REGULATORY INNOVATIONS FDA AND ANVISA COMPLIANCE TRENDS

SEPTEMBER 9TH, 2016

TRENDS ON FDA COMPLIANCE: REGISTRATIONS/ICHQ11/ICHQ12

MAGALY E. AHAM, VP COMPLIANCE AND US OPERATIONS, PHARMA-BIOSERV US, INC.

DISCLAIMER

• All the material included in this presentation was obtained from publicly

available sources.

PRESENTATION TOPICS

• US 2015 Novel Drugs Summary

Regulatory Pathways available for approval of innovative therapies

• ICHQ11 Development and Manufacture of Drug Substances

Background

Ultimate Goal

Elements

Control Strategy

• ICHQ12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

Background

Goals

FDA Six System Inspection Approach

General Site Expectations

PQS Expectations

Conclusions

WHAT IS A NOVEL DRUG?

• Innovative Products that serve previously unmet medical needs

• Significantly help to advance patient care and public health

• New Molecular Entities (NME)

• Chemical structures that have never been approved before and for this particular

summary those that offer unique clinical advantages over existing therapies.

CDER NEW MOLECULAR ENTITY (NME) AND NEW BIOLOGIC LICENSE APPLICATION (BLA) FILINGS AND APPROVALS

22

18

24 26

21

30

39

27

41

45

26

35 34 36

23

41 41

36

41

[VALUE]*

0

5

10

15

20

25

30

35

40

45

50

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

NME/BLA Approvals NME/BLA Filings

• The 2015 filed numbers include those filed in CY 2015 plus those currently pending filing (i.e., within their 60 day filing period) in CY 2015.

• From 2006 through 2014 CDER has average about 28 novel drug approvals per year, so 45 novel approvals in 2015 was significantly higher than average of

past 8 years.

Source: http://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm474696.htm

NOVEL DRUGS APPROVALS DISTRIBUTION

35%

47%

18%

First in Class Orphan Drugs Other Drugs

• First in Class = Mechanism of action is

different from existing therapies

• Orphan Drugs = Treat rare diseases that

affect 200,000 of fewer americans

METHODS FOR EXPEDITING INNOVATIVE DRUGS TO MARKET

Regulatory Strategy Benefits 2015 Novel Drugs Results

Fast Track (FT) Increases level of communication with

FDA, enables CDER to review

portions of application ahead of final

submission.

14 (31%)

Breakthrough Therapy Includes FT benefits, more intensive

FDA guidance on efficient drug

development program.

10 (22%)

Priority Review FDA review in 6 months instead of 10

months target.

24 (53%)

Accelerated Approval Approval based on “surrogate end

point” to predict clinical benefit

6 (13%)

CDER used a number of regulatory pathways to expedite the development and approval of novel drugs in 2015 which

included:

ICHQ11 DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES

(CHEMICAL ENTITIES AND BIOTECHNOLOGICAL /

BIOLOGICAL ENTITIES)

ICHQ11 BACKGROUND

• In 2008, ICH Steering Committee understood that concepts described on

ICHQ8, Q9 and Q10 applied to both drug substances and drug products,

however, manufacturing processes for drug substances were very different

from drug product (i.g. purification), therefore the need to provide further

clarity on how the principles applied to drug substances was needed along

with some examples.

ICHQ11 DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES

• ICH published guideline on May 1, 2012

• Problem Statement: “..to develop a new

tripartite high level technical guidance

harmonizing the scientific and technical

principles relevant to the design,

development and manufacture of drug

substances as part of a total control strategy

designed to ensure product quality and

consistency.”

Q11 FDA GUIDANCE

• FDA followed publishing “Guidance for

Industry, Q11 Development and Manufacture

of Drug Substances on November 2012.

