Category Archives: formulation

EMA Publishes Guidance on Stability Testing

Posted on September 12, 2011 by admin| Leave a comment

EMA Publishes Guidance on Stability Testing

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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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Posted in formulation, manufacturing

Tagged chemical active substance, specification, Stability, stability data, Stability Testing, Variation

EMA Publish Paper on Intravenous Liposomal Product Development

Posted on September 10, 2011 by admin| Leave a comment

EMA Publish Paper on Intravenous Liposomal Product Development

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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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Posted in clinical, formulation, pre-clinical

Tagged CHMP, clinical studies, comparability, EMA, Intravenous liposomes, Nonclinical, pharmaceutical quality, pharmacokinetics

EMA Publish Draft Reflection Paper on IV Micellar Systems

Posted on November 21, 2010 by admin| Leave a comment

EMA Publish Draft Reflection Paper on IV Micellar Systems

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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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Tagged CMC, intravenous, micelle, Solubilisation, surfactant

Drug Regulators, FDA, Publish Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions; Annex 6: Uniformity of Dosage Unites General Chapter

Posted on May 26, 2010 by admin| Leave a comment

Drug Regulators, FDA, Publish Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions; Annex 6: Uniformity of Dosage Unites General Chapter

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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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Tagged Annex 6, dosage, ICH, Q4B, Uniformity

Drug Regulators, European Medicines Agency, Publish Concept Paper on Revision of the Notes for Guidance on Gene Transfer Medicinal Products

Posted on January 19, 2010 by admin| Leave a comment

Drug Regulators, European Medicines Agency, Publish Concept Paper on Revision of the Notes for Guidance on Gene Transfer Medicinal Products

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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

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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Posted in biotechnology, clinical, formulation, manufacturing, pre-clinical

Tagged Advanced Therapy Medicinal Product, Bacterial Vector, clinical, Gene Therapy Medicinal Product, Genetically Modified Cell, Non-clinical, Oncolytic Virus, Quality, Viral Vector

Drug Regulators Publish Draft Guidance on Helicobacter pylori associated Duodenal Ulcer Treatments

Posted on November 5, 2009 by admin| Leave a comment

Drug Regulators, FDA, CDER, Publish Draft Guidance on Helicobacter pylori associated Duodenal Ulcer Treatments

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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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Tagged development, duodenal ulcer, helicobater pylori

Drug Regulatos Publish Draft Reflection Paper on In-vitro Cultured Chondrocyte Containing Products for Cartilage Repair

Posted on November 3, 2009 by admin| Leave a comment

Drug Regulators, EMEA, Publish Draft Reflection Paper on In-vitro Cultured Chondrocyte Containing Products for Cartilage Repair

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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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Tagged Advanced Therapies, autologous, Cartilage repair, Cell therapy, Chondrocytes, clinical, Nonclinical, Quality

FDA Publishes New Guidance Page – Memoranda to Blood Establishments

Posted on October 31, 2009 by admin| Leave a comment

FDA Publishes New Web Guidance Page – Memoranda to Blood Establishments

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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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<div id=”_mcePaste” style=”overflow: hidden; position: absolute; left: -10000px; top: 0px; width: 1px; height: 1px;”>recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.</div>

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Tagged Bloop Products, FDA

Drug Regulators Publish Concept Paper on CJD in Plasma-Derived and Urine-Derived Medical Products

Posted on September 30, 2009 by admin| Leave a comment

EMEA publishes a concept paper on the need for a position statement on CJD and Plasma-Derived and Urine-Derived Medical Products.

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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Posted in EMEA, formulation, manufacturing

Tagged Creutzfeldt-Jakob disease, plasma-derived medicinal products, prion infectivity reduction, urine-derived medicinal products, vCJD

Drug Regulatos, FDA, Reppost Guidance on CMC Submissions for Therapeutic Recombinant DNA-Derived Products or Monolconal Antibody Products

Posted on September 14, 2009 by admin| Leave a comment

The FDA has re-posted guidance first published in 1996 “FOR THE SUBMISSION OF CHEMISTRY, MANUFACTURING, AND CONTROLS INFORMATION FOR A THERAPEUTIC RECOMBINANT DNA-DERIVED PRODUCT OR A MONOCLONAL ANTIBODY PRODUCT FOR IN VIVO USE”

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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Tagged CBER, CMC, FDA

Drug Regulators Publish Concept Paper on CJD and Plasma-Derived Medicinal Products

Posted on September 8, 2009 by admin| Leave a comment

EMEA publishes Draft Guidance on Plasma and Urine Derived Medicinal Products and CJD

EMEA publishes “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 proposed document will replace the CHMP Position statement on Creutzfeld-Jakob Disease and plasma-derived and Urine Derived Medical Products (EMEA/CPMP/BWP/2879/02 Rev 1)

These guidelines need to be updated because there have been 4 cases of vCJD infection associated with blood transfusion of non-leucodepleted red blood cells. TSE infectivity has also been detected in urine in some animal models.

