FDA publishes List of Guidances planned for 2015



At the beginning of each year the FDA always publishes a list of the guidances it plans to publish during that year. It has done so again in 2015. The document is relatively comprehensive, containing five pages. Find out more about the Guidances the FDA plans on publishing in 2015.



At the beginning of each year the FDA always publishes a list of the guidances it plans to publish during that year. It has done so again in 2015. The document is relatively comprehensive, containing five pages. The list is subdivided into different categories. It contains for example also guidances planned in connection with the topics Clinical Pharmacology or Clinical/Statistical.

CGMP is a category of its own for which “only” three new guidances are planned for 2015:

  • A questions & answers (Q&A) paper on the topic data integrity
  • CGMP rules for outsourced facilities (pharmacy compounding)
  • Rules for the repackaging of certain drug products by pharmacies and outsourcing facilities

Especially the Q&A document could be interesting.
The guidances planned for the category “Pharmaceutical Quality/CMC” are also closely related to GMP. The following guidances are examples of the 13 guidances planned altogether in this category:

  • A guidance on the development of NIR procedures
  • A guidance on microbiological quality considerations in non-sterile drug product manufacturing
  • A guidance on quality metrics and risk-based inspections.

Concerning biotechnology specifically there are two separate categories with the topics biopharmaceutics and biosimilarity.

Conclusion: The number of new guidances in the GMP environment planned for 2015 is relatively limited but some of the topics (such as data integrity and quality metrics) could be very interesting. Furthermore, it remains to be seen if all of the planned guidances will really be published in 2015.

Please also see the “New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year 2015″.

Postscript: If you are interested in the topic quality metrics: In the framework of the 6th European GMP-Conference the ECA offers a Pre-Conference on this topic taking place in Heidelberg on 8 June 2015.



read at



methodology provides a risk-based approach to residual solvent
analysis that considers a patient’s exposure to a solvent residue
in the drug product. Solvents have been classified based on their
potential health risks into three main classes:
1. Class 1: Solvents should not be used because of the
unacceptable toxicities or deleterious environmental effects.
2. Class 2: Solvents should be limited because of inherent
3. Class 3: Solvents may be regarded as less toxic and of lower
risk to human health.
Testing is only required for those solvents used in the
manufacturing or purification process of drug substances, excipients
or products. This allows each company to determine which solvents
it uses in production and develop testing procedures that address
their specific needs. It is the responsibility of the drug manufacturer
to qualify the purity of all the components used in the manufacturing
of the drug product. This would pertain to items such as excipients,
of which some contain residual levels of Class 1 solvents by nature
of the manufacturing process and/or nature of the starting materials
(e.g. ethyl cellulose). The new 467 monograph provides an optional
method to determine when residual solvent testing is required for
Class 2 solvents. Each Class 2 solvent is assigned a permitted daily
exposure (PDE) limit, which is the pharmaceutically acceptable
intake level of a residual solvent.
The USP has provided a method for the identification, control,
and quantification of Class 1 and 2 residual solvents. The method
calls for a gas chromatographic (GC) analysis with flame ionization
detection (FID) and a headspace injection from either water or
organic diluent. The monograph has suggested two procedures:
Procedure A G43 (Zebron ZB-624) phase and Procedure B G16
(Zebron ZB-WAXplus) phase. Procedure A should be used first. If
a compound is determined to be above the specified concentration
limit, then Procedure B should be used to confirm its identity.
Since there are known co-elutions on both phases, the orthogonal
selectivity ensures that co-elutions on one phase will be resolved
on the other. Neither procedure is quantitative, so to determine
the concentration the monograph specifies Procedure C, which
utilizes whichever phase will give the fewest co-elutions. Class
3 solvents may be determined by 731-Loss on Drying unless the
level is expected to be >5000 ppm or 50 mg. If the loss on drying
is >0.5 %, then a water deterrmination should be performed using
921-Water Determination.
One of the most important considerations is that, once
implemented, the new method will pertain to all currently marketed
drug products as well as those in development and clinical trials8

United States Pharmacopoeia (USP):
In 1988, the United States Pharmacopoeia (USP) provided
control limits and testing criteria for seven organic volatile impurities
(OVIs) under official monograph 4678
. According to USP, testing
should be conducted only if a manufacturer has indicated the
possible presence of a solvent in a product. Testing may be avoided
when a manufacturer has assurance, based on the knowledge of
the manufacturing process and controlled handling, shipping, and
storage of the product, that no potential exists for specific solvents
to be present and that the product, if tested, will comply with the
accepted limit. Items shipped in airtight containers (such as those
used for food additives) can be considered not to have acquired
any solvents during transportation2
The compounds are chosen based on relative toxicity and only
applied to drug substances and some excipients8
. In addition, a
test for ethylene oxide is conducted if specified in the individual
monograph. Unless otherwise specified in the individual monograph,
the acceptable limit for ethylene oxide is 10 ppm. USP does not
address all other solvents mentioned in the ICH guideline2
In an effort to harmonize with the International Conference
for Harmonization (ICH), the USP has proposed the adoption of
a slightly modified version of ICH (Q3C) methodology, which has
been scheduled for implementation on July 1, 2007. The ICH Q3C

Organic Volatile Impurities
Of the solvents targeted in USP 26 General Chapter 467, only
methylene chloride may appear in bulk pharmaceutical products
manufactured by Pfizer at the Kalamazoo plant. For those products
where OVI testing is required, our material will meet the compendial
limits for methylene chloride and other solvents that may be added
to the target list in the future.
No OVI requirement exists in the USP 26 monograph
for Triamcinolone, but Triamcinolone from Pfizer meets the
requirements of USP 26 General Chapter 467.

