A brief understanding of the FDA General Principles on Process Validation

A brief understanding of the FDA General Principles on Process Validation

Key Takeaway:

The FDA has issued vastly improved and expanded general principles on process validation in January 2011. These build substantially on the previous issue of 1987.

The FDA describes Process Validation as "the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products".

Being a regulatory body, the FDA has assigned to itself the task of issuing guidelines to the industry on the principles of process validation (PV). FDA general principles on process validation, the latest of which were issued in 2011 replacing those of 1987, are aimed at facilitating:

• Modern manufacturing principles
• Sound science
• Risk assessment and mitigation
• Process improvement
• Innovation

Basis to the FDA general principles

FDA general principles on process validation are founded on the understanding of the following conditions:

How should product quality be ensured according to the FDA general principles on process validation?

FDA general principles on process validation of 2011 lay clear emphasis on the requirement of Quality. Accordingly, a product should show quality performance consistently in every batch and every unit.

What about PV?

Likewise, the FDA general principles on process validation tie process validation to the product lifecycle approach. In a nutshell, the lifecycle approach to PV binds product and process development to the commercial manufacturing process, and requires the process to be maintained in a state of control during routine production. The FDA believes that:

• Validation is a journey, not a destination
• Commercial production throws up more and more knowledge of PV
• In order to comprehend sources of variability and achieve an understanding of process; there is a need for comprehensive process design
• Risk management has to be built into process validation

The Three Stages of PV

According to the FDA general principles on process validation, Process Validation consists of three stages:

Implementation of FDA 21 CFR Part 11 Regulations optimizes an organization's capabilities

Implementation of FDA 21 CFR Part 11 Regulations optimizes an organization's capabilities

Key Takeaway:

On the surface, FDA 21 CFR Part 11 regulations appear confusing, but following a risk based approach to computer systems validation sorts these out, increases the organization's computer systems efficiency and reduces costs

FDA 21 CFR Part 11 regulations have been codified to ensure that companies implement good business practices into their computer systems. Implementation of FDA 21 CFR Part 11 regulations into an organization's computer systems is a sure way of enhancing the efficiency of employees, identifying risks and thereby reducing errors, and thus increasing the productivity in the organization.

Outstanding features of FDA 21 CFR Part 11 regulations

Before the advent of electronic records and approval signatures; these were being done on paper. The purpose of FDA 21 CFR Part 11 regulations is to ensure that an electronic record that replaces a paper record and an electronic signature that replaces a handwritten signature have to be authenticated. Regulatory authorities have to be convinced that these digital formats are as authentic and trustworthy as the physical ones they replace.

• FDA 21 CFR Part 11 regulations are part of the Code of Federal Regulations (CFR)
• CFR contains laws that each government agency has to fulfill
• The CFR has several titles, and each of these addresses a designated, regulated area
• Critical areas of laws under the CFR relate to electronic records and approval signatures.

Three primary areas of 21 CFR Part 11 compliance

Compliance with 21 CFR Part 11 regulations consists of three core areas:

FDA 21 CFR Part 11 Compliance

FDA 21 CFR Part 11 Compliance

Key Takeaway:

FDA 21 CFR Part 11 Compliance sets out benchmarks by which FDA-regulated industries' electronic signatures and other records are considered authentic. From 2007, a strong body of opinion has emerged challenging the stringency of these requirements, but nothing major has been diluted from these.

The regulations under FDA 21 CFR Part 11 Compliance set out criteria that the Food and Drug Agency (FDA) considers in order to deem electronic signatures authentic. The electronic records, electronic signatures, and handwritten signatures executed to electronic records of several FDA-regulated industries have to be compliant with the standards set out in FDA 21 CFR Part 11 Compliance to prove that these are authentic, safe and trustworthy. The operative factor is that the FDA has to consider these signatures as being on par with those done on paper.

Which industries are included in FDA 21 CFR Part 11 Compliance?

