Introduction
This document recommends the strategy for the filing of specifications for raw materials used in the manufacturing of Active Pharmaceutical Ingredients (APIs). A common strategy if used by all affiliate sites, will establish consistency in the API raw materials registered specification and insure that only the minimum appropriate specifications are filed. The strategy is designed primarily for new products filings.
Practice
Review of historical practices for filing API raw material specifications shows that the level of detail is varied across Site, from minimum filing appropriate for the intended use of the material, to large number of specifications of limited value and the related detailed analytical methods.
In order to provide consistency in filing API raw material specifications and regulatory flexibility, this guidance provides recommendations as to the level of specifications required for various categories of raw materials. The categories were defined based on common knowledge of manufacturing process and the level of specifications was established based on the nature of the material and its intended use of each category. Raw materials are categorized in six (6) groups.
General background
The major markets (USA, Europe, Canada, Australia, Japan, South Korea, Singapore) regulatory guidance’s do not provide specific instructions on what specifications to file for API raw materials but indicate that the specifications must be appropriate for their intended use. These major markets guidance’s are either directly using the ICH M4Q (guidance for the Common Technical Document (CTD)) or a slight modification of the M4Q guidance.
Extract fromM4Q, section 3.2.S.2.3: Control of Materials (Drug Substance):
“Materials used in the manufacturing of the drug substance (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided.
Information demonstrating that materials (including biologically-sourced material, e.g. media components, monoclonal antibodies, enzymes) meet standards appropriate for their intended use (including the clearance or control of adventitious agents) should be provided, as appropriate.”
This strategy addresses only the registered raw material specifications defined as the test technologies and limits provided to “external agencies and are legally binding”. It is expected that PGM API sites will evaluate whether additional internal targets to control the quality of the incoming raw materials are required. Limiting the registered specifications to the minimum requirements allows for future flexibility to adapt to the commodity market for API raw materials, to advances in analytical technology, and to implement improvements without the need for changes in the regulatory filing. Quality of the raw materials will not be compromised, as the sites will use systems and internal targets to control and monitor performance of the suppliers.
General requirements for filing
- Analytical method: Specifications should be limited to a listing of the appropriate technology or method (i.e. HPLC, GC, NIR) with the associated limit. The details of the actual analytical methods or reference numbers should not be included. There may be some rare instances (such as an advanced intermediate or starting material that are close to the final API) where the analytical methods may be required but this should be the exception.
- Grade: Grade or tradename of raw materials should not be registered (i.e. Nitrogen instead of Nitrogen NF, Oxygen instead of USP Oxygen) and generic description is preferred (i.e. Carbon black instead of the carbon grade such as Darco). If a particular attribute of a grade has impact on the process or the API quality, only that attribute should be specified.
- Hazardous materials: The regulatory filing should clearly indicate that due to the hazardous nature of the material, it will never be sampled and tested by Site. The material will be accepted on supplier Certificate of Analysis data.
Categories Definition and filing strategy
For the purpose of this guidance, API raw materials were categorized into several groups for which a different level of registered specifications would be required. The categories are defined based on general “intended use”.
Category 1:
Raw materials in this category contribute to a significant portion of the final API molecule. This would include the regulatory starting material and registered intermediates. This category requires the highest level of specifications and should include at a minimum identification and a measure of purity. The specifications may also include impurities, optical properties.
Category 2:
This category includes any raw material that has one or more attributes that could impact the process or the quality of the API. The specifications should include the basic specification for the category of the raw material and in addition, the critical attribute. For example if a solvent (a category 3 raw material) had a very low moisture requirement for a specific step, the specification would include the category 3 specifications plus the moisture requirement.
Category 3:
This category includes materials that have a minor contribution to the final API molecule (such as addition of a Carbon atom to the structure), or provide a protective group which is subsequently removed. This category also includes solvents, acids and bases. In addition to the identification test, typically a measure of the purity of the material would be required.
Category 4:
This category includes basic raw material such as salts. The recommendation is to limit the registered specification to the identification test. Category 4 also includes processing aids; however, according to ICH Q7A 7.32, these materials can be received on COA. The identification test in the case of processing aids, if registered, should be transcribed from the supplier’s Certificate of Analysis.
Category 5:
This category includes materials that are highly toxic or too hazardous to sample and test at the manufacturing site. The registered specifications should be limited to the requirement of the basic category of the raw material. The registration should clearly indicate that due to the hazardous nature of the material, it will never be sampled and tested by Site and will be accepted on supplier Certificate of Analysis data.
Category 6:
This category includes utilities such as nitrogen and water. Specifications in general should not be filed unless required by prevailing guidances. Specifications for water may be required depending where in the process water is used and how the API will be delivered to the patient. (See reference (2) for example of guidance that requires specification for water under specific conditions)
Summary of Filing Strategy
| Category | Minimum specification Filing |
| 1 | Identification, potency, purity (include main impurities, if appropriate). Attributes that impact API quality |
| 2 | Base specifications (using strategy below). Critical parameters |
| 3 | Identification, potency, purity (include main impurities, if appropriate). |
| 4 | Identification |
| 5 | Basic category requirements but specify that raw material is accepted on supplier COA |
| 6 | Preferably should not be filed |
Process flow for development of registered specifications
In general the primary responsibility for the development of raw materials specifications resides with Analytical Research and Development. The following process flow is recommended:
- R&D identifies the required raw materials for the synthesis of an API and any raw material quality attributes that impact the quality API during process development.
- R&D determines whether registered specifications for the raw materials are already available.
- If specifications are available, R&D evaluates the specification against any know quality attributes required for the process.
- If the specifications are acceptable, they are utilized for the new filing (the underlying assumption is that the existing specifications were established according to the strategy outlined in this document and therefore the specifications are acceptable to all stakeholder groups including the manufacturer. They should be revised if they do not meet the guidelines given in this document.
- If registered specifications do not exist or if quality attributes are required in addition to the current established specifications, R&D, in collaboration with the manufacturing site and the co-development team develops the new specifications based on the above strategy.
- R&D finalizes the specifications and creates the required Material Control Document