Quality and Regulatory Aspects in Early Phase Development

Quality and Regulatory Aspects in Early Phase Development of Pharmaceutical Products

PDA Israel

Key areas for strategic drug development

planning

Ramat Gan, 24th October 2018

Rivka Zaibel

והאיכותהרגולציה יסודות

מערך איכות –הביורפואיותאיכות בתעשיות אבטחת •

?cGMPמה זה •

•21 CFR 210, 21 CFR 211, 21 CFR 630

•ISO 13495, Quality System Regulation21 CFR 820

•EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines

•ICH Quality Guidelines

2

?איזה מערך איכות מתאים לי

:הגדרת המוצר

.השלב הראשון בקביעת הרגולציה ומערך האיכות המתאים הוא הגדרת המוצר

תרופה

מוצר ביולוגי

תרפיה תאית

תרפיה גנטית

אביזר רפואי

(Combination product)מוצר משולב

:מאפיינים אחרים שמשפיעים על מערך האיכות הם

תהליך הייצור

('השתלה וכו, משאף, קפסולה למתן אוראלי, משחה, זריקה)דרך מתן המוצר

3

? מה ניתן לעשות ומה צריך לעשות בתקופת החממה

First in manלהגיע עד : מטרה

לעשות את הדבר הנכון והנדרש ולא את מה שקל לעשות

הוכחת היתכנות

תהליך ייצור

פיתוח שיטות אנליטיות

כימות )ולידציה של שיטות אנליטיות התומכות בטוקסיקולוגיה ובקליניקה

(בדיקת הווצרות נוגדנים, חומר בפלסמה

GLPלא כולם מחייבים תנאי , מבחנים פרה קליניים

מתווה לניסוי קליני פאזה ראשונה

4

דרישות מיוחדות עבור מוצרים ביולוגיים

:ביולוגי/הביוטכנולוגימורכבות המוצר

, תאים מן הצומח, תאי יונקים, חיידקים)תלות במערכת ביולוגית בייצור

(תאים הומניים, מוצרי דם

ביולוגיות לקביעת פעילות, תלות בשיטות אנליטיות אימונולוגיות

חיידקים ומזהמים נוספים בלתי ידועים ומוגדרים , סכנת המצאות וירוסים

מראש

שימוש בחומרי גלם ממקור ביולוגי

מחסור במודלים לאיפיון המוצר ולפיתוח הפרה קליני שלו

ל מהווה אתגר למפתחים ומעלה את הדרישות הרגולטוריות הקיימות "כל הנ

לפני ביצוע ניסוי קליני כלשהו

5

הגדרה-אביזרים רפואיים

510K, PMA, CE mark

דהיינו אין , אביזר לשימוש ברפואה אשר אינו תרופה/אביזר רפואי הינו מוצר

.פיזיולוגית, לא פעילות מטבולית

קיימות שלוש רמות של אביזרים רפואיים לפי מידת המורכבות והנגיעה בגוף

Class 1, Class 2, Class 3, האדם

510K , דרך רישום של אביזרים רפואיים אשר נמצאוsubstantially equivalentבדרך כלל בדרך רישום זו . ב"לאביזרים רפואיים רשומים בארה

ניתן להמנע מניסויים קליניים

PMAב"רישום של אביזר רפואי חדש בארה.

