On 21 February 2022, EU GMP Guide Annex 21 Importation of Medicinal Products was published. It has come into force on 21 August 2022. Since GMP compliance is already anchored in national legislation, it will also be mandatory to implement Annex 21 from this date. The new annex was created to clarify and harmonise the GMP requirements for importing medicinal products into the EEA.
The main contents of the new Annex 21 are outlined and explained in this chapter. In addition, you get answers to four frequently asked questions about importing medicinal products.
(Simone Ferrante)

Chapter 2 Personnel

2.D Hygiene requirements for personnel

Hygiene programs include precautions for the examination of personnel, appropriate clothing in the respective production areas and rules of behavior for employees in the workplace. On the one hand, the regulations serve to protect the health of employees from production risks. On the other hand, they are also intended to protect products from contamination by employees.
Examinations of personnel have different objectives: The pre-employment examination serves to check whether a person is suitable for carrying out GMP relevant activities. A reporting obligation ensures that the quality of the products is not impaired by illnesses of the personnel. In addition, there are occupational preventive medical check-ups.
Protective clothing must be worn throughout the entire manufacturing area. It protects personnel from contamination by the product and the product from contamination by humans. Functionality and wearer comfort must be given equal consideration in the selection process. The gowning procedures must be described and trained in SOPs.
Workplace behavior should also be geared to ensuring both the safety of personnel and the quality of the product. In this context, training and effectiveness checks play an important role.
(Michael Hiob, PhD)

Chapter 3 Premises

3.A Official requirements for premises

Premises must facilitate proper operation. This applies, in particular, to proper manufacture, testing, storage, packaging and marketing of medicinal products. The individual requirements depend on the type and scope of production.
The proper condition of the operating premises is subject to regular inspection by the competent GMP supervising authority. During the plant inspection, attention is paid to plant hygiene, labelling, storage conditions, and personnel and material flows. The utility systems essential for rooms are also regularly examined during the site inspection. Information on production premises and supply systems is an integral part of the company description, which is made available to the authority for inspection preparation.
A user requirements specification should be created when planning the premises. Various legal requirements must be observed during planning and implementation. For this reason, all decision-makers should be involved in the project at an early stage. Reconstruction of existing buildings represents a particular challenge. Risk management plays a particularly important role here because of the high risk of contamination.
Technical or organisational measures can be taken to avoid cross-contamination. The focus must always be on prevention.
Before commissioning, qualification must be carried out to prove that a room is suitable for its intended purpose. The requirements are contained in the user requirements specification and functional specification as well as in the room book.
To ensure that the premises are in a proper condition during operation, they must be maintained and cleaned on a regular basis.
(Michael Hiob, PhD)

Chapter 16 Storage and transportation

16.F Standard storage at 15–25 °C? A case study challenging conventional limits

Guidance on storage conditions for medicinal products can be found in relevant WHO, ICH, and EMA guidelines, as well as in the EU GDP guidelines.
Neither ICH and EMA nor the GDP guidelines prescribe a mandatory temperature range of 15–25 °C for the storage and transport of standard medicinal products.
In fact, EMA and ICH explicitly advise against using terms such as "room temperature" or "ambient conditions" as storage instructions. In contrast, the new WHO-GSDP guideline, which consolidates and replaces the previous WHO guidelines on GSP and GDP, contains in Appendix 1 both the storage advice "15–25 °C" for storage at controlled room temperature and "15–30°C" for storage under "ambient conditions".
In practice, storage at "room temperature" is now usually equated with "15–25 °C" and understood as a necessity. To maintain this temperature range, however, energy must be used for heating; budgets, climate and the environment are needlessly burdened.
For this reason, a case study was carried out to examine whether a broadening of the temperature range to 9–25 °C would negatively affect the quality and safety of standard medicinal products and medical devices.
Data was generated that shows a reduction of the lower temperature limit to 9 °C with a warning limit of 10 °C does not have a negative effect on the products that were examined. Measures were subsequently taken so that products can be stored at 9–25 °C in the future. They included changing the warning and alarm limits, the installation of additional temperature sensors and the inclusion of new products in the existing risk analysis to determine the required storage conditions. The potential savings compared to constant storage at 15–25 °C are enormous. Each company should also check on its own responsibility whether cold-sensitive preparations must always be stored above 8 °C and whether storage at a further optimised 2–25 °C is not also possible for these.
The temperature range of 9–25 °C instead of 15–25 °C will also be applicable to the transportation of medicinal products. A short-term deviation from 2–30 °C over 12 hours during transportation will not affect the quality of preparations.
The requirements for the EU-wide implementation of the "Green Deal" as well as the Federal Climate Protection Act are clear: in future, the pharmaceutical industry must also do its part for climate protection under the terms "emission and environmental qualification". The declared goal is the continuous reduction of the companies' environmental impact.
High time to start and store medicines in a climate-friendly way instead of heating them senselessly!
(Christoph Frick, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.4.1.1 Annex 1 Manufacture of sterile medicinal products

