Quality of medicines questions and answers（中英文）

Quality of medicines questions and answers
These questions and answers address a number of questions that have been brought to
the attention of the Joint Committee for Medicinal Products for Human Use /
Committee for Medicinal Products for Veterinary Use Quality Working Party (QWP)
by marketing-authorisation holders (MAHs) or European Economic Area (EEA)
competent authorities, on matters related to the quality of medicines. They have been
developed and are maintained by the QWP.
They provide the EEA's harmonised position on issues that can be subject to
different interpretation or require clarification, typically arising from discussions or
correspondence during assessment procedures.
If a question is not addressed, marketing-authorisation holders are encouraged to

contact the European Medicines Agency for further information at
qwp@ema.europa.eu.
These questions have been produced to provide clarification or additional

information, and should be read in conjunction with the European Pharmacopoeia ,
quality guidelines and other guidance documents.
Key:
 H: applicable to medicinal products for human use

 V: applicable to veterinary medicinal products
Quality of medicines questions and answers: Part 1：
Active Substance - Active-substance-master-file procedure

1. Can a mixture of an active substance with an excipient be submitted through an
active-substance-master-file (ASMF) procedure? H+V August 2007.
No. A mixture of an active substance with an excipient cannot be submitted through
an ASMF procedure.
The blending of an active substance and an excipient is considered as the first step in
the manufacture of the medicinal product, and therefore does not fall under the
definition of an active substance.
The only exceptions can be made where the active substance cannot exist on its own,
for example, due to insufficient stability without a stabilising agent, or in the case of
herbal dry extracts if it is not possible to produce a solid extract without excipients.
Active substance - Declaration by the qualified person on the good-

manufacturing-practice status of the active substance manufacturer
1. The notice to applicants requires the submission of a declaration signed by the
qualified person that the active substance used is manufactured in accordance with
good manufacturing practice. The active substance in my product is widely used,
but not normally as a pharmaceutical active substance, and I am having some
difficulty in confirming compliance. What should I do to furnish the required
declaration? H+V September 2008
Full compliance with good manufacturing practice (GMP) for finished products and
active substances is a legal obligation for manufacturing-authorisation holders. It is
recognised that for a small number of medicinal products the primary use of the active
substance is not in a medicinal product and the producer may therefore not be aiming
to meet the specific requirements of pharmaceutical customers that represent an
insignificant volume of business. Alternative sources should normally be sought but
in exceptional circumstances the manufacturing-authorisation holder should assess
and document to which extent GMP is complied with and provide a risk-based
justification for the acceptance of any derogation. The declaration provided by the
qualified person should set out in detail the basis for declaring that the standards
applied provide the same level of assurance as GMP. The European Medicines
Agency will collect experience with this approach which can be used as a basis for
discussion on related amendments to guidelines in the future.
Active Substance - Good-manufacturing-practice compliance for

sterilisation of an active substance
1. What kind of good-manufacturing-practice documentation is needed for an active
substance manufacturer who performs sterilisation of an active substance? H+V
July 2010
The good-manufacturing-practice (GMP) basic requirements for active substances
used as starting materials (European Union (EU) GMP guide part II) only applies to
the manufacture of sterile active substances up to the point immediately prior to the
active substance being rendered sterile. The sterilisation and aseptic processing of
sterile active substances are not covered by this guideline and shall be performed in
accordance with GMP for medicinal products (Commission Directive 2003/94/EC; as
interpreted in the basic requirements for medicinal products including annex 1 of the
EU GMP Guide part I). This implies that for any active-substance manufacturer who
performs sterilisation and subsequent aseptic handling of the active substance, a valid
manufacturing authorisation or GMP certificate from an EEA authority or from an
authority of countries where mutual recognition or other Community arrangements
apply has to be submitted.
Also, the active-substance manufacturer has to submit data on the sterilisation process
of the active substance (including validation data) to the marketing-authorisation
applicant or holder for inclusion in the dossier submitted for the finished product and
approval by the licensing authority or authorities.
Active Substance - Starting materials of herbal origin

1. How should the quality of a starting material of herbal origin be controlled when it
is used to manufacture a semi-synthetic active substance? H+V February 2012
There are several types of starting materials of herbal origin used to manufacture
semi-synthetic active substances:
herbal drugs;herbal preparations (typically extracts);isolated plant constituents (no

additional synthetic steps).Starting materials of herbal origin should be characterised
to ascertain their suitability and a contaminant profile should be established and
submitted, taking into consideration the number of chemical steps between the
starting material and the semi-synthetic active substance.
In all cases, the scientific name (genus, species, variety and author) of the plant and
plant part used should be specified. If the starting material is an extract or an isolated
constituent, the extraction solvent and strength (e.g. ethanol 50% v/v) used for the
first extraction from the herbal drug should be specified as well.
The quality of the starting material of herbal origin should follow the principles set
out in the European Pharmacopoeia monographs on herbal drugs, herbal drug
preparations, extracts and essential oils, as applicable: the potential presence of
foreign matter, pesticides, microbiological contamination, total ash, heavy metals,
aflatoxins, ochratoxin A, radioactive contamination, residual solvents, and other
relevant impurities should be discussed.
Potential contaminants that may be carried through the extraction and purification
processes should be fully addressed taking into account the production of the herbal
drug, and the subsequent extraction and purification processes.
The specification for the starting material of herbal origin should be fully justified by
the applicant and should include suitable tests for identity, assay, impurities and
potential contaminants.
Compliance with the guideline on good agricultural and collection practice (GACP) is
not mandatory in the steps prior to the starting material of a semi-synthetic active
substance, since it applies to herbal medicinal products and traditional herbal
medicinal products. However, information on the geographical origin, collection or
cultivation, harvesting, and post-harvest treatments (possible pesticides and fumigants
used and possible radioactive contamination) could justify limited testing for
(possible) contaminants.
Data submission
1. Is the submission of data regarding manufacturing process validation, analytical
validation, and stability studies, produced only by the developer of the product
sufficient? Does it make any difference if the developer of the product is presented
as one of the product manufacturers or not? H+V July 2008
These questions and answers only concern products that are oral solid dosage forms
manufactured by standard manufacturing methods. The new product has the same
formula and manufacturing method of the developed product.
Provided that the formula, manufacturing process, analytical methods and packaging
materials are the same, data originating from the developer of the product is normally
sufficient. As regards manufacturing process validation, the marketing authorisation
holder, according to the guideline on process validation, must submit with the new
application the process validation scheme and the commitment to carry out process
validation and initiate stability studies along with the batch analysis for production
scale batches for the new manufacturing site. This is irrespective of whether the
product developer is one of the manufacturing sites of the new product or not.
2. Who is responsible to verify the production scale validation data when this is
available? H+V July 2008
These questions and answers only concern products that are oral solid dosage forms
manufactured by standard manufacturing methods. The new product has the same
formula and manufacturing method of the developed product.
According to the guideline on process validation, "the results can be subsequently

verified by supervising authority according to national procedure.” Depending on the
product and the concerns that may arise, in some countries this may be dealt with as a
post-authorisation commitment or it may be brought to the attention of good-
manufacturing-practice inspectors to be checked during their next inspection.
The marketing-authorisation holder is usually not expected to present these data with
the new application, unless it is requested by the licensing authorities.
3. Can the test product of a bioequivalence study be produced by the developer,
irrespective of whether that developer is one of the manufacturing sites of the new
product? H+V July 2008These questions and answers only concern products that are
oral solid dosage forms manufactured by standard manufacturing methods. The new
product has the same formula and manufacturing method of the developed product.
The product used in the bioequivalence study must be representative of the industrial
scale product to be marketed.
A bioequivalence study conducted using a test product produced by the developer is

acceptable if the developer is also one of the manufacturers of the new product.
If the developer is not one of the manufacturers of the new product, it has to be
demonstrated that the bioequivalence batch is representative of the industrial scale
product to be marketed.
For this the following applies:
The developer product and the new product must have identical formula,
specifications, manufacturing process and equipment;The active substance supplier is
the same or it is ensured that characteristics of the active substance that may have an
impact on the bioavailability are identical;The excipients characteristics which may
have an impact on the bioavailability of the active substance are identical;The
dissolution profiles of batches produced by the developer (including the biobatch) and
the product from the new manufacturer (at least pilot batches) must be
similar;Comparative pilot batch analysis between the developer product (including the
biobatch) and the new manufacturer product must be presented.
4. Is there any requirement for the marketing-authorisation holder to submit any kind
of proof (e.g. statement or contract) that it has obtained the dossier from the developer
legally? H+V July 2008These questions and answers only concern products that are
oral solid dosage forms manufactured by standard manufacturing methods. The new
product has the same formula and manufacturing method of the developed product.
No such proof is necessary to be presented in the application dossier.
European Pharmacopeia (Ph. Eur.) - Harmonised Ph. Eur. Chapters

2.6.12, 2.6.13 and 5.1.4
1. How should any update to the microbial quality control of a finished product,
specifically linked to the update to the International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH) harmonised Ph. Eur. methods (2.6.12 and 2.6.13) and limits (5.1.4) be
achieved? H+V February 2012
Any changes to implement the harmonised methods (2.6.12 and 2.6.13) should be
submitted under change code B.II.d.2.a (type IA).
Any changes to implement the harmonised limits (5.1.4) should be submitted as

follows:
Changes to the limits – B.II.d.1.a (type IA), but only in the following situations:
The currently registered microbial control limits (present situation) are totally in line
with the pre-January 2008 (non-harmonised) situation and did not include any
additional specified controls over and above the Pharmacopoeia requirements for that
particular dosage form. In addition, the proposed controls are totally in line with the
harmonised monograph.If for any reason these criteria are not met, a type IB variation
(B.II.d.1.z) should be submitted.
In accordance with current requirements, any changes should be clearly identified

(present / proposed) in the variation submission and the affected parts of the
marketing-authorisation dossier should be appropriately updated, including a
description of how the method is applied to the specific product.
Please note that this advice supersedes the questions and answers dated August 2007,
which are now out of date.
European Pharmacopeia - Monograph on tablets

1. How should industry apply the revised test subdivision of tablets in the European
Pharmacopeia monograph on tablets? H+V October 2006
The requirements of the European Pharmacopoeia (Ph. Eur.) general monograph on
tablets for tablets with one or more breaklines have been revised as of 1 July 2006.
The previous version of the monograph, which has been in force since April 2002,
requested compliance with either test A (uniformity of content of single-dose
preparations) or the test for uniformity of mass of single-dose preparations. It did not,
however, give any information on how to select the parts to be tested. Supplement 5.5
now provides background information on the use of breakmarks and describes the
sampling procedure and the number of tablet parts to be tested in detail. As a test
procedure, it prescribes determining uniformity of mass, while setting the somewhat
wider acceptance criteria of the test of content uniformity, namely 85 - 115% (in this
case of the average mass).
According to Directives 2001/83/EC and 2001/82/EC, the monographs of the Ph. Eur.
are the official standards of appropriate quality in the marketing authorisation
procedures. In the pharmacopoeia it is also stated that a preparation must comply with
the monograph throughout its period of validity.
As the revised text defines lesser requirements with wider acceptance criteria than the
previous version (see above), a decision has been taken by the regulatory authorities
of the European Union (EU) that the revised test on subdivision of tablets is to be
applied to all new applications for marketing authorisations as well as all existing
products. It is acknowledged, however, that the new test will not have been applied to
products which are in the final stages of their development. In order not to delay any
immediate applications and in line with the period of time defined in the variations
regulation, a transitional period of 6 months following the coming into force of Ph.
Eur. 5.5 has been defined, in which the EU regulatory authorities will accept
submission of results which have been generated using the previous version of the
monograph.
As the requirements on subdivision of tablets are listed in the production section of

the general monograph on tablets, it will normally be sufficient to perform the test
only in the framework of pharmaceutical development. There is no need to include the
test in the release specification. However, in situations where there is a significant
change in tablet hardness during storage, it may be necessary to repeat the test at the
end of shelf-life in order to ensure that the scorability has not changed as a function of
hardness.
European Pharmacopeia (Ph. Eur.) - Harmonised chapter uniformity

of dosage units
Background. H+V June 2012
Between 2004 and 2008, various questions and answers have been published on this
website to clarify how the harmonised European Pharmacopoeia (Ph. Eur.) chapter on
uniformity of dosage units (2.9.40) and the general chapters on uniformity of mass of
single-dose preparations (2.9.5) and uniformity of content of single-dose preparations
(2.9.6) should be applied in the European Union (EU), also in view of the compliance
objection made by the United States Food and Drug Administration to the USP on the
2% relative-standard-deviation clause in general chapter 2.9.40. This matter has been
recently reviewed by EU regulators and the resulting agreed position is presented in
the following questions and answers, which replace the previous questions and
answers 1 and 4 published on the same subject in 2004 and 2006, which have now
been deleted from the website.
1. How should industry demonstrate compliance with the European Pharmacopoeia
with regard to uniformity of dosage units? H+V June 2012
Medicinal products marketed in the European Union need to be in compliance with
the relevant requirements in the European Pharmacopoeia (Ph. Eur.).
From a pharmaceutical quality point of view, the approach taken in the harmonised
general chapter on uniformity of dosage units (2.9.40) is considered equivalent to
what was previously required in the Ph. Eur. through the general chapters on
uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of
single-dose preparations (2.9.6). These general chapters, 2.9.5 and 2.9.6, are still
included in the current version of the Ph. Eur.
Taking this into account, the decision on what approach to take is left to the applicant.
Application of either the Ph. Eur. harmonised general chapter on uniformity of dosage
units (2.9.40) or the Ph. Eur. general chapters on uniformity of mass of single-dose
preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6) are
both considered acceptable options to demonstrate compliance with the Ph. Eur. with
regard to uniformity of dosage units.
Please note that this advice supersedes the previous questions and answers 1 and 4
published on the same subject in 2004 and 2006. The remaining previously published
questions and answers on the use of the general chapter 2.9.40 (former questions and
answers 2, 3, 5 and 6) are still valid and remain published as questions and answers 2
to 5.
2. How should the new text be interpreted, in particular in relation to testing
frequency (routine test / skip test / test on validation batches only)? H+V March 2006
Where a dosage form monograph in the European Pharmacopoeia refers to this
general chapter, the product should comply. This is normally verified by routine
testing unless otherwise justified and authorised.
3. How can the text be interpreted in light of the compliance objection made by the
Food and Drug Administration to the United States Pharmacopeia on the 2% relative
standard deviation clause? H+V March 2006
The harmonised text is included in the European Pharmacopoeia and the 2% clause
will thus be valid in the European Union. This will not be dependent on the final
outcome of the discussion between the Food and Drug Administration and the United
States Pharmacopeia.
4. When can the requirements in the harmonised European Pharmacopoiea general
chapter on uniformity of dosage units (2.9.40) for mass variation, rather than content
uniformity, be applied with reference to a relative standard deviation (RSD) of not
more than 2%? Is it sufficient to determine the RSD on for example 3 validation
batches? H+V July 2008
It is the opinion of the Quality Working Party that the requirement in the harmonised
chapter 2.9.40 regarding the 2% relative-standard-deviation clause represents
minimum requirements. The use of this clause should be based on sufficient
experience. Normally, results from 3 validation batches are not sufficient. It is rather
to be used post-approval when more extensive production experience is gained.
5. What is meant by single component and multiple component in the harmonised
chapter 2.9.40? H+V July 2008
'Single component' means one active substance with no excipient. 'Multiple
component' could mean 'at least 2 active substances' or 'at least 1 active substance and
at least one excipient'; both cases are valid.
Impurities - Calculation of thresholds for impurities

