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2014 GMP MANUAL © Maas & Peither AG

22 Excipients
22.A Introduction
22.A.1 What is a Pharmaceutical Excipient?
22.A.2 Who supplies excipients?
22.A.3 Characteristics of the “Excipients Industry”

22.B Regulatory aspects and guidance documents

22.B.1 Legal position with regard to GMP for excipients
22.B.1.1 Situation in Europe
22.B.1.2 Situation in USA
22.B.1.3 Situation in other regions
22.B.1.4 Supervision and inspection of excipient suppliers

22.B.2 GMP-Standards for the manufacture of pharmaceutical excipients

22.B.3 Implementing the IPEC-PQG GMP Guide
22.B.3.1 What is GMP for excipients?
22.B.3.2 Key features of the IPEC-PQG GMP-Guide
22.B.3.3 Conclusions

22.B.4 IPEC, its role and activities

22.C Safety, toxicological, and precedence of use issues

22.C.1 Marketed excipients
22.C.2 New (novel) excipients

22.D Compendial monographs

22.D.1 Marketed excipients
22.D.1.1 United States Pharmacopeia- National Formulary
22.D.1.2 European Pharmacopoeia
22.D.1.3 Japanese Pharmacopoeia

22.D.2 New and novel excipients not listed in a pharmacopoeia

22.E Excipient master files and other filings

22.E.1 United States Drug Master Files
22.E.2 European Certificates of Suitability (CEP)
22.E.3 Japanese Drug Master Files

22.F Applicability of ICH Guidance to excipients

22.F.1 Q3A, Impurities in New Drug Substances
22.F.2 Q3C, Impurities: Guideline for Residual Solvents
22.G Other aspects critical to the marketing of excipients
22.H References
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22.A Introduction
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ What is a Pharmaceutical Excipient?
■ What are the functions and properties of Pharmaceutical Excipients?
■ Who supplies excipients?
■ What are the characteristics of excipient suppliers?

This chapter draws heavily on the documents and guides issued by the International Pharmaceutical Excipient Council (IPEC). The text in this chapter
has been adapted from the IPEC Guide on Qualification of Excipients for Pharmaceutical Use with permission from IPEC. A personal critique by the
author of the Joint IPEC-PQG1 GMP Guide for pharmaceutical excipients, issued in 2006, is also included. The chapter has been updated with inclusion
of some of the current GMP approaches for excipients detailed in the EXCiPACT™ Certification Standards for GMP and GDP and the forthcoming US
national standard for GMP for excipients (ANSI NSF 363). A new section highlighting recent developments with regard to joint auditing and certification of
excipient suppliers is also included. Relevant references are cited in Chapter 22.H References.
In this chapter the terms “supplier” and “user” are applied to describe an excipient manufacturer or distributor (supplier) and the pharmaceutical company
that formulates the excipient (user).

22.A.1 What is a Pharmaceutical Excipient?

The IPEC definition of a pharmaceutical excipient is anything that is intentionally added to the drug product that is not the Active Pharmaceutical
Ingredient (API). Note that this definition would exclude medical devices. The IPEC definition is given in Figure 22.A-1.
Figure 22.A-1 IPEC definition of excipients
IPEC definition of “Excipient”

Pharmaceutical excipients are substances other than the API, which have been appropriately evaluated for safety and are intentionally included in a
drug delivery system.

According to the IPEC definition excipients have several key properties:

■ Firstly, the phrase “other than the API” indicates that excipients have no therapeutic effect. That is they should be pharmacologically inert.
■Secondly, there is an expectation that the excipient has been appropriately evaluated for safety. This indicates that they should not harm the
patient who is being administered the drug product and that at some time there has been an evaluation to demonstrate that they are indeed safe.
■ Finally, the word “intentionally” indicates that the excipients are included in the drug product by design.

In terms of patient risks it is best to add as little as possible to the drug product that is not absolutely necessary. But in reality a dosage form that just
comprised the API would not be simple to administer especially for those that are very potent. Often it is the route of administration that determines the
other ingredients that aid delivery of the API. For example, a surfactant in the preparation of a cream for topical applications, a binder in a tablet and even
Water for Injection in a parenteral product; all of these additional ingredients are excipients.
There are other definitions of excipients, most notably the European Pharmacopoeia2 definition and the definition given in the Falsified Medicines
Directive.
The European Pharmacopoeia provides the following definition:
“Excipient (auxiliary substance): Any constituent of a medicinal product that is not an active substance. Adjuvants, stabilisers, antimicrobial
preservatives, diluents, antioxidants, for example, are excipients.”
However this definition does not include the word intentional and therefore would imply that any other ingredient than the API is an excipient. This could
mean impurities and other unplanned contaminants are defined as excipients. The inclusion of a list of functions that excipients perform is helpful but
incomplete.
The Falsified Medicines Directive (2011/62/EU) provides the following definition:
“Any constituent of a medicinal product other than the active substance and the packaging material.”
It is interesting to note the omission of the word “intentional” in this definition, too. It was explained by the authorities that this is implicit anyway in the
definition so the word was not required.
It is not surprising that the FMD definition lines up with the one from the European Pharmacopoeia, at least there is consistency in the approach in
Europe.
In all cases excipients are included in the drug product to perform a specific function, for example
■ to aid in the processing of the drug delivery system during its manufacture,
■ to protect, support or enhance stability, bioavailability or patient acceptability,
■ to assist in product identification to the patient,
■ to enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use.

Excipients have many functions some of which are listed in Figure 22.A-2. The United States Pharmacopeia contains a rather more comprehensive list of
functionalities3.
Figure 22.A-2 Possible functions of
excipients
Possible functions of excipients

■ Binder
■ Compression aid
■ Disintegrant
■ Colour/Flavour
■ Filler
■ Sweetener
■ Lubricant
■ Preservative
■ Glidant
■ Suspending/Dispersing Agent
■ Humectant
■ Buffer
■ Coating/Film former
■ Release modifier
■ Adhesive
■ Penetrant
■ Vehicle
■ Thickener
■ Solvation

Some excipients may have more than one function making them especially valuable. It is the function of an excipient that is its most important attribute.
Often functionality is a result of the fact that an excipient is a complex mixture of molecular entities, which is in sharp contrast to APIs.
As long as excipients are pharmacologically inert, safe to the patient and have the desired functionality then there is no restriction on what they may
actually be. In that regard excipients can be gases, liquids or solids. Their origins also encompass a broad spectrum including materials derived from
animals, minerals, vegetables, synthetic entities and all mixtures of these in almost any combination.
A survey of UK Marketing Authorisations revealed that over 1200 excipients were in use, excluding flavours and colours. Similarly a survey of the FDA
Inactive Ingredients Database4 indicated that a similar number of excipients were listed. If these numbers are repeated worldwide then it is likely that the
number of different excipients in use in the industry is very large indeed.
Another defining feature of excipients is that they are rarely designed for use in pharmaceutical applications. Typically they are entities that have been
created for other purposes, such as cosmetic ingredients, food additives etc.
Although, excipients have a great deal in common with APIs in that they are both components of drug products and so come into direct contact with the
patient, an overriding difference is that the excipient is pharmacologically inert and this can justify a different and less rigorous application of GMP in the
manufacture and distribution of excipients.
Whereas an API is only used in a limited number of drug products, an excipient can be used in a very large number of drug products. Thus one supplier
could provide an excipient to many users and therefore have an impact on a large number of drug products if the excipient was found to be improper by
its quality. This distinction sets excipients firmly apart from APIs where the API is most likely used by a smaller number of users, and in a more limited
set of dosage forms. It follows that the risks to patients posed by excipients are potentially more far-reaching than those related to APIs and it is all the
more surprising that there remains limited legislation that requires them to be manufactured and supplied in compliance with GMP and GDP.

22.A.2 Who supplies excipients?

The “Excipient Industry” does not exist as a defined entity, and it certainly has no common identity. IPEC is a trade association which has both
suppliers and users as members. But even IPEC would acknowledge that its members comprise only a limited part of the organizations that supply
excipients to users. The main reason for this is that few excipients are especially made for pharmaceutical use.
As excipients have applications other than in pharmaceuticals, such as food additives, cosmetics, or industrial products, the environmental conditions,
equipment, and operational techniques employed in excipient manufacture are often those of the chemical industry. Excipients may be manufactured for
example through significant chemical change, physical modification, blending, or purification which causes many of the other components present in the
starting materials to be removed or reduced.

22.A.3 Characteristics of the “Excipients Industry”

In many instances excipient suppliers only provide a small fraction of their total output to the pharmaceutical industry. For example, total cellulose
production is approximately 250 million tonnes per year. The use of cellulose products in pharmaceutical industry is approximately 50,000 tonnes per
year (0.02 % of total). This has crucial commercial consequences in terms of their ability to meet the pharmaceutical industry’s needs in terms of
supplier qualification (audits, agreements etc) as well as the implementation of GMP and Good Distribution Practice (GDP). The requirements of the
pharmaceutical industry in this regard are amongst the most demanding and many excipient suppliers are faced with the need to implement significant
enhancements to their business and quality management systems. These investments do not come without cost, and the suppliers will need to be
convinced that they can recover these from sales of the excipient. Obvious conflicts arise when this is not realized – particularly, when the
manufacturers’ main market is very price sensitive.
Thus the standards applied to manufacturing and distribution of such substances are focused on the compliance with the requirements of the
manufacturer’s intended market and often these may not require the application of GMP and GDP principles.
Although dosage form manufacturers may have some limited control over excipient quality through specifications, the excipient manufacturers must be
considered to have greater control over physical characteristics, quality, and the presence of other components in the excipient they produce. Control
over other components in the excipient should not be taken to mean minimizing or even eliminating concomitant components from the excipient5. The
presence of concomitant components in the excipient often has a beneficial effect on excipient performance, but control is needed to assure that the
presence of concomitant components is at a consistent level and other components are kept to a minimum.
In this regard the GMP maxim “you cannot inspect quality in” is never truer. For excipients the product specification is not a complete definition of
product quality. The functionality arises from composition of the excipient and the specification may not be specific enough to ensure that the excipient
is identical from batch to batch or from manufacturer to manufacturer. Thus it is crucial that the manufacturing process is controlled by the supplier to a
suitable extent so that the excipient functionality remains within acceptable limits.
Summary:
As defined by the IPEC, Pharmaceutical excipients are substances other than the API, which have been appropriately evaluated for safety and are
intentionally included in a drug delivery system. Excipients have many functions in pharmaceutical formulations, e.g. as binder, filler, disintegrant etc. In
the EU the new Falsified Medicines Directive defined excipients as “Any constituent of a medicinal product other than the active substance and the
packaging material.”
Other than the Pharmaceutical Industry, the manifold suppliers of excipients have no common identity as an “Excipient Industry”. In many instances
excipient suppliers only provide a small fraction of their total output to the pharmaceutical industry. Thus the standards applied to manufacturing and
distribution of such substances are focused on the compliance with the requirements of the manufacturer’s intended market and often these may not
require the application of GMP and GDP principles.

1 PQG – The Pharmaceutical Quality Group, a special interest group within the Chartered Quality Institute in the United Kingdom (see www.pqg.org)

2 European Pharmacopoeia, General Notices, 1.1. General Statements

3 “Excipients, USP and NF Excipients, listed by Category” ( appears in the early section of the NF section of the USP)

4 www.accessdata.fda.gov/scripts/cder/iig/index.cfm

5 IPEC Excipient Composition Guide 2009

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22.B Regulatory aspects and guidance documents
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ What is the legal position with regard to GMP for excipients?
■ What standards of GMP apply to the manufacture of Pharmaceutical Excipients?
■ What kind of guidance is given by the IPEC-PQG GMP Guide?
■ What is the IPEC and which objectives and activities does it pursue?
■ Which guidance documents are published by IPEC?

22.B.1 Legal position with regard to GMP for excipients

22.B.1.1 Situation in Europe
The EU Falsified Medicines Directive included a number of legal requirements for excipients for the first time:
■ A legal definition of an excipient (see Chapter 22.A.1 What is a Pharmaceutical Excipient?)
■ The right for the authorities to inspect excipient suppliers
■ Application of penalties for non-implementation of the requirements for excipients in the Directive
■The need for the pharmaceutical users to apply a risk assessment in order to determine if the GMP applied by the supplier is suitable for their
intended use