Residual solvents in pharmaceuticals, commonly known as
organic volatile impurities (OVIs), are chemicals that are either
used or produced during the manufacture of active pharmaceutical
ingredients (APIs), excipients and drug products1, 2
Organic solvents play an essential role in drug-substance and
excipient manufacture (e.g., reaction, separation and purification)
and in drug-product formulation (e.g., granulation and coating) 3
Some organic solvents are often used during the synthesis of active
pharmaceutical ingredients and excipients or during the preparation
of drug products to enhance the yield, increase solubility or aid
. These process solvents cannot be completely
removed by practical manufacturing practices such as freeze–drying
and drying at high temperature under vacuum. Therefore, some
residual solvents may remain in drug substance material4
. Typically,
the final purification step in many pharmaceutical drug-substance
processes involves a crystallization step, and the crystals thus
formed can entrap a finite amount of solvent from the mother liquor
that may cause degradation of the drug, OVIs may also contaminate
the products during packaging, storage in warehouses and/or during
While solvents play a key role in the production of
pharmaceuticals, there is also a downside, as many of the
solvents used have toxic or environmentally hazardous properties.
Complete removal of residual levels of solvents is impractical from a
manufacturing standpoint, so it is inevitable that traces will remain inthe final product. The presence of these unwanted chemicals even
in small amounts may influence the efficacy, safety and stability of
the pharmaceutical products. Because residual solvents have no
therapeutic benefits but may be hazardous to human health and
the environment, it must be ensured that they are either not present
in products or are only present below recommended acceptable
levels. It is a drug manufacturer’s responsibility to ensure that any
OVIs present in the final product are not harmful to humans and
that medicinal products do not contain levels of residual solvents
higher than recommended safety limits. Solvents known to cause
unacceptable toxicity should be avoided unless their use can be
justified on the basis of a risk-benefit assessment2
. Because of their
proven or potential toxicity, the level of residual solvents is controlled
through national and international guidelines, for example, through
the FDA and International Conference on Harmonization.

“All drug substances, excipients, and products are subject to
relevant control of residual solvents, even when no test is specified
in the individual monograph.”
Regulatory and Compliance Environment
One of the essential aspects of pharmaceutical manufacturing
is regulatory compliance, which typically encompasses two aspects.
The first is compliance with private sets of standards based on
an applicant filing with a regulatory agency, which requires the
applicant to report the determined residual solvent levels in a
number of representative batches of pharmaceutical product to
establish typical levels of solvent contamination that can routinely
be achieved. Based on a statistical evaluation of the reported
data, a specification is agreed for solvents used in the final step of
the process and a decision made on whether testing is required
for solvent used at earlier stages in the process. To arrive at a
specification that is a measure of the routine performance of the
process, regulatory agencies require numerical data rather than
reporting compliance with a limit test.

Internationally, there has been a need to establish regulatory
standard guidelines. In 1997, The International Conference on
Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), through its Q3C Expert
working group formed by regulators from the three ICH regions,
industry representatives and interested parties/observers, finalized
the Q3C guideline on residual solvents. Essentially, ICH has
consistently proposed that limits on organic solvents be set at levels
that can be justified by existing safety and toxicity data, and also kept
proposed limits within the level achievable by normal manufacturing
processes and within current analytic capabilities.
The second aspect is compliance with public standards set
by Pharmacopoeias from the three ICH regions (United States
Pharmacopoeia (USP), European Pharmacopoeia (Ph. Eur.) and
Japanese Pharmacopoeia (JP)) and also with local pharmacopoeias
from countries outside the ICH regions. In the recent past, guidelines
for organic residual solvents for public standards have generally
been vague and not up-to-date. The pharmacopoeial approach
was typically a limit test for residual solvents, employing standard
. The USP set the official limits in USP 23rd edition in the
general chapter 467, Organic Volatile Impurities5
. Very early on,
the Ph. Eur. employed the ICH Q3C regulatory approach and
updated the acceptance limits but kept the methodology as a limit
test based on standard addition. The general method in Ph. Eur. for
Identification and Control of Residual Solvents in drug substances
defines a general procedure and describes two complementary gas
chromatography (GC) conditions for identifying unknown solvents.
‘‘System A’’ is recommended for general use and is equivalent
to ‘‘Methods IV and V’’ of the USP for analysis of volatile organic
impurities ‘‘System B’’ is used to confirm identification and to solve
co-elutions. Implementation of this general method is a subject of
debate in the pharmaceutical industry due to its limited selectivity
and sensitivity3
. Historically, until its 27th edition, the USP restricted
its listing of residual solvents to those of Class 1 and neglected to

consider the wide range of organic solvents used routinely in the
pharmaceutical industry. Furthermore, the limits stated for Class 1
solvents like benzene, chloroform, 1, 4-dioxane, methylene chloride,
and 1, 1, 1-trichloroethane are in the range 2–600 (ppm) and are
therefore not in concordance with the ICH guideline. Residual
solvent testing using GC has been included in the pharmacopeias
for almost 20 years, while residual solvent-test methods have
been reported in the literature since before that. With USP 28, the
public standard for residual solvents was updated to comply with
the ICH Q3C guideline, but the methodology (the same limit-test
approach as Ph. Eur.) and the targeted monographs were not
considered appropriate by industry and regulators, leading to a
notice postponing implementation in USP 296
ICh Guideline
The objective of this guidance is to recommend acceptable
amounts for residual solvents in pharmaceuticals for the safety of
the patient. The guidance recommends use of less toxic solvents
and describes levels considered to be toxicologically acceptable
for some residual solvents.
Residual solvents in pharmaceuticals are defined here as
‘organic volatile chemicals that are used or produced in the
manufacture of drug substances or excipients, or in the preparation
of drug products’. This guidance does not address solvents
deliberately used as excipients nor does it address solvates.
However, the content of solvents in such products should be
evaluated and justified.
Since there is no therapeutic benefit from residual solvents,
all residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or other
quality-based requirements. Drug products should contain no higher
levels of residual solvents than can be supported by safety data.
Some solvents that are known to cause unacceptable toxicities
(Class 1) should be avoided in the production of drug substances,
excipients, or drug products unless their use can be strongly justified
in a risk-benefit assessment. Some solvents associated with less
severe toxicity (Class 2) should be limited in order to protect patients
from potential adverse effects. Ideally, less toxic solvents (Class 3)
should be used where practical7