1. What is the basis for the calculation of thresholds to set limits for impurities in the
finished product specification? H July 2009
The calculated thresholds should be based on the highest maximum daily dose of the
respective active substance in authorised medicinal products. The threshold for
impurities should be the same for all strengths.
The same rule applies for combination drugs; the highest possible combined strength
should be used for setting the thresholds.
The maximum daily dose used for threshold calculation should be the same for a
given active substance irrespective of the medicinal product.
Impurities - Harmonisation of policies on setting specifications for

potentially genotoxic impurities, heavy-metal-catalyst residues and
class-1 solvent residues
1. What is a reasonable policy for setting specifications for potentially genotoxic
impurities which are theoretical or actual impurities in a drug substance
manufacturing process? H June 2012
Different possible scenarios can be identified and the applicable policies to be applied
for each of them are described below:
Example 1 – A potential genotoxic impurity
The definition for a potential genotoxic impurity is derived from the definition for
'potential impurity': an impurity that theoretically can arise during manufacture or
storage. It may or may not actually appear in the (new) drug substance (ICH Q3A,
glossary).
If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical

considerations but not found in practice at any key stage in the manufacturing process
as demonstrated by studies during development of the manufacture, the impurity does
not need to be included in the drug substance specification or a specification of an
intermediate.
Example 2 – A (potentially) genotoxic impurity actually formed or introduced prior to

the final step of the synthesis
If a (potentially) genotoxic impurity is formed or introduced in a step before the final

synthesis step, it is considered possible to not include this impurity in the drug
substance specification if it is controlled by a suitable limit in a synthesis intermediate
and if it is unambiguously demonstrated by analysis results (use of spiking
experiments are encouraged) that presence of this impurity does not exceed 30 % of
the limit, derived either from threshold of toxicological concern (TTC) or otherwise
defined acceptable limit etc., in the drug substance.
It is considered possible to apply skip testing if the level of the impurity in a synthesis
intermediate does not exceed 30% of the limit, derived from either TTC or otherwise
defined acceptable limit etc, in the intermediate. Data should be presented for at least
6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is
not fulfilled, a routine test in the intermediate is needed. If the impurity exceeds 30%
of the limit, derived either from TTC or otherwise defined acceptable limit etc., in the
drug substance the impurity has to be included in the drug substance specification and
the test has to be carried out on a routine basis.
Should a genotoxic impurity not be controlled at the intermediate stage, then the
scenario of example 3 applies.
Example 3 - A (potentially) genotoxic impurity is formed or introduced in the last

synthesis step
If a (potentially) genotoxic impurity is formed or introduced in the final synthesis

step, it should be included in the specifications. However, it is considered possible to
apply skip testing if the level of the impurity does not exceed 30% of the limit,
derived from either TTC or otherwise defined acceptable limit etc., in the drug
substance. Data should be presented for at least 6 consecutive pilot scale or 3
consecutive production scale batches. If this condition is not fulfilled, a routine test in
the drug substance specification is needed.
Definitions:
For the purpose of these questions and answers, the following definitions apply:
Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an

appropriate genotoxicity test model, e.g. bacterial gene mutation (Ames)
test.Potentially genotoxic impurity: an impurity that shows (a) structural alert(s) for
genotoxicity but that has not been tested in an experimental test model. Here
potentially relates to genotoxicity, not to the presence or absence of this impurity.
2. In order to harmonise the policies to be applied for setting specifications for
genotoxic impurities and heavy-metal-catalyst residues, what are reasonable
policies to be applied when setting specifications for heavy-metal-catalyst
residues? H June 2012
In order to harmonise the policy for setting specifications for metal residues with that
for setting specifications for genotoxic impurities, some clarifications of the
interpretation of sections 4.5 and 4.6 of the heavy-metal-catalyst guideline
(EMEA/CHMP/SWP/4446/2000) are given below.
Since it is the class-1 metals that are the most toxic metals with permitted daily
exposures (PDEs) that approach the level of the threshold of toxicological concern
(TTC) applied for genotoxic impurities, it seems reasonable that class-1 metals are the
prime focus for harmonisation with the policy for genotoxic impurities while class-2
and 3 metals could be treated similarly but somewhat less strictly.
Example 1 – A class-1 metal is not used or suspected to be present in a synthesis

process
Metals are not expected to be formed in synthesis processes. Only if deliberately

introduced or suspected to be present for other reasons, residues of metals can be
expected. If not used or suspected to be present, the metal does not need to be
included in the drug substance specification or a specification of an intermediate.
Example 2 – A class-1 metal is formed or introduced prior to the final step of the
synthesis
If a class-1 metal is introduced in a step before the final synthesis step, it is considered
possible to not include this metal in the drug substance specification if it is controlled
by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated
by analysis results that the presence of this metal does not exceed 30% of the
guideline limit in the drug substance.
It is considered possible to apply skip testing if the level of the class-1 metal in a
synthesis intermediate does not exceed 30% of the guideline limit in the intermediate.
Data should be presented for at least 6 consecutive pilot scale or 3 consecutive
production scale batches. If this condition is not fulfilled, a routine test in the
intermediate is needed. If the class-1 metal exceeds 30% of the guideline limit in the
drug substance the impurity has to be included in the drug substance specification and
the test has to be carried out on a routine basis.
Should a class-1 metal not be controlled at the intermediate stage, then the scenario of
example 3 applies.
Example 3 – A class-1 metal is introduced in the last synthesis step
If a class-1 metal is introduced in the final synthesis step, it should be included in the
specifications. However, it is considered possible to apply skip testing if the level of
the metal does not exceed 30% of the guideline limit in the drug substance. Data
should be presented for at least 6 consecutive pilot scale or 3 consecutive production
scale batches. If this condition is not fulfilled, a routine test in the drug substance
specification is needed.
3. In order to harmonise the policies to be applied for setting specifications for
genotoxic impurities and class-1 solvent residues, what are reasonable policies to
be applied when setting specifications for class-1 solvent residues? H June 2012
In order to harmonise the policy for setting specifications for class-1 solvents with
that for setting specifications for genotoxic impurities, some clarifications of the
interpretation of annex I to the residual solvents guideline (CPMP/ICH/283/96 /
CVMP/VICH/502/99): Specifications for class 1 and class 2 residual solvents in
active substances (CPMP/QWP/450/03 / EMEA/CVMP/511/03) are given below.
Since it is the class-1 solvents that are most toxic solvents and have permitted daily
exposures (PDEs) that approach the level of the threshold of toxicological concern
(TTC) applied for genotoxic impurities, it seems reasonable that clas- 1 solvents are
the focus for harmonisation with the policy for genotoxic impurities.
Example 1 – A class-1 solvent is not used or suspected to be present in a synthesis

process
If a class-1 solvent is just a potential impurity, not used directly or found in practice as
demonstrated by studies during development of the manufacture, the class-1 solvent
does not need to be included in the drug substance specification or a specification of
an intermediate.
Example 2 – A class-1 solvent is formed or introduced prior to the final step of the
synthesis
If a class-1 solvent is formed or introduced in a step before the final synthesis step, it
is considered possible to not include this solvent in the drug substance specification if
it is controlled by a suitable limit in a starting material or synthesis intermediate and if
it is unambiguously demonstrated by analysis results that the presence of this solvent
does not exceed 30% of the guideline limit in the drug substance.
It is considered possible to apply skip testing if the level of the solvent in a synthesis
intermediate does not exceed 30% of the guideline limit in the intermediate. Data
should be presented for at least 6 consecutive pilot scale or 3 consecutive production
scale batches. If this condition is not fulfilled, a routine test in the intermediate is
needed. If the solvent exceeds 30% of the guideline limit in the drug substance the
solvent has to be included in the drug substance specification and the test has to be
carried out on a routine basis.
Should a class-1 solvent not be controlled at the starting material or intermediate

stage, then the scenario of example 3 applies.
Example 3 – A class-1 solvent is formed or introduced in the last synthesis step
If a class-1 solvent is formed or introduced in the final synthesis step, it should be

included in the specifications. However, it is considered possible to apply skip testing
if the level of the solvent does not exceed 30% of the guideline limit in the drug
substance. Data should be presented for at least 6 consecutive pilot scale or 3
consecutive production scale batches.
Impurities - Residual solvents

1. Is there a need to take the actual batch results into consideration when specifying
class-2 residual solvents for active substances or medicinal products? H+V August
2007
For class-2 residual solvents in active substances or medicinal products, it is sufficient
to restrict the specification to the concentration limit (parts per million) as defined in
the notes for guidance on impurities: residual solvents (CPMP/ICH/283/95 &
EMEA/CVMP/511/03) and related maintenance guidelines or to calculate it based on
the respective permitted daily exposure (mg/day) outlined in the guidelines.
It has been agreed by the QWP that there is no need for further tightening of the
specification in line with batch results, as the limits in the guideline are based on
safety assessment.
Manufacture of the medicinal products - Process control

1. When validating a manufacturing process, if a common bulk is used to
manufacture a series of products, how should the pilot batch size be decided
upon? H+V September 2007
It is the applicant’s responsibility to select and justify the pilot batch size.
The joint Committee for Medicinal Products for Human Use and Committee for
Medicinal Products for Veterinary Use guideline on process validation
(CPMP/QWP/848/96, CVMP/598/99) states that, “pilot-batch size should correspond
to at least 10% of the future industrial scale batch i.e. such that the multiplication
factor for scale-up does not exceed 10. For oral solid dosage forms this size should be
at least 10% or 100,000 units whichever is greater* unless otherwise justified”.
The guideline does not dictate that the 10% figure should always be linked to the
scale of manufacture of individual product presentations. In addition, it allows for
departures from the guidance where this is justified. Furthermore, the guideline does
not preclude the use of bracketing.
Certain bulk products are used to produce a series of presentations, for example a bulk
powder blend may be used to produce 50-mg, 100-mg and 200-mg direct compression
tablets with the same percentage composition. In such instances, as long as the
applicant can demonstrate a satisfactory link between the pilot batch size used for
validation and the routine production batch size, it will usually be acceptable to define
the pilot batch size as 10% of the planned production scale for the bulk product.
During the process validation study, the complete pilot scale bulk batch should be
used to manufacture the individual presentations. The division of the bulk batch
between the different presentations should also be justified.
*In the case of veterinary medicinal products, the minimum pilot size may be smaller
than 100,000 units where justified.
Variation
What is understood by “manufactured by complex manufacturing processes” in
change code B.II.b.4 (change in batch size of the finished product)? H+V October
2010
Complex manufacturing processes is intended to cover situations where the actual
manufacture of the finished product involves a process which includes one or more
processing steps that may give rise to scale-up difficulties. These will be considered
on a case by case basis.
Where relevant, if a change is submitted as a type IB variation, it is up to the applicant

to provide adequate justification for not considering a manufacturing process as a
'complex' one, in terms of scale-up. However, under the safeguard clause, it should be
noted that if the supplied justification is not accepted, it is possible for the competent
authority to upgrade the submission to a type II variation during the validation phase.
If unsure, applicants should consult the relevant competent authority before
submitting the variation.
药品的问题和答案的质量
药品质量的问题和答案：第 1 部分：
这些问题和答案解决的问题，已被人用/兽用质量工作组（QWP）医药产品委员会由市场
营销授权持有人（MAHS），或欧洲的医药产品要注意的联合委员会经济区（EEA）的主
管部门，药品质量有关的事项。他们已被开发，并保持由 QWP。
他们提供欧洲经济区的协调统一立场的问题上，可以作不同的解释或需要澄清，讨论或通
信过程中的评估程序通常产生的。
如果问题不解决，市场营销授权持有人的鼓励与欧洲药品局为进一步在
qwp@ema.europa.eu 的信息。
这些问题已澄清或提供补充资料，结合欧洲药典的质量方针及其他指导文件，应仔细阅读。
重点：
•H：适用于人用医药产品
•V：适用于兽药产品
活性物质 - 活性物质主文件程序
1。可以与赋形剂的混合物的活性物质，通过活性物质的主文件（ASMF）程序提交？ H +
V 2007 年 8 月。
编号 A 与赋形剂的混合物的活性物质不能提交通过 ASMF 程序。
被视为一种活性物质和赋形剂的混合的药用产品的制造中，作为第一步，因此不属于的定
义下的活性物质。
可以唯一的例外，其中的活性物质不能存在于它自己的，例如，未经稳定剂由于稳定性不
足，或在干燥的草药提取物的情况下，如果这是不可能的，以产生一个无赋形剂的固体提
取物。
活性物质 - 良好的生产实践状态的活性物质制造商的合资格人士的声明
1。通知申请人需要提交由合资格人士签署的声明，按照良好生产规范使用的活性物质，是
制造。在我的产品的活性物质被广泛使用，但不正常的药物活性物质，和我有一些困难，
在确认符合。提供所需的声明，我该怎么办？ H + V 2008 年 9 月
完全符合良好生产规范（GMP）的成品和活性物质，是制造授权持有人的法律义务。它被
确认，对于一个小数目的药用产品的活性物质的主要用途是没有一种药用产品中，因此，
生产者可以不旨在医药客户代表的业务量不大，以满足特定的要求。所有替代来源通常应
在找寻工作，但在特殊情况下，制造授权持有人应评估并记录在何种程度上符合 GMP 是
提供一个基于风险的理由接受任何减损。合资格人士提供的声明，应详细列明宣布，该标
准适用于提供相同水平的保证 GMP 的基础。欧洲药品管理局将收集的经验，这种方法可作
为讨论的基础，在未来的指导方针有关的修订。
杀菌的活性物质的活性物质 - 良好的制造实践的合规性
1。什么样的良好制造实践的文档，需要进行杀菌的活性物质的活性物质制造商？ H + V
2010 年 7 月
良好的制造规范（GMP）的基本要求（欧盟（EU）GMP 导向第二编）作为起始原料使用
的活性物质仅适用于无菌活性物质的制造点紧接所呈现的活性物质前不育。本准则未涉及
的消毒和灭菌处理的无菌活性物质，应进行符合 GMP 医药产品（委员会指令
2003/94/EC，医药产品的基本要求，包括附件 1 的欧盟解释 GMP 指南第一部分）。这意味
着，对于任何活性物质的制造商进行消毒和随后的无菌处理的活性物质，有效的生产许可
证或 GMP 证书从欧洲经济区的权力或权威的国家相互承认或其他社区安排的申请必须提
交。
此外，活性物质的制造商必须对灭菌过程的活性物质（包括验证数据）的营销授权申请或
持有人纳入发牌当局或当局提交的档案的成品和批准的提交数据。
活性物质 - 起始原料的草本来源
1。应该如何草本来源的起始原料的质量进行控制，当它是用来制造一种半合成的活性物质
时，？ H + V 2012 年 2 月
用于生产半合成的活性物质的草本来源的起始原料，有几种类型：
草本药物，草药制剂（通常提取物）;原料的草本来源的特点，以确定其是否适合，并应建
立一种污染物的配置文件和提交的，考虑到一些化学步骤孤立的植物成分（无需额外的合
成步骤）之间的起始材料和半合成的活性物质。
在所有情况下使用的植物和植物部分，学名（属，种，变种和作者），应符合规定。如果
起始材料的提取物或一个孤立的成分，提取溶剂和强度（例如：乙醇 50％体积/体积），
用于从草药的药物的第一提取应，以及指定。
草本来源的起始原料的质量应遵循的原则载于欧洲药典中药，中药制剂，提取物和精油
（如适用）：可能存在的异物，农药，微生物污染，总灰分，重金属，黄曲霉毒素，赭曲
霉毒素 A，放射性污染，残留溶剂，以及其他相关杂质进行讨论。
应完全解决潜在的污染物，可以通过提取和纯化过程中进行，考虑到生产的草药的药物，
以及随后的提取和纯化过程。
应该充分理据支持的规格为起始原料的草本来源的申请人，并应包括适当的身份测试，试
验，杂质和潜在的污染物。
遵循良好的农业和收集实践的指引（GACP），是不是强制性的前半合成活性物质的起始
原料的步骤，因为它适用于草药产品和传统草药产品。然而，信息的地理来源，收集，栽
培，收获，收获后处理（可能使用的杀虫剂和熏蒸剂和可能的放射性污染）可以证明（可
能）污染物的有限的测试。
数据提交
1。是提交的数据，对生产工艺验证，分析验证，稳定性研究，生产仅由开发商足够的产品
吗？这有什么区别，如果开发的产品为一体的产品制造商或？ H + V 2008 年 7 月
这些问题和答案，只关注产品，口服固体制剂制造标准制造方法。新产品具有同样的配方
及制造方法，开发的产品。
所提供的，该式中，制造过程中，分析方法和包装材料是相同的，通常是足够源自显影剂
的产品的数据。至于上市许可持有者，生产工艺验证，根据的指引工艺验证，必须提交新
的应用程序的过程验证计划和承诺，开展工艺验证和启动稳定性研究以及生产规模的批次
与批次分析新的生产基地。这是不论是否产品显影剂是一种新产品的制造场所或不。
2。负责验证生产规模的验证数据，这是？ H + V 2008 年 7 月
这些问题和答案，只关注产品，口服固体制剂制造标准制造方法。新产品具有同样的配方
及制造方法，开发的产品。
根据工艺验证的指引“，结果后来经主管机关根据国家程序。”根据产品的关注可能出现
的，在一些国家，这可能是处理作为授权后承诺或它可能带来的良好制造实践他们的下一
个检查过程中检查人员进行检查时要注意。
营销授权持有人通常预期不会呈现这些数据与新的应用程序，除非是发牌当局的要求。
3。测试产品的生物等效性研究，开发，生产，不论是否是新产品的生产基地之一，开发吗
H + V 七月 2008These 问题和答案只关注产品，口服固体制剂制造标准制造方法。新产品
具有同样的配方及制造方法，开发的产品。
生物等效性研究中使用的产品必须具有代表性的产业规模的产品在市场上销售。
使用测试产品的开发进行生物等效性研究是可以接受的，如果开发新产品的制造商之一。
如果开发人员没有一个新产品的制造商，它表明，代表的生物等效性批次的产品在市场上
销售的产业规模。
对于这一点适用以下情况：
的显影剂的产品和新产品必须具有相同的公式，规格，制造工艺和设备，将活性物质的供
应商是相同的，或者它是确保活性物质的特性，可以具有对生物利用度的影响是相同的;赋
形剂特性可能的活性物质的生物利用度的影响是相同的，所产生的显影剂（包括生物利用
度实验批次）和新的制造商的产品从（至少是中试批次）批次的溶出曲线必须是类似的;比
较导频批量分析之间的显影剂的产品（包括生物利用度实验批次）和新的制造商的产品必
须被呈现。
4。有什么要求的营销授权持有人提交任何形式的证明文件（例如，声明或合同），它已获
得了卷宗从开发商合法吗？ H + V 七月 2008These 问题和答案只关注产品，口服固体制剂
制造标准制造方法。新产品具有同样的配方及制造方法，开发的产品。
提交的申请材料中没有这样的证明是必要的。
欧洲药典（欧洲药典） - 调和欧洲药典。第 2.6.12，2.6.13 和 5.1.4