These developments bring excipients closer to the regulatory oversight applied to APIs. The right to perform inspections is qualified:
“Whenever [the competent authority] considers that there are grounds for suspecting non-compliance with the legal requirements laid down in this
Directive, including the principles and guidelines of good manufacturing practice and good distribution practices referred to in point (f) of Article 46 and in
Article 47, the competent authority may carry out inspections at the premises of: …
(b) manufacturers or importers of excipients ”
Although distributors of excipients are not explicitly mentioned here, the intent is clear, that if there are grounds for concern an inspection is a possibility.
However, there seem to be several aspects of this clause that indicate it may not be possible to implement it in practice. How will the competent
authority know where they have to go in order to inspect the excipient supplier? There is no requirement in this legislation for excipient suppliers to
register or be registered (in contrast to the recent US legislation – see Chapter 22.B.1.2 Situation in USA). In theory such inspections may be
unannounced, but the legal basis for demanding and receiving entry to the excipient’s suppliers‘ premises seems to be absent from the legislation. And
of course, if the legal position regarding the right to perform inspections is unclear within Europe, then there can be no legal right to perform inspections
for excipient suppliers who reside outside Europe. It is also not clear what the basis of the inspection would be, as there remains no legal definition of
GMP (or GDP) for excipients within Europe. So at first glance this appears to be a reasonable requirement to add to the legislation, but it seems to lack
detail to mean such inspections have any legal right of access or could be effective. No doubt, more details will be forthcoming as the guidance and
ancillary requirements are defined by the European authorities to make sure the details in the FMD are implementable.
The Directive also stated it would apply penalties for the non-compliance with the provisions laid down in this Directive on the use of excipients. Again it
is not explicit to whom the penalties would apply – the excipient supplier or the excipient user. Presumably the latter, as it is difficult to see how a
penalty could legally be applied to the excipient supplier when there is no official relationship between them and the authorities.
The Directive acknowledges that excipients are very diverse and that a range of good manufacturing practices can be applied in their manufacture. It
builds on this and goes on to require:
„The holder of the manufacturing authorisation shall ensure that the excipients are suitable for use in medicinal products by ascertaining what the
appropriate good manufacturing practice is.“
So as with much of recent EU regulation it is for the pharmaceutical user to justify what GMP should be used for their application of the excipient. In a
way this seems a big change, but in reality it is not. Those excipient users who have been auditing their excipient suppliers have always applied their
own “GMP” requirements which from the suppliers’ perspective have varied from customer to customer for exactly this reason. Clearly what the Directive
has done is to formalize this common practice and to make sure the excipient user can justify their selection of the GMP to be applied. The Directive
goes on to require a formalized risk assessment for this purpose and to indicate that the Commission shall issue guidelines on how to conduct this risk
assessment.
These guidelines have now been published – Guidelines on the Formalised Risk Assessment for Ascertaining the Appropriate Good Manufacturing
Practice for Excipients of Medicinal Products for Human Use1 which remains open for comments until 30th April 2013. This document gives pragmatic
guidance to determine the risks posed by the quality, safety and function of the excipient and to then classify each one for example as “high, medium or
low risk”. Details are given of the factors to be considered in this risk assessment, which should be straightforward for existing as well as new excipients.
The draft document then continues in that the Marketing Authorisation Holder should document the parts of EU GMP (i.e. elements of Part II AND Part 1)
which have to be applied by the excipient supplier. There then follows a list of high level “principles” of GMP which have to applied by all excipient
suppliers. Although the principles are readily adopted in the IPEC-PQG GMP Guide, the way these principles are written means that some of them will
result in standards being applied which exceed Part II GMPs for APIs. Otherwise the whole approach puts the responsibility on the excipient user, to
perform the risk assessment and justify the GMP applied by their suppliers.
There has to be evidence that the supplier actually applies the determined levels of GMP, through audits. The guide expressly indicates suitable 3rd
party audits would be acceptable – thereby acknowledging the audit burden facing industry and providing a suitable solution without compromise to
patient safety.
Once the evidence is gathered the excipient user has to perform another risk assessment to determine the controls necessary to further reduce the risks
resulting from any gaps in the GMPs that are applied by the excipient supplier.
An excellent document – it is to be hoped than when finalised some of the proscriptive elements are edited out without compromising the spirit of the
document. It certainly compliments the FMD very well.
Subsequent clauses in the FMD note:
„Such risk assessment shall take into account requirements under other appropriate quality systems as well as the source and intended use of the
excipients and previous instances of quality defects.“
This seems to suggest that other quality systems (e.g. ISO 9001) could be appropriate in certain circumstances, but only if the risk assessment
concludes that such a standard can provide an excipient of suitable quality for that application.
This development is to be welcomed, as it allows industry to define what is required and then seek suppliers who can meet these standards. Given the
breadth and complexity of excipients, a “one size fits all“-approach to GMP for excipients was going to cause more problems that it would solve.
A later paragraph requires the Marketing Authorisation Holder (MAH) to verify the authenticity as well as the quality of the excipient. Up to now
Pharmaceutical GMPs have always required the quality of the delivered excipient to be verified, but the requirement to confirm authenticity is new.
Unfortunately there is no further definition of „authenticity“ which in the context of the Directive would suggest that the MAH needs to understand
(control?) how the excipient was transported from the manufacturer to their premises.
Overall, at this time the way the Directive impacts excipients is to be commended. It uses a risk assessment approach with all its objectivity to allow the
MAH to select and use the best excipient for the task in hand.
22.B.1.2 Situation in USA
Meanwhile over the other side of the Atlantic, Congress has also been taking a keen interest in excipients, no doubt to the number of very well publicized
incidents involving counterfeit or otherwise low quality excipients and other additives that have reached consumers.
The U.S. Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012 which is the largest change for drug and
medical device regulations in many years. It redefined cGMP as:
„the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality,
including managing the risk of, and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.“
The FDA is now required to develop guidances or regulations concerning many different areas contained in the legislation including adding a significant
number of supplier controls throughout the lifecycle of the excipient into the cGMP requirements. For example: All excipient manufacturing sites must be
identified in drug registration documentation.
“(E) in the case of a drug contained in the applicable list, the name and place of business of each manufacturer of an excipient of the drug with which
the person listing the drug conducts business, including all establishments used in the production of such excipient, the unique facility identifier of each
such establishment, and a point of contact e-mail address for each such excipient manufacturer.”2
So all excipient manufacturers and suppliers will need to register with the FDA directly as well as be included in the details provided by the MAH to the
Agency in regulatory submissions. Not only this but the FDA is also required to report to Congress the number of national and international excipient
manufacturing inspections performed each year beginning in 2014. This would suggest that the registration process for excipient suppliers will now
trigger routine inspections as well.
22.B.1.3 Situation in other regions
Until recently, only Japan had legal requirements for excipients to be manufactured in compliance with GMP. But not only have the EU and the US
addressed this, but also China and Brasil have recently published additional controls to be applied to excipients as a means of improving standards.
In particular the publication of a full set of GMPs for excipients in Brasil is a first outside Japan in defining detailed GMPs. The first public draft contained
the same intent as that in the IPEC-PQG GMP Guide but some aspects seemed to be stricter and closer to those requirements for APIs. The health
Authority, ANVISA, published the detailed guidance on GMP for excipients in the Summer of 2012.
In China provision has been made for greater regulatory oversight of excipients and for greater responsibility to be taken by the excipient user in
qualifying excipient suppliers. In 2005, China had proposed a set of GMP requirements for excipients that matched or exceeded those for APIs in
Europe. Following representations from IPEC and further contact with the European and US authorities, the SFDA (Chinese FDA) has indicated that
developments will be postponed. More recently the SFDA published a set of GMPs covering finished dosage forms and APIs, but excipients were not
expressly included at this point.
In Japan excipients listed in the Japanese Pharmacopoeia are considered as “drugs” and the regulations for drugs are applied to these substances. No
marketing authorization is required, but a marketing notice is required instead. There are mandated GMP elements as a result, and these include
manufacturing control and Quality Controls (“GMP soft”) along with standards for buildings and facilities (“GMP hard”). There are some validation
requirements.
In all territories except Japan the onus is on the user to qualify the supplier and to demonstrate that the excipient is fit for purpose both from a chemical
entity and functionality viewpoint and from an ongoing supply viewpoint. It is the latter that requires the supplier to apply an appropriate degree of GMP
and GDP.
22.B.1.4 Supervision and inspection of excipient suppliers
The authorities in some territories of the EU will perform an inspection of an excipient supplier on a voluntary basis. Within the UK the MHRA will provide
this service. However an inspection can be very expensive (the fees are commensurate with the headcount in the organization). A letter showing that the
inspection occurred can be issued which can be very valuable in the supply of excipients to overseas countries, especially when they require a “GMP
Certificate”. On the other hand, the inspection can be of little value in Europe as it will not negate the need for the user to fully qualify the excipient
supplier, including a physical audit.
In the US the FDASIA will mean direct or routine supervision of excipient suppliers by the authorities. But with the legal framework excipients are “drugs”
and are treated as such. However inspections can still occur “for cause” or when the excipient is used as an Atypical Active3. The USP-NF General
Notices require the use of appropriate GMPs in the manufacture of compendial materials4. The same compendium has also published the IPEC-PQG
GMP Guide as an informational chapter (<1078>). So there is a requirement that excipients marketed as being compliant to the corresponding USP
monograph would be manufactured to that standard of GMP.
The authorities are now turning their full attention to excipients worldwide and some are now defining GMP for excipients. Nevertheless they still need to
be mindful of the “nightmare” scenario where many suppliers choose to stop supply rather than incur the increased costs associated with the
implementation of what they perceive as a disproportionate set of GMPs.

22.B.2 GMP-Standards for the manufacture of pharmaceutical excipients

In 1999 the World Health Organization (WHO) published a GMP guide for pharmaceutical excipients. This included many of the requirements that are
now familiar in Part II of the EU-GMP-Guide (see Chapter C.5).
ICH Q7, now elaborated as Part II of the EU-GMP-Guide, defined the GMP required for the manufacture of Active Pharmaceutical Ingredients. The design
of ICH Q7 started with the fact that many APIs are manufactured by chemical synthesis and so the detailed rules that were required to assure product
quality were different to those used in finished dosage form GMPs. Fundamentally the technology used to make APIs is different to the technology used
to make dosage forms and therefore the controls needed to assure patient safety have to be different. Although on the surface excipients would appear to
share many commonalities in their preparation and manufacture with APIs, there are crucial differences, and so it is not appropriate that Part II GMPs be
applied to all excipients. For this reason IPEC prepared a definition of GMP for these substances in collaboration with the UK Pharmaceutical Quality
Group. The Joint IPEC-PQG GMP Guide was published in 2006 and is based on guides previously independently published by both organizations.
As this guide was fully international in scope and proposed a pragmatic set of GMPs that covered most excipients in manufacture and use, there has
been very widespread uptake and use of the Guide by users and suppliers. Indeed IPEC-Americas were successful in getting the USP to adopt the text
as general chapter <1078> (the differences between <1078> and the IPEC-PQG GMP-Guide 2006 are editorial in nature to allow for publication in the
USP).
More recently IPEC has been developing certification schemes for GMP and GDP for excipients based on the IPEC-PQG GMP Guide. A development
led by Europe took the GMP and GDP Guides and converted them to an annex to ISO 9001:2008 for both GMP and GDP. In this manner suppliers could
be assessed by a suitable 3rd party for compliance to GMP and/or GDP aspects simultaneously with their ISO 9001 certification. This evolutionary
approach is called EXCiPACT (www.excipact.org) and has received widespread acceptance from regulatory bodies during its development and
publication. The certification scheme is due to be fully launched in early 2013. In a parallel activity a draft US National Standard (ANSI NSF 363) has
been developed for organizations that do not hold ISO 9001 certification (as is more common in the US). This standard is also based on the IPEC-PQG
GMP Guide, and has been developed with excipient users, excipient suppliers, academia and the FDA. This standard is due to be finalised and issued in
March 2013. GDP is not explicitly included in this US national standard because the FDA considers GDP to be a subset of GMP and therefore fully
covered in the GMP standard.
Both standards are “what to do” documents and not guidance, they therefore differ in detail from the Guides. To allow for the wide variety of excipients
both EXCiPACT and ANSI NSF 363 make full use of quality risk management principles, placing the responsibility on the excipient supplier to use risk
management to justify the implementation of the GMPs. The use of risk management is not so explicitly mentioned in the IPEC-PQG GMP and GDP
Guides, but it is widely indicated.
As a result of the development of these standards it is likely that the IPEC-PQG GMP and IPEC GDP Guides will be updated in the near future.
Nevertheless, GMP is only one component of assuring the quality of excipients, and like APIs, delivery to the pharmaceutical manufacturer needs to
follow the principles of Good Distribution and Trade Practice (GDP or GDTP). Apart from WHO, where GDP was initially defined, and the recent
introduction of the topic into the EU Falsified Medicine’s Directive, this aspect is relatively underdeveloped outside of the IPEC guides.

22.B.3 Implementing the IPEC-PQG GMP Guide

The consultation of the draft of EC-Directive 2001/83/EC, dealing with GMP for certain excipients, indicated that industry had voluntarily adopted the
IPEC-PQG GMP Guide in almost equal numbers with HACCP (food GMP) and Part II GMP. By far the greatest number of respondents had indicated
that they had ISO 9001:2000 as the basis of their quality management system. Interestingly GDP was also highly cited as being in place. With
international recognition and this level of voluntary uptake it is appropriate to review the contents of the IPEC-PQG GMP Guide and to provide some
further thoughts on the contents.
22.B.3.1 What is GMP for excipients?
IPEC has chosen to use the following commonly used definition of GMP:
“The part of Quality Assurance (QA) which is aimed at ensuring that products are consistently manufactured to a quality appropriate to their intended
use”
The term “consistently” means that it is not enough to make an occasional good product, but there is a strong requirement to make one of the same
quality batch after batch.
The term “intended use” indicates that the excipient has been manufactured and sold as suitable for pharmaceutical use. Strictly materials which are not
manufactured by intent for pharmaceutical use should not be used as excipients. However such idealism denies the commercial realities for many
excipient suppliers where their main markets are outside pharmaceuticals.
IPEC and PQG identified the core principles of GMP that are defined in ICH Q7 for APIs and developed their joint guide accordingly.
These principles are:
■ The product should not harm the patient.
■ The product should be pure and free from contaminants.
■ There should be defined manufacturing procedures which have been proven to be effective in making product of a consistent quality.
■There should be records of the manufacturing process that demonstrate that the product has been made in accordance with these planned
arrangements.
■ Personnel should be competent in the execution of their roles and have sufficient training.
■ Manufacturing equipment should be fit for purpose and maintained in that condition.
■ You cannot inspect quality into the final product.
■ Changes which impact excipient quality require prior review and approval, and as appropriate notification to the customer.

The first principle is the most fundamental – the product should not harm the patient. The remaining GMP principles provide assurance that the product
is safe to use.
Given that no excipient is added to a drug product without a purpose, then it becomes very important that the functionality of the excipient is consistent
from batch to batch, and yet in the vast majority of cases these performance requirements are not included directly in the specification: in many cases
there are no methods to judge the performance of the excipient. This is not a failing of the excipient supplier or indeed the user. In general, and even
today, there is a fundamental gap in science. While we may be able to determine the molecular structure of an excipient, we are not able to predict in
any detail the performance characteristics it will have.
As a result it becomes all the more important that the excipient user has to evaluate the excipient carefully and judge the spread of performance it may
exhibit whilst remaining within the physical and chemical specification. Likewise the excipient supplier has to be very careful in evaluating changes as
these may impact performance without changing any specification parameter.
Similarly, if a deviation occurred during manufacturing of the excipient, which causes some new harmful impurity to be formed, then testing to
specification would not look for it and the excipient would be assessed as suitable although it is not. The same situation could arise if there are changes
within the manufacturing operations. In both cases, assurance of functionality and of composition, the excipient supplier has to put change control in a
central position, hence its importance within the IPEC-PQG GMP Guide. However, it is a combination of all of the GMP principles that ensures these
and related excipient manufacturing risks to quality are controlled and mitigated.
22.B.3.2 Key features of the IPEC-PQG GMP-Guide
As the “Certain Excipients” consultation demonstrated, many organizations that manufacture chemicals are already registered to ISO 9001. This
familiarity with the requirements of that standard meant that ISO 9001 was an obvious choice for the structure of the IPEC-PQG GMP Guide rather than
ICH Q7/Part II. By aligning the clauses in the guide with the major headings in ISO 9001:20005, organizations will be able to see at a glance where their
management systems need to be enhanced and this allows for a simpler uptake than trying to map the new GMP requirements onto an existing quality
management system.
Yet in the development of both the IPEC and the PQG predecessor documents to the 2006 guide, the principles and GMP detailed in ICH Q7 were
extensively reviewed, adopted and adapted for excipients, resulting in an alignment of the GMP in the IPEC-PQG GMP Guide 2006 with that for APIs.
The Guide also owes much to the WHO GMP Guide for Excipients.
Sections 1 and 2: introduction and definitions
The Guide acknowledges that not all excipients are in scope, that those requiring a very high degree of quality assurance will need to apply additional
GMPs, particularly those destined for parenteral, inhalation and open wound application or those that are sterile and/or pyrogen free. In the latter case it
is generally accepted that such excipients need to comply with Part II general controls and those concerning sterile manufacture have to comply with
Part I annex 1. As a GMP Guide it also notes that GDP guidance is not included – that can be found in the companion volume, the IPEC GDP Guide
2006.
As a guide, the contents are indicative and should not be interpreted as hard and fast. Although the guide was written at a time before quality risk
management principles were widely adopted, it does strongly suggest that users of the guide evaluate the risks to excipient quality in their organizations
and identify those elements of the guide that best reduce those risks. Thus not all aspects of the guide have to be adopted in every instance. In this
respect the guide is not a standard6 (but EXCiPACT and ANSI NSF 363 are standards and in these cases the aspects do have to be adopted). The
Definitions in Section 2 are intended to align the remainder of the guide with the ISO 9001 clause structure.
Section 3: General guidance
Section 3 mirrors ICH Q7 / Part II in that the excipient supplier should determine from which point the GMP described in the Guide should be adopted
and implemented. Again reference is made to performing a suitable risk assessment to identify when this should happen. Organizations can choose to
apply the GMP from the receipt of their raw materials for practical reasons, as they can then apply one quality management system to the entire
organization.
Section 4: Quality Management System – Excipient Quality Systems
Within Section 4 the guide begins to elaborate the detailed guidance needed for pharmaceutical excipients. The emphasis is on the need for written
procedures to cover quality critical activities. In this respect the need for written documents is above that strictly required in ISO 9001:2000 which
somewhat famously only specifies that 6 documents are necessary. A quality management system with only 6 documents was felt to be outside the
core principles of GMP, where defined procedures are a core part of ensuring the consistent manufacture of excipients.
In addition to traditional GMP, but to draw upon the strengths of ISO 9001, there is an expectation that the supplier will have a Quality Manual in place.
In many cases this is very similar to a Site Master File (and creative organizations can combine the two) in that the Quality Manual provides a top level
view of the organizational arrangements for quality.
The remaining documentation controls within ISO 9001 and GMP are for the most part the same, although some of the more pedantic documentation
practices have been omitted (for example the need for QA to sign off every page of every quality document). Additionally not all documents have to be
signed off by QA, only the quality critical ones.
The Guide defines quality critical as cited in Figure 22.B-1.
Figure 22.B-1 Definition of “quality critical” (IPEC-PQG GMP Guide)
Definition of “quality critical”

