Quality of medicines questions and answers: Part 2 药品质量问答：第二部分 - 欧美法规

摘要： These questions and answers address a number of questions that have been brought to the attention of the Joint Committee for Medicinal Products for Human Use / Committee for Medicinal Products for Veterinary Use Quality Working Party (QWP) by marketing-authorisation holders (MAHs) or European Economic Area (EEA) competent authorities, on matters related to the quality of medicines. They have been developed and are maintained by the QWP.They provide the EEA's harmonised position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures.If a question is not addressed, marketing-authorisation holders are encouraged to contact the European Medicines Agency (EMA) for further information.These questions have been produced to provide clarification or additional information, and should be read in conjunction with the European Pharmacopoeia, quality guidelines and other guidance documents.

Acceptability of two different appearances (shape, dimensions, colour) for a single strength tablet in a single Marketing Authorisation 单一上市许可中单一规格片剂两种不同外观（形状、尺寸、颜色）的可接受性

[–] 1. Is it acceptable to propose two different appearances (shape, dimensions, colour) for a single strength tablet in a single Marketing Authorisation? H+V April 2014

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

Moreover, the introduction to the variation classification guidelines (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.

Appearance of tablets of different strengths 不同规格片剂的外观

[–] 1. If the applicant wishes to apply for more than one tablet strength, what level of difference in the appearance between the different tablet strengths would be required? H+V June 2011

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.

Definition of ‘active substance’ in relation to mixtures 混合物种“活性物质”的定义

[–] 1. In case more than one active substance produced at different manufacturing sites is mixed together at a different manufacturing site, is it possible to consider the mixing as active substance manufacture? H+V June 2011

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.

Active substance - Veterinary Medicinal Products (VMP) containing 100% Active Substance (V) 活性物质 - 含有100％活性物质（V）的兽用药产品（VMP）NEW Sept. 2018

[–] 1.Should a veterinary medicinal product be formulated without excipients when the batch-to-batch variation of the active substance is such that it does not ensure control of the active substances content in the finished product to ± 5 %? V NEW Sept. 2018

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.

Design of in-use shelf life for solid oral dosage forms in multi-dose containers (published January 2018) 多剂量包装的固体口服制剂开始使用后货架期设计

[–] 1. When is it necessary to perform in-use stability studies on solid oral dosage forms such as tablets and capsules in multi-dose containers? H+V January 2018

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.

[–] 2. If an in-use study is required, what length is appropriate? H+V January 2018

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.

[–] 3. Can an open dish stability study be used to assess in-use stability? H+V January 2018

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.

Claims for in-use shelf-life for solid oral dosage forms in multi-dose containers (published January 2018) 多剂量包装的固体口服制剂开始使用后货架期的要求

[–] 1. When is it necessary to claim an in-use shelf-life in the SPC for solid oral dosage forms such as tablets and capsules in multi-dose containers? H+V January 2018

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&A 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.

[–] 2. Can an applicant apply for an in-use shelf life even if not warranted by stability results? H+V January 2018

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.

Packaging 包装

[–] 1. No specific requirements or recommendations are provided in the European Union guideline on plastic immediate packaging materials, CPMP/QWP/4359/03 & EMEA/CVMP/205/04, in regard to acceptable quality standards for plastic materials to be used for containers for solid oral dosage forms and solid active substances. Should the materials always comply with the specifications in the European Pharmacopoiea and if not, which quality standards are considered to be acceptable? H+V January 2009

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.

[–] 2. Does 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 prevent the use of heat-labile plastic packaging materials and aseptic processing for sterile veterinary medicinal products? V February 2012

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.

[–] 3. What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process? H+V April 2016

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 activity ¹.

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:

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);
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);
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;
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);
I.S. EN ISO 11137-2:2015　　Sterilization of Health Care Products - Radiation - Part 2: Establishing the Sterilization Dose (ISO 11137-2:2013);
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.

Particles originated from the container closure system 来源于包装密闭系统的颗粒

[–] 1. If particles which originate from the container-closure system develop during the production, storage or handling of a liquid solution, is the inclusion of a mandatory filtration step in the SmPC or package leaflet acceptable to compensate for this? Examples include the introduction of glass particles due to delamination of glass walls and the introduction of rubber particles following puncture of the rubber stopper? (H+V) April 2014

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&A.

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.

Quality data requirements to demonstrate suitability of multidose containers for preservative free eye drops 证明多剂量包装的无防腐剂滴眼液稳定性的质量数据要求 NEW October 2018

[–] 1. What are the quality requirements for the design and functions of multidose containers for preservative-free eye drops?

