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The following guideline provides guidance on the stability data which have to be generated in order to support a variation to a Marketing Authorisation. The guideline provides general guidance on stability testing in case of type I (A and B) variations and addresses the data requirements for widely encountered cases of type II variations.

The following guideline sets out the stability testing requirements for variations to a Marketing Authorisation after approval. This guideline is an extension of the CHMP and CVMP Guidelines on Stability Testing of Existing Active Substances and Related Finished Products and the respective ICH/VICH Guidelines for New Active Substances and Drug Products. It is intended to be applied in the European Union.
The guideline seeks to exemplify the stability data required for variations to active substances and/or finished products. It is not always necessary to follow this when there are scientifically justifiable reasons for using alternative approaches.
The guideline provides a general indication on the requirement for stability testing, but leaves sufficient flexibility to encompass the variety of different practical situations required for specific scientific situations and characteristics of the material being evaluated.

The purpose of this guideline is to outline the stability data which have to be generated in case of variations. It is applicable to chemical active substances and related finished products, herbal drugs, herbal drug preparations and related herbal medicinal products, however not to radiopharmaceuticals, biologicals and products derived from biotechnology.
Variations for active substances and finished products encompass a wide range of situations. The Guideline provides general guidance on stability testing in case of type I (A and B) variations, furthermore, it addresses the information required for active substances and/or finished products in widely encountered cases of type II variations as listed in section 6.

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There has been a significant interest to develop drug delivery methods for potent albeit sometimes toxic, highly lipophilic/poorly water soluble, unstable compounds, or for tissue targeting of highly water soluble compounds. One of the strategies has been encapsulation of the active substance(s) in the aqueous phase of a liposome, or incorporation or binding to the lipid components. Liposomes are classically described as vesicles composed of one or more concentric lipidic bi-layers. Such variants include, but are not limited to, multi-vesicular liposomes, polymer-coated vesicles and lipidic complexes. In any given product, a proportion of the active substance could also be extra-liposomal, free in bulk solution.
Early parenteral liposomal products were found to have a number of critical pharmacokinetic properties including rapid recognition and removal by the monocyte phagocyte system (MPS) and premature drug-release (instability). It was also recognized that the physicochemical properties of the liposomes, such as particle size, membrane fluidity, surface-charge and composition were relevant determinants of such in vivo behaviour. Some formulations were found to benefit from the addition of sterols (e.g. cholesterol), size reduction and surface modification with covalently linked polymers (e.g. polyethylene glycol [PEG]), to provide significant improvements.
Contrary to products where the active substance is in simple solution, liposomal medicinal products have formulation-specific distribution characteristics in-vivo and similar plasma concentrations may not correlate to equivalent therapeutic performance. The complete characterisation of the pharmacokinetics and tissue distribution of a new liposomal product is critical to establish safe and effective use because formulation differences may substantially modify efficacy/safety due to specific cell interactions and distribution characteristics which are not detectable by conventional bioequivalence testing alone. The aims of developing the originator and the evidence supporting its use should be taken into account when designing the non-clinical and clinical programme for the liposomal products developed with reference to that particular originator.
The reference liposomal product used for comparability investigations should be sourced from within the EU and should be used as a comparator in all proposed characterization studies.
This document discusses the principles for assessing liposomal products developed with reference to an innovator liposomal product but does not aim to prescribe any particular analytical, nonclinical or clinical strategy.
This reflection paper should be read in connection with the following documents:
Directive 2001/83/EC, as amended
Part II of the Annex I of Directive 2001/83/EC, as amended
CHMP/437/04 Guideline on similar biological medicinal products
Annex II to Note for Guidance on Process Validation CHMP/QWP/848/99 and EMEA/CVMP/598/99 Non Standard Processes (CPMP/QWP/2054/03)
Guideline on similar medicinal products containing biotechnology-derived proteins as active substances: quality issues
ICH topic Q5E – Comparability of biotechnological/biological products
ICH topic S6 – Note for guidance on Pre-clinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (CPMP/ICH/302/95)

ICH topic E9 statistical principles for clinical trials – Note for guidance on statistical principles for clinical trials (CPMP/ICH/363/96)
ICH topic E10 – Note for guidance on choice of control group in clinical trials (Guideline on the choice of the non-inferiority margin (CPMP/EWP/2158/99)
Points to consider on switching between superiority and non-inferiority (CPMP/EWP/482/99)
Note for guidance of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98, rev 1 corr *)

