GMP Compliance Adviser Update No. 5/2021

With this GMP Compliance Adviser UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

GMP in Practice

Chapter 9

Computer System Validation

9.H Validation of Excel applications


Chapter 20

Active Pharmaceutical Ingredients

20.C Marketing authorisation documentation for active substances

20.F Chemical active substances


GMP Regulations

Chapter C

EU Directives and Guidelines

C.20 Guideline on quality documentation for medicinal products when used with a medical device

Chapter G

GMP of other Regions
Health Canada

G.2.2.1 Annex 7 to the Good manufacturing practices guide for drug products – Selected non-prescription drugs (GUI-0066)

GMP in Practice

Chapter 9 Computer system validation

9.H. Validation of Excel applications

An extremely wide spectrum of applications can be realised in MS-Excel® involving more or less effort. If macros are used, the possibilities are almost infinite.
It is important that these applications function properly and are reliable, especially with regard to data storage, and that they comply with the regulations.
Excel applications remain applications that are not very well-documented or validated. Excel developers are often self-taught developers who are very good at what they do, but they often lack a professional approach.

Excel applications are still widely used in quality control, development and validation and also as ad-hoc applications, e. g. for troubleshooting. The following should be considered:

  • The know-how for creating GxP-compliant Excel applications should be improved.
  • Standardised procedures should be established for the most important types of Excel applications to ensure greater security of the processes and offer rationalisation possibilities.
  • Forms should be developed that make documentation easier.
  • Tools should be developed that make it easier for users to plan the validation, implementation and documentation of the tests and to document the Excel worksheets (templates).

The requirements for Excel applications in the GMP Guidelines have to be implemented based on risk-based evaluations. (Thomas Trantow, PhD; Katrin Neubert, PhD; Jana Neubauer; Helge Jope, PhD)

Chapter 20 Active Pharmaceutical Ingredients

20.C Marketing authorisation documentation for active substances

For the approval of medicinal products, the applicant must also provide information on the quality of the active substances used. A special part of the marketing authorisation dossier is reserved for this purpose, Module 3.2.S. Alternatively, in certain cases, the applicant can also refer to a CEP or choose the ASMF procedure.

A CEP (Certificate of Suitability of Monographs of the European Pharmacopoeia) can be applied for by the active substance manufacturer at the EDQM for already known chemical or herbal active substances that are monographed in the European
Pharmacopoeia. When a drug is approved, the applicant can refer to this CEP instead of providing the required data on the quality of the active substance in the dossier. This procedure is intended to protect the manufacturer's technical expertise and to reduce the applicant's workload. However, there is also a risk that the drug manufacturer will not have access to any information beyond the content of the monograph or additional tests described in the CEP.

An ASMF (Active Substance Master File) is divided into two parts: the Restricted Part contains confidential information that the active substance manufacturer provides directly to the authority. The remaining information is provided by the active substance manufacturer to the drug manufacturer within the form of the Applicant’s Part. The latter must then incorporate the information into the marketing authorisation dossier for its drug. This procedure is applicable to both known and new active substances.

Regardless of which approval procedure is chosen, a comprehensive assessment of possible impurities of the active substance must be submitted to the authority. This covers the following categories of possible impurities:

  • Related substances
  • Genotoxic or mutagenic impurities
  • Residual solvents
  • Residues of metal catalysts, reagents and elemental impurities

ICH has published numerous guidelines for the assessment of impurities.