Scope of the Guidance
Residual solvents in drug substances, excipients, and drug
products are within the scope of this guidance. Therefore, testing
should be performed for residual solvents when production or
purification processes are known to result in the presence of such
solvents. It is only necessary to test for solvents that are used or
produced in the manufacture or purification of drug substances,
excipients, or drug products. Although manufacturers may choose
to test the drug product, a cumulative method may be used to
calculate the residual solvent levels in the drug product from the
levels in the ingredients used to produce the drug product. If the
calculation results in a level equal to or below that recommended
in this guidance, no testing of the drug product for residual solvents
need be considered. If, however, the calculated level is above the
recommended level, the drug product should be tested to ascertain
whether the formulation process has reduced the relevant solvent
level to within the acceptable amount. Drug product should also be
tested if a solvent is used during its manufacture.
This guidance does not apply to potential new drug substances,
excipients, or drug products used during the clinical research
stages of development, nor does it apply to existing marketed
drug products. The guidance applies to all dosage forms androutes of administration. Higher levels of residual solvents may be
acceptable in certain cases such as short-term (30 days or less)
or topical application. Justification for these levels should be made
on a case-by-case basis7
Classification of Residual Solvents
OVIs are classified into three classes on the basis of their
toxicity level and the degree to which they can be considered
an environmental hazard. The list provided in the guideline is
not exhaustive, and one should evaluate the synthesis and
manufacturing processes for all possible residual solvents.
The term, tolerable daily intake (TDI), is used by the International
Program on Chemical Safety (IPCS) to describe exposure limits
of toxic chemicals and the term, acceptable daily intake (ADI), is
used by the World Health Organization (WHO) and other national
and international health authorities and institutes. The new term,
permitted daily exposure (PDE), is defined in the present guidance
as a pharmaceutically acceptable intake of residual solvents to avoid
confusion of differing values for ADI’s of the same substance7
Residual solvents are classified on the basis
of risk assessment:
1. Class 1 solvents (Solvents to be avoided): Known human
carcinogens, strongly suspected human carcinogens, and
environmental hazards.
2. Class 2 solvents (Solvents to be limited): Non-genotoxic
animal carcinogens or possible causative agents of other
irreversible toxicity such as neurotoxicity or teratogenicity.3. Class 3 solvents (Solvents with low toxic potential): Solvents
with low toxic potential to man; no health-based exposure limit
is needed. Class 3 solvents have PDE’s of 50 milligrams (mg)
or more per day.
4. Class 4 solvents (Solvents for which no adequate
toxicological data was found): No adequate toxicological
data on which to base a PDE (permitted dose exposure) was
Environmental Regulation of Organic Volatile
Several of the residual solvents frequently used in the
production of pharmaceuticals are listed as toxic chemicals in
Environmental Health Criteria (EHC) monographs and in the
Integrated Risk Information System (IRIS). The objectives of such
groups as the International Programme on Chemical Safety (IPCS),
the U.S. Environmental Protection Agency (EPA), and the U.S.
Food and Drug Administration (FDA) include the determination
of acceptable exposure levels. The goal is protection of human
health and maintenance of environmental integrity against the
possible deleterious effects of chemicals resulting from long-term
environmental exposure. The methods involved in the estimation
of maximum safe exposure limits are usually based on long-term
studies. When long-term study data are unavailable, shorter term
study data can be used with modification of the approach such as
use of larger safety factors. The approach described therein relates
primarily to long-term or lifetime exposure of the general population
in the ambient environment (i.e., ambient air, food, drinking water,
and other media) 7
Limits of Residual Solvents
Solvents to Be Avoided: Solvents in Class 1 (Table 1) should
not be employed in the manufacture of drug substances, excipients,and drug products because of their unacceptable toxicity or their
deleterious environmental effect. However, if their use is unavoidable
in order to produce a drug product with a significant therapeutic
advance, then their levels should be restricted as shown in Table
1, unless otherwise justified. The solvent 1, 1, 1-Trichloroethane
is included in Table 1 because it is an environmental hazard. The
stated limit of 1,500 ppm is based on a review of the safety data

Analysis of Residual Solvent in
The analysis of residual solvents is an essential part in the
quality control of drug substances used in preclinical or clinical
trials as well as for use in commercial drug products. Residual
solvent analysis of bulk drug substance and finished pharmaceutical
products is necessary for a number of reasons such as –
1. High levels of residual organic solvents represent a risk to human
health because of their toxicity.
2. Residual organic solvents also play a role in the physicochemical
properties of the bulk drug substance. Crystalline nature of the
bulk drug substance can be affected. Differences in the crystal
structure of the bulk drug may lead to changes in dissolution
properties and problems with formulation of the finished
3. Finally, residual organic solvents can create odor problems
and color changes in the finished product and, thus, can lead
to consumer complaints.
4. Often, the main purpose for residual solvent testing is in its use
as a monitoring check for further drying of bulk pharmaceuticals
or as a final check of a finished product.

