As we know, Indian Incubators are growing swiftly and they offer a great support to the entry level entrepreneurs across India. But how talented the start-up’s are they need some external help. Because it takes some time to grow from seed level to a plant. These Indian Incubators form a perfect bridge from idea to execution. They nurture young firms and help them to survive in the early stage. Incubators are offered by non -profit organizations like government, business alliance etc.
Here are some special features of Incubators
- Tackle burdensome regulations
- They enable entrepreneurs to learn from each other
- They also promote cultural change and economic growth
- They offer one-stop facility for counsel, skills, shared facilities
- They provide networking to mobilize external services and mentoring
How to choose incubator
There are four main things to choose the right incubator
- First select the program type in which you want to enroll. i.e. accelerator (or) incubator
Incubators will nurture a business in its startup phase and allow it to develop at its own pace making them ideal for entrepreneurs who want to grow their company steadily over time.
- Second is location
It is better to select a program type that is located close to your city, in order to have more interaction with your mentors, partners etc. It is beneficial later. And also certain cities may be better for particular industries. Like New York for media, Los Angeles for entertainment etc,.
- The next is Industry focus, is another element yet to consider. You need to check the industry the incubator or accelerator specializes in. you need to choose an incubator that connect you to leaders in your industry, and also provide industry specific facilities.
- And finally, services that are provided by incubator. Make sure the services offered by incubators are completely desired. You need to find the one that offer necessary services for your startup.
First of all, make a list of your desired services first and then wanting your options accordingly.
TOP INSTITUTE STARTUP INCUBATORS IN INDIA
- TBI, BITS Pilani.
- TBI, VIT Vellore.
- RTBI, IIT Madras.
- SINE, IIT Bombay.
- CIIE, IIM Ahmadabad.
- SIDBI SIIC, IIT Kanpur.
- TREC STEP, NIT Trichy.
- NSRCEL, IIM Bangalore.
TOP STARTUP INCUBATORS IN INDIA
- Seed fund
- Angel Prime
- Khosla Labs
- Indian Angel Network
- Amity Innovation Incubator
- Science and Technology Entrepreneurship Park, -IITK
- Centre for Innovation Incubation and Entrepreneurship -IIMA
- Nadathur S Raghavan Centre for Entrepreneurial Learning (NSRCEL)
Author : Muthamizh selvi
Today we are going to discuss about Quality Risk Management process
Since a couple of years Quality Risk Management (QRM) has become a mandatory regulatory requirement towards healthcare organizations.
QRM is an overall and continuing process of minimizing risks to product quality throughout its life-cycle in order to optimize its benefit and balance the risk.
It is a systematic process for the evaluation, control, communication and review of risks to the quality of the medicinal product.
It supports science based and practical decisions when integrated into quality systems, examples of quality systems include Validation, Quality Defects – Investigation, Auditing, Inspection, Documentation, Training etc.
Quality Risk Management principles are effectively utilized in many areas including business, insurance, work related safety, public health, pharmacovigilance, and by agencies regulating these industries.
Even though there are some examples of the use of quality risk management in the pharmaceutical industry, today they are limited and do not represent the full contributions that risk management has to offer.
In relation to pharmaceuticals, though there are a variety of stakeholders, including medical practitioners and patients as well as government and industry, the safety of the patient by managing the risk to quality should be considered prime importance.
The manufacturing and use of a drug product, including its components, necessarily involve some degree of risk.
An effective QRM approach can further ensure the high quality of the drug product to the patient by identify and control potential quality issues during development and manufacturing.
Use of QRM can improve the decision making if a quality problem arises. Effective QRM implementation can facilitate better and well- versed decisions which can provide regulators with greater assurance of a company’s ability to deal with possible risks.
Principles of Quality Risk Management
Four primary principles of QRM are:
- The assessment of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.
- QRM should be dynamic, iterative and responsive to change.
- The level of effort, formality and documentation of the QRM process should be commensurate with the level of risk
- The capability for continual development and enhancement should be embedded in the QRM process.
General Quality Risk Management Process
Quality Risk Management is a systematic process for evaluation, control, communication and review of risks to the quality of the drug product across the product life cycle.