“… a material, process step or process condition, test requirement or any other relevant parameter that directly influences the quality attributes of the
excipient and which must be controlled within predetermined criteria”.

Whereas this definition may be considered obvious, it remains a challenge to consistently identify quality critical activities in an organization. At audits
the individual perceptions of what can and cannot affect excipient quality can lead to interesting debates. Experienced auditors will ask the organization
how it determined quality critical (they ought to know best after all) and then asses if there is a suitable focus to control those activities.
If something is defined as “critical” and then a certain set of actions follow, it should be recognized that some things can be “not critical” and so a
different action or indeed no actions follow. Without making this difference, everything can become “critical” which makes the word redundant. In the
development of the EXCiPACT and ANSI NSF standards quality risk management principles were used to ensure excipient suppliers defined “critical”
in the context of their operations.
The use of electronic document control was acknowledged but in a brave step (in 2006) the application of 21 CFR Part 11 was not mentioned. It was
already recognized within IPEC and PQG that this regulation was inhibiting innovation and so preventing the benefits to quality that can be achieved
through the use of computer technology. Nevertheless the principles in 21 CFR Part 11 were called for in the electronic controls needed to match the
ones applied to a paper system (echoing the same requirement in ISO 9001). The same guidance was offered considering electronic signatures.
The guidance for records were a match to those in ISO 9001 with additional comments concerning traceability to person, time and date of creation and
corrections to records.
In a departure from traditional pharmaceutical GMP the guide recommends that batch records be kept for a period that is aligned to the expiry or retest
date on the batch of excipient concerned. Traditional GMP requires records to be kept for a period of time equivalent to the date of distribution of the last
part of the batch and then a defined period afterwards. This is very onerous because organizations have to keep track of every last item of stock of the
batch and after selling it set the clock ticking for the disposal of the records. It is far simpler and just as robust that the clock be set ticking from the date
of manufacture.
There was however one major addition to ISO 9001 in this section, the inclusion of an additional clause, 4.3 Change Control. It was felt by both PQG and
IPEC that the significance of change control was not emphasized strongly enough within ISO 9001 and that users would benefit from some further
guidance on the subject in a stand-alone section. For example one key area that requires effective change control is managing the impact of altering the
origin of raw materials (e.g. animal, mineral or vegetable), particularly with respect to TSE (Transmissible Spongiform Encephalopathy). It was
considered that a basic ISO 9001 quality management system would not have enough sensitivity on this topic, and substituting one supplier of a raw
material would not trigger a suitable review of the impact on excipient quality. In this respect the change control process supports the principle that “you
cannot inspect quality into an excipient” as it is not possible to test the product for all contaminants or impurities.
Examples of the factors that should be considered as critical to quality are elaborated along with the requirement to evaluate the consequences to any
regulatory submissions that the excipient supplier may have (e.g. CEPs or DMFs) and the need to communicate significant changes to customers. In
this respect the guide mirrors the general expectations in Part I and Part II of the EU-GMP-Guide.
The Guide does not provide a definition of “significant” but makes reference to the IPEC-Americas Significant Change Guide as this document indicates
what changes would be considered significant. This change guide is also published in the USP as general chapter <1195>. It requires excipient suppliers
to place changes into two categories: “no customer notification required” and “notification required”. There are some worked examples in the Change
Guide to explain how seemingly insignificant changes to the excipient supplier can have a major impact on the excipient user.
Section 5: Management responsibility
Whereas much of GMP has traditionally placed the responsibility for quality firmly on the quality unit or on the qualified person, ISO 9001 takes a more
holistic view and starts at the top of the organization. The IPEC-PQG GMP Guide starts off by paraphrasing the ISO 9001 clauses for management
commitment, user focus and quality policy. These remain broad topics and introduce no new aspects than those in ISO 9001, but still emphasize the
need for continual improvement. However the user focus section requires that the supplier permits users to perform audits of their operations. This then
aligns with the user GMPs where there is an expectation that supplier qualification involves a physical audit of the supplier. Recent adverse events with
the supply of heparin and glycerine have again highlighted the criticality of physical audits of suppliers.
The guidance and good practices detailed in this section of the guide have recently been incorporated into ICH Q10 Pharmaceutical Quality Systems
(see Chapter E.10), which again requires organizations to continually improve their performance and quality.
The requirement for top management to commit to the principles and rules of GMP appears in the Quality Objectives section. Quality Objectives are set
by top management, and as this is the highest level of management in the organization there will be a demonstrable and clear commitment to GMP
throughout the organization. This is then backed up in the following section, Quality Management System Planning where top management is charged
with ensuring sufficient resources to be available to implement, maintain and develop the quality and GMP management systems. The section concludes
with a reminder that the quality management system has to be checked so that it is not adversely affected by changes. This recognizes that the
commitment to continuous improvement requires changes in all aspects of an organization, including the quality management systems. In this regard a
balance is being struck between the need for change (so as to improve) and the need to assure product quality at all times.
As in GMP, ISO 9001 makes a strong case for the definition of roles and responsibilities and the need to communicate these throughout the
organization. In keeping with standard GMPs there is a commitment that top management clearly defines the authority and responsibility for quality
within the organization. The IPEC-PQG GMP Guide then draws on the critical responsibilities of the quality unit as defined in Part II of the EU GMP
Guide and sets these to be assigned to “a unit independent of production”. It stops short of requiring that the quality unit be assigned these
responsibilities as it was recognized from the authors of the IPEC-PQG GMP Guide that some excipient suppliers did not have a recognizable quality
unit yet were still capable of supplying high quality products. However the requirement that the responsibilities be separate from those responsible for
actual manufacture was considered to be the minimum requirement.
Some delegation of the actual tasks is permitted (as it is in Part II of the EU GMP Guide) as long as suitable training and documentation are in place. In
cementing the responsibilities of quality there is the requirement to document the responsibilities in an organization chart. Finally there is a requirement
for written job descriptions, but only for those functions that have an impact on excipient quality.
The IPEC-PQG GMP Guide follows ISO 9001 in requiring a management representative who is fully authorized to ensure that the GMP in the guide is
implemented in the supplier’s organization. There remains a requirement that this individual reports back to top management on the performance of the
quality management system, and changes to user requirements. By adding to that clause that this individual also has to report changes in regulatory
requirements, there is now a need for the management representative to be alert and aware of any significant news and announcements in the field of
excipients and GMP in general. Membership of a trade association like IPEC or the PQG is an excellent way to achieve this.
Top management is charged with ensuring the need for GMP to be communicated throughout the organization in addition to any regulatory requirements.
It is only by ensuring that this message comes from the highest levels that we can be assured that the policies and procedures will be enacted and
implemented. After all, for excipient manufacturing and supply there is no legal requirement to implement GMP, unlike APIs or drug products.
Quality critical situations, including product recalls should be notified to top management in a timely fashion. Of course in many organizations a recall
could only be implemented with their authorization, but this is not the only quality critical situation that may demand their attention. The IPEC-PQG GMP
Guide uses the term “retrieval” for a product recall as the term “recall” has a specific reserved meaning in the US where it means that product is
withdrawn from the market with notification of that event to the FDA.
Section 5 concludes by setting out how an annual quality management system review should be conducted, in an excipient supplier. Thus the GMP
aspects have to be considered and factored in as well as those required in ISO 9001.
Section 6: Resource management
The previous sections set the scene for the design of the quality management system and for assigning responsibilities, but without resources,
particularly people, none of these plans can be realized. There is not an outright commitment that personnel should be competent in their assigned
tasks, but the guide does indicate that they should have an appropriate combination of education, training and experience. There is a reminder to ensure
consultants meet these requirements if they are employed by the company.
Training records are a key element, especially for those tasks that are quality critical and are a key component of GMP. An essential GMP principle is
then introduced in that all personnel have to understand how deviations from defined procedures can impact excipient quality – thus ensuring the
manufacturing process to be consistent from batch to batch.
This section of the IPEC-PQG GMP Guide has been reworked significantly in the EXCiPACT and ANSI NSF standards. Excipients suppliers are now
required to start with a quality risk assessment to identify what controls are needed to ensure excipient purity and freedom from contamination. Where
specific actions are identified by the excipient supplier then the controls highlighted in the Guide are recommended with the attendant GMP practices.
This approach allows excipient suppliers to justify the actions they take and to avoid unnecessary or low value controls that do little to assure excipient
quality. Key areas requiring this risk assessment approach include personnel hygiene, infrastructure and work environment.
Personnel hygiene Another section that is additional to ISO 9001 then follows, dealing with personnel hygiene. This aspect of GMP is of particular
concern when products are exposed to the manufacturing environment and operational personnel. At the time the guide was prepared quality risk
management principles were not well established, and this section contains the key phrase “where appropriate” in describing the controls to be applied
(e.g. head, face, hand and protective clothing). In modern terms this indicates that the organization should assess the risks to product quality in its
operations and take measures to control those risks that are presented through poor hygiene practices. In a continuous process with an excipient that is
never exposed to the environment it would be a waste of time and effort to demand that personnel wore protective clothing to protect the excipient –
although they may well do so anyway for health and safety reasons.
One potential risk to excipient quality arises when the product is exposed to the environment and operational personnel have an illness. The standard
GMP requirements are stated in the Guide in that personnel need to be aware of this risk factor and should report to line management if they have any
concerns. Where an organization has an occupation health practitioner then the quality unit should remember to inform him that the organization is
making pharmaceutical ingredients and that they also need to play a role in ensuring excipient quality by assessing personnel so that they do not pose
a risk to excipient quality.
Infrastructure The next two sections in ISO 9001 are critical to ensuring product quality, covering Infrastructure and the Work Environment. It is not
surprising that the IPEC-PQG GMP Guide expands on the very short sections in ISO 9001. They may be short but in actual fact they are right to the
point in instructing organizations on the key elements necessary to assure product quality. What ISO does not do is to provide any guidance on what
controls should be put in place to meet the requirements.
The core principle is that the infrastructure has to be managed, operated, cleaned and maintained to ensure excipient quality and to avoid contamination.
There is another hint that a risk assessment is needed here in that the Guide notes that particulate, microbiological and water quality issues should be
identified and suitably controlled. The theme of avoidance of contamination continues with a reminder that the buildings themselves can provide a risk to
excipient quality, if the product is exposed and the buildings are not maintained in a suitable condition. Where an organization is to construct new
facilities there is a requirement to ensure that the avoidance of excipient contamination is built into that design from the outset.
The requirement to avoid using highly toxic, sensitizing or otherwise potent materials in the same location is included in this section. Although it does
acknowledge that for some excipient manufacturers this prohibition is not always implementable. In these cases the guide recommends that suitable
measures (cleaning, inactivation etc.) be implemented to avoid cross contamination.
Although the Guide indicates that suitable facilities should be available for testing of raw materials, packaging components, intermediates and finished
excipients no other comments are made concerning where, what or how such facilities should be located, operated and maintained.
Manufacturing equipment Coming to the manufacturing equipment itself, the theme of protecting the excipient from contamination continues with a
matching requirement to that applied to the buildings and facilities: the equipment needs to be maintained and operated in a good condition. Reference
here is first made to continuous operation which is quite common in the chemical industry but only in the sense that the use of such techniques is
acknowledged in the guide. It follows that all equipment used in the manufacture of an excipient has to be maintained and operated in a defined manner
so as to assure excipient quality.
The term commissioning is used here as a bridge between traditional pharmaceutical and API GMPs which require equipment to be qualified and
validated. In the chemical industry in particular such activities are not dealt with in that manner, rather equipment is designed and built to that design.
Then the equipment is usually started up using safe materials (often water if a fluid is required) to demonstrate the completeness of the build and that the
equipment is capable of operating as intended. There then follows a steady introduction of real process chemicals until the first production actually takes
place. It can be clearly seen that these steps follow the validation lifecycle in that commissioning includes Design, Installation, Operational and
Performance Qualification activities. Often the only real difference between commissioning and qualification is the level of documentation that is
organized and retained afterwards. Clearly in the pharmaceutical industry this documentation is a central part of the GMP requirements and has to be
retained in an auditable manner. In the chemical industry there are few if any similar drivers to establish the protocols and keep such records, particularly
where the objective is for product quality purposes.
The Guide also educates pharmaceutical auditors into the fact that equipment can be located outside and even in the plain air. Processing hazardous
substances is often best done without containing them in a secondary barrier (i.e. a building) as this can lead to very substantial health, safety and
environmental concerns (e.g. processing with a highly toxic chemical such as ethylene oxide or hydrogen cyanide).
When looking at equipment construction, the Part II requirement that the equipment should not react with and therefore alter the product quality is
restated. The comments go on to recommend that lubricants and other processing aids are considered and the equipment designed to avoid contact
between them and the excipient. Where this is not possible then suitable grades should be used so that the risks to excipient quality are minimized,
e.g. food approved lubricants. This can be a little restrictive as in some cases it is possible to use one of the excipient starting materials as a lubricant,
and in this instance there would be minimal risk to excipient quality. What is required but not clearly indicated by the guide, is that lubricants that are
intended to come into contact with the excipient (e.g. stirrer glands) should be of a suitable quality such that the risks to the patient are minimized,
firstly by selecting a suitable material and then by ensuring that the lubricant itself is kept free of contamination. Best practice here recognizes the risks
and the purchase and storage of such lubricants are treated to the same extent as any other quality critical raw material.
Contamination from the external environment and the operators themselves needs to be controlled by careful design of operational equipment. Care also
needs to be applied to the choice of seals and packing materials that could come into contact with raw materials, intermediates or the excipient.
The design of the equipment is one part of the equation; the other is ensuring that the equipment is suitably maintained. The Guide recommends the
implementation of documented procedures covering maintenance activities and the retention of records of those activities. It is acceptable that those
records could be in electronic format.
Computer systems Computer systems play an ever increasing role in manufacturing and distribution operations, and the excipient industry is not
different in this respect. Whereas the Guide does not require the full implementation of the ISPE GAMP guidelines or 21 CFR Part 11, it does remind all
parties of the key principles where computer systems may impact excipient quality:
■ there should be suitable controls to prevent unauthorised access,
■ operation and maintenance activities should ensure that unauthorised changes cannot be made,
■ some checks should have been done to show that the computer system operates as intended and that it is checked at suitable intervals, and
■ Back up or archival systems are in place.

