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Page 2 of 32
Report of the Committee to assess the health
and environmental impact of the use of
Polyethylene Terephthalate (PET) or Plastic
containers for primary packaging of drug
formulations
Page 3 of 32
CONTENTS
SECTION-I BACKGROUND 3 – 7
SECTION -II SCIENTIFIC BACKGROUND 8-15
SECTION -III HIM JAGRITI & INDUSTRY
PRESENTATIONS AND INDIAN
PRODUCT TESTING
16-23
SECTION -IV REGULATORY REQUIREMENTS AND
STANDARDS
24-28
SECTION-V SPECIFIC RECOMMENDATIONS OF
THE COMMITTEE
29-31
ANNEXURES
ANNEXURE 1
ANNEXURE 2
ANNEXURE 3
ANNEXURE 4
ANNEXURE 5
ANNEXURE 6
ANNEXURE 7
ANNEXURE 8
ANNEXURE 8a
ANNEXURE 8b
ANNEXURE 8c
32-173
33-36
37-39
40-47
48-52
53-69
70-94
95-110
111-173
112-121
122-136
137-173
Page 4 of 32
BACKGROUND
Section - I
Page 5 of 32
Ministry of Health and Family Welfare, Government of India, vide order
No.X.11014/10/2013-DFQC (Vol.II) dated 14th August 2015 constituted a Committee
under the Chairmanship of Prof. M.K. Bhan, Former Secretary, Department of
Biotechnology, Ministry of Science and Technology, Govt. of India to assess the health
and environmental impact of the use of Polyethylene Terephthalate (PET) or plastic
containers for primary packaging of drug formulations. The membership and specific
terms of reference for the Committee are provided in the copy of the order provided
here with as Annexure 1.
The Committee members included Senior officials and Scientists of Government
Departments and relevant scientific institutions in the country including Directorate
General of Health Services (DGHS), Ministry of Health & Family Welfare, Central
Institute of Plastic Engineering & Technology (CIPET), Department of Chemicals &
Petrochemicals, Indian Council of Medical Research (ICMR), Department of Science
and Technology, Ministry of Micro, Small and Medium Enterprises, Department of
Pharmaceuticals, Department of Industrial Policy & Promotion, Ministry of Environment,
Forest and Climate Change, Central Drugs Standard Control Organisation (CDSCO),
Central Drugs Research Institute (CDRI), National Institute of Pharmaceutical Education
and Research (NIPER), Ahmedabad, Bureau of Indian Standards (BIS), Quality Council
of India, Indian Institute of Technology (IIT), Kharagpur and others.
In the meeting notice dated 6th October 2015, issued by the Department of Health and
Family Welfare, Ministry of Health & Family Welfare, four eminent scientists of the
country relevant to the subject, namely, Dr. V.M. Katoch, Ex. Secretary, Department of
Health Research & Director General, ICMR; Dr. Y.K. Gupta, Professor & Head,
Department of Pharmacology, AIIMS, New Delhi; Dr. P.K. Seth, CEO, Biotech Park,
Lucknow and Dr. R.S. Dhaliwal, Scientist F, ICMR were co-opted as members of the
Committee (Annexure 2).
The Committee adopted an open, participatory approach and invited various other
stakeholders such as representatives of organizations involved with standards,
regulation, manufacturing industry, environment including the appellant Him Jagriti.
They were invited not only to present their views but also asked to actively participate in
the entire deliberations with a view to achieve a transparent, Science driven evidence
synthesis and its objective interpretation. The Committee was also made aware of the
earlier judicial pronouncements and reports of the other Committees on the issue.
To achieve faster progress, a Sub-Committee chaired by Prof. Y K Gupta of AIIMS
including senior officers of Central Drugs Standard Control Organization (CDSCO) and
scientists from Indian Pharmacopeia Commission (IPC) and Bureau of Indian
Page 6 of 32
Standards (BIS) was constituted. The primary focus of the Committee’s investigation
has been on health impacts but issues related to environmental impact were also
discussed.
The meetings of the Committee with other stakeholders were held on 15-10-2015 and
04-02-2016. Additionally, many Sub-Committee meetings were held as requested by
the chair to examine relevant publications and reports in detail and brief the larger
Committee. The Sub-Committee met several times and undertook detailed critical
analysis of the available test reports, regulatory guidelines, scientific publications and
basic scientific facts about the plastic materials used in pharmaceutical packaging. Their
inputs were provided to the entire Committee.
At the first meeting of the full Committee held on 15th October 2015 at Nirman Bhawan,
Ministry of Health and Family Welfare, the approach and roadmap for examination of
the matter was finalized. The minutes of this meeting are provided as Annexure 3.
In this meeting, the Director (Drugs), the Member Secretary of the Committee explained
the core issue and the basis of the review as below.
The Government received a representation from a Non-Governmental organization,
Him Jagriti, raising concerns about harmful effects of use of PET/ Plastic bottles in
packaging of pharmaceutical products. The issue was subsequently considered by
an Expert Committee and Drug Technical Advisory Board (DTAB), a Statutory Board
under the Drugs & Cosmetics Act, 1940. Based on DTAB recommendations,
Ministry of Health and Family Welfare issued draft Rules on 29.09.2014, proposing a
ban on use of PET or plastic containers for liquid oral formulations for primary
packaging of drug formulations for pediatric use, geriatric use and for use in case of
pregnant women and women of reproductive age group. The Committee was
informed that an application seeking prohibition of use of plastics in consumables
and pharmaceuticals is under litigation in National Green Tribunal.
