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Accreditation and Standardization of Cellular

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Chandra Viswanathan Shabari Amit Sarang

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Volume 21, No. 2 April, 2015

Accreditation and Standardization of Cellular Therapies in India

Dr. Chandra Viswanathan

Dr. Shabari Sarang
Sushilkumar Ramdasi
Regenerative Medicine Group, Reliance Life Sciences Pvt Ltd.
Navi Mumbai, India

Introduction
Cell based therapies offer unique challenges to regulators, clinicians and manufacturers alike. The
rising incidence of therapeutic use of cells, sometimes classifying them as products and sometimes as
drugs, therefore needs to be regulated. Needless to say, there is increasing international commerce in
this area. The promises offered by these therapies are tremendous. Newer techniques are being
developed to manipulate human cells and tissue and the use of such cells outside their normal
functions is also being developed.
Peculiarly, in this area, industry standards are not always easy to follow, and many times
unenforceable. Therefore the general perception so far has been that this is a poorly regulated
industry. Lack of proper standards could thwart the successful translation of the impressive advances
taking place in this field into the clinic. Therefore it is imperative that this industry needs to be
regulated like the pharmaceuticals and biologics industry. However, since most of the existing
regulations were developed for drugs, proteins or genetic therapies, the use of cells as therapeutic
agents requires some redefining and refining of the existing regulations.
In a variety of different clinical settings we use cells as drugs. Existing therapies use cells available
from cell/tissue banks (allogeneic) or from the patient’s own system (autologous). The cells could be
stored frozen or fresh depending on their application and how long cellular viability and function can
be maintained in the cryopreserved state. Moreover such therapies could be structural or systemic.
Thus, Cellular Therapy has been a nascent field of medicine, but it is now coming of age! The pursuit
of quality in such newer disciplines is no easy task. It has been described as something close to the
quest for the Holy Grail. Increasingly, the global health care industry recognizes the development and
introduction of new standards as a method to measure quality. Aspiring service providers and
researchers are better equipped when they comply with accreditation standards as it raises their all-
around quality ahead of regulations.

The challenges of cellular therapies

Because Human Cell-based Products are derived from diverse and complex biological sources, their
conversion into therapies is difficult. Challenges include their potential to spread communicable
disease, the difficulty in adequately identifying the ‘active agent’ for identity and potency purposes, the
expense associated with large clinical trials to test these complex products and the difficulties
associated with shelf life of the cellular raw material and final formulation. From the regulatory
perspective, this therapy presents several problems. The chief among these are:
1. Comparability

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Product characterization is a key problem for these complex biologics. A major issue is the
paucity of demonstrable in vitro surrogates for assessing the functional viability or potency of
cells and tissues as they are processed into the final ‘product’. Such surrogates are needed to
establish testing criteria in the production of human cell based products. These tests include
acceptance testing to determine the suitability of incoming cellular raw materials, in process
testing to use as process controls and release testing to define adequacy of the finished
formulation. Surrogates are also required for comparisons when the manufacturing process is
changed. A further complication to this issue of comparability is that many Human Cells,
Tissues, and Cellular and Tissue-Based Products (HCT/Ps) is heterogeneous, containing a
variety of cell types. These heterogeneous products best demonstrate their clinical value
through their use in patients and determining the exact contribution of the inactive or
contaminating cell populations is difficult. Also when relevant in vitro tests are available, they
have read out times that exceed the product expiration, highlighting the need for developing
and validating real time tests for relevant functional release criteria.
2. Intrinsic variability
Typically, the readily definable final formulation of traditional drugs is manufactured in large
batches from well-characterized raw materials. These large batches are quarantined, a
representative portion is tested and the batch is released when predetermined specifications
are met. For many cell types however the therapeutic agent is patient specific. Given the
biologic variability in the cellular raw materials and in the characteristics of the final
formulation, the critical time and transit environment sensitivity of the raw materials and final
formulation and the inevitable co-ordination with patient and clinical schedules, this type of
treatment model will require a tailored manufacturing and delivery infrastructure for the product
to reach the right patients at the right time.
3. Donor eligibility
A key distinguishing component of Current Good Tissue Practices (cGTP) rules is the
emphasis on donor eligibility. This demonstrates that the regulators recognize that cells and
tissues taken from a donor as raw material for the manufacture of a cellular medicine may
carry communicable disease risks both for recipients of those cells and for recipients of cells
manufactured and/or stored in the same place or time. Given that these products provide no
opportunity for terminal sterilization before delivery, the donor eligibility determination serves
as a de facto safety qualification. Additional infectious agents may be tested depending on the
tissue and the risk of transmission of these agents through the particular cellular product, in
that geography.
4. Logistics
Manufactured under cGMP conditions, the cellular products and their cellular source materials
are often transported in an unregulated manner by various means including ground couriers,
commercial air and cargo airlines. Shippers of these products typically contract ‘freight
forwarders’ to co-ordinate the logistics of delivering the cellular product from origin to
destination. Commercial air carriers do not operate sufficiently tailored flight networks to
accommodate the products they are entrusted to deliver and few, if any, of the transportation
systems have been validated under manufacturing controls to ensure the quality of these new
age products from the point of collection to the processing facility and of the final products to
the patient. Further, inspection and/or exposure to radiation could adversely affect viability of

