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Thursday, 23 July 2020
Vaccine: Harvest and Clarification
Tuesday, 2 July 2019
Bio/Pharma Facilities Still Have a Lot to Learn
Bio/Pharma Facilities Still Have a Lot to Learn: FDA’s annual manufacturing report card shows more quality compliance is needed.
Sunday, 30 June 2019
Comparing Facility Layout Options for Managing Business and Operating Risks
Comparing Facility Layout Options for Managing Business and Operating Risks: The authors present a risk analysis of the impact of various business and operating risks on three facility layout strategies.
Sunday, 1 July 2018
HISTORY OF YELLOW FEVER: OPENING OF PANAMA CANAL TO ONLY NOBEL PRIZE FOR A VIRUS VACCINE (DR. MAX THEILER)
1916:
The newly established Rockefeller Foundation Yellow Fever Commission
visited suspected endemic countries in Ecuador Peru Colombia Venezuela Brazil South America was in Guayaquil , Ecuador West Africa .
The actual campaign for the
eradication of Yellow Fever from Guayaquil
was held up due to First World War. Preliminary
work however did get underway.
1918:
A special commission arrived in Guayaquil Guayaquil
The
full-scale campaign for the eradication
of Yellow Fever from Guayaquil
1919:
Dr.Hideyo Noguchi announced the discovery of leptospira that in
guinea-pigs produced lesions suggestive of yellow fever (Noguchi, 1919)
After much experimental work, Noguchi
decided (erroneously, as was proved
later) that this leptospira was the cause of yellow fever and named it Leptospira icteroides (Noguchi, 1925). He
found that the use of a potent immune serum in the treatment of experimental
infection of guinea pigs with L. icteroides
gave definite protection (Noguchi, 1920).
Experiments also showed that the injection of killed cultures of L. icteroides into susceptible animals
conferred on them a state of immunity that endured for at least 5 or 6 months
(Noguchi and Pareja, 1921). Both the serum and vaccine were put to trial in
humans without delay and some thousands of people received inoculations.
Thus the findings of Reed commission were contradicted and the etiology of Yellow Fever was again in a state
of confusion. The then lack of susceptible animals and proper tools for
diagnosis of Yellow Fever and its differentiation from spirochetal jaundice
misled Noguchi.
In June last case of Yellow Fever was
reported in Guayaquil Guayaquil
After this success Rockefeller
Foundation worked in many endemic areas. By the end of 1924 the disease had been eradicated from Mexico, Central America, and Ecuador. Other trouble areas in South America were being attacked.
1920:
The West Africa Commission recommended
that another, more fully equipped, commission be sent to carry out extensive
and prolonged investigation of the situation in West Africa, including a
laboratory study of the suspected fevers of the region.
1925:
The danger that the completion of Trans African Railways may carry the
fever to the East revived the fear, which the opening of Panama
Canal aroused.
Following the recommendations of the
Yellow Fever Commission to West Coast of Africa, in this year another
commission, under the leadership of Dr.
Henry Beeuwkes, was sent to West Africa Yellow Fever Commission established
headquarters in Lagos
During the first 2 years of the
operation the Commission failed to isolate Noguchi’s L. icteroides. In the meantime doubt as to validity of Noguchi’s
findings had also arisen in a number of other quarters in Brazil Cuba U.S.A.
Laboratory work on the disease was
very much handicapped by the lack of an experimental animal. This was so important an obstacle at this
juncture that the group in West Africa
concentrated on trying to overcome it. So, a systematic search began. The investigators tried guinea pigs, white
rats, and white mice imported from Europe, a number of species of African
monkeys, as well as pouched rats (Cricetomya
gambianus), puppies, kittens, goats, all the local fauna, but in vain
(Vincent, 1927; Stokes et. al., 1923 a).
In further effort to find such an
animal, Dr. Henry Beeuwkes, the Director of the Commission visited the firm of
Carl Hagenbeck in Hamburg and there chose animals
from parts of the world distant to West
Africa. They were Indian rhesus
and crown monkeys and Brazilian
marmosets (Stokes et. al., 1928, a).
1927:
In May during an epidemic of Yellow
Fever at Lareth, Gold Coast, West Africa ; six Indian Crown monkeys (Macacus sinicus) were inoculated with blood from patients with
Yellow Fever. Five of these developed fever and died, while one did not show any reaction, it was felt from further
studies that these animals are susceptible to Yellow Fever only to a moderate
degree (Stokes et. al., 1928, a).
On June 30 Dr. A. F. Mahaffy, a member
of the West Africa Commission stationed at Accra, obtained blood specimens from
two patients (in Kpev 100 miles of Accra) suspected of having mild infections,
one of whom was a 28 year old African
man named Asibi. Dr. Mahaffy and Bauer of the Commission’s laboratory staff
inoculated the blood into rhesus monkey
(Macacus rhesus), one marmoset and two guinea pigs.
Guinea pig and marmoset failed to show any reaction but the monkey developed
fever on the 4th day after inoculation, was found moribund and
eventually collapsed on following morning (Stokes et. al., 1928, b).
This first experimental transmission of the virus of
yellow fever to an animal other than man opened up entirely new possibilities
of laboratory and field research.