CE mark–אישור שיווק אביזרים רפואיים באירופה

6

ISO 9001-2000, ISO 13495, Quality System

Regulation

ר על פי הרגולציה האירופאית הוא "אחד ההבדלים העיקריים בין תרופות לאמ

. שלא ניתן להתחיל ניסוי בבני אדם לפני שמכינים תיק טכני

ISOלפי תקן Biocompatibilityלצורך כך יש להשלים מבחני בטיחות

.וכן הקמה של מערך איכות, 10993

7

אתגרים של טכנולוגיות מתקדמות

Combination Productsו

ההתפתחות שחלה בשנים האחרונות בחקר הרפואה

המותאמת אישית מעודדת גם פיתוח של טכנולוגיות

השילוב הזה . דיאגנוסטיות שלא היו ידועות עד היום

מעמיד בפני המפתח והרגולטור אתגרים נוספים

. בהקשר של הגדרת המוצר

יש לקיים דו שיח , עד אשר יכתבו הנחיות רלוונטיות

עם הרשויות הרגולטוריות על מנת להגיע להבנות

.לגבי מה שנדרש ומה יהיה מקובל

8

9

Development Phases

cGMP and Quality System Requirements

Through Development

10

cGMP Regulations

11

Definition of cGMP

“…the minimum current good manufacturing practice for

methods to be used in, and the facilities or controls to be

used for, the manufacture, processing, packing and holding

of a drug to assure that such drug meets the requirements of

the act as to safety, and has the identity and strength and

meets the quality and purity characteristics that it purports

or is represented to possess.”

-(21 CFR 210.1)

12

cGMP

current Good Manufacturing Practices

GMP is a dynamic concept and practice.

Staying “current” is driven by technology, improved practices

and regulatory issues.

13

Principles of cGMP

Essential Elements and Concepts of cGMP

• Good Documentation Practices

• Quality Systems (deviations; investigations; CAPA

and OOS)

• Facilities and Equipment Management

• Change Control Systems

• Materials Control

14

Compliance

Compliance with cGMP regulations is

the responsibility of the entire company

AND specifically the top management

15

Guidance for Industry

CGMP for Phase 1 Investigational Drugs

July 2008

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

Office of Regulatory Affairs (ORA)

cGMP for Phase 1 Investigational Drugs

16

Special Manufacturing Situations

Multi-Product Facilities

Biological and Biotechnological Products

Sterile Products/Aseptically Processed Products

cGMP for Phase 1 Investigational Drugs

17

Improve analytical methods, characterization and additional

aspects of product development

For Phase 3, The information amendment should include evidence

to support the elucidation and characterization of the structure.

This information can include elemental analysis, conformational

analysis, molecular weight determination, spectra from IR, NMR (1

H & 13C), UV, MS, optical activity, and if available, single crystal X-

ray diffraction data, if not previously provided. Analytical

procedures used to characterize the primary reference material

should also be provided in an information amendment.

Stress studies

cGMP for Phase 2 and 3 Investigational Drugs

18

EMA Guideline on the Requirements for the chemical and

pharmaceutical quality documentation concerning investigational

medicinal products in clinical trials

Final

May 2018

19

Information on chemical and pharmaceutical quality documentation

concerning investigational

medicinal products in clinical trials

IMPs should be produced in accordance with the principles and

the detailed guidelines of good manufacturing practices for

medicinal products (The rules governing medicinal products in

the European Community, Volume IV).

20

S.2.2.

A brief summary of the synthesis process, a flow chart of the

successive steps including, for each step the starting materials,

intermediates, solvents, catalysts and critical reagents used

should be provided. The manufacturing process and process

controls should be adequately described in such extent so it is

understood how impurities are introduced in the process, and

why the proposed control strategy is suitable.. During

development, as additional process knowledge is gained, further

details of IPCs should be provided and acceptance criteria

reviewed

Information on chemical and pharmaceutical quality

documentation concerning investigationalmedicinal products in clinical trials

21

S.2.4.

Control of Critical Steps and Intermediates

Tests and acceptance criteria for the control of critical steps in the synthesis process should be briefly summarised.

S.2.5.

Process Validation

Data on process validation should normally be collected throughout the development by the company, although they are not required to be submitted in the IMPD



22

S.2.6.

Manufacturing Process Development

It should be documented if the manufacturing process significantly

differs from that used for the production of the batches used in the

non-clinical studies.

Significant changes in the manufacturing process, which may

impact on quality, should be discussed.



23

S.4.

Control of the Drug Substance

3.4.1 Specification

The specifications, the tests and their acceptance criteria should be

specified for the batches of drug substances to be used in the clinical

trial.

Tests for identity, impurity and assay are mandatory

Upper limits should be set for impurities and they should be supported

by the impurity profile of the batches used in non-clinical studies.

The microbiological quality for drug substances used in aseptically

manufactured products should be specified.

Specifications and acceptance criteria should be reviewed and where appropriate adjusted to the current stage of development.



