Regulatory Aspects On Pharmaceutical Excipients By Mr. Pankaj Dhapade

Regulatory Aspects On Excipients

Mr. Pankaj Dhapade B. Pharma, MBA (Pharmaceuticals), PGDPRA

Wockhardt Ltd

Agenda

1. What are Excipients?

2. Types of Excipients

3. Classification of Excipients

4. DP v/s Excipients4. DP v/s Excipients

5. Composition profile of Excipients

6. Facts related to Excipients

7. Process Change

8. Information Disclosure

9. Difficulties and Challenges

10. Dossier Requirements

11. Development Pharmaceutics

12. Excipients Certification Scheme

What are Excipients?

Pharmaceutical excipients are substances other than the API, which have been

appropriately evaluated for safety and are intentionally included in a drug delivery system.

For example excipients can:

� aid in the processing of the drug delivery system during its manufacture,

� protect, support or enhance stability, bioavailability or patient acceptability,

� assist in product identification,

� enhance any other attribute of the overall safety, effectiveness or delivery of the drug

during storage or use.

Types of Excipients

Standard Excipients Mixed Excipients Co-processed Excipients

compendial or non-compendial

substances

a simple physical mixture of

two or more compendial or

non-compendial excipients

a combination of two or more

compendial or non-compendial

excipients

that are neither mixed excipients produced by means of a low- to designed to physically modify

nor co-processed excipients medium-shear process their properties in a manner not

achievable by simple physical

mixing, and without significant

chemical change

They may contain other

components including

concomitant components,

residual processing aids and/or

additives

where the individual

components are mixed but

remain as discrete chemical

entities, i.e. the nature of the

components is not chemically

changed

However in some instances,

formation of necessary

components may occur, such as

in-situ salt formation.

Types of Excipients Cont…….

Standard Excipients Mixed Excipients Co-processed Excipients

Simple physical mixing is typically

of short duration

mixing is typically of extended

duration

Ex: Lactose as a diluent

Magnesium Stearate as a

Mixed excipients may be either

solid or liquid

Many different co-processing

methods may be used, including Magnesium Stearate as a

lubricant etc

solid or liquid

Ex: Opadry (Grades)

Eudragit (Grades)

methods may be used, including

standard unit operations such as

granulation, spray drying, melt

extrusion, milling etc. The choice for

a specific application will depend on

the materials used, their form (e.g.

whether dry powders or liquid) and

the specific physical properties

desired. Likewise the ratios of the

components may vary depending on

the desired performance.

Co-processed Excipients Examples……

Classification of Excipients

Why should we classify excipients?

They have many diverse uses, functions, manufacturing processes and origins

So the risks posed to the patient are also very variableSo the risks posed to the patient are also very variable

Hence a one size fits all definition of GMP is not going to be enough

Classification of Excipients

The classification of excipients in three classes is based on,

1. Class I: The IPEC-PQG GMP Guide will be the foundation for class I

2. Class II: An intermediate class II between these should be defined

(Investment in the quality management system is high)

3. Class III: The highest class III should not exceed EU Part II / ICH Q7 GMP

DP v/s Excipients (Composition)

Drug Products Excipients

Active Pharmaceutical Ingredient(s):

APIs are potent component which show desired

actions

Nominal Component(s):

The component of an excipient being able to

perform its function in the drug product(s) in actions perform its function in the drug product(s) in

which it is used

Excipients:

Inert materials which influence the performance

of drug product

Concomitant component, Additives and

Processing aids:

Other necessary components which helps

excipients to perform their intended functions

Impurities:

Unreacted starting materials, by-products,

degradants and residual solvents

Impurities:

Unreacted starting materials, by-products,

degradants and residual solvents

Composition Profile of Excipients

The composition profile of excipients includes following components

� Nominal component

� Concomitant components� Concomitant components

� Additives

� Processing aid

� Degradants

� Residual solvents

� Other components

� Components having exposure concerns


� Nominal component:

The main components of an excipient are those which in most cases contribute to the

excipient being able to perform its function in the drug product(s) in which it is used

� Concomitant components:

The substances in addition to the main components should be considered as part of

the composition profile, and thus not be construed as being undesirable, nor

confused with the presence of added substances

� Additives:

Additives are chemical substances which are intentionally added to excipients to

improve their physico-chemical properties, e.g. antioxidants, stabilizers, pH

modifiers or flow aids.


� Processing aid:

Processing aids are chemical substances which are used for a specific processing

need or benefit in an excipients manufacturing process, e.g. filter aids

Processing aids may be or may not be removed during the excipient manufacturing

process process

� Degradants:

Some excipients may degrade with time due to a variety of factors. If the degradants

have any toxic potential, they should also be quantified.

