The EMA published a reflection paper on July 3, 2017, that addresses ‘the requirements for selection and justification of starting materials for the manufacture of chemical active substances.’ The intent of the reflection paper, prepared by the Quality Working Party, is to clarify expectations outlined in ICHQ11, Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological / Biological Entities). This document covers both human and veterinary medicinal products. ICH issued a Q&A regarding the selection and justification of starting materials, and the most recent draft is dated October 13, 2016. This reflection paper provides additional granularity on expectations of the EU regulatory authority beyond what is found in the ICH Q&A. Taken together, the reflection paper can be summarized as being ‘all about impurities’, both known and unknown. It also targets catalysts, solvents, and regents that are used in manufacturing starting materials and how they are controlled to ensure consistent manufacturing of the active substance.
The identification and justification of starting materials have seen varying levels of controversy as long as I’ve been in the industry. According to Q11 (see section 5.1.1), GMPs begin to apply with the ‘first use of a starting material.’ From a purely economic perspective, it thus becomes desirable to introduce the starting material as late in the process of API manufacturing as possible. This approach, however, must be balanced with the health authority perspective on the need for a formal control strategy to assure quality in the API manufacturing.
The new reflection paper includes 11 ‘explanatory notes’ that provide ‘commentary on EU expectations’. Overall, the notes provide detail on the need to understand and control the formation and removal of impurities in the API manufacturing process. These notes focus on sections 5.1 and 5.2 of the original Q11 guidance with seven (7) of the eleven (11) comments addressing section 5.1. Explanatory Note 2 is the longest and most detailed and addresses the ‘synthetic steps critical to the quality of the active substance.’ We will address each of the notes in turn below.
EXPLANATORY NOTE 1: This note addresses the first major bullet point and its sub-bullet point in ICH Q11, Section 5 that focuses on the relationship between risk to API and the number of purification steps between its introduction and the completion of the API manufacturing process. In general, changes in material attributes and operating conditions at the beginning of the manufacturing process pose less risk to product quality and patient safety. Note 1 concludes that ‘short synthetic routes will not normally be accepted’ and that a ‘sufficient number’ of purification steps are necessary in the API manufacturing process to effectively remove impurities. From this note, it is clear that multi-step reactions with isolation of intermediates are preferred over ‘one pot reactions’ which have fewer opportunities for removal of impurities. Processes that do not include robust impurity removal steps may result in an API of variable quality from lot to lot.
EXPLANATORY NOTE 2: This note also focuses on controls applied to critical manufacturing steps and should include discussion of the ‘formation, fate, and purge of actual and potential…impurities.’ First, the applicant is expected to identify and apply controls to ‘critical steps for active substance quality.’ The note gives seven (7) examples of what might constitute a ‘critical step.’ Tests and acceptance criteria should be established to control these critical steps. This note also suggests how to address the situation when an API intermediate is itself covered by a Ph.Eur monograph and when this intermediate may be an active substance in a drug product approved in the EU.
EXPLANATORY NOTE 3: This note is the most brief and states that ‘steps critical for the purity of the active substance should be performed under GMP, which forms an integral part of any control strategy.’ This suggests if the control of impurities in the manufacturing process (for example, genotoxic impurities) for starting materials is essential for the purity of the active substance, then this should be performed under GMP. This could potentially push back the starting boundary for GMP operations.
EXPLANATORY NOTE 4: This note explains the requirement in ICHQ7, ‘Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients’ that GMPs apply ‘beginning with the first use of the starting material’ in the manufacturing of the active ingredient. Once again, the note addresses both concerns about impurities introduced with starting materials and the expectation for multiple synthetic steps – including purification steps – in the API manufacturing process to ensure their adequate and consistent control. Adherence to GMPs ensure that the “validity of the control strategy do not change over time.” API starting materials are not addressed in the EU GMP guide, nor is there a legal framework to inspect manufacturing steps prior to the starting material for those who might offer to be inspected.
EXPLANATORY NOTE 5: This note addresses the term ‘significant structural fragment’ used in Q11 to characterize a starting material and states that it ‘applies to materials which contribute to the final molecular structure of the active substance’. This term does not apply to reagents, catalysts, or solvents used in the manufacturing process. Starting materials designation based solely on being a ‘significant structural fragment’ will generally not be acceptable.
EXPLANATORY NOTE 6: This note makes clear the need to consider the entire synthetic process and control strategy to justify identification of a material as a ‘starting material’. It is not acceptable to consider either the control strategy alone or a lengthy synthetic process as justification for identification as a starting material. Take a holistic view rather than simply applying a few convenient criteria to identify the starting material.
EXPLANATORY NOTE 7: This note applies to semi-synthetic starting materials and states that these should comply with the information provided in Note 6. Where a fermentation or an extraction step is determined to be critical (see note 2), then the process should be carried out under GMPs. In my experience, fermentation processes are complex and, thus, would generally be conducted as a GMP operation.
EXPLANATORY NOTE 8: This note addresses information to be submitted in the application for starting materials and includes the name, address, and synthetic route including all reagents, catalysts, and solvents employed. Specifications of starting materials should address both known and unknown impurities, limits for solvents and catalysts, and isomeric impurities (where applicable). Analytical methods for these determinations should be validated.
EXPLANATORY NOTE 9: This note addresses the need to justify the acceptability of the starting material taking a holistic approach to the principles identified in ICH Q11 section 5.1 rather than against each requirement individually. Again, the issue of impurities, residual solvents, and catalysts must be discussed and justified. The note ends with the statement that ‘An inadequate discussion on impurities renders evaluation of the proposed starting materials and their specifications impossible.’ This is similar to Note 6 in the expectation to take a holistic approach to identifying materials with this designation.
EXPLANATORY NOTE 10: This note addresses the need to include information in the application on the manufacturer of the starting material and the synthetic route used. Reference is made to Note 2 regarding the need to identify any critical steps in the manufacturing of the starting material and the potential impurity profile. The note further reminds the MAH that they have the legal responsibility to maintain the quality of the active substance through its expiry date, and that this may be sensitive to changes in specifications or manufacturer of the starting material.
EXPLANATORY NOTE 11: The final note addresses what constitutes a ‘commercially available’ starting material. Commercial availability alone may not provide significant justification for its designation. It is the responsibility of the MAH to show that the starting material is adequate for its intended purpose and ‘…that a commercially available starting material is not custom synthesized, but a commodity material used in a non-pharmaceutical market, and to provide supportive documentation in the dossier demonstrating so.’ And, again, if the commercially available material is subject to additional purification, the ‘impurity profile should be presented for assessment.’
In conclusion, the reflection paper focuses on understanding, justifying, and controlling the impurities in starting materials to ensure consistent manufacturing of active substances. The reflection paper provides additional granularity beyond what the original ICHQ11 and the associated Q&A document provides. What may be lost in perceived flexibility for manufacturers may be made up by reducing the risk that starting material choices will be deemed acceptable in Marketing Applications.
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