This presentation covers latest understanding and regulatory scenario on pharmaceutical excipients. 1. What are Excipients? 2. Types of Excipients 3. Classification of Excipients 4. 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

1. Regulatory Aspects On
Excipients
Mr. Pankaj Dhapade
B. Pharma, MBA (Pharmaceuticals), PGDPRA
Wockhardt Ltd

2. Agenda
1. What are Excipients?
2. Types of Excipients
3. Classification of Excipients
4. 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

3. 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.

4. 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
nor co-processed excipients
produced by means of a low- to
medium-shear process
designed to physically modify
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.

5. Types of Excipients
Standard Excipients
Mixed Excipients
Cont…….
Co-processed Excipients
Simple physical mixing is typically mixing is typically of extended
of short duration
duration
Ex: Lactose as a diluent
Magnesium Stearate as a
lubricant etc
Mixed excipients may be either
solid or liquid
Ex: Opadry (Grades)
Eudragit (Grades)
Many different co-processing
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.

6. Co-processed Excipients Examples…
…

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

8. 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

9. 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
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

10. Composition Profile of Excipients
The composition profile of excipients includes following components
Nominal component
Concomitant components
Additives
Processing aid
Degradants
Residual solvents
Other components
Components having exposure concerns

11. Composition Profile of Excipients
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.

12. Composition Profile of Excipients
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
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.

13. Composition Profile of 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.
e.g. unreacted starting materials, residual catalyst or metal reagents, reaction byproduct 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.

14. 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 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

15. 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. 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

16. 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
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.

17. Information disclosure
The IPEC Excipient Information Package should contain the standard information
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.

18. 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
manufacturers
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

19. Dossier requirements
The dossier requirements of excipients are ,
1. 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.

20. Development Pharmaceutics
The development pharmaceutics requires following information on excipients,
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.

21. 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 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

22. Excipients Certification Scheme
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

23. Excipients Certification Scheme
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 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

24. Excipients Certification Scheme
Solution!
The use of 3rd party audit organisations is ACCEPTABLE

25. Excipients Certification Scheme
EXCiPACT is a new, voluntary, international scheme
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.

26. Excipients Certification Scheme
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 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

27. Excipients Certification Scheme
Excipact Goals
Acceptance by all stakeholders
Acceptance 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

28. Excipients Certification Scheme
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/GDP
compliance
3. Worldwide acceptance: building on existing ISO standards, and supported by major
industry organizations

29. Excipients Certification Scheme
Why Certification?
Absence of regulations for GMP or GDP for excipients
More 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

30. Excipients Certification Scheme
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

31. Excipients Certification Scheme
Quality of Auditors is Critical
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

32. Excipients Certification Scheme
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

33. Excipients Certification Scheme
Auditor Competency & Qualification
1. Required knowledge & audit skills
a. 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

34. Excipients Certification Scheme
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

35. Excipients Certification Scheme
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

36. Thank You!!!