� Residual solvents:

Residual solvents are either organic or inorganic liquids (regardless of the source)

that remain in the excipient due to incomplete removal via the manufacturing

process. No specific guideline exists for directly addressing residual solvents in

excipients.


� Other components:

In addition to the components listed above, other components that may be present

are either organic or inorganic substances that are not the defined entity

(main/concomitant components) of the excipient, but are present as a direct result of

variables in the excipients manufacturing process.variables in the excipients manufacturing process.

e.g. unreacted starting materials, residual catalyst or metal reagents, reaction by-

product and raw material components

� Components having exposure concerns:

Where possible, excipient manufacturers should identify and set appropriate limits

for any components having exposure concerns, e.g. endocrine disrupters, allergens,

genotoxins, endotoxins in excipients for parenteral use, etc.

Facts related Excipients

1. The proprietary or trade secret information could be shared via DMF, CDA and CEP

2. No comparable excipients DMF system is available in Europe but the proprietary or2. No comparable excipients DMF system is available in Europe but the proprietary or

trade secret information could be shared via CDA and CEP

3. Contaminants would not be regarded as part of the composition profile. however,

they should be controlled through Good Manufacturing Practices (GMP)

4. Where feasible the generation of a composition profile should involve the

identification, classification and quantification (expressed as a range) of each

component or, if unidentified, an appropriate qualitative description such as peak

retention time

Facts related Excipients

5. For excipients for which purity can be measured directly, any undesirable organic and

inorganic components present at or above 0.1% should be identified and assessed to

determine the need (if any) for quantitative limits

6. If quantitative limits are needed, appropriate analytical techniques should be used. If6. If quantitative limits are needed, appropriate analytical techniques should be used. If

identification/quantification is not possible, a qualitative description, such as

chromatographic retention time should be assigned

7. For excipients for which direct measurement of purity is not feasible, indirect

techniques (such as assay minima, extractable maxima, LOD or ROI) should be used

to provide an estimate of overall excipient purity

8. Levels of residual solvents, potentially toxic components and genotoxic components

should be assessed and reported in line with the guidelines

Process Change

If the excipient manufacturer decides to modify the process, they should use the

IPEC Significant Change Guide to determine if the process changes will require IPEC Significant Change Guide to determine if the process changes will require

customer notification.

The composition profile may not be fully disclosed to the customer.

However, it will be an important consideration in evaluating the effects of a change.

Information disclosure

The IPEC Excipient Information Package should contain the standard information

to be disclosed to the excipient user, including non-confidential composition profile to be disclosed to the excipient user, including non-confidential composition profile

information.

Additional information relating to the composition profile may be available upon

request, subject to a Confidential Disclosure Agreement if necessary.

Difficulties and Challenges

The difficulties and challenges in regulation of excipients are

� No explicit requirement for GMP for excipients

� Different awareness of specific pharma requirements amongst excipients

manufacturersmanufacturers

� Pharmaceutical manufacturers are struggling with comprehensive

- Supplier qualification, supplier audits and testing on delivery

� Pharmaceutical user audits are important but infrequent/incomplete

� Lack of human resources with regulators to perform audit

� GDP (Good Distribution Practice) needs to be included

� Ways have to be found to engage the entire excipient industry despite its diversity

� Practically, QP has responsibility for the quality of excipients based on internal

standards

Dossier requirements

The dossier requirements of excipients are ,

1. Specification1. Specification

2. Analytical procedures

3. Validation of analytical procedures

4. COAs

5. TSE/BSE certificates/MSDS

6. Justification of specifications

7. The qualitative and quantitative composition of the mixed excipient should be

submitted, the specifications of the mixture as a whole and of each component

should be stated.

Development Pharmaceutics

The development pharmaceutics requires following information on excipients,

The excipients chosen, their concentration, and the characteristics that can influence the The excipients chosen, their concentration, and the characteristics that can influence the

drug product performance (e.g. stability, bioavailability) or manufacturability should be

discussed relative to the respective function of each excipient.

The ability of excipients (e.g. antioxidants, penetration enhancers, disintegrants, release

controlling agents) to provide their intended functionality, and to perform throughout

the intended drug product shelf life, should also be demonstrated.

Excipients Certification Scheme

Excipients are critical components of medicines and they have no therapeutic activity.

Value of the global excipients market: approx. $5.8 bn

Expected value of the global excipients market 2018: approx. $ 8.8 bnExpected value of the global excipients market 2018: approx. $ 8.8 bn

Excipients have a high influence on the potency and bioavailability of the active ingredient

In practice, the innovator pharma companies have been qualifying their excipients suppliers

to build quality in their products and they are achieving through physical audit.

