[Stability Testing related News – vol.57]

◆  APIC: Update of the ICH Q7 “How to do” Document (21-Dec-21 ECA)

The latest version (version 15) of the “How to do” document – Interpretation of ICH Q7 Guide and “Review form” for APIs was finalised and published on the APIC website in July 2021. It is also intended to facilitate the implementation of the ICH Q7 Guideline and provides recommendations on how to interpret it.

The responsible Task Force of the Quality Group of APIC, which is a sector group of the European Chemical Industry Council (CEFIC), has mainly completed and updated chapters (7) Materials Management, (8) Production and In-Process Controls, (10) Storage and Distribution, (11) Laboratory Controls and (14) Rejection and Reuse of Materials as well as chapter (17) Agents, Brokers, Traders, Distributors, Repackers and Relabellers.

Chapter (7) “Materials Management” and (8) “Production and In-Process Controls
In Chapter (7), only the last section on highly toxic raw materials in paragraph 7.3 “Sampling and Testing of Materials” has been updated.

The latest version of chapter (8) “Production and In-Process Controls” contains, in addition to formal adjustments, changes primarily in sections 8.1 “Production Operations”, 8.3 “In-process Sampling and Controls” and 8.5 “Contamination Control”.
In paragraph 8.15, for example, the procedure for regularly occurring deviations has been included, and changes can also be found in paragraphs 8.10, 8.12 and 8.13.
In section 8.3, in particular, paragraphs 8.35 and 8.36 have been supplemented with the sentences “Cleaning status of the sampling tools should be identified.” and “For these cases the level of investigation (in the lab,sampling, number of replicates) should be defined.”
Section 8.5 also includes updates in two sections (8.51 and 8.52), citing the current ISPE Guideline information for APIs.

Chapter (10) “Storage and Distribution” and (11) “Laboratory Controls”
Chapter (10) “Storage and Distribution” now shows in the current version, besides formal changes, mainly adjustments in paragraphs 10.10, 10.11 and 10.20, which mostly contain rewordings and new formulations of the texts.

In chapter (11) “Laboratory Controls”, the additional sentence “There should be SOPs (approved by the Quality Unit)…” has been inserted in paragraph 11.1 General Control in section 11.11 only.

Chapter (14) “Rejection and Reuse of Materials” and (17) “Agents, Brokers, Traders, Distributors, Repackers and Relabellers”
Chapter (14) “Rejection and Reuse of Materials” shows in the latest version besides formal adjustments some changes in the topics Reprocessing (14.2), Recovery of Materials and Solvents (14.4) and Returns (14.5). These updates take into account, for example, the topic of nitrosamine contamination.
In Chapter (17) “Agents, Brokers, Traders, Distributors, Repackers and Relabellers”, only formal changes were made.


◆  Q&As: China GMP and Registration of APIs (05-Jan-22 ECA)

In December 2021, the ECA offered the Live Online Training “China GMP and Registration of APIs”. During the Q&A sessions, many interesting questions were posed to the speakers’ team.

With regard to China GMP requirements, a set of the most important questions raised during the training and the respective answers provided by our speaker Mr Francois Vandeweyer, VDWcGMP Consulting, Belgium, are listed in the following. All answers reflect the opinion of the speaker based on his experience.

Question 1: Does China’s Health Authority normally conduct inspections at API manufacturers in Europe?

China’s Health Authority, the so called National Medical Products Administration (NMPA), has initiated overseas inspections about four to five years ago. They performed these inspections risk based giving highest priority to sterile Active Pharmaceutical Ingredients (APIs), aseptic sterile APIs and low bioburden APIs (used in injections). Non sterile APIs were not excluded but only rarely inspected.
Since the Covid-19 pandemic, these overseas inspection visits have been stopped. But the program will be continued in the future.

Question 2: What’s different to the EU GMP requirements/guidelines? Could you please provide three examples?


  • The main difference is in fact that final API manufacturing steps (from final crystallization and steps afterwards including milling/sieving) are part of the Drug Product (DP) guidelines and not API guidelines. This means that also for non-sterile APIs Grade D environmental controls and conditions are required.
  • The qualification requirements for the head of production management are as follows: College degree in pharmaceutical or relevant specialties (or with an intermediate professional technique certificate or a pharmacist’s license), with at least three years of practical experience in pharmaceutical production and quality management, among which at least one year in production management, with necessary training relating to the products being manufactured.The qualification requirements for the head of quality management are as follows: College degree in pharmaceutical or relevant specialties (or with an intermediate professional technique certificate or a pharmacist’s license), with at least five years of practical experience in pharmaceutical production and quality management, among which at least one year in quality management, with necessary training relating to the products being manufactured.
  • Testing is required according to Chinese Pharmacopeia. As an example, water for pharmaceutical use should be suitable for its intended use, and meet the specifications of the Chinese Pharmacopeia and the related requirements.

Question 3: Do the Chinese GMP requirements also apply to APIs manufactured in Europe and used in a drug product manufactured in Europe and then imported to China?

Yes! Remember the final manufacturing steps of API manufacturing are part of the China’s Drug Product guidelines! So the same requirements are expected for the final APIs steps and DP manufactured in the EU, before these are placed on the Chinese market.
For intermediates in API manufacturing Chinese GMP is following the ICH Q7 guideline.

Question 4: Is there a specific API labelling needed?

No, the labelling requirements are the same as specified in ICH Q7.

Question 5: Is it required to provide audit reports for Regulatory Starting Material (RSM) suppliers?

No, audit reports of RSM suppliers for API manufacturing do not need to be provided to the NMPA with the regulatory filing.
For EU and FDA, if the Health Authorities request the audit report of a RSM you need to share the reports during the on-site inspection.
For China, I would handle this the same way. Share on-site during the inspection.

For customers, it is the company’s decision, if they want to share the RSM audit report during on-site inspections or not.

◆ FDA: Delays in Resumption of Inspections (26-Jan-22 ECA)

The FDA announced in its FDA Roundup of 4 January that the agency is adjusting its planned inspection activities to the developing COVID-19 pandemic and the spread of the Omicron variant. The agency has therefore temporarily postponed certain inspection activities in the hope of resuming them as soon as possible.

The FDA will continue to conduct so-called mission-critical inspections in the US and abroad, but will reassess plans to do so as needed. The agency is also postponing plans for surveillance inspections abroad, which were supposed to begin in February 2022.

In doing so, the FDA will continue its type of “remote foreign supplier verification programme activities” to maintain surveillance of food, drugs, medical devices and tobacco products. Last year, the FDA published a Guidance for Industry that addressed this issue. However, those who hoped that this would enable the FDA to carry out remote evaluations with the same or comparable significance of an on-site inspection were deceived. Even the title “Remote Interactive Evaluations” avoided the word inspection or audit. A footnote explained that these remote evaluations do not meet the legal definition of an inspection. Ultimately, such a remote evaluation serves as a supplement to an inspection. The procedure described is very similar to a virtual inspection, so “livestreaming walkthroughs of the facility” and interviews can be conducted. Following the publication of the above guidance, FDA then updated its Question and Answer document, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections during COVID-19 Public Health Emergency”, which explains some of the actions to be taken when the agency cannot conduct an on-site inspection of a facility.

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