An understanding of Pharmaceutical Regulatory Affairs

Regulatory Affairs sit at the center of an industry like pharmaceuticals. Given the importance this industry and the products its manufactures have on the health of human beings; it is imperative that there should be regulations in the industry at every stage of the process of manufacturing and marketing of pharmaceuticals.

pharmaceuticalRegulatoryAffairsThe primary aim of Pharmaceutical Regulatory Affairs is to ensure compliance with regulations that apply to every stage and process of the manufacturing and subsequent activities with the appropriate laws and regulations that apply to the industry.

Pharmaceutical Regulatory Affairs has evolved over a long time

Pharmaceutical Regulatory Affairs, like Rome, was not built in a day. The earliest attempts at making an activity or profession like Regulatory Affairs a discipline in itself can be traced to at least a century. The Diphtheria Epidemic of 1902 and a few other continental and global pharmaceutical disasters in subsequent years, such as the vaccine tragedy, sulfanilamide and thalidomide events made the authorities realize the need for framing initiatives to check the occurrence of such events. Pharmaceutical Regulatory Affairs can be said to have its origins in these events.

pharmaceuticalRegulatoryAffairsEssentially, Pharmaceutical Regulatory Affairs is about providing direction and focus to the strategy, tactics and operations aspects of the industry. It can be termed as a scientific system of surveillance. Pharmaceutical Regulatory Affairs concerns itself with every activity from start to finish and puts regulations in place to ensure that each activity is technically correctly carried out in accordance with these regulations and is in tune with sound scientific principles and practices.


All round and comprehensive

The important point to note about Pharmaceutical Regulatory Affairs is that it deals with every stage of production, starting with procurement of the raw materials or molecules needed for developing the drug, the clinical trial process, the manufacturing process, the packaging, the marketing and even post-consumption of the product by patients, ensuring that along every step, scientific methods and best practices are adhered to and are in accordance with rules, regulations and requirements set out by the regulatory authorities.

Different set of regulations in different markets

In most cases, it is not only one regulatory body whose regulations and requirements need to be adhered to. When a pharmaceutical product has to be marketed globally, it has to meet the regulatory requirements of all the countries or markets in which it is being sold, individually, unless the rule specifies otherwise.

pharmaceuticalRegulatoryAffairsIn the process of working on all these, the Pharmaceutical Regulatory Affairs profession entails having to take steps to see to it that the product is in some way different from what already exists in the market. All these make Pharmaceutical Regulatory Affairs a challenging profession.

This being the case, Pharmaceutical Regulatory Affairs professionals have their own clearly defined roles on what they need to do in order to ensure that they carry out these activities.

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Biocompatibility testing and evaluations for medical devices

Biocompatibility testing and evaluations for medical devices is a vital component of patient safety, for it is the only effective means to ensuring that a medical device or any related material, when it happens to come into contact with the patient’s body has to not only perform its intended purpose and function; it should also not result in adverse reactions for the patient.

When medical devices and/or materials come into contact with the patient’s body, they can cause problems or what may be termed adverse effects that can be either short-term or long-term adverse effects to the body. These effects, called acute to chronic, can result in mutagenic effects. It is to prevent the occurrence of such events that biocompatibility testing and evaluations for medical devices has to be carried out.

These evaluations for biocompatibility of medical devices are done to evaluate the interaction between a device and anything it comes into contact with within the patient’s body, such as cells, tissue or body fluids. Essentially, device biocompatibility is assessed to prevent biological risks from happening to the patient.

ISO standard for biocompatibility testing and evaluations for medical devices

The International Standards Organization (ISO) has a specific standard for carrying out and ensuring biocompatibility testing and evaluations for medical devices. It is called ISO 10993-1: 2009, and makes biological evaluation part of a structured biological evaluation program that comes under a risk management process. All these are carried out in accordance with ISO 14971.