In order to help the CHMP with developing this position statement they are seeking input from Industry and the Public.

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Tagged Creutzfeldt-Jakob disease, plasma-derived medicinal products, prion infectivity reduction, urine-derived medicinal products, vCJD

Drug Regulators EMEA Publish Concept Paper on the Need to Revise the Guidlines on the use of Transgenic Animals in Biological Manufacture.

Posted on August 18, 2009 by admin| Leave a comment

Drug Regulators, Manufacturing, EMEA publish concept paper on using transgenic animals for biological manufacturing.

Following rapid changes in the area and products making it to the market (related article) The EMEA has published the following “CONCEPT PAPER ON THE NEED TO REVISE THE GUIDELINE ON THE USE OF TRANSGENIC ANIMALS IN THE MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (3AB7A OF JULY 1995)”

Introduction to Regulations

Recombinant proteins for medicinal use are routinely produced in bacterial or mammalian cell lines. The regulatory requirements to make and test the production lines and cell banks, and the subsequent manufacture and testing of the medicinal product are well established. Many relevant Guidelines are available for production in cell lines. An alternative production platform for recombinant proteins is transgenic animals, where a foreign gene, which codes for a therapeutically useful protein, is inserted into the genome of the chosen
species and is expressed under the close control of a promoter. The recombinant protein is generally expressed in some easily harvested body component such as milk or eggs and does not harm the animal.

The Problem to Tackle

A guideline was prepared by CPMP and entered into force in July 1995 (3AB7A). Although it contains advice which was useful for a technology platform which was in its infancy, since it came into force, this production method has progressed significantly and the guidance has not been revised to take account of these advances. The current guideline was prepared at a time when the scientific possibilities for transgenic animals were being investigated and no product had been generated for commercial or clinical trial purposes. In addition, many relevant guidelines, such as the ICH Q5 series had not been prepared.

Discussion on the Problem

It is proposed that the scope of the guidance covers the quality issues regarding biological active substances produced by the expression of one or more transgenes stably located in the genome of animals. Production using cloned animals falls outside the scope.

The following improvements to the published guideline have been identified:

The current document contains too many references to the benefits of transgenic technology but is not sufficiently detailed technically. A complete re-write to bring the structure of the document in line with the current format of CHMP guidance documents is needed.
The lay-out of the document is not logical or easy to follow. It is not broken down into logical sections which follow CTD headings and concepts.
There is no specific section on pathogen safety.
There is no discussion of specific Quality systems, particularly for generation of transgenic lines, breeding and maintenance of production animals.
A discussion on product characterisation is omitted.
Breeding strategy is not mentioned, nor the concept of master and working cell/transgenic banks.
Control of active substance or raw material is not adequately covered.
Advice on residual Host Cell Proteins and DNA is incomplete.
Since products from transgenic animals are (to date) the product of sexual reproduction, and not of cloned animals, the potential inherent variability of transgenic proteins needs to be explicitly discussed and the regulatory requirements to map this variability should be updated.
Advice on the information which is required regarding development genetics is confusing and should be clarified.
Advice is given that material from different genetic lines should not be mixed when producing product for a single license. This advice needs to be reviewed in light of more recent regulatory considerations.

The Biologics Working Party recommends developing a guideline on the use of transgenic animals in the manufacture of biological medicinal products for human use to replace the existing guideline.

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Tagged Biologicals, EMEA, GMP, ICH, ICH Q5, Transgenic animals

Drug Development Regulations – Q4B Annex

Posted on July 16, 2009 by admin| Leave a comment

Drug Regulator, EMEA, publishes input into ICH Q4B Tablet Friability

EMEA publishes ANNEX 6 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON TABLET FRIABILITY GENERAL CHAPTER (EMEA/CHMP/ICH/379801/2009)

Analytical Procedures

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the analytical procedures described in the official pharmacopoeial texts, Ph.Eur. 2.9.7. Friability of Uncoated Tablets, JP General Information 26. Tablet Friability Test, and USP <1216> Tablet Friability, can be used as interchangeable in the ICH regions.

Acceptance Criteria

For interchangeability, the loss of mass for a single determination should be not more than 1.0 percent, unless otherwise specified in the dossier. When three determinations are conducted, then the mean loss of mass for the three determinations should be not more than 1.0 percent, unless otherwise specified in the dossier.

