An Impact assessment of Post-Approval Regulatory and Quality Compliance at a UK – Only Pharmaceutical Manufacturer
Abstract
Purpose: To assess the regulatory compliance of operational processes at a British pharmaceutical manufacturing company (Company X). Provide remediation strategies for any compliance gaps identified to align operations with regulatory approvals. Ultimately, to assure Qualified Persons that finished pharmaceutical products released for sale are compliant with regulatory approvals and manufactured to current quality standards.
Materials and methods: A gap analysis between regulatory-approved CTD sections and operational documentation is conducted for a single marketed product at Company X. Inclusion of CTD sections for review is determined according to those likely to contain Established Conditions (EC) as specified in the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use Q12 guideline. A three-tiered review process is used to identify Established Conditions and describe compliance. Tier 3 (Student) identifies Established Conditions by comparing like-for-like (compliant), equivocal (further assessment required) and opposing (non-compliant) terminology in the CTD sections compared to operational documentation. Tier 2 (Subject Matter Experts (SMEs)) reviews and approves Tier 1 outputs. Equivocal terminology is assessed as either compliant or non-compliant. Non-compliant conditions are assessed as regulatory gaps if they deviate from the CTD or quality gaps if they are compliant with the CTD but deviate from Good Manufacturing Practices (GMP). A risk assessment is conducted using a risk priority numbering (RPN) tool and remediation proposals are made. Tier 1 (Governance) reviews and confirms Tier 2 compliance gap outputs and ratifies a final adjudication and remediation strategy.
Results and discussion: Data outputs for this study could only be generated at Tier 3 and Tier 2 levels due to time constraints. A total of 62 compliance-related Established Conditions (EC) were identified with 37 representing compliance gaps. 49% (30 conditions) related to regulatory compliance gaps, 40% (25 conditions) were compliant and 11% (7 conditions) were quality compliance gaps. Six categories of regulatory compliance gaps were identified with the most commonly observed being the unavailability of regulatory-approved CTD sections for review. Three categories of quality compliance gaps were identified with the most commonly observed being the misalignment of operational and validating documentation.
Conclusions: Company X is presently in a state of non-compliance. The unavailability of regulatory-approved documentation emerges as the most common compliance issue suggesting insufficiencies in regulatory document control may currently exist. A root cause analysis coupled with a corrective and preventative action plan may be beneficial to support sustained compliance. Further work is required to remediate identified compliance gaps to bring operations into regulatory compliance.
Downloads
References
2. International Council for Harmonisation. Q12: Technical and regulatory considerations for pharmaceutical product lifecycle management [Internet]. ICH; 2019 Nov 20 [cited 2024 Aug 14]. Available from:
https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf
3. Medicines and Healthcare Products Regulatory Agency. Rules and guidance for pharmaceutical manufacturers and distributors. 11th ed. The Orange Guide; 2022.
4. Medicine and Healthcare Products Regulatory Agency (MHRA). Guidance: Apply for a licence to market a medicine in the UK. The National Archives [Internet]. Gov.uk; 2014 Dec 18 [cited 2024 Aug 14]. Available from:
https://www.gov.uk/guidance/apply-for-a-licence-to-market-a-medicine-in-the-uk
5. Government of the United Kingdom. The Human Medicines Regulations 2012. London: The Stationery Office. Internet]. Gov.uk; 2024 Nov 20 [cited 2024 Nov 24]. Available from: https://www.gov.uk/guidance/mhra-windsor-framework-webinar-recordings
6. Government of the United Kingdom. The Windsor Framework - further detail and publications. The National Archives [Internet]. Gov.uk; 2023 Sep 29 [cited 2024 Aug 14]. Available from:
https://www.gov.uk/government/collections/the-windsor-framework-further-detail-and-publications
7. International Council for Harmonisation. M4: The common technical document [Internet]. ICH; 2024. [cited 2024 Aug 14]. Available from:
https://www.ich.org/page/ctd
8. Government of the United Kingdom. The Windsor Framework: a new way forward. London: The Stationery Office [Internet]. Gov.uk; 2023 [cited 2024 Aug 14]. Available from:
https://www.gov.uk/guidance/mhra-windsor-framework-webinar-recordings
9. European Commission. The rules governing medicinal products in the European Union. Volume 2B: Notice to applicants, medicinal products for human use, presentation and format of the dossier common technical document (CTD). The Publications Office of the European Commission; 2008.