Subsequently, various stakeholders including PET Container Manufacturers
Association and Pharmaceutical industry submitted their representations to the
Ministry on the draft Rules.
In view of these developments, the current Committee was asked by the Ministry of
Health and Family Welfare to examine the issue afresh, taking into account all the
scientific evidence and information related to linkage between the use of PET and
plastic containers for packaging of Pharmaceutical preparations and health effects.
Page 7 of 32
STANDARDIZATION OF THE COMMITTEE’S WORK PROCESSES
The following working process was agreed to in the first meeting of the Committee held
on 15th October 2015.
To follow a process comprising of systemic collection of evidence, critical analysis,
documentation of issues arising from discussions and the views from experts in
arriving at the final conclusions and recommendations.
To do critical analysis of the tests reports submitted by the appellant on PET bottles
from different laboratories/test house
To examine the pertinent requirements/ guidelines/ procedures including those of
USFDA, European Medicines Agency, and WHO
To examine and do a comparative analysis of the standards prescribed in Indian
Pharmacopeia and other pharmacopeias (USP, EP, BP, etc.)
The Sub-Committee was requested by the Chair to perform the above detailed
analysis and brief the Committee.
The application pending in National Green Tribunal came up for hearing on 20th
January, 2016 & subsequently on 22nd January, 2016. In compliance with the order of
the Tribunal dated 20th January, 2016, the Chairman of the Committee, senior officials
of Ministry of Health & Family Welfare and CDSCO were present at the Tribunal and
received directions regarding acceleration of the Committee’s work and submission of
the report.
The Sub-Committee was requested to prepare a first draft report for consideration of the
Committee.
The second meeting of the full Committee was held on 4th February 2016 at Nirman
Bhawan, New Delhi. The meeting notice is provided as Annexure 4 and the minutes of
the meeting along with list of participants are provided as Annexure 5. Dr. Y.K. Gupta
presented a detailed and structured questionnaire for collection of evidence,
documentation of practices, various standards/ procedures followed in India and other
countries, critical analysis of published literature on use of PET/Plastic bottles and its
effect on health. This process was concurred by the full Committee.
Page 8 of 32
In this meeting, presentations were made by representatives of PET Containers
Manufacturers Association (PCMA) and the representatives of Him Jagriti.
PCMA made presentation on behalf of all industry associations present in the meeting.
The presentation by PCMA and Him Jagriti are provided as Annexure 6 & 7
respectively.
The third and final meeting of the committee was held on 7th March 2016 at CDSCO
Head Quarters, FDA Bhavan, Kotla Road, New Delhi. The draft report prepared by the
drafting Sub-Committee was discussed in the meeting. The consensus achieved in this
meeting forms the basis of this report.
Page 9 of 32
SCIENTIFIC BACKGROUND
Section - II
Page 10 of 32
PACKAGING OF PHARMACEUTICAL PRODUCTS
Primarily two types of materials are most commonly used for preparing containers for
pharmaceutical packaging viz. glass and plastic.
Glass:
For large number of pharmaceutical products glass containers are used. Different types
of glass may be necessary for packaging of pharmaceutical products depending on
nature of the product, dosage forms and routes of administration.
Type 1, Borosilicate glass is highly resistant to hydrolysis and is chemical inert.
Type 2, Treated soda-lime glass is characterized by high hydrolytic resistance and is
more susceptible to leaching than type 1 glass.
Type 3, Regular soda-lime glass is untreated soda-lime glass with moderate hydrolytic
resistance and has more leachable oxides than type 2 glass.
Plastics:
Plastics are composed of a mixture of polymers having a range of molecular weights.
Plastic materials commonly used for pharmaceutical packaging include;
Polyethylene (low density polyethylene (LDPE) and high density polyethylene (HDPE),
Polypropylene, Polyvinyl chloride, Polystyrene and Polyethylene Terephthalate (PET)
Plastic containers have several advantages compared with glass containers such as
they are unbreakable, collapsible and light
As mentioned in Indian Standard, IS 14534 ‘Guidelines for the Recovery and Recycling
of Plastics Wastes’, Resin identification code given by Society of Plastics International
distinguishes various polymers from each other. The code given for different types of
plastic polymers along with monomer (raw material) used is summarized below.
Page 11 of 32
Resin Identification Code Type of plastic polymer Monomers used to
prepare the plastic
Polyethylene
terephthalate (PET)
Terephthalic acid,
Isophthalic acid,
Monoethylene glycol
High density polyethylene
(HDPE) Ethylene
Polyvinyl chloride (PVC) Vinyl Chloride monomer
Low density polyethylene
(LDPE) Ethylene
Polypropylene (PP) Propylene
Polystyrene (PS) Styrene
Other plastics [often
Polycarbonate (PC) or
Acrylonitrile butadine
styrene (ABS)]
Polycarbonate:
Bisphenol-A, Diphenyl
carbonate or phosgene
ABS: Acrylonitrile,
butadiene, styrene
Page 12 of 32
PET:
PET stands for ‘Polyethylene Terephthalate’, a long chain polymer belonging to
polyester family. It is made by reacting purified terephthalic acid (PTA) or dimethyl
terephthalate and monoethylene glycol (MEG) in presence of very small amount of
catalyst. Antimony trioxide is the preferred catalyst used for production of PET.
