Pharma Knowhow

There is no Active Substance Master File for Biological Active Substances (ASMF) in the EU - Why not?


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Drug master files (DMF, US) or the European equivalents Active Substance Master Files (ASMF) are very common in regulatory submissions. Both the Food and Drug Administration (FDA) in the USA and the competent regulatory authorities in the European Union (EU) accept DMFs/ASMFs. The objective of an ASMF is to allow valuable confidential intellectual property or ‘know-how’ of the manufacturer of the active substance to be protected, while at the same time allowing the Applicant or license/marketing authorisation holder (MAH) to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities (FDA/European Medicines Agency [EMA]/national EU authorities) thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.


In the US, DMFs could contain information of the kind required for any submission to the agency, including information about the following (21CFR314.420)

  • Drug substance, drug substance intermediate, and materials used in their preparation, or drug product;
  • Packaging materials;
  • Excipient, colorant, flavor, essence, or materials used in their preparation;
  • FDA-accepted reference information (supporting data in a drug master file (DMF) that is not covered by Types II through IV DMF’s)

In the US, DMFs are accepted in support of applications and supplements, such as investigational new drug applications (IND), biologics license applications (BLA) and new drug applications (NDA).


Although biologicals are not explicitly excluded it is recommended only referring to master files in certain circumstances, e.g. noncompendial test procedures or with regard to containers and closures (Guidance for Industry – Cooperative Manufacturing Arrangements for Licensed Biologics FDA 2008).


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In the EU, Directive 2003/63/EC Annex I part I refers to well defined active substance for which ASMF can be submitted including information on

  • detailed description of the manufacturing process,
  • quality control during manufacture, and
  • process validation

The EU “Guideline On Active Substance Master File Procedure (CHMP/QWP/227/02) specifies that the ASMF concept is not applicable to biological active substances. The guideline points out that the characterisation and determination of biological active substances’ quality requires not only a combination of physico-chemical and biological testing, but also extensive knowledge of the production process and its control. Furthermore, the MAH/applicant of a biological medicinal product could therefore not comply with the requirement to “take responsibility for the medicinal product” without having full and transparent access to these quality-related data. The use of an ASMF would prevent such access, and should therefore not be allowed for biological active substances.


In the life science industry outsourcing is an important topic. There are numerous contract manufacturers for small molecules as well as biotechnology derived products. Especially, small to medium size innovative companies rely on contract manufacturer for establishing the manufacturing processes for their biotech product as well as for the commercial production.  Generic drug companies often do not development their biosimilars but acquire licenses from manufacturers of the active substances. For example filgrastim of the biosimilar products Ratiograstim (ratiopharm), Biograstim (CT Arzneimittel GmbH), Tevagrastim (MAH Teva) is manufactured by SICOR Biotech UAB, Vilnius or Erythropoietin alpha of the biosimilars Abseamed (Medice Arzneimittel Pütter GmbH & Co. KG), Binocrit (Sandoz), Epoetin Alfa Hexal (Hexal) is manufactured by Rentschler GmbH.


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In none of these cases a DMF/ASMF for the active substance would have been acceptable in the EU. As demanded by the EU Agencies, all these MAHs need to have full access to all relevant quality data. The question is how this is reached in real life. The companies have to set up contracts which specify the exchange of information from early on – beginning with the first-in-man studies – the companies have to make sure that they are in control of the manufacturing process. It is not enough that the manufacturers provide the companies with the summary information for the IMPD or MAA. This is indeed a challenge particularly for start-up companies often not so experienced in the regulatory requirements and it is advisable for these companies to seek support when selecting contract manufacturers and negotiating contracts.


The ICH guideline Q10 Pharmaceutical Quality System which is important to both, products containing small molecules and biological, includes a dedicated chapter on the management of outsourced activities and purchased material. In addition, the FDA provides companies with guidance on how contracts with contract manufacturers of biologicals should be written; see Guidance for Industry – Cooperative Manufacturing Arrangements for Licensed Biologics FDA 2008.


The Applicant or MAH needs to ensure that the CMO is able to provide the requested services and complies with applicable product and establishment standards what will have to be defined in contracts so that the applicant or MAH will be enabled to fulfill their responsibilities.


However, does the MAH really receive the full access to and responsibility on the manufacturing process by all these contracts and agreements? Is not the CMO still in control of the manufacturing process?


The question is: Is this situation so much different from an ASMF?


In principle, there could also be an ASMF for biologicals which would have to be accompanied by adequate contractual arrangements related to the communication and information exchange between the CMO and the MAH. This means that the CMO would have to commit itself to the responsibility to produce the active substance in compliance with the approved manufacturing process, in accordance to GMP as well as other regulatory standards; the CMO would have to ensure batch to batch consistency and to confirm not to change the manufacturing process. Necessary changes would have to be discussed between the CMO and the MAH and would have to be dealt with in accordance to current EU regulations. The CMO could communicate and submit all necessary data, information, documentation to the competent EU Authorities keeping the MAH informed as required. Thus introducing the ASMF for biologicals would be a simplification and an adaption to the current trends in outsourcing of the manufacturing of biologics.


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