A very brief overview of Post marketing Safety Management

Post marketing Safety Management is a very important area of a Good Clinical Practice (GCP) and Good Vigilance Practice (GVP). This is why the FDA has very detailed and clearly laid out requirements that organizations and sponsors of clinical research have to comply with as part of meeting safety requirements.

The FDA’s requirements on post marketing safety management are laid out in a number of its sections, namely 21 CFR 310.305, 314.80, 314.98, 600.80, and 600.81. Primarily, these sections of the FDA require organizations or sponsors to report the following:

  • Serious and unexpected adverse experiences that can occur from either foreign or domestic sources
  • Spontaneously reported adverse experiences that occur domestically and that belong to any of these categories:
    • Serious and expected
    • Nonserious and unexpected
    • Nonserious and expected

Who should report post marketing safety management?

Post marketing safety management is to be taken care of and reported by personnel who have been entrusted responsibilities relating to safety reporting. These include:


What is to be reported as part of post marketing safety management?

The FDA states clearly that the following need to be reported as part of post marketing safety management:

  • Any adverse event associated with the use of a drug or a biological product
  • Serious adverse experiences, whose reporting is necessitated by any of the following:
    • Death
    • An experience in which the subject felt that her life was threatened
    • Any experience that causes the patient’s stay in hospital to be prolonged
    • An experience in which the patient was left with a debilitating condition on account of the clinical research
    • A defect that occurs in the womb
    • Post marketing safety management also requires reporting on experiences in which the patient (or subject) develops an allergic bronchospasm that requires intensive intervention and hospitalization

Read More: https://www.linkedin.com/pulse/very-brief-overview-post-marketing-safety-management-ronald-gardner?published=t

Validation of Pharmaceutical Water Systems

Thorough and proper validation of pharmaceutical water systems is highly essential for ensuring that the pharmaceutical unit uses the right quality of water. This is very important, because water is not only the source of life for humans; it enjoys the same importance in pharmaceuticals.

A very important reason for which validation of pharmaceutical water systems is necessary is that water is not only the most widely used raw material or substance in pharmaceuticals; it is also put to a number of uses in the pharmaceutical industry, such as Quality Control, process, production and formulation. Further, water comes with its own set of unique chemical properties that are obtained because of the hydrogen bonds present in it and its polarity. This makes water versatile, since it allows the dissolution, absorption, adsorption or suspension of various different compounds.

Pharmaceutical water systems

Process for pharmaceutical water systems validation

Validation of pharmaceutical water systems is carried out in three phases:

Phase I, which is the investigational phase

Phase II, the short term control phase, and

Phase III, which is the long-term control phase

Pharmaceutical water systems are validated through these three steps or stages to demonstrate and ensure that the facility using pharmaceutical water systems has water under its control and is on the right track for production of the right quality and quantity of water in the short, medium and long terms.

Validation through commissioning and qualification

Pharmaceutical water systems validation is carried out through two important steps, namely commissioning and qualification. Commissioning is about putting the validation of pharmaceutical water systems through the required phases using the prerequisite methods of documentation. This documentation is a core part of pharmaceutical water systems validation because it allows for different personnel in the organization to not only keep track of the processes involved, but also make changes when necessary.

Qualification as part of pharmaceutical water systems validation

Qualification is the next important stage of pharmaceutical water systems validation. Here, before a pharmaceutical water systems validation process is started, the pharmaceutical facility should implement the following important steps:

  • Design qualification (DQ)
  • Installation qualification (IQ) and
  • Operational qualification (OQ)

Phase I:

In Phase I, the pharmaceuticals facility samples and tests water sampling for anywhere between two and four weeks for monitoring the water system. If the water system is free of failure during this phase, it is considered a successful phase of pharmaceutical water systems validation.

Phase II:

In this phase of pharmaceutical water systems validation too, the water system sample is tested intensively for two to four weeks, during which the water sample should show that it is producing the right quantity of water under conditions of stated SOP.

