Regulatory Affairs Strategies for C M C

23 March 2021|C M C

Author : SANYAM GANDHI , Regulatory Strategy Lead , Takeda : LINKEDIN

Profile https://www.linkedin.com/in/sanyam-gandhi-87079314/

This article describes a drug registration process to facilitate the creation and commercial
implementation of Chemistry, Manufacturing, and Controls (CMC) strategy for marketing
applications and post approval changes for all marketed products. The process is intended to
implement the necessary controls throughout the product development and commercialization
process to assure consistency between operational cGMP documents and filed CMC dossiers
approved by Health Authorities for commercial products.
Chemistry, Manufacturing and Controls (CMC) can be defined as part of pharmaceutical
development that deals with the nature of the drug substance and drug product, the manner in
which both are made, and by which the manufacturing process is shown to be under control. This
information is provided in CTD Modules 2 and 3 of submission documentation as mentioned in
following diagram.

Different CMC Strategies are required for the new clinical trial submission, new marketing
authorization application (MAA) and change management.
Clinical Trial Submission:
investigational medicinal product dossier (IMPD) in EU and investigational new drug application
(IND) in US has information related to CMC. Applicant cover detailed plan about the Drug
substance and product in these sections.
At this stage product is in clinical trial phases so there are constant changes in the product
development. These changes may or may not require approval from health authorities depending
on the type of changes. Usually minor changes are not reportable and major changes are required
approval from health authorities.
Regulatory Affairs department develop strategy based on the type of product, dosage forms,
medical devise, orphan designation, rare disease etc. For example, if any devise is applicable in
drug administration then many drug-devise interaction studies needs to perform. Quality control
and specification needs to develop at this stage as well depending on the type of dosage forms.
Another example is Drug substance impurities needs to identify and assess with the respective
limits. R&D department quality these impurities based on the regulatory guidelines and control
them in final product. Few impurities are classified as degradation impurities which appear in
product as well over the time, so these impurities need to quantify and qualify in finished product
as well.

diagram 2: Reg CMC Strategies are applicable for each element mentioned in the for each step during clinical trials.

New marketing authorization application (MAA):

Regulatory Intelligence is first step to plan regulatory strategy for new marketing authorization
application. On same note, Reg CMC strategist must understand local requirements, where
products need to register and share relevant information to respective stakeholders in
organization which may be quality control, quality assurance, drug development, technology
transfer and many others.
For example, few countries require GMP (good manufacturing practices) inspection and approval
before submission of new MAA, while some countries allow GMP inspection along with MAA
review like Turkey, Russia. In many GCC countries GMP inspection is not required if site is audited
by the European or US health authorities. So, CMC Strategist will carefully plan MA submission
based on the local requirement.

Diagram 3 CMC Strategies vary in different scenarios

In addition to above, it also matters that which regulatory mechanism is being used for the drug
registration with health authorities as mentioned in diagram 4. Few mechanisms like accelerated
approval pathway, fast-track designation still require full CMC data compared to breakthrough
Therapy designation.

Change Management
Health Authorities issue license once review, and assessment of product is completed. This license
is required life cycle management activities forever. There might be many changes in drug product
and substance related to process, quality control, packaging, and batch sizes. These all changes
need to carefully evaluate within the company and with different health authorities.
There are variation guidelines with different health authorities which describes that which
changes are reportable, and which are not. Major changes like changes in manufacturing site,
batch size and specification require prior approval changes from health authorities. However
minor changes can be notified on annual basis.
Pre-agreement between agency and applicant also cover future changes and it cover major
variations, following is the definition:
a. EU Definition – A post approval change management protocol (PACMP) describes specific
changes that a company would like to implement during the lifecycle of the product and how
these would be prepared and verified.
b. US Definition – A comparability protocol is a comprehensive, prospectively written plan for
assessing the effect of a proposed CMC post approval change(s) on the identity, strength, quality,
purity, and potency of a drug product or a biological product (i.e., product), as these factors may
relate to the safety or effectiveness of the product (i.e., product quality).
Detailed guidelines are mentioned in the ICHQ12 and following diagram 5 covers different
elements of it.

Detailed guidelines are mentioned in the ICHQ12 and following diagram 5 covers different elements of it.
Challenges of the Regulatory CMC Strategies:
a. Regulatory compliance:
Within the EU, the marketing authorization holder and Qualified Person will be held responsible if
the manufacture of a medicinal product is not undertaken according to the details supplied in the
CMC section (CTD, Module 3 or equivalent) of the approved dossier. The legal framework in the
EU is defined in Directive 2001/83/EC, as amended, with key statements found within Articles 20,
23 and 51. Similar principles apply to the US and other international markets.
So, any CMC strategist must create fine balance between commercial demand and meeting
compliance requirement in timely manner.
b. Change in inevitable:
Generally pharmaceutical product faces vigorous changes from Drug Discovery to commercial
supply. These changes many be for commercial, compliance or any other reasons.
So, CMC strategist must understand all these changes with subject matter expert in detail and
analysis implications of it from different perspectives.
c. Regulatory intelligence
As global expansion plan, CMC strategist must collect local requirements in detail for each country
and it can be challenging task in implementing. For example, any pork origin excipient or API is not
allowed in many GCC markets. Brazil has very specific requirement for the analytical development
in linearity factor. Stability requirement are different from zone 1 to Zone IVb.
So, CMC strategist must understand local requirements well in advance before submission of
MAA. These local requirements should be presented to R&D functions to relevant reports can be
generated.
d. Commercial expectation:
As CMC strategist one should be able to assist commercial expectations related to product
launches on time, cost cutting projects and support for out licensing, merger. For example, many
times manufacturing sites change due to low cost productions or merger acquisition.
So, CMC Strategist should have ability meet commercial goals in timely manner with managing
compliance and regulation.