EMEA publishes input into ICH Q4B Polyacrylamide Gel Electrophoresis

EMEA publshes ANNEX 6 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON POLYACRYLAMIDE GEL ELECTROPHORESIS GENERAL CHAPTER (EMEA/CHMP/ICH/381133/2009)

Analytical Procedure

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, the section in Ph.Eur. 2.2.31. Electrophoresis entitled “Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS-PAGE)”, JP General Information 23. SDS-Polyacrylamide Gel Electrophoresis, and USP <1056> Biotechnology-derived Articles – Polyacrylamide Gel Electrophoresis, can be used as interchangeable in the ICH regions.

Acceptance Criteria

The texts evaluated did not contain acceptance criteria

EMEA Publishes ICH input Q4B Sterility Test

The EMEA Publishes ANNEX 6 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON STERILITY TEST GENERAL CHAPTER (EMEA/CHMP/ICH/645592/2008)

Analytical Procedure

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph. Eur. 2.6.1. Sterility, JP 4.06 Sterility Test, and USP <71> Sterility Tests, can be used as interchangeable in the ICH regions subject to the conditions detailed below. Testing conditions for medical devices, such as sutures, are outside the scope of the ICH recommendation.

Diluting and rinsing fluids should not have antibacterial or antifungal properties if they are to be considered suitable for dissolving, diluting, or rinsing an article under test for sterility.
When testing liquid parenteral preparations with a nominal volume of 100 milliliters in batches of more than 500 containers, the test is considered interchangeable if the minimum number of containers selected is either 20 or is 2 percent of the total number of containers, whichever is lower.

Acceptance Criteria

The acceptance criteria are harmonized between the three pharmacopoeias.

EMEA Publishes ICH input on Q4B Disintigraion Test

The EMEA Publishes ANNEX 5 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON DISINTEGRATION TEST GENERAL CHAPTER (EMEA/CHMP/ICH/308895/2008)

Analytical Procedure

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that for tablets and capsules, the official pharmacopoeial texts, Ph. Eur. 2.9.1. Disintegration of Tablets and Capsules, JP 6.09 Disintegration Test, and USP <701> Disintegration, can be used as interchangeable in the ICH regions subject to the conditions detailed below. Testing conditions for specific dosage forms are outside the scope of the harmonization of this chapter.

For tablets and capsules larger than 18 millimeters (mm) long for which a different apparatus is used, the Disintegration Test is not considered to be interchangeable in the three regions.
The Disintegration Test is not considered to be interchangeable in the three regions for dosage forms referred to in the regional compendia as delayed-release, gastro-resistant, or enteric-coated.
Product-specific parameters such as media and the use of discs should be specified in the application dossier.

Acceptance Criteria

Acceptance criteria are outside the scope of the harmonization of this chapter and should be specified in the application dossier.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

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Tagged Disintigration Test, EMEA, ICH Q4B, polyacrylamide Gel Electrophoresis, Q4B, Sterility Test, Tablet Friability

Rapid Drug Discovery and Development Facilitated by ICH

Posted on July 8, 2009 by admin| Leave a comment

ICH Meeting June 6th to 11th

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, steering committee and expert working groups met in Yokohama in June (6th to 11th) and a number of highlights are outlined below. What the ICH agree will shape the regulations to come.

Non-Clinical Safety

A significant milestone was achieved in Yokohama with the finalization of the revision of the M3 Guideline “Non-clinical Safety Studies for the Conduct of Human Clinical Trials and for Marketing Authorizations”. The new M3 Guideline promotes more rapid discovery and development of innovative medicines, by reducing the reliance on animals required in drug development studies. These efforts continue ICH’s commitment to the 3Rs (Reduction, Refinement and Replacement) of animal testing.

Clinical Safety and Efficacy

The ICH Guideline E16 “Genomic Biomarkers Related to Drug Response: Context, Structure and Format of Qualification Submissions” reached Step 2. The guideline provides recommendations on the context, structure and format of regulatory submissions for genomic biomarker qualification in order to facilitate submission and review of biomarker qualification data among regions. Public comments on the ICH Guideline E2F “Developmental Safety Update Reports” have been taken into account and made good progress toward Step 4. The guideline will harmonize the requirements for annual clinical trial reporting to the regulators in the three regions and will provide an additional level of protection for patients in clinical trials.