The transmission of infection from
this monkey to others was done serially (by injecting citrated blood/serum or
by bite of Aedes aegypti mosquito)
and more than 50 of the monkeys were tried without failure. The same workers confirmed definitely that
the causative agent of yellow fever was filterable virus.
Propagation of
now famous “Asibi strain” of yellow fever virus also began with this experiment (Stokes et. al., 1928, a).
In December Mathis, Sellard and
Laigret isolated another strain of yellow fever virus at Institute Pasteur at
Dakar during the yellow fever epidemic, which broke out in Senegal, 1927
(Durieux, 1959; Lloyd, Theiler & Ricci, 1936). This virus had been
transmitted to Macacus rhesus monkey
by the bite of Aedes aegypti fed 24
and 31 days earlier on the patient suffering from mild yellow fever, a Syrian man named Francois Mayali
(Monath, 2004). The virulent organs from one of the monkeys infected in this
way were transported in frozen state to Europe and America, where they were
placed at the disposal of various labs under the name of “French strain” (also known
as Dakar Virus).
Isolation of the
“Asibi” and “French” strains in 1927 enabled the development of vaccines, and
research was initiated immediately in England, the United States, West Africa
and Brazil (Monath,
2004).
Asibi, West African yellow fever survivor, who provided a blood sample from which the virus, used in extensive future research, was isolated. (Image Source)
1928:
Edward Hindle of the Wellcome
Research Laboratories, London
On
June 24, 1928 Yellow Fever Laboratory was established by International Health
Division in Rockefeller Institute New York as Dr. Wilbur A. Sawyer as Director.
1928-1930:
Different
workers reported transmission of Yellow Fever other than A.aegypti.
Dr.
J H Bauer: A.leutocephalus, A.apicoannulatus and
Eretmapodites
chrysogaster (Bauer, 1928).
Cornelious
B Philip: A.vitattus, A.africanus and
A.simpsoni
(Philip
1928).
Davis and
Shannon: Aedes (Ochlerotatus) scapularis (Davis and Shanon).
Dinger et.al: Aedes (Stegomyia) albopictus (Dinger et.al.1929).
Philip: Taeniorrhynchus (Mansonioides) africanus Theobald
(Philip, 1930 a, b, c)
1929-30:
Cross immunity tests with different
strains of viruses settled the issue, that yellow fever of West
Africa and America
1930:
Dr.
Max Theiler of the Department of
Tropical Medicine of the Harvard
Medical School, working with French strain of virus, made the important
discovery that white mice were susceptible to yellow fever if inoculated
intracerebrally and that a fixed virus
for mice with a shortened incubation period and heightened virulence, could be
produced by repeated passage through these animals (Theiler, 1930).
1931:
Theiler described the use of mice in
testing sera for protective substances against yellow fever virus (Theiler, 1931).
This mouse
protection test of Theiler’s as modified by Sawyer and Lloyd, became one of the
principal tools in yellow fever research and epidemiologic investigation
(Sawyer and Lloyd, 1931).
In the 5 years following isolation of yellow fever virus,
32 cases (5 fatal) had occurred among laboratory workers (Berry and
Kitchen, 1931).
Some form of
protective immunization was obviously in order.
Dr.
Wilbur A Sawyer and his associates, as well as other investigators,
observed that monkeys inoculated with highly virulent strains of yellow fever
virus 4 to 6 hours following an injection of immune serum possessed a solid
active immunity after passive immunity had disappeared. Sawyer using a less virulent French strain (established in
mice by Theiler) devised a vaccine
consisting of a 10 percent suspension of infected mouse brain tissue in fresh,
sterile, human immune serum. This material when used with supplementary
immune serum, gave solid immunity in monkeys without the development of
symptoms. After thorough testing in monkeys, 10 persons were vaccinated between
May 13 and June 29, 1931
(Sawyer, Kitchen, and Lloyd, 1931, 1932).
This was the
first vaccine against yellow fever and after its introduction no further cases
of disease occurred in the International Health Division Laboratories.
1932:
Sellard and Laigret tested the French
mouse brain virus without immune serum in humans (Sellard and Laigret, 1932).
Mathis and Coworkers described the field trials of this vaccine (Mathis,
Laigret, Durieux, 1934). Vaccine came to
be known as “Dakar” vaccine.
First tissue culture experiments with
yellow fever virus were reported by Haagen and Theiler (1932). They tested
various fragments of tissue, using French neurotropic strain, but inspite of
good tissue growth, the virus disappeared from the majority in a few days.
Finally the best results were obtained when chick embryo was used as tissue
component. The tissue component consisted of finally minced chick embryo, and
the fluid portion was Tyrode’s solution containing normal monkey serum.
January to April there was a wholly
rural epidemic of yellow fever in the Valle do Chanaan Espirito Santo, Brazil,
in which A.aegypti could definitely
be ruled out as vector. The epidemic was
described in details by Soper, Penna, et al (1933). Workers proposed jungle
cycle of yellow fever transmission by mosquito other than A. aegypti between monkey and accidentally from monkey to man. The
complexity of the problem was further accentuated by the repeated detection of
yellow fever of jungle origin in Brazil
During 1936 to 1950 the laboratories
and epidemiologists in Rio de Janeiro Bogota , Colombia Entebba , Uganda Lagos , Nigeria America Africa by solving the riddles like its
transmission, vectors involved, maintenance in nature, etc.
