GMP’s for Early Stage Development of New Drug substances and products
|Description||range of colour|
|identification||conforms to a reference spectrum|
|assay||97–103% on a dry basis|
|impurities||NMT 3.0% total, NMT 1.0% each|
|mutagenic||follow EMA guidelines (pending ICH M7 guidance)|
|inorganic||follow EMA guidelines (pending ICH Q3D guidance)|
|residual solvents||use ICH Q3C limits or other justified limits for solvents used in final synthetic step|
|water content||report results|
|solid form||report results|
|particle size||report results|
|residue on ignition||NMT 1.0%|
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
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The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.
The following details the necessary procedure for the commencement of manufacture (or importing) of drugs in Mie Prefecture, Japan.
Note: The procedures described below are applicable in Mie Prefecture, Japan, as of April 2002. Due to future amendments and the disparities of laws in different prefectures, it is necessary to be informed as to the correct application procedures directly by the relevant prefecture.
1. For Manufacture (or Importing) of Drugs
Approval for the manufacture (importing) of each item, and a manufacturing (importing) license are required for the manufacture (or importing) of drugs.
|Drug Manufacture||Approval||The quality, effectiveness and safety of the drug under application must pass the examination. However, drugs listed on the Pharmacopoeia of Japan do not require approval.|
|License||The structural conditions (building and facilities) and human resource requirements (e.g. Administrators) of the drug manufacturing facilities must pass the examination to acquire a business license.|
2. Standard Period for the Administrative Process
There is a standard period for the administrative process of the approval and licensing examinations. Unless there are irregularities in the application or supplied data, the examinations are generally completed within the time specified.
|*Approval||Ethical Drugs||(new drugs)||1 year|
|(branded generic drugs)||1 year|
|Non-prescription drugs||10 months|
|IVD (in vitro diagnostic)||6 months
(approval for modification of storage conditions and period of effectiveness: 3 months)
|*Mie Prefectural License
(for manufacture or importing)
|Drugs, quasi-drugs, cosmetics, or new medical devices||56 days|
(1) The above periods for approval and licensing are applicable only in Mie Prefecture. Be aware that the standard periods for the administration process may differ in other prefectures. Further, the above period may be extended where a replacement of the application documents is required.
(2) Please feel free to contact us if you have any further questions.
3. Drug Approval Inspection
Apart from those drugs which do not require approval, most drugs are approved by the Minister of Health, Labor and Welfare, and some are approved by the Governor. However, approval and receipt of applications based on both national and prefectural standards will occur at the prefectural government. The drug approval process is detailed below.
Quasi-drugs, and medical devices are approved under the same process as drugs. As for cosmetics, those which contain ingredients that are not displayed, require approval.
4. License for Drug Manufacture (or Importing)
Below is a flowchart illustrating the license application process in Mie Prefecture. Applications are accepted by the Mie Prefectural Government.
At present, provided that there are no problems found at the site inspection, licensing will take 2 weeks. If you require licensing within 2 weeks due to your production schedule, with advance notice, we may give you special consideration and shorten the duration of the licensing process.
The license is valid for 5 years, and must be renewed after 5 years. In addition, the application process for the business license for manufacturers (and importers) of quasi-drugs, cosmetics, and medical devices is the same as for a drug manufacturer (or importer).
Pharmaceutical Affairs Food Team, Mie Prefectural Government
13 Komei-cho,Tsu City,Mie Prefecture 514-8570 Japan
TEL +81-59-224-2330 or 2331/FAX +81-59-224-2344/E-mail firstname.lastname@example.org
WHAT IS MIE PERFECTURE..SEE………http://en.wikipedia.org/wiki/Mie_Prefecture
With an improved clinical trial infrastructure now a high priority, Japan offers an advantageous development environment for pharmaceutical, biotechnology, and medical device companies. To address a decade-long downward trend in trial applications and a lag in the availability of drugs within the country as compared to other developed nations, Japan’s Ministry of Health, Labor and Welfare (MHLW) has ushered in significant changes in recent years. These include bold steps to create a more welcoming and efficient approach to trials while maintaining global standards such as those of the International Conference on Harmonization/ Good Clinical Practice (ICH-GCP).
Revisions to the Pharmaceutical Affairs Law (PAL) of 2005 indicate that indeed the Japanese regulatory review process is in a new era. While the process continues to pose challenges, significant development opportunities now exist for organizations that successfully navigate this transitional terrain.
This article presents an overview of the Japanese population for clinical studies as well as the regulatory environment, with emphasis on how regulations differ from ICH-GCP standards.