Utilities Other factors that can impact excipient quality in the infrastructure include the utilities used to operate the equipment. The guide recommends
that those utilities that come into contact with the excipient should be assessed and suitable controls put in place to ensure the excipient is not
contaminated. Of all utilities water is the one most likely to be a threat, especially where it comes into contact with the excipient. The guide
recommends that potable water is used as the minimum quality where it does come into contact with the excipient. Where potable water is not enough
then the guide indicates that suitable specifications (for example including microbial contamination and endotoxins) are established. Such water should
then be treated and monitored against these specifications. The section concludes with a reminder that water systems can be at risk of back flow and
that this should be reflected in the design and operation of the system.
Work environment ISO 9001 is famously terse on the subject of Work Environment: “The organization shall determine and manage the work
environment needed to achieve conformity to product requirements.”
What more is there to say? Even for excipients, this indicates that the supplier has to understand how the work environment poses a risk to product
quality (“determine”) and that management systems have to be developed to ensure that these risks are not realized. So from the viewpoint of an auditor
or setting the standard on what to do, there is indeed nothing more to add. Of course the Guide seeks to be more helpful than ISO 9001 and sets out to
provide excipient suppliers with some ideas about how to control the work environment.
As a key issue it is recognized that control of the Work Environment is only needed when the excipient is exposed to that environment. If this is not the
case, then little or no controls are needed (e.g. equipment located outside). Aspects covered here include air handling, with a recognition that in the
chemical industry “air handling” could be misinterpreted as local exhaust ventilation (i.e. a health and safety system designed to protect the operator
from the product) and as such is not installed to protect the excipient – so it should not be subjected to the recommendations on the controls over air
handling systems. Pragmatic and reasonable suggestions are made for air handling systems that are designed to protect the excipient.
The Guide mentions a “controlled environment” as a means of protecting the excipient from contamination or degradation. This is not necessarily a clean
room, although it could be, but rather a more general recognition that some excipients are sensitive to the environment and so require additional
protection from it. Where systems are in place to achieve this then they should be demonstrated to function as intended (but this does not require that
they are validated in the pharmaceutical sense). It recommends that inert gases be treated as a raw material where they are used to protect the
excipient.
Cleanliness is a central tenet in GMP and the IPEC-PQG GMP Guide makes no apologies for emphasizing that this is also true for excipients. But the
guide again hints at the risk assessment that is required in terms of defining the risks to excipient quality that could arise from the facilities. So where
excipients are exposed to that environment then documented cleaning procedures and records should be in place. There is a reminder that waste can
pose a risk to excipient quality, therefore it should be segregated and disposed of in a timely and appropriate manner.
The Guide indicates that buildings should be free from infestation with rodents, birds, insects and other vermin but surprisingly does not indicate that a
pest control program should be in place nor documented. EXCiPACT and ANSI NSF 363 have corrected this oversight and do require a documented pest
control program, but only where the excipient supplier has determined through a quality risk assessment that one is needed. Thus operations that
occur outdoors as a result of the technology used would not need a pest control program in most cases and this can be justified by the excipient
supplier in this manner.
This section concludes with traditional GMP requirements for adequate lighting, suitable drainage systems, and washing and toilet facilities. Oddly the
latter are not required to be separated from areas where the excipient may be exposed.
With the infrastructure and facilities now in place the Guide turns its attention to the planning necessary to manufacture the excipient.
Section 7: Product Realisation
Planning of product realisation The IPEC-PQG GMP Guide paraphrases ISO 9001 in section 7.1, and requires that the GMP principles of
documented plans be put in place, which include specifications and testing schedules with suitable product release procedures. Additional requirements
include the generation of suitable records so that planned arrangements can be shown to have been met, and to allow traceability (see Section 7.5.3.1).
Having plans is not enough as already highlighted - there has to be suitable and sufficient resources to realize these plans along with all the GMP
controls discussed in the previous sections on buildings, facilities and infrastructure.
Customer-related processes In section 7.2 the Guide reminds organizations to make sure that contract review with the user includes a dialogue
concerning GMP and other requirements that are stipulated by the users. This can include compendial compliance etc. There is an emphasis on seeking
agreement with the user but the Guide stops short of recommending that a Quality Agreement7 be established between the two parties. A Quality
Agreement is a good idea if the needs of the user are more substantial than the good practices in the Guide. The problem with many Quality Agreements
is that they are written as legal documents and therefore require the lawyers on both parties to review and agree the content. This is very time consuming
and an excipient supplier who has many users will probably not wish to engage in the protracted negotiations that can arise with each and every user.
The section also repeats the ISO 9001 requirement that a supplier implements the necessary conditions that the product demands where its intended
use is known. In this instance if the use is known to be as a pharmaceutical excipient then the adoption of a suitable GMP within the organization’s
quality management system is clearly necessary.
There is a clear requirement that the supplier and user should mutually agree on the requirements identified in the previous section, and that this should
happen before supply commences. In many industries this “contract review” can be very short just covering a specification and material safety data sheet
in extreme cases, for the supply of pharmaceutical excipients rather more is required. Amongst these additional requirements is the fact that the
manufacturing process should be able to consistently meet the user’s specification. Although this is not calling for process validation, it is a direct
reference that the manufacturing process should be sufficiently well controlled so that a consistent product can be produced time after time. Once this
contract review is concluded, there is a link back to Section 4.3 Change Control with the reminder that if anything that has been agreed in the contract
review has changed then this should be re-reviewed following notification to the user8.
Clear processes for user communication are essential to GMP and are emphasized in the section of the same name. Additionally the Guide
recommends that product specifications and other quality critical records be treated as controlled documents (see Section 4.2.3). The guide stipulates
that user complaints should be documented, an element of best practice that transcends GMP.
Further details on the negotiation that can occur between a supplier and a user of excipients can be found in the IPEC Qualification Guide. Additionally
IPEC has prepared the Excipient Information Package Guide and templates as a means of aiding in the communication between a supplier and a user.
This covers both the excipient manufacturer’s quality management system as well as their distribution practices for delivering the excipient to users.
There is also a product information template which is used to communicate details about the product over and above the specification (e.g. origin,
TSE/BSE, residual solvent, metal catalysts and similar statements).
Design and development In section 7.3 the guide makes no additional comments other than to follow ISO 9001, acknowledging that GMP does not
usually apply to the development of excipients unless they are known to be used for pharmaceutical development (e.g. clinical trials). Much here hinges
on the user notifying the supplier that this is the case. Where this is known the Guide recommends the principles in the remainder of the guide are
applied to the preparation of these development materials but stops short of making any specific recommendations on what the GMP should be. This is
in contrast to Part II / ICH Q7 which does make specific recommendations for materials made for this purpose. It should be noted that the guide predates
the concepts of Quality by Design which are described in ICH Q8 (see Chapter E.8). To remedy this gap IPEC has prepared some guidance on the
application of ICH Q8 to excipients.
Purchasing controls Controls over purchasing (Section 7.4) are crucial in GMP and the Guide requires that the quality unit approves suppliers of quality
critical materials. Whereas it states that the excipient manufacturer’s quality unit should evaluate their supplier’s quality management system, it does
not call for periodic physical audits although it recognizes that such activities can play a key part in qualification. This is an area where quality risk
management principles are now widely applied. A risk assessment is performed with regard to the impact the supplier of raw materials and process aids
may have on excipient manufacture and supply. The output of the risk assessment can be a classification in which high risk raw material and process
aid suppliers are subject to additional controls including physical audits. However, the Guide predates the widespread application of such approaches
and perhaps this is an area where revision of the Guide is warranted.
Not only do the excipient manufacturer’s suppliers have to be approved, but also specifications for purchased materials need to be agreed with them. The
purchasing information (for example contained on a purchase order) needs to be explicit enough so that the excipient manufacturer’s supplier knows
exactly what they need to provide. Amongst these is the adoption by the supplier of the relevant sections of the Guide in the manufacture of their
materials. The Guide does not further elaborate which parts of the Guide need to be adopted by the excipient manufacturer’s suppliers which is a pity.
Ensuring the product is free from contamination and that all operations and raw materials are traceable would be a good starting point. As elsewhere
there is a requirement that the excipient manufacturer’s supplier notifies the excipient manufacturer if there have been significant changes in the
manufacture of their material.
Once the material is purchased then it requires confirmation that the right material is actually delivered to the excipient manufacturer (see Chapter
11.M.9.1 Receipt). The verification activities include the need to quarantine deliveries from subsequent use until they have been suitably checked. The
Guide recognises that the quarantine can be a physical one or one operated by a computer system. The concept of quarantine applies to materials that
are delivered in containers of some description. For materials supplied by a pipeline then quarantine may not be possible and the guide requires that an
agreement be in place with the supplier in such cases so that prompt notification is received if the material is not in specification.
Any sampling activities (see Chapter 14.A Sampling) performed on delivered materials should not place these materials at risk of contamination. Such
sampling should be conducted on quality critical materials where at least an identity test should be performed. However some materials are hazardous
and it can be undesirable to sample and test them, in which case alternative means to verify the quality are required. Unfortunately the Guide suggests
verification against the supplier’s certificate of analysis (CoA), but as recent adverse events have shown, particularly with glycerine, this is not enough
when the material is critical to quality9.
Bulk tanker deliveries pose additional risks to material quality and so checks should be performed on the cleaning certificates. Some users require that
tankers be food grade, but this is problematic for the supply of substances that are defined as chemicals because these cannot be placed in bulk
tankers that are assigned for food use. It is however possible to clean a chemical tanker in the chemical cleaning station and then immediately subject it
to cleaning in the food cleaning station, albeit by incurring additional costs thereby rendering it “cleaned to food standards”.
Excipient manufacturing The IPEC-PQG GMP Guide now spends some time discussing how to control the manufacture of an excipient. It notes that
some of the guidance in section 7.5 is not applicable in all circumstances thereby noting the diversity of excipient manufacture.
Record keeping is a central plank in GMP especially of quality critical activities and none more so than in the manufacturing operation itself. The batch
records should be derived from a master document that is fully controlled (see section 4.2.3). The Guide again acknowledges that these may not be a
familiar batch record when the excipient is prepared using continuous processing technology and specifies that the manner of record keeping be defined
in this instance – either as a time based or on a defined quantity basis.
The records should show the complete history of the manufacture of the excipient and should include:
■ Date/time that each step occurred
■ Identification of the person performing or directly supervising each significant step
■ Identification of the major equipment used
■ Material inputs to enable traceability
■ Sampling and In-process laboratory tests and results
■ The quantity produced and, where indicative of excipient quality, the yield achieved
■ Line clearance on the packing area including labelling operations
■ Packaging used
■ Any failures or deviations that happened during the processing with their subsequent investigations
■ The results of the final inspection