Risk can be defined as the combination of the probability of occurrence of harm and the severity of that harm
Initiating a Quality Risk Management Process
Quality Risk Management should include systematic processes designed to organise, facilitate and improve science-based decision making with respect to risk. Steps used to initiate and plan a quality risk management process might include the following:
- Define the problem and/or risk question, including relevant assumptions identify the potential for risk.
- Assemble background information and/or data on the potential hazard, harm or human health impact applicable to the risk assessment.
- Specify a timeline, and appropriate level of decision making for the risk management process.
Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.
It includes risk identification, risk analysis and risk evaluation. Three fundamental questions are often helpful.
- What might go wrong?
- What is the possibility that it will go wrong?
- What are the consequences?
Risk identification is a organized use of information to identify hazards referring to the risk.
Information can include historical data, theoretical analysis, and the concerns of stakeholders.
Risk identification addresses the “What might go wrong?” question, including identifying the possible consequences.
This provides the basis for further steps in the quality risk management process.
Risk analysis is the estimation of the risk associated with the identified hazards.
It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms.
In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.
Risk evaluation compares the identified and analysed risk against given risk criteria.
Risk evaluations consider the strength of evidence for all three of the fundamental questions.
Different Steps Involved In the Risk Assessment Are
- Collect & organise the information
- Formulate the Risk Question
- Choose Tool different tools include
- Identify Risks Factors and Related Hazards
- Define the Risk Components &Scales
- Evaluate the risk for each hazard
- Determine acceptability of risks
- Determine Action Threshold
- Apply the tool
Risk control includes decision making to reduce and/or accept risks.
The intention of risk control is to reduce the risk to an acceptable level.
The amount of effort used for risk control should be proportional to the significance of the risk
Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds a specified level.
Risk reduction might include actions taken to mitigate the severity and probability of harm.
The implementation of risk reduction measures can introduce new risks into the system or increase the significance of other existing risks.
Hence, it might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk after implementing a risk reduction process.
Risk acceptance is a decision to accept risk.
For some types of harms, even the best quality risk management practices might not entirely eliminate risk.
In these circumstances, it might be agreed that an appropriate quality risk management strategy has been applied and that quality risk is reduced to a specified (acceptable) level.
This (specified) acceptable level will depend on many parameters and should be decided on a case-by-case basis.
Risk Review is the output/results of the risk management process should be reviewed to take into account new knowledge and experience.
Once a quality risk management process has been initiated, that process should continue to be utilized for events that might impact the original quality risk management decision.
Risk review might include reconsideration of risk acceptance decisions
Risk Communication is the sharing of information about risk and risk management between the decision makers and others.
The output/result of the quality risk management process should be appropriately communicated and documented.
The included information might relate to the existence, nature, form, probability, severity, acceptability, control, treatment, detectability or other aspects of risks to quality.
Quality Risk Management is a systematic process for evaluation, control, communication and review of risks to the quality of the drug product across the product lifecycle.
Effective Quality Risk Management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks, and might affect the extent and level of direct regulatory oversight.
Today We are going to discuss on eCTD
CTD is an ICH standard that FDA adopted in a consensus process, as a member of ICH, together with other member regions, Europe and Japan Currently global format for regulatory submissions Consistent data organization Method to electronically transfer product information and data Collection of electronic files organized according to guidelines defining file format, folder/files naming convention, document specifications etc. Applies to all NDAs, ANDAs, BLAs, INDs and master files.
The eCTD challenge In the US, eCTD-only NDAs, BLAs and INDs are accepted – no paper necessary eCTD plus paper still needed for Medical authorities in EU Paper is still the official archival copy of the EU MA EU wants eCTD as preferred format for all Marketing Authorisation Applications(MAAs) and variations Only eCTD for MA for all EU members states by 1 Jan 2010 Health Canada wants eCTD format on CD/DVD plus paper
NEED FOR ELECTRONIC SUBMISSIONS
Designed with consideration that facilitate Creation Review Assists project management and information management Life cycle management (the history of a product application) Archiving Drug development planning
Current Status of US eCTD Submissions FDA Office of Chief Information Officer Quarterly briefing, 12 Dec 2008 During the period 2005 to 2008, eCTD submission volume grew at a compounded annual growth rate of approximately 300%.