As a by product of the study of jungle yellow fever by
the Rockefeller Foundation quite a number of unknown viruses were isolated form
man and mosquitoes such as Ilheus from South America and West Nile; Uganda
S, Ntaya and Zika from Africa (Yellow
Fever Conference, 1954).
1936:
Lloyd, Theiler, and Ricci successfully
established highly virulent Asibi strain (after 53 monkey passage and more than
3 years without intervening passage through an animal host) in a culture medium
containing embryonic mouse tissue and 10 percent monkey serum in Tyrode’s
solution for 13 subcultures. Then separate batch of this was cultivated in a
medium containing minced whole chick embryo for 58 subcultures. Thereafter the
medium was modified by removing the brain and spinal cord from the chick embryo
before mincing. The virus was maintained
for 160 subcultures. The resultant
strain was designated as 17D
(Theiler & Smith, 1937 a).
The viscerotropic
and neurotropic virulence of this virus had been markedly reduced between 89th
and the 114th subculture in vitro.
1937:
Elmendorf and Smith (1937) first
reported of the successful infection of the developing chick embryo through chorio-allantoic membrane and direct
inoculation of the embryo itself with Yellow Fever Virus.
Theiler
and Smith, after prolonged and careful study in laboratory animals began human immunization (starting November, 1936) with a single
inoculation of modified 17D strain of
virus, without immune serum (Smith, Penna and Paoliello, 1938; Theiler and
Smith, 1937, b). However, normal human serum was added to vaccine as
stabilizer. Thus named as “17D serum
based’’ vaccine by Hargett, Burruss and Donovan (1943).
The
vaccine entered field trial in Brazil in June, 1937 (Smith, Penna and
Paoliello, 1938). The vaccine became
famous by name of “17-D Vaccine”.
1938:
Over 1 million Brazilians had received
the 17 D Vaccine (Monath T.P., 1996) and over 100,000 persons in French West Africa have received the French Neurotropic
Vaccine (FNV) (Durieux, 1956).
1939:
Peltier, Durieux et al., reported
application of neurotropic mouse brain vaccine to skin by mild scarification,
known as “Scratch” or topical method.
1940:
In December Fox et. al., prepared
experimental batches of 17D serum-based vaccine from which serum was eliminated
(Fox et al., 1942). Working independently Hargett et al., found that
satisfactory vaccine could be prepared using distilled water as diluent and
coined this preparation as “17D aqueous base” vaccine (Hargett et al., 1943).
1941:
Out
break of encephalitis occurred in Brazil
1942:
The technique of vaccine production was altered; so that all vaccines
to be used for immunization were
initiated from primary and secondary seed lots of known character only and
thus the difficulties associated with the properties of virus itself are
eliminated (Fox, Kossobudzles & Fonsela Da Cunha, 1943).
The successful utilization of Yellow
Fever Vaccine in the 1940 and effective antimosquito measures, and
disappearance of disease from urban areas, however, led to a loss of interest
among scientists in the disease and thus not
much work was done till 1970 i.e. till the development of molecular techniques.
1951:
Dr. Max Theiler was awarded Nobel Prize for Physiology
and Medicine in 1951 for his unparallel contribution in the research of yellow
fever.
After
he retired from the Rockefeller Foundation in 1964, Dr Theiler became professor
of epidemiology and microbiology at Yale University, where he remained until
1967. He died of lung cancer on 11 August 1972, at the age of 73. Singapore Med J 2017; 58(4): 223-224
Max Theiler receives the Nobel Prize in Physiology or Medicine from the hands of His Majesty the King Gustaf Adolf VI on December 10, 1951. Photo by the Karolinska Institutet. (Image Source)
Yellow fever vaccination certificate
References for History of Yellow Fever Series will be updated soon.
Monday, 25 June 2018
HISTORY OF YELLOW FEVER- OPENING OF PANAMA CANAL
In all of ancient medical literature there is no
reference to Yellow Fever, by that or any other name. Since epidemic yellow
fever is a dramatic disease, it seems unlikely that it could have escaped the
attention of even very early medical writers. It is perhaps reasonable to
conclude that the disease did not exist
in ancient civilizations (Warren, 1951).
There
are reports of disease with clinical description similar to yellow fever in 1498 in San Domingo and 1585 in West Africa (Scott, 1939).
Carter found the earliest record in a Mayan
manuscript describing an epidemic with hematemesis (black vomit, or “xekik”) in the Yucatan in 1648, and suggested that
the virus and mosquito vector were
introduced from Africa during the slave
trade (Carter, 1931).
According
to Garrison (1929) the term yellow fever was first employed by Griffin Hughes
in his “Natural History of Barbados” (1750). The yellow in yellow fever does
not indicate the association of the disease with jaundice but is derived from
the yellow quarantine flag used by
the ships during the 17th century (Singh and Bhatia, 1993).
Yellow
Fever was responsible for several epidemics
among the settlers in tropical areas of the Americas and Africa during the
17th to the 19th centuries. In addition, epidemics were
also reported in Europe following
importation of the virus in sailing ships. However, the origin of the disease is in doubt but the susceptibility of ‘New
World Monkeys’ but not African monkeys to latent infection by yellow fever
indicates African origin of disease
(Monath, 1994).