Phase III:

Phase III of pharmaceutical water systems validation is the longest and most arduous period, running to one year after completion of Phase I and Phase II. When the water sample passes through this phase, it is said to have completed the process of pharmaceutical water systems validation and is considered fit for pharmaceutical use.

Read More: https://www.linkedin.com/pulse/validation-pharmaceutical-water-systems-ronald-gardner?published=t

Understanding the Pharmaceutical Batch Record Review

The pharmaceutical batch record review is a very crucial tool for ensuring both quality of the product process and compliance with regulatory requirements. It is an important means by which pharmaceutical organizations can formulate two important strategies:

  1. A pharmaceutical batch record review is a very effective medium for keeping complete track of the firm’s day-to-day operations. A pharmaceutical batch record review helps the organization track its product from start to finish, thereby leaving no scope for ambiguity or uncertainty anywhere in the chain;
  2. It helps the organization adhere in letter and spirit to regulatory requirements. Being in compliance with regulatory requirements is the surest means to avoiding collisions with regulatory authorities such as the FDA and others.


Regulatory guidelines from any regulatory body around the globe have a common requirement: that of maintenance or adherence to pharmaceutical batch record review standards if regulatory compliance is to be achieved. Review of production and quality control records are built into the approval process of a batch release. These are to be implemented at all the stages of the pharmaceutical batch record review, namely creation or alteration of master documents, along its distribution chain, records collection, and process for archiving and retrieving.

All regulatory authorities insist on the need and imperative of manufacturers to identify and exhaustively investigate the failure of a batch to meet its required specifications.

Another important requirement of a pharmaceutical batch record review is that investigation of a batch’s divergence, big or small, or inability for meeting specifications should be extendable to remaining batches of the same product, as well as related products which may have been involved in or associated with that particular failure or deviation or one similar to it. Pharmaceutical batch record review requires the organizations to write down records of the investigation and mention what corrective action was initiated, and what status this action has.

Regulations relating to pharmaceutical batch record review

All around the world, regulatory authorities have their respective regulations and standards pertaining to their requirements for meeting pharmaceutical batch record review standards. These are the current pharmaceutical batch record review standards around the globe:

  • EU Regulations
  • FDA
  • ICH Q7 requirements
  • Updates to ICH Q9/Q10 and EU-GMP Chapter 1
  • Updates to the Counterfeit Directive

Read More: https://www.linkedin.com/pulse/understanding-pharmaceutical-batch-record-review-ronald-gardner?published=t



Orphan Drugs in the USA

Orphan drugs are drugs that are exclusively developed and used for treating rare diseases. Orphan drugs are not researched and developed for widespread use, since by their nature, they are meant only for rare diseases. Since by definition, a rare disease is not likely to have too many patients; orphan drugs are limited in their research, development and eventually, the market.

Situation governing orphan drugs in the USA

Different countries and markets have their own rules for how orphan drugs are developed and marketed. Orphan drugs in the USA have rules designated as to their application. Three major aspects mark out the rules relating to orphan drugs in the USA:


Liberal rules for clinical research

One, there are sufficient leniencies relating to the conduct of the clinical research for the orphan drugs in the USA. The requirement that non- orphan drugs in the USA need to make in relation to sample size does not apply to orphan drugs in the USA. This is natural, considering that fixing a sample size for the clinical research makes no sense, since in many cases, the full number of people suffering from the rare disease, that is, the people for whom the drug is being developed, could be quite nominal. In such instances, it will not be possible for the study to gather a big sample trial size.

Stresses the role of governments

Secondly, research and development of orphan drugs in the USA requires the intervention of the government, not-for-profit organizations that fund such activities, and philanthropy for support. In the case of non-orphan drugs in the USA; there are sufficient incentives for full-scale development and monetization. This is not so in the case of orphan drugs, since as noted, the population needing the drug could be miniscule.