24

S.4.3.

Validation of Analytical Procedure

•Validation of analytical procedures during clinical development is seen

as an evolving process.

•Analytical procedures, which are either described in Ph.Eur., the

pharmacopoeia of a Member State, USP or JP general chapter, or are linked to a product specific monograph, are considered as validated.

25



•For phase 1, the suitability of the analytical methods used should be

confirmed. The acceptance limits (e.g. acceptance limits for the control

of impurities, where relevant) and the parameters (specificity, linearity,

range, accuracy, precision, quantification and detection limit, as

appropriate) for performing validation of the analytical methods should

be presented in a tabulated form. Information for phase 2 and 3 clinical

trials. the suitability of the analytical methods used should be

demonstrated. Validation of the analytical methods used for release

and stability testing is expected. A tabulated summary of the results of

the validation carried out should be provided (e.g. results or values

found for specificity, linearity, range, accuracy, precision, quantification

and detection limit, as appropriate). It is not necessary to provide a full

validation report.

•In case of major changes in analytical methods, cross-validation data

should be presented. Re-analysis of preclinical batch with the new method should be considered



26

P. Drug Product

P.1 Description and composition of the investigational medicinal

product

The qualitative and quantitative composition of the IMP should be stated.

The information provided should include:

• a short statement or a tabulation of the dosage form and the function of

each excipient should be included.

• composition, i.e. list of all components of the dosage form and their amount

on a per-unit basis (including overages, if any), the function of the

components, and a reference to their quality standards (e.g. compendial

monographs or manufacturer’s specifications)



27

P.2 Pharmaceutical development

A short description of formulation development, including justification of

any new pharmaceutical form or excipient should be provided.

If changes in the formulation or dosage form compared to the IMP used

in earlier trials have been made, the relevance of the earlier material

compared to the product under testing should be described.

P.2.1 Manufacturing process development

Changes in the current manufacturing process compared to the ones

used in earlier trials should be explained, special consideration for changes in quality parameters with clinical relevance.



28

Process and Method Validation During

Development

FDA and EMA expect that the aseptic process is validated prior

to use of a sterile product in human. Validation is done by media

fill process simulation.

Bioburden, sterility and endotoxin should also be validated prior

to use of a sterile product in human.

For biological products, as relevant, viral clearance studies

should also be conducted prior to use in human.

29

Guideline on the requirements for quality documentation

concerning biological investigational medicinal products in

clinical trials

September 2017

30

International Conference on Harmonisation

“International Conference on Harmonisation (ICH) of

Technical Requirements for Registration of Pharmaceuticals

for Human Use”

Established in 1990

Documents issued through a 4-step process

Regulatory authorities and experts from the

pharmaceutical industry in Europe, Japan and the United

States are the official governing bodies.

Other world regulatory bodies recognize the ICH

documents.

31


Objectives

Achieve more economical use of human, animal and material

resources

Eliminate unnecessary delay in the global development and

availability of new medicines

Maintain safeguards on quality, safety and efficacy, and

regulatory obligations to protect public health

http://www.ich.org

32


Guidelines

The ICH process results in recommendations (issue

guidelines) on ways to achieve greater harmonization in the

interpretation and application of technical issues and

requirements for product registration and compliance.

These guidelines provide more detail regarding “how” to

achieve appropriate levels of technical standards, quality

oversight and level of detail for regulatory filings.

33

ICH Topics and Guidelines

Q = Quality: Product and testing quality

S = Safety: Topics relating to pre-clinical studies

E = Efficacy: Clinical studies in humans

M = Multidisciplinary: Cross-cutting topics

34

ICH Guidance Documents

ICH “Q” Guidance Documents to Note

Q1: StabilityQ2: Analytical ValidationQ3: ImpuritiesQ4: PharmacopeiasQ5: Biotech Products

