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Ingredients & Formulation

Critical Good Manufacturing Practice Aspects to Consider for

Pharmaceutical Excipients
a report by

D r P a t r i c i a R a f i d i s o n and K a t h e r i n e U l m a n
Global Life Sciences Quality and Regulatory Affairs Manager and Health Care Risk Manager, and
Healthcare Industries Global Regulatory Manager for Quality, Dow Corning Corporation

Dr Patricia Rafidison currently holds

positions as both the Global Life
Sciences Quality and Regulatory
Affairs Manager and the Health
Care Risk Manager for Dow Corning
Corporation. She has more than
20 years of previous experience as
a quality and regulatory affairs
manager for healthcare raw
materials and finished products in
both the pharmaceutical and
chemical industries. She is currently
an executive board member of
the International Pharmaceutical
Excipients Council (IPEC) in Europe,
chairs the International Excipient
Council Europe Good Manufacturing
Practice (GMP) committee and is part
of the World Health Organization
(WHO) expert network for quality
standards. Dr Rafidison graduated
with her PhD as a pharmacist from
the University of Paris XI, France, and
received her senior MBA from the
French Hautes Etudes Commerciales
Center for Management Proficiency
(HEC-CPA) school in 1995.
Katherine Ulman is Healthcare
Industries Global Regulatory
Manager for Quality for Dow
Corning Corporation. Much of her
early career was dedicated to the
synthesis of novel silicone monomers
and polymers/copolymers, development
of silicone pressure-sensitive adhesives
and defining the relationship
between novel silicone materials
and their impact on both drug
and gas delivery rates. Ms Ulman is
a member of the American Chemical
Society, American Association of
Pharmaceutical Scientists, Control
Release Society and the IPEC of the
Americas. She has published and
presented several papers in her field
and has taught international courses
on silicones for pharmaceutical/
biomedical applications and medical
adhesives through Technomic
Publishing Co. Ms Ulman earned
her BSc in Chemistry from the
South Dakota School of Mines and
Technology in 1976.

118

Abstract

Pharmaceutical
manufacturers
have
the
responsibility of developing safe products through
the proper selection of ingredients, product
formulation and safety substantiation. They are also
responsible for the quality of the raw materials they
purchase. In the current climate, understanding only
raw material science will not be enough. Suppliers
will need to integrate environment impact with the
pharmaceutical industry in order to build the proper
level of controls into their manufacturing and
distribution practices.
These trends become increasingly important as
pharmaceutical companies require improved Good
Manufacturing Practice (GMP) expectations from
their suppliers due to greater regulatory demand
for safe products throughout the entire supply
chain. Price pressures from competition and cheap
sources of material of questionable quality also
need to be considered. It is essential that parameters
such as traceability, change control, notification
and contamination control are addressed by
excipient suppliers.

role in pharmaceutical products can vary from noncritical to highly sophisticated/functional, depending
on the drug and dosage form/design (for example
control rate of delivery, flavouring, stabiliser,
emulsifier and colourant, etc.).
Today, most countries worldwide have
requirements for reviewing and approving
pharmaceutical products, or are currently working
to establish them in order to ensure product
quality, safety, efficacy and traceability; however,
current legislation and/or guidance documents are
targeted mainly at regulating compliance for APIs1
and finished pharmaceutical products2.
Currently, control of excipient manufacturing and
distribution is not a key priority for regulatory
authorities or pharmaceutical manufacturers, perhaps
due to the fact that most of these excipients
originated from the food industry and have generally
recognised as safe (GRAS) status. However, with
the emergence of novel excipients and delivery
systems, better control of these materials becomes
increasingly important.
The Importance of GMPs

Introduction

Pharmaceutical excipients (inactive ingredients that,

when combined with active pharmaceutical
ingredients (APIs), produce a drug dosage form)
typically make up about 99% of a finished drug
product. These excipients are derived from various
sources (natural, biological and chemical, etc.) and
can be targeted for use in a variety of products
intended for very diverse businesses (food, general
industrial, cosmetics and pharmaceutical, etc.). Their

In general, excipients have not been a major source of

concern; however, even today, examples exist where
identified issues may have been minimised or
eliminated using better control of the essential elements
of GMPs: traceability, change control/customer
notification, contamination control. For example,
nearly 100 deaths resulted from cough syrup
(distributed to children in Haiti between 1995 and
1996) that was contaminated with diethylene glycol,
according to the World Health Organization (WHO).3

