GMP

Ebola survivor study expanded to include new technologies

In addition to supporting ongoing response to Ebola outbreaks in the Democratic Republic of the Congo (DRC), FDA and government partners are conducting studies in West Africa to better understand how Ebola affects patients who have survived, and to learn how to more effectively treat these patients’ chronic health problems

In 2016, FDA awarded a contract to Stanford University to help the global scientific community better understand the course of Ebola virus infection—an important factor in finding new treatments. In 2017, research was expanded to include Zika virus infection.
In September 2019, the project was again expanded, to apply a new method to the study of Ebola and Zika tissue samples. The Stanford laboratory will use multiplexed ion beam imaging (MIBI) to identify viral reservoirs—cells or anatomical sites where viruses accumulate and persist—for both Ebola and Zika infection, ultimately facilitating the deployment of novel, effective analytical technologies into federal laboratory space.

FWQRC, GMP, Life Sciences, Pharma

Need for a proactive approach-To protect our loved one and also to continue the business without financial drop down.

We have heard the presence of NDMA impurities in Sartans and Ranitidine drugs. Initially it was only sartans, later Ranitidine and what’s next now?

Now let’s extend the concept to OTC drugs that may contain Nitrosamines impurity. Lets us review the sources of Nitrosoamines.

  1. Solvents:

The source for nitroso amines may also be from solvents.

DMF: NDMA can also be formed from Dimethyl formamide as shown below.

DMA is present as an impurity in DMF, a precursor in the industrial DMF process. It may also formed as a degradant during storage of the solvent.

DEA:

Similar to DMA formation, DEA could be formed by degradation of triethylamine (TEA) or exist as impurity in TEA raw material.

Some common organic solvents (e.g. NMP which could give rise to 4- (methyl)(nitroso)amino)butanoic acid = NMBA) and amine bases (e.g. diisopropylamine = DIPEA which could give rise to N-Nitrosodiisopropylamine (DIPNA) and N-Nitrosoethylisopropylamine (EIPNA)) would present such risks.

  • Reagents Like piperazine, a secondary amine, reacts slowly with NOx in the presence of O2 to form a nitrosamine derivative under conditions similar to those found in industrial amine-based post-combustion CO2 capture processes.

The genotoxic and mutagenic assessment is at most performed for Raw materials, reagents, catalysts etc., But do we really assess the Recycled solvents, reagents and catalysts and this may be chance for nitrosamine formation due to the presence of amines in the waste streams sent for recovery and the subsequent quenching of these materials with nitrous acid to destroy residual azide, without adequate control of nitrosamine formation or adequate purification.

Examples of recycled materials observed to be contaminated with nitrosamines include orthoxylene and tributyltin chloride (used as a source of tributyltin azide). Nitrosamines may be entrained if they have similar boiling points or solubility properties to recovered materials depending on how recovery and subsequent purification takes place (e.g. aqueous washes or distillation).

Simple checks during the manufacturing process can identify the impurities and avoids the market recall.

  1. Evaluate the solvents, reagents for the structural alert that are similar like nitrosoamines.
  2. Recovered solvents, recovered materials that are outsourced by a third party vendor.
  3. Evaluation of drug product formulation and process.

In-depth analysis during drug development should actually identify all the issues.

Budding and Small-scale industries who cannot identify the sources of the impurity or who cannot have sufficient capacity to analyse the drugs can take the help of qualified labs/ consultancies as a onetime activity.

Best advice is our cost saving should not cost the life of our fellow citizens.

A proactive approach for the high market value molecules to avoid any surprise in the future.

OTC Drugs

  • Drugs that contains Piperazine ring are Ranolazine, Trimetazidine, Amoxapine, Amoxapine, Befuraline, Buspirone, Flesinoxan, Ipsapirone, Nefazodone, Piberaline, Tandospirone, Trazodone, Vilazodone, Zalospirone, Meclozine, Cinnarizine, Hydroxyzine, Cetrizine, Levo citrizine, Niaprazine, Fluphenazine, PERPHENAZINE, Prochlorperazine, THIOTHIXENE, Quipazine, Imatinib, Benzylpiperazine, Buclizine, Ziprasidone,Etc…

Out of the above drugs listed, The OTC drugs are Cetirizine, Hydroxyzine etc are into the consideration of Nitrosoamine impurities and other prescription should also be taken into consideration.

  • One of the article which was published in the year 2001, has concluded that nitrosoamine was detected in the patients urine, who is consuming the long term treatment with Omeprazole, a Proton pump inhibitor.

Omeprazole, with the maximum daily dose of 360 mg/day is prescribed for some patients with Zollinger-Ellison Syndrome for treatment period longer than 5 years.

Since, these OTC drugs are easily available in the market and consumed without doctors prescription, there is a quick need for evaluation and control of   these impurities in the Drug substance as well as drug product.

The above statement is just an example and further evaluation is REQUIRED.

Since the method for the detection of the nitrosamines is available, why delay, start assessing and perform a risk assessment for your drugs.

Assess, Analyse, Announce your results and be responsible for public health, since these are OTC drugs.