1。应如何更新到成品的微生物质量控制的，特别是联系在一起的更新问题国际会议
（ICH）统一的欧洲药典的人用药品注册技术要求协调。方法（2.6.12 和 2.6.13）和限制
（5.1.4）实现吗？ H + V 2012 年 2 月
实施协调一致的方法（ 2.6.12 和 2.6.13 ）应提交的任何变化，根据变化：代码
B.II.d.2.a（IA）型。
实施统一的限制（5.1.4）应提交的任何更改如下：
的变化的限制 - B.II.d.1.a 的（IA）型，但只有在下列情况下：
目前登记的微生物控制的限制（目前的情况）是完全一致的 2008 年 1 月（非统一）的情

况，并没有包括任何额外的控制及以上的药典要求，具体剂型。此外，建议的管制措施是
完全符合的统一 monograph.If 的任何理由不符合这些标准，一类 IB 的变化（B.II.d.1.z）
应提交。
按照目前的需求，应清楚地识别任何变化，（现在/建议）提交的变化和受影响地区的营销
许可档案应适当更新，包括说明如何将该方法应用于特定的产品。
请注意，这个建议取代了 2007 年 8 月的问题和答案，这是现在已经过时。
欧洲药典 - 专论片
1。行业应如何适用修订后的欧洲药典专着片测试片细分？ H + V 2006 年 10 月
欧洲药典（Ph. Eur。）一般专着平板电脑的平板电脑与一个或多个特征线的要求已作修订，
2006 年 7 月 1 日。以前的版本的专着，2002 年 4 月以来，一直在力 A（单剂量的药物制剂
的含量均匀度）或单剂量的药物制剂质量的均匀性的测试或者测试要求符合。，但是，没
有提供任何资料如何选择的部分进行测试。补充 5.5 现在提供的背景资料，使用
breakmarks，描述了抽样程序及平板电脑进行测试，在细节部分的数量。作为一个测试过
程中，它规定确定质量的均匀性，同时设置稍宽验收标准的测试，含量均匀度，即 85 -
115％（在这种情况下的平均质量）。
根据指令 2001/83/EC 和 2001/82/EC，欧洲药典专着。官方相应的质量标准，在营销授权

程序。在药典中也表示，准备工作必须遵守的专着整个有效期内。
由于经修订的文本定义较小的要求，更广泛的接受标准比以前的版本（见上文），已决定
采取的监管机构，欧洲联盟（欧盟），修改后的测试是适用于所有细分片剂新的应用程序
对营销授权以及现有的所有产品。这是公认的，但是，新的测试将不会被应用的产品，在
其发展的最后阶段。为了不耽误任何直接的应用和线的变化规例“中定义的时间内，6 个月
的过渡期后，进入欧洲药典力。5.5 被定义，在欧盟监管机构将接受提交使用以前版本的专
着已经生成的结果。
细分片剂由于要求中列出的一般专着于片剂生产部，通常会是足够的测试执行仅在药物开
发的框架。有没有必要测试包括在释放规范。然而，在那里有一个片剂硬度的显着变化，在
储存过程中的情况下，它可能有必要在保质期的结尾，以便确保的 scorability 已经没有改
变硬度的函数，重复该测试。
欧洲药典（欧洲药典） - 调和章节的剂量单位的均匀性
背景。 H + V 2012 年 6 月
2004 年至 2008 年间，各种问题和答案已经公布在本网站，如何协调欧洲药典（ Ph.
Eur。）澄清质量均匀性的单章，含量均匀度（40 年 2 月 9 日）和一般章节在欧洲联盟（欧
盟），也应适用于在遵守反对由美国食品和药物管理局（FDA）的剂量的药物制剂内容单
一剂量的药物制剂（2.9.6）（2.9.5）和均匀性 USP 的 2％，相对标准偏差一般章节的条
款，40 年 9 月 2 日。这件事最近已通过欧盟监管机构审查，并得到的一致立场是在以下几
个问题和答案，取代了前面的问题及答案 1 和 4 就同一主题发表于 2004 年和 2006 年，现
在已经被删除的网站。
1。行业应如何证明符合欧洲药典含量均匀度方面？ H + V 2012 年 6 月
在欧盟市场上销售的医药产品必须符合欧洲药典（Ph. Eur。）的有关规定。
从药品质量的角度来看，含量均匀度（40 年 2 月 9 日）在统一的总章所采取的方法被认为
是相当于以前需要在欧洲药典。单剂量的药物制剂的单剂量制剂（2.9.6）的内容（2.9.5）
和均匀性的质量的均匀性，通过一般的章节。这些一般章节，2.9.5 和 2.9.6，仍然包括在当
前版本中的欧洲药典。
考虑到这一点，决定采取什么方式的申请人。在欧洲药典中的应用。统一的含量均匀度（40
年 2 月 9 日）或欧洲药典的一般章节。章一般都认为是可以接受的方案，以证明符合欧洲药
典质量的单剂量的药物制剂（ 2.9.5 ）和单剂量的药物制剂的含量均匀度的均匀性
（2.9.6）。剂量单位的均匀性方面。
请注意，这个建议取代了前面的问题及答案 1，在 2004 年和 2006 年发表的关于同一主题

的。剩下的以前发布的问题和答案，一般章 40 年 2 月 9 日（原问题和答案，2，3，5 和
6）的使用仍然有效，仍然公布的问题和答案 2 至 5。
2。新的文本应该如何解释，特别是在测试频率（常规测试/只跳过测试/测试验证批次）？
H + V 2006 年 3 月
这章一般是指一个剂型在欧洲药典专着，产品应符合。这通常是通过常规测试验证，除非
有正当理由，并授权。
3。由美国食品和药物管理局（FDA），美国药典的 2％，相对标准偏差条款的合规异议的
文本可以被解释如何？ H + V 2006 年 3 月
统一的文本包含在欧洲药典和在欧盟 2％的条款是有效的。这会不会是依赖于美国食品和药
物管理局（FDA）和美国药典之间的讨论的最终结果。
4。什么时候可以在统一的欧洲药典“一般章，含量均匀度（40 年 9 月 2 日）的质量变化，
而不是内容的均匀性，适用于不超过 2％，相对标准偏差（RSD）的要求呢？是否足够，
以确定 RSD 例如 3 验证批次吗？ H + V 2008 年 7 月
这是意见的质量工作小组，在统一 40 年 2 月 9 日就 2％的相对标准偏差条款的要求是最低
要求。使用足够的经验，应根据本条款。通常情况下，从 3 验证批次的结果是不够的。这是
相当批准后使用时获得更丰富的生产经验。
5。单组分和多组分的统一章节 40 年 2 月 9 日是什么意思？ H + V 2008 年 7 月
“单组分”是指没有赋形剂的一种活性物质。 '多组分“可能意味着'至少为 2 的活性物质
的'或'至少为 1 的活性物质和至少一种赋形剂”，这两种情况下都是有效的。
杂质 - 杂质的阈值计算
1。阈值的计算设限的杂质在成品规格的基础是什么？ Ĥ2009 年 7 月
最高法定药用产品的各自的活性物质的每天最大剂量应根据所计算出的阈值。杂质的阈值
应该是相同的所有优势。
同样的规则也适用于复方药物，应使用尽可能高的结合强度设定的阈值。
用于阈值计算的最大值每日剂量应为一个给定的活性物质的药用产品，无论是相同的。
杂质 - 政策协调的潜在的基因毒性杂质，重金属的催化剂残留物和 1 类溶剂残留的设置规
格
1。设置规范合理的政策理论或实际的杂质在原料药生产过程中潜在的基因毒性杂质是什么
Ĥ2012 年 6 月
可以识别不同的可能出现的情况，并为他们每个人适用的政策，适用于描述如下：
例 1 - 一个潜在的基因毒性杂质
来自'潜在杂质“：从定义的杂质，理论上可以在生产或贮存期间产生的一个潜在的遗传毒
性杂质的定义。它可能会或可能不会实际出现在（新的）原料药（ICH Q3A，术语）。
如果一个潜在的遗传毒性杂质只是理论上的杂质，即基于理论考虑，但没有在实践中发现
在制造过程中制造的开发过程中，所进行的研究表明在任何关键阶段不需要被包含在药物
物质，杂质说明书或规范的中间。
例 2 - A 基因毒性杂质（潜在的）实际上形成或引进合成的最后一步之前
如果一个（潜在的）基因毒性杂质的形成或引入步骤前的最后的合成步骤中，它被认为是
可能不包括此药物物质规范中的杂质，如果它是由一个合适的限制控制的合成中间体中，
如果它是明确地表明，分析结果（使用的尖峰实验是鼓励）的存在，这种杂质不超过 30％
的限制，从阈值（TTC）的毒理学或另有规定的可接受的限制等，在原料药的衍生。
它被认为是可能的申请跳到测试，如果的合成中间体中的杂质水平的不超过 30％的极限，
来自 TTC 或另有界定可接受的限制等，在中间。数据应至少连续 6 个中试规模或连续 3 批
生产规模。如果这个条件没有被满足，在中间的常规测试是必要的。，如果杂质的限制，超
过 30％时，无论是从 TTC 衍生或定义的可接受的限制等，在原料药的杂质必须被包括在
原料药的规范和测试具有在常规基础上进行。
基因毒性杂质不应该被控制在中间阶段，那么实施例 3 的情况下适用。
例 3 - A（潜在的）基因毒性杂质形成或引进的最后的合成步骤
如果一个（潜在的）基因毒性杂质的形成，或者在最后的合成步骤中引入的，它应包括在
规格内。然而，它被认为是可以适用跳到测试，如果杂质的水平，不超过 30％的极限，来
自 TTC 或另有界定可接受的限制等，在原料药的。数据应至少连续 6 个中试规模或连续 3
批生产规模。如果这个条件没有被满足，例行试验在原料药的规范是必要的。
定义：
对于这些问题和答案的目的，下列定义适用于：
遗传毒性杂质：杂质已被证明是在适当的遗传毒性试验模型基因毒性，例如细菌基因突变
（Ames 试验）test.Potentially 基因毒性杂质：（a）结构警报（S）的遗传毒性，但尚未
经过测试，在实验测试模型的杂质。这里可能涉及遗传毒性，不这种杂质的存在或不存在。
2。为了协调政策，申请设置规格，什么是合理的政策设置时所采用的规格重金属的催化剂
残留物的基因毒性杂质和重金属的催化剂残留物呢？ Ĥ2012 年 6 月
为了协调政策与金属残留物的规范设置，设置规格为基因毒性杂质，重金属的催化剂指引
“第 4.5 和 4.6 条的解释（EMEA/CHMP/SWP/4446/2000 一些澄清）在下面给出。
由于这是 1 类金属，是最有毒的金属，允许日常风险（PDE）的接近水平的阈值（TTC）
的基因毒性杂质的毒理学，它似乎是合理的 1 类金属的主要集中协调与基因毒性杂质的政
策，而金属可以被视为-2 级和 3 类似，但少了几分严格。
示例 1 - 1 类金属不使用或怀疑是在合成过程中
金属不预期要在合成过程中形成的。只有故意或怀疑存在其他原因，金属的残留物可以预
期的。如果不使用，或怀疑是本不需要被包含在药物物质规范或规范的中间，该金属。
实施例 2 - 1 A 类金属形成或引入之前，在合成的最后一步
如果一个类-1 金属被引入在一个步骤之前的最后的合成步骤，它被认为是在原料药的规范，
可以不包括这种金属如果它是由一个合适的限制控制的合成中间体中，如果它被明确地表
明分析的结果，该金属的存在下，不超过 30％的药物物质的指引限制。
它被认为是可能的申请跳到测试，如果-1 之类的金属中的合成中间体的水平不超过 30％的

在中间的指引限制。数据应至少连续 6 个中试规模或连续 3 批生产规模。如果这个条件没有
被满足，在中间的常规测试是必要的。如果类-1 金属超过 30％的药物物质的限制，必须被
包括在原料药的规范和测试具有在常规基础上进行的杂质的指引。
-1 金属一类不应该被控制在中间阶段，那么实施例 3 的情况下适用。
实施例 3 - 在最后的合成步骤 A 类-1 金属被引入
如果一个类-1 金属被引入在最后的合成步骤中，它应包含在规格内。然而，它被认为是能
够适用跳到测试的金属的水平，如果不超过 30％的药物物质的指引限制。数据应至少连续
6 个中试规模或连续 3 批生产规模。如果这个条件没有被满足，例行试验在原料药的规范是
必要的。
3。为了协调政策，申请设置规格为基因毒性杂质和 1 类溶剂残留量，什么是合理的政策设
置时所采用的规格为 1 类溶剂残留？ Ĥ2012 年 6 月
为了协调的政策，规格为 1 类溶剂设定为基因毒性杂质的规格，附件一的解释澄清的残留
溶剂指导原则（CPMP/ICH/283/96 / CVMP/VICH/502 / 99）：下面给出了 1 类和 2 类活性
物质的有机溶剂残留量（CPMP/QWP/450/03 / EMEA/CVMP/511/03）。
由于这是 1 类溶剂，是最有毒的溶剂，并允许接近的水平（TTC）的基因毒性杂质的毒理
学阈值的的每日风险（PDE）的，它似乎是合理的，传统的溶剂是重点基因毒性杂质的政
策的统一。
示例 1 - 1 类溶剂，不使用或怀疑是在合成过程中
如果一个类-1 溶剂仅仅是一个潜在的杂质，而不是直接使用，或在实践中发现，如在制造
的发展过程中所进行的研究表明，1 类溶剂不需要被包括在原料药的规范或规范的中间。
实施例 2 - 1 类溶剂之前，在合成的最后步骤中形成或引入
如果一个类-1 形成溶剂或引入前的最后的合成步骤中的步骤，它被认为是可能不包括该溶
剂中的药物物质规范，如果它是由一个合适的限制控制中的起始原料或合成中间体，如果
这明确地表明，这种溶剂的存在下，不超过 30％的药物物质的指引限制在由分析结果。
它被认为是可能的申请跳到测试，如果电平的合成中间体中的溶剂不超过 30％的在中间的
指引限制。数据应至少连续 6 个中试规模或连续 3 批生产规模。如果这个条件没有被满足，
在中间的常规测试是必要的。如果溶剂超过 30％的指引，在药物的溶剂的物质必须被包括
在原料药的规范和测试具有在常规基础上进行限制。
如果一个类-1 溶剂不能被控制的起始原料或中间体的阶段，那么实施例 3 的情况下适用。
示例 3 - 1 类溶剂形成或引进的最后的合成步骤
如果一个类-1 形成溶剂，或者在最后的合成步骤中引入的，它应包括在规格内。然而，它
被认为是可以适用跳到测试，如果溶剂的水平的不超过 30％的药物物质的指引限制。数据
应至少连续 6 个中试规模或连续 3 批生产规模。
杂质 - 残留溶剂
1。是否有必要采取实际的批处理结果时，考虑到指定类的有机溶剂残留量的活性物质或药
用产品吗？ H + V 2007 年 8 月
类活性物质或药物产品中的残留溶剂，它是足以限制附注中杂质的指导规范（百万分之
一）浓度限值的定义：有机溶剂残留量（CPMP/ICH/283/95＆ EMEA/CVMP/511/03）和
相关的维修指引或计算的基础上允许各自的日常接触（mg /天）中所列的指导原则。
它已同意 QWP，也没有必要进一步紧缩的批处理结果中的规范，限制的方针，根据安全
评估。
生产的医药产品 - 过程控制
1。当验证的制造过程中，如果一个共同的批量用于生产一个系列的产品，应该如何试批量
的大小决定呢？ H + V 2007 年 9 月
试批量的大小选择和证明它是申请人的责任。
人用医药产品委员会兽用指引工艺验证（CPMP/QWP/848/96，CVMP/598/99）的联合医
药产品委员会指出，“试点批量大小应符合至少 10 未来产业规模批次，即规模的倍增因子
不超过 10％。对于口服固体剂型的大小应至少有 10％或 10 万个单位，以较高者为准*除非
另有理由“。
指引并没有规定，10％的数字应始终连接到规模生产的个别产品演示。此外，它允许偏离
的指导下，这是有道理的。此外，该指引并不排除使用包围。
某些大宗产品被用来制造一系列的演讲，，例如散装粉混合可用于生产 50 毫克，100 毫克
和 200 毫克直接压片用相同的比例组成。在这种情况下，只要作为申请人链路的导频之间
的批次大小用于验证和的常规生产批次大小，可以展示出一种令人满意的，它将通常是可
以接受的定义的导频批次大小为 10％的计划生产规模为散装产品。在这个过程中的验证研
究，完整的中试规模散批应用于制造个别发言。不同的表现形式散批之间的分工也应该是
合理的。
*兽药产品的情况下，最低试点规模可能在有理据支持的情况下，小于 10 万台。
变异
由“制造的复杂的制造工艺”变化的代码 B.II.b.4（成品批次大小变化）在理解什么？ H +
V 2010 年 10 月
复杂的制造过程，旨在覆盖的实际制造的成品的情况下，涉及的处理，其中包括一个或多
个处理步骤，可能会引起规模困难。这将是一个按个别情况考虑。
在相关情况下，如果更改被提交作为一种 IB 变化，它是向申请人提供足够的理由不考虑制
造一个“复杂”的过程，在规模方面。然而，根据保障条款，应该注意的是，如果所提供
的理由不被接受，有可能升级为主管机关提交的Ⅱ型变异在验证阶段。
如果不能确定，申请人应征询有关主管机关才递交的变化。
Quality of medicines questions and answers: Part 2
Reduced testing of starting materials
1. What information should be included in marketing-authorisation dossiers regarding
the actual testing that is carried out on any starting materials, e.g. active substances,
excipients and packaging materials, on receipt by a finished product manufacturer?
H+V June 2011
Although some parameters should always be tested on receipt by the finished product
manufacturer e.g. diethylene glycol in glycerol, what is actually tested on receipt is
fully covered under good manufacturing practice and should be justified based upon
risk assessments, based on historical data backed by supplier audit. Consequently, the
relevant registered specifications in the marketing-authorisation application should
not include any reference at all to reduced testing on receipt by the finished product
manufacturer.
Definition of ‘active substance’ in relation to mixtures