ISO 10993-1, Biological Evaluation of Medical Devices – Part 1 The basis for biocompatibility testing and evaluations for medical devices is the Risk Management Process. This is the most prevalent standard for assessing biocompatibility testing and making evaluations for medical devices. In requiring biocompatibility testing and evaluations for medical devices to be conducted in compliance with Principles of Good Laboratory Practice (GLP) and/or ISO/IEC 17025 and requiring the consideration of evaluation of local and systemic risk factors; the ISO 10993-1 is considered the basis for determining the subsequent, necessary biocompatibility testing and evaluations for medical devices.

What factors are tested? In line with the principles set out in ISO 10993-1: 2009 on biocompatibility testing and evaluations for medical devices, specific testing is prescribed based on two factors: a) the type and the intended use of a medical device or related material, and b) the kind, tenure and extent of contact the medical device makes with the body.

ISO 10993-1: 2009 on biocompatibility testing and evaluations for medical devices requires assessment to be made for the following among others:

  • Cytotoxicity
  • Genotoxicity
  • Sub chronic toxicity
  • Sensitization
  • Irritation or intra-cutaneous reactivity
  • Implantation
  • Haemocompatibility
  • Systemic toxicity, etc.

3D Printing: FDA Finalizes Guidance for Medical Devices


The US Food and Drug Administration (FDA) on Monday finalized guidance on medical device additive manufacturing, also known as 3D printing.

The guidance finalizes the draft version from May 2016 and largely keeps intact the recommendations and considerations laid out in the draft.

FDA Commissioner Scott Gottlieb said Monday that the guidance “will help manufacturers bring their innovations to market more efficiently by providing a transparent process for future submissions and [ensures] our regulatory approach is properly tailored to the unique opportunities and challenges posed by this new technology.”

Gottlieb also said that FDA has now reviewed more than 100 3D printed medical device applications, including knee replacements and implants used for facial reconstruction, up from the 85 reviewed at the time the draft was released.

FDA describes the guidance as a “leap-frog” guidance in that it is meant to provide manufacturers about its initial thinking on manufacturing 3D-printed devices and how to characterize and validate such devices. The final guidance also emphasizes that the recommendations made will not be applicable to all 3D-printed devices due to the wide array of available additive manufacturing technologies and materials.

Some changes in the final guidance include new considerations for handling complex design files and cybersecurity considerations for patient-matched devices.

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The role of Quality Agreements in Contract Manufacturing Organizations (CMO)

The role of contract manufacturing in the pharmaceutical and life sciences industries cannot be overlooked. It has gained favor with organizations in these industries, as it allows them the luxury of outsourcing their processes relating to manufacturing or other activities to a third party, saving them costs and hassles in the short and long terms. Entrusting their processes to Contract Manufacturing Organizations (CMO’s) enables them to concentrate on their core activities such as research and new drug discovery.

With the global economy more open than it perhaps has been at any other point of time in history, and with almost no economy of any country being isolated from the forces of globalization; CMO’s are a very viable option for pharmaceutical and related companies. As long ago as 2010; the global CMO size was put at over $26 billion, with a healthy CAGR of over 10 percent. With the global pharma market having crossed a trillion dollars in 2015; there is heavy optimism for the growth of CMO in the coming years.

While these figures look encouraging; a whole lot of issues need to be considered before embarking on contract manufacturing. The most important of these is quality. Ensuring that the supplier maintains the high quality standards set out by the contracting company is a major challenge for the client company.

The Quality Agreement

Quality Agreements are a very strong tool in addressing this issue. A Quality Agreement is a contract reached between a pharmaceutical firm and a GMP Contract Manufacturer, in which the responsibilities each of these parties has towards assuring the quality, safety and efficacy of the manufactured drug, are spelt out in detailed and clear terms. This is the only real means to ensure oversight of the processes and the quality of the products. Ensuring that they comply with the GMP regulations is at the core of these requirements and expectations.

