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IMPORTING INTO THE EU PHARMACEUTICALS AND COSMETICS MANUFACTURED IN THIRD COUNTRIES

According to current EU regulations, pharmaceuticals and cosmetics, manufactured in third countries and imported into the EU, have to be certified for its quality and compliance with Good Manufacturing Practices by an authorized importer with a qualified team. You will find a review of the current regulations in the following sections.

If you have interest in importing such products Inkemia may help you in all or part of the process.

EUROPEAN PROVISIONS FOR IMPORTING PHARMACEUTICALS FROM THIRD COUNTRIES

European requirements, described in annex 16 to the  European Union (EU) guide to Good Manufacturing Practices of medicinal products (GMP),  indicate that in order to introduce a pharmaceutical product in the EU a pharmaceutical laboratory physically located therein has to perform the quality control of each batch of product (unless there is an agreement of mutual recognition), its QP (qualified person) has to certify the batch and finally issue the certificate of release. The laboratory responsible for carrying out these activities is called "importer” and has to be specifically authorized as such.

Obligations related to batch certification are listed in Annex 16 and include:

• Compliance of the batch  with the specifications defined in the marketing authorization.
• The manufacturing conditions are in accordance with the provisions of the marketing authorization.
• The storage and distribution conditions are appropriate.
• Assurance as to knowledge and control of the supply chain of the starting materials.
• Ensure that the manufacture has been performed according to European GMP or equivalent practices.
• Validation of the manufacturing processes and the analytical methods.
• Ensure that the established and scheduled audits are carried out.
• Review of the deviations and changes in the manufacturing process and quality control.
• Review of the batch documentation in terms of content and integrity.

However, the publication of a new annex to the rules of GMP dedicated to import of drugs (Annex 21) is expected this year. In this text the most relevant requirements, from the point of view of GMP, for importers and the different entities involved in import activities will be highlighted.

INKEMIA AT YOUR SERVICE IMPORTING PHARMACEUTICAL PRODUCTS TO THE EUROPEAN UNION

As a consequence, IUCT widens its range of services by adding quality control, batch certification and release in Europe of pharmaceutical products manufactured in third countries.

Additionally, in an effort to provide a global service, IUCT also offers support in other activities related to the import and marketing of pharmaceutical products in the European Union. Within the range of services IUCT offers you can find: preparation and submission of dossiers in the European countries of your interest, support in getting GMP certification of the manufacturer's facilities, transport & customs and pharmacovigilance services, audit services, among others.

IMPORTING COSMETICS FROM COUNTRIES OUTSIDE OF THE EU

Cosmetics within European countries are regulated by Regulation (EC) No 1223/2009 since 11th July 2013,  meaning that  its provisions  will  be  of  application  in  all  Member  States,  without  being  subject  to potential  alterations  when translated into national legislations. Summarizing, the main requirements that a cosmetic product has to comply with are:

• Products have to fit into the cosmetic product definition (art. 2).
• A responsible Person (RP) in the EU has to be designated (art. 4).
• Manufacturing activities have to be done in compliance with good manufacturing practice (art. 8).
• Obligation for a manufacturer to prepare product information file with a safety assessment (art. 11).
• All products to be marketed in the EU must be notified to the Cosmetic Products Notification Portal (CPNP) before being placed on the market (art. 13).
• Its composition must take into account the established restrictions for certain substances (Chapter IV).
• Labeling must comply with the provisions of Article 19. Furthermore, in accordance with the provisions of the Spanish legislation, the following information must be included in Spanish: the nominal content at packaging date, date of minimum durability, any special precautions to be observed in use and the function of the product (unless it is clear from the presentation).
• Registration of the importing company. The registration process is regulated by each EU country and may differ among them.

In Spain, the cosmetics import activities are subject to a notification procedure based on a responsible declaration, governed by Article 71a of Law 30/1992 of 26 November. This responsible statement must be submitted to the Spanish Agency for Medicines and Health Products (AEMPS). That submission will allow the start of activities, without prejudice to subsequent verification by the AEMPS, through documentary verification and, where appropriate, inspection of the elements and circumstances revealed in the declaration of responsibility.

