Post approval drug manufacturing supplement for NDAs/ ANDA submitted to FDA for Major or Moderate manufacturing change.
If a manufacturing change is considered to be major, an applicant must submit and receive FDA approval of a prior-approval supplement (PAS) before the drug product made with the change is distributed.
If a manufacturing change is considered to be moderate, an applicant must submit a supplement at least 30 days before the drug product is distributed (a CBE-30 supplement) or, in some cases, submit a supplement at the time of distribution (a CBE-0 supplement). “CBE” means “changes-being-effected”.
2. CBE 30 (Change being effected before 30 days):
3. PAS (Prior approval supplement):
i.e. - Change in storage condition.
i.e. - Relaxation of approved specification.
Management of Drug Submissions (drugs for human use)
Management of Regulatory
Submissions (drugs for veterinary use).
1. Level
I ‐ Supplements (major quality changes)
Level I ‐ Supplements
(Major Quality Changes) are changes that have a substantial potential to have
an adverse effect on the identity, strength, quality, purity, or potency of a
drug product as these factors may relate to the safety or effectiveness of the
drug product.
In general, a change that
is supported by extensive documentation and/or requiring extensive assessment
of the supporting documentation would be considered a Level I ‐ Supplement (Major
Quality Change) (e.g., a change supported by in vivo studies). This is to allow
Health Canada the opportunity to apply the principles of risk management by
having the necessary time for an appropriate assessment of the documentation.
This assessment will take into consideration any potential impact upon market
availability as well as the adverse effects on the identity, strength, quality,
purity, or potency of the drug product.
The changes included in
this reporting category shall be filed, along with the recommended
supporting data, to Health
Canada as a Supplement to a New Drug Submission (SNDS) or a
Supplement to an
Abbreviated New Drug Submission (SANDS). The change may not be
implemented by the sponsor
until a NOC has been issued.
2. Level
II ‐ Notifiable Changes (moderate quality changes)
Level II ‐ Notifiable
Changes (Moderate Quality Changes) are changes that have a moderate potential
to have an adverse effect on the identity, strength, quality, purity, or
potency of the drug product as these factors may relate to the safety or
effectiveness of the drug product.
The changes included in
this reporting category should be filed, along with the recommended supporting
data, to Health Canada as a Notifiable Change.
All Level II changes
should not be implemented by the sponsor until a No Objection Letter (NOL) has
been issued.
3. Level
III ‐ Annual Notification (minor quality changes)
Level III ‐ Annual Notification
(Minor Quality Changes) are changes that have minimal potential to have an
adverse effect on the identity, strength, quality, purity, or potency of the
drug product as these factors may relate to the safety or effectiveness of the
drug product.
The changes included in
this reporting category may be implemented by the sponsor without the prior
review by Health Canada of the data supporting such a change. All Level III
changes should be submitted using the Post‐Notice of Compliance Changes:
Notices of Change (Level III) Form. Supporting
data for the Level III changes recommended in this guidance document should
not be submitted; however, the data should be available to Health Canada
within thirty (30) calendar days, if requested at any time.
4. Level
IV Changes ‐ record of changes
ICH
Q12 - TECHNICAL AND REGULATORY CONSIDERATIONS FOR PHARMACEUTICAL PRODUCT
LIFECYCLE MANAGEMENT
This guidance is part of other ICH
guidelines based on quality evaluation of the drug product ICH Q8, Q9 and Q10.
It describes the concepts and directives to use the pharmaceutical industry
knowledge of the product to propose regulatory classification to the post approval
changes. In this way the guidance is amplifying the scope described in the
previous ICH guidance of the "quality by design" concept to the
marketed products.
ICH Q12 describes that the change
being proposed could be summarized in a post
approval management protocol (PACMP) that is applied to the
evaluation of the regulatory agency. This protocol needs also to describe
the established conditions (EC).