5. Testing for solvent content in intermediates may need to be
performed if a critical amount of residual solvent(s) remaining
in the intermediate can alter the next step of the process.
6. Knowledge of the solvent content in the starting materials may
help to the development chemist to understand the synthetic
routes and predict potential process related impurities.
7. Knowing the solvents used in the process allows the development
chemist to look for possible compound- solvent interactions
which can lead to the formation of impurities5, 16
Residual solvent analysis can be performed with a large array of
analytical techniques17. The most popular, and the most appropriate,
specific solvent analysis is testing by gas chromatography (GC).
Modern capillary-column gas chromatographs can separate a large
number of volatile components, permitting identification through
retention characteristics and detection at ppm levels using a broad
range of detectors5
.Gas chromatographic testing can be categorized
into three main procedures according to the means of introducing
the sample into the instrument. A direct gas chromatographic
procedure is one in which a portion of the actual drug substance
or formulation is injected into a GC system. The drug substance
is usually dissolved in an appropriate solvent and loaded into a
syringe and injected. Headspace analysis, on the other hand, is
an indirect testing procedure. The analysis is conducted when a
volume of gas above the drug substance or formulation is collected
and analyzed by a gas chromatograph. Finally, solid-phase microextraction (SPME) is making much progress in recent years for
residual solvent testing. In SPME, a silica fiber coated with a sorbent
is used to collect and concentrate the volatile solvents. The volatiles
are then thermally desorbed in the inlet of the gas chromatograph
and analyzed18
Many alternatives to gas chromatography have been used to
determine the level of residual solvent in pharmaceutical products.
Many of these procedures are either nonspecific—that is, the
solvents are not identified—or they have high detection limits, so
they are inappropriate for the detailed product characterization
required for a regulatory submission. The oldest and simplest
method for determining the quantity of volatile residue is measuring

the weight loss of a sample during heating. LOD method is widely
used, particularly for Class 3 solvents, due to its simplicity and
ease of introduction into even the most basic analytical laboratory5
Another approach is to use thermogravimetric analysis (TGA),
which is a well-known method for the quantitative analysis of the
loss of volatile components from a sample18. Spectroscopic and
spectrometric methods have generally lacked the low detection
limits needed for toxic residual solvents, although the detection limits
would be applicable for ICH class 2 and 3 solvents. In the case of
Infrared Spectroscopy (IR), a detection limit above 100 ppm and
lack of accuracy at low concentrations of residual solvent has been
reported. For NMR also high detection limit has been reported5
Whenever organic solvents are used in the production of
pharmaceutical products, especially in the last processing steps,
the content of residual solvent in the final product should be
analyzed. The complete removal of residual level of these solvents
is impracticable and traces always remain in the final products.
The presence of these residual solvents even in small amounts
has a negative influence not only on the quality of products but
also on human health. Acceptability of residual solvents seems to
be best judged following the ICH residual solvent guideline which
is adopted by the USP, EP and JP; it classifies the solvent into
four groups. In class 1 are included the most toxic solvents which,
unless strongly justified, should be avoided. For the toxic solvents
of class 2, the limits are expressed as concentrations (ppm) and
additionally in the case of known daily drug intake, by the very
important ‘permitted daily exposure’ (PDE). The class 3 includes
the solvents with low toxic potential for which the general limit is
set at 0.5%. The class 4 includes solvents for which no adequate
toxicological data was found.

1. Michulec M., Wardenki, W.; Development of headspace solid-
phase micro-extraction-gas chromatography method for the
determination of solvent residues in edible oils and pharmaceuticals,
J. Chromatogr, 2005; 1071: 119-124.
2. Dwivedi A. M., Residual solvent analysis in pharmaceuticals.
Pharmaceutical Technology 2002; 42-46.
3. Camarasu C., Unknown residual solvents-identification in
drug products by headspace solid phase microextraction gas
chromatography and mass spectroscopy, Chromatographia 2002;
56: S131-S135.
4. Rocheleau M J., Measuring residual solvents in pharmaceutical
samples using fast gas chromatography techniques, J. Chromatogr.
B 2004; 805: 77-86.
5. B’Hymer C., Residual solvent testing: A review of gas chromatographic
and alternative techniques, Pharm. Res. 2003; 20, 337-343.
6. Otero, R., Carrera, G., Static headspace gas chromatographic
method for quantitative determination of residual solvents
in pharmaceutical drug substances according to European
pharmacopoeia requirements, J. Chromatogr. A 2004; 1057: 193-
7. ICH Q3(C), Impurities: residual solvents, 1997.
8. Countrymen, S. Understanding the revision to USP monograph 467;
residual solvents, phenomenex Inc. Torrance, CA, USA, 2007.
9. General chapters 466; «Ordinary impurities» and 1086, «Impurities
in official articles,» in USP 28–NF 23. US Pharmacopoeia. 12601
Twin brook Parkway, Rockville, Maryland 20852, USA, 2004.
10. European pharmacopoeia, Identification and control of residual
solvents (2.4.24), directorate for the quality of medicines of the

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WHO publishes revised draft on GTDP for pharmaceutical starting material

WHO publishes revised draft on GTDP for pharmaceutical starting material

The WHO has published a proposal to revise the Good Trade and Distribuiton Practices for Pharmaceutical Starting Materials. Read more.


EMA publishes revised dossier-submission requirements for active-substance master files


The European Medicines Agency has updated its pre-authorisation procedural advice for users of the centralised procedure to reflect new requirements for the submission of active-substance-master-file (ASMF) dossiers as part of human or veterinary marketing-authorisation or variation applications. Go here to read more.