To achieve transparency in the PET bottles, purified isophthalic acid (PIA), about 2-3%,
is used as a co-monomer to the base formulation. A higher molecular weight is needed
to enable PET to be blown into bottles. This is achieved by ‘solid-state polymerization’
which is done by heating the base resin without the addition of any other chemical or
catalyst.
Terephthalic acid and isophthalic acid are the two isomers that permits building of
properties in PET and allows it to be converted into bottles or other containers. PET is
the material most commonly used to make clear plastic bottles used for packaging of
drinking water. It is also used for packaging of soda beverages, sports drinks, food,
cosmetics, pharmaceuticals etc.
Phthalates, bisphenol-A and heavy metals except antimony are not used in the
manufacture of PET. PET is recyclable. The industry representative emphasized that
the recycled PET material is not used for making containers for pharmaceutical
packaging and is indeed commercially unattractive. Recycled PET is however used for
other purposes like fibers, strappings, cushions, curtains, mattresses, pillows, etc.
USE OF PLASTIC/ PET IN PHARMACEUTICAL PACKAGING
As per the information submitted by the industry associations/ BIS/ IPC, the PET/plastic
bottles are used world-wide for packaging of food stuffs, drinking water and aerated
drinks since 1970s. Since 1980s, the PET/plastic bottles are also used in India for the
packaging of food stuffs, drinking water and aerated drinks. Further these bottles are
being used for packaging of alcoholic drinks and pharmaceuticals late 80s or early 90s.
However no official date of approval of PET/Plastic bottles for the above use is
available.
Page 13 of 32
To the best of our knowledge, the year of first appearance of standards of PET/plastic
for packaging of pharmaceutical products in different Pharmacopeia and BIS standards
are given in the table below.
Pharmacopeia/ Agency Year of first
appearance (Plastic)
Year of first appearance
(PET)
USP 1965 1995
BP 1968 1973
IP 1985 1996
BIS 1987 1987
Overall, the PET/Plastic bottles are in use for at least more than 30 years in developed
countries as well in India and standards have been prescribed by various Pharmacopeia
for its use in pharmaceutical packaging. The risk assessment instruments and
regulatory requirements have been updated periodically but not in any substantial
manner.
PHTHALATES IN PLASTICS/ PET:
Phthalates are esters of phthalic acid. To make plastics (especially polyvinyl chloride)
more flexible and durable, phthalates are used as plasticizers. The term ‘phthalates’
refer to ‘orthophthalates’ (esters of 1,2-benzene dicarboxylic acid). PET contains
terephthalic acid (1,4‐benzene dicarboxylic acid) and isophthalic acid (1,3-benzene
dicarboxylic acid). Orthophthalates are not present in PET and PET does not require
use of phthalates or other plasticizers during manufacturing process.
PHTHALATES AS EXCIPIENTS IN PHARMACEUTICAL PRODUCTS
Certain phthalates are used as excipients in many pharmaceutical formulations. They
are most commonly used as plasticizing agents in enteric film-coating materials or as a
matrix binder for tablets, capsules, beads and granules. Commonly used phthalates in
pharmaceutical products are: dibutyl phthalate (DBP), diethyl phthalate (DEP),
Page 14 of 32
diethylhexyl phthalate (DEHP), polyvinyl acetate phthalate (PVAP), cellulose acetate
phthalate (CAP) and hydroxypropylmethylcellulose phthalate (HPMCP).
The ortho-phthalate esters DBP and DEP are low-molecular weight diesters of ortho-
phthalic acid (also called phthalic acid), formed from short-chain alcohols. The high-
molecular-weight phthalate polymers; CAP, HPMCP and PVAP, are polymers modified
by esterification with ortho-phthalic acid groups.
Some phthalates like Diethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP) are
suspected to be endocrine disruptors. In some animal studies, phthalates were shown
to affect male reproductive system and were associated with infertility, decreased sperm
count, cryptorchidism, hypospadias and other reproductive tract abnormalities. In animal
model, all phthalates do not exhibit the same toxicity profile. Among the several
varieties of phthalates, some are more toxic, while others are not. Phthalates with linear
ester side chains having 4-6 carbon atoms are considered to be potentially more toxic
with regards to reproductive effects. Among the phthalates, dibutyl phthalate and
diethylhexyl phthalate are considered to be most toxic.
The human studies overall are limited in number and scope and there is large
inconsistency in the finding of available human studies. The reproductive and
developmental effects of phthalates claimed in some observational human studies
include shortened anogenital distance in newborn boys, shortened pregnancy, lower
sex hormone levels, and reduced sperm quality in adults. Diethylhexyl phthalate
(DEHP) is suspected to be carcinogenic in humans.
Major regulatory Authorities such as USFDA, EMA have developed detailed guidelines
regulating the use of phthalates as excipients in pharmaceuticals.
As per USFDA Guidance for Industry: Limiting the Use of Certain Phthalates as
Excipients in CDER-Regulated Products, December 2012, there is evidence that
exposure to DBP and DEHP from pharmaceuticals presents a potential risk of
developmental and reproductive toxicity. Therefore, the agency has recommended
avoidance of use of DBP and DEHP as excipients in the drugs and biologic products
regulated by them.