1. In case more than one active substance produced at different manufacturing sites is
mixed together at a different manufacturing site, is it possible to consider the mixing
as active substance manufacture? H+V June 2011
No. The mixing of active substances that can exist and are produced on their own
should be considered as the first step of the manufacture of the finished product.
It should be noted that the definition of active substance given in part II of the
European Union (EU) good-manufacturing-practice (GMP) guide (active substances)
states that an active substance is a substance or a ‘mixture of substances’, but this
definition takes into account cases when active substances are not single chemically
defined substances (e.g. herbal extracts) and it is not meant to allow a mixture of
chemically defined active substances to be considered as a single active substance.
As a consequence of what is stated above, the mixing of active substances is subject
to compliance with part I of the EU GMP Guide (finished products) and it is not
possible to present a single active substance master file for the mixture.
Appearance of tablets of different strengths

1. If the applicant wishes to apply for more than one tablet strength, what level of
difference in the appearance between the different tablet strengths would be required?
H+V June 2011
In the case of applications for more than one tablet strength, the different tablet
strengths should be distinguishable at a level sufficient to avoid mistakes between the
different strengths by the final user. Distinguishing tablet strengths by colour / shape
and marking / embossing is preferable.
Specific types of product - Graduation of measuring
devices for liquid dosage forms
1. What are the requirements for the graduation of measuring devices for liquid
dosage forms of medicinal products for human use, in particular in relation to the
suitability of the graduation of the measuring device regarding dosing accuracy and
dosing precision of the related product and the suitability of the measuring device for
the related product? H September 2006
The points discussed below are applicable to new marketing-authorisation
applications or fully reformulated existing medicinal products. These points should be
considered referring to the graduation of a measuring device for a liquid dosage form
of a medicinal product for human use, such as solutions, suspensions and emulsions,
in section 3.2.P.2: pharmaceutical development of the Common Technical Document.
They should be part of the justification of the suitability of the graduation of the
measuring device for dosing the medicinal product under application. The measuring
device shall comply as well with the relevant parts of the requirements given in the
Medical Device Directive 93/42/EEC and with International Organization for
Standardization (ISO) standards, as applicable.
Measuring devices may be required to deliver oral, parenteral, nasal, vaginal, and
rectal liquid dosage forms to patients. The measuring device can be marketed together
with the medicinal product, e.g. syringes without needles to administer oral liquid
preparations, measuring cups, spoons or beakers, pipette applicators, or can be
incorporated as integral part of the medicinal product, e.g. pre-filled syringes.
Manner of graduation: The graduation should be applied to the measuring device in
such a manner that accurate and precise dosing is guaranteed. The graduation can be
embossed in the material. The graduation can also be printed on the material of the
measuring device.
This precision and accuracy of dosing should be guaranteed from release throughout
storage until the end of shelf life and also during the use of the particular measuring
device under the conditions recommended in the summary of product characteristics
(SmPC). Attention should be paid to the possibility of fading of the printing ink.
Glueing of a label with a printed graduation to the measuring device is not generally
favoured, because of the potential for dislocation of the glued label during storage and
use. If a glued label is used, the effectiveness of the adhesive / label system under
normal conditions of storage and use should be demonstrated.
Graduated scale: The graduated scale should correspond with the dosing advice as
stated in section 4.2: posology and method of administration of the SmPC. This
applies in principle to all measuring devices. Attention should among others be paid
to the following items:
 Possibility of the measuring device to supply the minimal and maximal dose
per single dose (nominal capacity);
 Suitability of the scale intervals in relation to the dosing advice or the dosage
range when posology is stated per kilogram bodyweight or square metre body surface;
 Ease of interpretation of the graduated scale: readability of the graduation
numbers and the graduation lines, and distinction between the intervals of the scale.
European or international standards (European Committee for Standardization or ISO)
may be available, e.g. for syringes recommendations are given on tolerances,
graduated capacity, and graduated scale in ISO standards. These recommendations
can be applied without further justification.
Suitability of measuring device for the medicinal product: The suitability of the
measuring device for the medicinal product should be addressed. Attention should be
paid to the following items:
 Dosing accuracy and precision in relation to the therapeutic window of the
drug substance;
 The risk of overdosing in relation to the measuring device. If possible,
overdosing should be prevented. If the risk of overdosing cannot be avoided,
appropriate care should be taken in the design of the scale graduation to prevent
overdosing;
 The physical characteristics of the liquid in relation to the measuring device.
The combination should assure accurate and precise dosing. Considerations can be for
instance the needle diameter and the particle size of suspensions in injectables, the
homogeneity (resuspendability) of suspensions and emulsions prior to and during the
application of the measuring device, or residual amounts of liquid in the measuring
device after administration of the dose to the patient.
Furthermore, suitability of the measuring device and its graduation for the intended
patient population should also be taken into account.
Acceptance criteria: The graduation of the measuring device should be suitable to
meet the acceptance criteria of the dose of medicinal product under application, as
measured with the measuring device under application. These acceptance criteria
should be in line with European Pharmacopoeia (Ph. Eur.) requirements, if applicable
(for example Ph. Eur. 2.9.27: uniformity of mass of delivered doses from multidose
containers), or other accepted pharmacopoeias. For single-dose containers, where not
necessarily the whole content of the product needs to be administered to the patient,
the same requirements can be applied as for multidose containers.
Specific types of product - Quality of investigational

medicinal products
1. Setting specifications for impurities (2.2.1.S.4.1, 2.2.1.S.4.5, 2.2.1.P.5.1 and
2.2.1.P.5.6): On which basis should specifications for related impurities be set? H
January 2011
Reference to relevant paragraphs of the guideline on the requirements to the chemical
and pharmaceutical quality documentation concerning investigational medicinal
products in clinical trials (CHMP/QWP/185401/2004) is given for each question.
Safety considerations should be taken into account. The limits should be supported by
the impurity profiles of batches of active substance used in non-clinical and clinical
studies. Results between batches should be consistent (or the clinical batches should
show better purity results than non-clinical and previous clinical batches).
Compliance with International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) requirements
is not required, if proper justification is provided.
Where specifications are set for potential genotoxic impurities, the guidance given in
questions and answers on the guideline on limits of genotoxic impurities
(EMEA/CHMP/SWP/431994/2007) should be taken into consideration (question 6:
staged threshold-of-toxicological-concern approach).
2. Substantial amendments (chapter 8): How should industry notify amendments?
January 2011 (corrected November 2011)
The table in the guideline on the requirements to the chemical and pharmaceutical
quality documentation concerning investigational medicinal products in clinical trials
(CHMP/QWP/185401/2004) gives examples of what should be notified as substantial
amendments and of changes where a notification will not be necessary. The list is not
exhaustive, and the sponsor should decide on a case-by-case basis if an amendment is
to be classified as substantial or not.
For non-substantial amendments documentation should not be proactively submitted,
but the relevant internal and study documentation supporting the change should be
recorded within the company and if appropriate, at the investigator site. At the time
of an overall investigational medicinal product dossier update or submission of a
substantial amendment the non-substantial changes can be incorporated into the
updated documentation. There is no need to use the notification of amendment form
for these changes.
3. Shelf-life extensions (2.2.1.P.8 and chapter 8): What information should be
included in the file in order to make shelf life extensions without notification of a
substantial amendment? H January 2009
The criteria based on which it is intended to extend shelf life during an ongoing study
should be given. The information should include extension protocol limiting the
maximum time period for extrapolation. In the case of any significant negative trend
for stability data observed during long-term and accelerated testing, the sponsor
should commit to notify any shelf-life extension as a substantial amendment.
4. Batch data (2.2.1.S.4.4 and 2.2.1.P.5.4): Are certificates of analysis needed? H
January 2009
No, tabulated batch results are sufficient. Data for representative batches should be
included in the batch analysis table of the investigational medicinal product dossier.
Results for batches controlled according to previous, wider specifications are
acceptable if the results comply with the specification for the planned clinical trial.
The results should cover the relevant strengths, but the batches do not need to be the
same that will be used in the clinical trial.
5. Drug substance and drug product batch data for proposed manufacturing sites: Are
drug substance and drug product batch data for all proposed manufacturing sites listed
in S.2.1/P.3.1 required to be submitted in the investigational medicinal product
dossier, or provided as a substantial amendment prior to use in a study? H January
2011 (corrected November 2011)
Data from representative batches should be provided. This implies that data should be
provided for each proposed site. However, where one legal entity has multiple sites
(in the same country), then batch data from one site only would be sufficient.
For non-substantial amendments documentation should not be proactively submitted,
but the relevant internal and study documentation supporting the change should be
recorded within the company and if appropriate, at the investigator site. At the time of
an overall investigational medicinal product dossier update or submission of a
substantial amendment the non-substantial changes can be incorporated into the
updated documentation. There is no need to use the notification of amendment form
for these changes.
Specific types of product - Need for in-vitro

dissolution studies with alcohol for modified-release
oral products including opioid drug products
1. What are the likely implications of the various observed in-vitro effects of alcohol
on the dissolution of different prolonged release opioid products at various
concentrations and durations of exposure? H April 2009
In the absence of clinical data, the results of in-vitro observations with alcohol
(ethanol) may be considered, as a minimum, evidence of a possible physicochemical
incompatibility with alcoholic drinks. The possibility of such an incompatibility with
alcoholic drinks should be considered for all modified release products.
The general methods of in-vitro release testing are considered capable of providing
sufficient evidence of alcohol incompatibility. In the case where in-vitro alcohol
incompatibility of the drug product is demonstrated, then appropriate warnings should
be included in the summary of product characteristics, in line with current guidelines.
2. Is it considered that in future in-vitro studies investigating the effect of alcohol /
ethanol on dissolution / release should be required for the following cases? H April
2009
The interaction with alcohol observed in vitro should be considered as a
physicochemical incompatibility of the drug product. In line with current regulatory
practice, reference to this incompatibility, albeit dietary rather than medicinal, has
been included in the product literature to supplement the current pharmacological
warning to avoid alcohol.
In-vitro studies investigating the effect of alcohol / ethanol on dissolution / release are
recommended for all opioid modified-release products where applicants consider the
potential for incompatibility with alcohol exists.
To minimise the risk, it is recommended that the product design, if possible and
practical, should be such that a physicochemical incompatibility with alcohol is
avoided. This advice is especially important for drug substances with a narrow
therapeutic index.
3. Is it considered that in-vitro studies investigating the effect of alcohol / ethanol on
dissolution / release might also be required for oral prolonged release formulations
containing active substances other than opioids? If so, should they be required only
where rapid dose dumping of the active substance might be expected to cause
clinically hazardous overdose, or should they be required for all oral prolonged-
release products containing any active substance? H April 2009
Where there are scientific grounds that the defined-release characteristics of the oral
drug may be adversely affected by the presence of alcohol, then alcohol
physicochemical incompatibility should be considered by the applicant. This would
apply to all oral prolonged (and delayed and modified) release products.
4. How might the methodological requirements for in vitro testing of the potential for
accelerated release in the presence of alcohol be established, ensuring maximum
relevance to the clinical situation? H April 2009
At this point in time, it is not possible to provide authoritative methodological
requirements.
In-vitro studies are considered sufficient to show evidence of alcohol incompatibility,
with a consequential effect on the quality of the drug product, with respect to release
performance.
It is noted that in-vitro release testing primarily relates to the quality control of drug
products, with limits set to be in line with those batches used for clinical studies for
which satisfactory safety and efficacy has been established.
Taking this into account, if the presence of alcohol in the dissolution medium of the
in-vitro release test produces out of specification results, then this may be considered
sufficient evidence of an incompatibility with alcohol i.e. that alcohol adversely
affects the quality of the drug product.
In the first instance, the applicant should consider the possibility of physicochemical
incompatibility with alcohol. This should include a discussion of the solubility of the
release controlling excipients in alcohol and the impact this may have on the in-vitro
release performance of the drug product. Where solubility or other information cannot
exclude the possibility of physicochemical incompatibility with alcohol, then in-vitro
release data should also be provided to assess the extent of interaction.
The dissolution medium should be the same as that proposed for routine testing, but
with a justified range of alcohol added. The range of alcohol in the medium should
mimic levels that are likely to be reached in the fluid of the stomach and proximal
gastrointestinal tract following alcohol consumption e.g. 5%, 10% and 20%.
The applicant should discuss the significance of any out of specification results,
particularly at the early time points, together with consideration of the risks of dose
dumping and accelerated release. Appropriate warnings in the summary of product
characteristics should be proposed and justified.
5. Are further measures needed to gain better understanding of the release
characteristics of oral prolonged release products in the presence of alcohol and their
relevance to the clinical situation, for example by in vitro – in vivo correlation? If in-
vitro testing demonstrates a potential for alcohol to enhance opioid / active product
release, should the applicant be required to investigate the clinical relevance of the
effect in in-vivo studies? H April 2009
It should be acknowledged that the clinical relevance of physicochemical
incompatibility with co-administered alcohol is debatable, at the present time. The
published literature is limited.
Where incompatibility with alcohol is evident, it is currently sufficient to address
safety or other concerns by the inclusion of appropriate warnings in the product
literature unless serious concerns are raised with respect to efficacy and safety.
Specific types of product - Veterinary medicinal