About Authors:
Salem – 636308, Tamil Nadu

Healthcare Regulatory Affair Professional with their experience and strong motivation to excel in the Regulatory field has an ability to motivate & give support and strengthen to teams members, involved in process ofproduct registration. Professional has taught a self-starter with the proven ability to prioritize and manage projects in a busy, fast-paced, multitasking environment, along with their experience in establishing relationship with the decision makers & coordinator. The Pharmaceutical industries are among the most highly regulated industries in the country. As India is growing very rapidly in pharmaceutical sector, there is a need of regulatory affairs professionals to cater the current needs of industries for the global competition. Regulatory affairs professionals are the link between pharmaceutical industries and worldwide regulatory agencies. They are required to be well versed in the laws, regulations, guidelines and guidance of the regulatory agencies. There is a growing need to incorporate the current requirements of pharmaceutical industries in the standard curriculum of pharmacy colleges to prepare the students with the latest developments to serve the industries. The present article discusses the regulatory education and its need, learning resources, courses available,syllabus contents and job opportunities in regulatory affairs.

read full article at



Good Manufacturing Practices (GMP) are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods, pharmaceutical products, and medical devices.

Most of the countries have their own regulation for GMP. I would like to discuss on how EMA (EU) GMP differ with the US FDA GMP.
After evaluation of the GMP regulatory comparison of both regulatory authorities, I found that compliance with EU GMPs will most likely also ensure compliance with FDA GMPs because EMA are much more specific and detailed in their guidances as compared to the US FDA
EMA GMP vs. US FDA GMP (A general comparison):
1. Cleaning Validation:
EMA: Annex 15,Clause 41-“Test until clean” is not considered an appropriate alternative to cleaning validation.
FDA: 2 Test until clean- For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases (correspondence to EMA, clause 41, but used in rare cases)
2. Personal training:
a. EMA: Chapter 2, clause 2.9- Continuing training should also be given, and its practical effectiveness should be periodically assessed.
No FDA correspondence for periodic assessment
b. EMA: Chapter 2, clause 2.8- The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel
No FDA correspondence
3. Sample:
a. FDA uses the term reserve sample while EMA categorize sample into two types- retention and reference sample. EMA has additional guidance for retention sample.
b. There is no EMA correspondence to US FDA 21 CFR 211.176 (penicillin contamination)
4. Internal audits:
FDA does not specifically address the requirement to conduct, or to keep records of, internal quality assurance audits. EMA has a chapter on Self Inspection in their guidance documents (Chapter 9: Self Inspection)
5. Air room classification:
a. FDA classifies air on the basis of 0.5 micron only. EMA classifies air into 0.5 and 5 micron, respectively.
b. FDA provides air classification requirement for “in operation” only. EMA provides air classification for “dynamic” and “in operation”, respectively.
c. ISO 6 classification is defined only in FDA.
d. EMA provides the description of clothing required for each grade of cleanroom.
e. Blow/fill/seal technology- FDA: The classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room.
EMA: Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used.
f. EMA- For classification purposes in Grade A zones, a minimum sample volume of 1m cubic should be taken per sample location (No FDA correspondence)
6. Outdoor clothing:
EMA Annex 1, Clause 44- Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. (No FDA correspondence)
7. Labeling requirement for Investigational medicinal product (IMP):
EMA requires expiry date in the label of IMP {Annex 13, clause 26(j)}. FDA exempts the requirement of expiry date for IMP, except when the new drug is reconstituted at the time of dispensing. (21 CFR 211.137)
8. Packaging control for tamper-evident packaging:
FDA (21 CFR 211.132) provides regulation for tamper-evident packaging requirements for over-the-counter (OTC) human drug products. (No EMA correspondence).
A detailed information on GMP regulation can be found in EU legislation-Eudralex: Volume 4 of “The rules governing medicinal products in the European Union”containing guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human use and US FDA 21 CFR 210 and 21 CFR 211

CHUAN YAO Senior Consultant , Singapore



Senior Consultant


  1. Professional Consultancy
  1. Wyeth / Pfizer,
  2. Go Medical Industries Pty Ltd, Australia,
  3. Pacific Pharmaceuticals Ltd (Merck Group)
  1. Auckland University of Technology




25+ years of experience in the Pharmaceutical/Medical Device industry
Senior positions in the areas of Quality Assurance, Regulatory Compliance and Regulatory Affairs –Merck, Wyeth, Pfizer (China, New Zealand, Australia and Singapore)

Areas of Expertise

US FDA, CFDA, PIC/s, EU GMP and ISO(17025, 14971, 13485, 14644) Compliance
QA and Risk Assessment in Pharmaceuticals and Devices
Compliance Auditing and Gap Analysis
Regulatory Affairs and Compliance
GxP Training
Analytical Testing
Process Capability


Chao wrote to me

Dear Anthony,

Thank you very much for adding me to your professional connection. I would like to introduce myself as I don’t have the pleasure to meet you personally.

My name is Chuan Yao, and I have had over 25 years’ experience in the pharmaceutical and medical device industry and have held senior positions in the areas of Quality Assurance, Regulatory Compliance and Regulatory Affairs. I have worked in the industry in China, New Zealand, Australia, Singapore and other ASEAN countries. I am currently working as a senior consultant for a consultancy company and am based in Singapore. My areas of expertise include –
 US FDA, CFDA, PIC/s, EU GMP, GxP and ISO Compliance
 QA and Risk Assessment in Pharmaceuticals and Devices
 Compliance Auditing and Gap Analysis
 Regulatory Affairs and Compliance
 GxP Training
 Analytical Testing
 Process Capability

I hope we can co-operate on a project and work together in the near future. Don’t hesitate to contact me for any questions or future request. Please keep in touch, My business email address is chuan.yao@chempharm.asia

Thank you !