As per the EMA Guidelines on the use of phthalates as excipients in human medicinal
products, dated 20 November 2014, certain phthalates are associated with effects on
reproduction and development in relation to their hormonal (anti-androgenic) properties.
Page 15 of 32
After reviewing the data, EMA has concluded that there are, presently, no data
indicating that the presence of CAP, PVAP and HPMCP in human medicinal products
constitutes a potential risk for human safety. For DBP and DEP, adverse reproductive
and/or developmental effects have been observed in non-clinical studies and as a
consequence, Permitted Daily Exposures (PDEs) values of 0.01 and 4 mg/kg/day for
DBP and DEP respectively have been recommended.
OTHER USES OF PHTHALATES:
Phthalates are also found in other products for uses such as, solvents in perfumes, and
additives to nail polish, as well as in lubricants and insect repellents.
Data from the National Health and Nutrition Examination Survey (NHANES), USA
indicated widespread exposure of the general population to phthalates in USA. Humans
are exposed to phthalates by multiple routes, including inhalation, ingestion, and to a
lesser degree absorption through the skin. Several observational human studies have
reported an association between exposure to certain phthalates and adverse
developmental and reproductive effects. The ubiquitous presence of phthalates in the
environment and the potential consequences of human exposure to phthalates have
raised concerns, particularly in vulnerable populations such as pregnant women and
infants.
Some countries have banned the use of certain phthalates in toys and childcare articles.
This does not include pharmaceutical containers.
ANTIMONY, OTHER HEAVY METALS AND BISPHENOL-A IN PLASTICS/PET
Antimony is used as catalyst in the manufacturing of PET resin in a quantity < 300ppm
and it is fixed in the polymer matrix. Other heavy metals like Cadmium, Chromium,
Lead, Aluminium, Arsenic, Mercury, Tin and Zinc are not used in the manufacturing
process of PET. Bisphenol-A is used in the manufacturing of polycarbonate plastics.
BPA is reported to be a possible endocrine disruptor causing harmful effects in
reproductive system. It is not used in manufacturing PET resins.
Whether PET is contaminated with heavy metals from other sources in the
manufacturing process needs further research. In this regards, water used in
manufacturing process, type of metals and containers used should be taken into
consideration for careful examination.
Page 16 of 32
LEACHING OF PHTHALATES AND OTHER CHEMICALS:
Since phthalates are not added in manufacturing of PET, a general consideration would
be that phthalates cannot leach from PET. However, some publications have raised
concerns about the presence of phthalates in drinking water, beverages and other food
substances packaged in PET containers. Source of such substances remains largely
unanswered.
Various explanations have been given for the presence of phthalates in drinking water,
beverages, etc. in few studies that reported such findings. The source of such
substances, as reported, could be containers, cap-sealing resins, water/ content, use of
recycled PET, contamination of the drinking water with phthalates before packaging,
improper analytical procedures, lack of standard operating procedures, etc.
The research is not exhaustive enough to demonstrate the reproducibility of the findings
that PET material is the source of phthalates in the drinking water, beverages and
others. Nevertheless, it is important to take note of any report showing the presence of
phthalate and other chemicals in PET bottles.
Majority of the publications on PET are not on pharmaceutical products. There are
paucity of reports in indexed journals indicating leaching from PET/plastic bottles used
in pharmaceutical packaging. Many publications have concluded that there is a need of
further investigation/ research to find out the harmful effects, if any, associated with the
use of plastic/PET packaging materials.
Form the view point of consumption, packaged water and pharmaceutical product may
differ in respect of, quantity of consumption per day/ total consumption, frequency, pH,
content and other aspects
Page 17 of 32
HIM JAGRITI & INDUSTRY PRESENTATIONS
AND INDIAN PRODUCT TESTING
Section - III
Page 18 of 32
PET CONTAINERS MANUFACTURERS ASSOCIATION (PCMA) PRESENTATION
The significant points in the PCMA presentation
In its presentation PCMA reviewed the chemistry of PET, other plastics, emphasized
that PET does not contain orthophthalates, heavy metals and Bisphenol-A; that
Antimony is used in very small amount (<300 ppm) as a catalyst in manufacturing PET
resin and that it is completely fixed in the polymer matrix; that Antimony leaching, if any,
is well below the migration limits set by the governmental and regulatory body world-
wide (BIS:12252-1987, USFDA 21 CFR §177.1630 & EU 10/2011 regulation); that
Colourants used in Pharmaceutical PET bottles are compliant with FDA and other food
regulations; that Endocrine disrupting chemicals are neither used nor generated by PET
containers; that PET is completely recyclable and has lowest carbon footprint compared
to glass, Aluminium and paper. The PCMA also cited WHO documents on
pharmaceutical packaging indicating “PET bottles usually used for liquid preparations
have good gas and fair moisture barrier properties and good safety profile”
The PCMA also pointed out that in the entire process of PET manufacture, there is no
presence of any heavy metals like Lead, Arsenic, Cadmium, Chromium, Mercury and
phthalates and bisphenol-A. It was pointed out that Polyethylene Terephthalate (PET) is
not a toxicological case, and that assessment profile for PET differs chemically and
toxicologically from that for phthalates (e.g.orthophthalates) which have been
considered to be potential endocrine disruptors.