Until
the 20th century, yellow fever was widely believed to be an airborne
“miasma” arising from filth, sewage,
and rotting organic matter. The series of developments thereafter in disease
etiology, etiological agent, epidemiology and vaccine are given below:
1848:
View,
that spread of yellow fever required the presence of an intermediate host,
appears to have first advanced by Dr.
Josiah Clark Nott of Mobile, Alabama. Nott suggested the mosquito as a possible agent for the
dissociation of both yellow fever and malaria (Warren, 1951). Dr Louis Daniel Beauperthuy in
Venezuela made a similar suggestion in 1854.
1880:
The
first attempt to dig Panama Canal in
1880-88 failed after 52000 cases of
yellow fever and malaria were reported among the 85000 workers (Bres,
1986).
1881:
The
first really serious proponent of the mosquito transmission in yellow fever was
Dr. Carlos J. Finlay of Havana, Cuba
(Warren, 1951; Burke and Monath, 2001; WHO, 1998).
1897:
Dr. Giuseppe Sanarelli, an Italian
bacteriologist working in the islands of Flores off Montevideo announced that
he had discovered the cause of yellow fever to be a bacillus present in about
50% of patients examined by him. He named it Bacillus icteroides (Sanarelli, 1897).
1900:
In
May United States Army organized a
commission to study the infectious diseases of Cuba but more specifically yellow fever. Dr. Walter Reed was appointed as president.
Dr.
Reed and colleagues from their studies concluded that “Bacillus icteroides” stand in no causative relation to yellow
fever, but when present should be considered as a secondary invader in this
disease” (Reed, Carrol et. al., 1900).
Influenced by the work of Sir Ronald Ross
and of Italian observers on the propagation of malaria by the mosquito the
commission directed their attention on the Finlay’s theory of the propagation
of yellow fever by mosquito (Warren, 1951).
The
Reed Commission recorded 3 cases of yellow fever transmission by mosquitoes that had fed previously on patients
clinically ill with yellow fever.
Subsequent work of the commission proved
conclusively that:
a)
the mosquito
was a vector of yellow fever;
b)
there was an
interval of about twelve days
between the time the mosquito took an infectious blood meal and the time it
could convey the infection to another human being;
c)
yellow fever
could be produced experimentally by subcutaneous injection of blood taken from
the general circulation of a yellow fever patient during the 1st and
2nd days his illness; and
d)
yellow fever
was not conveyed by fomites.
In
the consequence of these findings, Reed and his coworkers (Dr.James Carrol,
Dr.Jesse, W.Lazear, and Dr.Aristides Agramonte) suggested that the spread of
yellow fever could be most effectively controlled by antimosquito measures and the protection of sick from the bites of
mosquitoes (Reed, Carrol and Agramonte, 1901).
1901:
On
October 15, Reed and Carrol injected subcutaneously 3cc of diluted filtered
serum from an experimentally infected yellow fever patient into three
non-immune persons. Two of these developed clinical yellow fever (Reed and
Carrol, 1902).
Thus for
the first time a filterable virus was proved to be the cause of specific human
disease.
In
February the Chief sanitary officer in Havana, then Major William C. Gorgas
instituted measures to wipe out yellow fever which were based entirely on
conclusions of the yellow fever commission. The
results were as dramatic as the scientific findings of the commission. By
September, 1901 the disease had been completely eradicated, and it has not
reappeared. The antimosquito measures in Havana, in addition to eliminating
yellow fever, greatly reduced the incidence of malaria. Gorgas in Panama
applied similar approach. Eradication of
yellow fever from Panama led to the resumption of work of Panama Canal in 1904
and its completion in 1914 (Warren, 1951).
The Havana and
Panama campaigns now constitute an epic chapter in the history of sanitation
and preventive medicine.
1913:
The Rockefeller
Foundation was organized for “the
well-being of mankind throughout the world”.
The International
Health Commission of the Foundation was created the same year, with
Mr. Wickliffe Rose as its director.
The foundation began its work when the real danger of
spreading the disease to countries with high density of population, such as
India and Far Eastern countries became obvious as a consequence to the opening
of the Panama Canal. Dr. S. P. James of the Indian Medical Service
made a thorough investigation of the situation on behalf of the Indian
Government and reported that the menace was sufficiently great to call for a permanent
quarantine force in Panama, Hong Kong or Singapore,
to be maintained at the expense of the English colonies in the East.
Fortunate we are
that the disease has not reached India so far, although Aedes ageypti is found
in abundance in this country.
Rockefeller Institute of Medical Research
Panama Canal Route Map
Why has Yellow Fever never been seen in Asia?
This question has been raised since the opening of Panama Canal (August 15, 1914).
It was known at that time that the biologic environment for Yellow
Fever propagation and maintenance appears to be favorable, A.aegypti is
widely distributed, and susceptible animal hosts, both man and monkey, are
abundant. There is no evidence that the people of India posses any racial
resistance to infection with yellow fever virus or unusual tolerance to the
disease. The rhesus monkey of India is one of the most susceptible of all the
primates and is much less tolerant to the disease than any of the African
monkeys.