The EC can be described as the
summary of the important characteristics of the product that, when changed,
could cause an impact to its quality and/or safety. The PACMP in this context,
is a document that will summarize the change itself as well as the evaluation
of each EC when applying the proposed change, evaluating the risk of the
change. Depending on the knowledge of the product and the impact of the
proposed change, the company could propose a regulatory classification
different from described in previous post approval guidance. So, a change that
previously was being classified as type II variation could be classified even
as a notification depending on the PACMP information.
The PACMP has two steps: one is
the application of the protocol itself and the evaluation of the overall
strategy by the regulatory agency. In this step regulatory agency could agree
(or not) with the strategy, studies and the proposed regulatory classification.
The second step is the application of the results obtained following the PACMP.
The results could corroborate the initial protocol and, in this case, the
change could be implemented as defined in the protocol, or can be against what
was initially assumed. In this last case the change needs to be applied as a
post approval change to be evaluated by the Agency.
A last document is the product
lifecycle management (PLCM). This documents poses as a
"live" information of the product characteristics and the history of
the changes. It must be updated when a post approval or a PACMP is submitted or
evaluated and needs to reflect the actual regulatory status of the product
within the Agency. Is part of the quality system of the MAH.
The knowledge of the product not
only serves as an important part of the process to have a lower regulatory
classification but also serves to change the EC of the product. Depending on
the knowledge of the product an EC could be included, changed or excluded. This
changes on EC needs to be applied and approved by the Agency as well.
How this proposal fits to the
Brazilian regulation on post approval changes?
ANVISA is the regulatory Agency in
Brazil. The post approval change process in Brazil was totally changed by the
new regulation, RDC 73/2016, that replaced RDC 48/2009. Different from other
post approval changes regulation in high regulated countries as FDA and EMA,
the major changes are described in RDC 73/2016 and the document list for this
changes are also described in details within the regulation.
RDC 73/2016 describes categories
of variation that could range from an Annual reports to a post approval change
but all them are described and categorized. There is little to no room for
discussion in respect of regulatory classification for the proposed the change.
Also
RDC 73/2016 brought a document called "PATE" that is similar to the
"AF" in Japan and the PACMP described in ICH Q12. It needs to be
filled in each post approval change application and the company should describe
the product characteristics according to the last approval by the Agency
(similar to the EC) and the change itself evaluating how the change impacts the
controls, quality and efficacy of the drug product, very similar to the PACMP
process described in ICHQ12. The difference relies on the fact that, in Brazil,
no matter how do you know your product, there is little chance on classifying
it differently than described in RDC 73/2016. There is some room to apply to a
different classification when the change is related to the manufacturing
process and the company has process validation showing that the proposed change
does not affect the quality of the product, in this case the change could be
classified as minor and the regulatory classification will be by immediate
implementation. For other changes there is no space for discussion on regulatory
classification of the variation.
There is also no evaluation of
this PATE prior to the conduction of the studies. The company is responsible
for regulatory classification and the studies to be conducted according to it.
Once the documents for post approval application are finalized, the company
should apply them to ANVISA´s evaluation. If the company applied by wrong
regulatory classification (especially a minor instead of major change), the
company could be punished with the withdrawal of the application by immediate
implementation for all products within an year. This could make the companies
always apply for the worst scenario (post approval application) instead of
encourage them to use the knowledge to have a lower regulatory classification.
PATE could works as a PLCM
described in ICH because the company should have the PATE updated with the
change and ANVISA´s approval history.
As a member of ICH ANVISA will
need to comply at some time to the ICH Q12 guidance and the process of
evaluation is being conducted by the industry.
improvements, variability reduction, innovations and pharmaceutical quality system enhancements, thereby increasing the ability to fulfil quality needs consistently. Quality risk management can be useful for identifying and prioritising areas for continual improvement.
• Basic risk management facilitation methods
(flowcharts, check sheets etc.);
• Failure Mode Effects Analysis (FMEA);
• Failure Mode, Effects and Criticality Analysis (FMECA);
• Fault Tree Analysis (FTA);
• Hazard Analysis and Critical Control Points (HACCP);
• Hazard Operability Analysis (HAZOP);
• Preliminary Hazard Analysis (PHA);
• Risk ranking and filtering;
• Supporting statistical tools.
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