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the product. To obtain public trust in cellular therapeutics, the cellular source materials and
finished formulations must be fully integrated into a chain of control from the time of cellular
collection to the time of use of the product at the bedside. Accreditations and quality stamp
from reputed agencies helps address many of these questions.

Understanding Accreditation
Applicants for accreditation programs in the cellular therapy space get sensitized about quality issues
prior to the development of any formal accreditation efforts. The importance of quality in meeting
customer demands, and the pressure to remain competitive in their respective fields contributing to
improved profits is well recognized. Verification of meeting changing quality standards has grown in
importance in recent years due to expectations of various users of products and services, and the
need to provide proof of achieving acceptable levels of quality as determined by peer leadership in a
specific service/industry, is only an extension of the same. Unlike traditional treatment options, cellular
therapies are aimed at addressing unmet medical needs, which is a combination of cells, sometimes
more than one type, with or without a scaffold. Some regulators want to call it a new drug, while a few
call it a device, and a few others are still undecided on classification. Under such conditions,
accreditation from well-known agencies help set up the standards ahead of regulations.
Accreditation in itself is a way to continuous learning of processes, trainings and documentation. The
entire process has a more personal touch as processes and processes can be adjusted as per our
specifications and expectations. The accreditation agencies are more open to discussions and
acceptance of views and ideas that may help improve the quality of such new processes or the
products. It is a more comprehensive process and detailed terms of reference on all parameters are
available for consultation and negotiation. Finally, the accreditation process helps in increasing global
visibility, as they cover larger geographies, thereby helping in bringing about more harmonization.
Regulations in the cellular therapy area are just evolving. Regulations in some countries have many
points of similarity, while some of them have none at all. As expected, there are ambiguities that exist
between clauses, which are interpreted differently by different people. Guidance documents are
seldom available, with no room for negotiation. In the Indian context, the Indian Council of Medical
Research (ICMR) released draft guidelines in 2007 followed by the next version in 2013.1,2 In such a
scenario, where the regulatory framework is still evolving, when the country is witnessing an increase
in stem cell activity, in academia and in the private sector, accreditation is the best option to exercise.
Understanding the inherent issues with cellular therapies, organizations like the Foundation for the
Accreditation of Cellular Therapy (FACT) and American Association of Blood Banks (AABB) have
developed and implemented programs for voluntary inspection and accreditation for cellular therapies.
They have published standards, documents, guidance manuals, accreditation checklists, and
inspection documents; they have trained inspectors with large number of professionals active in the
field. All inspectors have a minimum of 5 years of experience in the area they inspect.
Significant opportunities and challenges exist for the accreditation bodies in the future, including
keeping standards and guidance materials current and relevant, recruiting and retaining expert
inspectors, and establishing collaborations to develop standards and accreditation systems for
emerging new cellular products, and tissue engineered cellular products. We recognize that a
continuing dialogue with the regulatory agencies helps ensure that they are aware of such
accomplishments of voluntary accreditations. Other potential avenues of communication, cooperation
and engagement between regulatory agencies and accreditation bodies like Occupational Safety and