These requirements are all quite “normal” for GMP operations. The Guide does not specify that these records may be retained separately, although it
does require that they can be readily retrieved when necessary, e.g. at audit.
Equipment cleaning The Guide provides some hints and tips on how to design and justify cleaning procedures. There is no requirement to validate
these but there is a need to provide some evidence that they are effective. In this regard the evidence can be any science-based approach that generates
data to support the cleaning process (also called “good science”). For multi-purpose plants it is suggested to use a “model approach”. This is where one
product from those that are made on the facility is chosen as the benchmark (the “model”) and the evidence of cleaning gathered on that material. The
model product is usually chosen as a worst case so that the results can be “read across” to the other ones that are made on the facility. This approach
is comparable to the bracketing approach sometimes used for cleaning validation studies (see Chapter 8.D.1 Bracketing: determination of critical
substances). It is important that records of previous use should be available for multi-purpose plants so that it is possible to investigate causes of cross-
contamination.
There are reminders that other sources of contamination should also be controlled with suitable cleaning operations, for example utensils.
Recognition is made to the practice of campaigning several batches of the same product without intermediate cleaning; this is not usually a cause for
concern. An extreme instance of this is with continuous processing. Here the Guide recommends that the frequency of cleaning should be determined
by the manufacturer based on a suitable justification.
Recycling, blending and mixing Where solvents, mother liquors, reactants or intermediates are recycled in the manufacturing process then these
should be suitably controlled. Appropriate testing should be performed to ensure that the quality of these recycled substances is suitable. It is good
practice to include the use of these recycle streams in the batch record as this is then deemed to be normal manufacturing as opposed to reprocessing
or rework (see sections 8.3.1. and 8.3.2.).
This theme of defining planned arrangements in the batch record is continued with the comments concerning blending and mixing. These are common
processes particularly in the chemical industry where blending can be used to increase batch sizes. There is a requirement that such processes should
ensure the resultant blend is homogeneous. It should be noted that this is a valid comment for excipients that are in the solid form (e.g. a powder) but for
the majority of liquid excipients no such evidence is required.
In-process controls In-process sampling and testing is a key part of process control. The Guide requires that these operations are suitably controlled so
that the sample is representative of the batch and that the results are recorded. Where test results do not meet specifications then defined actions
should be taken to bring the batch back into control. Samples that have been tested should not be returned to the final batch, but can be returned to an
earlier stage of the process. In some parts of the chemical industry in-process testing can be performed by production personnel, and where this is the
case the Guide indicates that these personnel should be suitably trained.
Packaging and labelling Packaging and labelling activities can be amongst the most critical operations, especially where more than one batch is
being filled off at a time. Thus there need to be suitable controls to ensure that the risk of mix-ups is minimized. Line clearance activities are expressly
mentioned here, particularly with ensuring the correct labels are available and that all excess labels are destroyed or returned to controlled storage. The
key principle here is that excess labels are not left lying around where they might be applied to another batch.
Records Finally there should be records of quality critical equipment use, not only detailing the batches manufactured but also any maintenance and
cleaning.
Validation Much is made of the importance of validation in Pharmaceutical GMP and this is entirely appropriate, after all much of pharmaceutical
manufacturing involves generating a product that cannot be individually tested, e.g. tablets. In the original versions of ISO 9001 this was termed a “special
process” and its main characteristic was that you could not inspect the product to assure that it meets the specification. In these circumstances ISO
9001 still requires that the manufacturing process be validated instead of relying on an inspection procedure to confirm product quality and hence batch
release. However ISO 9001 does not require that final product inspection AND process validation be performed. This is a major difference in the
assurance of product quality between ISO 9001 and pharmaceutical GMP. The origin is that it is not possible to inspect for everything that may (or may
not) be present in a product.
The IPEC-PQG GMP Guide acknowledges the limitation of inspection; you can only test for what you know about. Thus if an unknown impurity is formed
from a lack of control in the manufacturing process then final testing is not likely to determine that it is present. Hence there needs to be suitable control
of the manufacturing process so that a consistent product can be made, and in this respect the Guide recommends that an excipient manufacturer be
able to demonstrate this. However it also notes that pharmaceutical validation activities (e.g. plans, protocols and qualification activities) are rarely
performed in the excipient industry and so it rightly places emphasis on having the scientific data that show the manufacturing process is in control. In
many cases a simple process capability study (reporting Cp or Cpk) is perfect in this respect (see Chapter 20.C.2.10).
The current preference to this approach is that there should be a formal report in the organization that scientifically justifies the critical control points in
the process, and then the evaluation of the process capabilities Cp and Cpk for these attributes. As this kind of report is clearly quality related the
Quality Unit would be expected to approve it. In this respect this approach supports the recent publication of the latest FDA thinking on Process
validation.
Identification and traceability Identification and traceability is another key element of GMP and the Guide requires suppliers to be able to trace both
forwards and backwards from each batch or lot of excipient that is made. Backwards here refers to identifying the batch and supplier identity of the raw
materials used in the manufacture of excipients. Similarly forwards traceability enables the supplier to identify all the users who have received that batch.
Where the excipient is made using continuous processing then precision in backwards traceability is not possible which certainly the Guide
acknowledges, especially where bulk tanks are involved. It does not offer any solutions to these problems but for bulk tanks the basis of traceability
should be documented, as either first in – first out or perfect mixing when one batch is placed on top of a previous quantity in that tank. The Guide states
that excipients manufactured by continuous processing should at least record the timeframe when the “batch” was made.
Similar problems arise with continuous processing and the need to identify the test status of an intermediate or product. The guide states the manner
with which this is done should be defined by the excipient manufacturer, noting that any method that allows suitable control will be acceptable.
Identification and traceability hinge on the information contained on the labels on the packaged excipient.
There are a number of best practices recommended here, including as a minimum:
■ The name and grade of the excipient
■ The manufacturer’s or distributor’s name and address
■ The batch number
■ Any special storage conditions that are required to preserve excipient quality (see also 7.5.5).

The controls needed to assure user property are not materially different to those in ISO 9001, although note is made that some kinds of user property is
of the intellectual kind.
Preservation of excipients Storage of excipients and their raw materials is often important in ensuring their quality. Thus all materials need to be
stored under conditions that protect them from deterioration. Outdoor storage is only appropriate when the conditions are not likely to affect material
quality. Where specific conditions are required (e.g. protect from water, avoid contact with air, etc) those conditions should be maintained and labels
carrying appropriate warnings should be placed on containers (e.g. “Avoid high humidity”, “blanketed with nitrogen”). Where storage conditions are crucial
to material quality then these should be monitored and controlled to the degree necessary (see Chapter 11.M.6 Storage conditions).
It follows that packaging systems should protect the excipient to the degree required, and do not react with it. The Guide requires the application of
tamper evident seals on all containers, something that has been demonstrated to be increasingly important for all starting materials used in the
pharmaceutical industry (see Chapter 11.H.2 Labelling of starting materials). The Guide also states that packaging is quality critical and therefore should
have a documented specification. It recommends that packaging should be subject to verification activities as for any other purchased product. In these
cases the verification is more likely to be a visual inspection of the packaging and a check on the delivery documentation. Full visual inspection of every
container is not usually practical and also raises issues of contamination from the environment at the inspection point.
Reuse of containers is acknowledged and the guide indicates that suitable controls need to be applied here to ensure excipient quality, for example to
remove all previous labels and to make sure the containers are clean.
As mentioned earlier, forward traceability is required to ensure that all users of a batch can be notified if a problem is subsequently discovered. These
records should be traceable through any distributors or agents so that a retrieval (“recall”) can be affected should the need arise. Where an excipient
requires controlled conditions (temperature, humidity etc.) to assure quality then these should be maintained in the supply chain.
Calibration The section concludes with requirements for calibration. In this regard GMP and ISO 9001 are in full agreement and the guide introduces no
new requirements than those already mentioned by ISO. However it is worth reminding organizations that if an instrument is discovered to be out of
calibration then a risk assessment has to be performed to identify all previous uses of that instrument since it was last calibrated and to assess the
calibration then a risk assessment has to be performed to identify all previous uses of that instrument since it was last calibrated and to assess the
impact this may have on the quality of the excipients manufactured since that time.
Section 8: Measurement, analysis and improvement
A central theme of ISO 9001 is that measurement of the quality management system itself is used to objectively seek opportunities for improvement to
both the management systems and products.
The sections concerning user satisfaction and internal audit are not materially different to ISO 9001. Whereas user satisfaction is not a concept that is
currently represented in pharmaceutical GMP (no doubt due to their position in the supply chain) it is an important component for excipient suppliers.
The guide rephrases ISO 9001 in that internal audits should focus on those activities that are critical to excipient quality. One way to justify auditing
activities at a different frequency is through the documentation of a risk assessment. The Guide includes a substantial annex which provides further
information that will be of value to auditors when they are assessing an excipient manufacturer against the GMP requirements in the guide. A more
comprehensive offering was made available by IPEC on this topic with the publication of the stand-alone GMP and GDP Audit Guides, but these guides
are now better replaced with the EXCiPACT and ANSI NSF Certification standards. As standards they are designed to be used for auditing and will
provide the experienced auditor with an excellent assessment tool.
Monitoring of processes and products The requirement to monitor and measure manufacturing processes was made earlier in Section 7. Reference is
again made to the fact that corrective action is required when deviations from those planned results occur. The Guide stops short of recommending an
Annual Product Review as is commonplace for APIs and drug products but it does suggest a periodic review is a valuable means of identifying
improvements.
Monitoring and measuring of product (Section 8.2.4) is another significant and important section. The thrust here is to ensure that the excipient is tested
and meets its specification. To that end test methods should be fit for purpose. The Guide does not call for test method validation, but suggests
suppliers use compendial or other standard methods.
Test methods Where a supplier claims that a certain material is compliant to a pharmacopoeial monograph then the supplier has to use the compendial
test method to demonstrate this. If he uses other methods, then the alternative method has to be demonstrated to be equivalent to the compendial
method. The usual manner to achieve this involves replication of testing on several batches of excipient using the compendial and non-compendial
methods. To perform this activity “in house” involves setting up and running the compendial method which tends to negate the advantage of not using the
compendial method.
There should be traceability in the analytical testing records to:
■ The batch in question (number of other identity)
■ The sample taken
■ The analyst(s) performing the testing
■ The raw data used to calculate the analytical result (e.g. weighings, titrations, charts and other print outs etc)
■ The calculations performed to determine the result
■ Comparison of the result with the specification

Laboratory reagents and solutions should also have a complete set of records that meet these requirements, be they used as reagents or standards
within the laboratory (see Chapter 14.B Reagents).
The guide provides best practices for the handling and use of reference standards where these are used by the excipient supplier (see Chapter 14.C
Standards and reference substances). Such materials can be used to help perform an assay or unique identification of the excipient. They tend to find
more use in the user’s laboratory especially for complex excipients which do not have a traditional analytical assay (e.g. Polysorbates, lanolin etc).
Final batch testing and release For final batch testing the IPEC-PQG GMP Guide requires each batch to be tested and that appropriate manufacturing
records for that batch are reviewed prior to release. Thus the decision to release a batch should be made based on the results of testing and an
examination of appropriate manufacturing records. This mirrors Part II/ICH Q7 requirements where all critical manufacturing records have to be examined
as part of batch release. Appropriate manufacturing records can include deviations or other adverse event reports on the basis that the batch otherwise
went to plan, so little more would be gained from an examination of the remaining manufacturing records. If there is no manufacturing deviation system
then some other method of reviewing the manufacturing records would be needed, for example a review of the in-process testing results. Such a review
can be a good way of meeting this requirement for excipients manufactured by continuous processes.
Out-of-Specification procedure There is a requirement in the IPEC-PQG GMP Guide that excipient suppliers should have a documented out of
specification (OOS) procedure. The key principle in the Guide is that the OOS procedure should be predefined and then followed in the instance of an out
of specification result. The guide allows for retest samples to be used to the original result if there is documented justification for discounting the original
result. However where no error in the original result can be found then a statistical treatment of all results is indicated, so long as the statistical analysis
is predefined in the OOS procedure. This could be simple averaging or the use of a statistical method for identifying outliers. The Guide also notes that
inhomogeneous batches may cause an OOS but the same principles still need to be applied to the OOS result.
Retention samples The Guide acknowledges that for some excipients it may not be possible to keep a representative sample of the batch (for example
for health and safety reasons). The retention period of any such samples that are kept should be appropriate to the retest or expiry date of the batch. In
effect this aligns the retention period to the date of manufacture of the batch (as the retest and expiry intervals are only defined from that point onwards).
This is in contrast to GMP requirements for drug substance and API where the retention period is defined as an interval that commences once the final
part of the batch has been distributed. There is no question that such a method of determining the retention period means the samples are available for
the maximum interval, but fortunately this method of defining retention intervals has been avoided for excipients. It is very cumbersome and expensive to
have to keep asking for each batch – “do we have any stock?” and then once the answer is “no” to set the storage interval for the retain samples. It is
simpler and indeed in most cases more robust to just use an interval keyed from the date of manufacture.
Certificates of analysis Certificates of Analysis are valuable documents to users. The Guide recognizes this by requiring them to be supplied and
pointing readers to the IPEC-Americas Guide on the topic and the UK’s “Orange Guide” for details on their content.
Impurities The Guide recommends that known impurities are suitably controlled through GMP consideration and by appropriate analysis. It also states
that solvents are a special class of impurity and these also need to be controlled in the same manner.
It is worth noting the definition of an impurity that is used in the Guide: “A component of an excipient that is not intended to be present but arises as a
consequence of the manufacturing process.”
Thus for excipients that are complex mixtures of molecules then those molecules that are intended to be present in the final excipient are not impurities
(they are the components of the excipient). For example, many excipients are polymeric and thus the excipient is not composed of a single molecular
entity. All the molecules with a different molecular weight are clearly not impurities. These components can be present in the raw materials used in the
manufacturing process or be generated by that process. In either case these are not impurities. For this reason the Guide opens this section with “where
possible” as for many excipients it is not possible to define the product at a level that can identify a component as an impurity.
Stability Stability of an excipient is an important attribute, but only while the material is in the supply chain. Once it has been formulated into a drug
product then the interactions between the excipient and the other components in the drug product will have a greater influence on excipient stability than
any other factor. For this reason the Guide indicates that retest and even expiry dates can be derived from experience with the supply of the excipient
over many years, the so called “historic data”. For many excipients it can be difficult to determine the impurities amongst many intended components in
the excipient, and therefore the evaluation of stability becomes challenging. For such complex excipients there is often no such thing as an assay and
so this cannot be used to indicate stability. Other analytical approaches have to be used to signify stability, for example increase in oxidation as
measured by a peroxide value. It should be kept in mind what an excipient stability program is designed to achieve – to demonstrate the stability of the
excipient from the date of its manufacturing up to the time point it is put into a drug product formulation. Thus any science-based study and analysis will
yield useful and valuable information on this topic.
The Guide reminds suppliers and users of excipients that changes in the manufacturing process can have an impact on excipient stability. Where this is
considered a risk, suitable tests should be conducted to ensure that these changes are quantified.
Usefully on this topic the Guide introduces the concept of a “model” excipient on which stability studies can be conducted and then a “read across” to
other excipients that share the same characteristics. In 2010, IPEC has published a stand-alone Guide on the subject of designing and performing
stability studies on excipients, the Excipient Stability Study Program Guide. The outcome of the stability evaluation should be that a retest or expiry
interval is assigned for an excipient and the Guide acknowledges that a retest interval is by far the more common of the two terms. Either or both
intervals should be communicated to the user, and it is common to do this on the Certificate of Analysis.
Non-conforming materials One risk to excipient quality comes from non-conforming materials. The Guide requires suitable controls on such materials
so that they are not used without further consideration (i.e. a risk assessment in modern terminology).
This section also reiterates the requirement to have a documented procedure that describes how an excipient can be retrieved from the market (i.e. a
product recall).
Non-conforming material should have suitable records to show the origin of the material and what is wrong with it as well as an investigation to ensure
that the reasons for the failure have been understood. The investigation will play a crucial role in the decision concerning the fate of the non-conforming
material and must be completed before any rework is attempted.
Documented procedures are required to describe the disposition of the non-conforming material, and the guide suggests four outcomes:
1. The material is regraded for other applications.
2. The material is sold to a user with a suitable written and documented agreement between the two parties that indicates the user is aware of the
problem with the material and has accepted delivery on that basis.
3. The material is reprocessed or reworked, or
4. The material is destroyed (scrapped).