In short, the obligations for a importer of cosmetics products detailed in the responsible statement are:

1. Assign to an appropriately qualified technician the responsibility for supervising import activities and compliance with the European requirements of imported products.
2. Have an updated quality system designed to ensure that imported products have been manufactured in accordance with Good Manufacturing Practice (GMP) and the applicable principles of GMP are observed in imported products.
3. Have an organizational structure capable of ensuring the implementation of suitable procedures and controls to document all aspects required in the product information file.
4. Have suitable facilities, equipment and qualified personnel to perform import activities, labeling (if any), storage and control.
5. Maintain written Standard Operation Procedures (SOPs) for labeling, where appropriate, storage and control activities, for keeping traceability, for archiving documents, specifications, transcripts and records required by regulation and for monitoring products on the market.
6. In case of outsourced activities, the parties have to sign technical agreements in which the activities and responsibilities are described and assigned. In addition the importer has to verify through regular audits the capacity and compliance of the outsourcer.

INKEMIA AT YOUR SERVICE TO HELP YOU IMPORTING COSMETICS TO THE EUROPEAN UNION

Inkemia can help you when importing cosmetics manufactured in third countries into the EU in different ways, such as:

• Prepare the Product Information File and the safety assessment.
• Notify to the Cosmetic Products Notification Portal (CPNP).
• Review labeling.
• Inkemia can act as an importer and submit the responsible statement to the AGEMED.
• Members of our qualified team can act as responsible person.
• Inkemia can be your quality control laboratory for cosmetics. Our facilities were audited and are approved for that activity by the AGEMED.

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Nowadays, Nuclear Magnetic Resonance Spectroscopy (NMR) has become a very relevant analytical technique with a wide number of applications in many disciplines of scientific research and medicine plus in various industries (pharmaceuticals, food, agrochemicals, etc). The developments in both methodology and instrumentation in the past two decades, has made of NMR one of the most sophisticated, powerful and versatile techniques for the qualitative and quantitative analysis of complex mixtures and natural products.

Inkemia has been working on this field over the last ten years. The company currently has a qualified equipment working within a Good Manufacturing Practice (GMP) environment and it is able to give various solutions to industries of the lifescience sector.  

In this newsletter you will find a brief overwiew on the advantages of NMR and its various applications.

INTRODUCTION

Nuclear magnetic resonance (NMR) spectroscopy is based on  the use of absorption and re-emission of electromagnetic radiation occuring when the nuclei of certain atoms are immersed in a static magnetic field and then exposed to a second oscillating magnetic field.
 
Since NMR is sensitive to compounds bearing 1H or 13C, 19F, 15N, 31P, it can be regarded as a quasi-universal detector of organic compounds.
 
No other analytical technique provides such qualitative and quantitative information in a single analysis, without using external standards or isolation of the different components contained in the sample.
 
NMR is a robust analytical technique of non-destructive nature which provides solutions to industries allowing easy and simple sample preparation and method development.
 
The main applications of NMR analysis are:

• Structural elucidation of organic molecules.
• Deformulation of products in order to identify individual components of a formulated product.
• Identification of impurities and unknown compounds in complex samples.
• Quantification of mixture components.
• Quality control of bulk chemicals, pharmaceutical products, natural products, food and nutraceuticals.
• Raw materials fingerprinting.
• Kinetic and temperature studies of reaction mixtures.
• Determination of enantiomeric.

Among those applications listed above, quantitative analysis using NMR and its use in pharmaceuticals, food and agrochemicals  are reviewed in the following sections.