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Health Administration (OSHA), International Organization Standardization (ISO), National

Accreditation Board for Testing and Calibration Laboratories (NABL), National Accreditation Board for
Hospitals and Healthcare (NABH), College of American Pathologists (CAP), etc. need to be
investigated and evaluated. Each of these organizations will welcome inputs from newer areas that
pose concerns while handling of standards.
Cell-based therapies are either autologous or allogeneic. This distinction drives the product safety and
efficacy model and the basic approach to manufacturing, transportation and clinical delivery of the
product. In turn, this dictates the technical and regulatory challenges for development and
commercialization of safe, effective and reproducible cell-based therapies at the required scale and
cost. In addition, cellular therapies are further complicated with the use of various cell combinations
and / or scaffolds for expansion and delivery. Despite the rich pipeline of cellular therapies that are in
clinical development, only a limited number have been taken down the established regulatory pathway
for cellular products and translated into products. The lack of regulatory harmonization has been cited
as a major hurdle in the development of cellular therapies. Thus, in the absence of a proper regulatory
framework, the management of various institutes and organizations normally move through
professional bodies, agencies to embark on certain standards.3,4 When tested and inspected by such
accredited agencies, there is clear benefit to consumers in the form of greater assurance that
products truly meet the quality, performance and safety standards. Once accredited and is under
surveillance, conformity of acceptable operation/performance play a key role in quality improvement
activities in the industry/sector.
As the company who established stem cell research and the first public cord blood repository in India
in 2002, we are the pioneers in this area.6 We found the accreditation process very friendly and
educative. The level of quality was defined by the organization after a careful review of our capabilities
and resources. To keep organizations heading in the right direction, and on a continuous basis,
national and international professional bodies in consultation with regulatory agencies and health
departments advocate raising the bar on quality standards. The accrediting organizations thus play a
crucial role in bringing uniformity in the quality of the products and services by making ‘standards’.
Needless to say that besides elevating trust and confidence of consumers, it also builds stronger
market loyalty and consequently company’s performance and equity. 5, 7, 8
Interestingly, accreditation bodies also play the role of a change agent, especially when research and
clinical transformation path is fuzzy. One of the ways that this role is accomplished in accreditation
programs is by involving the top leadership on accreditation applications so that the organization
agrees to follow the accreditation program standards, commit to a program of continual compliance
and quality improvement, and comply with a required code of conduct/ethics as a condition of
achieving accreditation. These commitments clarify the role of accreditation as a long-term
improvement process rather than a single performance evaluation experience. It is pertinent to add
here that this spirit of commitment trickles down to all team members.
Talking about quality of the product, accreditation standards involve multiple agencies that affect
quality at each related steps during the entire process. Several accreditation agencies are involved
including those that audit the raw materials, logistics, manufacturing, storage and the transplantation.
In case of cellular therapies, globally many accreditation or licensing agencies support certain aspects
of safety & quality of cell-based products for human use. These organizations include but not limited
to AABB, FACT, World Health Organization (WHO), ICCBBA’s ISBT 128 labeling standard, and the
list extends on and on.

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Global scenario
Customers, in this century of IT, are well aware of what their needs are in terms of quality and cost of
the product or service. The internal quality system demands endorsement from national and
international regulatory and quality organizations.
The regulatory and legal framework for managing stem cell research in the US is one of the most
stringent among the nations involved in stem cell research and therapy. The US FDA principles often
form the basis of guidelines drafted by some of the other countries. Though there is a lack of specific
stem cell legislation owing to its atypical nature, the existing regulations are strict, however, allow for
some degree of flexibility. It was worthwhile therefore for regulators to review the framework under
construction in UK, Japan, China, Korea, Singapore and Malaysia to get an all-around view of the
developments.