10. International Council for Harmonisation. M4 (R4): Organisation of the common technical document for the registration of pharmaceuticals for human use [Internet]. ICH; 2016. [cited 2024 Aug 14]. Available from:
https://database.ich.org/sites/default/files/M4_R4__Guideline.pdf.
11. International Council for Harmonisation. The common technical document for the registration of pharmaceuticals for human use: quality - M4Q(R1), quality overall summary of module 2 and module 3: quality; 2002.
12. European Commission. Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products. The Publications Office of the European Union [Internet]. eur-lex.europa; 2008 Nov 24 [cited 2024 Aug 17]. Available from:
https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:334:0007:0024:en:PDF
13. Bao Y, Buhay N, Zheng Q. A dynamic model for GMP compliance and regulatory science. J Pharm Innov. 2024;19(3):25.
14. International Council for Harmonisation. The common technical document for the registration of pharmaceuticals for human use: safety – M4S(R2) nonclinical overview and nonclinical summaries of module 2 and organisation of module 4. [Internet]. EMEA; 2003 Nov 01 [cited 2024 Aug 15]. Available from:
https://www.ema.europa.eu/en/ich-m4s-common-technical-document-registration-pharmaceuticals-human-use-safety-questions-answers-scientific-guideline
15. International Council for Harmonisation. Revision of M4E guideline on enhancing the format and structure of benefit-risk information in ICH efficacy - M4E(R2); 2016.
16. European Commission. Reflection paper on good manufacturing practice and marketing authorisation holders [Internet]. EMEA; 2022 Jan 10 [cited 2024 Aug 15]. Available from:
https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-good-manufacturing-practice-and-marketing-authorisation-holders_en.pdf
17. European Medicines Agency. Clinical trials in human medicine [Internet]. EMEA; 2024 [cited 2024 Aug 18]. Available from:
https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials-human-medicines
18. Millichamp LN, Bohl G, Robin K. ICH Q12: How it impacts the management of your CMC post-approval changes. Regul Rapporteur. 2020;17(7/8):27–31.
19. Royal Pharmaceutical Society, Royal Society of Biology, Royal Society of Chemistry. Qualified person involved in the manufacture of pharmaceuticals: QP code of practice [Internet]. The Joint Professional Bodies; 2024 Apr [cited 2024 Aug 14]. Available from:
https://www.rpharms.com/Portals/0/RPS%20document%20library/Qualified%20Person%20Documents/QP%20Code%20of%20Practice%202024.pdf
20. Haleem RM, Salem MY, Fatahallah FA, Abdelfattah LE. Quality in the pharmaceutical industry – a literature review. Saudi Pharm J. 2015;23(5):463–9.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The International Journal of Drug Regulatory affairs require a formal written transfer of copyright from the author(s) for each article published. We therefore ask you to complete and return this form, retaining a copy for your records. Your cooperation is essential and appreciated. Any delay will result in a delay in publication.
I/we have read and agree with the terms and conditions stated Page 2 of this agreement and I/we hereby confirm the transfer of all copyrights in and relating to the above-named manuscript, in all forms and media, now or hereafter known, to the International Journal of Drug Regulatory affairs, effective from the date stated below. I/we acknowledge that the IJDRA is relying on this agreement in publishing the above-named manuscript. However, this agreement will be null and void if the manuscript is not published in the IJDRA.
Download link for COPYRIGHT FORM