All PET containers, including coloured are collected, sorted and more than 70% PET
gets recycled. Recycling of PET is preferred by the waste collectors due to its light
weight, higher remuneration and safe handling compared to glass. PET has a lower
carbon footprint than glass.
Page 19 of 32
HIM JAGRITI PRESENTATION
Him Jagriti during their presentation, emphasized the following points
PET may yield endocrine disruptors; that Phthalates leach from PET/plastic bottles; that
Bisphenol-A, Antimony and other heavy metals leach from PET bottles; that leaching
takes place under varying storage-temperature conditions and age of the packaging;
that the leached elements can cause several diseases including cancer and physical
infirmities; that many chemical additives that give plastic products desirable
performance properties have grave negative environmental and human health effects
like direct toxicity, as in the case of lead, cadmium and mercury; carcinogens, as in the
case of diethylhexyl phthalate (DEHP) and endocrine disruption, birth defects, immune
system, suppression and developmental problems in children.
Him Jagriti also presented the test reports on PET conducted by Indian Institute of
Toxicological Research (IITR), All India Institute of Hygiene & Public Health, Kolkata
and National Test House (NTH), Kolkata.
The reports of testing by these institutes are given as Annexure 8; 8a, 8b, 8c. The
Committee carefully examined all these reports as well as the publications cited by the
representatives of HIM Jagriti at the second meeting The responses to the structured
questionnaire, received from several organizations, were all discussed. These
organizations are Organization of Pharmaceutical Producers of India (OPPI), Bureau of
Indian Standards (BIS), Indian Drugs Manufacturers’ Association (IDMA), Pandit
Deendayal Upadhyay Smriti Sansthan, Indian Pharmacopeia Commission (IPC) and
Confederation of Indian Pharmaceutical Industry (CIPI).
The Committee also obtained, to best of its ability, the available peer reviewed literature
and technical guidelines/ requirements/ reports of the major regulatory and technical
agencies of not for profit nature and reviewed these analysis and recommendations.
The guidelines/ requirements/ reports of leading regulatory agencies such as United
States Food and Drug Administration (USFDA), European Medicines Agency (EMA),
United States Pharmacopeia (USP), British Pharmacopeia (BP), European
Pharmacopeia (EP), World Health Organization (WHO) guidelines, European Union
Commission Regulation and other relevant guidelines, vis-à-vis that of Indian
Regulatory authorities, Indian Pharmacopeia (IP), Bureau of Indian Standards (BIS),
were critically examined at the Sub-Committee and full Committee level.
Page 20 of 32
A DETAILED ANALYSIS OF THE TEST REPORTS SUBMITTED BY HIM JAGRITI
AND ENSUING DISCUSSION BY THE COMMITTEE WITH THE OTHER
STAKEHOLDERS IS SUMMARIZED BELOW:
IITR report titled “Migration testing of metals and phthalates from plastic bottles
in different samples”; IITR report code no.: SSP-273 dated 16th September 2014.
The supplier of the test materials was Him Jagriti. Samples provided for testing were
aerated drink, liquor, cough syrup and hair oil. The only medicine tested here was
cough syrup.
These samples were tested for migration of Bisphenol-A, Diethylhexyl phthalate
(DEHP), Diethyl phthalate (DEP), Dibutyl phthalate (DBP), Dimethyl phthalate (DMP)
and heavy metals (Lead, Cadmium and Chromium).
Heavy metals were analyzed using Atomic Absorption Spectroscopy- Graphite tube
atomization technique and phthalates were estimated using GCMS/MS.
The concentration of Bisphenol-A was below detection limit in all the samples tested at
different conditions. Migration of Diethylhexyl phthalate (DEHP) and Diethyl phthalate
(DEP) was found to be comparatively higher in hair oil than other samples tested.
Several scientific experts expressed concerns about the processes followed and
reporting of results as under.
The source from where these substances were procured is not mentioned.
The details of the product (batch number, mfg. date and exp. date) is not
mentioned in the provided report. Further, it is not mentioned whether all the
samples belonged to the same batch number.
From the report provided, it is not clear whether the analytes were tested in the
pharmaceutical formulation or in the bottle material or in the extract.
Although the limit of quantification for each of the analytes is given, the limit of
detection for the analytes is not mentioned in the provided report.
Page 21 of 32
The data on pH of the tested samples is not provided. pH is known to alter
leachability. The details about sample preparation procedures, equipment used
with specifications, including details of detectors, etc., is not mentioned
Standard Operating Procedures of the lab giving details of type, grade and
quality of solvents, reagents, chemicals, certified reference materials (CRMs),
etc. used during sample preparation and testing are not provided. Information on
measurement uncertainty for each set of tests conducted, and accreditation
certificate of the lab as applicable during the time of the study is not available in
the report.
Only two bottles of each sample were tested in each category- at room
temperature, 40° C and 60° C. It is unclear whether the values given for each
analyte represents the mean value or the value for a single sample. If it is for two
samples, then both values and coefficient of variation of the measurements
should have been provided.
The migration of some of the phthalates was less at 60° C compared to 40° C.
which is contrary to the published reports stating that the migration increases
with temperature. This raises the concerns about the quality of the tests.