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. Container design and functions

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. Design Verification and Robustness Testing

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.

[–] 1.3. Microbial Stress Testing

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.

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.

[–] 1.4. Container Closure System Control Strategy

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. Risk Management

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.

Reduced testing of starting materials 起始物料减少检测

[–] 1. What information should be included in marketing-authorisation dossiers regarding the actual testing that is carried out on any starting materials, e.g. active substances, excipients and packaging materials, on receipt by a finished product manufacturer? H+V June 2011

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.

Setting specifications for impurities in veterinary medicinal products 兽用药品杂质质量标准设定

[–] 1. Different positions regarding the setting of specifications for both single identified and unidentified impurities observed below 1.0% in the finished product specifications (release and shelf-life), in veterinary medicinal products, appear to have arisen from the wording of VICH Guidelines GL11 and GL39 (mainly decision tree 2) being interpreted in two different ways. What limits should therefore be applied for impurities in veterinary medicinal products? Should these limits be set to < 1.0% (the VICH guideline GL11 identification threshold limits) regardless of the batch analyses and stability study data? Or should they be set based on the results observed in the batch analyses and stability studies? V July 2013

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.

Specific type of products – Dry product inhalers 特定类型药品：干粉吸收剂

[–] 1. Should dropping of an inhalation device be investigated during development? H June 2012

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.

Specific types of product - Graduation of measuring devices for liquid dosage forms 特定类型药品：液体剂型测量装置刻录

[–] 1. What are the requirements for the graduation of measuring devices for liquid dosage forms of medicinal products for human use, in particular in relation to the suitability of the graduation of the measuring device regarding dosing accuracy and dosing precision of the related product and the suitability of the measuring device for the related product? H September 2006

The points discussed below are applicable to new marketing-authorisation applications or fully reformulated existing medicinal products. These points should be considered referring to the graduation of a measuring device for a liquid dosage form of a medicinal product for human use, such as solutions, suspensions and emulsions, in section 3.2.P.2: pharmaceutical development of the Common Technical Document. They should be part of the justification of the suitability of the graduation of the measuring device for dosing the medicinal product under application. The measuring device shall comply as well with the relevant parts of the requirements given in the Medical Device Directive 93/42/EECand with International Organization for Standardization (ISO) standards, as applicable.

Measuring devices may be required to deliver oral, parenteral, nasal, vaginal, and rectal liquid dosage forms to patients. 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. pre-filled syringes.

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 in the material. The graduation can also be printed on the material of the measuring device.

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 (SmPC). Attention should be paid to the possibility of fading of the printing ink. Glueing 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 dosing advice as stated in section 4.2: posology and method of administration of the SmPC. This applies in principle to all measuring devices. Attention should among others be paid to the following items:

Possibility of the measuring device to supply the minimal and maximal dose per single dose (nominal capacity);
Suitability of the scale intervals in relation to the dosing advice or the dosage range when posology is stated per kilogram bodyweight or square metre body surface;
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 measuring device for the medicinal product: The suitability of the measuring device for the medicinal product should be addressed. Attention should be paid to the following items:

Dosing accuracy and precision in relation to the therapeutic window of the drug 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 care should be taken in the design of the scale graduation to prevent overdosing;
The physical characteristics of the liquid in relation to the measuring device. The combination should assure accurate and precise dosing. Considerations can be for instance the needle diameter and the particle size of suspensions in injectables, the homogeneity (resuspendability) of suspensions and emulsions prior to and during the application of the measuring device, or residual amounts of liquid in the measuring device after administration of the dose to the patient.

Furthermore, 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 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 multidose containers), or other accepted pharmacopoeias. For single-dose containers, where not necessarily the whole content of the product needs to be administered to the patient, the same requirements can be applied as for multidose containers.

Specific types of product - Need for in-vitro dissolution studies with alcohol for modified-release oral products including opioid drug products 特定类型药品：缓释药品（包括阿片类药品）应进行使用乙醇的体外溶出度研究

[–] 1. What are the likely implications of the various observed in-vitro effects of alcohol on the dissolution of different prolonged release opioid products at various concentrations and durations of exposure? H April 2009

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.

[–] 2. Is it considered that in future in-vitro studies investigating the effect of alcohol / ethanol on dissolution / release should be required for the following cases? H April 2009

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.