Reprocessing and reworking The Guide then gives some more details concerning reprocessing and reworking. The former, reprocessing, is defined as
repeating an existing manufacturing step again. Thus these manufacturing steps should have been planned and defined as described in Section 7.1 and
be implemented according to Section 7.5.1. The records of these activities should clearly show that the batch has been reprocessed. The manufacturer
should document that reprocessing is permissible in the design and definition of the manufacturing process. Thus reprocessing is part of the planned
activities to manufacture the excipient, otherwise the activities are considered to be reworking. In this regard reworking is considered to be any activity
that is undertaken to recover a non-conforming material. Initially at least this is something that happens once when there is a problem and as such the
Guide requires a documented assessment of risk to the quality of the excipient which is signed off by the quality unit.
As with all risk assessments a multi-disciplinary approach is needed and the Guide recommends that the assessment considers:
■ New impurities that may be formed as a result
■ Additional testing either to monitor or detect the new impurities as well as to control the reworking activity itself
■ Records to allow traceability to actions and materials used
■ Suitable additional acceptance criteria for the resultant excipient that may be in addition to the specification
■ Consideration of any impact on the defined retest or expiry interval of the excipient
■ Consideration of any impact on the performance of the excipient

This guidance represents a pragmatic and best practice approach to rework. However GMP remains saddled with specific GMP clauses that were
originally designed for drug products and the Guide feels compelled to quote one of these here, that the act of blending one non-conforming batch into
another which is conforming in an attempt to hide the sub-standard material is not acceptable. This would appear to be a blanket prohibition of blending
as a means of reworking, but are there situations where such activities could be permissible? For example a material is non-conforming on water
content, with water addition during the final manufacturing step. The nonconforming batch is then blended with batch(es) that do conform. The rework risk
assessment concludes that there are no new impurities formed as a result, that the existing testing controls the process and permits batch release, and
that there is no impact on the stability of the excipient nor on its performance. Such kind of action has in the past resulted in many animated
discussions between excipient suppliers and users with both sides arguing their case!
But now EXCiPACT and ANSI NSF 363 Certification standards have consigned this price of GMP for drug products to the dustbin of history. The phrase
has been rewritten as: “blending of contaminated or adulterated batches to reduce the contamination or adulteration below an acceptable or detectable
limit is not acceptable”.
Thus blending itself is not forbidden unless the intent is to dilute the adulterant or contaminant to a lower level. Thus if there is no adulterant or
contaminant to begin, as in the example above, blending is a viable rework option so long as the conditions in the risk assessment are satisfied. It may
take industry some time to get used to this very significant change.
Returns Returned excipients are mentioned and the disposition of such materials should be controlled, until their quality has been evaluated. Then they
can be re-sold or subjected to the controls of the non-conforming materials discussed above. Naturally they should be treated as non-conforming until
found otherwise. Suitable records to show this evaluation and to maintain traceability should be retained.
Corrective and Preventive Actions (CAPA) The Guide then concludes with a review of the ISO 9001 clauses on Analysis of Data (Section 8.4) and
Improvement (8.5). The Guide correctly uses the ISO 9001 terms corrective and preventive action as defined in ISO 9000. There remains a
misconception about the meaning of these terms, even in English speaking countries. It is disappointing therefore that the ISO 9001:2008 version did not
clarify matters – especially as this edition was intended to make interpretation clearer both in English and when translated into other languages.
When something goes wrong then there are 3 sets of actions that should happen:
1. Fix it
2. Learn from it and stop it happening again
3. Consider if it could happen somewhere else

The first action “fix it” is often confused with corrective action, i.e. actions taken to remedy the problem. ISO 9001 deals with this kind of action in section
8.3 (Control of non-conforming product). Usually these actions are instinctive. For example an out of specification result is obtained on an in-process test
and the documented plans for production indicate an alteration of the conditions to remedy the situation.
The second action is what ISO 9001 calls “corrective action”. The key point here is that this is not the “fix it” action above. This is where a strong quality
management system comes into play and ensures that an investigation to identify what went wrong occurs and that actions are implemented to stop it
happening again.
The third action is an advanced quality assurance tool. Here a risk assessment is required to consider if the circumstances causing the failure may
repeat elsewhere, even though no such failure has (yet) happened there. This action is a preventive one. General information about corrective and
preventive action can be found in Chapter 19.D.
22.B.3.3 Conclusions
The IPEC-PQG GMP Guide 2006 was developed at a time when the early drafts and thoughts of ICH Q9 Quality Risk Management (see Chapter E.9)
were available and its influence is felt throughout the document. As a result the Guide allows for a wide range of situations and so meets the majority of
the needs of the diverse excipient industry.
Since its initial publication the Guide has become well known and has been adopted in both user and supplier communities which ensures that it retains
a high profile. Any limitations in this edition are far outweighed by the benefits of having a widely accepted and international Guide for GMP for
excipients. This matches the increasing globalization of excipient supply.
It should be noted that the IPEC-PQG GMP Guide indicates that it is not applicable to excipients that claim to be sterile. As a baseline GMP for the
majority of excipients it may not always be suitable for excipients which pose particular risks to patients, either due to their method of manufacture or
the nature of their application. Although it is argued that the IPEC-PQG GMP Guide is the minimum GMP for all excipients, some users have utilized
excipients that are made according to other standards, notably excipients that are food quality and which are used in oral applications. In such cases it
remains the responsibility of the user to decide if the quality management system the excipient supplier uses is sufficient to assure the quality and purity
of the excipient. As always having a “standard” in place provides a simpler approach for both excipient supplier and user – something that EXCiPACT and
ANSI NSF 363 have been designed to solve.

22.B.4 IPEC, its role and activities

IPEC is an international industry association formed in 1991 by manufacturers and end-users of excipients. It is an association comprising four regional
pharmaceutical excipient industry associations covering the United States, Europe, Japan (which is known as JPEC) and China. The latter was
established in 2008. Although formally independent organizations, collectively they are known as the IPEC Federation. Their objective is to contribute to
the development and harmonization of international excipient standards, facilitate the introduction of useful new excipients to the marketplace and the
development of best practice and guidance concerning excipients.
IPEC has three major stakeholder groups:
1. Excipient manufacturers and distributors, who are considered suppliers in this document,
2. Pharmaceutical manufacturers, who are called users, and
3. Regulatory authorities who regulate medicines.

In this respect IPEC is dissimilar to other trade associations in that it is comprised of both suppliers and users. This fusion of both parties is what makes
their guidance balanced and especially valuable.
IPEC has published a large number of guidance documents which are available from the respective websites after a short period of exclusivity to
members. An overview is given in Chapter 22.H References.
Summary:
No legal requirements exist for excipients to be manufactured in compliance with GMP, excepted for Japan. The European Union has mandated to
apply GMP-principles to certain critical excipient. After all, the user is obliged to qualify the supplier and to demonstrate that the excipient is fit for
purpose. This can only be achieved by applying an appropriate degree of GMP and GDP.
In 1999 the World Health Organization (WHO) published a GMP guide for pharmaceutical excipients. This included many of the requirements that are
now familiar in Part II of the EU GMP Guide. Although excipients would appear to share many commonalities in their preparation and manufacture with
APIs, there are crucial differences, and so it is not appropriate that Part II GMPs be applied to all excipients. For this reason IPEC prepared a definition
of GMP for these substances in collaboration with the UK Pharmaceutical Quality Group. The Joint IPEC-PQG GMP Guide was published in 2006 and
is based on guides previously independently published by both organizations.
The IPEC-PQG GMP Guide is structured in analogy to the ISO 9001, because many organizations that manufacture chemicals are already registered
to ISO 9001 and are familiar with its requirements. Moreover, the principles and GMP detailed in ICH Q7 / Part II of the EU GMP Guide were extensively
reviewed, adopted and adapted for excipients, resulting in an alignment of the GMP in the IPEC-PQG GMP Guide with that for APIs. The Guide also
owes much to the WHO GMP Guide for Excipients.
IPEC is an international industry association comprising four regional pharmaceutical excipient industry associations covering the United States,
Europe, Japan (which is known as JPEC) and China. Their objective is to contribute to the development and harmonization of international excipient
standards, to facilitate the introduction of useful new excipients to the marketplace and to promote the development of best practice and guidance
concerning excipients.
The IPEC published numerous guidance which are available at the IPEC website.

1http://ec.europa.eu/health/files/gmp/2013-02_guidelines_excipients_cons.pdf

2 Section 510(j)(1) (21 U.S.C. 360(j)(1)) is amended by adding to point 3

3 An Atypical Active is usually an excipient which is registered by the Manufacturing Authorisation Holder as an API. The European Authorities
recognise these materials and have made a derogation to relax the requirements for Part II GMP for APIs in these cases.
4 USP-NF General Notices subsection Ingredients and Processes, second paragraph.

5 ISO 9001 was updated and reissued in 2008, however the changes were exceptionally minor and involved correction of the English to make
interpretation easier to non-native speakers. The only changes of note were to alter a few section headings. Thus the alignment of the IPEC-PQG GMP
Guide with ISO 9001 has not been altered by the revision to ISO 9001 in 2008.
6 IPEC, PQG and other trade associations in Europe and the US are converting the IPEC-PQG GMP Guide into a certifiable standard which will allow 3rd
party audit organizations to aid in the qualification of excipient suppliers.
7 IPEC Quality Agreement Guide and Template 2009, contains a useful template from which to base excipient quality agreements.

8 IPEC Americas Significant Change Guide 2009

9 The UK MHRA and the Irish IMB have stated pharmaceutical manufacturers must sample every drum of glycerine for at least an ethylene glycol
discriminating identity test if the material is supplied via a broker.
Printed by: 168305-3 Date: 24.04.2014 GMP MANUAL © Maas & Peither AG
22.C Safety, toxicological, and precedence of use issues
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ How can precedence of use be assessed for marketed excipients?
■ How can safety be assessed for a chemical to be used as new excipient?

22.C.1 Marketed excipients

Potentially any substance could be used as an excipient as long as it has no therapeutic effect and is safe to the patient. However, there are several
safety related issues that should be assessed by the potential excipient manufacturer as part of its decision to introduce an excipient to the
pharmaceutical market.
First an assessment should be made as to whether there is a precedence of use for the material in a drug product or a similar application such as a food
additive or food contact packaging component. If a precedence of use can be shown in applications where there is human exposure, the safety of the
material might already be appropriate for potential application as an excipient in the pharmaceutical industry.
In the U.S., the Food and Drug Administration (FDA) maintains a database of excipients that is posted on their website as the Inactive Ingredient
Database (IID)1. The IID should be used to establish precedence of use since it lists each excipient which has been allowed as a consequence of its
presence in an approved innovator drug product. Each excipient is listed by name, dosage form, and the maximum amount of excipient contained in an
approved drug of that listed dosage form. Care must be exercised in searching the database because an excipient can be listed by various names,
including trade name, compendia name, chemical name, or generic description (for dyes and flavours).
In Japan, an assessment for precedence of use can be made by referring to the Japanese Pharmaceutical Excipients Dictionary (JPED) which is edited
by the Japan Pharmaceutical Excipients Council in conjunction with the Ministry of Health, Labor, and Welfare. The JPED is a compilation of all
excipients for which there is a precedence of use in drug products in Japan. It includes monographs from the JP or Japanese Pharmaceutical Excipients
(JPE) as well as all non-monograph excipients that have been previously used. Each monograph lists the non-proprietary name and synonyms along with
the application and maximum dosages for the various routes of administration in approved drugs2.
In Europe, there is no comprehensive European Union list of excipients that have been approved in drug products. Therefore, in order to establish
precedence of use, it is necessary to review the drug catalogues such as the “Dictionnaire Vidal” (France), “Die Rote Liste” (Germany), or “The Electronic
Medicines Compendium” (UK).
Note: If there is no precedence of use in a drug product, then the material is to be considered a new excipient and should be introduced according to
local regulations.

22.C.2 New (novel) excipients

An excipient used for the first time in a drug product or by a new route of administration is classified as new according to the ICH Guideline M4
Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use . Conversely, this guideline defines known
excipients as “excipients that are well-established and commonly used in registered drug products and are usually included in pharmacopoeias”.
When an excipient has not previously been used in a pharmaceutical dosage form then there are a number of conditions set out by the US and European
regulatory authorities to allow for its use.
The U.S. FDA has issued a Guidance concerning the safety testing required for novel excipients3 as has IPEC in their IPEC New Excipient Safety
Evaluation Procedure4. The latter were the basis for the USP-NF 26 General Chapter <1074> Excipient Biological Safety Evaluation Guidelines on this
topic. The information contained in these documents is useful for assessing the safety of a chemical for use as an excipient. The IPEC Europe Safety
Committee has published a similar guideline5. The manufacturer of a new or novel excipient should develop the safety information recommended in these
guidelines appropriate to their intended use. This information provides the basis for establishing the suitability of the material for use as an excipient in a
particular type of dosage form.
The terms “new” and “novel” as related to excipients are difficult to define precisely. Clearly an excipient is new if it is not listed in the FDA Inactive
Ingredient Database, any of the 3 major compendia, U.S. Pharmacopeia (USP-NF), European Pharmacopoeia (Ph. Eur.), or Japanese Pharmacopoeia
(JP), or other widely known compendia such as the Handbook of Pharmaceutical Excipients or Fiedler: Lexikon der Hilfsstoffe für Pharmazie, Kosmetik
und angrenzende Gebiete (Encyclopedia of excipients for pharmaceutical, cosmetic and related use).
The industry recognizes that any change in the chemical composition of an excipient produces a new excipient, no matter how minor the modification to
the chemical composition is in fact. Mixtures of excipient ingredients can result in a “new” excipient when the subject mixture is to be used in a dosage
form for which its constituent excipients have not already independently been used in that intended route of administration. Physical modification of an
excipient, such as micronizing or compaction does not generally produce a new or novel excipient.
However, co-processing can produce a synergistic physical interaction between two or more excipients that is patentable and create unique properties
that cannot be achieved through simple blending. The safety assessment for these co-processed excipients made with commonly used pharmaceutical
excipients will generally be less stringent than for a new chemical entity.
If the excipient is already described in a pharmacopoeia or used as such in other pharmaceutical dosage forms, the excipient is neither new nor novel
and the detailed safety review recommended in the above guidelines will not be necessary.
Summary:
For marketed excipients, precedence of use can be assessed by reference to FDA’s Inactive Ingredients Database (IID), the Japanese Pharmaceutical
Excipients Dictionary (JPED), and drug catalogues such as Dictionnaire Vidal or Rote Liste. If a precedence of use can be shown in applications where
there is human exposure, the safety of the material might already be appropriate for potential application as an excipient in the pharmaceutical industry.
When an excipient has not previously been used in a pharmaceutical dosage form then there are a number of conditions set out by the US and
European regulatory authorities to allow for its use. Relevant guidance is given by FDA, IPEC and US/NF. The manufacturer of a new or novel excipient
should develop the safety information recommended in these guidelines appropriate to their intended use. This information provides the basis for
establishing the suitability of the material for use as an excipient in a particular type of dosage form.

1Database: www.accessdata.fda.gov/scripts/cder/iig

2 Maximum dosage information is only contained in the Japanese language version of the JPED.

3 U.S. FDA, Nonclinical Studies for Development of Pharmaceutical Excipients (final version May 2005)

4http://ipecamericas.org/content/ipec-novel-excipient-safety-evaluation-procedure

5 The Proposed Guidelines for the Safety Evaluation of New Excipients (European Pharmaceutical Review, November 1997)
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22.D Compendial monographs
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ What kind of advantages offers the description of an excipient in a compendial monograph?
■ What procedures are to be followed when introducing an excipient to a pharmacopoeia?
■ What are the contents of an excipient monograph?
■ Which requirements have to be fulfilled for new and novel excipients?