Richards
in 1951 proposed the probable explanation of the absence of the disease in
India or elsewhere in the tropical Far East is that the virus was never
introduced. Formerly there were two overseas
routes that the virus might have taken in reaching India from Africa- the
more direct route from the east coast of Africa to India, and the longer route from the west coast around the Cape of Good Hope.
Though immunity surveys have revealed the existence of immunes in East African ports, the proportion of immunes is low. These low immunity rates imply
that the disease is infrequent and rarely,
if ever, reaches epidemic proportions.
Under such conditions the chances that the most direct route from East Africa
might convey the disease are not very great. It has been pointed out that
rather special conditions are
required for overseas transport, and the longer the voyage the less likely that
these conditions will be fulfilled. The voyage
from tropical West Africa to India is long, and in rounding the cape climatic conditions are frequently
encountered that are unfavorable to
the survival of the mosquito vector.
Theoretically, the risk of yellow fever in Asia is greater now than in the past
because of rapid modern transport, which can introduce viraemic persons or infected
mosquitoes in any of the receptive areas. Experimentally, A.aegypti mosquitoes collected in different places of Asia are able to transmit the virus to monkeys or newborn mice with variable
success, depending on their origin and the strain of virus utilized. This
conclusion has been extended to some other Asian mosquitoes such as A.pseudoscutellaris, A.polynesiensis and might be applicable
to A.albopictus (Bres, 1986). Today,
the possible reasons for its absence include both demographic and biologic factors.
Hypotheses include:
· Yellow Fever occurs in remote
areas and affects individuals engaged in subsistence farming, who are infrequent international travelers.
· Biologic factors that limit the risk of introduction include cross-protection, principally by dengue, against which nearly all
persons residing in Asia are immune.
· A third hypothesis is that A.aegypti strains in Asia have low vector competence for yellow fever
virus (Aitken et al., 1977).
It is
likely that all three mechanisms combine to reduce the likelihood of
introduction and spread of yellow fever virus in Asia (Monath, 2004).
Refrences:
- Richard M. Taylor (1951): Epidemiology. In: Strode G.K. (ed). Yellow Fever,McGraw Hill, N.Y.
- Bres, P.L.J. (1986): A century of progress in combating yellow fever.Bulletin of WHO. 64: (6), 775-786.
- Aitken T.H.G., Downs W.G., Shope R.E (1977): Aedes aegypti strain fitness for yellow fever transmission. Am.J.Trop.Med.Hyg.26: 985 – 989.
- Monath Thomas P. (2004): Yellow Fever Vaccine. Chapter 41. In Plotkin S.A. and Orienstein W.A. Vaccines 4th edition. Saunders
Wednesday, 6 June 2018
Material Control Strategies in Product Development
Section 501 (21 U.S.C. 351) is amended by adding at the end the
following flush text: ‘‘For purposes of paragraph (a)(2)(B), the term ‘current
good manufacturing practice’ includes the implementation of oversight and controls
over the manufacture of drugs to ensure quality, including managing the risk of
and establishing the safety of raw materials, materials used in the
manufacturing of drugs, and finished drug products.’’.
INTRODUCTION:
Selection of raw materials and
excipients to be used in manufacturing process and identification of critical
material attributes to define material control strategies at development stage
of product life cycle, this includes the following:
·
Discovery research (including all stages of
clone development) and
·
Toxicology studies
All users involved in vector development, clone development and process
development shall follow the procedure defined below.
Note: As activities of clone
development are considered as critical for product lifecycle, a diligent
material control with traceability of materials used in each stage shall be
demonstrated (Refer ICH Q5B & Q5D and EP 5.2.12).
CONTROL STRATEGY:
MATERIAL CLASSIFICATION:
Biological product development and manufacturing uses diverse range of
raw materials. These materials can be categorized as below:
A.
Base
on composition materials can be categorized as:
·
Inorganic Salts and liquids,
·
Organic Salts and liquids,
·
Complex chemically defined mixtures of
organic/ inorganic origin),
·
Complex materials of biological origin,
including animal origin (defined),
·
Complex materials of biological origin,
including animal origin (undefined),
·
Complex semi defined mixtures (containing
above materials),
Note: In addition to above category
there are few fixed materials used in process which though are not categorized
as raw materials but are product contact and have tendency of leaching (process)
impurities in the product e.g., filters and TFF membranes, chromatography media
etc. Criticality of such materials shall be assessed and capture in process
development report as part of process impurities.
B. Based on usage in
manufacturing process materials can be categorized as:
·
Product contact materials and
·
Product non-contact materials (such as
cleaning agents)
However, there are chances of product contamination through product
non-contact materials if cleaning procedures are not validated and may directly
impact the product CQAs.
C. Based material control strategy the materials used in manufacturing
process can be classified as under:
·
Biological Starting Materials
·
Raw Materials
·
Drug Substance (Active Pharmaceutical
Ingredient)
·
API Starting Material
·
Excipients
Note: Specific requirements for Biological Starting
material are outside scope of this document.
MATERIAL CONTROL STRATEGY:
Material control at development stage is
limited to first two elements; other elements shall be covered in the
subsequent stages of product life cycle.