Unencumbered approval process

As an offshoot of these two factors, the FDA has made the approval process of orphan drugs in the USA extremely easy and simple. Again, this is also based on the same logic that governs the entire nature of orphan drugs in the USA: their need in people who do not belong to the general population. To bring about incentives for orphan drugs in the USA; the federal government has passed The Orphan Drug Act.

The Orphan Drug Act

As a means to concretize the role of orphan drugs in the USA; the US administration passed the Orphan Drug Act in 1983. Aimed at encouraging firms to take up development of drugs for products with a very limited market, the Orphan Drug Act has the following features:

  • It makes manufacturers of orphan drugs eligible for incentives such as a seven-year exclusivity
  • It offers tax rebates of up to half of all their costs spent on research and development, and several other tax incentives for clinical trials of orphan drugs in the USA.

Read More:https://www.linkedin.com/pulse/orphan-drugs-usa-ronald-gardner

Orphan Drugs in the European Union

Rules concerning orphan drugs in the European Union are largely inspired by those concerning orphan drugs in the US. Orphan drugs in the European Union are based on and built on the same premise, namely offering support to pharmaceutical companies that manufacture drugs to treat rare diseases.

Regulations on orphan drugs in the European Union

The European Medicines Evaluation Agency (EMEA) has made regulations for the conduct of orphan drugs in the European Union. The whole set of regulations was built on the need for developing rare drugs and making them available at the most affordable cost and in the quickest possible time for the patient.

January 1, 1995 can be considered the date from which rule concerning orphan drugs in the European Union came into existence across the board in the European Union. Till then, the EU was in the process of synchronizing and unifying the fragmented laws on orphan drugs in the European Union across its many countries. From this date, the rules for orphan drugs in the European Union have been uniform across the bloc.

Regulation n° 141/2000

Regulation n° 141/2000 was the first and most important regulation that the EU passed as part of regulation of orphan drugs in the European Union. Passed by the European Parliament in December 1999; its salient features include the following:

Read More:https://www.linkedin.com/pulse/orphan-drugs-european-union-ronald-gardner?trk=prof-post

Rule relating to orphan drugs in Japan

Orphan drugs are those that are developed purely to treat rare diseases. The nature of orphan drugs is a little piquant: on the one hand, rare diseases affect very few people, but these cannot be ignored. On the other hand, orphan drugs, since they are so few in number, are not taken up usually by profit-driven organizations because they offer very less scope for large-scale production and monetization.

Different countries such as the US and Japan, and blocs such as the European Union have their own unique rules regarding orphan drugs. Rules relating to orphan drugs in Japan too, have their unique and salient features.

A look at the uniqueness of rules relating to orphan drugs in Japan

Orphan drugs in Japan are governed by five incentives:

  • Subsidies
  • Consultation
  • Tax preferences
  • Priority review
  • Reexamination period review

Briefly, this is how each of these is carried out in practice:

Subsidies:The Japanese government has a fund of close to a billion yen that is used to subsidize orphan drug applicants. This grant, given through the National Institute of Biomedical Innovation (NIBIO), is aimed at helping manufacturers to ease the costs associated with development of orphan drugs in Japan.

Consultation:Under this system, the Japanese government offers priorities for manufacturers of orphan drugs in Japan. Called the Priority Consultation System; this process is offered in two ways:

One, when a sponsor of orphan drugs in Japan approaches the PMDA; the application is never rejected. Clinical data is discussed with each sponsor, at which all the aspects of orphan drugs in Japan are considered. Areas taken up for discussion include the number of patients, the intensity of the disease, the integrity and safety of the data, and so on.

Two, the fee category is also considerably lower for orphan drugs in Japan, with these manufacturers given about 25 percent discount. An application made for developing orphan drugs in Japan is put for consolation with a team of Technical Experts, who are selected from the Office of New Drug Review team, the Office of Cellular and Tissue-based Products Review team, and the Office of Medical Devices Review team. In addition, fee categories are drastically lower for orphan drugs in Japan when they are being developed by small companies or research institutes. These categories have a whopping 90 percent discount.

