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ICH Q6A specifications: Test procedures and acceptance criteria for new drug substances and new drug products: chemical substances

Specifications (test and acceptance criteria) for active pharmaceutical ingredients (APIs) and drug products are defined in ICH Q6A. It ‘establishes a set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use.’ The guidance is sub-divided into universal tests applicable to all APIs and drug products, i.e. description, identity, assay and impurities; as well as those specific tests which are applicable on a case-by-case basis. Thus, specifications are critical quality criteria that are proposed and justified by the manufacturer and subsequently approved by the licensing authority.

Specifications form one facet of the control strategy intended to ensure product quality and process / batch consistency, supplemented by current Good Manufacturing Practices (cGMP) and thorough product understanding.

The guidance was developed for the approval of commercial products and was not intended for clinical development, although the concepts are still applicable. During development, knowledge of critical quality attributes (CQAs) may be limited, as significant changes in both synthesis / process (API) and formulation / process (drug product) would be anticipated. ICH M3 provides some useful insight for qualifying impurities during the development phase:

“The approaches for qualifying impurities and degradants are outlined in ICH Q3A and Q3B. If specific studies are warranted to qualify an impurity or degradant, generally these studies are not warranted before Phase III, unless there are changes that result in a significant new impurity profile (e.g., a new synthetic pathway, a new degradant formed by interactions between the components of the formulation).”

As the API and drug product evolve towards the final commercial processes, CQAs will be identified, trended and specified. There may be a requirement to manufacture batches at the proposed commercial scale in order to fully specify CQA limits or proven acceptable ranges (PARs). However, it is important to realise that not all CQAs need to be included in the specification. For example, ICH M7 allows for four options to control genotoxic impurities (GTIs), only one of which includes control of GTI on API specification (Option 1). Options 2 and 3 specify some levels of in-process control, whereas Option 4 is based on process understanding alone.

The main quality drivers that need to be considered during specification development are:

  • manufacturing process capability
  • analytical methods capability
  • release and stability data
  • regulatory and safety limits on impurities, e.g. ICH Q3C, ICH M3, ICH M7
  • specific regulatory / compendia requirements, e.g. assay, uniformity, sterility, etc.

The relationship between process capability and specifications are key, but are often misunderstood. For instance, if the proposed specification is tightened (after regulatory review) it will adversely impact on process capability and vice versa.

There is also a relationship between process capability and safety limits, exemplified by ICH Q3C and ICH M7.The former guideline identifies the limits that are placed on Class 1, 2 or 3 solvents in APIs. These residual solvent limits are based on safety data and typically defined as PDEs (personal daily exposure) and converted into ppm limits on the specification. However, ICH Q3C also states:

“provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process and the limits should reflect contemporary manufacturing standards.”

So in reality, process capability typically supersedes the safety driven limits given in the ICH Q3C guidance, but not in the ICH M7 guidance.

In principle, in a non-Quality by Design (QbD) environment, the specifications are the primary means of control (along with cGMP, supplemented by relevant ICH guidelines) and are based on batch data available at the time of registration. In contrast, in a QbD paradigm, specifications are part of the overall quality control strategy based on the desired product performance with relevant supporting data; i.e. the Design Space, CQAs, Critical Process Attributes (CPAs) and PARs.

However, industry has expressed recent concern about the potential for misalignment and resultant inconsistency between ICH Q6 and the emerging QbD concepts. Additionally, continuous processing can blur the definitions of a ‘batch’, whilst the use of on-line or at-line testing (process analytical testing (PAT)) leading to ‘real-time’ release can also blur the designation of specifications and therefore challenge our perceptions of the applicability of the supporting control measures.

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