How do contracting pharmaceutical and life sciences firms draft Quality Agreements that comply with the regulatory requirements and ensure the quality of products from the supplier? What are the elements of a Quality Agreement? What due diligence and scrutiny does the contracting organization need to keep in mind when drafting a Quality Agreement?

Complete learning on all aspects of the Quality Agreement

The nitty-gritty of these elements will be taught at a webinar that is being organized by Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance. This webinar’s speaker, Roger Cowan, is the founder and owner of R Cowan Consulting Services LLC, a consulting company specializing primarily in the area of pharmaceutical contract manufacturing. The experience he has gained in the industry after having worked in it for 37 years will be in full flow at this webinar.

Please register for this webinar by visiting Contract Manufacturing Arrangements for Drugs

In-depth look at the two recent FDA and EU guidelines

Roger will explain the dynamics of a CMO Quality Agreement at this webinar. He will discuss the two recent regulatory guidelines: the EU GMP Chapter 7 “Outsourced Activities” (Revised) issued by the EU, and the Draft Guidance for Industry – “Contract Manufacturing Arrangements for Drugs: Quality Agreements”, which was issued by the FDA in May 2013. These two guidelines are important from the CMO perspective, as they offer greater depth of understanding and clarity on quality contracts.

Roger will explain what aspects of Quality Agreements need to be taken care of from a regulatory perspective. Both the FDA and the EU have laid sufficient emphasis on the control of suppliers such as CMO’s. It is expected that these new these new regulatory documents will introduce written documentation of this control. Evidence of this kind of control can be presented to FDA/EU inspectors in the form of a Quality Agreement which is specific to a particular CMO.

Writing a Quality Agreement in line with the new guidelines

The speaker will help participants gain a thorough understanding of the Quality Agreement by fully analyzing each proposed section. He will suggest how to write it keeping the new guidelines in mind. He will also detail the comparisons between the two regulatory documents and will highlight their differences. Topics of critical importance in the Quality Agreement, such as change control, documentation, facilities and equipment, lab controls, sub-contracting, etc., will be examined. He will also present an analysis of the current status of the FDA draft guidance and will review the comments that this guidance has received from the industry.

Roger will cover the following areas at this session:

o  The Who and What of a good Quality Agreement

o  What a Quality Agreement is – and is not

o  Responsibilities of the owner vs. contract facility

o  GMP responsibilities

o  A comparison of the new guidelines from the FDA and the EU.

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Q7 and Other Requirements for Active Pharmaceutical Ingredient (ASM) GMP

In late 2016, the FDA published the revised the Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Guidance for Industry. The aim of this revision is to address Good Manufacturing Practices (GMPs) for a Quality Management System for Active Pharmaceutical Ingredients (API’s). Another of its aims is to help companies ensure that they meet the requirements of API quality and purity characteristics. While replacing Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; this guidance amends the International Council for Harmonization (ICH) codification from Q7A to Q7.

All aspects of API manufacture are addressed by this revised guidance. These include:

o  The principles set out for Quality Management

o  The quality unit’s responsibilities

o  Activities relating to production

o  Internal audits

o  Product quality reviews

o  Qualifications expected from personnel

o  Their hygiene standards

o  The qualification that consultants need to have.

The GMP requirements for facility design and construction and equipment used are also included in this FDA Q7 GMP guidance for API revision. Several other API manufacturing topics are also part of this revision. Some of these include:

o  Management of materials

o  Process controls

o  Laboratory controls

o  Packaging

o  Storage and distribution

o  Validation

o  Change Control.

Clarity on the FDA’s revised standard

A webinar from Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance, will explain the FDA’s API Quality System revision in detail.