Basics of eCTD The ICH M4 Expert Working Group (EWG) has defined the Common Technical Document (CTD). The ICH M2 EWG has defined, in the current document, the specification for the Electronic Common Technical Document (eCTD). There are 5 modules in the submission report. A hierarchical cabinet/folder structure containing the electronic documents (PDF). An XML backbone that provides a structure to display the PDF documents in the eCTD format (eCTD viewer)
- CDER Contact for information on eCTD submissions email@example.com
- CDER Contact for information on SDTM submission firstname.lastname@example.org Electronic
- Regulatory Submissions and Review website http://www.fda.gov/cder/regulatory/ersr/default.htm
- International Conference on Harmonization http://www.ich.org
- All FDA Guidances on Electronic Submissions http://www.fda.gov/cder/guidance/index.htm#electronic_submissions
Good evening everyone………..
Today we are going to discuss on Data integrity issues
What is Data Integrity?
- Complete, consistent, and accurate data to assure patient safety and product quality.
- Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded,original or a ‘true copy’, and accurate (ALCOA).
- Good Documentation Practices for Static and Dynamic Records.
- Data integrity should be maintained throughout the data life cycle, including, but not limited to data creation, processing, archiving and disposition after record’s retention period
What is ALCOA?
- Attributable – Traceable to a unique individual
- Legible – Data must be recorded permanently and be readable
- Contemporaneously – Activities must be recorded at the time they occur
- Original or a true copy – first capture of data (not transcribed
data), must review the original record, must retain the original or certified copy of the original record.
- Accurate – records must be accurate, which is achieved thru the Quality Management System
What are the Regulations?
- Data in accordance with cGMP requirements for drugs (i.e., as required by 21 CFR parts 210, 211,and 212).
- Part 210 – Current Good Manufacturing Practice in Manufacturing,Processing,
- Packing, or Holding of Drugs; General.
- Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals.
- Part 212 – Current Good Manufacturing Practice for Positron Emission Tomography Drugs.
- Q7A – Active Pharmaceutical Ingredients.
Regulations – Data Integrity : Requirements with respect to data integrity in parts 211 and 212 continued:
- 211.188, 211.194, and 212.60(g) (requires “complete information,” “complete data derived from all tests,” “complete record of all data,” “original records have been reviewed for accuracy, completeness, and compliance with established standards,” and “complete records of all tests performed”).
- 211.192 (requires production and control records be “reviewed”) 211.101(c) and (d), 211.103, 211.182, 211.186(a), 211.188(b)(11), and 211.194(a)(8) require records be “reviewed” by a second person.
Why is Data Integrity Important?
- FDA cGMP inspection(s) have uncovered violations with data integrity issues.
- Data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s ability to protect the public health.
- Data integrity-related cGMP violations may lead to regulatory actions, including warning letters, import alerts, and consent decrees.
- The underlying premise in 210.1 and 212.2 is that cGMPs sets forth minimum requirements to assure drugs meet standards of the Federal Food, Drug, and Cosmetic Act (FD&C Act) regarding safety, identity, strength, quality, and
- FDA’s authority for cGMP comes from FD&C Act section 501(a)(2)(B).
- 501(a)(2)(B) states: a drug shall be deemed adulterated if “the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirement of the act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”
- Reliability on the information used to ensure the quality of the drugs that
consumers will take
- Data integrity problems break trust
- FDA rely on firm’s to do the right thing when FDA is not present.
Examples of significant issues
- No raw data to support records
- Creating inaccurate and incomplete records
- Test results for one batch used to release other batches
- Fabricating data
- Discarding data
- Repeated tests, trial runs, sample runs (testing into compliance)
- Changing integration parameters of chromatographic data to obtain passing results
- Deletion/manipulation of electronic records
- Turning off audit trail
- Sharing password
- Inadequate controls for access privileges
- Inadequate/incomplete computer validation
- Inadequate investigations
- Inaccurate reporting of microbial, sterility, or endotoxin data results
- Loss of data during changes to the system
- Activities not recorded contemporaneously
- Employees that sign that they completed manufacturing steps when the employees were not on premises at the time the steps were completed.
Things to consider…
- Is data integrity a problem at your facility? What measures are in place to prevent data integrity problems?
