• on January 6, 2024, the Indian Ministry of Health notified the revision of GMP rules in accordance with Schedule M of the Drug and Cosmetic Regulation, with the aim of ensuring robust quality control for pharmaceutical and biopharmaceutical products.

    With this revision, the emphasis is placed on enhancing and updating the existing GMP framework to align with the global standards and international expectations, in particular those of the World Health Organization (WHO). The review was also driven by the rapid evolution of the manufacturing and quality domain and the need to keep pace with the latest technological advances.

    With the amendment, the term ‘Good Manufacturing Practices’ (GMP) has been replaced with “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products”.

    Some of the major changes introduced in the revised Schedule M include the introduction of a pharmaceutical quality system (PQS), quality risk management (QRM), product quality review (PQR), qualification and validation of equipment, and a computerised storage system for all drug products.

    The revised Schedule M has 13 parts which provide GMP guidelines for the specific requirements for manufacturing pharmaceutical drugs and also include five new categories of drugs that were not previously covered under the rules.

    The new categories include pharmaceutical products containing hazardous substances such as sex hormones, steroids (anabolic and androgenic), cytotoxic substances, biological products, radiopharmaceuticals, phytopharmaceuticals, and investigational pharmaceutical products for clinical trials for humans.

    The manufacturer must assume responsibility for the quality of pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the licence, and do not place patients at risk due to inadequate safety, quality, or efficacy. The manufacturer must also market a finished product only after getting satisfactory results from tests of the ingredients and retain enough samples of intermediate and final products to allow repeated testing or verification of a batch.” [Health Ministry notifies revised Pharma manufacturing rules under schedule M to ensure quality control – The Hindu].


On October 31st, the Swiss Medicines Inspectorate published a technical interpretation of GMP Annex 1. The interpretation focuses on some of the most significant changes of the revision 2022 of Annex 1 “Manufacture of Sterile Medicinal Products”. It also addresses aspects that were already included in the previous guideline version and have consistently prompted questions.

It should be noted that the document references the revised Annex 1 of the PIC/S GMP Guideline (PE 009) about the manufacture of sterile medicinal products. This was adopted on 9 September 2022 by the PIC/S Committee and came into force on 25 August 2023 (with the exception of point 8.123, which will become binding from 25 August 2024).


Contents of the document

The document consists of a list of questions regarding chapters of Annex 1 and the corresponding answers as interpreted by SwissMedic.

It includes the following sections:


  1. Purpose and scope
  2. Basics
  3. Definitions and abbreviations
  4. Interpretation: Questions and Answers

4.1     Scope (Annex 1, Chapter 1)

4.2     Premises (Annex 1, Chapter 4)

4.3     Utilities (Annex 1, Chapter 6)

4.4     Personnel/Training (Annex 1, Chapter 7)

4.5     Production and Specific Technologies (Annex 1, Chapter 8)

4.6     Environmental & Process monitoring (Annex 1, Chapter 9)

4.7     Quality Control (QC) (Annex 1, Chapter 10)

  1. Changes to the previous version


Some questions aim to provide further clarification on the language used in the document, but there are also several inquiries regarding the assessments of single-use systems (SUS).

The document contains a total of forty-six questions and their corresponding answers.



Interpretation of GMP Annex 1 2022 (Rev. 1).

The European Medicines Agency (EMA) has updated the Questions and Answers on the outsourced activities chapter to include “Chains of Contracts” in the pharmaceutical industry, a “setup” where one or more parties (sites/companies) are acting as signatory in a chain of contracts that links them together.

This new setup represents an innovative approach that allows greater flexibility in contractual relationships between different entities involved in the production of medicines, while maintaining high quality and safety standards.

Therefore, the setup introduces one or several separate legal entities between the contract giver such as MAH and MIA holder responsible for QP certification of the product and the contract manufacturer or any other entities included in the manufacturing/supply chain as a contract acceptor. In fact, the GMP activities concerned are sub-contracted over one or several levels”.