The 127 million people of Japan make up a population whose total has remained unchanged for the last 20 years due to a declining birthrate. The population is aging and boasts the world’s longest average lifespan at 79.19 years for men and 85.99 years for women, according to the CIA World Factbook, 2009.
Japan is the second largest market worldwide in terms of pharmaceutical sales, behind the US and just ahead of China. According to IMS Health, sales grew 7.6% in 2009 over 2008. This high rate of pharmaceutical consumption is an irony given the fact that many top-selling products globally have not even been made available in Japan due to the lengthy and expensive trial and approval process.
Primary health conditions and treatment needs in Japan are in the areas of: Oncology, Diabetes, Gastroenteritis, Diseases of the Elderly, Respiratory Diseases, Cardiovascular Diseases, Hepatitis, Infectious Diseases, Central Nervous System (CNS) Diseases, Musculoskeletal and Joint Disorders, Immunology, and Vaccines.
National Healthcare Provision
Healthcare services in Japan are provided by national and local governments offering relative equality of access, with fees set by committee. People without insurance from employers can participate in a national program administered by the local government. All elderly are also covered by a government program. Patients may select physicians and facilities of their choice.
A Fresh, Welcoming Environment
With recent amendments to PAL, drug and device developers can now plan and conduct clinical trials in Japan under Clinical Trial Notifications (CTNs), which are reviewed in just 30 days, a turnaround time comparable to that achieved in the US. A grant program subsidized by MHLW is designed to accelerate the development of high-priority drugs and medical devices recommended by the member societies of the Japanese Association of Medical Sciences (JAMS) that are:
- Widely used as standard treatment in the US or Europe but not yet approved in Japan
- Already marketed in Japan and commonly used for off-label indications1
Interest in revitalizing the clinical trials process in Japan is increasingly obvious through improved infrastructure, IT investments, and education of physicians and patients on the need for reform. The Japanese market offers dedicated research teams within national and university hospitals across a variety of therapy areas. Networks such as the National Hospital Organization facilitate reaching into both large- and medium-sized cities with multiinstitutional studies and clinical trials. Such an environment offers direct access to healthcare professionals, including a solid network of primary care physicians.
The Japanese market also can make accessible large groups of aging, recurrent patients in specific therapy areas. And, although a variety of dialects are spoken, the Japanese communicate via one standard language, making communicating with patients and investigators easier.
Japanese investigators participate in international conferences and are ICH-GCP and Japan GCP compliant. As the government wants to maintain and encourage further research within the country, both on-site and centralized Institutional Review Boards (IRBs) convene regularly (as often as once a month) to keep the clinical study process moving. Centralized IRBs that are managed by Site Management Organizations (SMOs) are especially flexible in this regard.
Another advantage is that smaller communities within hospital regions develop strong patient/research links, so patients tend to be compliant, and sites increasingly deliver the predicted patient numbers.
Remaining Hurdles Require In-Country Expertise
Although Japan provides high-density populations in urban areas, patients can be difficult to recruit because of their easy access to healthcare coverage. The lack of an incentive to participate, coupled with little awareness of the need for trials, continues to be problematic and adds to the trial timeline.
What is more, the cost of conducting clinical trials in Japan remains higher than in the West because of the need to use SMOs, which add labor costs. There is no specialized research hospital in Japan, so SMOs, having access to a pool of patients, are essential.
Trials also tend to take longer for a range of reasons – from the lack of patient incentives and lower physician incentives to the still maturing infrastructure.
Due to the complexities of conducting research in Japan, corporate sponsors should ensure that they have ready access to in-country experts.
The Regulatory Landscape
Recent changes to the regulatory system for pharmaceuticals and medical devices have enabled Japan to align its safety measures more closely with those of other developed nations. Since its establishment in 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) has provided comprehensive risk management from pre-clinical research to approval through three functions: review (risk reduction), safety (continuous risk mitigation), and relief (services for adverse health effects).
Improving the infrastructure for clinical trials has been a primary focus in Japan. The Center for Clinical Trials of the JMA (JMACCT) was also established in 2004 to promptly provide the public with medically necessary or new pharmaceutical products and medical devices, organize multiple medical institutions into a network, and conduct model clinical trials.
The current regulatory environment in Japan encompasses:
Procedures for Drug Approval Applications (NDAs)
- The application is made after completion of nonclinical and clinical trials
- Required GCP, GLP, and GMP surveys should be applied for immediately after the NDA submission
- The manufacturer and/or distributor must be authorized and, if a manufacturing plant is overseas, the appropriate accreditation must be obtained
- Information must include the origin or background of discovery, characteristics and efficacy, records of consultation with PMDA, a list of drugs of the same type/indication, conditions of use in other countries, and package inserts
NDA Review Process
PMDA frequently performs a team review with experts in quality, nonclinical, and clinical trials, biostatistics, and other fields.