products
1. What limits for microbiological quality are considered appropriate for premixes for
medicated feeding stuffs which contain excipients of natural origin (e.g. soya bean
husks, maize meal, etc)? V October 2010
Ideally, compendial grade excipients should be used in new veterinary medicinal
products and in these cases compliance with the general chapter 5.1.4:
microbiological quality of non-sterile pharmaceutical preparations and substances for
pharmaceutical use is considered appropriate. For premixes for medicated feeding
stuffs for veterinary use containing excipients of natural origin, application of these
limits may not be possible. European Pharmacopoeia (Ph. Eur.) 5.1.4: microbiological
quality of non-sterile pharmaceutical preparations and substances for pharmaceutical
use is a general chapter and is not specifically referenced in the Ph. Eur. monograph
for premixes for medicated feedingstuffs and is therefore not mandatory. The general
chapter has essentially the same status as a guideline, that is, it represents the
preferred option but it should be possible to accept deviation from it where
justified. In case of premixes containing excipients of natural origin, the Agency
would recommend following criteria as requested under special Ph. Eur. provision for
oral dosage forms containing raw materials of natural origin. In exceptional cases, if
this cannot be fulfilled, the applicant could apply other limits, e.g. the limits detailed
in section C of 5.1.8: microbiological quality of herbal medicinal products for oral
use, but only if fully justified.
In cases where an oral powder and a premix for medicated feedingstuffs have the
identical composition, it would be expected that the same microbiological limits
would be applied to both pharmaceutical forms. In this case the stricter limits are
applicable (normally those for oral powders requested in chapter 5.1.4: non-aqueous
preparations for oral use).
2. Is it possible to grant a marketing authorisation for a product which is not soluble
over the pH ranges described in the guideline on quality aspects of pharmaceutical
veterinary medicines for administration via drinking water (EMEA/CVMP/540/03-
Rev.)? Could a recommendation be added in the summary of product characteristics /
product information that, for solubility reasons, the pH of the drinking water has to be
adjusted with acid / base before adding the medicinal product? V October 2010
The guideline on quality aspects of pharmaceutical veterinary medicines for
administration via drinking water (EMEA/CVMP/540/03-Rev.1) sets out how the
solubility of a product in drinking water should be tested (soft water / low pH with a
pH range from 5.0 to 7.0 and hard water / high pH with a pH range from 8.0 to 9.0).
In principle, a veterinary medicinal product can only be authorised if it fully dissolves
(and remains in solution) without further aid in drinking water of the usual pH range
(which is usually a pH range between 5.0 and 9.0). If a pH adjustment of the drinking
water is necessary this should be done with excipients (acid, base or buffer) included
as part of the authorised veterinary medicinal product. Exclusions are only acceptable
if justified (e.g. it has been shown that other formulation principles have been
excluded).
The use of unlicensed acids or alkalis for the pH adjustment of the drinking water
before (or after) adding the veterinary medicinal product in order to achieve the
necessary solubility is not acceptable unless justified.
3. Is it permitted to have a multidose (parenteral) veterinary medicinal product for use
both as an intramuscular injection and also an intramammary preparation? V October
2010
Such an example would be considered to be two different pharmaceutical forms (and
also in this specific problem case, routes of administration) and therefore to need two
different marketing authorisation (sub)numbers, as well as two different summaries of
product characteristics.
In the European Union, different marketing authorisations (sub)numbers are necessary
for different pharmaceutical forms. See the guideline on the categorisation of new
applications versus variation applications.
Another reason is that using multidose containers for both intramammary and
parenteral use may result in an increased risk of microbial contamination of the
product in its multidose container.
4. Rubber stoppers (bungs) used for vial closures for multidose veterinary injectables
are often punctured many times during use. Therefore suitable criteria regarding
fragmentation (and self-sealing) are required. Problems can mainly arise in large
multidose injectables which can be used for different target species and / or ages of
animals, but particularly for smaller animals where dose volumes are small, and so the
pack could be punctured many times (e.g. in extreme cases in excess of 100
punctures). Should the general chapter on rubber closures for containers for aqueous
parenteral preparations, for powders and for freeze-dried powders (3.2.9) be applied
in these cases? Which criteria for the maximum number of rubber fragments are
deemed acceptable for a test design which is a multiple of the number of punctures
described by Ph. Eur. 3.2.9? Should a worst-case scenario be used? V October 2010
The general chapter on rubber closures for containers for aqueous parenteral
preparations, for powders and for freeze-dried powders (3.2.9) is not mandatory on its
own. If suitable justification is provided, the requirement (maximum of 5 fragments)
contained in this chapter does not necessarily need to be applied. It is noteworthy that
the European Pharmacopoeia (Ph. Eur.) test is designed to demonstrate that a stopper
fulfills the general minimum requirements that are expected for rubber stoppers for
medicinal products, but this can of course not cover all their potential uses.
The pack concerned should be proven to meet the requirements of the Ph. Eur. test
modified to use the maximum number of punctures expected in relation to the target
species, dose and route of administration (using the appropriate needle size for that
scenario). Note that the maximum number of fragments expected remains exactly as
in the Ph. Eur. test.
The summary of product characteristics (SmPC) and other product information should
then reflect the number of punctures for which the closure has been demonstrated to
meet the requirements of the Ph. Eur. test. For example, if the closure has been shown
capable of withstanding X punctures with fragmentation and self-sealing
characteristics which meet the relevant Ph. Eur. requirements. That is, with no
additional increase in fragments for the increased number of punctures.
Risk management tools
Some examples of advice (if necessary in combination) which could be included in
the SmPC (section 4.9) and other product literature to reduce potential damage to the
stopper from excessive numbers of punctures:
 “The cap may be safely punctured up to X times.”
 “When treating groups of animals in one run, use a draw-off needle that has
been placed in the vial stopper to avoid excess broaching of the stopper. The draw-off
needle should be removed after treatment.”
 “Only the xx ml vial should be used to treat small piglets.”
 “As the vial should not be broached more than X times the user should select
the most appropriate vial size according to the target species to be treated.”
 “When treating large groups of animals use only an automatic dosing device
(with vented draw off apparatus when using the xx ml vial).”
 “For xxx pack sizes, use only automatic syringe equipment.” (Applicable for
large collapsible packs where a large number of doses may be withdrawn from the
vial and concern about the stopper integrity exist.)
 “For xxx pack sizes, use of a multiple dose syringe is
recommended.” (Applicable for large non-collapsible packs where a large number of
doses may be withdrawn from the vial and concern about the stopper integrity exist.)
Storage
1. What are the requirements for storage orientation recommendations in the product
information for pressurised metered dose inhalers? H December 2008
During product development, the effect of orientation should be investigated in the
priming and re-priming studies according to the guideline on the pharmaceutical
quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005). If storage
orientation has a significant effect on the delivered dose during these studies (i.e.
different repriming periods / number of actuations are required for re-priming when
stored in different orientations) a storage orientation recommendation should be added
to the product information (summary of product characteristics, package leaflet and
label). The preferred storage orientation should be detailed. As it cannot be
guaranteed that the product will always be stored in the preferred orientation, the re-
priming instructions in the product information should be based on the worst-case
scenario (i.e. the orientation which requires the shortest re-priming period and / or the
highest number of re-priming actuations).
Packaging
1. No specific requirements or recommendations are provided in the European Union
guideline on plastic immediate packaging materials, CPMP/QWP/4359/03 &
EMEA/CVMP/205/04, in regard to acceptable quality standards for plastic materials
to be used for containers for solid oral dosage forms and solid active substances.
Should the materials always comply with the specifications in the European
Pharmacopoiea and if not, which quality standards are considered to be acceptable?
H+V January 2009
The chapters of the European Pharmacopoeia (Ph. Eur.) that describe materials and
containers are not exhaustive with regard to all different types of plastic materials and
additives. Reference to the specifications published in the Ph. Eur. is therefore not
always possible. As outlined in the Ph. Eur. general notices 1.3, it is not obligatory
that only materials complying with a given specification in a chapter of the Ph. Eur.
can be used as immediate packaging materials. Materials with a different formulation,
complying with a different specification may be used, if justified, and subject to
agreement by the competent authority. For solid oral dosage forms and solid active
substances, it has been agreed by the Joint Committee for Medicinal Products for
Human Use / Committee for Medicinal Products for Veterinary Use Quality Working
Party that plastic materials compliant with the relevant European Union (EU) food
legislation relating to plastic materials and articles intended to come into contact with
foodstuffs are considered acceptable. A specification elaborated in accordance with
the provisions described in the EU guideline on plastic immediate packaging
materials (CPMP/QWP/4359/03) should be laid down.
2. Does the European Medicines Agency / Committee for Medicinal Products for
Veterinary Use guideline on development pharmaceutics for veterinary medicinal
products and its annex decision trees for the selection of sterilisation methods prevent
the use of heat-labile plastic packaging materials and aseptic processing for sterile
veterinary medicinal products? V February 2012
Ensuring the sterility of medicinal products is the main issue when considering the
packaging for sterile products, and therefore the method of choice for the production
of any sterile products should be terminal sterilisation.
The European Medicines Agency / Committee for Medicinal Products for Veterinary
Use guideline on development pharmaceutics for veterinary medicinal products and
its annex decision trees for the selection of sterilisation methods currently state in the
introduction to the annex that, “the use of an inappropriate heat-labile packaging
material cannot in itself be the sole reason for adoption of aseptic processing.
Manufacturers should choose the best sterilisation method achievable for a given
formulation and select the packaging material for the product accordingly. However,
it may be that the choice of a packaging material for a given product has to take into
account factors other than the method of sterilisation. In such cases these other factors
need to be clearly documented, explained and scientifically justified in the marketing
authorisation dossier.”
Aseptic processing cannot be considered as a simple replacement for terminal
sterilisation. The European Pharmacopoeia (Ph. Eur.) general text 5.1.1: methods of
preparation of sterile products states that, “wherever possible, a process in which the
product is sterilised in its final container (terminal sterilisation) is chosen,” and that,
“if terminal sterilisation is not possible, filtration through a bacteria-retentive filter or
aseptic processing is used; wherever possible, appropriate additional treatment of the
product (for example, heating of the product) in its final container is applied.” Such a
combination of aseptic processing with non-standard lower temperature heat
treatments, either before aseptic filling, or after aseptic filling, should be pursued
where possible in line with the recommendations of the Ph. Eur.
The guideline therefore does not prevent the use of heat-labile packaging materials for
sterile products, but there must be justified reasons for having such packaging for
sterile products, and these must be supported by the overall benefit:risk balance of the
product.
Stability - Stability issues of pharmaceutical bulk

products use in manufacture of the finished product
Background
Finished product stability guidance does not address storage of bulk product during
the manufacturing process. The purpose of these questions and answers is to address
the information to be provided in the marketing-authorisation dossier to support
storage and / or transportation of bulk product during the manufacturing process.
Good-manufacturing-practice guidance indicates that bulk products should be stored
under ‘appropriate conditions’ and therefore, the data provided in the dossier should
be aimed to demonstrate the suitability of these conditions in relation to the intended
storage and / or transportation arrangements of a bulk product and the effect of these
on the quality of the given finished product over its declared shelf-life.
The objective is to increase the transparency of the supporting data required and not to
introduce any new regulatory requirements.
The data required will depend on the type of product and the activities performed (i.e.
prolonged storage and / or transportation) and a risk-based approach is encouraged in
order to demonstrate the suitability of the data generated in each individual case.
The described framework is intended to cover all pharmaceutical bulk products.
However, it is understood that the requirements for some specific types of products
(e.g. biological products) may require additional data relevant to the type of product
and this should be taken into consideration depending on the characteristics of that
particular product.
1. What is the definition of bulk storage? H+V February 2012
The question most frequently arises in relation to solid oral dosage forms (particularly
tablet cores before coating and / or packaging) but could be applicable at any stage in
the manufacturing process of any pharmaceutical product where bulk is held in
storage prior to further processing (e.g. bulk solution prior to filling, granulates, etc.).
2. What information should be provided on the bulk container? H+V February 2012
In general, the level of information to be provided will be dependent on the nature of
the bulk product. The qualitative and quantitative (if required) composition of the
bulk container should be described in the dossier and its control specification stated
(module 3.2.P.3.4 or part 2.B).
3. What information should be provided on the storage conditions? H+V February
2012
It should be stated whether the bulk product is to be stored (and if relevant,
transported) under controlled or non-controlled storage conditions.
4. What information is necessary regarding the transportation of bulk products
between manufacturing sites? H+V Feb 2012
Where bulk product is transported between manufacturing sites, the transportation
arrangements should be described in general terms (bulk container / storage and
transportation conditions / monitoring arrangements) in the dossier (module 3.2.P.3.4
or part 2.B).
According to the guideline on good distribution practice, the following should be
taken into consideration:
Principle:
 Good manufacturing practice quality should be maintained throughout the
distribution network;
 Storage conditions should be observed at all times, including during
transportation.
Storage:
 Temperature should be monitored and recorded periodically;
 Records should be reviewed regularly.
5. What data should be provided to support bulk storage and transportation
arrangements? H+V February 2012
The maximum storage interval for the bulk product should be declared in the
marketing authorisation dossier, or alternatively, the maximum batch manufacturing
time from start of product manufacture to completion of packaging in the final
primary container for marketing.
When storage is prolonged (i.e. more than 30 days for solid oral dosage forms; more
than 24 hours for sterile products), evidence of the suitability of the proposed
container, storage interval and / or transportation arrangements should be included in
the dossier. The data to be provided will be dependent on results of development
studies that represent the conditions proposed.
In line with the principles described for finished products in the relevant International
Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH)or International Cooperation on Harmonisation
of Technical Requirements for Registration of Veterinary Products (VICH)
guidelines, it is expected that data from pilot scale batches (minimum of 2 batches)
stored under conditions that represent the storage conditions for the bulk product will
be provided to support the storage of bulk products. Unless provided in the dossier,
these data should be verified in post-approval stability commitments on commercial
scale batches.
Where transportation of bulk between manufacturing sites is proposed, the impact of
excursions outside of the original storage conditions should be discussed and, where
necessary, supported by accelerated stability data.
6. How should the calculation of a product’s shelf-life be performed? H+V February
2012
Calculation of the product’s shelf-life should be in accordance with the Committee for
Medicinal Products for Human Use / Committee for Medicinal Products for
Veterinary Use note for guidance on the start of shelf-life of the finished dosage form
(CPMP/QWP/072/96 / EMEA/CVMP/453/01). If other methods are proposed, these
should be declared and justified through inclusion of batches that represent the full
proposed holding intervals of the bulk product (intermediate) in the finished product
stability programme.
7. Which stability conditions should be chosen to support bulk storage? H+V Feb
2012
It is not necessary to conduct stability studies on bulk according to International
Pharmaceuticals for Human Use (ICH) or International Cooperation on
Harmonisation of Technical Requirements for Registration of Veterinary Products
(VICH) recommendations (temperature or humidity). Stability studies on bulk should
reflect real storage conditions in the standard container foreseen at the manufacturing
site.
In the event that more than one manufacturing site is involved, the stability studies
should also cover any transportation (duration and conditions).
Stability - Declaration of storage conditions

1. What is the declaration of storage conditions to be used in the product information,
for products which require to be stored and transported refrigerated? H+V August
2007
As foreseen by the note for guidance on declaration of storage conditions, when a
product needs to be stored refrigerated, the wording “store in a refrigerator” should be
used in the labelling, and a reference to the temperature range, e.g. 2°C to 8°C, should
be included in the summary of product characteristics (SmPC) and in the package
leaflet.
According to the same note for guidance, when the need for refrigerated transport
(cool chain), in addition to refrigerated storage, is envisaged, the following statement
should be used: “store and transport refrigerated”.
2. How should expiry dates be calculated and expressed? H+V July 2008
Guidance can be found in the note for guidance on the start of shelf-life of the
finished product (CPMP/QWP/072/96 / EMEA/CVMP/453/01) and the Committees
for Mutual Recognition and Decentralised Procedures and Quality Review of
Documents product information templates. In summary, the expiry date should be
calculated from the date of release or in case the period between the date of
production and the date of release exceeds 30 days, from the date of production. The
expiry date should be expressed as MM/YYYY. The product expires at the end of the
specified month.
In the worst case, this method of calculation results in an extension of the expiry date
of two months. See table 1.
Table 1: Example of the calculation of the expiry date of a tablet with a shelf-life of
24 months
Date ofDate ofDate ofExpiry InterpretationTotal timeRecalculated
first packaging release date fit for use from start ofexpiry date
blending manufacture
step to end of
shelf-life
28/01/200529/01/2005 30/01/200501/2007until 312 years 301/2007
January 2007 days
03/01/200504/01/2005 05/01/200501/2007until 312 years 2812/2006
January 2007 days
03/01/200519/07/2005*21/07/200501/2007until 312 years 2812/20061
January 2007 days
03/01/200504/01/2005 01/02/200502/2007until 282 years 5601/20071
February 2007 days
* The bulk compressed tablets have been stored for 6 months. It is expected that a
shelf-life for the intermediate product is detailed in the dossier and stability data to
support this are also presented in the dossier.
Particularly for products with a shelf-life of less than twelve months, this is not
considered acceptable. The expiry date should therefore be calculated on a
DD/MM/YYYY basis starting from the date of release, or if applicable from the date
of production, and rounded up or down to MM/YYYY according to the following
example: 14/01/2007 becomes 12/2006 and 15/01/2007 becomes 01/2007. See table 1
for recalculated expiry dates.
1
Note: This question and answer was first published in July 2008 with a mistake (the
recalculated date for examples 3 and 4 were mixed-up). Later the mistake was
identified by QWP and in March 2009 the present corrected version was published.
Stability - Article 58 products

