Pharmaceutical Development
It is
proposed that a new tripartite guideline be developed that would describe, at a
high level, the harmonised contents of Section 3.2.P.2. (Pharmaceutical
Development) within the Quality Module of the Common Technical Document. It is anticipated that the guideline will be written at a level that is commensurate with the intended purpose of
the Pharmaceutical Development Report, for example enabling the information
contained to be used for risk assessment.
Thus, the interpretation of the phrase “at a high level” should reflect
this intended purpose. By
this it is also meant that the guideline should be developed to describe ‘what’
is to be discussed in Section P.2 but the guideline generally would not define
the ‘how’ – the details of the studies that should be carried out. This guideline will focus on principles of
quality by design, and will incorporate concepts from the parallel discussions
of risk management that should emerge from the proposed EWG on this topic.
Currently,
the EU has an implemented guideline (Note for Guidance on Development
Pharmaceutics) that describes what might be included in Section P2. More recently, the FDA has issued a draft
guidance that proposes the content of P2, tailored to US regulatory
expectations. However, it has been agreed within the CTD-Q IWG that a
harmonised guideline would be beneficial since there is not a consistent
approach for providing and evaluating this information across the three
regions. Industry will benefit by being
able to design scientifically based development studies to meet a single set of
expectations for the ICH regions. Regulators will benefit in that they can
apply their resources to the critical-to-quality elements of the product and
process in a more focused and guided way.
As agreed
in the discussions during the development of the CTD, CTD-Q provides a Section
3.2.P.2 where the applicant can include information on pharmaceutical
development studies. The proposed guideline will elaborate the knowledge
requirements that guide the technical and scientific studies that might be
carried out to establish that, for example, the dosage form, formulation,
manufacturing process and development, container closure system, and
microbiological attributes are appropriate for the product described in the
application. These are generally ‘one
time’ studies that the applicant carried out in the course of the development
of the drug product and are part of a background and context of scientific
information that assists the Regulatory Reviewer in understanding the
critical-to-quality attributes of the drug product and its manufacturing
process. Potential topics to be addressed within P2 are illustrated below and
could include sections on
Drug substance
·
Key
physicochemical characteristics and
their impact on formulation and/or manufacturing process design
·
Compatibility
(with excipients and packaging materials)
Excipients
·
Key
physicochemical and/or biopharmaceutical characteristics
Drug Product
·
Rationale
for type of product
·
Formulation
development
·
Overages
·
Physicochemical
and biological properties and their impact on product quality (risk analysis)
·
Performance
testing
Manufacturing Development
·
Critical
to quality manufacturing steps and process controls and their contribution to
or interdependency with final product quality (risk analysis)
·
Choice
of sterilisation method
·
Relationship
of manufacturing performance and controls to end product testing (risk
analysis)
Container closure system (and delivery devices)
Microbiological attributes
Scope: what
is included from e.g.,
In summary, it is proposed that the scope be the combination of the scopes described in Q6a and Q6b. In terms of the process, however, it is envisaged that the majority of the activities will use experts knowledgeable about new chemical entities: Biotech input would also be sought at the appropriate times.
Additionally,
there may be merit in considering constructing the guideline to address
particular unit operations in design and manufacturing processes.
The types of studies and information that should go in this section so
as to be acceptable in the three regions.
Discussions
are also proposed to determine the role of this section in the overall
assessment process. This understanding will help frame the contents of the
guideline.
The primary purpose of this section is to provide information on how
development data have been transformed into knowledge of the manufacturing
science and technology thus helping reviewers to gain a better understanding of
product and process attributes that can influence product performance and
product quality. By
providing reviewers with the knowledge basis the applicant uses to judge
continuous improvement initiatives, it is hoped that the requirements for the
prior approval of changes might be moderated.
A goal for the section is to help developers and manufacturers to conduct successful technology transfers and manufacturing change controls throughout the life cycle of the product. How to achieve this should be discussed.
Another key
goal will be to develop a guideline that will help route field investigators
through the inspection process so they can focus their inspections on the
critical process steps and controls.
Initially, the Pharmaceutical Development section of CTD-Q will be used as regulatory submission document with a historical perspective. However, the knowledge and science-based discussion included within Pharmaceutical Development is intended to be applicable over the lifecycle of the product and may need to be updated as new information on the manufacturing science and technology become available. Specific topics to be addressed would be those described in the relevant sections of 3.2.P.2 of CTD-Q.
Background
to the Proposal
During the
development of the CTD-Q format document, there was consensus among the six
parties to consolidate the information described above within a single section
in the registration dossier: P.2.
However, the CTD-Q guideline describes the format of the section, not
its content. The IWG has discussed which
one of the CTD sections would most benefit from a guideline that would address
content, where such a guideline does not already exist. Section P.2 was considered to be the most
valuable, and this guideline will address the contents, at a high level, of
this section.
It is
proposed that this guideline be developed and implemented in phases. While elements of risk management and the
application of this guideline during the inspection process will eventually be
included, initial guideline development will focus mainly on those issues that
need to be addressed for the first regulatory submission and its review
process. Sections on risk management and
integration of the inspection process will require close linkages with the EWG
on Risk Management when that group is established.
Type
of Expert Working Group and Resources
A new
Quality EWG should be formed that is based on the CTD-Q IWG. This is because it would be extremely
beneficial if several of the EWG members were those involved in the development
of CTD-Q. Additionally, as it is the
intent of this guideline to reflect the needs of an integrated quality system
(review and inspection), ultimately it will be necessary for the composition of
the EWG to include industry and regulator members with inspection
experience. To keep the size of the EWG
manageable, it is suggested that the core group comprise two members from each
of the ICH parties and the overall EWG be comprised of not more than
three representatives from each of the ICH parties and one representative from
each observer. It is recommended that the third member, that is one with
manufacturing/inspection experience, be one of the members of a parallel EWG,
ideally Risk Management (assuming adoption of the topic).
Completion
of Concept Paper
Submission
to Steering Committee
Adoption of
topic by ICH Steering committee October 2003
First EWG -
Step 2
document end
2004
(dependent on progress by Risk Analysis EWG)