QbD: new Guidance from EMA and FDA
The European Medicine Agency (EMA) and the U.S. Food and Drug Agency (FDA) have published a joint question-and-answer document that provides further guidance on the quality-by-design concept. Read more.
The Quality by Design (QbD) concept has been introduced by the International Conference on Harmonisation (ICH) document Q8, supported by Q9, Q10 and also Q11. In the meantime it is well-known within the pharmaceutical industry. However many companies still struggle with the implementation. Both the European Medicine Agency (EMA) and the U.S. Food and Drug Agency (FDA) are supporting the pharmaceutical industry in the employment of the paradigm. Now, EMA and FDA have published a second joint question-and-answer document that provides further guidance on the quality-by-design concept.
The new document focuses on ‘design space verification’ and reflects conclusions reached in the on-going parallel assessment, which was launched in 2011. The objective of the parallel assessment is to share knowledge, facilitate a consistent implementation of the international guidelines on the implementation of the quality-by-design concept and promote the availability of medicines of consistent quality throughout the European Union (EU) and the USA.
The EMA and the US FDA will publish further conclusions on other quality-by-design-related topics as the pilot programme continues and more parallel assessments are conducted.
Source: EMA press release
The European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) have published a second joint question-and-answer document that provides guidance on the quality-by-design concept.
Quality-by-design is a science and risk-based approach to pharmaceutical development and manufacturing. It involves designing and developing pharmaceutical formulations and manufacturing processes to help ensure product quality; these concepts are described in the international guidelines ICH Q8, Q9, Q10 and Q11.
The document published today focuses on ‘design space verification’, a demonstration that the combination of the process parameters and material attributes established at pilot scale during pharmaceutical development are capable of delivering a product of appropriate quality on a commercial scale.
In March 2011, the EMA and US FDA launched a three-year pilot programme for the parallel assessment of certain quality or chemistry manufacturing and control (CMC) sections of applications that are relevant to quality-by-design. With the agreement of the applicants, experts from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) participate as observers in the programme.
The objective of the parallel assessment is to share knowledge, facilitate a consistent implementation of the international guidelines on the implementation of the quality-by-design concept and promote the availability of medicines of consistent quality throughout the European Union (EU) and the USA.
The question-and-answer document published today reflects the conclusions reached by the EU and US regulators on the specific topic of design space verification as part of their parallel assessment.
The EMA and the US FDA will publish further conclusions on other quality-by-design-related topics as the pilot programme continues and more parallel assessments are conducted.
The pilot programme is open to selected procedures, including applications for initial marketing authorisations, type-II variations and scientific advice. Participation in the pilot is voluntary. Interested applicants and sponsors should notify both agencies three months prior to submission of an application.
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
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
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
. 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
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
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
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;
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
back to home for more updates
DR ANTHONY MELVIN CRASTO Ph.D
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.
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.
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 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
LIST OF STANDARD OPERATING PROCEDURES FOR 21 CFR PART 11 COMPLIANCE IN CLINICAL TRAILINVESTIAGTONS. (IT MAY BE BIGGER LIST AS REQUIRED BY INDIVIDUAL ORGANISATION)
*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
*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
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.
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.
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 makers, medical 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. 
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. 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.
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.”
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