Elements of material control strategies ensure
the safety (including risk of adventitious agent contamination), quality and
efficacy of the biological molecule to be manufactured. These are:
1. Selection
of material and understanding the role of the raw materials in the process and
criticality assessment of material
2. Identification
of material quality attributes
3. Developing
material testing strategies to ensure raw material quality and evaluating
specific tests to ensure consistent material quality
4. Setting
up material/supplier risk assessments for supplier qualification program
5. Having
a supplier qualification system in place which assesses all risks of a raw
material: origin risk (safety), supply risk (availability, back-up options,
audits, contractual agreements) and quality risk (testing, evaluation of
lot-to-lot consistency).
Note:
All the elements shall be revisited during initiation of cGMP manufacturing
operations such as MCB and WCB preparation, clinical batch manufacturing,
process performance qualification (validation) batch manufacturing and
commercial manufacturing.
SELECTION OF MATERIAL AND CRITICALITY ASSESSMENT:
Material for each process stage shall have
scientific basis for selection and following criteria shall be considered:
1. Role
of material in process stage
2. Impact
of the material on quality attribute of the subsequent stage product
3. Introduction
of impurities in manufacturing process (including adventitious agents).
To ensure material control, user shall
perform material risk assessment as per the table below:
Sr.
No
|
Assessment Question
|
Answer
(Yes/No)
|
Risk
(High/Medium/Low)
|
Comments/
Justification
|
1
|
Is the RM complex?
|
|||
2
|
Is the RM well defined?
|
|||
3
|
Is the material of animal/human origin?
|
|||
4
|
Is the TSE/BSE assessment available?
|
|||
5
|
Is the RM added in the late steps of the
process?
|
|||
6
|
Is there a need to demonstrate that the
process will reduce the RM level to a safe residual level?
|
|||
7
|
Is a relevant analytical method available
to assess its clearance?
|
|||
8
|
Is the level of quality of RM susceptible
to impact product CQA?
|
|||
9
|
Is the production process of the RM
generating high variability in the RM quality attributes
|
|||
Remarks: (For additional assessment and comments)
|
||||
Raw Material categorized
as: Critical ¨ /
Non-Critical ¨
|
||||
Note
1: Excipients are not
accessed based on above criteria. Procedure for excipient selection and
assessment is provided below.
Note
2: Assessment shall be performed
for all raw materials, including chromatography resins and media. In column
for ‘Answer’ enter ‘Yes’ or ‘No’, identify the risk associated in each
evaluation step and provide comments and justification for each risk
categorized (irrespective of low, medium, high) with current and recommended
mitigation plan.
|
||||
From
the above assessment a list of critical and non-critical materials will be
generated.
FOR CRITICAL MATERIALS: Higher grade material with more control on material
attributes shall be selected, preferable to use compendial grade material
manufactured under cGMP environment.
FOR NON-CRITICAL MATERIALS: Grade of material is
flexible however consistency in supply of material with identified attributes
shall be ensured.
SELECTION OF EXCIPIENTS:
Excipients are added for the purpose of production enhancement, patient
acceptability, improving stability, controlling release etc. Though termed as
inactive components, excipients can have an impact on the absorption,
distribution, metabolism and elimination process of the co-administered drug,
which is important information when selecting excipient for any formulation.
As manufacturer of the chemicals supply their material for different
applications and end users (such as cosmetics, food additives etc.), it is
responsibility of the user to select the excipient of appropriate type and
grade to meet additional quality functionality and safety requirements.
Below are the basic check points used during
selection of excipients:
1.
|
Name
of the excipient in the formulation:
|
2.
|
Is the excipient complex chemical: (Define physical and chemical properties, material
(excipient) specifications including impurities and residual solvent)
|
3.
|
Is the excipient well defined: Define physical and chemical properties, material
(excipient) specifications including impurities and residual solvent)
|
4.
|
Is the proposed material (excipient) of
animal/human origin:
|
5.
|
Is
the production process of the material (excipient ) anticipated to generate high
variability in the quality attributes:
|
6.
|
Is
the level of quality of material (excipient) susceptible to impact product
CQA. List and define critical material attributes (CMA) of the material
(excipient):
|
7.
|
Is the TSE/BSE assessment available for the
excipient:
|
8.
|
Mention
role of material (excipient) in the formulation (such as diluent, buffering
compound, antioxidant, stabilizer, enhances solubility, enhances
bioavailability etc.):
|
9.
|
Mention
intended route of administration of finished product (topical, ophthalmic,
oral, parenteral etc.):
|
10.
|
Is
the material previously selected as excipient for intended route of delivery:
|
11.
|
Is the proposed material identified as
established excipient:
(If yes,
in which IPEC category does it fall)
1.
Existing chemical excipient- first in human:
(These are
class of excipients where animal safety data does exist, as data may have
been used in another regulatory
applications)
2.
Existing chemical excipient:
(These are
excipients that have been used in man, but for another route of
administration, higher dose etc., and additional safety may be required)
3.