- Are internal audit procedures adequate? What measures are in place and will they detect data integrity issues?
- Does senior management cultivate adequate and accurate reporting of events when things go wrong during manufacturing…during testing?
- Train personnel to detect and prevent data integrity as part of routine cGMP training.
Where does the Agency find Data Integrity Issues?
- Domestic and international facilities
- Small and large pharmaceuticals companies
- Manufacturing operations
- Quality units, including quality control laboratories (chemistry and microbiology)
- Clinical Trials
Things to consider…
- Existing systems should be able to ensure data integrity, traceability and reliability
- Firms who outsource operations should have robust systems in place to verify and compare data generated by the contractor
- Once data integrity issues are found during an inspection, a change to a written
procedure or firing an employee is not enough
- Quality Risk Management approaches to prevent, detect and control potential risk
FDA recommends that data integrity problems identified during inspections
- The firm should demonstrate effective remediation. For example, By:
- Hire a third party auditor
- Determine the extent/scope of the problem
- Implement a global corrective action plan
- Removing individuals responsible for problems from cGMP positions
- Part 210 – Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General.
- Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals.
- Part 212 – Current Good Manufacturing Practice for Positron Emission Tomography Drugs.
- Q7A – Active Pharmaceutical Ingredients.
Before starting the discussion about the deficiencies that we receive from the agencies…
Let me ask a question to all of the readers!
Have you received a CEP certificate without a single deficiency letter or request for additional information?
The answer might be big “NO”.
So the today article mainly focuses on the top 10 deficiencies that we frequently receive from the regulatory authorities or agencies.
This article is in conjugation with PA/PH/CEP (16) 58 document, discussed to avoid the receipt of the deficiency letters. Because the management of CEP application policy allows only two deficiency letters to be issued to the manufacturing companies. If the dossier is still considered deficient the CEP application may be rejected.
So, by following the below checks, which are listed in the top 10 deficiencies in the CEP PA/PH/CEP (16) 58 document, while preparing the dossier may avoid the queries in the deficiency letter.
Number 1: Genotoxic/ Mutagenic impurities
The CEP applications which are being filled by the manufacturing companies are lacking the discussion on Genotoxic and mutagenic impurities. Identifying the compounds that possess a structural alert and controlling the compounds below the TTC level could be the solution.
- Perform the genotoxic assessment of the Active pharmaceutical ingredient right from the Route of synthesis of the starting material.
- Calculate the TTC value and identify a suitable analytical method to show the absence or control measure in the final drug substance.
Number 2: Choose a suitable starting material
The 50% of the pharmaceutical companies receive this most common deficiency for choosing a suitable starting material for the API.
- The starting material should be choosed based on the ICH Q11 guideline.
- The starting material should not possess a complex structure and it should not have a major portion of the API.
Number 3: Inadequate discussion of the manufacturing process.
The regulatory agencies look for the detailed information about the manufacturing process and the API manufacturers should completely provide the documents related to the manufacturing process.
- Recovery processes and Recovery solvents batch processing records are expected to be present in the section 3.2.S.2.2.
- Batch size mentioned in the section 3.2.S.2.2 should match with the Batch analysis section 3.2.S.4.4.
Number 4: Carryover of starting material impurities to the final drug substances
Choosing the suitable starting material is a task, and setting a proper specification to the starting material is another task.
- Most of the starting materials may be isomers, so controlling the relative isomers in the starting material is one major check. In the current scenario, the regulatory agency asks the manufacturer to show the absence of isomers in the final drug substance.
- The specification of the starting material should have an identification test, limit for specified, unspecified and total impurities.
Number 5: Improper Justification of the starting material specification
Even though the starting material specification is set with the limits with specified, unspecified and total impurities, without proper justification for set limits, the agency could not accept the specification and hence leads to the deficiency letter.
- The justification of the specification should include the evaluation of the risks and the ability of the subsequent steps to purge impurities.
- Technical write up for the process to purge the impurities should be included in the dossier.
Number 6: Inadequate specifications for the solvents (recycled and recovered) used in the manufacturing process.
The usage of recovered solvents is not restricted in the manufacturing process but the specification should be set and testing should be performed to prove that the use of recovered solvents does not affect the quality of the drug substance.