Regulations for Cellular Therapy in India

The Department of Health Research, Ministry of Health and Family Welfare, Government of India
constituted an apex body, the National Apex Committee for Stem Cell Research and Therapy (NAC-
SCRT). NAC-SCRT acts as a watchdog for the activities in the field of stem cell research in India.
They are responsible for drafting of guidelines and policies regarding stem cell research and also
review the progress of stem cell research across various institutions in the country. The Ministry of
Health and Family Welfare, Government of India constituted a core Investigational New Drug (IND)
panel of experts namely “Cellular Biology Based Therapeutic Drug Evaluation Committee”
(CBBTDEC) under the chairmanship of Director General, ICMR to advice the Drug Controller (DCGI)
in matters pertaining to regulatory pathways leading to the approval of clinical trials and market
authorization of cellular based therapies. Generally, biologicals need to be manufactured in a
schedule ‘M’ compliant environment, a requirement by the regulations. The definitions and scope of
regulatory guidelines for cellular therapy in India are not yet clear and definitely needs further
expansion in an attempt to include all cellular therapy products and services and bring about more
clarity.9

Accreditations - Our Experience

The process of Accreditation was a wonderful learning experience, and the ease with which we sailed
through several subsequent audits in the last six years only tells us that a proper guidance and a clear
understanding of expectation from the involved groups was the key to success. Moreover, unlike
regulatory agencies, accrediting agencies are extremely open to suggestions, knowledge sharing and
unconditional advice. This is what researchers and physicians expect as they tread an untraveled
path. More accreditations to a production or clinical facility only speak volumes about management’s
emphasis on quality. It is evident from the fact that increasing numbers of organizations strive to
achieve quality through multiple accreditations, despite that being purely voluntary.

As we went through this accreditation process, we also had the other support functions accredited by
different agencies. The laboratory carrying out the testing for all our products is accredited by NABL
and CAP, which are generally obtained by laboratories in India. We have successfully obtained a five-
star rating for safety on our campus from the British Safety Council (BSC). Our in-house developed
software programs are also accredited by the agencies in their respective fields. These audits and

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accreditations have helped us to graduate to electronic documentation systems and become proficient
in laboratory information systems at the press of a button. Our robust quality system captures any
unusual observations in the form of deviations and assesses its effect on the products or services.
Wherever it necessitates, corrective and preventive actions are taken, implemented and documented
to avoid recurrence of the deviation. Such incidences are assessed by regulatory and accrediting
agencies during routine audits which ensure patient safety.
When standards undergo revision, auditees and auditors make combined efforts to lay down and
harmonize standards that are totally acceptable, doable and enhance quality of a larger group of
participants. India has a handful of accredited cord blood storage facilities, but cellular therapies
facilities are just moving in that direction. Therefore, even when regulatory framework gets
established, accreditations can rightfully claim credit in improving quality of product and services, in
the lead role.

Acknowledgement
We thank the management of Reliance Life Sciences for the continuous support in the furtherance of
stem cell research.

References
1. National Guidelines for stem cell research, ICMR 2013.
2. Press Information Bureau, Government of India, Ministry of Health and Family Welfare
3. Quality Improvement Initiatives in Accreditation: Private Sector Examples and Key Lessons for
Public Health by Michael S. Hamm, CMC Michael Hamm & Associates, Submitted to Carol Chang,
Program Officer, R&E Director/HSS, February 1, 2007
4. Quality and accreditation in health care services - A global review by Evidence and Information
for Policy Department of Health Service Provision WORLD HEALTH ORGANIZATION, Geneva
(2003)
5. Buzzell RD, Gale BD, The PIMS Principles. Linking Strategy to Performance. New York: The
Free Press; 1987.
6. Viswanathan C, Kabra P, Nazareth V, Kulkarni M, Roy A. India’s first public cord blood
repository – looking back and moving forwards. Indian J Hematol Blood Transfus 25(3):111–117.
7. Ryan J. Making the economic case for quality. An ASQ white paper. American Society for
Quality. (cited 2013 March 14). Available from: http://rube.asq.org/pdf/economiccase/economic-
case.pdf.
8. The Effect of Accreditation on International Trade by C. P. Ramani, P.E., C.B.O., IAS
President and David S. Nelson, Ph.D., P.E., IAS Senior Policy Advisor.
9. Chandra Viswanathan, Vivek Tanavde: Regulatory approach to hematopoietic stem cell
therapy, Hematology Today,2006:291-299.

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