Eyal Lerner, owner of ELC Consulting Services which offers the pharmaceutical and medical devices industries support in all quality related issues, will be the speaker at this webinar. To gain understanding of how to apply the FDA’s revised API Quality Systems GMP requirements; please register for this webinar by visiting API (ASM) GMP

Explanation of API quality requirements

This webinar will explain the basic requirements and fundamentals of API QS. It will review the quality requirements for API in accordance to global API GMP- ICH Q7. The explanations will be based on practical experience and other relevant guidelines. Eyal will review the requirements of FDA and EMA. All the areas such as materials, Active Pharmaceutical Ingredient and Advanced Starting Materials (ASM) will be discussed along with their definitions. He will also explain the distinctions between these.

Administrative issues such as registration issues concerning filling, annual review and change report to file would be discussed. In this section, Eyal will lay emphasis on the section: “Registration standard: Common Technical Document (CTD)”, as it relates to the ICH M4.

Anyone, whose work concerns the area of development and manufacture of API, such as those in R&D, Regulatory Affairs, Quality Assurance and Quality Control, who wish to get an in-depth background and understanding of API QS; will find this webinar valuable.

Which leads to fines in the millions of dollars per intrusion

Developments in the area of medical device software –i.e., the software that is put to use in medical devices –have been taking place at such a torrid pace that regulatory agencies such as the FDA have been unable to keep pace with them. Almost invariably, every development in medical device software brings about a new level of complexity.

Also, the classification of the device is another factor the FDA and other regulatory agencies have had to contend with: Different regulations have to be made depending on whether the software in medical devices is to be classified as a device itself, is used to alter the performance of the device, or is used for computing values. The inability of the regulatory agencies to catch up with the speed of developments in the medical device software arena has had the agency scurrying for quick solutions.

Among these are its decision to integrate the current provisions of voluntary standards developed by the National Institute of Standards and Technology (NIST), which it considers as a useful guidance for medical software professionals and voluntary information sharing organizations to meet cybersecurity challenges into its regulatory oversight. The onus of being knowledgeable about FDA regulations thus rests on firms that design and market software.

Learning on all the aspects of medical device cybersecurity

A formal learning session that examines this complex relationship is being organized by Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance. The speaker at this webinar is Casper Uldriks, ex-FDA Expert and former Associate, Center Director of CDRH. Participants who wish to gain clarity on these aspects of medical device cybersecurity can register for this webinar by visiting National Institute of Standards and Technology

The speaker at this webinar will seek to help participants identify the FDA’s fundamental premarket and postmarket requirements that involve software. When medical device companies go to the FDA for approval to market their product; they need to be very well informed about everything that the FDA states and requires in this regard, because, as we have examined, the burden of design factors requires well informed considerations about how medical device manufacturers protect their product’s software and how they outsmart increasingly sophisticated cyber attackers.

All-round plans

At the same time, device manufacturers also need to be totally compliant with the regulatory options and responsibilities lie with them when a cybersecurity problem is located in their device. Their responsibilities include plans about how to recover and publicly disclose cyberattacks, especially when private medical records are involved. Not getting this right leads to fines that run into millions of dollars for every breach.

So, their cybersecurity efforts should be inclusive of important factors such as these among others:

o  Design planning

o  Postmarket vigilance

o  Training for employees

o  An action plan for managing an attack.

Learning on the factors to consider

Casper will help participants identify these basic considerations at this webinar. He will explain the kind of device cybersecurity programs that protect and foster the performance of device based software or standalone software that device manufacturers need to instill in order to assure the safe use of the device. Such programs need to use the FDA’s premarket and postmarket information requirements when entering and staying in the market.

This session is of very high value to professionals who deal with some or another form of medical device software and its marketing. This includes those in Regulatory Affairs, Quality Assurance, Software Design Engineers, Manufacturing, the Complaint Department, Hospital Risk Department, and those who market their own labels.

Casper will cover the following areas at this webinar:

o  FDA’s Cybersecurity Premarket Design Information

o  FDA’s Postmarket Controls

o  Voluntary Controls

o  Cybersecurity Training

o  Recovery Plans.