• Addresses aspects of the development and

manufacture of drug substances designed to

reduce impurities

• Further clarification on Q8, Q9 and Q10 for drug

substances

ICHQ11 ELEMENTS

• Manufacturing Process Development

• Description of Manufacturing Process and Process Controls

• Selection of Starting Materials and Source Materials

• Control Strategy

• Process Validation / Evaluation

• Submission of Manufacturing Process Development and Related Information in CTD Format

• Lifecycle Management

CRITICAL QUALITY ATTRIBUTE

Physical

Range

Limit

Chemical Microbiological

Biological

Desired

Product

Quality

GENERAL PRINCIPLES - PROCESS DEVELOPMENT

The goal of manufacturing process

development for DS is to establish a

commercial manufacturing process

that consistently produces a DS of

intended quality.

Quality Target Product Profile

(QTPP), potential DP CQA’s and

previous experience from related

products can help identify CQA’s for

DS.

DEVELOPMENT PROCESS

Quality Target Product Profile (QTPP)

Determine “Potential” Critical Quality Attributes

Link raw material attributes and process parameters to CQA’s and perform

risk assessment

Develop a design space (optional not required)

Develop and implement a control strategy

Manage product lifecycle and continual improvement

CONTROL STRATEGY

• Planned set of controls derived from product and process understanding that

assures process performance and product quality.

• Every DS whether developed through a traditional or an enhanced approach (or some

combination thereof), has an associated control strategy which can include, but it is not

limited to the following:

• Controls on material attributes (e.g., of raw materials, starting materials, intermediates..);

• Controls implicit in the design of the manufacturing process (e.g. sequence of purification steps

(biotech DS), or order of addition of reagents (chemical entities);

• In-process controls (including in-process tests and process parameters);

• Controls on drug substance (e.g. release testing)

CONTROL STRATEGY APPROACHES

Traditional Approach Enhanced Approached

Set points and operating ranges are typically set

narrowly based on the observed data to ensure

consistency

Better process and product understanding than the

traditional approach, so sources of variability can be

identified in a more systematic way

Emphasis placed on assessment of CQA’s at the

stage of DS (i.e. end product testing)

Allows for development of more meaningful and

efficient parametric, attribute and procedural

controls

Limited flexibility in operating ranges to address

variability

Can provide flexibility in operating ranges to

address variability

ICHQ11 ULTIMATE GOAL

• To ensure there is solid understanding of the drug substance for its intended use, this includes:

Inputs to DS manufacturing process (raw materials, risk assessment, criticality)

DS CQA’s

Intended use

Process Development, enhanced approach will provide additional process understanding and ability to

react to process issues based on DS and process understanding

Control Strategy for the DS that ultimately will allow for increased flexibility from the regulatory

authorities as companies will be able to demonstrate they understand their process and the design space

of the DS.

ICHQ12 TECHNICAL AND REGULATORY CONSIDERATIONS FOR PHARMACEUTICAL

PRODUCT LIFECYCLE MANAGEMENT

“THE ROBUST PQS”

ICHQ12 BACKGROUND

• What problem / issue is the proposal expected to tackle?

• Lack of a harmonized approach on technical and regulatory considerations for lifecycle

management. While the concepts in ICHQ8, Q9, Q10 and Q11 provide opportunities for a more

science and risk-based approach for assessing changes across the lifecycle, several gaps exist which

limit full realization of intended benefits. The envisioned post approval “operational flexibility” has

not been achieved.

• An ICH harmonized approach on technical and regulatory considerations for lifecycle management

will benefit industry, regulators and patients by supporting continued assurance and supply of high

quality product.

