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Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7

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Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7

The APIC has thoroughly revised the “How to do” document that explains the guideline ICH Q7. Here you can see how the new document interprets the requirements concerning a GMP compliant manufacture of active pharmaceutical ingredients against the background of the current developments.

 

Shortly after the entry into force of the Good Manufacturing Guide for Active Pharmaceutical Ingredients ICH Q7 in the year 2000 the Active Pharmaceutical Ingredients Committee APIC wrote the “How to do” document which clarifies the requirements of the guideline on the basis of experience gained from operational practice. The present document aims at providing practical advice for the implementation and maintenance of GMP standards during the production of active pharmaceutical ingredients concerning those provisions of ICH Q7 that require further interpretation. The “How to do” document is a “living” document as it is revised in irregular intervals in order to keep pace with the constantly changing state of scientific and technical knowledge.

The recently revised version of the document was published as “Version 8” on the APIC publications website in August 2015. As compared to the last revision (August 2012) the chapters 10 “Storage and Distribution”, 11 “Laboratory Controls”, 12 “Validation” and 15 “Complaints and Recalls” were revised. The following is a selection of the most important changes:

Chapter 10 Storage and Distribution

  • This chapter points out the importance of controlling the temperature distribution in warehouses taking into account seasonal temperature changes. The document indicates sets of rules that describe concretely how to perform a temperature mapping (section 10.10.).
  • It stresses the necessity of physical separation between released and returned material, preferably by storing them in different rooms. Storage conditions for intermediates are based on development data and knowledge (section 10.11).
  • The document points out that logistics companies should be qualified (quality agreement). The shipping conditions records should be reviewed. If deviations occurred an investigation should be initiated and appropriate measures be carried out and documented (section 10.21).

Chapter 11 Laboratory Controls

  • This chapter expressly points out that analytical methods have to be validated and that the integrity of analytical data has to be ensured by means of controls (section 11.11).
  • Rounding rules and the process used for averaging should be described in a SOP (section 11.11.).
  • In chapter 11.13 ICH M7 and ICH Q3D have been added to the list of ICH guidelines. Furthermore, it is pointed out that the design of experiments approach can also be used within the framework of design space when defining specifications.
  • Chapter 11.15 contains detailed guidance on the FDA requirements for active pharmaceutical ingredients that are exported to the USA and sold there, especially on the handling of OOS results.

Chapter 12 Validation

  • Chapter 12.11 explains more in detail the handling of critical parameters and quality attributes referring to the actual ICH guidelines ICH Q8 and Q11 as well as to FDA and EMA guidelines.
  • It indicates that the 3 consecutive validation batches should be considered as an orientation. The actual number of validation batches has to be pre-defined and to be justified (section 12.50).
  • The process validation report has to contain all critical quality attributes compared to the reference batches. These attributes should be comparable to or better than the reference batches. The rationale for selecting the reference batches must be justified (section 12.52).

Chapter 15 Complaints and Recalls

  • This chapter refers to the necessity to include other batches potentially connected with the batch affected by the complaint or recall in the complaint investigation and to define a period to close complaint investigations (section 15.10).
  • It points out that a recall cannot be carried out by the API manufacturer himself. This is the responsibility of the finished dosage form manufacturer. The notification of the authorities (such as public health departments) can also only be carried out in close cooperation with the finished dosage form manufacturer (section 15.10).

As a whole the revised “How to do” document is a valuable aid for the implementation of the Good Manufacturing Practice in the production of active pharmaceutical ingredients. Due to the thorough revision of many sections it offers an up-to-date practice-oriented assistance every API manufacturing site can profit from

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Herbal Medicinal Products

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Herb leaf selection © Marilyn Barbone - Fotolia.com

EU legislation on pharmaceutical products for human use also applies in general to traditional herbal medicines. However, in order to overcome difficulties encountered by Member States in applying pharmaceutical legislation to traditional herbal medicinal products in a uniform manner, a simplified registration procedure was introduced in 2004.

 

General Information

The simplified procedure was introduced by Directive 2004/24/ECpdf of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/ECpdf on the Community code relating to medicinal products for human use.

A brief description of the procedure is available under point 3.4 of the Notice to Applicants Volume 2A – Procedures for marketing authorisation, Chapter 1 – Marketing Authorisation.

The simplified registration procedure aims to safeguard public health, remove the differences and uncertainties about the status of traditional herbal medicinal products that existed in the past in the Member States and facilitate the free movement of such products by introducing harmonised rules in this area.

Herbal medicinal products are defined as any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.

This simplified registration procedure is intended for herbal medicinal products with a long tradition, which do not fulfil the requirements for a marketing authorisation, in particular those requirements whereby an applicant can demonstrate by detailed references to published scientific literature that the constituent or the constituents of the medicinal products has or have a well-established medicinal use with recognised efficacy and level of safety (so-called “well established use”).