[–] 3. Is it considered that in-vitro studies investigating the effect of alcohol / ethanol on dissolution / release might also be required for oral prolonged release formulations containing active substances other than opioids? If so, should they be required only where rapid dose dumping of the active substance might be expected to cause clinically hazardous overdose, or should they be required for all oral prolonged-release products containing any active substance? H April 2009

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.

[–] 4. How might the methodological requirements for in vitro testing of the potential for accelerated release in the presence of alcohol be established, ensuring maximum relevance to the clinical situation? H April 2009

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.

[–] 5. Are further measures needed to gain better understanding of the release characteristics of oral prolonged release products in the presence of alcohol and their relevance to the clinical situation, for example by in vitro – in vivo correlation? If in-vitro testing demonstrates a potential for alcohol to enhance opioid / active product release, should the applicant be required to investigate the clinical relevance of the effect in in-vivo studies? H April 2009

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.

Specific types of product - Needle safety systems (published September 2017) 特定类型药品-针安全系统

[–] 1. When does needle stick injury commonly occur and what are the risks associated with it? H September 2017

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).

[–] 2. Does Directive 2010/32/EU on the prevention of sharps injuries apply to the regulation of medicinal products? H September 2017

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.

[–] 3. Do medicines agencies have other ways of regulating the needle safety of medicinal products? H September 2017

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.

[–] 4. Should every new medicinal product incorporate a needle safety system? H September 2017

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.

[–] 5. What information on needle safety systems is expected in regulatory submissions and in which part of the dossier? H September 2017

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.

[–] 6. How should information about the needle safety system be presented in the SmPC, labelling and package leaflet? H September 2017

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.

Specific types of product - Orally inhaled products ( published 06/03/2017) 特定类型药品：吸入制剂

[–] 1. What is considered as an acceptable range of fine particle dose (FPD) in the finished product specification?

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.

[–] 2. The batches of the test and the comparator chosen for the PK study need to be representative. What is considered as a representative batch?

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.

[–] 3. How to demonstrate dose proportionality in vitro for waiving of PK studies?

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.

[–] 4. How to study flow-rate dependency in vitro for waiving PK data in patients?

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.

Specific types of product - Quality of investigational medicinal products 特定类型药品：临床研究用药品质量

[–] 1. Setting specifications for impurities (2.2.1.S.4.1, 2.2.1.S.4.5, 2.2.1.P.5.1 and 2.2.1.P.5.6): On which basis should specifications for related impurities be set? H January 2011

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).

[–] 2. Substantial amendments (chapter 8): How should industry notify amendments? January 2011 (corrected November 2011)

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.

[–] 3. Shelf-life extensions (2.2.1.P.8 and chapter 8): What information should be included in the file in order to make shelf life extensions without notification of a substantial amendment? H January 2009

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.

[–] 4. Batch data (2.2.1.S.4.4 and 2.2.1.P.5.4): Are certificates of analysis needed? H January 2009

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.

[–] 5. Drug substance and drug product batch data for proposed manufacturing sites: Are drug substance and drug product batch data for all proposed manufacturing sites listed in S.2.1/P.3.1 required to be submitted in the investigational medicinal product dossier, or provided as a substantial amendment prior to use in a study? H January 2011 (corrected November 2011)

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.

Specific types of product - Eye drops 特定类型药品：滴眼剂

[–] 1. What information on the functional qualities of plastic containers for eye drops should be included in the MAA dossier? H+V May 2015

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.

Specific types of product - Veterinary medicinal products 特定类型药品：兽用药

[–] Collapse

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.

[–] 2. What limits for microbiological quality are considered appropriate for premixes for medicated feeding stuffs which contain excipients of natural origin (e.g. soya bean husks, maize meal, etc.)? V January 2014

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).

[–] 2. Is it possible to grant a marketing authorisation for a product which is not soluble over the pH ranges described in the guideline on quality aspects of pharmaceutical veterinary medicines for administration via drinking water (EMEA/CVMP/540/03-Rev.)? Could a recommendation be added in the summary of product characteristics / product information that, for solubility reasons, the pH of the drinking water has to be adjusted with acid / base before adding the medicinal product? V October 2010

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.

[–] 3. Is it permitted to have a multidose (parenteral) veterinary medicinal product for use both as an intramuscular injection and also an intramammary preparation? V October 2010

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.

[–] 4. 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 October 2010

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 5 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.)

[–] 6. What information on the functional qualities of plastic containers for eye drops should be included in the MAA dossier? H+V May 2015

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.

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.