1. What kind of stability data are required for applications according to Article 58 of
Regulation EC/726/2004? H July 2006
Article 58 of Regulation (EC) 726/2004 widens the scope of the European Medicines
Agency and the Committee for Medicinal Products for Human Use to include
applications for certain medicinal products intended exclusively for markets outside
the Community, e.g. for antiretroviral therapy:
“1. The Agency may give a scientific opinion, in the context of cooperation with the
World Health Organization, for the evaluation of certain medicinal products for
human use intended exclusively for markets outside the Community. For this purpose,
an application shall be submitted to the Agency in accordance with the provisions of
Article 65. The Committee for Medicinal Products for Human Use may, after
consulting the World Health Organization, draw up a scientific opinion in accordance
with Articles 6 to 9. The provisions of Article 10 shall not apply.”
For these applications, it is of great importance to apply standards that ensure the
same adequate product quality as for products to be marketed in the European Union
(EU). In this context, stability data need to be submitted by the applicant that
demonstrate stability of the medicinal product throughout its intended shelf-life under
the climatic conditions prevalent in the target countries, i.e. countries in climatic
zones III and IV. Merely applying the same requirements as for the use in the EU, i.e.
countries in climatic zone I / II, could potentially lead to substandard products when
marketed in climatic zones III and IV. The guideline stability data package for
registration in climatic zones III and IV (ICH Q1 F) was officially withdrawn by the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) steering committee in June
2006 due to controversial discussions about the adequacy of storage conditions
defined. The World Health Organization (WHO) expert committee on specifications
for pharmaceutical preparations has decided to split climatic zone IV into zone IVa
(hot and humid) with storage conditions of 30°C/65% relative humidity (RH) and
zone IVb (hot and extremely humid) with storage conditions of 30°C/75% RH; the
WHO stability guideline will be revised accordingly.
When evaluating applications under Article 58 of Regulation EC/726/2004, it has to
be assumed that the respective medicinal product will be used in all sub-zones of
climatic zones III and IV, unless otherwise confirmed by the applicant. Therefore, in
order to safeguard product quality throughout its entire intended shelf-life, stability
studies under the conditions defined for climatic zones IVb need to be performed, i.e.
the shelf-life needs to be established based on long-term data at 30°C/75 % RH,
supported by 6 months of data at 40°C/75 % RH. The principles of extrapolation
described in the note for guidance on evaluation of stability data (CPMP/ICH/420/02)
as well as reduced testing designs as described in the note for guidance on bracketing
and matrixing designs for stability testing of drug substances and drug products
(CPMP/ICH/4104/00) may be applied. In cases where these data demonstrate stability
over the required period of time, no special storage conditions need to be labelled.
If an application under Article 58 of Regulation EC/726/2004 only contains data
adequate for climatic zones I / II, the list of questions should request the respective
data appropriate for climatic zones III and IV. If the data show stability problems at
30°C/75% RH with regard to humidity, the circulation and use of the product should
preferably be restricted to those countries and regions that are covered by data, e.g.
the product should only be used in countries within climatic zones III and IVa. As an
alternative, storage conditions need to be labelled, including humidity, e.g. “keep
protected from ambient humidity” as especially for climatic zone IVb humidity may
be the stability limiting factor.
However, it has to be noted that due to the technical equipment and logistics available
in some of the climatic zone IV countries as well as the education and compliance of
patients in the respective area, exposure of the medicinal products to higher
temperatures and humidity cannot be ruled out. This needs to be taken into account
when defining shelf-life and storage conditions. For products to be stored at “normal
conditions”, i.e. stable at 30°C, submission of accelerated data, i.e. 40°C/75% RH,
can not be waived as they are needed to assess the impact of extreme temperature /
humidity conditions that may occur in climatic zone IV, even though a product may
not be stable for 6 months at these storage conditions.
Please note that for aqueous products in semi-permeable containers to be marketed in
climatic zone III, i.e. regions of extreme temperature, long-term testing should be
performed at 30°C/35% RH. As an alternative, the calculation factors described in
section 2.2.7.3 “Drug products packaged in semi-permeable containers” of the note
for guidance on stability testing of new drug substances and products
(CPMP/ICH/2736/99) may be applied.
Stability - Reduced design in stability studies

1. Can reduced designs be used when performing stability studies on veterinary
medicinal products? V October 2006
Yes, as long as the selected design is explained and justified. The International
Pharmaceuticals for Human Use (ICH) guideline bracketing and matrixing designs for
stability testing of drug substances and drug products (CPMP/ICH/4104/00), is
applicable to new drug substances and products used in human medicine. However,
veterinary companies may elect to follow this guideline. Where the guideline is
followed, all aspects of the guideline should be followed.
Stability - Endotoxin testing and sterility testing at

the end of shelf-life
1. Is endotoxin testing considered essential at the end of shelf life to confirm
parenterals to be pyrogen-free?
Endotoxin testing is not requested at the end of shelf life, taking into account the fact
that it is not considered a stability-indicating parameter. The shelf-life specification
should be completed with a footnote stating that endotoxins are not tested during
stability studies.
2. Is sterility testing considered essential at the end of shelf life to confirm parenterals
to be sterile? H+V May 2009
Sterility is part of the shelf-life specification.
Sterility testing should be performed at least at the end of shelf life but it can be
replaced by testing of the container closure integrity. Depending on the nature of the
container, intermittent integrity testing might be envisaged, independent of whether
the sterility testing is replaced or not.
Water
1. What is the regulatory consequence of implementing an alternative method for
rapid control of microbiological quality of water for injection and purified water?
H+V July 2005
According to European Union legislation, pharmaceutical manufacturers are required
to use European Pharmacopoeial standard water in the manufacture of medicinal
products.
The European Pharmacopoeia (Ph. Eur.) has recently introduced a chapter making
reference to the acceptability of rapid microbial methods to replace the standard
Pharmacopoeial methods provided appropriate validation has been performed.
Following discussions at the QWP and the ad-hoc good-manufacturing-practice
inspectors' group, it is suggested that the introduction of such methods might require
specific review to ensure that the appropriate validation steps have been followed and
that the water continues to meet the Ph. Eur. specifications. Since, in the case of
water, the validation will not be product specific, it is suggested that a company could
request the supervisory authority to carry out a specific site inspection. The
performance of such an inspection would be at the discretion of the supervisory
authority and could involve a pharmaceutical assessor where necessary.
Since it is expected that the water will continue to meet Ph. Eur. specifications, if
tested, no change to dossier requirements* (variations) would be involved and
therefore no regulatory impact on individual products would normally be anticipated.
* This will depend on the level of detail in the original dossiers concerned.
2. Is sterility testing considered essential at the end of shelf life to confirm parenterals
to be sterile? H+V May 2009
Sterility is part of the shelf-life specification.
Sterility testing should be performed at least at the end of shelf life but it can be
replaced by testing of the container closure integrity. Depending on the nature of the
container, intermittent integrity testing might be envisaged, independent of whether
the sterility testing is replaced or not.
Specific type of products – Dry product inhalers

