Methods for stability of APIs and drug products. Batches of API and drug product are typically exposed to accelerated stress conditions and tested at timed intervals to assess
whether any degradation has occurred. The shelf-life of the API or drug product—that is, the time period of storage at a specified
condition within which the drug substance and drug product still meets its established specifications, is based on analytical
data generated from these studies. For this application, analytical methods need to be stability-indicating (e.g., capable
of detection and quantitation of the degradants) to ensure quality, safety, and efficacy of a drug substance and drug product.
Often, the analytical methods used to perform stability tests are the same methods used to test against a specification for
release testing; these methods should be validated. However, if additional tests are performed which are not included in the
established specification, they may be qualified for their intended use, rather than validated.
In-process testing methods. In-process testing (IPT) during manufacturing of drug substance and drug product can be done on-line, in-line, or off-line.
The results generated from IPT are used to monitor processes involving reaction completion, removal of solvents, removal of
impurities, and blend content uniformity. Manufacturing parameters may be adjusted based on IPT results. IPT methods are often
very limited in scope. In early development, the primary benefit of performing IPTs is the generation of process knowledge,
and not as a control or specification. As a result, even though IPT is essential for manufacture of drug substance and drug
product, method qualification for an IPT method is appropriate in early-phase development.
Documentation and other requirements. The extent of documentation and associated practices in early development should be aligned with the appropriate level of
method validation as discussed above. In this paper, the authors provide a perspective on the appropriate level of documentation,
protocol and acceptance-criteria generation, instrument qualification, and oversight of the quality assurance unit for early-phase
method validation and qualification. This approach provides development scientists with flexibility to efficiently adapt to
the dynamic environment typical within early phase pharmaceutical development, while ensuring patient safety and the scientific
integrity of the validation process.
With respect to documentation, it the IQ perspective that the raw data which is generated during early phase method validation
should be generated and maintained in a compliant data storage format. The integrity of raw data should be controlled such
that it can be retrieved to address future technical and compliance-related questions. Proper documentation of data and validation
experiments should also be considered an important aspect of early phase validation. The availability of electronic notebook
(ELN) systems has provided a viable, more efficient alternative to the use of traditional bound-paper notebooks. In developing
policies to implement ELNs, the goal should not be that all documentation practices used with paper notebooks are replicated.
Rather, the ELN should possess sufficient controls for the intended use of the data. In many cases, electronic systems such
as ELNs will transform the work process, and the controls it provides will be achieved in a completely novel manner compared
to the outdated system being replaced.
Although data needs to be documented as described above, it is the authors' position that formal, detailed method and validation
reports are not required to ensure compliance in early development. Adequate controls need to be in place to ensure method
parameters used to execute validated methods are equivalent to parameters used during validation. Generation of brief method
and validation summary reports are required only when needed to fulfill regulatory filing requirements or to address requests
or questions from health authorities. Validation summaries are not required to present all of the validation data, but rather
a summary of the pertinent studies sufficient to demonstrate that the method is validated to meet the requirements of its
intended use. Once reports are generated and approved internally, approved change control procedures should be available and
followed to maintain an appropriate state of control over method execution and report availability.
Although the authors' perspective is that a validation plan needs to exist for early phase method validation, analytical organizations
could consider different mechanisms to fulfill this need. For example, internal guidelines or best practice documents may
sufficiently outline validation requirements such that a separate validation plan need not be generated for each method. In
the absence of such a guideline or procedure, a validation plan could be documented in a laboratory notebook or ELN which
includes a brief description of validation elements and procedures to be evaluated. Validation plans should ensure that the
method will be appropriate for its intended use. The use of strict validation criteria within the validation plan should be
limited at these early stages of development. Validation studies for early development methods may be performed on fit-for-purpose
instruments which are calibrated and maintained, but not necessarily qualified or under strict change-control standards.
The role of the pharmaceutical quality system and the oversight over early phase method validation practices and documentation
is another area for consideration. In the pharmaceutical industry, quality management is overseen by a "Quality Unit" that
qualifies and oversees activities in the areas of GMP materials such as laboratory controls. In practice, the size and complexity
of the Quality Unit overseeing GMP manufacturing varies based on a manufacturer's size and stage of drug development. Regardless,
the basic aspects of a quality system must be in place. In early development, IQ's position is that, because API and drug-product
manufacturing processes are evolving, the analytical methods do not yet require full validation as prescribed in ICH Q2. Correspondingly,
the quality system implemented during early phases could consider that evolving analytical methods are intrinsic to the work
being performed to develop the final API and drug product processes and could allow flexibility to readily implement method
changes during early development. For example the Quality Unit should delegate oversight for validation plan approval, change
control, approval of deviations and reports to the analytical departments prior to finalization and performing full ICH Q2
validation of the analytical methods. This approach would be consistent with Chapter 19 of ICH Q7A. However, analytical departments
must ensure that early phase validation studies are conducted by qualified personnel with supervisory oversight who follow
approved departmental procedures. Clearly, agreements between Quality Units and analytical departments to implement an appropriate
strategic, phase-based quality oversight system would provide many benefits within the industry.