FWQRC, GMP, Life Sciences, Pharma

NDMA-Genotoxic Impurity

Hello Readers!!!

mutation-3-28-18
Today’s discussion is about the hottest topic in the pharmaceutical industry, where many industries producing the Ranitidine and Valsartan drugs recalled the batches from the MARKET due to the presence of this impurity in the drug above the acceptance criteria.

First of all, What is NMDA and NDEA impurity?
N-Nitrosodimethylamine (NDMA), also known as dimethylnitrosamine (DMN) and N-nitrosodiethylamine, the member N-nitrosoamine class is a semi-volatile organic chemical, produced as a byproduct in chemical synthesis or as a whole.

A bit more about NDMA & NDEA impurities.

NDMA

300px-Hatzinger1w2_Fig1

NDEA

Nitrosodiethylamine.svg

Numerous studies were conducted in vitro in bacterial and mammalian cells, there has been overwhelming evidence that NDMA is not only a mutagenic but also clastogenic. The NDMA impurity increased the frequencies of gene mutations, chromosomal damage, sister chromatid exchange, and unscheduled DNA synthesis in a wide variety of cell types including human and rodent cells.

The evidence of genetic effects has also been observed in in vivo studies. Clastogenic effects (e.g., micronuclei, sister chromatid exchange, chromosomal aberrations) in, bone marrow cells, spleen cells and peripheral blood lymphocytes, as well as in oesophageal, kidney cells have been observed in rodents (rats, mice, or hamsters) administered NDMA either orally or by intraperitoneal injection.
Evidence of genotoxicity (e.g., chromosomal aberrations, micronuclei, gene mutation,DNA strand breaks) has also been observed in the offspring of hamsters and mice.

How does it reacts with the human body?
NDMA is metabolized by CYP2E1 enzyme in the liver, which hydroxylates one methyl group. The resulting hydroxymethyl nitrosamine is unstable and decomposes to formaldehyde, which is also used to quantify the metabolic rate and methane-diazonium-ion, which methylates DNA and protein or reacts with water to methanol. The electrophilic intermediates produced by metabolic activation of nitrosamines, react rapidly with cellular nucleophiles and target for carcinogens during tumor initiation.

WhatsApp Image 2019-10-28 at 21.12.11

The discussion about the NDMA impurities has been conversed previously.

  • In ICH M4 guideline “ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK”- Dated March 31, 2017.

  • World Health Organization Guidelines for Drinking-Water Quality, 3rd edition including 1st and 2nd addenda, 2008.

The topic is not only limited to Ranitidine and Valsartan drugs but it is applicable to all the drugs. All the drug substances should be assessed for the NDMA impurity and necessary controls should be taken.

Lets not wait for the regulatory authorities to take action upon the manufacturers. It is the Pharmaceutical manufacturers responsibility to deliver the right drugs to ensure the patient safety…

GMP

Business Incubators

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

  1. Tackle burdensome regulations
  2. They enable entrepreneurs to learn from each other
  3. They also promote cultural change and economic growth
  4. They offer one-stop facility for counsel, skills, shared facilities
  5. 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.

incubator image

Image source: https://media1.picsearch.com/is?gpc0LlhBtU-2axkHhvkdANipP-KeWULjKOxQlbra_ao&height=272

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

  • iCreate 
  • Indavest
  • 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 

 

 

GMP

QUALITY RISK MANAGEMENT

Hi Everyone

Good evening……..

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:

  1. The assessment of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the  patient.
  2. QRM should be dynamic, iterative and responsive to change.
  3. The level of effort, formality and documentation of the QRM  process should be commensurate with the level of risk
  4. The capability for continual development and enhancement should be embedded in the QRM process.

General Quality Risk Management Process

QRM 1

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:

  1. Define the problem and/or risk question, including relevant assumptions identify the potential for risk.
  2. Assemble background information and/or data on the potential hazard, harm or human health impact applicable to the risk assessment.
  3. Specify a timeline, and appropriate level of decision making for the risk management process.

Risk Assessment

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.

  1. What might go wrong?
  2. What is the possibility that it will go wrong?
  3. What are the consequences?

Risk identification

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

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

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

  1. Collect & organise the information
  2. Formulate the Risk Question
  3. Choose Tool different tools include
  4. Identify Risks Factors and Related Hazards
  5. Define the Risk Components &Scales
  6. Evaluate the risk for each hazard
  7. Determine acceptability of risks
  8. Determine Action Threshold
  9. Apply the tool

Risk control

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.

Conclusion:

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.

GMP

WHAT IS COMMON TECHNICAL DOCUMENT?

Hi Everyone

Good evening………………………

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.

eCTD_viewer1eCTD_viewer2

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)

References

GMP

Data Integrity Issues & Concerns

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

Information Security addresses picture style 3 Stock Photo - 27100602

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
    purity.
  • 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
  • Backdating
  • 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

Conclusion

  • 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
    are essential

FDA recommends that data integrity problems identified during inspections
be addressed?

  • 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

References

  • 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.

                                                                          Thank you………..