Top 10 Validation Errors for Health Canada
The AAPS Workshop on Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now! was held March 9-11, 2009. There were some great presentations, and best of all they are publically available. The agenda contains links to the presentations.
All the presentations were good but some of the highlights for me appear below. There’s great information on Japan and Health Canada that has been rather hard to locate recently, and lots of discussion about some of the more puzzling and problematic aspects of eCTD as they relate to CMC in particular – so you know there will be discussions about metadata, granularity, and the tradeoffs in structuring M2 and M3.
Updates from the Regulators
Evdokia Korakianiti of EMEA presented eCTD: EMEA Experiences containing FAQs received by the EMEA, concerning CMC metadata, CEPs, ASMF – plus some great key messages for industry.
The presentation eCTD in Japan by Harve Martins has lots of good info on eCTD in Japan that has not been readily available – such as details and examples on lifecycle (handled in an accumulative approach in Japan), Module 1 TOC, cover letter and form information, module 5 unique requirements, validation details, submission instructions, etc. I’ve reproduced the update on the number of sequences received in Japan (keep in mind that a reference application is something like Health Canada’s co-submission – in effect a review aid for a paper submission.)
Health Canada’s Vianney Caron presented e-Submissions at Health Canada which reviewed HC’s history anfuture direction with eCTD, challenges and issues with CMC documents, especially the QOS. Health Canada also presented statistics on the number of eCTDs they have been receiving (they now get about 7% of their regulatory activities in eCTD format).
Regulatory Activities in eCTD format (NDS, SNDS, ANDS, SANDS, NC)
About 8.2% of submissions are currently failing validation, well down from the 31% experienced in early days. Following the lead of FDA and EMEA, they have provided their top 10 list of validation errors:
1. Inactive bookmarks -no link destination
2. Inactive hyperlinks -no link destination
3. External links -pointing to the folder or destination that does not exist in the folder structure on the CD/DVD. The folder or destination would only exist in the sponsor’s repository.
4. Incorrect naming of the 3011 form (correct name is hc-sc-3011-en.pdf)
5. Unreferenced files in the index.xml or ca.regional.xml
6. Life cycle management of the document: invalid file reference or no previous ID found
7. Subfolders created in ca regional folder
8. Missing top level folder
9. Missing attestation letter; content as per eCTD Guidance, letter needs to be dated and signed
10.Printed content of MD-5 Checksum does not match the one in the index-md5.txt file
Health Canada strongly recommends electronic submissions in eCTD format, and they plan to expand the existing architecture to support as many application types across product line as possible. Some of their next steps in support of eCTD include:
Perform assessment of the hybrid pilot
Widen the scope to more electronic data in eCTD format
Implement two-way secure electronic communication (secure channel, secure email and gateway)
Improve tracking system and integrate it with a workflow system
Strengthen international collaborations
Announce a date (TBD) for accepting electronic-only submissions
The eCTD Industry Forums –Europe presentation by Phyllis Thomas of AstraZeneca UK summarizes discussions by the CMC eCTD informal industry group and EFPIA eCTD-Q topic team. It has lots of discussion about metadata and repeating section issues, including illustrative examples. It also discusses issues and areas that lack clarity that have been passed on as Q&A and in turn referred to the harmonization taskforce (some of them not yet resolved).
ICH & Regional Guidance and Terminology by Hans van Bruggen provides a comprehensive summary of eCTD status in many regions (including individual EU countries). Again, this is information that is hard to find and nearly impossible to find in one place.
Industry Best Practices
In Points to Consider for Case Studies in Lifecycle-Biologics, Colleen Godshall of Merck addresses some of the issues that have always caused me to hold CMC people in awe: however do they perform impact analysis of change and manage the approvals and notifications requirements that are so different in every region? Concrete examples are provided, such as “Adding a New Air Handler to a Class 100 Area used to manufacture multiple vaccines”. Ms. Godshall also talks about managing 3.2.A.1 for both US applications, which allow cross-applikcation linking, and International Marketing Authorizations, which do not.
A presentation by Pamela Cafiero of Boehringer Ingelheim, Simultaneous eCTD Applications in US and EU: Similarities/Differences and the Reasons Behind them, gives detail on a subject I’ve been asked about many times – what are the real differences in content between US and EU Module 3?
She also gives recommendations about document identification (header/footer), Referencing between CMC documents, referencing and linking within Module 3 (her minimalist approach resulted in about two dozen links between Module 3 documents and was the same in US and EU), and recommendations and examples of CMC metadata, leaf titles and the relationships between them.
Phyllis Thomas of AstraZeneca UK also spoke about USING MODULE 3 (FOR INDs). She focused on encouraging the use of granularity in IND M3 (even though it is not required) and some special considerations for INDs such as Placebos, Comparators, and Introductory CMC text.