Tax incentive: Manufacturers involved in developing and manufacturing orphan drugs in Japan are given a 12 percent reduction as tax credits for expenses incurred during the NIBIO subsidy payment period.

Priority review:Manufacturers of orphan drugs in Japan are offered a priority review by the PMDA. While the median standard review time is one year for non-orphan drugs, that for orphan drugs in Japan is nine months.

Reexamination period review: The Reexamination period review for orphan drugs in Japan is also relaxed. It is fixed at eight years for orphan drugs in Japan, while this period is ten years for non-orphan drugs in Japan.

Read More: https://www.linkedin.com/pulse/rule-relating-orphan-drugs-japan-ronald-gardner

Tips for managing CRO’s

The role of clinical contract research organizations (CRO’s) has come into focus of late, with the burgeoning growth of the outsourced model for business. In the clinical research industry, CRO’s are considered viable alternatives to expensive domestic players. This is because since it is the clinical study process that needs to be outsourced to developing countries; this can happen at a more economical rate than when insourced to clinical contractors in developed economies.

Pros and cons of managing CRO’s

Undoubtedly, the biggest advantage a pharmaceutical company or any other sponsor gains by outsourcing its clinical research is that it saves humungous amounts of money. This is the most obvious no-brainer, because huge cost advantages exist between developed and developing economies.

In addition, there is also the assurance of quality delivery. A CRO is legally contracted to supply the process and results of a remote clinical trial on time with almost no use of resources from the outsourcing organization.

Of course, there are downsides in managing CRO’s, as there are in any business process. CRO’s that outsource their clinical research need to be in control of the whole process, right from start till finish. Unlike say, manufacturing or software, in which the business deals with nonliving products and technologies; sponsors have to constantly be on their toes in monitoring process, results and quality of their outsourced activity, which can vary with the slightest change in input.

So, what do sponsors need to do for managing CRO’s?

First, the aims and objectives of the clinical research need to be very clearly spelt out. All the steps and processes involved in managing CRO’s need to be mentioned very clearly in writing at the beginning of the outsourcing activity, as any ambiguity at any stage will open the way for interpretation and is likely to lead to unpleasantness

Keeping control over the process remotely is a way of managing CRO’s. In a remote, virtual clinical trial, the integrity of data has to be ensured at all stages and approved, so that the next phase is cleared for starting after the previous one has been validated and approved by the sponsor. Putting these steps in place goes a long way in helping sponsors manage CRO’s effectively.

Read More:https://www.linkedin.com/pulse/tips-managing-cros-ronald-gardner

Laboratory Safety Management should be thorough and comprehensive

Laboratory safety management is about being alert and on one’s toes all the time and every time. This is easier said than done, because laboratories, being the location at which various tests and experiments take place, are a source of many dangers and contaminants.

Laboratory safety management is imbibed in Good Laboratory Practices (GLP). In addition, laboratories have to also comply with guidelines set out in Section 5(a) (1) of the Occupational Health Act (OSHA) of 1970, which requires employees to “furnish to each of employees employment and a place of employment which are free from recognized hazards that are causing or likely to cause death or serious physical harm to his employees”.

FDA guidelines on laboratory safety management

The FDA has guidelines on laboratory safety management. Covered under 21 CFR 58; laboratory safety management guidelines cover areas such as animal testing, animal health products, and other test articles, but exclude cosmetics and processed foods, although broadly speaking, they are also laboratory practices. Also, FDA guidelines on laboratory safety management do not regulate on the nature of sponsor and contractor of a clinical trial. It leaves it to the parties to devise ways by which they work with each other. Adherence to both these is a requirement of laboratory safety management.