This reflection paper is intended to assist in the generation of relevant quality, non-clinical and clinical data to support a marketing authorisation of intravenous liposomal products developed with reference to an innovator liposomal product. Hence, this document should facilitate a decision on the following issues:
pharmaceutical data needed as evidence of product comparability between test and reference or after changes to a liposomal product, to support comparative safety and efficacy

Necessity of pre-clinical and clinical studies (including ‘usual’ bioequivalence studies) and circumstances which may allow to waive certain studies
The principles outlined in this reflection paper might also be considered to be applicable to other novel types of “liposome-like” and vesicular products which may be under development including those to be administered by routes other than intravenous administration.

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This paper describes a basic package of information which could be relevant to confirm the sound pharmaceutical development and full characterisation of products of this type.
In particular, this text applies in the following contexts cumulatively:
• medicinal products for intravenous injection or infusion which contain active substances, which have a low aqueous solubility and which are therefore solubilised in an aqueous micellar system1, where the main objective of the development is to solubilise the drug, and not to create a system where special size- or surface-dependent properties of the disperse phase are critical factors in the kinetics and disposition of the drug.
• it is particularly relevant to ‘traditional’ or ‘established’ ‘small molecule, non-polymeric’ surfactants which are sensitive to dilution effects during slow intravenous administration, which are quickly metabolised and which therefore do not have a long halflife in plasma, e.g. polysorbate 80.
Additional considerations may apply to certain polymeric surfactant systems developed to create a ‘delivery system’ in addition to a solubilising system and which have special properties affecting kinetics and distribution in vivo, e.g. very low critical micelle concentration (cmc) or prolonged half-life2 (e.g. innovative block co-polymer surfactants) or those oncology products designed to utilise the EPR effect3 (Enhanced Permeability and Retention). Such systems may indeed be characterised in partby the following tests, but it is likely that additional studies could be needed to fully characterise thesproducts in a relevant way.
In micellar solutions, there exists, in rapid dynamic equilibrium, different species of the drug substance (as aqueous solute or drug substance solubilised in the micelle) and surfactant (as monomer or in micelle form). In this way, the drug substance is maintained in solubilsed form and precipitation is avoided. These drug products are normally presented as stable sterile concentrates (e.g. powder and solvent for concentrate solution for infusion, sterile concentrate and solvent for solution for infusion, concentrate for solution for infusion).
The micellar solution is normally prepared for intravenous infusion by dilution with a large volume of aqueous 0.9% sodium chloride or 5% dextrose injection.
On slow intravenous infusion of the products described by the bullet points above, the micellar solution is deaggregated such that the drug substance is presented to the blood compartment in a ‘free’ rather than ‘solubilised’ form. Nevertheless, it should be acknowledged that these are generalisations and that the specific qualities and attributes of the both the drug substance and micellar and formulation excipients need to be specifically considered on a case by case basis.
Given the complexity of micelle systems, a comprehensive pharmaceutical development is necessary, needing an understanding of what happens to the product after administration. It is acknowledged that this development may involve some tests which are not currently well-reported, and applicants are encouraged to develop and validate such techniques for themselves, particularly those which give information on the likely state of these systems in vivo. Therefore, applicants are advised to discuss the pharmaceutical development with the regulatory authorities and/or to seek Scientific Advice from the CHMP.

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This annex is the result of the Q4B process for Uniformity of Dosage Units. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG).

Q4B OUTCOME
Analytical Procedures

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph.Eur. 2.9.40. Uniformity of Dosage Units, JP 6.02 Uniformity of Dosage Units, and USP General Chapter <905> Uniformity of Dosage Units, can be used as interchangeable in the ICH regions subject to the following conditions:

The Uniformity of Dosage Unit test is not considered to be interchangeable in the three regions unless the target test sample amount at time of manufacture (T) is 100% (i.e., T=100%).

Unless the 25 milligrams (mg)/25% threshold limit is met, the use of theMass/Weight Variation test as an alternative test for Content Uniformity is not considered interchangeable in all ICH regions.