New modification of existing excipient:
(Established
excipient is the new modifications of combinations, which would not require
safety evaluation)
|
12.
|
Is
the excipient approved by any of the regulatory agencies: (Refer
different resources and mention wherever listed, such as EMA's Excipients Drafting
Group (ExcpDG), FDA Inactive ingredient database, Safety
and Toxicity of Excipients for Paediatrics (STEP) Database,
listed in GRAS database, FAP database, wherever available DMF File number
shall be provided).
|
13.
|
Is
an official monograph available in any of Pharmacopeia (USP-NF, EP, JP, IP
etc.):
|
14.
|
Is
the material identified as new chemical excipient:
|
15.
|
Does
the selected vendor follow IPEC (The International Pharmaceutical Excipients Council)
cGMP Guidelines:
|
16.
|
Does
the selected vendor has ISO 9001 certification:
|
17.
|
Does
the selected vendor has EXCiPACT certification:
|
18.
|
Does
the selected vendor material meet the designated Pharmacopeial requirements,
if yes, mention the pharmacopeia (attach monograph copy):
|
19.
|
Note: Though supply security and
quality agreements are not expected during discovery research and toxicology
studies, however given the criticality of the excipient and impact of change
on regulatory filing, wherever possible below expectations shall be ensured:
·
Manufacturing
process for excipient shall be sought from vendor,
·
Understanding
with the manufacturer to ensure change notification in manufacturing process
and CQA of material
·
Long
term supply commitment
Note: Regulatory filing process for
new excipients is outside the scope of this document.
|
User shall compile all the above information with relevant evidences as
annexures in single report for excipient selected.
MATERIAL CONTROL STRATEGY
As the scope of this document is limited to discovery research and toxicology
studies, material control strategy for these stages is defined below.
Drug Discovery:
·
Material and vendor selection as per study
plan (assessment defined in 5.3.2 can be performed and recorded)
·
COA and expiry of all incoming process material
documented for use in relevant documents (LNBs, protocols & records etc.)
·
Material (Safety Data Sheet) (MSDS/ SDS)
understood and to be made available at site of usage for ready reference along
with COA.
·
Storage and expiry as per vendor recommendation.
·
Material for each unit operation stage is
fixed based on the development data (assessment defined in 5.3.2 mandatory and
shall be compiled in single report with relevant annexures). Specification of
all the materials to be listed with test method references wherever available.
Toxicology
Studies:
·
Material and vendor selection performed as
per 5.5.1 point number v. Refer table in section 5.6 for requirements for each
stage.
·
Details of expiry of all incoming process
material documented in Batch Manufacturing Record and COA’s attached to it
·
MSDS understood and to be made available at
site of usage for ready reference.
·
Storage and expiry as per vendor
recommendation.
·
Compilation of material and vendor
documentation in a single report.
DOCUMENTATION DURING DEVELOPMENT AND TOXICOLOGY BATCH
MANUFACTURING:
Collection of following documents for all
materials (where applicable) as below:
Material Documentation Requirements
|
Drug Discovery
|
Toxicology Batch
|
- Material
Name
|
ü
|
ü
|
- Material
grade
|
ü
|
ü
|
- Vendor
Name
|
ü
|
ü
|
- Vendors
Address
|
ü
|
ü
|
- Vendor
Catalogue Number
|
ü
|
ü
|
- Vendor
Specification
|
ü
|
ü
|
- Vendor
COA
|
ü
|
ü (multiple batches)
|
- List
of potential impurities
|
ü
|
ü
|
- List
of solvents used in process and residual solvents in product, if any
|
ü
|
ü
|
- MSDS/
SDS
|
ü
|
ü
|
- Certificate
of Material Origin
|
ü
|
ü
|
- Certificate
for TSE/BSE
|
ü
|
ü
|
- Risk
of Viral and other adventitious agents
|
ü
|
ü
|
- Kosher
/ HALA certifications
|
Optional
|
ü
|
- Allergen
certificate
|
Optional
|
ü
|
- Aflatoxin
certificates
|
Optional
|
ü
|
- Certification/
accreditations of vendor
|
Optional
|
ü
|
- Manufacturing
Process Flow
|
Optional
|
ü
|
- Characterization
Data
|
Optional
|
ü
|
- Toxicological
data
|
Optional
|
ü
|
- Logistic
mapping and supply change map
|
Optional
|
ü
|
Note: Material control strategy for
clinical and commercial manufacturing are part of corporate/global systems,
however for the sake for clarity highlights of material control strategy for
subsequent stages of product life cycle are listed below:
Ø Clinical Phase 1 / 2
Manufacturing:
-
Identification
of CMA and preparation of material control specification
-
Development
of non compendial test methods
-
Verification
of vendor COA for received material against specifications
-
Testing
and release of material for parameters such as identification, appearance,
safety (bioburden, endotoxin etc) and identified CMA. Availability of approved
test methods for these attributes.
- Vendor qualification for material
traceability, supply security with logistic mapping
Ø Clinical Phase 3
Manufacturing:
-
Material
(customer) specification finalization with all CMA listed
-
Availability
of test methods for verification of all listed specification parameters for
materials.
-
Testing
and release of material as per customers’ specification. Full testing for all
critical materials.
-
Test
values vs material attributes (as per specification) to be trended for better
material control as per QMS requirements
-
Risk
assessment to be revisited for all critical materials.
-
Due
diligence and vendor audits to be performed based on risk assessment.
-
Detailed
vendor assessment and qualification.
-
Quality
agreements, supply security agreements to be executed and made available.
Ø Marketing (including
PPQ) and Post Marketing:
-
Material
to be qualified and trends for high critical tests for critical materials made
available. Specifications can be revisited for better control.
-
Vendors
to be audited and compliance ensured. All agreements in place.
