API Starting Material Designation - Where Does cGMP Start?

API Starting Material Designation - Where Does cGMP Start?
API starting material designation continues to be a troublesome issue.

1. API Starting Material Designation Where Does cGMP Start?

2. API starting material designation continues to be a troublesome issue. Historically, API suppliers (DMF holders) have relied on the 1987 Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacturers of Drug Substances , International Conference on Harmonization (ICH)  Q7A  (good manufacturing practice starting material), and recommendations from 2004 and 2006 working groups for help in defining a starting material for the API manufacturing process. Background & History CH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000). http:// www.ich.org /LOB/media/MEDIA433.pdf

3. ICH  Q11: Development and Manufacture of Drug Substances  provides recommendations for API process controls and starting material considerations. The API supplier's decision of how far back in the synthesis to go before designating the regulatory starting material is impacted by the cost of current good manufacturing practice (CGMP) compliance, publishing proprietary information, and the necessity of reporting any future changes to the process. FDA uses a risk-based approach to determine where CGMPs should commence and defines the regulatory starting material accordingly. Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (1987) http:// www.fda.gov /downloads/Drugs/ GuidanceComplianceRegulatoryInformation / Guidances /ucm070632.pdf Current Approach

4. Increasingly, DMF holders define a key intermediate as the starting material and outsource the synthesis without due consideration to quality. In some cases, multiple suppliers of the outsourced starting material are provided, each with either a DMF or technical dossier requiring review. Considerations Illing , GT, Timko , RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

5. The starting material should be removed from the finished product by multiple synthetic steps with intermediates isolated and in-process controls specified. Salt interconversions, saponifications , esterifications , recrystallization steps, resolution of racemates , and  in-situ reactions with no intermediate isolated do not count as synthetic steps. Considerations Illing , GT, Timko , RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

6. If a molecule is "well defined" in the literature, then the literature should be cited along with appropriate detailed comparative structural analysis from the DMF holder against the literature values (e.g., published papers and patents). It is recommended that data from multiple lots using the commercial process to demonstrate sameness be provided for review. Considerations Illing , GT, Timko , RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

7. Commercially available starting materials need not be justified. In this context and per the draft ICH  Q11,  commercially available means "a chemical that is sold as a commodity in a pre-existing, non-pharmaceutical market.” In contrast, chemicals for which a contract manufacturer custom synthesizes a predefined amount of material specifically for the DMF holder are not considered "commercially available." Considerations Illing , GT, Timko , RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

8. ICH Q7 defined an API starting material as follows : “An “API starting material” is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.” History – ICH Q7 Guidelines CH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000). http:// www.ich.org /LOB/media/MEDIA433.pdf

9. Ambiguous? This definition of API starting material does not talk about multiple synthetically relevant steps that should separate the starting material and the final API.   Based on this definition of API starting material, a downstream intermediate (even the crude API), manufactured under non-cGMP conditions, purchased from custom manufacturers around the world meets the ICH Q7 criteria. CH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000). http:// www.ich.org /LOB/media/MEDIA433.pdf

10. ICH Q11, Development And Manufacture Of Drug Substances (Chemical Entities And Biotechnological/Biological Entities)   Sections 5.1 and 5.2 of ICH Q11 talks about the selection of starting materials and source materials for APIs. https:// www.ich.org / fileadmin / Public_Web_Site / ICH_Products /Guidelines/Quality/Q11/Q11_Step_4.pdf

11. The information in ICH Q11 regarding starting materials can be summarized as follows:   For API manufacturing process, cGMP applies from starting material onwards   Starting material should be a substance of defined chemical properties and structure – not a non-isolated intermediate.   Starting material should contain a distinct structural fragment of the API – differentiates it from common agents for esterification, salt formation etc. https:// www.ich.org / fileadmin / Public_Web_Site / ICH_Products /Guidelines/Quality/Q11/Q11_Step_4.pdf

12. Commercially available chemicals, with pre-existing non-pharmaceutical market need not be justified as starting material Enough of API manufacturing process must be disclosed in the dossier so that the impurity fate/purge can be understood Manufacturing steps which impact the impurity profile of the API should be part of the process description It needs to be established that the changes in material attributes/process conditions upstream (starting material manufacturing steps) may have lower potential to affect the API quality. https:// www.fda.gov /downloads/drugs/ guidances /ucm261078.pdf Clearing Up Ambiguity