The Questions and Answers clarifies in which exceptional cases such a “chain of contract” setup would be acceptable instead of direct written contracts, the conditions to be met are as follows:

  • robust and timely communication – It should be ensured that robust and timely communication between the MAH, the MIA holder responsible for QP certification and the contract manufacturers is secured through the “chain of contracts”.
  • Access to contracts – The MIA holder and the QP should have access to all of the contracts in the “chain of contracts”. Contract manufacturers should have access to those contracts relevant to the activities they perform and the associated responsibilities. As per EU GMP Chapter 4 all these contracts are to be considered as part of the Pharmaceutical Quality System.
  • Written assessment – The MIA holder and the QP should perform a written assessment of the suitability and functionality of such a setup.
  • Notification of changes – Any changes in the “chain of contracts” must be notified to and approved by the MIA holder and the QP prior to the change of the respective contracts being implemented.
  • Audited and evaluated according to EU-GMP standards – All parties involved in the “chain of contracts” setup should be audited and evaluated in accordance with Chapter 7 and Annex 16 of the EU-GMP and should also be reflected in the supply chain diagram.
  • PQR – All contracts within the “chain of contracts” setup are reviewed as part of the product quality review (PQR) process.

Nonostante l’introduzione di questa nuova configurazione, l’EMA ha sottolineato che i “contratti scritti diretti” rimangono ancora la preferenza principale. I contratti scritti diretti sono quelli firmati tra le parti coinvolte direttamente nell’esecuzione delle attività specificate e offrono maggiore chiarezza e trasparenza nel processo.

Despite the introduction of this new setup, EMA underlined that “direct written contracts” are still prefererred. Direct written contracts are those “signed between the parties, that actually perform the activities stated in the contract”.


Guidance on good manufacturing practice and good distribution practice: Questions and answers

The Mutual Recognition Agreement (MRA) between Switzerland and the United States in Good Manufacturing Practice (GMP) for medicinal products has entered into force from 27 July 2023.

This agreement in principle establishes a mechanism whereby each country recognises GMP inspections carried out by the regulatory authority of the other, i.e. Swissmedic for Switzerland and the Food and Drug Administration (FDA) for the United States.

Both authorities are thus able to mutually use GMP inspections and their results in order to avoid duplicate inspections.

A significant aspect of this MRA is that it is not only limited to human medicines, but also includes veterinary medicines

In addition to the FDA and Swissmedic, the Office of the U.S. Trade Representative and the State Secretariat for Economic Affairs of Switzerland had also signed the agreement. These institutions play an important role in facilitating negotiations and cooperation between the two nations to ensure the proper implementation of the agreement.

The Mutual Recognition Agreement is based on the Food and Drug Administration Safety and Innovation Act, enacted in 2012, which allows the FDA to enter into agreements with other regulatory authorities to recognise inspections performed by them. This regulatory environment has created a favourable environment for international collaboration and mutual exchange of information.




The current EU GMP Guidance Annex 11 “Computerised Systems” has been issued in 2011 and does not give sufficient guidance within several areas. There has been discussion for some time about revising this annex to meet current technological and regulatory developments. On 16 November 2022, the EMA (European Medicines Agency) published a “Concept-Paper on the revision of Annex 11 of the guidelines on Good Manufacturing Practice for medicinal products – Computerised Systems” that addresses the need to update Annex 11.


Proposed timetable until the publication of the new EU GMP Annex 11

  • Deadline for comments on the concept paper: 16 November 2023.
  • Publication and commenting of a draft of the new Annex 11: March 2025.
  • Approval and publication by the European Commission: June 2026.
  • Reasons for the revision of Annex 11.


Where is there a need for change and adaptation?

In 33 points, based on the structure and chapters of the current Annex 11, new points to be included and topics to be updated are presented.

Which topics should be included in the new Annex 11?

