortest repriming period or the highest number of repriming actuations).

According to European Union legislation, pharmaceutical manufacturers are required to use European Pharmacopoeial standard water in the manufacture of medicinal products.

The European Pharmacopoeia (Ph. Eur.) has recently introduced a chapter making reference to the acceptability of rapid microbial methods to replace the standard Pharmacopoeial methods provided appropriate validation has been performed.

Following discussions at the QWP and the ad hoc good-manufacturing-practice inspectors' group, it is suggested that the introduction of such methods might require specific review to ensure that the appropriate validation steps have been followed and that the water continues to meet the Ph. Eur. specifications. Since, in the case of water, the validation will not be product specific, it is suggested that a company could request the supervisory authority to carry out a specific site inspection. The performance of such an inspection would be at the discretion of the supervisory authority and could involve a pharmaceutical assessor where necessary.

Since it is expected that the water will continue to meet Ph. Eur. specifications, if tested, no change to dossier requirements* (variations) would be involved and therefore no regulatory impact on individual products would normally be anticipated.

Sterility is part of the shelf-life specification.

Sterility testing should be performed at least at the end of shelf life but it can be replaced by testing of the container closure integrity. Depending on the nature of the container, intermittent integrity testing might be envisaged, independent of whether the sterility testing is replaced or not.