This kind of approach of innovator pharma companies is increasing the expectations of

regulators to audit all excipients suppliers by drug products manufactures or third party


The purpose of this qualification is to ensure that the safety of the drug product is not

compromised by the excipient

Both manufacturing (GMP) and distribution (GDP) aspects need to be covered

Patient Safety = Excipient Specification + GMP + GDP


There are issues to perform physical audit of excipient suppliers.

A. MAH Perspective

1. Suppliers will not agree to an audit

2. Not enough days in the year for an audit to audit every supplier2. Not enough days in the year for an audit to audit every supplier

3. Travel costs continue to rise and employees don’t want to travel

4. Language barriers

6. In house auditors are not familiar with chemical processing etc resulting in less

effective audits

B. Supplier Perspective

1. Not enough days in the year for an audit from every customer

2. Language barriers

3. Value of business with user does not justify audit time and cost


Solution!

The use of 3rd party audit organisations is ACCEPTABLE


EXCiPACT is a new, voluntary, international scheme

that provides for the high quality, independent certification of that provides for the high quality, independent certification of

manufacturers and suppliers of pharmaceutical excipients

to prescribed cGMP and cGDP standards,

as a means of ensuring patient safety through supplier quality,

while minimising the overall supply chain costs.


The excipient certification scheme (EXCIPACT) was commenced in May 2008 with

EFCG and IPEC Europe, now comprises 5 trade associations

1. FECC - European Association of Chemical Distributors1. FECC - European Association of Chemical Distributors

2. IPEC - Americas (International Pharmaceutical Excipients Council - Americas)

3. IPEC - Europe (International Pharmaceutical Excipients Council - Europe)

4. PQG - Pharmaceutical Quality Group (UK)

5. EFCG – European Fine Chemical Group


Excipact Goals

Acceptance by all stakeholders

Acceptance of certificates globallyAcceptance of certificates globally

Building on existing guides and new standards

Guides easy to understand and apply for all stakeholders

Guides should be applicable to as many excipients as possible

Certification assessable for as many accredited 3rd party organizations as possible


Excipact Benefits

1. More safety: through certified compliance to recognized GMP and GDP standard

2. Cost and time savings: only a single audit is needed to prove GMP/GDP2. Cost and time savings: only a single audit is needed to prove GMP/GDP

compliance

3. Worldwide acceptance: building on existing ISO standards, and supported by major

industry organizations


Why Certification?

Absence of regulations for GMP or GDP for excipients

More formal an objective than self assessmentMore formal an objective than self assessment

Permits industry self regulation

Ability for supplier to initiate process

Applicability to manufacturers and distributors of excipients

Well developed and accepted assessment model using 3rd party certification

organisations


Certification & 3rd Party Audits

Provides information on Supplier’s GMP practices from experienced auditors with

knowledge of excipient manufacturing & GMPs

Allow companies to focus resources on excipients with highest risk

Reduces audit load for suppliers and users

Helps define a level playing field for all

Helps small companies (both users and suppliers) and those with limited budgets

Makes 100% audit verification of suppliers practical


Quality of Auditors is Critical

All authorities and others have expressly stated that 3rd party auditors can only be All authorities and others have expressly stated that 3rd party auditors can only be

valuable if the auditors are competent.

Competency like quality is something we all understand but is difficult to define –

Excipact has included a section devoted to just this aspect.

Competency: the ability to apply knowledge and skills to achieve intended results


Quality of Auditors is Critical

Competency framework defined using ISO 19011 standards

Alternative starting routes to qualification possible i.e. experienced in ISO 9001, GMP

or GDP

Considered best practices e.g. Qualified Person assessment processes

Training programme for auditors to be developed


Auditor Competency & Qualification

1. Required knowledge & audit skills

a. Tertiary scientific educationa. Tertiary scientific education

b. Work and Audit experience

c. ISO 9001 knowledge

d. GMP/GDP knowledge

e. Excipient Knowledge

2. Knowledge assessed orally or by exam

3. Supervised first audit


Certification Scheme: Program Elements

Excipact to be a Legal Entity representing partner organizations

Certification Body: Accredited to ISO 9001, ISO/IEC Guide 65, ISO 17021 or

equivalent and verified by Excipact

Excipient suppliers to be certified on a 3 year cycle

Annual site surveillance audit

Triennial recertification audit


Certification Scheme: Audit Documentation

1. Audit Report lists observations and rates findings as critical, major or minor

2. 3rd Party Technical Experts review audit report and findings, recommend

certification if,

No critical, no major without CAPA, no minors that indicate failure of quality

system element

3. Audit Report available to pharmaceutical customer from excipient supplier

Thank You!!!

Regulatory Aspects On Pharmaceutical Excipients By Mr. Pankaj Dhapade

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Transcript of Regulatory Aspects On Pharmaceutical Excipients By Mr. Pankaj Dhapade