- The set specification should include a purity test and the reasonable mass balance is expected to be in place.
Number 7: Inadequate specifications for the reagents and elemental impurities
The manufacturing process may or may not use metals, but the manufacturing process including equipment, utilities should be screened for the presence of elemental impurities. The ICH Q3D guideline defines the elemental impurities and divided the elements into three classes namely 1, 2A, 2B and Class 3. The regulatory agencies expects a risk assessment summary for the 24 elements.
- Provide a risk assessment for all the 24 elements in the dossier section 3.2.S.3.2.
- Elements such as Boron, aluminium etc if used in the synthesis of the drug substance, a discussion about their absence in the final drug substances is expected.
Number 8: Inadequate specifications for the isolated intermediates
It is presumed that the specification of the intermediates should be set in such a way that it captures all the related impurities in the intermediate specification.
Number 9: Justification and carryover of isolated impurities
The impurities captured in the intermediate specification should have definite limit, justification is supposed to the set limit and if any impurity limit in the intermediate is set more than 1.0%, then it absence in the final drug substance should be shown. The risks of having uncontrolled impurities in the final substance potentially above acceptable limits should be addressed
Number 10: In adequate information about the starting materials.
The following information about the starting materials is necessary to be present in the dossier.
- Route of synthesis
- Address of the manufacturer
- Brief description with flow chart.
If more than one source of starting material is used in the process, batch equivalency report is to be provided in the dossier.
Avoiding the above checks could bring us the quick approval.
ALL THE BEST
Today we are going to discuss on the purpose of a quality management system.
QMS is to help businesses improve abilities to consistently meet customer or regulatory requirements, according to the American Society for Quality.
A major component of a successful system is a corrective action program that adequately addresses non-conformance. The problem is that many systems become a burden rather than a tool for improvement, generally, because they are not well-planned prior to implementation.
- Root cause investigation
- Conclusion & Quality design
- Action plan
- Implementation and follow up
- Tie CAPA implementation to:
- Document control for products and processes
- Change control
- Ensure that controlled documents are reviewed and approved if changes are made.
NOTE: Closing CAPAs when actions are implemented, and tracking the effectiveness checks for CAPAs as a separate quality system metric. If closure takes more than 90 days, the CAPA should probably be converted to a Quality Plan. This is NOT intended to be a “work around” to give companies a way to extend CAPAs that are not making progress in a timely manner.
Today we are going to discuss on the Genotoxic Impurities and its assessments.
The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals.
From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as short-term exposure periods.
For determination of acceptable levels of exposure to genotoxic carcinogens considerations of possible mechanisms of action and of the dose-response relationship are important components. Based on the above considerations genotoxic impurities may be distinguished into the following two classes:
- Genotoxic compounds with sufficient (experimental) evidence for a threshold-related mechanism
This approach calculates a “Permitted Daily Exposure” (PDE), which is derived from the NOEL, or the lowest- observed effect level (LOEL) in the most relevant (animal) study using “uncertainty factors” (UF).
- Genotoxic compounds without sufficient (experimental) evidence for a threshold-related mechanism
The assessment of acceptability of genotoxic impurities for which no threshold mechanisms are identified should include both pharmaceutical and toxicological evaluations. In general, pharmaceutical measurements should be guided by a policy of controlling levels to “as low as reasonably practicable” (ALARP principle), where avoiding is not possible. Levels considered being consistent with the ALARP principle following pharmaceutical assessment should be assessed for acceptability from a toxicological point of view.
A TTC value higher than 1.5 µg/day may be acceptable under certain conditions, e.g. short-term exposure, for treatment of a life-threatening condition, when life expectancy is less than 5 years, or where the impurity is a known substance and human exposure will be much greater from other sources (e.g. food). Genotoxic impurities that are also significant metabolites may be assessed based on the acceptability of the metabolites.
The concentration limits in ppm of genotoxic impurity in drug substance derived from the TTC can be calculated based on the expected daily dose to the patient using equation (1).
(1) Concentration limit (ppm) = TTC [µg/day]/dose (g/day]
The TTC concept should not be applied to carcinogens where adequate toxicity data (long-term studies) are available and allow for a compound-specific risk assessment.
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