The simplified procedure allows the registration of herbal medicinal products without requiring particulars and documents on tests and trials on safety and efficacy, provided that there is sufficient evidence of the medicinal use of the product throughout a period of at least 30 years, including at least 15 years in the Community.

With regard to the manufacturing of these products and their quality, applications for registration of traditional herbal medicinal products have to fulfil the same requirements as applications for a marketing authorisation.

In view of the particularities of herbal medicinal products, a Committee for Herbal Medicinal Products (HMPC) has been established at the European Medicines Agency. A major task for the HMPC is to establish Community monographs for traditional herbal medicinal products, and, with the objective of further facilitating registration and harmonisation in the field of traditional herbal medicinal products, prepare a draft list of herbal substances which have been in medicinal use for a sufficiently long time, and hence are considered not to be harmful under normal conditions of use.

List of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products

With a view to further facilitating the registration of certain traditional herbal medicinal products in the EU, a list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products has been established on the basis of the scientific opinion of the HMPC. As regards the safety and efficacy of a traditional herbal medicinal product, applicants can refer to the list. However they would still need to demonstrate the quality of the medicinal products they seek to register.

The list was established by Commission Decision 2008/911/EC of 21 November 2008pdf .

The decision has been amended to include:

  • ‘Calendula officinalis (L.)’ and ‘Pimpinella anisum (L.)’
  • ‘Eleutherococcus senticosus (Rupr. et Maxim.) Maxim’ and ‘Echinacea purpurea (L.) Moench’
  • ‘Mentha x piperita L.’
  • Hamamelis virginiana L.’
  • ‘Thymus vulgaris L’ and ‘Thymus zygis Loefl. ex L’
  • ‘Vitis vinifera L’.

All documents in all available languages >>

Commission implementing decision of 3 February 2012 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products.

  • Commission implementing decision of 3 February 2012 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products was published in the Official Journal on 7 February 2012. This decision includes ‘Vitis vinifera L’. in the list of herbal substances.
    The text of the decision is available herepdf.

Commission implementing decision of 3 February 2012 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products.

  • Commission implementing decision of 3 February 2012 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products was published in the Official Journal on 7 February 2012. This decision includes ‘Thymus vulgaris L’ and ‘Thymus zygis Loefl. ex L’ in the list of herbal substances.
    The text of the decision is available herepdf.

Commission implementing decision of 28 November 2011 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products.

  • Commission implementing decission of 28 November 2011 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products was published in the Official Journal on 2 December 2011. This decision includes ‘Hamamelis virginianaL.’ in the list of herbal substances.
    The text of the decision is available herepdf.

Commission decision of 25 March 2010 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products.

  • Commission Decision of 25 March 2010 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products was published in the Official Journal on 26 March 2010. This decision includes ‘Mentha x piperita L.’ in the list of herbal substances.
    The text of the decision is available herepdf.

Commission decision of 9 December 2009 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products.

  • Commission Decision of 9 December 2009 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products was published in the Official Journal on 19 January 2010. This decision includes ‘Eleutherococcus senticosus (Rupr. et Maxim.) Maxim’ and ‘Echinacea purpurea (L.) Moench’ in the list of herbal substances.
    The text of the decision is available herepdf

Commission decision of 28 July 2009 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products.

  • Commission Decision of 28 July 2009 amending the list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products was published in the Official Journal on 16 January 2010. This decision includes ‘Calendula officinalis (L.)’ and ‘Pimpinella anisum (L.)’ in the list of herbal substances.
    The text of the decision is available here.pdf

HMPC Q&A Documents on Herbal Medicinal Products published

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HMPC Q&A Documents on Herbal Medicinal Products published
Current questions and answers about the framework for herbal medicinal products and traditional herbal medicinal products are addressed in a new EMA/HMPC document. The document also addresses herbal medicinal products which don’t have a European tradition. Read more in this News.

http://www.gmp-compliance.org/enews_4341_HMPC%20Q%26A%20Documents%20on%20Herbal%20Medicinal%20Products%20published_8483,8430,8368,Z-QCM_n.html

 

HMPC Q&A Documents on Herbal Medicinal Products published

On 12 May 2014, the EMA’s HMPC (Committee on Herbal Medicinal Products) published the Questions & Answers document on (traditional) herbal medicinal products. The document also addresses herbal medicinal products which don’t have a European tradition.

The Q&A document contains Questions & Answers about the following topics:

  • Regulation of herbal medicinal products in the EU ( (Q&A 1 – 7)
  • Specific provisions for traditional herbal medicinal products (Q&A 8 – 17)
  • Type and role of monographs in the European framework (Q&A 18 – 21)
  • Advice, procedures and relevant institutions (Q&A 22 – 24)

The table included in the answer to question 24 is particularly interesting. There you can find which authorities are responsible for individual decisions.

For further information please see the complete “Questions & Answers on the EU framework for (traditional) herbal medicinal products, including those from a non-European tradition“.