Another important point in the quality dossier for active substances is the definition and justification of the active substance starting material. This is a raw material, intermediate or active substance that is used for the production of an active substance and is incorporated into the structure of the active substance as an important structural element. All manufacturing steps that follow the starting material must be carried out under GMP. The starting material itself does not have to be produced under GMP, but in an appropriately controlled form. The active substance starting material is determined by the active substance manufacturer and is in most cases beyond the control of the marketing authorization applicant and/or marketing authorization holder. The authorities require that in principle all critical steps of active substance manufacture must be carried out under GMP and that the definition of active substance starting materials should be exclusively risk-based. In addition, a detailed presentation of all synthesis steps under GMP in the active substance dossier is required. There must also be a risk-based summary description and justification of the active substance starting materials defined in each case. A non-negligible area of contention arises from the fact that, from the point of view of the authorities, the applicant for marketing authorisation bears responsibility for the appropriate definition of the active substance starting material, although the applicant generally has no influence on this. (Markus Veit, PhD)

20.F Chemical active substances

Chemical active substances are obtained by chemical reaction of specified active substance starting materials followed by purification steps. These active substances represent the largest group of active substances in terms of both quantity and number.

Due to the chemical reaction(s) during production, they differ fundamentally from biological/biotechnological and plant-based active substances in terms of possible undesirable impurities and GMP risks during production.

The starting point of compliance with GMP regulations must be defined and justified by the active substance manufacturer. Although this is somewhat imprecisely defined in the EU GMP Guidelines Part II, the introduction of an important structural element into the structure of the active substance is now regarded by the majority of parties as the latest starting point for compliance with the GMP regulations, in accordance with the specification of ICH Q11. Consequently, purification of a "crude active substance" as the sole GMP required step is no longer accepted by the authorities.

Special risks in the production of chemical active substances are contamination with organic impurities (starting materials, intermediates, by-products and degradation products), inorganic impurities (elemental impurities) and residual solvents. Adequate treatment of these risks has to be proven by documented risk management and appropriate risk control strategies in the registration documents
as well as by on-site audits.

During audits of active substance manufacturers, GMP deficits are found in various areas. The application of quality management instruments (e.g. deviation and risk management) often remains superficial and thus misses the actual point. Deficiencies are also frequently found in the area of documentation and (electronic) data management. GMP deficiencies can also be found in materials management, production and laboratory controls, as well as in other quality-relevant areas. Overall, the observed deficiencies do not differ fundamentally from deficiencies that are also observed in the production of medicinal products. (Stefan Kettelhoit, PhD; Norbert Waldöfner, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.20 Guideline on quality documentation for medicinal products when used with a medical device

Following a two-years drafting process, the CHMP of the EMA has adopted the final guideline on quality documentation for medicinal products when used with a medical device.

The focus of the 22-page document is on product-specific quality aspects of a medical device and/or part of a medical device that may have an impact on the quality, safety, or efficacy of a medicinal product, whether of chemical, biological or radiopharmaceutical type. It is of interest not only for MAHs, but also for manufacturers of such “combination products”.

The guidance is applicable for:

  • MPs where the medical device and/or device part and the medicinal product form an integral product that is not reusable (integral) and where the action of the medicinal product is principal
  • MPs placed on the market by the MAH, where the medical device is packed together with the medicinal product (co-packaged)
  • MPs where the product information refers to a specific medical device to be used with the medicinal product, and the medical device is obtained separately by the user of the medicinal product (referenced)

Not covered are:

  • Veterinary products
  • In vitro diagnostic devices (including companion diagnostics)
  • System and procedure packs (MDR Article 22)
  • Devices where reference is directly made, or inferred, in the product information
  • Products falling under the first sub-paragraph of MDR Article 1(8).

The guideline adopted on July 22, 2021, will become effective on January 1, 2022.

Chapter G GMP of other Regions – Health Canada

G.2.2.1 Annex 7 to the Good manufacturing practices guide for drug products – Selected non-prescription drugs (GUI-0066)

This document is an annex to the Canadian GMP Guide (GUI-0001) and has thus to be read in conjunction with it. Compared to the previous version, the revised version of the annex 7 applies to an expanded list of drugs and, as such, the title has been changed to refer to “selected non-prescription drugs. The document clarifies those aspects of GMP that are relevant to the fabrication, packaging/ labelling, testing, importation, and distribution of selected non-prescription drugs, that are different to those in GUI-0001.

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