1. Should dropping of an inhalation device be investigated during development? H
June 2012
Dropping of the device should be investigated as part of the robustness study defined
in the guideline on the pharmaceutical quality of inhalation and nasal products
(section 4.2.18).
The product performance should be investigated under conditions to simulate use by
patients.
The delivery device should be carried between use and actuated at the frequency
indicated in the instructions for use. Simulation of dropping the delivery device and
the robustness of any lockout mechanism should be investigated. The dropping
simulation should be performed towards the end of the life of the product (e.g. at dose
180 for a 200-dose product) in order to assess the effect of drug accumulated on the
mouthpiece, or any other part of the device, during the lifetime of the device being
dislodged. If the device is designed to have the mouthpiece removed for periodical
cleaning, testing should be performed both with the mouthpiece removed and cleaned
in accordance with instructions for use during the test, and, as a worst case, without
removal and cleaning. Significant variations in the delivered dose and/or fine particle
mass should be fully discussed in terms of the safety and efficacy of the product.
Appropriate handling instructions to the patients should be established, based on the
results obtained.
药品质量的问题和答案：第 2 部分
减少测试的起始原料
1。什么样的信息应该包括在营销许可文件进行实际的测试在任何材料，例如：活性物质，
赋形剂和包装材料，在收到由成品制造者？ H + V 2011 年 6 月
虽然一些参数应始终在收到成品制造商，例如测试甘油二甘醇，实际上是在收到测试完全
覆盖良好生产规范下，应根据风险评估，根据历史数据支持的供应商审核是合理的。因此
有关登记规范的营销授权申请应在收到成品制造商减少测试不包括任何参考。
活性物质的混合物的定义
1。如有多于一间在不同的生产基地生产的活性物质混合在一起的不同的生产地点，是可以
考虑作为活性物质的混合制造的吗？ H + V 2011 年 6 月
号的混合活性物质，可以存在的，并应被视为产生自己的第一步骤的制造成品。
应该指出的是，定义在第二部分中的欧洲联盟（EU）良好制造规范（GMP）指南（活性
物质）状态的活性物质的活性物质是一种物质或物质的混合物，但这个定义时，需要考虑
到例活性物质不是单一的化学上确定的物质（例如，草药提取物），它并不意味着允许被
视为一个单一的活性物质的化学上确定的活性物质的混合物。
由于上述的结果，活性物质的混合须符合第一部分欧盟 GMP 指南（成品），并提供一个
单一的活性物质主文件的混合物，它是不可能的。
片剂外观的不同优势
1。如果申请人希望申请一个以上的片剂强度，将需要什么水平的差异之间的不同平板电脑
的优势在外观吗？ H + V 2011 年 6 月
申请一个以上的片剂强度的情况下，应有所区别不同的平板电脑的优势在足够的水平，最
终用户之间的不同优势，以避免错误。颜色/形状区分平板电脑的优势和标记/压花是可取的。
特定类型的产品 - 毕业液体剂型的测量设备
1。液体剂型的药用产品供人类使用的测量装置，用于为毕业有什么要求，特别是在有关的
适宜的测量装置的毕业关于计量精度和计量精度相关的产品的适宜性测量装置相关的产品
吗？ Ĥ2006 年 9 月
下面的讨论是适用于新的营销授权申请或完全改写现有的医药产品。这些点，应考虑参照
供人类使用，如溶液，悬浮液和乳液的液体剂型的医药产品中的测量装置的毕业，在第
3.2.P.2：医药发展的通用技术文件。他们应该毕业的适宜剂量的药用产品应用的测量设备
的一部分的理由。测量装置应符合以及在医疗器械指令 93/42/EEC 的要求，并与国际组织
标准化组织（ISO）标准，适用的相关部分。
测量装置，可能需要提供给患者口服，肠胃外，鼻腔，阴道和直肠的液体剂型。测量装置
可以在市场上销售一起的药用产品，如服用口服的液体制剂，测量杯，勺或烧杯，吸管施
加器，或无针注射器的药用产品的不可分割的一部分，例如，可以掺入预充式注射器。
毕业：毕业方式应施加到测量装置，以这样的方式，保证准确和精确的剂量。在材料中的
毕业可压花。毕业也可以被印刷在材料上的测量装置。
这在投药后的精度和准确度应保证在整个存储从释放直到保质期结束，并在摘要中的产品
特性（的 SmPC）建议的条件下，在使用过程中的特定的测量装置。要注意的印刷油墨褪
色的可能性。胶粘标签印刷毕业测量装置还没有普遍青睐，因为在储存和使用过程中的位
错的胶粘标签的潜力。如果粘标签被使用时，在正常的储存和使用条件下的粘接剂/标签系
统的有效性应当证明。
刻度尺：在毕业的规模应与第 4.2 节中的剂量建议：剂量以及辅助医疗业管理局的管理方
法。这在原则上适用于所有的测量设备。在其他应注意以下项目：
•测量装置的可能性，以提供每单次剂量（标称容量）的最小和最大的剂量;
•适合定量给料的建议或用法用量说明时，每公斤体重平方米体表的剂量范围内的规模间隔;
•易于解释的刻度：毕业和毕业线的可读性，并区分之间的时间间隔的规模。
欧洲或国际标准（欧洲标准化委员会或 ISO）是可用的，例如：注射器建议公差，毕业于
能力，并毕业规模在 ISO 标准。这些建议可以应用于没有进一步说明理由。
适宜的药用产品的测量装置，用于：测量装置的适宜的药用产品的应予以解决。应注意以
下事项：
•计量准确度和精确度有关的药物物质的治疗时间窗;
•，就测量装置中过量的风险。如果可能的话，应防止过量。如果无法避免过量的风险，应采
取适当的照顾，在毕业的规模，以防止过量的设计;
•有关的测量的移动设备中的液体的物理特性。组合应保证准确和精确计量。可以考虑例如针
直径和粒子尺寸，在注射剂的悬浮液，悬浮液和乳液的均一性（resuspendability）和在应
用程序中的测量装置的测量装置，或液体的残留量给药后的前剂量给病人。
此外，适宜的测量装置和其预期的患者人群的毕业也应该被考虑。
验收标准：测量装置的毕业应该是合适的应用程序，以满足下剂量的药用产品的验收标准
测量与测量装置所申请。这些验收标准应符合欧洲药典（欧洲药典）的要求，如果适用
（例如欧洲药典 27 年 9 月 2 日剂量容器的质量交付的剂量均匀性），或其他公认的药典。
对于单剂量容器中，其中不一定的产品的全部内容，需要给患者服用，相同的要求，可应
用于为剂量容器。
特定类型的产品 - 研究用药品的质量
1。设置的杂质（2.2.1.S.4.1，2.2.1.S.4.5，2.2.1.P.5.1 和 2.2.1.P.5.6）：在其中的基础上，
应设置相关杂质的规格吗？ Ĥ2011 年 1 月
关于研究用药品的临床试验的化学品和药品质量文件的要求的指引参考有关段落
（CHMP/QWP/185401/2004）每题所给的。
应考虑安全方面的考虑。应支持非临床和临床研究中使用的活性物质批次的杂质分布的限
制。批与批之间的结果应该是一致的（或临床批次的纯度应该有更好的结果比非临床和以
前的临床批次）。
不是必需的，如果有适当的理由是符合人用（ICH）的要求的药品注册技术要求协调国际
会议。
规格设置应考虑潜在的基因毒性杂质，给出的问题和答案上的基因毒性的杂质
（EMEA/CHMP/SWP/431994/2007）的限制的方针的指导（第 6 题：上演的毒理学阈值
经营方式）。
2。主要的修改单（第 8 章）：行业应如何通知修订？ 2011 年 1 月（校正后的 2011 年 11
月）
指引的要求，化学品和药品的质量文件，关于研究用药品的临床试验中的表
（CHMP/QWP/185401/2004）给出的例子应该是什么通知大幅修订和更改通知将不必要
的。这份名单是并不详尽，如果修正案是被归类为主要或保荐人应在逐案基础决定。
对于非实质性的修改文件不应该主动提交，但相关的内部和研究的文件的变化应记录在公
司内部，如果合适的话，在研究者的网站。在一个整体的研究药用产品资料更新或提交的
大幅修改的时候，非实质性的变化可以被纳入更新的文档。有没有必要使用这些变化的修
正形式通知。
3。保质期的扩展（2.2.1.P.8 和第 8 章）：什么样的信息应该包含在该文件中，为了使保质
期扩展了大幅修改，恕不另行通知？ Ĥ2009 年 1 月
标准，在此基础上，在正在进行的研究，它的目的是延长保质期。信息应包括扩展协议限
制的最大时间周期外推。在稳定性方面的长期和加速试验过程中观察到的数据进行任何显
着的负增长趋势的情况下，保荐人应承诺通知任何大幅修正的保质期延长。
4。批量数据（2.2.1.S.4.4 和 2.2.1.P.5.4）：证书所需的分析吗？ Ĥ2009 年 1 月
没有，汇总批处理结果就足够了。代表批次的数据应包括在批次分析的研究药用产品资料
表。根据以前的，更广泛的规格批次控制的结果是可以接受的，如果结果符合规范的临床
试验计划。结果应涵盖有关的长处，但不需要是相同的，将被用在临床试验的批次。
5。原料药和制剂产品的批次数据，建议生产基地：原料药和制剂产品的批量数据对所有建
议的生产基地需要在 S.2.1/P.3.1 所列的须提交研究用药品的产品资料，或提供的大量修正
在使用之前，一项研究吗？ Ĥ2011（校正后的 2011 年 11 月）
代表性的批次应提供的数据。这意味着，每个建议网站应提供的数据。但是，如果一个法律
实体有多个站点（在同一个国家），然后批量数据从一个网站只将足够了。
对于非实质性的修改文件不应该主动提交，但相关的内部和研究的文件的变化应记录在公
司内部，如果合适的话，在研究者的网站。在一个整体的研究药用产品资料更新或提交的
大幅修改的时候，非实质性的变化可以被纳入更新的文档。有没有必要使用这些变化的修
正形式通知。
特定类型的产品 - 修饰释放的阿片类药物产品的口服产品，包括在与醇的体外溶解研究极
品
1。在体外观察酒精对解散不同的缓释阿片类药物的产品暴露在不同浓度和持续时间的各种
可能造成的影响是什么？ Ĥ2009 年 4 月
在临床数据的情况下，用酒精（乙醇）在体外观察的结果可以认为，作为最低限度，与酒
精饮料的一个可能的物理化学不相容性的证据。这样的酒精饮料不兼容的可能性，应考虑
所有修改过的版本。
在体外释放测试的一般方法，被认为是能够提供足够的证据证明酒精不兼容。在证明在体
外醇的药物产品不兼容的情况下，适当的警告应包含在产品特性概要，在目前的指导方针。
2。是它认为，在未来的体外研究调查的影响，酒精/乙醇溶出度/释放应在以下情况下需要？
Ĥ2009 年 4 月
应被视为在体外观察到的相互作用与酒精的药物产品的物理化学不相容。在目前的监管实
践中，引用这个不兼容问题，尽管饮食，而不是药材，已被列入产品资料中，以补充药理
警告，避免饮酒。
在体外溶出度/释放的影响，酒精/乙醇研究，建议所有阿片类药物的修饰释放申请人认为产
品存在潜在的不符合酒精。
的风险降到最低，建议，该产品的设计，如果可能的和实际的，应该是这样的，避免与醇
的物理化学不相容。这个建议是特别重要的一个狭窄的治疗指数的药物。
3。是它认为，可能还需要口服含有活性物质以外的其他阿片类药物的缓释制剂的体外研究
调查的影响，酒精/乙醇溶出度/释放？如果是这样的话，他们只需要快速剂量倾卸的活性物
质可能会造成临床有害过量的，或他们需要长时间释放所有口服产品中含有任何活性物质
Ĥ2009 年 4 月
哪里有科学依据，明确的释放特性的口服药物可能受到不利影响的存在酒精，再用酒精的
物理化学配伍禁忌，应考虑由申请人承担。这将适用于所有的口头延长（延迟和修改）发
布产品。
4。可能的方法要求在醇存在下，在体外测试的潜在加速释放如何建立，以确保最大的相关
的临床情况？ Ĥ2009 年 4 月
在这个时间点上，这是不可能提供权威的方法学要求。
体外研究被认为有足够的证据表明酒精不兼容，对药品的质量造成相应影响，就释放性能。
值得注意的是，在体外释放测试主要涉及的药物产品的质量控制中，与设定为符合令人满
意的安全性和有效性的临床研究已经建立用于与这些批次的限制。
考虑到这一点，如果含有酒精的溶出介质的体外释放试验产生的规范的结果，那么这可能
会被认为有足够的证据证明，酒精与酒精，即产生不利影响的药物产品的质量的不兼容。
在一审中，申请人应考虑是否有可能与酒精的物理化学配伍禁忌。这应包括讨论的控制释
放的赋形剂在酒精和上的体外释放的药物产品的性能的影响，这可具有的溶解度。在哪里
溶解度或其他信息与酒精的物理化学配伍禁忌的可能性不能排除，然后在体外释放数据也
可以提供给评估相互作用的程度。
溶解介质应该是例行测试所提出的相同，但与添加的合理范围内酒精。在培养基中醇的范
围应该模仿在流体中的胃和近端消化道以下饮酒，例如，可能要达到的水平 5％，10％和
20％。
申请人应讨论的意义，任何超出规范的结果，尤其是在早期的时间点，连同剂量倾销和加
速释放风险的考虑。在产品特性概要，应该提出适当的警告，并说明理由。
5。是否需要采取进一步的措施，以获得更好地了解口服的缓释产品中存在的酒精及其相关
临床情况的释放特性的，例如在体外 - 体内外相关性？如果在体外测试表明，酒精，以提
高阿片类药物/活动产品发布的一个潜在的，应要求申请人在体内研究探讨其临床相关性的
影响呢？ Ĥ2009 年 4 月
应该承认，共同管理醇的理化配伍禁忌的临床意义是值得商榷的，在目前的时间。已发表
的文献是有限的。
凡不符合酒精是显而易见的，它是目前不足以解决安全或其他问题的产品资料中包括适当
的警告，除非方面的有效性和安全性提出了严重关切。
特定类型的产品 - 兽药产品
1。什么限制了微生物的质量被认为是适合预混料药饲料含有天然来源的辅料（如黄豆壳，
玉米粉，等）吗？ V 2010 年 10 月
理想的情况下，药典等级辅料应使用新的兽药产品，并在这些情况下，符合一般的篇章
5.1.4：非无菌药物制剂和药品使用的物质的微生物质量被认为是适当的。预混料药喂养饲
料兽药使用含有天然辅料的，应用这些限制可能是不可能的。欧洲药典（欧洲药典） 5.1.4
非无菌药物制剂和药品使用的物质的微生物质量是一个普遍的章节和欧洲药典中明确提到
的。药饲料预混料的专着，因此不是强制性的。章有本质上相同的地位的指导方针，那就是，
它代表的优先选择，但它应该是可以接受偏离合理。在预混料含有赋形剂，天然来源的情
况下，该机构建议以下标准，在特殊药典的要求。提供口服剂型，原料中的天然来源。在特
殊情况下，如果不能满足，申请人可以申请其他限制，例如：详情载于 C 节 5.1.8：口服使
用的草药产品的微生物质量的限制，但只有在理由充分的。
在口腔粉末和药饲料的预混物的情况下，具有相同的组合物，将它预期相同的微生物的限
制将适用于两种药物形式。在这种情况下，更严格的限制适用（通常那些请求在 5.1.4 章用
于口服粉剂：用于口服使用的非水制剂）。
2。是否有可能授予上市许可的产品是不溶于过的 pH 值范围在医药兽药管理质量等方面的
指引通过饮用水（EMEA/CVMP/540/03-Rev）的吗？的建议可以被添加在摘要中的产品特
性/产品信息，溶解度的原因，与酸/碱之前加入的药用产品的饮用水的 pH 值必须被调整？
V 2010 年 10 月
医药兽药管理通过饮用水（EMEA/CVMP/540/03-Rev.1）的质量方面的指引，如何饮用水
中的溶解度的产品进行测试（软水/低 pH 值，pH 值范围从 5.0 到 7.0 和硬水/高 pH 值从
8.0 至 9.0 的 pH 范围内）。
原则上，一种兽药产品可以仅被授权，如果是完全溶解（和留在溶液中），未经进一步借
助于通常的 pH 值范围内（通常是在 5.0 和 9.0 之间的 pH 范围内）的饮用水。如果饮用水的
pH 值调整是必要的，应该是这样的作为授权的兽药产品的一部分包括与赋形剂（酸，碱或
缓冲液）。如果排除是唯一可以接受的合理的（例如，它已被证明，其他配方原则已被排
除）。
无牌之前（或之后）的饮用水添加兽药产品，以实现必要的溶解度为调整 pH 值的酸或碱
的使用是不能接受的，除非对齐。
3。它允许多剂量（注射）兽药产品同时使用肌肉注射，也是一个乳房内准备？ V 2010 年
10 月
将被认为是这样的一个例子，是两种不同的药物形式（也是在这一特定问题的情况下，给
药途径），因此，需要两个不同的营销授权（分）号码，以及两种不同的产品特性的摘要。
在欧盟，不同的营销授权数（次）不同的药物形式是必要的。新的应用程序的分类与变更
申请的指引。
另一个原因是，在使用多剂量的容器乳房内和非肠道使用的，可能会导致在其的多剂量容
器中的产品的微生物污染的风险增加。
4。在使用过程中，使用为多剂量兽医注射剂瓶封的胶塞（输出接口）经常被刺破多次。因
此关于碎片（自密封）的合适的标准是必需的。存在的问题主要是可以出现在大型多剂量
注射剂，它可用于不同的目标物种和/或动物的年龄，但特别是对于较小的剂量体积是小的
动物，所以包可以被穿刺多次（例如，在极端的情况下，过量的的 100 穿孔）。一般的篇
章上胶塞的容器非口服制剂，适用于水性，粉末和冷冻干燥的粉末（ 3.2.9）在这种情况下
呢？哪些标准橡胶片段的最大数量被视为可接受的是欧洲药典所描述的穿刺的数目的倍数
的试验设计。 3.2.9 吗？如果最坏的情况下使用呢？ V 2010 年 10 月
一般章非口服制剂，适用于水性，粉末和冻干粉末的容器胶塞（ 3.2.9）是不是自己的强制
性的。如果有合适的理由是，本章所载的要求（最多 5 个片段）并不一定需要得到应用。值
得注意的是，欧洲药典（Ph. Eur。）试验的目的是证明，塞满足一般预计橡胶塞医药产品
的最低要求，但是这当然不能涵盖所有的潜在用途。
包应证明符合欧洲药典的要求。测试修改，以使用最多的穿刺预期目标的种类，剂量及给
药途径（使用适当的针头大小的那种情况下）。需要注意的是预期的最大数目的片段中的
完全如在欧洲药典。测试。
摘要应反映产品特性（SMPC）和其他产品信息穿刺关闭已被证明符合欧洲药典的要求。测
试。例如，如果封闭件已被证明能够承受 X 穿刺与符合欧洲药典有关的碎片和自密封特性。
的要求。即，在数量增加的穿刺片段没有额外的增加。
风险管理工具
建议（如果有必要的组合）的一些例子可以列入辅助医疗业管理局（4.9 节）和其他产品
文学，以减少潜在的损害瓶塞穿刺过多的：
•“帽可被安全地穿刺到 X 倍”。
•“当在一次运行中，治疗组动物的使用已放置在小瓶中的止动件的止动件，以避免过量的
拉床的拉伸针。抽奖针治疗后，应删除。“
“只有 XX 毫升小瓶应该用于治疗小小猪”。
•“作为小瓶不应该酝酿超过 X 次，用户应选择最适当的小瓶大小根据被处理的目标物种。”
•“当处理大组动物仅使用自动加药装置与通风设备时使用的 xx 毫升小瓶划断。”
•“XXX 包的大小，只使用自动注射器。”（适用于大型可折叠的包从样品瓶和关注塞完整性
存在大量的剂量可能被撤销。）
•“XXX 包的大小，使用多剂量注射器建议。”（适用于非可折叠的大包从样品瓶和关注塞完
整性存在大量的剂量可能被撤销。）
存储
1。压力定量吸入器的产品信息存储方向的建议中的要求是什么？ Ĥ2008 年 12 月
方向的影响，在产品开发过程中，应进行调查的起动和重新启动的研究，根据药品质量吸
入和鼻产品（EMEA/CHMP/QWP/49313/2005）的方针。如果存储的方向交付的剂量上具
有显着的效果，在这些研究期间（即不同的补缀期间/数量的致动所需的再吸时，存储在不
同的取向）的存储取向建议应该被添加到的产品信息（产品概要特性，包装说明书和标
签）。应详细的首选存储方向。由于它可以不被保证，该产品将总是被存储在的择优取向，
在重新-吸指令的产品信息中应该可以基于在最坏情况下的情况下（即在方向需要的最短重
新-吸期间和/或的重新启动致动次数最多的）。
包装
1 。无特殊要求或建议中所提供的塑料内包装的材料， CPMP/QWP/4359/03 ＆
EMEA/CVMP/205/04 欧洲联盟指引，在可接受的质量标准方面的塑料材料被用于容器的固
体口服剂型和固体活性物质。如果材料符合欧洲药典“，如果没有，被认为是可以接受的
质量标准中的规范吗？ H + V 2009 年 1 月
并非详尽无遗的章节，欧洲药典（Ph. Eur。），描述材料和容器方面的各种不同类型的塑
料材料和添加剂。发表在欧洲药典规格的参考。因此，并不总是可能的。欧洲药典中列出的。
一般注意事项 1.3，这是不是强制性的，只有材料符合欧洲药典的一章在一个给定的规范。
可以用作即时包装材料。如果合理的话，使用不同的配方，符合不同规格的材料，可用于
和协议，由主管机关。对于固体口服剂型和固体物质，它已同意的人用/医药产品委员会兽
用质量工作小组的医药产品，塑胶原料符合相关欧洲联盟（欧盟）的食品法规的有关联合
委员会塑料材料和制品接触到食品被认为是可以接受的。应制定一个规范阐述了在塑料直
接接触药品的包装的材料（CPMP/QWP/4359/03）按照规定在欧盟的指引。
2。是否欧洲药品局/委员会兽用指引药品研发医药产品的灭菌方法的选择，避免使用不耐热
的塑料包装材料和无菌处理，无菌兽药产品的兽药产品及其附件的决策树？ V 2012 年 2
月
确保的药用产品的无菌是考虑包装无菌产品时的主要问题，并且因此，所选择的方法，用
于生产任何无菌产品应该是终端灭菌。
欧洲药品管理局/兽医兽药产品及其附件决策树的灭菌方法的选择目前状态中引入的附件使
用指引药品研发医药产品委员会认为，“使用了不合适的不耐热包装材料本身不能采用无
菌处理的唯一原因。制造商应选择最佳的灭菌方法实现给定的配方，并选择相应的产品的
包装材料。然而，这可能是因为对于一个给定的产品的包装材料的选择考虑到比杀菌的方
法，其他的因素。在这种情况下，这些因素都需要有明确记载，解释和科学合理的上市许
可档案。“
不能被视为一个简单的替换最终灭菌无菌加工。欧洲药典（欧洲药典）一般文本 5.1.1：制
备无菌产品状态的方法，“在可能的情况下，该产品是一种方法，其中在其最终容器（终
端灭菌）灭菌选择”，而且如果终端灭菌“是不可能的，通过细菌保留过滤器或无菌加工
的过滤使用;在可能的情况下，适当的附加处理的产品（例如，加热的产品）被施加在其最
终容器中。”这样的非标准较低的温度下热处理，不论是无菌灌装前，或后无菌灌装的无
菌加工相结合，在可能的情况下，应继续符合欧洲药典的建议。
因此，该指引并没有阻止不耐热无菌产品的包装材料的使用，但必须有正当理由有这样的
无菌产品的包装，而这些必须支持的整体利益风险平衡的产品。
成品的制造中使用的药物散装产品的稳定性 - 稳定性问题
背景
成品稳定性指导并不解决贮存散装产品在制造过程中。这些问题和答案的目的是为了解决
支持的营销许可档案，储存和/或运输散装产品在生产过程中提供的信息。
良好的制造实践指导指示散装产品应存储“适当的条件”下，因此，在申请文件中提供的
数据应旨在证明这些条件的适宜性有关的预期的存储和/或运输的安排大宗产品超过其宣称
的保质期给定的成品的质量和效果。
我们的目标是增加透明度的支持所需的数据，而不是引入任何新的监管要求。
所需的数据，将取决于产品的类型和所进行的活动（即长时间贮存和/或运输）和以风险为
基础的方法，鼓励以证明是否适合在各种情况下产生的数据。
所描述的框架的目的是涵盖所有制药原料产品。然而，可以理解的是，对于一些特定类型
的产品（例如，生物制品）的要求可能需要额外的数据有关的产品的类型，并根据该特定
产品的特性，这应该予以考虑。
1。大容量存储的定义是什么？ H + V 2012 年 2 月
最经常出现的问题有关的固体口服剂型（特别是片芯之前，涂层和/或包装）中，但也可以
是适用的任何阶段的任何药剂制品在制造过程中被保持在存储散货进一步处理之前，（例
如在灌装之前，颗粒，等）的本体溶液。
2。散装容器应提供什么样的信息？ H + V 2012 年 2 月
在一般情况下，要提供的信息的级别，将依赖于批量产品的性质。的定性和定量（如需
要）组成的散装容器应在申请文件中，其控制规范说明（3.2.P.3.4 模块或 2.B）。
3。上的储存条件，应提供什么样的信息？ H + V 2012 年 2 月
应当指出的是散装产品是否被存储（如果有关，运输）下控制或不控制的储存条件下。
4。什么样的信息是必要的生产基地之间的运输的大宗产品吗？ H + V 2012 年 2 月
如散装产品生产基地之间的运输，交通安排，应描述在一般条款（散装容器/储存和运输条
件/监测安排）在申请文件中（模块 3.2.P.3.4 或部分 2.B）。
良好的销售实践的指引，应采取以下考虑：
原理：
•良好生产规范质量应保持在整个分销网络;
在任何时候，包括在运输过程中，应遵守•储存条件。
储存：
•温度应定期监测和记录;
•记录应定期检讨。
5。应提供什么样的数据，支持大容量存储及运输安排？ H + V 2012 年 2 月
散装产品的最大存储时间间隔应宣布在的营销许可档案，或可选地，从开始的产品制造完
成营销的最后的主容器的包装的最大批处理制造时间。
存储时间延长时（即超过 30 天，固体口服制剂，无菌产品超过 24 小时），证据的适用性
的建议容器，储存间隔和/或交通安排，应包括在申请文件中。要提供的数据，将依赖于发
展的研究结果表示提出的条件。
在与成品的人用（ICH）或国际合作协调的技术要求注册的兽药产品（VICH）的指导方针
药品注册技术要求协调在相关国际会议上所描述的原则，预计从批中试规模（最小的 2 个
批次）的条件下，代表大宗产品的存储条件存储的数据将提供支持大宗产品的存储。除非
在申请文件中提供的验证，这些数据应该在批准后的稳定性承诺在商业规模的批次。
建议的大宗生产基地之间的交通，游览外的原始存储条件的影响，应进行讨论，并在必要
的情况下，通过加速稳定性试验数据的支持。
6。产品的保质期应该如何计算？ H + V 2012 年 2 月
计算产品的保质期应该是按照医药产品委员会的人用/医药产品委员会兽医指导使用注意保
质期的成品剂型的开始（CPMP/QWP/072 / 96 / EMEA/CVMP/453/01）。如果其他方法都
提出，应通过包含代表的大宗产品的全部建议持有时间间隔（中间）在成品稳定程序的批
次宣派及合理。
7。稳定的条件下，应选择支持大容量存储？ H + V 2012 年 2 月
这是没有必要根据国际上的人用（ ICH ）的技术要求国际协调合作的兽药产品注册
（VICH）的建议（药品注册技术要求协调会议，进行稳定性研究，对大宗温度或湿度）。
散装稳定性研究应反映在标准集装箱，预计在生产现场的实际储存条件。
事件涉及一个以上的生产基地，稳定的研究还应该包括任何运输（期限和条件）。
稳定性 - 储存条件的宣言
1。申报的产品信息中的存储条件下被使用，需要被储存和运输冷藏的产品是什么？ H + V
2007 年 8 月
申报的储存条件下，当一个产品需要冷藏的指导说明所预见的，“存放在冰箱的措辞”应
在标签中使用，和温度范围内的参考，例如： 2°C 至 8°C，应包括产品的特性（SMPC）
和包装说明书的摘要。
据为指导，当需要冷藏运输冷链，冷藏储存，预计为同一个音符，可以使用下面的语句：
“储存和运输冷藏”。
2。到期日应如何计算和表达呢？ H + V 2008 年 7 月
指导意见中可以找到指导说明保质期的的的成品（ CPMP/QWP/072/96 /
EMEA/CVMP/453/01）和委员会开始相互承认和分散式的程序和质量评审文档产品信息模
板。总之，到期日应自发布之日起计算的情况下，期间的生产日期和发布之日起超过 30 天，
从生产之日起。到期日应表示为 MM / YYYY。该产品到期结束时的指定月份。
在最坏的情况下，这种方法的计算结果在两个月届满日期的延伸。见表 1。
表 1：示例平板电脑的到期日计算的保质期为 24 个月
第一个混合的步骤日期的包装发布日期到期日释义适合使用的总时间，从开始的制造到保
质期结束的日期重新计算到期日
直到 31 月 1 日 2007 年 3 日 01/2007 28/01/2005 29/01/2005 30/01/2005 01/2007
直到 31 月 1 日 2007 年 2 年 28 日 12/2006 03/01/2005 04/01/2005 05/01/2005 01/2007
03/01/2005 19/07/2005 21/07/2005 01/2007，直到 2007 年 1 月 31 日 2 年 28 天二万零六
十一分之十二
03/01/2005 04/01/2005 01/02/2005 02/2007 年 2 月直到 5 月 28 日 2007 年 2 年 56 日
01/20071
*的堆积压缩片剂已保存 6 个月。据预计，中间产品的保质期是详细的的档案和稳定的数据
支持也提出在申请文件中。
不到 12 个月的保质期的产品，特别是对于不认为是可以接受的。因此，到期日应计算在一
个 DD / MM / YYYY 的基础上，从发布之日起，或（如适用）从生产之日起，向上或向下
调整，以 MM / YYYY 根据下面的例子： 14/01 / 2007 变为 12/2006 15/01/2007 变为
01/2007。请参阅表 1 计算到期日。
________________________________________
首次出版于 2008 年 7 月 1 注：这个问题的回答是一个错误（例 3 和例 4 日重新计算混合）。
后来的错误是确定的 QWP，并发表在 2009 年 3 月本修正版本。
稳定性 - 第 58 个产品
1。什么样的稳定性数据的应用程序所需的根据规例 EC/726/2004 第 58 条？ Ĥ2006 年 7 月
法规（EC）726/2004 第 58 条的范围扩大欧洲药品管理局人用医药产品委员会，包括申请
一定的药用产品专供社区以外的市场，如抗逆转录病毒疗法：
“1。在与世界卫生组织合作的背景下，该机构可能会科学的意见，供人类使用专供社区以外
的市场一定的药用产品的评价。为了这个目的，一个应用程序，应提交该机构按照第 65 条
的规定。人用医药产品委员会，世界卫生组织协商后，制定了科学的意见，按照第 6 至第
9。第 10 条规定将不适用。“
对于这些应用程序，它是非常重要的应用标准，以确保足够的产品质量在市场上销售的产
品在欧洲联盟（欧盟）。在这种情况下，稳定的数据需要提交由申请人在其拟定的保质期
普遍在目标国家的气候条件下，即国家在气候区 III 和 IV 表现出稳定的药用产品。仅仅适用
在欧盟的使用相同的要求，即国家在气候区 I / II，可能会导致不合格的产品在市场上销售
时，III 和 IV 气候区。人用（ICH）指导委员会于 2006 年 6 月药品注册技术要求协调国际会
议上正式撤销登记的气候带 III 和 IV（ICH Q1 F）的指引稳定的数据包，由于有争议的讨
论定义是否有足够的储存条件。世界卫生组织（WHO）药物制剂规格专家委员会已决定分
割区（IVA 炎热和潮湿）30°C/65％相对湿度（RH）储存条件和区域 IVB（热和气候带 IV
非常潮湿），30°C/75％RH 贮存条件;世界卫生组织稳定指引将作相应的修改。
在评估的应用程序根据规例 EC/726/2004 第 58 条，它必须承担各自的药用产品将被用在
所有子区的气候带 III 和 IV，除非另有由申请人确认。因此，为了保障产品质量，打算在其
整个货架寿命，稳定性研究气候区第 IVb 需要执行规定的条件下，即保质期，需要建立长
期的数据的基础上，在 30°C / 75％RH 环境下，支持 6 个月的数据，在 40℃75％RH。推断
说明中所描述的原则为指导评价的稳定性数据（CPMP/ICH/420/02），以及减少测试设计
说明中所描述的指导包围和矩阵设计，原料药和制剂的稳定性试验可施加产品
（CPMP/ICH/4104/00）。在情况下，这些数据表明，超过所需的一段时间的稳定性，没有
特殊的储存条件需要以被标记。
如果只根据条例 EC/726/2004“第 58 条的应用程序包含足够的气候区 I / II，列表中的问题，
应要求各自适合的气候带 III 和 IV 的数据的数据。如果数据显示稳定性的问题，在
30℃75％RH 湿度方面，循环和使用的产品应优选被限制到所覆盖的数据的那些国家和地
区，例如产品应使用国家内的气候带 III 和Ⅳ。作为一种替代方法，储存条件需要被标记，
包括湿度，例如“保持”，特别是对气候区第 IVb 湿度不受环境湿度的稳定性限制因素。
然而，它具有到被指出，由于技术的设备和物流可用部分的气候区 IV 国家以及的教育和遵
守在各自区域中的病人，药用产品暴露到较高的温度和湿度可以不是排除了。限定的保质
期和储存条件时，这需要被考虑。对于要存储在“正常状态”，即稳定在 30°C，加速数据
的提交，即 40°C/75％RH，不能放弃，因为他们需要评估的影响，极端温度/湿度条件的产
品中可能发生的气候区 IV，即使产品可能不是在这些存储条件下 6 个月稳定。
请注意，在半透的容器中的水性产品在市场上销售的气候区 III，即区域的极端温度的环境
下，进行长期测试应在 30°C/35％RH。作为一种替代方法，节 2.2.7.3 中所描述的计算因子
“药物产品包装在半透容器”指导新药物物质和产品（CPMP/ICH/2736/99）的稳定性测
试的说明可能被应用。
稳定性 - 减少设计中的稳定性研究
1。能减少设计时所使用的兽药产品的稳定性研究？ V 2006 年 10 月
是的，只要选定的设计进行解释和说明。适用于新的药物和产品的人用（ICH）指导包围和
稳定性测试的药物和药品（CPMP/ICH/4104/00）的矩阵化设计，药品注册技术要求协调
国际会议人类医学中使用。然而，兽药公司可能会选择遵循此准则。的方针是其次，各方面
应遵循的指引。
稳定性 - 内毒素试验和无菌试验结束时保质期
1。内毒素检测认为必须在确认非肠道的货架期终点是无热原？
内毒素测试还没有请求的保质期结束时，要考虑到的事实，即它不被认为是稳定的指示参
数。有一个脚注，说明内毒素不稳定性研究测试规范应完成的保质期。
2。无菌试验认为必须在保质期结束确认非肠道是无菌的吗？ H + V 2009 年 5 月
雄性不育的货架寿命规范的一部分。
无菌测试应至少执行结束时的保质期，但它可以被替换的容器封闭件的完整性通过测试。
间歇完整性测试可能根据所述容器的性质上，可以设想，无菌试验是否是取代或未无关。
水
1。实施快速的注射用水和纯净水的微生物质量控制的另一种方法是监管的后果是什么呢？
H + V 2005 年 7 月
根据欧盟的法规，在药品制造，药品制造商需要使用欧洲药典标准的水。
欧洲药典（Ph. Eur。）最近推出了一个章节参考的接受程度快速微生物方法来取代标准的
药典方法进行适当的验证。
QWP 特设良好制造实践的检验人员的组讨论后，建议采用这种方法可能需要特定的审查，
以确保适当的验证步骤之后，水继续满足欧洲药典。规格。因为，在水的情况下，验证将不
特定产品，建议公司可以要求监察机关进行具体的现场检查。的表现，这样的检查将在监
管机构的自由裁量权，并在必要时可能涉及药品的评估。
由于它是预期的水将继续满足欧洲药典。规格，测试，不改变文件要求 *（变化）将参与，
因此没有对个别产品的规管影响通常会被预期。
这将取决于在原来的卷宗上的详细程度。
2。无菌试验认为必须在保质期结束确认非肠道是无菌的吗？ H + V 2009 年 5 月
雄性不育的货架寿命规范的一部分。
无菌测试应至少执行结束时的保质期，但它可以被替换的容器封闭件的完整性通过测试。
间歇完整性测试可能根据所述容器的性质上，可以设想，无菌试验是否是取代或未无关。
特定类型的产品 - 干品吸入器
1。应该下降的吸入装置在开发过程中进行调查？ Ĥ2012 年 6 月
删除的设备应进行调查的方针，对药品质量的吸入和鼻产品（4.2.18 节）定义的鲁棒性研
究的一部分。
应进行调查，产品性能的条件下，模拟病人使用。
应进行输送装置的使用与动作指示的频率中的使用说明。模拟传送装置和任何锁定机制的
鲁棒性下降应进行调查。实现在产品生命周期的末尾（例如为 200 剂量产品剂量 180），应
执行的落下模拟，以评估咬嘴上累积的药物的效果，或任何其他部分的设备，在设备的使
用寿命被驱离。如果该设备被设计成具有用于定期清洗除去瓶口，测试应该都进行与瓶口
按照使用说明中在测试过程中移除和清洗，和，作为最坏的情况下，无需拆卸和清洗。交
付的剂量和/或微粒的质量的显着变化，应充分讨论的产品的安全性和有效性方面。应建立
适当的处理指令的患者，根据所得到的结果