-
Alternate
vendor development can be initiated.
-
Risk
assessment based reduced testing can be explored.
DEFINITIONS
Active Pharmaceutical
Ingredient (API) (or Drug Substance): Any substance or mixture of substances intended to be used in the manufacture
of a drug (medicinal) product and that, when used in the production of a drug,
becomes an active ingredient of the drug product. Such substances are intended
to furnish pharmacological activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease or to affect the
structure and function of the body. (Reference ICH Q7).
API Starting Material: A raw material, intermediate, or an API
that is used in the production of an API and that is incorporated as a significant
structural fragment into the structure of the API. An API starting material can
be an article of commerce, a material purchased from one or more suppliers
under contract or commercial agreement, or produced in-house. API starting
materials are normally of defined chemical properties and structure. (Reference ICH Q7).
Contamination: The undesired introduction of impurities of
a chemical or microbiological nature, or of foreign matter, into or onto a raw
material, intermediate, or API during production, sampling, packaging, or
repackaging, storage or transport. (Reference ICH Q7)
Control Strategy:
A planned set of controls, derived from current product and process
understanding, that assures process performance and product quality. The
controls can include parameters and attributes related to drug substance and
drug product materials and components, facility and equipment operating conditions,
in-process controls, finished product specifications, and the associated
methods and frequency of monitoring and control. (Reference ICH Q10)
Critical Material Attribute:
A physical, chemical, biological or microbiological property or characteristic
of an input material that should be within an appropriate limit, range, or
distribution to ensure the desired quality of output material. (Reference Raw
Materials in the Manufacture of Biotechnology Products: Regulatory
Considerations Ruth Cordoba-Rodriguez of the FDA’s Center for Drug Evaluation
and Research (CDER in Bethesda, MD)
Excipient: Substances other
than the API that have been appropriately evaluated for safety and are
intentionally included in a drug delivery
system. (Reference: USP <1078>)
Impurity: Any
component present in the intermediate or API that is not the desired entity. (Reference ICH Q7)
Lifecycle:
All phases in the life
of a product from the initial development through marketing until the product’s
discontinuation (Reference ICH Q8)
Raw material: Any element or component used in the
manufacture of a biotechnology product that comes in contact with the API or
the API starting material. A raw material can be reactive or non-reactive with
the API. (Reference Raw Materials in the Manufacture of Biotechnology
Products: Regulatory Considerations Ruth Cordoba-Rodriguez of the FDA’s Center
for Drug Evaluation and Research (CDER in Bethesda, MD)
Materials: A general term used to denote starting
materials, reagents, and solvents intended for use in the production of
intermediates or APIs. (Reference ICH Q7)
Starting material for biological
medicinal products: Any
substance of biological origin such as micro-organisms, organs and tissues of
either plant or animal origin, cells or fluids (including blood or plasma) of
human or animal origin, and biotechnological cell constructs (cell substrates,
whether they are recombinant or not, including primary cells).” (Reference Dir. 2001/83/EC)
Biological starting materials: starting materials derived from a
biological source that mark the beginning of the manufacturing process of a
drug, as described in a marketing authorization or licence application, and
from which the active ingredient is derived either directly (for example,
plasma derivatives, ascitic fluid and bovine lung) or indirectly (for example,
cell substrates, host/ vector production cells, eggs and viral strains). (WHO TRS 999, Annex 2)
REFERENCES:
BioProcess International September
2009: Raw Material Control Strategies
for Bioprocesses by Gregory Beck, Mark Schenerman, John Dougherty, Ruth
Cordoba-Rodriguez, Christopher Joneckis, Anthony Mire-Sluis, and Lorna D.
McLeod.
EBE Concept Paper: Management and Control of Raw Materials
Used in the Manufacture of Biological Medicinal Products, 29 November 2017, Version 1.
European Journal of
Pharmaceutical Sciences, 2015: Pharmaceutical excipients — quality, regulatory and biopharmaceutical
considerations. David P. Elder, Martin Kuentz, René Holm.
Dir. 2001/83/EC: Directive 2001/83/EC of The European
Parliament and of the Council. The Community Code Relating To Medicinal
Products For Human Use.
EP 5.2.12: Raw
materials of biological origin for the production of cell-based and gene
therapy medicinal products.
ICH Q5B: Quality of Biotechnological Products:
Analysis of the expression Construct in Cells used for Production of r-DNA
Derived Protein Products.
ICH Q5D: Derivation and Characterisation of Cell
Substrates Used for Production of Biotechnological/Biological Products.
ICH Q10: Pharmaceutical Quality System.
ICH Q11: Development and Manufacture
of Drug Substances (Chemical Entities and Biotechnological/ Biological
Entities).
ICH Q7: Good Manufacturing Practice.
ICH Q8 Pharmaceutical Development.
ICH Q9: Quality Risk Management.
IPEC Europe, 2008: Qualification of Excipients for
Pharmaceutical Use.
PDA TR 56 (Revised 2016): Application of Phase-Appropriate Quality
System and cGMP to the Development of Therapeutic Protein Drug Substances (API
of Biological Active Substance).
USP 1078: Good
Manufacturing Practices for Bulk Pharmaceutical Excipients.
WHO TRS 999, Annex 2: WHO good manufacturing practices for biological products.
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