Quality of Pharmaceuticals

Progress was made on the harmonization of pharmacopoeia texts in the three regions, which will reduce testing requirements for the industry. Two annexes to the Q4B Guideline (Annex 5 on “Disintegration Test” and Annex 8 on “Sterility Test”) reached Step 4 and another two (Annex 9 on “Tablet Friability” and Annex 10 on “PAGE”) reached Step 2. The Quality Implementation Working Group delivered a set of Q&As to answer questions arising from the Q8, Q9, and Q10 Guidelines. Also of note, was a meeting of the Q11 Expert Working Group “Development and Manufacture of Drug Substances,” covering both chemical and biological substances with wider participation from some non-ICH countries. Work on the topic continued to progress.

The next ICH meeting will be held in St. Louis, MO, USA from October 24-29, 2009.

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If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

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Posted in clinical, formulation, manufacturing, pre-clinical, regulatory

Tagged ICH, ICH E16, ICH E2F, ICH M3, ICH Q4B, International Committee on Harmonisation

Non GMP stock allowable for Human Radiolabled PK studies

Posted on June 25, 2009 by admin| Leave a comment

I have just received an interesting letter from Charles Rivers Edinburgh and there are a few interesting points I wanted to share with you.

“Since 2004, there has been a clear requirement to manufacture the IP (drug product) to Good Manufacturing Practice (GMP), however the quality standard required for the radiolabeled Active Pharmaceutical Ingredient (API) was open to interpretation. Following the implementation of GMP Annex 20 on Quality Risk Management in March 2008, and with the amendment to GMP Part II (Basic Requirements for APIs used as Starting Materials) in draft, a risk management approach to the assessment of the quality of the API has been adopted”

So if you wish to use radiolabeled products for human PK it does not necessary need to be GMP stock, this is a great and important point and can be truly valuable to companies planning risk management microdosing studies, but it does need to be assessed for potential risks. its an important point that needs considering.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

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Tagged GMP stock, human PK studies, radiolabled studies, Regulations

EMEA issue draft guidance on plasma-derived medicinal products

Posted on June 2, 2009 by admin| Leave a comment

EMEA has issued guidance on plasma derived medicinal products. This guidance lays down the requirements of the collection of starting material, the manufacturing and the quality control of plasma derived medicinal products. Specific attention will be given to the viral safety of these products.

This is the fourth edition of the guidelines to be published, and include an update on the legal framework as well is an update on specific guidance.

Human plasma contains many proteins, extraction and purification of which are of great medicinal importance. Improvements in protein purification and molecular separation technology has made available a wide variety of products, with medicinal applications covering a large field, the therapeutic value of these products is unquestioned. However, the potential for viral transmission is well recognised, and because of the large number of donations which are pooled, a single contaminated batch of plasma drug product, with the contamination possibly originating from a single source donation, and transmit viral disease to a large number of recipients.

The prevention of such contamination is the main focus of these guidelines. They cover the whole process from the collection and testing of the starting material through quality-control manufacturing and preparation processes, a great deal of emphasis is put upon donor selection, traceability and post collection measures including look-back procedures. Process validation during manufacturing is also covered in the guidance, as well as quality control. These products have specific requirements for stability which are also covered.

This guidance is essential reading than anybody developing plasma derived therapeutic products.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

As you know this website is a great resourse for keeping up to date with developments and regulations, why not get our FREE monthly regulatory and market round up. You can un-subscribe at any time and we do not share your details with anybody.

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Posted in formulation, regulatory

Tagged development, drug products, EMEA, guidance, plasma-derived medicinal products, regulatory guidance

FDA guidance – Submission of Bioequivalence data for ANDA’s

Posted on May 18, 2009 by admin| 3 Comments

The FDA published this guidance back in April but we have just now had the time to review it.

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) in complying with FDA’s new requirements for the submission of bioequivalence (BE) data.

FDA’s final rule on “Requirements for Submission of Bioequivalence Data” (the BE data rule) requires ANDA applicants to submit data from all BE studies the applicant conducts on a drug product formulation submitted for approval, including studies that do not demonstrate that the generic product meets the current bioequivalence criteria.

This guidance provides information on the following subjects:

The types of ANDA submissions covered by the BE data rule
A recommended format for summary reports of BE studies
The types of formulations FDA considers to be the same drug product formulation for
Different dosage forms based on differences in composition.

The important points of this guidance is that all studies must be submitted for ANDA applications and a format for those submissions is advised:

“For a suggested format for summary reports, please refer to the Office of Generic Drugs (OGD) Web page.6 The Division of Bioequivalence has developed model data summary tables in a concise format consistent with the ICH Common Technical Document (CTD). The tables, under the heading “Model Bioequivalence Data Summary Tables,” are available in Word and PDF formats. The FDA recommends that these table formats be used to organize the data for summary reports required by the BE data rule”

Drug Formulation

FDA amended the regulations to require an applicant to submit data from all BE studies conducted on the same formulation of the drug product submitted for approval.