Quality of medicines questions and answers（中英文）

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Quality of medicines questions and answers

If a question is not addressed, marketing-authorisation holders are encouraged to

These questions have been produced to provide clarification or additional

 H: applicable to medicinal products for human use

Quality of medicines questions and answers: Part 1：

Active Substance - Active-substance-master-file procedure

Active substance - Declaration by the qualified person on the good-

Active Substance - Good-manufacturing-practice compliance for

Active Substance - Starting materials of herbal origin

herbal drugs;herbal preparations (typically extracts);isolated plant constituents (no

According to the guideline on process validation, "the results can be subsequently

A bioequivalence study conducted using a test product produced by the developer is

For this the following applies:

No such proof is necessary to be presented in the application dossier.

European Pharmacopeia (Ph. Eur.) - Harmonised Ph. Eur. Chapters

Any changes to implement the harmonised limits (5.1.4) should be submitted as

In accordance with current requirements, any changes should be clearly identified

European Pharmacopeia - Monograph on tablets

As the requirements on subdivision of tablets are listed in the production section of

European Pharmacopeia (Ph. Eur.) - Harmonised chapter uniformity

Impurities - Calculation of thresholds for impurities

Impurities - Harmonisation of policies on setting specifications for

Example 1 – A potential genotoxic impurity

If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical

Example 2 – A (potentially) genotoxic impurity actually formed or introduced prior to

If a (potentially) genotoxic impurity is formed or introduced in a step before the final

Example 3 - A (potentially) genotoxic impurity is formed or introduced in the last

If a (potentially) genotoxic impurity is formed or introduced in the final synthesis

Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an

Example 1 – A class-1 metal is not used or suspected to be present in a synthesis

Metals are not expected to be formed in synthesis processes. Only if deliberately

Example 3 – A class-1 metal is introduced in the last synthesis step

Example 1 – A class-1 solvent is not used or suspected to be present in a synthesis

Should a class-1 solvent not be controlled at the starting material or intermediate

Example 3 – A class-1 solvent is formed or introduced in the last synthesis step

If a class-1 solvent is formed or introduced in the final synthesis step, it should be

Impurities - Residual solvents

Manufacture of the medicinal products - Process control

Where relevant, if a change is submitted as a type IB variation, it is up to the applicant

欧洲药典（欧洲药典） - 调和欧洲药典。第 2.6.12，2.6.13 和 5.1.4

的变化的限制 - B.II.d.1.a 的（IA）型，但只有在下列情况下：

目前登记的微生物控制的限制（目前的情况）是完全一致的 2008 年 1 月（非统一）的情

请注意，这个建议取代了 2007 年 8 月的问题和答案，这是现在已经过时。

根据指令 2001/83/EC 和 2001/82/EC，欧洲药典专着。官方相应的质量标准，在营销授权

请注意，这个建议取代了前面的问题及答案 1，在 2004 年和 2006 年发表的关于同一主题

它被认为是可能的申请跳到测试，如果-1 之类的金属中的合成中间体的水平不超过 30％的

实施例 3 - 在最后的合成步骤 A 类-1 金属被引入

如果一个类-1 溶剂不能被控制的起始原料或中间体的阶段，那么实施例 3 的情况下适用。

Definition of ‘active substance’ in relation to mixtures

Appearance of tablets of different strengths

Specific types of product - Quality of investigational

Specific types of product - Need for in-vitro

Specific types of product - Veterinary medicinal

Stability - Stability issues of pharmaceutical bulk

Stability - Declaration of storage conditions

Stability - Article 58 products

Stability - Reduced design in stability studies

Stability - Endotoxin testing and sterility testing at

Specific type of products – Dry product inhalers

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