Notification of Clinical Trial Plan
The Minister in charge of Clinical Trial Protocols must be notified in advance of trials for drugs with new active ingredients, new routes of administration, new combination drugs, new indications, new dosages, and biologics.
Scope of Reporting
When performing a clinical trial, the following information must be reported:
- Unexpected death or cases of adverse experiences potentially leading to death
- Other unexpected serious events, adverse experiences requiring hospitalization, disability, adverse experiences leading to disability, congenital disease or abnormality in a subsequent generation
- Measures taken in foreign countries to prevent the occurrence or spread of risk to public health and hygiene (including discontinuation of manufacturing, import, or marketing or withdrawal or disposal of an item with ingredients equivalent to those of test products; also including revision of the precautions, accompanied by a letter to the distributing doctor)
- Research reports indicating the possibility of the drug causing cancer or any other serious disease due to adverse reactions or showing a lack of anticipated efficacy or clinical benefit
While the precise wording differs, the reporting requirements in Japan reflect the spirit of those in Western markets. The EU, for example, requires that sponsors report untoward medical occurrences from any dose that result in death, are life threatening, require or prolong hospitalization, lead to persistent or significant disability, or a congenital anomaly or birth defect.
Differences Between Japan’s GCP and ICH-GCP
Japanese regulatory authorities are particularly eager to avoid any misconduct related to clinical trials, such as past deficiencies in case report forms (CRFs), informed consent, institutional review board practices, and protocol deviations. Transparency is a primary goal for the revised process.
Japan’s GCP places greater responsibility on the institute and its head such that:
- The contract is between the sponsor and the institute, not between the sponsor and the investigator
- Items covered in the contract must be defined
- Each institute must have an IRB
- The sponsor must prepare a policy for compensating trial participants for any injuries during the trial prior to submitting documents to the IRB. This policy must be included while obtaining informed consent. In the case of injury, “the subject should be adequately compensated regardless of whether or not the injury is due to negligence. The subject is not burdened with providing a causal relationship.”
- A sponsor that does not have an address in Japan must select an In-Country Caretaker (ICC). A CRO in Japan can act as the ICC on behalf of the sponsor. (See sidebar on ICC Responsibilities.)
- Product labels must be in Japanese.
Safety information must be reported periodically (such as every six months) after submission of the initial Clinical Trial Notification (CTN) and within two months after the study is completed.
According to the ICH guidelines, (sections, 5.16.1/2 and 5.17) sponsors are to promptly notify all concerned investigators, institutions, and authorities of findings that could adversely affect subjects’ safety or the course of the trial. Suspected, unexpected serious adverse reactions require expedited reporting, while all other safety information can be included in an annual safety report.
While many of the provisions are similar, any differences between Japan’s GCP and ICH-GCP must be understood and acted upon. The sponsor should be certain that a regulatory expert is engaged and available for consultation during the clinical trial process.
In the realm of clinical trials, Japan may still be a “developing” country, but is certainly one focused on revitalization and global harmonization. Increased demand and resources for pharmaceutical and medical device research have spurred a new era of reform with the budgets and resources required. Not all the challenges have been addressed, but a more stable and effective infrastructure, network, and standards are now in place. In planning for global studies, sponsors can now be assured that Japan is ready to participate from the outset and is governed by regulations that are tracked closely with the International Conference on Harmonization standards.
The In-Country Caretaker (ICC) is responsible for the progress of clinical trials and must be the primary contact for any regulatory interaction on behalf of the sponsor company. The ICC oversees:
- All clinical development work on behalf of the sponsor
- Submission of a Clinical Trial Notification (CTN) to the PMDA
- Replies to questions raised by the PMDA
- Supply of the investigational drug, including customs clearance, requests made to the drug depot or the contract manufacturing organization (CMO), and the checking of manufacturing records and QC tests
- Monitoring of the clinical trial and preparation of the Clinical Study Report (CSR)
- Collection and reporting of information on adverse reactions, including from overseas
- Translation of documents and data (English to Japanese / Japanese to English)
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
How much does quality cost? Most companies would be hard-pressed to translate “quality” into dollars and cents. What they realize, however, is that a lack of quality could cost millions of dollars in rework, scrap, recall, or even liability lawsuits.
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