1. Many other countries are currently implementing regulations based on the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) GMP guidelines for APIs (ICH Q7A)
ICH Q7A Good Manufacturing Practices for Active Pharmaceutical Ingredients. Implementation in the three ICH regions
(European Union, Japan, US): European Union adopted by Committee for Proprietary Medicinal Products (CPMP),
November 2000, issued as CPMP/ICH/1935/00; Japan Ministry of Health, Labor and Welfare (MHLW), Adopted
2 November 2001, Pharmaceutical and Medical Safety Bureau (PMSB), Notification No. 1,200; US US Food and Drug
Administration (FDA), Published in the Federal Register, 25 Sept. 2001, Vol. 66, No. 186, pp. 49,02849,029.
2. The FDA has established GMP regulations and guidelines for APIs and finished drugs (FDA Title 21, Code of Federal
Regulations (CFR), Parts 210 and 211).
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Table 1: Differences Between Excipients and Actives

Active Ingredient

Excipient

Manufacturing plans dedicated to pharmacy

High value, small volume
Limited source of products
More regulated
Clear rules imposed
GMP practices
Process/batch system
More experts in regulatory affairs in pharmaceutical world

Multiple usage away from pharmaceutical industry

High volume, low value
Multiple sources
Less regulated, voluntary systems
Customer-oriented food/cosmetics/general market
Quality management culture
Continuous process, bulk process
No specific expertise in pharmaceutical market

In 1999, some poultry, swine and ruminants (cattle,

sheep and goats) were fed food contaminated with
dioxins and polychlorinated biphenyls (PCBs), thus
contaminating the animals with both dioxins and
PCBs. As a result, it became important for
manufacturers using materials from animal origins to
verify the source (traceability) of their raw materials
to ensure that they are not contaminated.4
The current trend is to use risk assessment or risk
management as a foundation for defining the
appropriate level of GMPs.5 Caution should be taken
when using these tools since they involve a complete
understanding of the end-use applications (for
example dosage forms, drug types and delivery
mechanisms, etc.). Today, the excipients industry
does not necessarily have access to this information,
nor does the pharmaceutical industry provide this
type of information to their raw material providers.
Therefore, if this approach is taken, it will require a
lot of collaboration and investment from both
parties. This situation becomes much more complex
when distributors and brokers are involved.
Product Traceability
Managing the Total Supply Chain

Currently, the way that international trade operates is

that excipients are handled as commodities that are
controlled more by price and less by quality.
Distribution channels do not allow for the knowledge
of where their products are going or how they are
being used. There is free circulation of goods, thus
inhibiting regulatory agencies from having complete

120

control. There is no formal system to regulate supply

chain practices for excipients. It is essential to be able
to trace the excipients throughout their supply chain
in order to ensure that they meet GMP requirements
appropriate for their intended applications.
Defining a standard that would be applicable
universally to all types of excipients may be
impossible; however, in an effort to assist the
chemical industry and pharmaceutical manufacturers
in developing a set of cGMP guidelines targeted at
excipients, both the International Pharmaceutical
Excipients Council (IPEC)6 and the WHO7 have
published cGMP guidelines for bulk pharmaceutical
excipients. These guidelines target understanding and
implementing the key principles of GMPs, such as:
documentation and traceability;
change control and customer notification; and
contamination control.
Addressing these needs in an affordable manner is just
as important as delivering the critical principles noted
in this article. Thus, a balanced approach must be
used when establishing key GMP rules.
Quality System Key Elements to
Consider for Excipients

Because of the diverse nature of excipients, it is

expected that the foundation for the excipients
industry would be based on International
Organization for Standardization (ISO) quality
standards. Although ISO standard guidelines provide

3. Starting Materials for Pharmaceutical Products: Control and Safe Trade, WHO/PHARM/98.605, Geneva, 2527
May 1998.
4. FDA, Guidance for Industry: Possible Dioxin/PCB Contamination of Drug and Biological Products, US Department
of Health and Human Services, FDA, August 1999, Office of Compliance, http://www.fda.gov/cber/gdlns/dioxpcb.pdf
5. FDA, A Risk-Based Approach to Pharmaceutical Current Good Manufacturing Practices (cGMP) for the 21st Century:
A Progress Report, http://www.fda.gov/cder/gmp/index.htm
6. IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients, revised 2001, published by the European
Pharmacopoeia in Pharmeuropa, April 2002, Vol. 14, No. 2, p. 238 and by the United States Pharmacopoeia,
USP25/NF20 information chapter 1,078.
7. Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients, WHO Expert
Committee on Specifications for Pharmaceutical Preparations, 35th report, Geneva, WHO, 1999, Annex 5
(WHO Technical Report Series, No. 885).

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Critical Good Manufacturing Practice Aspects to Consider for Pharmaceutical Excipients

a valuable framework for quality systems, they focus
mainly on the what rather than the how. The
addition of current GMPs is a vital complement to
the successful production, handling and distribution
of pharmaceutical products, but selecting the
appropriate guidelines/level of cGMPs can pose a
challenge for developers, raw material suppliers and
drug manufacturers. Following are some examples of
criteria that may be considered for raw materials being
used for pharmaceutical applications (see Figure 1):
raw material source;
material tracking;
product status and labelling (upstream and
downstream);
contamination/cross-contamination prevention;
repackaging/relabelling controls;
distribution channel; and
change control and customer notification.