Chuan Yao



Nice to know you through LinkedIn. Please see below my contact details.

ChemPharm is a professional full service consulting firm that has extensive practical expertise of supporting Pharmaceutical, Biotechnology, Medical Devices and Traditional Chinese Medicine (TCM) industries. ChemPharm is able to provide specialist expertise across all areas including: QA, QC, Production, Logistics, Product Development and Regulatory Affairs. Our Services include, review and remediation of existing GMP standards, development and implementation of Quality Management Systems, Validation Services, GMP/GDP/GLP Auditing including Pre-approval Inspection (PIA) and Supply Chain Auditing, DMF and product registration (especially in ASEAN countries and China).

ChemPharm consultants have extensive in-depth working knowledge and experience in International Regulations, Codes and Standards. This includes the major GMP regulations, codes and standards as follows:
◦PIC/S Part 1, Part 2 and Annexes
◦EU/UK EMEA, MHRA Eudralex Volume 4 (Orange Book)
◦US FDA 21CFR Parts 210 and 211,
◦US FDA 21 CFR Part 11 (Computers)
◦US FDA 21 CFR Part 820 (Devices)
◦WHO Guide to GMP 2007
◦ASEAN Code of GMP
◦ICH Q1, Q2, Q7, Q9, Q10
◦ISO 17025, 14971, 13485,
◦Industry Guidance Documents (PDA, GAMP, ISPE)

We stay current with regulatory changes in the USA, Europe and Asia to ensure that it meets a truly upfront global perspective. We are based in Singapore but service our client globally.

I hope we can co-operate a project and work together in near future. Please don’t hesitate to contact me for any question or future request.

Kind Regards,

Chuan Yao
Principal Consultant
ChemPharm (S) Pte Ltd
21 Jalan Sempadan #03-08
Singapore 457398
Tel: +65 6699 9007
Fax: +65 6699 9008
Mobile: +65 9673 1061

Email: chuan.yao@chempharm.asia

Skype: chuanyao1

What is 21 CFR Part 11

Title 21 in the federal regulations are regulations which regulates the Food and Drugs in United States of America. Part 11 within this Code of Federal Regulations is related to US Food and Drug Administration (FDA) guidelines about electronic records and electronic signatures.
The regulations in this part set forth the criteria under which the US FDA considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper. 21 cfr Part 11 became effective in August 1997

21 CFR Part 11, states the requirements for procedures for creating, modifying, maintaining, archiving, retrieving, and transmitting electronic records and electronic signatures by virtue of which they can be considered or rendered to be trustworthy, reliable and equivalent to paper records.

CFR 21 Part 11 requires that a drug manufacturer ,medical device manufacturer and biologics developers and all other industries regulated by FDA to implement controls for their electronic system, like audits, documentation for software , system validations, audit trails, electronic signatures, and for systems which are handling the electronic data which is required to be maintained by the FDA predicate rules or the systems which process data used for demonstration of compliance of a requirement or a rule.

CFR21 part 11 also applies to the electronic submissions made to FDA like ANDA, NDA.
Many drug manufacturers and felt that the 21CFR11 is bit difficult to implement in the way it is desired in the regulations and US FDA has listed the points why they gave relaxations at some points of implementation in CFR 21 part 11 are as follows.

1.Unnecessarily restrict the use of electronic technology in a manner that is inconsistent with FDA’s stated intent in issuing the rule.
2.Significantly increase the costs of compliance to an extent that was not contemplated at the time the rule was drafted.
3.Discourage innovation and technological advances without providing a significant public health benefit.
In an effort towards proper implementation US FDA released a guidance document in August of 2003 the

US FDA published the ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance which describes how US FDA intends to exercise enforcement discretion and sets forth the following considerations related to Part 11:

US FDA has made an announcement on 8-july-2010 with respect to implementation of cfr 21 part 11 as follows

The US (FDA) will be conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance (Guidance). The Agency intends to take appropriate action to enforce Part 11 requirements for issues raised during the inspections that do not fall under the enforcement discretion discussed in the Guidance.

1. CFR 21 Part 11 remains in effect since the issuance of the guidance and the exercise of enforcement discretion applies as identified in the guidance.
2.The guidance sets out certain conditions related to the validation, audit trail, record retention, record copying, and legacy systemswhere the US FDA says they do not intend to take enforcement action to enforce compliance. also FDA mentions that ‘Conversely, violations of CFR 21 part 11 requirements that do not fall within the guidance’s discretion can lead to enforcement action to enforce compliance depending on the importance of the violation’.
3.Records must also be maintained or submitted in accordance with regulatory requirements outside of Part 11, and we will enforce all predicate rule requirements, including predicate rule record and recordkeeping requirements.

Only part so far routinely enforced is access control, where as 21CFR11 the “predicate rules” which required the records to be kept in the first place are still in effect. If electronic records are illegible, inaccessible, or corrupted the manufacturers are still subject to those requirements.

Paper documents are still considered if a pharma company keeps “hard copies” of all mandatory records, for regulatory purpose the paper documents are also considered as authoritative documents.
A drug manufacturer is required to make a claim very carefully about the “hard copies” of mandatory records are authoritative document. Hence to the “hard copy should be an accurate and complete copy of its electronic source and can be used for regulatory purposes.

US FDA is expected to begin conducting the CFR 21 Part 11 focused inspections soon.

Also see CFR 21 part 11 and its application on computarised systems used in clinical trials US FDA guidelines, below

CFR 21 part 11 and its application on computarised systems used in clinical trials

CFR 21 part 11 and its application on computerised systems used in clinical trials , clinical studies , clinical investigations.