22.D.1 Marketed excipients

There are three major compendia that are routinely referenced globally:
■ United States Pharmacopeia – National Formulary (USP-NF)
■ European Pharmacopoeia (Ph.Eur.)
■ Japanese Pharmacopoeia (JP)

These compendia describe the quality of substances to be regularly used in pharmaceutical products and how to test them. They also describe general
conditions required to assure the quality of pharmaceutical substances so that they are not harmful to the patient. The descriptions of substances for
pharmaceutical use are called monographs and these list the analytical specifications and other quality attributes required to assure the safety and
quality of the excipient (see Chapter 14.L Pharmacopoeias).
In order to market an excipient, there is no regulatory requirement that there must be a compendial monograph for the material. However, if a compendial
monograph exists for an excipient in a particular region’s pharmacopoeia, then the excipient should comply with that monograph because the regulatory
authorities require conformance. However, other regulations may define a suitable quality which could be used (e.g. Food Chemical Codex). In all cases,
the use of a specification that at least meets a compendial monograph or a similar standard is preferable to the supplier’s own internal document. In
particular, conformance to a pharmacopoeial monograph and other relevant general notices and chapters of the compendia means that the excipient
already has a suitably defined quality for pharmaceutical use.
In the United States, certain food additive materials are produced in conformance with the Food Chemical Codex (FCC). In Japan, there is the Japanese
Pharmaceutical Codex and also a series of supplementary books called the Japanese Pharmaceutical Excipients (JPE). Many other national
pharmacopoeias delineate the quality requirements of pharmaceutical ingredients and these will take precedence over the three major pharmacopoeias.
Where an excipient is described in a pharmacopoeia, the quality of material for pharmaceutical use should comply with this monograph unless the user
can provide a compelling case for not adopting that standard. The compendia are concerned with the presence of additives and processing aids in
excipients. While the issue is still under active consideration by the pharmacopoeias, suppliers should be prepared to declare information on the identity
and quantity of additives and processing aids that are present in their excipients.
For an excipient listed in multiple compendia that may be marketed for global use, the manufacturer is advised to ascertain the conformance of the
excipient to the monograph requirements found in all those compendia. While considerable efforts are underway to harmonize the requirements for
excipients with monographs in the three major compendia (see Chapter 14.L.9 Harmonization), currently there are often different monograph
requirements found in one or more of these compendia. Even for excipients whose monographs have completed the harmonization process, they may
still contain non-harmonized attributes. As a consequence, it is advisable to tabulate all monograph testing requirements from all compendia having an
appropriate monograph. Such a table should contain not only the test name and specification range but a brief description of the test method since often
the method of analysis differs between compendia. Once the tabulation is complete, the excipient supplier can develop a testing plan to ensure
conformance to all monograph requirements in the various compendia. Where multiple test methods are referenced for the same property (attribute), it
would be satisfactory to validate the manufacturer’s method to demonstrate it provides assurance that the excipient, when tested to each monograph
method, will conform to each monograph requirements.
The commercial relevance of an excipient and therefore the use of the excipient in at least one approved drug product is a prerequisite for inclusion of a
monograph in the Ph.Eur., USP-NF, or JP/JPE. Both users and suppliers of excipients may request their local pharmacopeia to develop a new
monograph once a material’s use in a commercial pharmaceutical product has occurred. When there is no pharmacopoeia or other compendial
monograph, the manufacturer can establish its own specification, based on an existing similar pharmacopoeia monograph. If not available, the
specification can be based on its own experience and the excipient’s chemical and physical properties and intended use.
22.D.1.1 United States Pharmacopeia– National Formulary
The USP and NF are legally separate compendia officially mandated in the U.S. Federal Food, Drug and Cosmetics Act. However, they are published
together in a single book (see Chapter 14.L.6 United States Pharmacopeia (USP)).
To be considered for inclusion in the USP-NF, a new excipient should have been used in an approved drug product or be listed in another
pharmacopoeia. A monograph is prepared for the new excipient with input from both the excipient manufacturers and pharmaceutical users. The draft
monograph is then published for comment in the Pharmacopeial Forum and then submitted to the USP for approval.
The USP-NF General Notices require the use of appropriate GMPs in the manufacture of compendial materials1. The USP-NF includes a General
Information Chapter which elaborates on the GMP requirements for producing an excipient.2 The USP-NF also specifies the requirements for properly
testing an excipient both in terms of the requirements for validated test methods as well as by detailing specific test methodology. Generally, excipient
monographs (specifications) are contained in that portion of the USP-NF called the National Formulary (NF) unless they also have been used in a dosage
form where they function as the Active Pharmaceutical Ingredient (API), in which case they are contained in the United States Pharmacopoeia (USP).
The monographs detail the test methods and specification limits which must be achieved in order to market an excipient as compendial grade. Certain
monographs also contain additional information such as labelling and storage requirements.
In order to label an excipient as compendial grade, regardless of the pharmacopoeia, all monograph and appropriate General Chapter or Notices
requirements ordinarily must be met. There is an exception to this for USP and NF grade excipients, under certain circumstances, as noted in the USP-
NF General Notices3. Nevertheless, alternative test methods used must be validated4 and shown to produce results comparable to those obtained using
the compendial method. Non-compendial test methods used must be validated.
22.D.1.2 European Pharmacopoeia
For a new excipient to be added to Ph.Eur., it must have been a component of a previously approved drug product and no longer protected by patent. The
drug product formulated with the new excipient is reviewed and approved by the member state(s) to which the application has been submitted. Once
used in an approved drug product, the new excipient must be included in the work program of the European Pharmacopoeia Commission in order to be
added to the Ph.Eur.. Addition to the work program typically requires the support of several member states at the biannual meeting of the Commission.
The excipient is usually assigned to an expert group and the secretariat will identify the excipient manufacturers. The excipient suppliers are then asked
to provide specifications, test methods, and samples from which the expert group will develop a draft monograph. The draft monograph is published in
PharmEuropa for public review and subsequent approval by the European Pharmacopoeia Commission. Upon approval by the Commission, the excipient
is added to Ph.Eur. (see Chapter 14.L.4 European Pharmacopoeia (Ph Eur)).

22.D.1.3 Japanese Pharmacopoeia

In Japan, new excipients are also approved as a consequence of the approval of a drug product application containing the excipient. The pharmaceutical
manufacturer makes an application through a prefectural office to the Pharmaceuticals and Medical Devices Agency (PMDA). If the drug formulation
contains an excipient with no precedence of use in Japan, the application goes to the Subcommittee on Pharmaceutical Excipients of the Central
Pharmaceutical Affairs Council (CPAC). Their review of the quality attributes and safety of the excipient is done concurrently with the drug product
approval conducted by the Subcommittee on New Drugs of CPAC. The Subcommittee reports are used by the Evaluation and Licensing Division to
approve the drug product. Once the drug product has been approved, the Japanese Pharmacopoeia can consider the addition of a monograph (see
Chapter 14.L.7 Japanese Pharmacopoeia (JP)).

22.D.2 New and novel excipients not listed in a pharmacopoeia

An ingredient can be used in a pharmaceutical product as an excipient even when there is no monograph for the material in a compendium. Regulatory
authorities require a full safety and toxicological evaluation. Once a regulatory authority has approved a drug application containing such an excipient,
that excipient is generally considered acceptable for the same route of administration up to the same level of use providing the same specifications are
met as those used in the previously approved drug.
For new excipients a toxicological assessment should be made to demonstrate the safety of the material in the intended pharmaceutical application at
the specified use level. The USP-NF Excipient Biological Safety Evaluation Guidelines <1074> provide guidance on conducting a safety assessment for
a novel excipient. In the U.S., the FDA has also issued guidance on non-clinical studies for new excipients.
When new excipients are developed and being used in an approved drug, the manufacturer may request that a monograph for the excipient is added to
the compendia. “The purpose of a pharmacopoeial excipient monograph is to provide standards to assure the excipient’s quality in pharmaceutical use.
The tests, procedures, and acceptance criteria for an excipient specification should address: appearance, identity, chemical purity, microbiological
purity, physical characteristics (e.g., optical rotation), packaging, labelling, and storage.”5
Generally an excipient monograph contains the information shown in Figure 22.D-16.
Figure 22.D-1 Contents of an excipient monograph
Monograph The name by which the excipient will be primarily found in the compendia
Name

Official Title The name by which the excipient is generally known in industry

Definition The acceptance criteria for the assay often expressed as a percentage range

Packaging Special packaging or storage conditions necessary to protect the excipient

and Storage

Labelling Special requirements for labelling to differentiate various grades of the excipient such as by molecular weight or listing of additives present

Description The excipient is characterized as to chemical structure, molecular weight, physical form, and solubility

Identification There should be a test or tests that confirm the identity of the excipient

Composition There should be specific tests, where possible, for concomitant and other components especially for those above 0.1%. There should be
tests, where appropriate, for organic, inorganic and heavy metal components as well as residual solvent(s)

Assay There should be a test to quantify the excipient content, where possible

Other tests Where further characterization is needed, other tests such as pH, preservative content, or bacterial endotoxin should be recommended

For excipients that are not listed in the Ph.Eur., the European Medicines Agency (EMEA) also requires the following information7:
■ Physical Characteristics
■ Tests for parameters that may influence the performance in the dosage form called functionality-related characteristics.

This list is not exhaustive but is intended to provide preliminary guidance on the content of a proposed monograph. Note that the compendia recognise
that it may not be possible to define an assay for an excipient, especially where the excipient is a complex mixture of chemical species (e.g.
Polysorbates).
In addition, the manufacturer will have to submit information about the appearance and solubility characteristics of the new excipient. This information
appears in a separate section of the USP-NF. In Europe, the user will also have to justify the specifications for the excipient. For new or novel excipients,
there should be documentation in accordance with their Guideline on The Chemistry of New Active Substances8.
Summary:
Conformance to a monograph and other relevant general notices and chapters of a pharmacopoeia means that the excipient already has a suitably
defined quality for pharmaceutical use.
To be considered for inclusion in a pharmacopoeia, a new excipient should have been used in an approved drug product or be listed in another
pharmacopoeia. A monograph is prepared for the new excipient with input from the excipient manufacturers, pharmaceutical users and/or expert
working groups. The draft monograph is then published for comment and finally submitted to the relevant committee for approval. This is the general
procedure which applies to USP, Ph.Eur. and JP with slight differences in organizational aspects and responsibilities.
The purpose of a pharmacopoeial excipient monograph is to provide standards to assure the excipient’s quality in pharmaceutical use. The tests,
procedures, and acceptance criteria for an excipient specification should address: appearance, identity, chemical purity, microbiological purity,
physical characteristics (e.g., optical rotation), packaging, labelling, and storage.
For new excipients a toxicological assessment should be made to demonstrate the safety of the material in the intended pharmaceutical application at
the specified use level. The USP-NF Excipient Biological Safety Evaluation Guidelines <1074> provide guidance on conducting a safety assessment for
a novel excipient. In the U.S., the FDA has also issued guidance on non-clinical studies for new excipients. When new excipients are developed and
being used in an approved drug, the manufacturer may request that a monograph for the excipient is added to the compendia.

1 USP-NF General Notices subsection Ingredients and Processes, second paragraph.

2 USP-NF <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients

3 USP-NF General Notices subsection Official and Official Articles, fourth paragraph.

4 USP-NF <1225> Validation of Compendial Methods

5 Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, page 67 October 8, 2003

6 Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, pp 57-64 October 8, 2003

7 The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use, Note for Guidance on Excipients, Antioxidants
and Antimicrobial Preservatives in the Dossier for Application for Marketing Authorisation of a Medicinal Product, (DRAFT) CPMP/QWP/419/03, February
2003
8 The European Agency for the Evaluation of Medicinal Products, Guideline on The Chemistry of New Active Substances, CPMP/QWP/130/96/Rev 1,
February 2004
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22.E Excipient master files and other filings
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ What is a Drug Master File?
■ What is a certificate of Suitability?
■ What are the differences in forwarding information about excipients to the regulatory authorities within the three regions USA, Europe and Japan?

A Drug Master File(DMF) is a compilation of technical details related to the manufacture of the excipient and can be formatted so that it is aligned with
the ICH Common Technical Document (CTD) format for easy future application. The DMF typically includes specifications and test methods for raw
materials, in-process testing, the final excipient specification, a complete description of the manufacturing process, safety data, packaging details, and
label content.
In the U.S., an excipient supplier will often submit a DMF to the Food and Drug Administration to provide confidential information relative to the excipient,
its safety, and conformance with appropriate GMP requirements. A similar system of DMF exists in both Canada and Japan. In Europe, for materials
where a Certificate of Suitability is not available, such confidential information needed to support the drug product filing by a pharmaceutical manufacturer
must be supplied directly to the user for inclusion in his marketing authorization, using confidentiality agreements where necessary.

22.E.1 United States Drug Master Files

Submission of an excipient Drug Master File (DMF) to the FDA is not required by law or FDA regulations1. A Type IV DMF for Chemistry, Manufacturing
and Controls (CMC) information, or a Type V DMF for excipient safety information can be used to submit this type of data. The DMF may be used to
support an Investigational New Drug Application (IND), New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Biological License
Application (BLA), Veterinary Drug Application, another DMF, or an Export Application. The FDA assigns a unique number to each DMF but does not
approve or disapprove them. The FDA maintains the DMF as a confidential document that cannot be referenced by third parties without the written
agreement of the excipient DMF holder.
The FDA references the DMF only in conjunction with their review of a submission or application to the FDA in the form of a drug application (IND, NDA,
ANDA etc.). The review occurs when the excipient DMF holder has given the drug formulator permission to reference the DMF in their drug filing to the
FDA. In the FDA review of the drug filing, when the agency requires details concerning the manufacture of the excipient, the FDA will review the
information in the DMF. The excipient DMF holder has the obligation to assure the content of their DMF remains current and should update the DMF on
an annual basis or indicate to the FDA that no changes are required.
In 2004, IPEC Americas has issued a guideline that describes the organization and composition of an excipient DMF the Excipient Master File Guide.

22.E.2 European Certificates of Suitability (CEP)

The system in the European Union (EU) is somewhat different from other areas. There are three types of marketing authorization procedures for drug
products which use DMFs or CEPs as applicable:
■Centralized procedure:
submission to the European Medicines Agency EMA, London, UK obligatory for biological and biotech products, certain therapeutic indications
and open to innovations;
two countries are identified as rapporteur and co-rapporteur each evaluating the dossier.
■Mutual Recognition Procedure (MRP): submission to and approval by one EU member state which then becomes the reference country for
extension within the EU.
■Decentralized procedure: submission to all EU countries desired, one of them identified as the reference country. The procedure is similar to, but
quicker than, the MRP.