Managing for Change

Keeping the Customer in the Loop

Quality improvements are seen in the excipients

industry as a way of life; however, those
improvements may lead to changes that might have an
impact on downstream products and delivery systems
(for example drug availability, safety and purity, etc.).
Suppliers of raw materials and components of drug
products should manage for significant changes
that could impact the quality of the material that a
drug manufacturer would receive, including a
mechanism to notify pharmaceutical manufacturers
of significant change.
IPEC America has established a significant change
guideline8 that recommends that excipient
manufacturers consider changes to raw materials,
packaging, specifications, manufacturing site, scale,
equipment and process.
Items to consider in determining change include
potential changes in excipients chemical properties,
physical properties and impurity profile.

8. GMP Guide for Bulk Pharmaceutical Excipients, IPEC-Americas Significant Change Guide for Bulk Pharmaceutical
Excipients, 2000, ipecamer@aol.com

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Figure 1: Key Supply Chain Elements

Purchase

Receive

Produce

Test

Package/Label

Handle/Store

Distribute

Change Control
Evaluate change (raw materials, process, package, etc.) and notify customers if needed

ISO 9000:2000 Quality Standards

Traceability
Document
vendors and
raw materials
origin

ID test for
batches of
critical raw
materials

QA review/
approve batch
record

Approve
quality critical
material
suppliers

Segregate
materials until
approved for
use

Identify all
containers,
equipment
and lines

Retain sample
of each batch

Document
recall
process

Certificate
of analysis
for each
batch/material

Maintain
product
integrity &
identity

Maintain
complete
traceability

Use tamperevident seal

for primary
packaging

Contamination Control

Purchase

Prevent
contamination
during
sampling

Cleaning,
personal
hygiene,
environment
control

Receive

Produce

Record
container
cleaning/reuse,
deface/destroy
old label
Test

Package/Label

Handle/Store

Distribute

Key Added Practices to ISO 9000:2000

122

Other sources of information for how to manage

change have been developed by both the European9
and the US Food and Drug Administration
(FDA).1012

equipment/facilities consider cross-contamination

in the design of the manufacturing process and
facility, especially when multipurpose operations are
involved;

Since the effects of change might be unknown in

downstream applications, continuous dialogue
between the raw material suppliers and their
pharmaceutical customers should be implemented in
order to ensure the effectiveness of the change
control process.

raw materials consider impurity profiles when

changing vendors/sources of raw material;

Contamination Understanding
Sources and Potential Risk

packaging consider tamper-evident seals for

primary packaging of shipped material.

Contamination could originate from a number of

sources, for example:

The raw material supplier should base their level

for controls on several factors, including targeted

people consider excluding unhealthy operators

from making or coming into contact with the
product (at all stages); and

9. Commission regulation (EC) 542-95 of 10 March 1995 concerning the examination of variation to the terms of a marketing
authorisation falling within the scope of council regulation (EEC) 2309-93.
10. Guidance for Industry, BACPAC I: Intermediates in Drug Substance Synthesis, Bulk Actives Post approval Changes:
Chemistry, Manufacturing, and Controls Documentation, February 2001, http://www.fda.gov/cder/guidance/3629fnl.htm
11. Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms, Scale-Up and Post approval Changes:
Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation,
September 1997, http://www.fda.gov/cder/guidance/1214fnl.pdf
12. FDA QA letter to all NDA, ANDA and AADA Holders in regards to Guidance for Industry, SUPAC-MR, 18
February 1997, http://www.fda.gov/cder/guidance/qaletter.htm

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use, nature of product, open versus closed systems,
type of material (liquid, water-based and powder,
etc.), complexity/stage of processing, degree
of environmental control/exposure and ease/
thoroughness of cleaning.

effective in terms of their identity, purity and dosage

level. Although ISO registration plays an important
role in manufacturing quality systems, it is
not the total quality solution for healthcare
applications.

...pharmaceutical companies require improved GMP

expectations from their suppliers due to greater regulatory
demand for safe products throughout the entire supply chain.
Understanding and using this information, in
conjunction with gaining knowledge of their
technology and processes, should help raw material
suppliers establish an appropriate level of control for
their materials and hopefully avoid unnecessary
investments.
Conclusion

From the perspective of suppliers and manufacturers,

quality contributions will ultimately find their way to
patients. The concerns of patients and their families
centre on confidence that products are safe and

With the addition of these key elements of cGMPs

(addressed through the Hazard Analysis and
Critical Control Point for the food industry), the
pharmaceutical industry gains an added measure of
confidence in the excipients they purchase.
Learning more about the critical/strategic role of
excipients, concerns/issues with complaints and/or
recalls, as well as the requirements of dealing with
emerging pharmaceutical applications, will help
ensure that raw material suppliers meet the quality
needs of the pharmaceutical industry and the
customers they serve.