FDA DRAFT GUIDANCE: ESTABLISHED CONDITIONS

• May 2015 published draft guidance for

Reportable CMC changes for Approved Drug

and Biologic Products which is aligned to

goals of ICHQ12

• Differentiates between “Established

Condition” versus “Regulatory Commitment”

information included in the CMC section

• Intend is to clarify what post approval

changes can be managed under the company’s

PQS without the need to report to FDA

ESTABLISHED CONDITIONS

• Description of the product, manufacturing process, facilities and equipment, and elements of

the associated control strategy, as defined in an application, that assure process performance

and quality of an approved drug. Changes to the established conditions must be reported

to FDA. Examples include:

Parameters and attributes related to DS, excipients, in-process materials, DP

Facility and equipment operating conditions

Methods of sampling, testing and control

Container Closure system, components and specifications

LINKING ESTABLISHED CONDITIONS TO CONTROL STRATEGY

Established Conditions

Control Strategy

Control Strategy Elements

Reported in an Application

Overall control strategy

including facility environmental

controls, batch records,

development data (not typically

reported in submission)

Supportive of product,

process, controls, etc

Elements necessary to

assure process

performance and

product quality

ICHQ12 GOALS

• Provide a framework to facilitate the management of post approval CMC changes in a more

transparent and efficient manner across the product lifecycle. Adoption of this guideline will

promote innovation and continual improvement and strengthen quality assurance and reliable

supply for product. It will allow regulators (assessors and inspectors) to better understand ,

and have more confidence and trust in a firm’s Pharmaceutical Quality System (PQS) for

management of post approval changes. ICHQ12 is intended to compliment the existing

ICHQ8-11 guidelines.

ICHQ12 AND THE ROBUST PHARMACEUTICAL QUALITY SYSTEM (PQS)

• Will tackle a key issue, management of the quality systems.

• Most companies have instituted quality systems, however major issues are constantly

surrounding how these systems are managed; training, system administration, management

controls and oversight.

FDA SIX (6) SYSTEM INSPECTION APPROACH

• Under this approach, QS is at the center and is always covered, a failure in this system is a

failure of the inspection.

Why?

Because QS are the backbone

of other instituted systems

GENERAL SITE EXPECTATIONS

• Sites must operate in conference with cGMP

• Must have robust manufacturing processes and controls

• Must have adequate governing systems (i.e. six systems)

PQS EXPECTATIONS

• Process Performance and Product Quality Monitoring system (PPPQMS) used across the

product lifecycle

• Expert teams to lead CAPA and changes

• Formal approach to change management

• Knowledge management and accessible across product lifecycle

• QRM a foundational driver of PQS

• Management Commitment to Quality

• Prioritizes complying with established quality and patient needs

PQS EXPECTATIONS

Pharmaceutical

Development

Technology Transfer Commercial

Manufacturing

Product

Discontinuation

PPPQMS PPPQMS PPPQMS PPPQMS

CAPA CAPA CAPA CAPA

Change Management Change Management Change Management Change Management

Management Review Management Review Management Review Management Review

Implementation across product lifecycle and multi dimensional integration

CONCLUSION

• In order to achieve the desired state, PQS must meet goals covered in ICHQ10

• Regulators must recognize that the PQS is robust when inspecting

• Knowledge management must be integrated across lifecycle

• Initial established conditions (EC’s) were reached through sound processes

• There is effective post approval control and adherence to EC

• EC’s remain current based on current process knowledge

ICHQ12 ADOPTION OF STEP 4 DOCUMENT

• Targeted for 2Q 2017

OVERALL CONCLUSIONS

• In order to get product approvals, companies must devise a scientific and risk based approach to

their product lifecycle.

• The more knowledge you have about your processes, the more in control you can be. Risk

Management and Knowledge management should be at the center of these strategies as depicted

in ICHQ10 as “enablers”

• Process Understanding will aid in establishing control strategies to ensure your DS and ultimately

your DP meet desired quality.

• You cannot demonstrate control if your PQS is not robust. There should be constant monitoring

and establishment of key performance indicators (KPI’s) to aid in diagnostic and continual

improvement.

• The more control you demonstrate, more regulatory flexibility will be afforded.

REFERENCES

• International Conference of Harmonization Website;

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

• Food and Drug Administration Website; http://www.fda.gov/

• Novel Drugs Summary 2015;

http://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm474696.htm

CONTACT INFO: MAGALY E. AHAM MAHAM@PHARMABIOSERV.COM

MOBILE: 215-272-7975