For specific dosage forms which have been indicated in local text in the pharmacopoeias by enclosing the text within the black diamond symbols, application of the Uniformity of Dosage Units test is not considered interchangeable in all ICH regions.

For Mass/Weight Variation, the PDG-harmonised definition for ‘W Bar’ should be used.

If a correction factor is called for when different procedures are used for assay of the preparation and for the Content Uniformity Test, the correction factor should be specified and justified in the application dossier.

Acceptance Criteria
The acceptance criteria are harmonized between the three pharmacopoeias.

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This Concept Paper proposes a revision of the Note for Guidance on the Quality, Preclinical and Clinical Aspects of Gene Transfer Medicinal Products (CPMP/BWP/3088/99) that came into effect in 2001. The revision of the Note for Guidance, Guideline according to the new terminology, will address the issues identified from clinical experience and provision of Scientific Advice on gene therapy medicinal products and will lay down detailed and updated requirements for the quality, nonclinical and clinical aspects of gene therapy medicinal products. The revised Guideline will refer to a number of recently developed scientific guidelines and will comply with Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products and the Commission Directive 2009/120/EC amending of the Annex I Part IV of Directive 2001/83/EC

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The purpose of this guidance is to assist sponsors in clinical drug development for the treatment of adults with duodenal ulcers caused by Helicobacter pylori (H. pylori) for the reduction of duodenal ulcer recurrence. Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the overall development program and clinical trial designs to support antimicrobial-containing H. pylori treatment regimens. This guidance intends to serve as a focus for continued discussions among the Division of Special Pathogen and Transplant Products, pharmaceutical sponsors, the academic community, and the public. As the science of this indication evolves, this guidance may be revised as new information accumulates.
This guidance pertains to development of drugs for the treatment of adults with duodenal ulcers. It does not address treatment of children, or those with other conditions also associated with H. pylori, including gastric ulcers and non-ulcer dyspepsia. If sponsors are interested in pursuing an indication for the treatment of patients with other conditions associated with H. pylori infection or other endpoints not mentioned in this guidance, they are encouraged to discuss their proposals with the division. Sponsors desiring to pursue an indication for ulcers caused by clarithromycin-resistant organisms should discuss the types of data needed to support such a claim with the division early in drug development.

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This reflection paper addresses specific points related to products containing autologous chondrocytes intended for the repair of lesion of cartilage of the knee not discussed in the ‘Guideline on human cell based medicinal products’ (EMEA/CHMP/410869/2006) and therefore it should be read in conjunction with the guideline. – Deadline for comments is 31st December 2009.

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Blood memoranda have not been issued since January 1997. This information is now being issued as guidance documents.

The memoranda on this page are arranged in order by date, with the most recent memo added to the top of the list.

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CONCEPT PAPER ON THE NEED TO UPDATE THE CHMP POSITION STATEMENT ON CJD AND PLASMA-DERIVED AND URINE-DERIVED MEDICINAL PRODUCTS
(EMEA/CPMP/BWP/2879/02 REV. 1)

The last revision of the “CHMP position statement on CJD and plasma-derived and urine-derived medicinal products” (EMEA/CHMP/BWP/2879/02/rev.1) was published in June 2004.
The document is the current EMEA/CHMP guidance on CJD and vCJD and plasma-derived and urine-derived medicinal products. It includes recommendations for these products based on the knowledge on CJD and vCJD epidemiology, human tissue distribution of infectivity/abnormal prion protein and infectivity in blood.

The current position statement dates from 2004. Additional information has been accrued in this field since 2004 including the finding of four cases of vCJD infection associated with blood transfusion of non-leucodepleted red blood cells.1,2 TSE infectivity has also been detected in urine in some animal models3,4,5,6 in the clinical phase of the disease.
The CHMP opinion and recommendations reflected in the position statement were based on the knowledge on CJD and vCJD at the time of publishing. The progress in the field during the subsequent years reinforces the need to update the content of the document and to review the recommendations for these products.
The current position statement covers plasma-derived medicinal products and urine-derived medicinal products. Currently, there is no specific guidance on CJD and vCJD and advanced therapy medicinal products based on human tissues.

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This guidance provides a section by section description of the Chemistry, manufacturing and control section of an FDA submission, its aimed specifically at Specific Biotech products, but should be considered by other related technologies. There is no apparent reason for the re-posting but it could be the FDA is planning an update.

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