There is an increasing use of computerized systems in clinical trials to generate and maintain
source data and source documentation on each clinical trial subject. Such electronic source data and source documentation must meet the same fundamental elements of data quality (e.g.,attributable, legible, contemporaneous, original and accurate) that are expected of paper records and must comply with all applicable statutory and regulatory requirements. FDA’s acceptance of data fromclinical trials for decision-making purposes depends on US FDA’s ability to verify the quality and integrity of the data during US FDA’S on-site inspections and audits. (21 CFR 312, 511.1(b), and 812).

21 CFR part 11 was issued in march 1997 which provides criteria for acceptance by US FDA,under certain circumstances, of electronic records, electronic signatures, and handwritten signatures executed to electronic records as equivalent to paper records and handwritten signatures executed on paper.

After the effective date of 21 CFR part 11, significant concerns regarding the interpretation and implementation of part 11 were raised by both US FDA and Industry. As a result, US FDA had decided to reexamine 21 CFR part 11 with the possibility of proposing additional rulemaking, and exercising enforcement discretion regarding enforcement of certain part 11 requirements in the interim.

In May 2007 US FDA issued a guidance to address above issue , ie. Computerized Systems Used in Clinical Investigations , the recommendations made by US FDA are not legally enforceable but is the current thinking of US FDA and one should learn through this about how to implement 21 cfr part 11 in computerized systems used in clinical trials , clinical studies , clinical investigations .

It has given recommendations to sponsors of clinical trial , clinical study , contract research organizations (CROs), data management centers, clinical investigators, and institutional review boards (IRBs), regarding the use of computerized systems in clinical investigations. The computerized system applies to records in electronic form that are used to create, modify, maintain, archive, retrieve, or transmit clinical data required to be maintained, or submitted to the FDA. Because the source data are necessary for the reconstruction and evaluation of the study to determine the safety of food and color additives and safety and effectiveness of new human and animal drugs and medical devices,

Standard Operating Procedures with respect to CFR 21 PART 11. 

There should be specific procedures and controls in place when using computerized systems to create, modify, maintain, or transmit electronic records, including when collecting source data at clinical trial sites. A list of recommended standard operating procedures(SOPs) is provided in such SOPs should be maintained either on-site or be remotely accessible through electronic files as part of the specific study records, and the SOPs should be made available for use by personnel and for inspection by FDA.

Standard operating procedures (SOPs) and documentation pertinent to the use of a computerized
system should be made available for use by appropriate study personnel at the clinical site or
remotely and for inspection by FDA. The SOPs should include, but are not limited to, the
following processes.


*System setup/installation (including the description and specific use of software,
hardware, and physical environment and the relationship)
*System operating manual
*Validation and functionality testing
*Data collection and handling (including data archiving, audit trails, and risk assessment)
*System maintenance (including system decommissioning)
*System security measures
*Change control
*Data backup, recovery, and contingency plans
*Alternative recording methods (in the case of system unavailability)
*Computer user training
*Roles and responsibilities of sponsors, clinical sites and other parties with respect to the
use of computerized systems in the clinical trials

Also see 
Continue reading this article here 21 cfr part 11 FDA guidelines regarding the use of computerized systems in clinical investigations. as shown below

US FDA revised and issued rule for reporting safety information /adverse events / adverse reactions during clinical trials.

US FDA revised and issued rule for reporting safety information /adverse events / adverse reactions during clinical trials.

The United States Food and Drug Administration on 28-09-2010 has revised and issued its final rule for reporting an adverse reaction or adverse event in any clinical trial , where in earlier rule it was not mandatory to report certain adverse reaction or adverse event .

This rule has made it mandatory for a sponsor or investigator of a clinical trial to report with in 15 days of becoming aware about adverse reaction or adverse event.

The reports should include following findings.
1.Findings from clinical or epidemiological studies that suggest a significant risk to study participants
2.Serious suspected adverse reactions that occur at a rate higher than expected
3.Serious adverse events from bioavailability studies which determine what percentage and at what rate drug is absorbed by the bloodstream and bioequivalence studies which determine whether a generic drug has the same bioavailability as the brand name drug

This rule also specifies with example about when one should immediately report an ADR or ADE to US FDA and when one should wait till next event to be observed so that it will clarify all questions and drought amongst sponsors or investigators of a clinical trial of a of investigational drugs and biologics.

US FDA has also made it mandatory to report all adverse reactions and adverse event to be reported while performing, bioeqivalencestudy for ANDA and .Bioavailability and pharmacokinetic studies and any epidemiological study which suggest that the adverse reaction or adverse event may cause serious harm to public health.

It is one of the remarkable steps towards ensuring public health, in some of latest happening.
This final rule will make easier for US FDA to review of critical safety information and help them to monitor the safety of investigational drugs and biologics

These changes will be able to protect health of people participated in a clinical trials, also in new rule some definitions and reporting standards are also revised so as to make them more consistent with those by ICH (International organizations, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ) and the World Health Organization’s Council for International Organizations of Medical Sciences. The new rule is made to ensure harmonized reporting of globally conducted clinical trials.

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Title 21 CFR Part 11 of the Code of Federal Regulations deals with the United States Food and Drug Administration (FDA) guidelines on electronic records and electronic signatures (ERES). Part 11, as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records (Title 21 CFR Part 11 Section 11.1 (a)).

