Quality of medicines questions and answers: Part 2

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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 for further information at qwp@ema.europa.eu.

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.

Key:

  • H: applicable to medicinal products for human use
  • V: applicable to veterinary medicinal products

Table of contents

Quality by design - Cooperation between assessors and inspectors when real-time release testing (RTRT) is applied - New June 2013

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1. Are good-manufacturing-practice (GMP) inspectors involved in approval of RTRT submissions? H+V June 2013

The level of interaction during (and possibly after) the assessment process will depend upon what is actually proposed, which could be quite varied and of different levels of complexity. Where needed, a discussion between assessor and inspector is important to achieve a common understanding of the applicant’s proposal and its potential impact on the marketing-authorisation dossier and on-site situation.

The potential requirement for an inspection will depend upon the applicant's approach to and justification for RTRT and on existing experience of the manufacturer with this approach, i.e what the basis is for RTRT and what in-process controls will be applied and how this will be done e.g. the technology applied. If complex technology (such as near-infrared or Raman spectroscopy) is used for RTRT for the first time at a manufacturing site, a product-specific inspection is likely to be requested. If the RTRT approach merely involves an increased level of at line testing in lieu of finished product testing, then this would not necessarily require a product-specific inspection prior to approval, but will be taken into consideration as part of a future routine GMP inspection.

2. When should collaboration between inspector and assessors in relation to RTRT start? H+V June 2013

Collaboration between inspectors and assessors on RTRT may be initiated by inclusion of a proposal for introduction of RTRT in a new marketing-authorisation (MA) or variation application. In such cases, the assessor should contact the relevant supervisory authority at the earliest opportunity in the assessment procedure to discuss the potential implications for the MA dossier and discuss the need to trigger a GMP inspection. When an inspection is triggered for a specific product, the timing of the inspection will depend on the availability of relevant data generated at the commercial scale.

3. Are data generated during the running in period (parallel testing) requested before approval of RTRT? H+V June 2013

For biological products or when models (design-space or calibration models for complex technology such as near infrared, etc.) are part of the RTRT scheme, results of parallel testing on commercial-scale batches should normally be included in the MA or variation submission.

In event that parallel testing of a sufficient number of batches is not complete at the time of submission or approval, this may be completed by inclusion in a post-approval change-management protocol and the MA can be granted on the grounds of finished product testing.

Once parallel testing is complete, RTRT may be implemented by either notification to (type IA), or approval by, the competent authority (type IB) as appropriate. The route for implementation will be indicated to the applicant during the assessment of the initial application.

Reduced testing of starting materials

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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.

Definition of ‘active substance’ in relation to mixtures

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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.

Appearance of tablets of different strengths

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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.

Specific types of product - Graduation of measuring devices for liquid dosage forms

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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/EEC and 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. prefilled 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 - Quality of investigational medicinal products

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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)

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

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

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

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

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

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

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

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

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

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)

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

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

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

Specific types of product - Need for in vitro dissolution studies with alcohol for modified-release oral products including opioid drug products

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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 - Veterinary medicinal products

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1. 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 October 2010

Ideally, compendial grade excipients should be used in new veterinary medicinal products and in these cases compliance with the general chapter 5.1.4: microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use is considered appropriate. For premixes for medicated feeding stuffs for veterinary use containing excipients of natural origin, application of these limits may not be possible. European Pharmacopoeia (Ph. Eur.) 5.1.4: microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use is a general chapter and is not specifically referenced in the Ph. Eur. monograph for premixes for medicated feedingstuffs and is therefore not mandatory.

The general chapter has essentially the same status as a guideline, that is, it represents the preferred option but it should be possible to accept deviation from it where justified. In case of premixes containing excipients of natural origin, the Agency would recommend following criteria as requested under special Ph. Eur. provision for oral dosage forms containing raw materials of natural origin. In exceptional cases, if this cannot be fulfilled, the applicant could apply other limits, e.g. the limits detailed in section C of 5.1.8: microbiological quality of herbal medicinal products for oral use, but only if fully justified.

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 five fragments) contained in this chapter does not necessarily need to be applied. It is noteworthy that the European Pharmacopoeia (Ph. Eur.) test is designed to demonstrate that a stopper fulfills the general minimum requirements that are expected for rubber stoppers for medicinal products, but this can of course not cover all their potential uses.

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

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

Risk-management tools

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

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

Storage

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

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

Packaging

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1. No specific requirements or recommendations are provided in the European Union guideline on plastic immediate packaging materials, CPMP/QWP/4359/03 and 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.

Stability - Stability issues of pharmaceutical bulk products use in manufacture of the finished product

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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 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 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 or transportation arrangements should be included in the dossier. The data to be provided will be dependent on results of development studies that represent the conditions proposed.

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

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

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).

Stability - Declaration of storage conditions

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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:

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

Date of first blending stepDate of packagingDate of releaseExpiry dateInterpretation fit for useTotal time from start of manufacture to end of shelf-lifeRecalculated expiry date
28/01/200529/01/200530/01/200501/2007Until 31 January 20072 years 3 days01/2007
03/01/200504/01/200505/01/200501/2007Until 31 January 20072 years 28 days12/2006
03/01/200519/07/2005*21/07/200501/2007Until 31 January 20072 years 28 days12/20061
03/01/200504/01/200501/02/200502/2007Until 28 February 20072 years 56 days01/20071

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

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

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

Stability - Article-58 products

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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 SIX months of data at 40°C/75% RH. The principles of extrapolation described in the note for guidance on evaluation of stability data (CPMP/ICH/420/02) as well as reduced testing designs as described in the note for guidance on bracketing and matrixing designs for stability testing of drug substances and drug products (CPMP/ICH/4104/00) may be applied. In cases where these data demonstrate stability over the required period of time, no special storage conditions need to be labelled.

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

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

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

Stability - Reduced design in stability studies

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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 - Endotoxin testing and sterility testing at the end of shelf-life

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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.

Water

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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 Pharmacopoeial standard water in the manufacture of medicinal products.

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

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

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

*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 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.

Specific type of products – Dry product inhalers

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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.

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