Employer’s responsibility under OSHA

As part of OSHA, employers who employ personnel in laboratories have to ensure that employers are not exposed to agents of hazard, such as chemicals and fire. Laboratory safety management is further fortified by regulations covering potentially hazardous objects such as naked flames (such as Bunsen burners), sharps, glassware, hot surfaces, pressurized gas cylinders, and heat from exothermic reaction and very cold media, including cryogenic liquids.

What happens when laboratory safety management guidelines are not adhered to?

When the FDA finds out that a laboratory is infringing on laboratory safety management practices and guidelines, it issues that lab a 483. This is a note to the facility to state that it is not in compliance with FDA guidelines in this regard. After deliberation of the 483; the FDA gives the lab some time to correct its discrepancies. If a lab fails at this, it is deemed to be noncompliant with laboratory safety management principles, and legal action follows.

OSHA has its own prescriptions for labs that do not adhere to its guidelines. It suggests suitable penalties and ways by which to take corrective measures within a timeframe, allowing the company to implement sound laboratory safety management principles.

Read More: https://www.linkedin.com/pulse/laboratory-safety-management-should-thorough-ronald-gardner

Japanese Institutions and Regulatory Authorities

Japanese institutions and regulatory authorities are organized in a rather complex way, with a few institutions and regulatory authorities being responsible for the oversight of regulating pharmaceuticals, and a few others, purely for developing pharmaceuticals.

The overall regulator of the Japanese institutions and regulatory authorities is the Japanese Ministry of Health, Labor, and Welfare (MHLW), which is an offshoot of the Ministry of Health and Welfare (MHW), with which the credit for framing and implementing most of the current regulations lies.

Japanese institutions and regulatory authorities for regulating pharmaceuticals

The Pharmaceutical and Food Safety Bureau (PFSB), which comes under the MHLW, is the pharmaceutical regulatory authority of Japan. This body is the one that takes decisions relating to application approval.

In addition, Japanese institutions and regulatory authorities consist of two other bodies that work with the pharmaceutical industry on a day-to-day basis. These are:

Although it is admitted that the organization of Japanese institutions and regulatory authorities in such a manner is rather confusing and an effort is underway to merge these three institutions; as of now, this is yet to materialize. There has been some ongoing movement towards creating a superstructure of these three Japanese institutions and regulatory authorities, creating an FDA-like body.

Japanese institutions and regulatory authorities in relation to development of pharmaceuticals

Japanese institutions and regulatory authorities in relation to development of pharmaceuticals are organized in the following manner:

Read More:https://www.linkedin.com/pulse/japanese-institutions-regulatory-authorities-ronald-gardner?trk=prof-post

The ISO 9001:2015 – the latest revision to the ISO

The ISO 9001:2015 is the latest revision to the set of ISO standards, and is considered a major update to the existing standard. The ISO consists of a set of standards, implementing which an organization can bring about improvements into the auditing of its Quality Management Systems.

First, an understanding of Quality Management System

A Quality Management System is defined by the ISO as a set of procedures, processes and policies an organization requires to plan and execute into its central business area, meaning areas that affect the organization’s ability for meeting customer requirements. The ISO has different quality management standards for different areas. For example, the ISO 13485 series is meant for bringing in processes into the medical devices industry, the ISO 20252 for market research, and so on.

The ISO issues standards that are numbered by the unique and distinctive field to which they belong. The ISO standards thus signify a simple and commonsensical way to approach a particular business.

First change in seven years

The ISO keeps significantly updating requirements to meet current market best practice. This is done because market best practices evolve and change over time. Accordingly, the ISO 9001 standard, which relates to Quality Management Systems, has undergone its first change since 2008 in 2015.

Called the ISO 9001:2015; the latest offering from the ISO brings in several changes into the previous version. Some of the core areas in which the ISO 2015 differs from ISO 2008:


Read More:https://www.linkedin.com/pulse/iso-90012015-latest-revision-ronald-gardner?trk=prof-post