Practically speaking, Part 11 requires drug makersmedical device manufacturers, biotech companies, biologics developers, CROs, and other FDA-regulated industries, with some specific exceptions, to implement controls, including audits, system validations, audit trails, electronic signatures, and documentation for software and systems involved in processing electronic data that are (a) required to be maintained by the FDA predicate rules or (b) used to demonstrate compliance to a predicate rule. A predicate rule is any requirement set forth in the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, or any FDA regulation other than Part 11. [1]

The rule also applies to submissions made to the FDA in electronic format (e.g., a New Drug Application) but not to paper submissions by electronic methods (i.e., faxes). It specifically does not require the 21CFR11 requirement for record retention for tracebacks by food manufacturers. Most food manufacturers are not otherwise explicitly required to keep detailed records, but electronic documentation kept for HACCP and similar requirements must meet these requirements.

As of 2007, broad sections of the regulation have been challenged as excessive, and the FDA has stated in guidance that it will exercise enforcement discretion on many parts of the rule. This has led to confusion on exactly what is required, and the rule is being revised. (An update was posted on April 1, 2010 on the FDA Website). In practice, the requirements on access controls are the only part routinely enforced. The “predicate rules” which required the records to be kept in the first place are still in effect. If electronic records are illegible, inaccessible, or corrupted the manufacturers are still subject to those requirements.

If a regulated firm keeps “hard copies” of all required records, the paper documents can be considered to be the authoritative document for regulatory purposes and the computer system need not meet these requirements.[citation needed] Firms should be careful to make a claim that “hard copies” of required records are authoritative document. In order for the “hard copy” produced from its electronic source be considered as the authoritative document, the “hard copy” must (a) be a complete and accurate copy of its electronic source and (b) be used exclusively for regulated activities. The current technical architecture of computer systems increasingly makes the burden of proof for the complete and accurate copy requirement extremely high.[citation needed]


  • Subpart A – General Provisions
    • Scope
    • Implementation
    • Definitions
  • Subpart B – Electronic Records
    • Controls for closed systems
    • Controls for open systems
    • Signature manifestations
    • Signature/record linking
  • Subpart C – Electronic Signatures
    • General requirements
    • Electronic signatures and controls
    • Controls for identification codes/passwords


Various keynote speeches by FDA insiders early in the 21st century (in addition to high-profile audit findings focusing on computer system compliance) resulted in many companies scrambling to mount a defense against rule enforcement that they were procedurally and technologically unprepared for. Many vendors of software and instrumentation released Part 11 “compliant” updates, which proved to be either incomplete or insufficient to fully comply with the rule. Complaints about the wasting of critical resources, non-value added aspects, in addition to confusion within the drug, medical device, biotech/biologic and other industries about the true scope and enforcement aspects of Part 11 resulted in the FDA release of:

This document was intended to clarify how Part 11 should be implemented and would be enforced. But, as with all FDA guidances, it was not intended to convey the full force of law—rather, it expressed the FDA’s “current thinking” on Part 11 compliance. Many within the industry, while pleased with the more limited scope defined in the guidance, complained that, in some areas, the 2003 guidance contradicted requirements in the 1997 Final Rule.

In May 2007, the FDA issued the final version of their guidance on computerized systems in clinical investigations. This guidance supersedes the guidance of the same name dated April 1999; and supplements the guidance for industry on Part 11, Electronic Records; Electronic Signatures — Scope and Application and the Agency’s international harmonization efforts when applying these guidances to source data generated at clinical study sites.

FDA had previously announced that a new Part 11 would be released late 2006. The Agency has since pushed that release date back. The FDA has not announced a revised time of release. John Murray, member of the Part 11 Working Group (the team at FDA developing the new Part 11), has publicly stated that the timetable for release is “flexible.”

See also

External links

Good Weighing practice for lab and production balance

Good Weighing practice for lab and production balance


Weighing raw materials, product, reagents, excipients and other product related materials is a risk procedure in the Biotechnology and Pharmaceutical areas. Any weighing mistake in case not detected immediately, may affects the final drug substance/drug product purity, strength, quality and safety and may lead to recall or even to harm the patient health.

As part of GMP audits, many FDA 483 warning letters included comments regarding inappropriate balance and weighing process in production departments as well as in QC laboratory. Very often we face pharmaceutical and biotechnology companies using balance which does not comply the required characteristics such as minimum weight, certainty, accuracy etc…….

read all at


FDA publishes ICH Q4B – Annex 13 on Density of Powders

FDA publishes ICH Q4B – Annex 13 on Density of Powders

The ICH Guideline on Density of Powders has now been published by the FDA and has thus come into force in the USA. Read more in the News about the possible restrictions of the FDA.



On 28 May 2013, the FDA also finally published the ICH harmonised Guideline entitled “Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Bulk Density and Tapped Density of Powders – General Chapter (Q4B Annex 13)”.

This ICH Guideline thus came into force in the USA, too.

The objective of the ICH Q4B Working Group is to reach mutual recognition by regulatory authorities in the ICH regions for all testing methods listed in the ICH Q6A Guideline on Specifications.

Through this, comparable testing laid down in the different pharmacopoeias shouldn’t be performed separately when it has been assessed by authorities that those are similar and interchangeable.

Nevertheless, the FDA might request – if necessary – that a company demonstrates that the chosen method is acceptable and suitable for a specific material or product, irrespective of the origin of the method. This “Disclaimer” can be found in all the ICH Q4B Annexes. No one knows whether the FDA has already posed such questions.

For details please see the FDA Q4B – Annex 13.

Regulatory aspect of pharmaceutical change control system by DeveshDRA

CHANGE CONTROL,BENEFITS OF CHANGE CONTROL SYSTEM,MANAGEMENT OF CHANGE AND CONTINUOUS IMPROVEMENT(Prepare a Change Proposal ,Classify & Approve Proposed Changes,Develop an Implementation Plan

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