The long-awaited final version of the new EU Annex 1 was published on 25 August 2022. The completely new approach of the document not only adds clarity to the requirements on the sterile manufacturing of medicinal products and introduces the principles of Quality Risk Management, but also allows for the inclusion of new technologies and innovative processes.
The deadline for entry into force is 25 August 2023.
Regarding section 8.123 on freeze-drying and product transfer, the deadline for entry into force is two years from now and will thus become mandatory on 25 August 2024:

“8.123 Lyophilizers and associated product transfer and loading/unloading areas should be designed to minimize operator intervention as far as possible. The frequency of lyophilizer sterilisation should be determined based on the design and risks related to system contamination during use. Lyophilizers that are manually loaded or unloaded with no barrier technology separation should be sterilised before each load. For lyophilizers loaded and unloaded by automated systems or protected by closed barrier systems, the frequency of sterilisation should be justified and documented as part of the CCS.”

With 58 pages, the document has grown by another six pages compared to the draft of 2020, but its basic structure into eleven areas has remained the same. Among these, the topics of isolators and RABS (4.18) and the section on "Form-Fill-Seal (FFS)" (8.96) are mainly to be mentioned. Isolators and RABS have been subdivided into independent sections and further deepened, which also applies to the topic of FFS, which has been significantly expanded.

C.4.1.1 EXTRA to Annex 1, Manufacture of Sterile Medicinal Products: The Annex 1 Comparison from Draft to Final

This hands-on working tool compiled by our expert Fritz Röder, supports you in implementing the new Annex 1 requirements you must meet in August 2023. A criticality ranking and the author’s concise comments are on point to identify your needs to be fully compliant.

Chapter D USA: CFR and FDA Guidelines

D.9 Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

The US FDA has revised its 16-year-old guidance on how to investigate out-of-specification (OOS) test results in laboratories. The document includes all necessary steps to be taken when investigating OOS test results. It also considers the responsibilities of the analyst and the laboratory supervisor in case of OOS results being identified, along with additional testing steps and a final evaluation of all results.
The term OOS results according to the FDA includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.
The 17-page guideline follows a clear step-by-step approach in close linkage with 21 CFR 211 on

Identifying and Assessing OOS Test Results – Phase I: Laboratory Investigation
Investigating OOS Test Results – Phase II: Full-scale OOS Investigation
Concluding the Investigation
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Chapter E GMP of other regions

E.3.D ICH Q3D (R2): Guideline for Elemental Impurities

ICH Q3D (R2) was adopted on 26 April 2022 by the Regulatory Members of the ICH and has reached Step 4 of the ICH-Process. It will now be distributed to the Member States for implementation.
The revision (R2) focused on the establishment of limits for elemental impurities by the dermal route of exposure, summarized in a new Appendix 5 Limits for Elemental Impurities by the Cutaneous and Transcutaneous Route and error corrections of the PDEs for Silver (oral), Gold (oral, parenteral and inhalation) and Nickel (inhalation).
The newly established PDEs:

The corrected parenteral PDE for Silver is 15 μg/day.
The corrected PDE of Gold by oral, parenteral or inhalation routes is identified as 300, 300, 3 μg/day.
The corrected PDE of Nickel by inhalation is now listed with 6 μg/day.
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