Q6: Specifications

Q7: Active Pharmaceuticals Ingredients

Q8: Pharmaceutical Development

Q9: Quality Risk Management

Q10: Pharmaceutical Quality Systems

Q11: Development And Manufacture Of Drug Substances

35

36

משרד הבריאות הישראלי

תיק איכות

נדרש להגיש תיק איכות עבור מוצרים שמוגדרים

כתרפיה תאית

של אתרי GMPלכל שאר המוצרים נדרשת הצהרת

הייצור

עבור מוצרים להזרקה יידרש עכשיו גם הגשת תיק

ולידציה של , איכות עם דגש על שמירת הסטריליות

ואנדוטוקסיןסטריליטי, ביוברדןשיטות

משרד הבריאות הישראלי אימץ את הדרישות

האירופאיות מתוקף הסכמי ההכרה ההדדית עם EMA .37

History of FDA

The following slides present key points in the history of the FDA. It is interesting to understand that the development of FDA is directly related to failures or misuse of products.

38

History of FDA

Regulatory actionYear

Creation of the U.S. Pharmacopeia. Eleven physicians meet in Washington, D.C. to compile

the first list of standard drugs for the United States.

1820

Creation of the Bureau of Chemistry, precursor to the FDA. President Lincoln appoints chemist

C.M. Wetherill to the new Department of Agriculture.

1862

Biologics control act (virus Toxin Lax) later called the Public Health Service Act – Required

licensing of manufacturers and establishments, provided inspection authority and regulated

interstate sale of serum, vaccines and related products

1902

Congress passes the Biologics Control Act to ensure purity and safety of serums and vaccines.

That same year congress approved the study of chemical preservatives and color.

1902

First biologics regulations by publich health service Hygienic Laboratory- "Poison Squad," effect

of food preservatives and artificial colors on public health

1903

Congress passes The Food and Drug Act prohibiting interstate commerce of misbranded food

and beverages.

The Meat Inspection Act is passed on the same day due to insanitary conditions and the use of

poisonous preservatives and dyes.

1906

Pure Food and Drugs Act-Prohibited "misbranding and adulteration"1906

39

History of FDA


The Harrison Narcotic Act requires prescriptions for products exceeding allowable limits of

narcotics.

1914

U.S. v. 95 Barrels of Apple Cider Vinegar. The Supreme Court rules the Food and Drugs Act

allows condemning misleading labels

1924

The official name is given to the Food and Drug Administration.

1937: The Sulfanilamide Elixir Tragedy. 107 people, including many children, die as a result of

diethylene glycol contamination.

1930

PHS Hygienic Lab became NIH1930

NIH reorganized, Hygienic Lab became division of biologics Standardization 1937

Congress passes the Federal Food, Drug and Cosmetic Act (FDC). This law provides for

control of cosmetic devices, drug safety before marketing, standards of identity and quality,

authorizing factory inspections and adding the remedy of court injunctions for penalties.

1938

Food, Drug and Cosmetics Act (FD&C Act)- products must be shown to be 'safe'; authorized

factory inspections

1938

The U.S. v. Dotterweich. The Supreme Court rules that responsible officials and the

corporation itself may be prosecuted for violations of applicable laws. It is not necessary to

prove the violation was intended! Important GLP ramifications.

1943

40

History of FDA


PHS Act- Required Product License Application/ Establishment License Application (PLA/ELA,

precursor to the BLA); gave seizure power

1944

The FDA provides their first guidance document “Procedures for the Appraisal of the Toxicity

of Chemicals in Food”.

1949

The Division of Biologics Control becomes an independent entity of in the NIH after improperly

inactivated polio vaccines resulted in approximately 260 cases of polio.

1955

The Kefauver-Harris Drug Amendments are enacted to ensure drug efficacy and safety is

proven before marketing.

Thalidomide. The FDA did not allow this in the US and as a result there was increased

support for stronger drug regulations

1962

Division of Biologics Standardization transferred from NIH to FDA, became what is now called

CBER

1972

The FDA inspects Searle Laboratories and finds significant deficiencies in data recording,

training, analysis and data review. These findings resulted in the drafting of a Good

Laboratory Practice document. Adherence was voluntary.

1975

Food and Drug Administration Modernization Act (FDAMA)- Revised PHS Act and eliminated

the ELA

1997

Review of "well-characterized" proteins transferred to CDER2003

Patient Protection and Affordable Care Act (Obamacare)2010

41

THANKS

Rivka Zaibel