As per the report, the samples were tested in duplicate. It is important to know
whether both the values are close to each other. The report provides only a
single value without indicating if it is an average or the higher of the duplicate
values
Test report of Plastic Hazards Committee, All India Institute of Hygiene and Public
Health, Kolkata (No. EPI/BNC/PHC/2015/266 dated 30-07-2015)
The levels of heavy metals (Lead, Antimony, Cadmium and Chromium) and DEHP in
five different pharmaceutical preparations were analyzed and presented in this report.
The report mentions that “DEHP was estimated by GCMS method and heavy metals by
AAS and ICP-OES method. The samples were kept incubated in specific storage
conditions i.e. at room temperature, 40 degrees C and 60 degrees C for a duration of 10
days as per EU 10/2011 for accelerated testing using equipment’s like GC-MS, ICP,
AAS”.
Page 22 of 32
Several issues of the concerns were raised by the experts in the committee
The report does not clarify which of the both methods, ICP and AAS, was used
for estimation of heavy metals.
The details about the number of samples analyzed for each pharmaceutical
preparation is not mentioned.
Batch number, manufacturing date, expiry date of the pharmaceutical
preparations are not mentioned in the report.
From the report provided, it is not clear whether the analytes were tested in the
pharmaceutical formulation or in the bottle material or in the extract.
The data regarding limit of detection and limit of quantification for each analyte
are not provided
The safety limits mentioned in the report is for packaged drinking water and not
for pharmaceutical preparations, which is scientifically inappropriate.
The details about sample preparation procedures, equipments used with
specifications, including details of detectors, etc., are not mentioned
Standard Operating Procedures of the lab giving details of type, grade and
quality of solvents, reagents, chemicals, certified reference materials (CRMs),
etc. used during sample preparation and testing are not provided. Information on
measurement uncertainty for each set of tests conducted, and accreditation
certificate of the lab as applicable during the time of the study are not available.
National Test House (Eastern Region) Test Report
Levels of Antimony, Lead, Cadmium, Chromium and DEHP in Asocoril+ syrup
(Certificate No. NTH(ER)/CH(S)/2014/0068A dated 23-06-2014), Benadryl (Certificate
No. NTH(ER)/CH(S)/2014/0029A dated 14-03-2014), Dabur Amla Hair oil (Certificate
No. NTH(ER)/CH(OF)/2014/0042A dated 18-03-2014), Sprite soft drink (Certificate No.
NTH(ER)/CH(S)/2014/0030A dated 14-03-2014), McDowell’s Green Label liquor
Page 23 of 32
(Certificate No. NTH(ER)/CH(OF)/2014/0043A dated 18-03-2014) and Haywards-501
(Certificate No. NTH(ER)/CH(OF)/2014/0098A dated 23-06-2014) were analyzed using
AAS and GCMS. The supplier of the test materials was Him Jagriti.
The concern raised by the experts of the Committee
The details about the number of samples analyzed for each preparation are not
provided. The data regarding limit of detection and limit of quantification for each
analyte are not provided.
From the report provided, it is not clear whether the analytes were tested in the
pharmaceutical formulation or in the bottle material or in the extract.
The details about sample preparation procedures, equipment used with
specifications, including details of detectors, etc., are not provided
Standard Operating Procedures of the lab giving details of type, grade and
quality of solvents, reagents, chemicals, certified reference materials (CRMs),
etc. used during sample preparation and testing are not provided in Information
on measurement uncertainty for each set of tests conducted, and accreditation
certificate of the lab as applicable during the time of the study are not provided
INFERENCE OF THE STUDY REPORTS
The Committee noted that the above mentioned labs have not consistently used
rigorous methods for all the estimations, reporting of results and choice of standards.
The Committee requested Him Jagriti to provide additional information in the test
reports which requires clarification. Him Jagriti very kindly and promptly provided a
response but, the core concerns raised by the experts remain unaddressed making it
difficult to arrive at reliable conclusion in either direction.
Common features of the submitted reports are inadequate standardization, inconsistent
findings which are difficult to explain and use of inappropriate reference values for
interpreting results.
According to the test results, the migration of the phthalates and other chemicals is less
than the limits mentioned in European Regulation EU 10/2011 on plastic materials and
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articles intended to come into contact with food. Also the levels of DEHP and DBP are
less than the recommended oral reference dose (RfD) formulated by US Environmental
Protection Agency (USEPA).
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REGULATORY REQUIREMENTS AND STANDARDS
Section - IV
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REGULATORY CONSIDERATIONS
Regulatory Requirements and Evaluation Process in Major Countries
PET/Plastic bottles are used for packaging of pharmaceutical products all over
the world including US, UK, Europe, etc. In these countries detailed standards,
guidelines and requirements have been specified for use of PET/plastic bottles in
pharmaceutical packaging so as to ensure that the use of plastic/PET bottle does
not alter the safety, efficacy and quality aspects of the pharmaceutical products
and not lead to harmful effects to the patients being treated with the product. In
such countries, the manufacturers are required to generate information regarding
suitability of specific plastic/ PET containers intended for use of specific
pharmaceutical product and submit the same to the regulatory authority as part
of marketing authorization application. This is particularly important due to huge
complexity involved in plastic/ PET materials and pharmaceutical active
ingredients, excipients and solvents used in manufacturing of pharmaceutical
products in variety of dosage forms and route of administration. It is therefore
necessary that plastic materials used in packaging system is fully characterized
and tested. This is especially important for those packaging component which
comes in direct contact with the pharmaceutical products.