13. API Starting Material – Best Practice The criteria used to define the API SM should be scientifically justified. A risk-based control strategy should be developed that includes not only SM specifications but also downstream GMP controls, in-process tests, operating conditions and validation of the API manufacturing process. The API manufacturer should demonstrate a thorough knowledge of the quality of the SM and its impact on the quality and safety of the final API. The SM specifications and overall control strategy should be based on this knowledge. https:// www.fda.gov /downloads/drugs/ guidances /ucm261078.pdf

14. The SM should be appropriately characterized, with a well-defined impurity profile. The fate of potential impurities (related substances, solvents, metals, potential genotoxic impurities) in the downstream manufacturing process should be well understood and documented. The capability of the downstream process to remove impurities and/or their derivatives should be established. Potential impurities that are critical to the quality and safety of the API should be appropriately controlled, using suitable analytical methods, depending on whether they are carried through to the API or reliably removed during processing. API Starting Material – Best Practice https:// www.fda.gov /downloads/drugs/ guidances /ucm261078.pdf

15. In some cases, a late stage intermediate may be appropriate as SM; in other cases it may be necessary to go further back in the synthetic route. The focus should be on the level of understanding and control. Non-science-based criteria should not be applied in the definition of the SM. These include: Number of synthetic steps Structural complexity Commercial availability Significant structural fragment API Starting Material – Best Practice https:// www.fda.gov /downloads/drugs/ guidances /ucm261078.pdf

16. The term “significant structural fragment” should be used as stated in ICH Q11, i.e. to distinguish SMs from reagents, solvents and other raw materials. It should not trigger a search for the earliest possible substance that is a structural fragment. A commercially available material may be classified as a SM but only if it meets the scientific criteria.   Regarding the introduction of stereochemistry into the synthesis, this may occur before the designated SM if justified (as in example 4 in section 10.4 of ICH Q11). API Starting Material – Best Practice https:// www.fda.gov /downloads/drugs/ guidances /ucm261078.pdf

17. Production of API Starting Materials In accordance with ICH Q7 and Q11, GMP begins with the first use of an API SM. Manufacture of the SM itself is not subject to GMP requirements. Under GMP, the API manufacturer is required to have systems in place to cover supplier qualification. GMP compliance of the API manufacturer, including their supplier qualification program, should be enforced during site inspection by the authorities. Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http:// www.sciencedirect.com /science?_ ob = ArticleURL &_ udi =B6TGX-4JRVDX0-

18. Industry’s quality management of the SM manufacture should incorporate risk assessment. The qualification process should include a quality agreement / contract between the API manufacturer and SM manufacturer to ensure that the impact of changes in the manufacture of the SM can be adequately assessed by the API manufacturer. The SM manufacturer should have an appropriate quality system in place and on-going monitoring / evaluation should be performed by the API manufacturer. Production of API Starting Materials Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http:// www.sciencedirect.com /science?_ ob = ArticleURL &_ udi =B6TGX-4JRVDX0-

19. The name and address of the SM manufacturer and qualification documentation should be available for review during site inspections. A risk-based control strategy is key.   The SM is not the only substance contributing to impurities in the API . The API is not the only substance contributing to impurities in the drug product. Production of API Starting Materials Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http:// www.sciencedirect.com /science?_ ob = ArticleURL &_ udi =B6TGX-4JRVDX0-

20. There should be an appropriate balance between assessment of the SM and other process risks, e.g. other raw materials, design of the manufacturing process.   Manufacture of APIs under GMP is a critical part of the control strategy and this includes supplier qualification. Adequate supplier qualification is a GMP requirement that must be managed by the API manufacturer and verified by inspection. More paper work is not a solution. Describing an excessive number of steps in the dossier is no guarantee of a safe API. Production of API Starting Materials Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http:// www.sciencedirect.com /science?_ ob = ArticleURL &_ udi =B6TGX-4JRVDX0-

21. The goal of working with regulators in the area of starting material selection, then, should be to provide a solid, data-driven case that the choice of starting material is backed up by sufficiently discriminating analytical methodology, appropriately set starting material acceptance criteria, and effective purification processes that we are certain that we know what is in the medicine we will be giving to patients.

22. Stuart Silverman CEO & Founder RyMat Incorporated [phone] [email protected] RyMat Incorporated