[–] 7. Can an active substance be used in either powdered or granulated forms in a single marketing authorisation for a veterinary medicinal product containing 100% of the active substance? V April 2016

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Stability - Article 58 products 稳定性：适用第58条的产品

[–] 1. What kind of stability data are required for applications according to Article 58 of Regulation EC/726/2004? H July 2006

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 6 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 the 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 / humidity conditions that may occur in climatic zone IV, even though a product may not be stable for 6 months at these storage conditions.

Please note that for aqueous products in semi-permeable 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.

Stability - Declaration of storage conditions 稳定性：贮存条件声明

[–] 1. What is the declaration of storage conditions to be used in the product information, for products which require to be stored and transported refrigerated? H+V August 2007

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”.

[–] 2. How should expiry dates be calculated and expressed? H+V July 2008

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. See table 1.

Table 1: Example of the calculation of the expiry date of a tablet with a shelf-life of 24 months
Date of first blending step	Date of packaging	Date of release	Expiry date	Interpretation fit for use	Total time from start of manufacture to end of shelf-life	Recalculated expiry date
28/01/2005	29/01/2005	30/01/2005	01/2007	until 31 January 2007	2 years 3 days	01/2007
03/01/2005	04/01/2005	05/01/2005	01/2007	until 31 January 2007	2 years 28 days	12/2006
12/2006	19/07/2005*	21/07/2005	01/2007	until 31 January 2007	2 years 28 days	12/20061
12/20061	04/01/2005	01/02/2005	02/2007	until 28 February 2007	2 years 56 days	01/20071

* The bulk compressed tablets have been stored for 6 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.

¹ Note: 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.

Stability - Endotoxin testing and sterility testing at the end of shelf-life 稳定性：近效期时的内毒素检测和无菌检测

[–] 1. Is endotoxin testing considered essential at the end of shelf life to confirm parenterals to be pyrogen-free?

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.

[–] 2. Is sterility testing considered essential at the end of shelf life to confirm parenterals to be sterile? H+V May 2009

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.

Stability - Generics versus the innovator product 稳定性：仿制药vs 新药

[–] 1. Is it allowed that the in-use stability of one product deviates from other authorised products (e.g regarding storage time, storage conditions)? H+V March 2014

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.

[–] 2. Is it allowed that the storage condition of one product deviates from other authorised products (e.g. storage in refrigerator versus storage at temperatures not exceeding 25°C)? H+V March 2014

In principle, each product will be assessed on its own merits and differences may exist. However, when the difference in storagetemperature 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.

Stability - Reduced design in stability studies 稳定性：稳定性研究中减少试验的设计

[–] 1. Can reduced designs be used when performing stability studies on veterinary medicinal products? V October 2006

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.

Stability - Stability issues of pharmaceutical bulk products use in manufacture of the finished product 稳定性：药品生产用药用大宗产品的稳定性问题

[–] Background

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 and / 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.

[–] 1. What is the definition of bulk storage? H+V February 2012

The question most frequently arises in relation to solid oral dosage forms (particularly tablet cores before coating and / 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.).

[–] 2. What information should be provided on the bulk container? H+V February 2012

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).

[–] 3. What information should be provided on the storage conditions? H+V February 2012

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

[–] 4. What information is necessary regarding the transportation of bulk products between manufacturing sites? H+V Feb 2012

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:

Good manufacturing practice 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.

[–] 5. What data should be provided to support bulk storage and transportation arrangements? H+V February 2012

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 and / 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 2 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.

[–] 6. How should the calculation of a product’s shelf-life be performed? H+V February 2012

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.

[–] 7. Which stability conditions should be chosen to support bulk storage? H+V Feb 2012

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).

Storage 贮存

[–] 1. What are the requirements for storage orientation recommendations in the product information for pressurised metered dose inhalers? H December 2008

During product development, the effect of orientation should be investigated in the priming and re-priming 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 re-priming instructions in the product information should be based on the worst-case scenario (i.e. the orientation which requires the shortest re-priming period and / or the highest number of re-priming actuations).

Water 水

[–] 1. What is the regulatory consequence of implementing an alternative method for rapid control of microbiological quality of water for injection and purified water? H+V July 2005

According to European Union legislation, pharmaceutical manufacturers are required to use European Pharmacopoeialstandard 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.

* This will depend on the level of detail in the original dossiers concerned.

[–] 2. Is sterility testing considered essential at the end of shelf life to confirm parenterals to be sterile? H+V May 2009

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 closureintegrity. Depending on the nature of the container, intermittent integrity testing might be envisaged, independent of whether the sterility testing is replaced or not.