No matter which procedure applies, pertinent excipient data must be provided directly to the pharmaceutical company for inclusion in their drug product
dossier. It is recommended that it be provided under a suitable confidentiality agreement.
Although a DMF system exists for drug substances (APIs) at this time, this system is not available for excipients, and thus presents a major constraint
on the introduction of new and novel excipients in Europe.
The lack of an excipient DMF system in Europe hinders innovation and the introduction of new excipients. The only way a new excipient can become
accepted for pharmaceutical use in Europe is to submit all of the data in the pharmaceutical drug product manufacturer’s Marketing Authorization. This
can pose serious challenges when the excipient manufacturer wishes to secure his intellectual property that has been invested in the development of the
new excipient.
There are two types of CEP; the “ordinary” one can be obtained by excipient manufacturers for an excipient described in a Ph.Eur. monograph by
submitting a file using the Common Technical Document (CTD) format to the European Directorate for the Quality of Medicines (EDQM) in Strasbourg,
France. The CEP acts in much the same way as a U.S. Type IV Drug Master file and allows the excipient supplier to retain confidential information
which is not shared with the excipient user. These Certificates of Suitability are not available for excipients for which there is no monograph in the
Ph.Eur.
A second type of CEP exists to document that there is no potential concern about Transmissible Spongiform Encephalopathies (TSE; including Bovine
Spongiform Encephalopathy – BSE) which is open to APIs and excipients (even those without a pharmacopoeia monograph). Granting this kind of CEP
indicates that the excipient is of low or no risk of transmission of TSE to humans through the drug product.

22.E.3 Japanese Drug Master Files

In Japan the drug product application is submitted to the regulatory authorities by the pharmaceutical company typically containing all relevant details
concerning the excipient. The new excipient Drug Master File system in Japan can be used in certain circumstances; however this system is still
undergoing some changes to allow it to be used for all types of excipients and applications. Currently, this system can be used fairly easily for individual
excipients. However, it is not designed to easily handle multiple excipient grades or combinations of excipients which are part of a range of products that
comprise an excipient family. Since a unique file would be needed for each formulation or grade, this makes the system somewhat burdensome.

Summary:
In USA, a Drug Master File (DMF) is a compilation of technical details related to the manufacture of the excipient and typically includes specifications
and test methods for raw materials, in-process testing, the final excipient specification, a complete description of the manufacturing process, safety
data, packaging details, and label content. The excipient manufacturer forwards the DMF directly to the FDA. The FDA references the DMF in
conjunction with the review of a submission or application to the FDA in the form of a drug application (IND, NDA, ANDA etc.), provided the excipient
DMF holder has given the drug formulator permission to reference the DMF in their drug filing to the FDA.
In Europe, there is no DMF system for excipients, but there are two types of CEP which contain comparable information on the excipient. The
“ordinary” CEP which is directly forwarded to the EDQM is only applicable to excipients listed in the Ph.Eur. The only way a new excipient can become
accepted for pharmaceutical use in Europe is to submit all of the data in the pharmaceutical drug product manufacturer’s Marketing Authorization,
which represents a constraint to the introduction of new excipients.
In Japan the drug product application is submitted to the regulatory authorities by the pharmaceutical company typically containing all relevant details
concerning the excipient. There exists also a new DMF system which is still evolving.

1 FDA Guideline for Drug Master Files, September 1989.

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22.F Applicability of ICH Guidance to excipients
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ How should impurities or other components in excipients be handled?
■ How should residual solvents in excipients be handled?

The International Conference on Harmonisation (ICH) was organized to develop uniform global requirements for various technical aspects of
pharmaceutical product registration. ICH has approved guidance documents on the technical requirements for drug products containing new ingredients.
While the focus is primarily on the dosage form and active ingredients, several of the guidelines have an impact on excipients and can affect the
marketing of an excipient. Excipient suppliers should familiarize themselves with the following two documents in particular as pharmaceutical users will
expect to see compliance to these guidelines.

22.F.1 Q3A, Impurities in New Drug Substances

ICH has issued the guideline Q3A Impurities in New Drug Substances (see Chapter E.3.A) which recommends steps for qualifying impurities in the
active pharmaceutical ingredient. Since such materials when found in excipients are often beneficial to excipient performance, they are referred to as
other components. While ICH Q3A guideline is not specifically intended for excipients, it is suggested that other components which are potentially
harmful or do not contribute to the performance of the excipient are identified and reported using the provisions of the guideline. Where appropriate,
consideration should be given to establishing specification limits for certain other components.
It is suggested that a composition profile is developed so that:
■ The potential for drug interactions with other components can be determined by the user.
■The impact on the composition can be assessed following changes to:
■ The Manufacturing Process
■ Raw materials
■ Packaging

The composition profile defines all components that comprise the excipient.

22.F.2 Q3C, Impurities: Guideline for Residual Solvents

ICH has also issued the guideline Q3C Impurities: Guideline for Residual Solvents (see Chapter E.3.C) which lists various organic solvents in one of four
classifications. They include solvents to be avoided, solvents to be limited, solvents with low toxic potential, and solvents for which no adequate
toxicological data was found. The presence in the excipient of any solvent listed in the ICH guideline should be within the limits specified in the guideline
for the intended application. However, it is important to note that these levels are for the presence of the stated solvent in the drug product and not in the
individual excipient ingredients. Therefore, in calculating the maximum allowable residual solvent level in the excipient, the intended use concentration of
the excipient in the finished drug product along with other sources of the listed solvent must be taken into account. Residual solvents should be limited
as much as possible in the excipients so that they are below those listed in Q3C or are present at only very low levels in the drug product. This will then
reduce or limit the need for routine testing of residual solvents in the drug product, except for those used in its manufacture. If the level of residual solvent
exceeds those in the Q3C guideline, the manufacturer should measure and report the quantity of the residual solvent in each lot of excipient and report
on the Certificate of Analysis. In the absence of information concerning the usage level of the excipient in the drug product, the levels in Q3C should be
adopted.
This ICH guideline for Residual Solvents has been adopted by the Ph.Eur. as Chapter 5.4, and the USP has replaced the General Chapter <467>
Organic Volatile Impurities with the Q3C text which is now General Chapter <467>Residual Solvents. The publication in the USP has only occurred in
2009. Unfortunately the FDA interpretation of the guideline is much stricter and more severe than has hitherto been accepted in Europe. The FDA has
recently published a guidance document on this subject1 and those impacted are advised to study it carefully so that they can support the use of their
excipients in the USA.

Summary:
It is suggested that other components which are potentially harmful or do not contribute to the performance of the excipient are identified and reported
using the provisions of the ICH Q3A guideline. Where appropriate, consideration should be given to establishing specification limits for certain other
components.
If any solvent listed in the ICH Q3C guideline is present in the excipient, its amount should be within the limits specified in the guideline for the intended
application. However, it is important to note that these levels are for the presence of the stated solvent in the drug product and not in the individual
excipient ingredients. The ICH Q3C guideline has been adopted by Ph. Eur. and USP.

1 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070621.pdf
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22.G Other aspects critical to the marketing of excipients
Up15 Iain Moore

In this chapter you will find answers to the following questions:

■ Why is it important to know the origin of a raw material used for excipient manufacture?
■ What other information is relevant to assure excipient quality and safety?

Depending on applicability, excipient suppliers should have knowledge of and control over the following aspects of excipient quality since they may also
have implications for end user safety:
■Origin of raw materials
■ Animal derived materials lead to concern for issues related to BSE or other TSE which can restrict acceptance.
■Issues may also arise if raw materials are derived from certain other natural substances (e.g. peanuts) since some of these materials can lead to
allergic reactions in the patient.

■Finally, concerns may arise about excipients produced from genetically modified organisms (GMOs) such as corn (maize) or soy products. These
issues may restrict the acceptance and use of excipients. It is therefore critical that the excipient supplier determines and controls the origin of
their raw materials.
■Viral safety information may be needed in case of excipient raw materials of human or animal origin. For such materials, viral safety evaluation
study results may be required. They should demonstrate that materials used in production of the excipient are considered safe and that the
approaches (methods) used to test, evaluate, and eliminate potential risks during the manufacturing are suitable.
■Degradation products of the excipient: For a well established excipient, the excipient supplier will often know how it changes as a result of atypical
processing conditions or due to thermal and related stresses to which it may be exposed in the supply chain. Such knowledge should be made
available to the user. Where formal stability studies on the excipient are conducted, such studies can provide similar information.
■Presence of catalyst residues, decomposition or degradation products, and process related components: this is particularly relevant where the
catalyst residues are heavy metals1.
■The presence of additives and process aids in the excipient such as biocides, anti-oxidants, or stabilizers can lead to safety concerns for the user,
and their selection should be carefully reviewed and assessed for acceptability in the intended market application. A composition profile should be
developed for the purpose of establishing the presence of process-related components and the quantity present. The excipient supplier should
endeavour to provide a consistent quantity of these components in the excipient.

While safety issues such as these may be evident in the excipient, it is not suggested that this precludes their acceptance in all instances. It is
important that the original manufacturer evaluates their effect as part of the regulatory assessment.

Summary
The origin of raw materials used for excipient manufacture plays an important role for the acceptance and safety of the finished excipient. Knowledge
about excipient stability under stress conditions is also valuable. Last but not least the excipient manufacturer should carefully review the presence of
process aids and additives.

1 See EMEA Note for Guidance Guideline on the Specifications Limits for Residues of Metal Catalysts or Metal Reagents,
EMEA/CHMP/SWP/4446/2000
Printed by: 168305-3 Date: 24.04.2014 GMP MANUAL © Maas & Peither AG
22.H References
Up15
Regulatory Requirements and Guidelines, Europe
1. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community Code
relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products
(“counterfeit directive”)
2. Specific Conditions of the Application of the Principles and Guidelines of Good Manufacturing Practice for Certain Excipients,
EC-Directive 2001/83/EC, as amended by EC-Directive 2004/27/EC (31 March 2004)
3. The Rules and Guidance for Pharmaceutical Manufacturers and Distributors (Orange Guide), The Pharmaceutical Press, 2007 ISBN 978 0 85369
719 0
4. The European Agency for the Evaluation of Medicinal Products:
Evaluation of Medicines for Human Use, Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for
Application for Marketing Authorisation of a Medicinal Product, (Draft) CPMP/QWP/419/03, February 2003
5. The European Agency for the Evaluation of Medicinal Products: Guideline on The Chemistry of New Active Substances, CPMP/QWP/130/96/Rev
1, February 2004
6. EMEA Note for Guidance: Guideline on the Specifications Limits for Residues of Metal Catalysts or Metal Reagents,
EMEA/CHMP/SWP/4446/2000
7. European Pharmacopoeia, Council of Europe, Strasbourg:
1.1. General Statements

Regulatory Requirements and Guidelines, US

8. FDA, Guideline for Drug Master Files, September 1989.
www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/ucm073164.htm
9. FDA, Guidance for Industry: Nonclinical Studies for the safety evaluation of Pharmaceutical Excipients, May 2005,
www.fda.gov/ohrms/dockets/98fr/2002d-0389-gdl0002.pdf
10. FDA, Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States, November 2009;
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070621.pdf
11. USP Guideline for Submitting Requests for Revision of the USP-NF, Chapter Three Excipients, V3.1, April 2007,
www.usp.org/sites/default/files/usp_pdf/EN/USPNF/chapter3.pdf
12. USP Monographs, in: USP/NF, United States Pharmacopoeial Convention, Inc., 12601 Rockville, MD; www.usp.org
General Notices, subsection Ingredients and Processes
General Chapter <1074> Excipient Biological Safety Evaluation Guidelines
General Chapter <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients
General Chapter <1225> Validation of Compendial Methods

ICH (www.ich.org)
13. ICH M4, Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use, 2004.
14. ICH Q3A(R2): Impurities in New Drug Substances (Revised Guideline), 2006 (see Chapter E.3.A)
15. ICH Q3C(R5): Impurities: Guideline for Residual Solvents, 2011 (see Chapter E.3.C)
16. ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, 2000 (see Chapter E.7)
17. ICH Q8(R2): Pharmaceutical Development, 2009 (see Chapter E.8)

ISPE (www.ispe.org)
18. ISPE GAMP Publications : GAMP® 5 and GAMP® Good Practice Guides,
www.ispe.org/cs/gamp_publications_section/gamp_publications_overview

WHO (www.who.int)
19. WHO Good Manufacturing Practices, www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/

IPEC (www.ipec-europe.org, www.ipecamericas.org)

and PQG (www.pqg.org)
20. IPEC-PQG, Good Manufacturing Practices Guideline for Pharmaceutical Excipients, 2006
21. IPEC-PQG, Good Manufacturing Practices Audit Guideline for Pharmaceutical Excipients, 2008
22. IPEC, Good Distribution Practices Guideline, 2006
23. IPEC, Good Distribution Practices Audit Guideline for Pharmaceutical Excipients, 2011
24. IPEC, Qualification of Excipient for Pharmaceutical Use, 2008
25. IPEC, Excipient Composition Guide, 2009
26. IPEC, Quality Agreement Guide and Template, 2009
27. IPEC, Excipient Information Package and Templates, 2009
28. IPEC, Excipient Stability Program Guide, 2010
29. IPEC-Americas, Certificate of Analysis Guide for Bulk Pharmaceutical Excipients, 2000 (currently under review)
30. The International Pharmaceutical Excipients Council of the Americas, Significant Change Guide for Bulk Pharmaceutical Excipients, 2009.
31. IPEC-Americas, Excipient Master File Guide, 2004.
32. IPEC New Excipient Safety Evaluation Procedure http://ipecamericas.org/content/ipec-novel-excipient-safety-evaluation-procedure
International Standards
33. EN ISO 9001:2008 „Quality Management Systems – Requirements“

Publications
34. Steinberg M., Borzelleca J.F., Enters E.K., Kinoshita F.K., Loper A., Mitchell D.B., Tamulinas C. B., and Weiner M. L.: A New Approach to the
Safety Assessment of Pharmaceutical Excipients. In: Regulatory Toxicology and Pharmacology, 24, 2, 1996.
35. The Proposed Guidelines for the Safety Evaluation of New Excipients. In: European Pharmaceutical Review, November 1997
36. APIC-CEFIC: „How to do“ document – Interpretation of the ICH Q7a Guide, 2010 (see Chapter E.7)

Links to the World Wide Web:

37. www.ema.europa.eu
38. Inactive Ingredient Search for Approved Drug Products (Database),
www.accessdata.fda.gov/scripts/cder/iig/
39. Electronic Medicines Compendium (contains information about UK licensed medicines): www.medicines.org.uk/emc.aspx
40. www.excipact.org

Editor’s note:
The web links have been checked for correctness in January 2013.