QUANTITATIVE NMR APPLICATIONS

Quantitative NMR spectroscopy (qNMR) is one of the most informative methods for the identification, authentication, and detailed analysis of the structures of any organic compound and their mixtures. It is described in the European Pharmacopoeia as one of the suitable analytical techniques to be used for qualitative and quantitative purposes. The main advantages of the NMR are:

1. Integrated NMR intensities of the signals are directly proportional to the number of atoms of the molecular group responsible for that signal.
2. Therefore, complicated samples can be analyzed without using external standards and references, which is unavoidable in chromatographic, mass spectrometric, photometric, and other analytical methods used.
3. Requirement of determining response factors can be avoided since protons are detected with the same sensitivity, regardless of the chemical environment.
4. Besides, there is also a linear relationship between the integrated intensities of the resonances from separate components in the spectrum and their contents in the studied substances so multiple components can be quantified in a complex samplein one experiment without previous separation.

NMR APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY

NMR spectroscopy has evolved as one of the most powerful analytical techniques for the pharmaceutical industry. European Pharmacopoeia and US Pharmacopoeia (USP) have recognized its value and have developed general chapters describing the equipment, techniques, as well as the quantitative and qualitative methodology to be used. Both Pharmacopeias also have official monographs with tests based on NMR techniques, particularly for more complex natural and biological substances. In general NMR is used for identification and assay of active substances or for related substances and other impurity tests. Among the main applications of NMR analysis  are:

• Quantitative NMR spectroscopy (qNMR):  Due to equal response for any dissolved compound, NMR spectroscopy is an excellent technique for quantification of any substance.
  • Some examples of qNMR include determination of the purity of Active Pharmaceutical Ingredients (APIs) as well as quantification of active ingredients, excipients and impurities in pharmaceutical products. Residual solvents, isomers, diastereomers and enantiomeric excess can also be determined.
  • Quantitative NMR techniques can be advantageously used as an alternative to conventional high-performance liquid chromatography (HPLC) when  impurity standards are not available,  as in early stages of drug development.
• Impurity profile studies: NMR spectroscopy has evolved into an irreplaceable approach for pharmaceutical quality assessment, currently playing a critical role in unequivocal structure identification as well as structural confirmation.
  • NMR analysis can provide detailed information about molecular structures and helps to confirm and establish the identity of pharmaceutical substances and impurities.
  • The capability of the NMR analysis to perform concurrent identification and quantification of impurities turns qHNMR into an unique analytical tool for the pharmaceutical industry.
• Drug discovery research: NMR is being used widely in the area of drug design. Such studies usually aim to obtatin:
  • The structure of the drug molecule, its receptor bound conformation as well as its dynamics at the receptor site.
  • The structure of the receptor and its complex with the drug, which provides the information on the binding site and functional group interaction participating in the ligand recognition and its binding.

NMR APPLICATIONS IN FOOD AND AGRICULTURE

During the last two decades, the use of NMR spectroscopy for the characterization and analysis of food and agrochemical materials has flourished, and this trend continues to increase today.

Some examples are described below.

• Wine analysis for detection of variety, geographical origin and adulterations, which allows the creation of a fingerprint database of the different wines.
• Analysis of olive oil, multinuclear (1H, 13C, 31P) NMR spectroscopy is a valuable tool for the determination of several bioactive compounds, its evaluation and authentication purposes.
• Honey analysis for the detection of exogenous sugars.
• Coffee analysis: Colombian coffees authentification using 1H-NMR fingerprints.

INKEMIA EXPERTISE IN NMR ANALYSIS

InKemia has a large expertise and know-how in the application of NMR techniques to support chemical and pharmaceutical industry in both, qualitative and quantitative analysis.

Inkemia offers high resolution NMR analysis, which includes a qualified 400 MHz spectrometer working in a Good Manufacturing Practice (GMP) environment. That means all data generated can be used to support regulatory submissions and also can support pharmaceutical development from early stage through to post-approval.

The main services offered are:

1. Qualitative NMR analysis for structural elucidation purposes:
   • Identification of unknown substances.
   • Determination of reaction intermediates.
   • Identification of impurity profile and unknowns in APIs or formulated products.
2. Development of routine qualitative and quantitative analysis for screening of a large number of related samples.
3. The development of qualitative and quantitative NMR validated methods, ensuring the right approaches are applied to the client specific requirements.
4. Chiral purity determination.