A clear process for compliant laboratory OOS investigations

The core of successful operation by a drug maker is laboratory testing. current Good Manufacturing Practices (cGMP) regulations require a drug manufacturer to use laboratory testing as a tool to validate that everything that goes into a laboratory product, such as in-process materials, finished materials, and containers adhere to set specifications. When all these are done, a major challenge for laboratories is in how to deal with a test that shows an Out of Specification (OOS) result.

Out of Specification results are viewed very seriously by the FDA

The FDA is uncompromising when it comes to dealing with Out of Specification results in laboratories. Its inspections of laboratory operations are very meticulous. It requires complete adherence to its guidances on how the laboratory has to investigate its Out of Specification and Out-of-Tolerance observations.

The ways by which finished Out of Specification products have to conform to set specifications, safety standards and other quality standards are specified in cGMP regulation Sec 211.165. Any lab whose result fails to do this gets summarily rejected. Another iteration of these cGMP regulations is that any unexplained deviation from the set specifications of a batch or its contents, whose test results show an Out of Specification result, will be subject to thorough investigation. Whether batches have only been manufactured and are yet to be distributed, or already are; the same rule applies.

Ways of dealing with Out of Specification results

This is the protocol that the cGMP regulation makes for dealing with Out of Specification testing:

o  Out of Specification testing is mandatory for the release of a test batch

o  The batch in which an Out of Specification result is confirmed gets rejected

o  The company’s Quality Assurance (QA) will have to state the reasons for the release of a batch that has an element of ambiguity in the result, and has to justify it.

The requirement that current Good Manufacturing Practices need to go into the manufacture of both active pharmaceutical ingredient and finished pharmaceuticals is stated in Section 501(a) 2 (b) of cGMP guidelines on Out of Specification. Also, all aspects such as active pharmaceutical ingredients, raw material testing, in-process and stability testing and Process Validation come under the ambit of the cGMP guidelines.

The FDA guidance on Out of Specification relates to the following products:

o  Human drugs

o  Combination products

o  Biology and biotechnological products

o  Type A medicated articles

o  Transplantation of human tissues

o  Finished products & active pharmaceutical ingredients

o  Medicated feed

o  Dietary supplements

o  Veterinary drugs

Out of Specification needs to be understood fully first

A reading of the above attests to the fact that a thorough understanding of the nature of the issues relating to Out of Specification results needs to be made for a laboratory to meet the required results. All the concerned persons should have complete knowledge of the FDA expectations for Out of Specification results.

It is this knowledge that needs to be applied to put in place procedures that define a complete, scientifically sound investigation of each Out of Specification and Out-of-Trend laboratory observation, as well as for establishing evidence that laboratory personnel conform to the procedures.

A proper learning session on dealing with Out of Specification results

A webinar from Compliance4All, a leading provider of cost-effective professional trainings for all the areas of regulatory compliance, will be providing learning on these aspects.

Jerry Lanese, an independent consultant who focuses on Quality Systems and the components of an effective Quality System, will be the speaker. Please visit Out-Of-Specification Laboratory Results to enroll for this highly educative session.

Tools for dealing with Out of Specification results

The speaker of this webinar will help participants build a basis for the implementation of adequate procedures that help avoid Out of Specification results. He will also review existing procedures and practices. Any laboratory personnel, who need understanding of the steps that a compliant laboratory has to take to handle the investigation of Out of Specification test results, will find this session very useful.

The ways in which the laboratory has to interface with other units through the laboratory investigation process will be explained. The speaker will dwell mainly on the FDA guidance on handling OOS laboratory results and will suggest a clear process for compliant laboratory Out of Specification investigations.

The following areas will be covered at this webinar:

o  Why the regulators are concerned about the handling of OOS investigations

o  The FDA model for handling OOS investigations

o  Commonly accepted terminology such as repeat testing and retesting

o  How the laboratory can meet regulatory expectations for OOS investigations.

o  The interaction between the laboratory and other units in the organization.