The following is an excerpt from the Concept Paper of some chapters in Annex 11 that have been identified as needing adaptation:

  1. Suppliers and Service Providers

The topic of cloud service providers should be addressed in particular:

  • [3,1] “For critical systems validated and/or operated by service providers (e.g. ‘cloud’ services), expectations should go beyond that “formal agreements must exist”. Regulated users should have access to the complete documentation for validation and safe operation of a system and be able to present this during regulatory inspections, e.g. with the help of the service provider.”
  1. Validation
  • [4.1] The meaning of the term ‘validation’ (and ‘qualification’), needs to be clarified. It should be emphasised that both activities consist of a verification of required and specified functionality as described in user requirements specifications (URS) or similar.
  • [4.1] Following a risk-based approach, system qualification and validation should especially challenge critical parts of systems which are used to make GMP decisions, parts which ensure product quality and data integrity and parts, which have been specifically designed or customised.

The topic of “agile methods” should be integrated here regarding deviations from previous classic development documents.

  • [4.5] It should be acknowledged and addressed that software development today very often follows agile development processes, and criteria for accepting such products and corresponding documentation, which may not consist of traditional documents, should be clarified.
  1. Audit Trails

Most of the new topics are mentioned here. What has been a very short chapter so far, topic should be described much more comprehensively in the new Annex 11. The points to be addressed include:

  • Audit trails must not be editable
  • Audit trails must not be able to be switched off for the “normal user” of a system.
  • Statements should be made about the frequency of audit trail reviews.
  • Audit trail data as GMP requirements are often created together with log data. It should be possible to be able to sort these data.
  1. Security

This topic should also be integrated more strongly under the aspect of external threats.

  • [12.1] The current section has only focus on restricting system access to authorised individuals; however, there are other important topics. In line with ISO 27001, a section on IT security should include a focus on system and data confidentiality, integrity and availability.

Security techniques, information security management systems and requirements are specifically mentioned here.

  • [12.1] The current version says that “Physical and/or logical controls should be in place to restrict access to computerised system to authorised persons”. However, it is necessary to be more specific and to name some of the expected controls, e.g. multi-factor authentication, firewalls, platform management, security patching, virus scanning and intrusion detection/prevention.
  • [12.1] It should be specified that authentication on critical systems should identify the regulated user with a high degree of certainty. Therefore, authentication only by means of a ‘pass card’ might not be sufficient, as it could have been dropped and later found by anyone.
  • [12.1] Two important expectations for allocation of system accesses should be added either here or elsewhere; i.e. ‘segregation of duties’, that day-to-day users of a system do not have admin rights, and the ‘least privilege principle’, that users of a system do not have higher access rights than what is necessary for their job function.



The current Annex 11 is partly superseded by technological and regulatory developments and that there is a corresponding need for adaptation.

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has adapted EU GMP Annex 16 (“Certification by a Qualified Person and Batch Release”) and calls it “Certification by the Authorised Person and Batch Release“.

In Europe, each holder of a manufacturing authorisation for medicinal products needs to name at least one Qualified Person (QP). The legal basis for the appointment of a QP is defined in the DIRECTIVE 2001/83/ EC and in DIRECTIVE 2001/82/EC; these directives clearly determine the educational background and professional experience a professional requires to act as a QP as well as the duties and responsibilities associated with this function.

Annex 16 of the EU GMP Guide covers in depth the activities related to certification and batch release and all the responsibilities that fall to the QP.

Until now, PIC/S had not adapted EU Annex 16, as it considered it too EU-specific and difficult to implement for PIC/S purposes. The decision to address an implementation of the Annex shows the international harmonization effort.

The new PIC/S GMP Guide (PE 009-16), updated with the revised Annex 13 and the new Annex 16 entered into force on February 1, 2022. All Participating Regulatory Authorities of PIC/S Committee and non-EEA/EU applicants have been invited to transpose Annexes 13 and 16 into their own GMP Guides.

It will be interesting to see how these Authorities approach a possible implementation.