The plastic/PET packaging system suitability is evaluated by assessing the ability
of the system to protect the pharmaceutical product from external
factors/influences like light, moisture, oxygen etc.; compatibility of the packaging
system with the pharmaceutical product i.e. the product will not interact with the
packaging system causing undesirable changes in safety, efficacy or quality
aspects of the products and the system should not release any substance to an
extent sufficient to cause toxicity to the patient being treated with the product.
The manufacturer is required to provide justification for using a particular
packaging system of material(s)
Plastic Container and the Content Interaction
Contents can vary widely depending on the formulation. Different formulation
may have different pharmaceutical ingredients, different solvents, excipients,
dosage forms and routes of administration prepared at different pH and having
different storage conditions, shelf life and different recommended duration of use.
The leaching/ Migration studies do not adequately address all the above
mentioned issues. Because of the above complexity, no single standardized
approach is applicable for different types of pharmaceutical products. For each
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pharmaceutical product appropriate interaction and stability studies with the
intended packaging materials are desired.
Indian Regulatory Requirements
In India, manufacture, import, sale and distribution of drugs are regulated under
the provision of the Drugs and Cosmetics Act, 1940 and Rules, 1945 made
thereunder. Under the Act and Rules, the regulatory control over the drugs
imported in to the country is exercised by the Central Government through the
Central Drugs Standard Control Organization (CDSCO) headed by Drugs
Controller General(India),while the manufacture, sale and distribution of drugs is
regulated under by the State Licensing Authorities (SLAs) appointed by the State
Governments. However, for manufacture of any new drug, prior permission from
DCG(I) is required to be obtained before obtaining manufacturing license from
the SLA. No drug can be manufactured for sale in the country except under and
in accordance with the conditions of license granted by the SLA. Similarly, no
drug can be imported and marketed in the country except under and in
accordance with the conditions of license granted by DCG(I).
Good Manufacturing Practices and requirements of premises, plant and
equipment for manufacturer of pharmaceutical products are specified in
Schedule M to the Drugs and Cosmetics Rules. As per Schedule M, all
containers and closures intended for use shall comply with the Pharmacopeial
and other specified requirements. Suitable samples sizes, specifications, test
methods, cleaning procedures and sterilization procedures, shall be used to
assure that containers, closures and other component parts of drug packages
are suitable and are not reactive, additive, adsorptive or leachable or presents
the risk of toxicity to an extent that significantly affects the quality or purity of the
drug. No second hand or used containers and closures shall be used. The
Committee, however, observed that there is no such specific requirements/
guidelines requiring the pharmaceutical manufacturers to provide the above
information to the Regulatory Authority for review of suitability of the container
closure systems intended to be used for pharmaceutical products.
Pharmaceutical manufacturers are required to follow the Standards laid down in
Indian Pharmacopeia. It appears that industry’s interpretation of current Indian
Pharmacopeia description as referring only to 6.2.3 being relevant to oral
pharmaceutical preparations. So no chemical analysis appears to be warranted
for oral pharmaceutical preparations as per this section in Indian Pharmacopeia.
Hence the contents of this section in Indian Pharmacopeia need to be updated.
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Presently, Indian Pharmacopoeia does not prescribe the requirements of basic
polymeric resins used for manufacture of containers for different pharmaceutical
uses. However, US Pharmacopoeia (USP 38) mentions that the plastic materials
for manufacture of containers for pharmaceutical use shall meet the
requirements for food contact as provided in Code of Federal Regulations, Title
21 in addition to the requirements prescribed in Chapter 661 “Containers –
Plastics” of USP 38. Similarly, Indian Pharmacopeia should refer to Indian
Standards on Polymer resin specifications (13 in nos.) which prescribe the
requirements of Basic Resin, Residual Monomers, Pigments and Colorants,
Overall Migration, Storage and Control, Packing & Marking and Methods of
Sampling etc. This would help in better regulation of plastic material use for
manufacture of containers for pharmaceutical use.
Indian Pharmacopeia does not mention any Standards about the limits of heavy
metals, total terephthaloyl moieties and ethylene glycol content in PET bottles
used for pharmaceutical packaging. The Standards for the same have been
exclusively set in United States Pharmacopeia, British Pharmacopeia and
European Pharmacopeia. It is necessary to prepare Indian Pharmacopeial
standards in this regard for PET and other plastic materials used in
pharmaceutical packaging and revise the relevant Section with regards to raw
materials and finished PET/ plastic containers in Indian Pharmacopeia.
In India, the sources of raw material used in manufacturing PET container may
vary in quality and compliance when compared to western countries. Hence, it is
open to question whether the global research findings on safety of PET
containers can be applicable to Indian Sub-continent where there are extremes
of temperature. This requires research by independent research institutions in
India utilizing validated methods for which detection limits, reproducibility, and
agreement or disagreement with reference labs is well documented.
The above observations emphasize the need for improved regulatory guidelines
and requirements for approval/ licensing of pharmaceutical products.