“Same drug product formulation means the formulation of the drug product submitted for approval and any formulations that have minor differences in composition or method of manufacture from the formulation submitted for approval, but are similar enough to be relevant to the FDA’s determination of bioequivalence”

The guidance goes into greater detail on this point, this forms the bulk of the guidelines.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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Posted in clinical, formulation, regulatory

Tagged bioequivalence, FDA, Guidlines, Regulations

Eden Biodesign – Accelerating Novel Vaccine Development

Posted on December 8, 2008 by admin| Leave a comment

I have just spent a good 30mins listening to a webinar from Eden Biodesign. The topic of discussion was the challenges facing those developing Novel Vaccines and what Eden are doing to help overcome them.

Challenges

Lots of vaccines are becoming “small molecule like”
There is no platform technology for novel vaccine production everything is bespoke
There is limited support available (regulatory and production expertise)

Dynamic Market

mAb is a large market – in vaccines its now bigger than small mollecules
Its a growing market
Deep product pipeline

Novel Vaccines

New Producs constantley emerging
Pandemic infection preparation
Growing markets in developing world
Bioterrorism preparation
Offer good economics
Growth of therapeutic vaccines
Still lots of interest from Big Pharma

Manufacturing changes

Traditional techniques are still important
Mammalian cell lines
Microbial fermentation
Chromatographic purification techniques

All associated with analytical challanges

Monoclonals are becoming “small molecule like”

Mainstream technology
Platform manufacturing is now becoming a reality
Greater availability of expertise
Commercial scale ready systems available
Easily outsources production
Regulations have matured, comparability guidelines and FDA, CDER control rather than CBER control

Challenges for novel vaccine process development

Speed, robustness and transferability
Cost of goods pressure
Production expertise is limited
Hard to characterise
Challenging to validate and reproduce processes
No pre-determined acceptance criteria
No dominant production platform
Constraints on process change
Processes can be difficult to scale up and transfer
Limited expert skills and knowledge available

In order to overcome these issues people are investing in dedicated facilities early on which significantly raises the financial risks associate with a programme.

How are Eden meeting these challenges

Innovative facility design
New analytical tools
More platform like technologies
knowledge management focused on product quality
Contained facilities
Disposable technologies
Skid mounted unit operations (facilities that can be flexible to requirements)
Wide range of expertise and experience in house

Important regulatory changes – FDA published a CFR that Live Vaccines can be be produced in multi product facilities.

This webinar series is ongoing so I suggest you have a look (link)

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology), we work with our clients to define a development target, define a development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch using the contact form or email Damien at damien.bove@idaconsultants.com

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Posted in formulation, manufacturing, regulatory, vaccine

Tagged biologics, Eden Biodesign, FDA, manufacturing

Fast Solubilisation for Proof of Concept and Safety Animal Work

Posted on November 25, 2008 by admin| Leave a comment

Poor solubility is an increasingley common problem in Drug Development and Discovery, it impacts on a technology in two main ways. A soluble formulation is required early on for early animal proof of concept studies which adds to the project risk if large amounts of money are going to be spent before you know if you have a good product opportunity. Secondly it will add to your cost of materials once your product is finally developed.

The first of these risks however can be manged, one of Damien’s clients, Agenda1, has developed a service that can help. SOLENT (SOLubility ENhancement Technology), the foundation is a proprietary pre-formulation matrix, comprising a wide variety of combinations of liquid-based GRAS (generally regarded as safe) formulation excipients approved for preclinical and clinical use (including pH adjustment, co-solvents, mico-emulations, SEDDS, oils, lipids and cyclodextrins).

The technology enables products to be “screened” in various potential formulations to quickly ascertain potential formulations, its quick and cheep enough to get your product into animals and man for Proof of concept and early safety studies. Then with a positive result you can confidently invest in a full formulation programme.

Link to Agenda1 website

For more information on this vital new service contact: Ian Siragher at Agenda1 on 01274 326073

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Posted in formulation

Tagged Agenda1, drug solubility, formulation, SOLENT

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EMA Publishes Guidance on Stability Testing

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EMA Publish Draft Reflection Paper on IV Micellar Systems

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Drug Regulators, FDA, Publish Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions; Annex 6: Uniformity of Dosage Unites General Chapter

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Drug Regulator, EMEA, publishes input into ICH Q4B Tablet Friability

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EMEA publishes input into ICH Q4B Polyacrylamide Gel Electrophoresis

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EMEA Publishes ICH input Q4B Sterility Test

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EMEA Publishes ICH input on Q4B Disintigraion Test

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