As against current practice and to ensure that the plastic container used for
packaging of a drug product is suitable for the intended use, the manufacturer
while applying for grant of approval of new drug or license to manufacture or
import of drug should provide information on suitability of the plastic materials
and containers used for immediate packaging (Primary Packaging) as part of
their application.
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Further, testing of random samples of manufactured pharmaceutical products by
regulatory authorities would help ensure compliance by manufacturers with good
manufacturing practices even after licensure. To be effective, lab facilities testing
such samples should be accredited and ensure continued, periodic assessment
of validity and reproducibility. An early priority is to reassess randomly selected
samples of pharmaceutical preparations packaged in PET/ other plastics using
rigorously methods to evaluate whether the source of phthalates and heavy
metals in medicinal products is detectable and if yes, is it as a result of leaching
from PET/plastic bottles, or from extraneous sources such as water, tubings and
reagents used in laboratories etc. Such testing is necessary to be responsive to
concerns raised and not because we have any scientific concerns in use of PET
in packaging of pharmaceuticals.
Environmental impacts of use of PET/Plastic bottles in pharmaceutical
packaging:
Pharmaceutical packaging represents a very small percentage of waste, but its disposal
can cause problems for the environment. Environmental problems result from the
methods used for waste disposal, and will depend on the type of plastic packaging
waste concerned. Such waste may include uncontaminated waste and contaminated
waste, e.g. waste that has been in contact with blood, blood-derived products,
radioactive products or cytotoxic products. The method of disposal will therefore vary.
Contaminated packaging is often incinerated.
Considering these aspects, WHO in its guidelines on packaging for pharmaceutical
products, has specified that incineration is “highly recommended”, recycling is
“recommended” and landfill is classified as “acceptable” for disposal of uncontaminated
plastic packaging.
The Committee felt that greater attention should be paid to the disposal and recycling of
pharmaceutical packaging waste and the Indian drug regulatory guidelines/
requirements in this regard, should be strengthened so as to avoid environmental
hazards.
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SPECIFIC RECOMMENDATIONS OF THE COMMITTEE
Section V
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RECOMMENDATIONS OF THE COMMITTEE
I. There is no conclusive, reproducible evidence to suggest that use of PET or the
additive used with it such as antimony, for pharmaceutical packaging may leach
substance(s) beyond limits that pose threat to human health. There is also no
conclusive, reproducible evidence that such use has ill effects on human health.
Within a robust regulatory system and process with clearly defined standards and
requirements, the use of PET as packaging material for pharmaceuticals can be
practiced with assurance of safety. In this regard, some directions for updating
the regulatory standards and requirements are provided.
II. Several types of plastics may have phthalates as additives when used as
packaging materials for pharmaceuticals. Animal studies and basic chemistry
suggest that phthalates vary in their potential for toxicity and lack of it. Therefore,
a case-by-case approach is prudent. Among these, exposure of certain
phthalates may be associated with potential health effects. Animal studies
indicate greater potential for toxicity with diethylhexyl phthalate (DEHP),
dibutylphthalate (DBP) and diethylphthalate (DEP). The use of these phthalates
should be practiced by increasing the stringency in the conditions under which
their use is permitted. This would require a review and up-gradation of the
current regulatory norms and requirements. The Committee recommends that
such review be taken as priority.
III. Phthalates are also used as excipients in pharmaceutical products. In this regard,
certain phthalates namely diethylhexyl phthalate (DEHP), dibutylphthalate (DBP)
and diethylphthalate (DEP) have attracted the attention of other major regulatory
authorities. The regulatory standards and requirements should be upgraded to
minimize their use and to provide more stringent norms for the circumstances
where their use is inescapable, including Permissible Daily Exposures, in line
with international regulatory guidelines.
IV. Establish better standards, regulatory requirements and risk assessment
strategies in India.
The regulatory guidelines and requirements should be specific and prescriptive,
so that the manufacturers are clear about the expectations, documentation and
compliance. Measures to enforce compliance with the revised regulatory
guidelines should also be put in place including clear standards for use of
additives.
Considering that the lack of specific regulatory provisions for disposal of waste
from pharmaceutical packaging, including plastics, may contribute to the
environmental hazards, the Committee recommends that the regulatory
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guidelines/ requirements should be strengthened by prescribing specific methods
for disposal of pharmaceutical packaging wastes.
V. Further research on Indian products using PET/Plastics for packaging
Since a concern has been raised, and because the limitations of the tests did not
allow the issue to be satisfactorily addressed, it is recommended that a random
sample of currently marketed pharmaceutical products using PET material or
other plastics should be carried out to asses leaching/migration. If presence of
phthalates or heavy metals are detected, it would be desirable to assess if the
levels exceed a level which may cause adverse health effect, whether the source
is leaching from the containers, or from other sources.
The conduct of such studies may be complex in nature due to various
compounding factors involved such as complexity of plastic/PET materials used,
active ingredients, excipients and solvents used in various dosage forms. The
specific design and protocol of such study may be developed in consultation with
experts representing pharmaceutical, chemical/ plastics, statistics and toxicology
field and the study be conducted in accredited laboratories/ institutions taking
samples from across the country.
This testify has been requested to assure public concern and not because of any
doubt in the committee about the scientific basis of safety of PET for packaging.
VI. Ongoing research is important to improve guidance on product development and
manufacturing process to achieve the highest possible level of safety. Such
research must be supported and pursued with rigor.
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