FDA 21 CFR Part 11 Compliance applies to nearly all FDA-regulated industries, including but not restricted to:

• Medical device manufacturers
• Drug makers
• CROs
• Biotech companies, and
• Biologics developers

The Aim of FDA 21 CFR Part 11 Compliance

The aim of FDA 21 CFR Part 11 Compliance is to ensure that specified FDA-regulated industries such as those mentioned above (with specific exceptions) implement controls -which could include audits, audit trails, documentation, system validations, and electronic signatures -for software and systems involved in processing electronic data that are:

• Required to be maintained by the FDA predicate rules or
• Used to demonstrate compliance to a predicate rule. The FDA describes a predicate rule as any requirement set forth in the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, or any FDA regulation other than Part 11. FDA 21 CFR Part 11 Compliance also applies to submissions made to the FDA in electronic format, such as a new drug application.

Which industries are exempt from FDA 21 CFR Part 11 Compliance?

Interestingly, exceptions are allowed within the same industry, based on the format of filing. For example, while FDA 21 CFR Part 11 Compliance applies to submissions made to the FDA in electronic format; it does not apply to a paper submission for the same made in electronic format, such as fax.

Also, FDA 21 CFR Part 11 compliance is not required for record retention for trace backs by food manufacturers. Similar to the logic used in the mode of filing as noted above; most food manufacturers are not otherwise explicitly required to keep detailed records, but when organizations keep electronic documentation for HACCP and similar requirements; this documentation must meet these requirements.

Going by the FDA 21 CFR Part 11 Checklist is a good way to stay on track

Going by the FDA 21 CFR Part 11 Checklist is a good way to stay on track

Key Takeaway:

It makes sense for organizations that are part of 21 CFR Part 11 to have a checklist of requirements, as this helps eliminate thorny issues.

There is considerable confusion about the requirements of electronic signatures set out by 21 CFR Part 11. Many organizations get confused about areas like the mode of signatures, as there are different requirements for electronic and paper formats of the same regulation. In order to resolve confusion arising out these and other issues, making an FDA 21 CFR Part 11 checklist is a good solution.

The benefits of charting out an FDA 21 CFR Part 11 checklist are many:

• It acts as a guideline in helping organizations comply with the requirements set out in this regulation;
• It helps to overcome oversight, as there is a fairly high possibility of its occurrence;
• It helps to put necessary and appropriate regulatory requirements and standards in place to tackle the huge list of requirements in this regulation.

Going by this checklist is of immense value to organizations

The numerous advantages of EHRs notwithstanding; some concerns abound about its usage.

Electronic Health Records -an understanding

Electronic Health Records -an understanding

Key Takeaway:

EHRs are a shining example of the advancements being made in the technology the American healthcare system uses. They need to be comprehended properly to facilitate their adaption.

The terms Electronic Health Record (EHR) is self-explanatory: it signifies an electronic version of paper medical records of a patient. Since these are digitized records; they are real time, with instant access and updating over all the sources and locations at which it is available. If a new value gets entered or deleted or altered; the same gets updated at all locations. This means that any authorized user having access to a patient's EHR gets the latest record, making decision-making easier and faster.

Features/advantages of electronic health records

• Electronic Health Records contain all details of a patient's medical history, such as diagnosis, medication routine, treatments advised, immunization protocols and related information
• Gives importance to processes, because of which it gives access to evidence-based tools which help healthcare providers take important decisions about a patient's care. It ensures accuracy of diagnoses and health outcomes irrespective of which medical center or healthcare professional is attending to the patient;
• In totally automating and streamlining provider workflow, EHRs make patient information instant and current across all locations, no matter in which geography that record is being accessed;
• It brings about an improvement in the quality, as well as convenience of patient care;
• Fosters increases patient participation;
• Since electronic health records are spread across the length and breadth of the country; they improve practice reduce costs.

Concerns about EHRs

The numerous advantages of EHRs notwithstanding; some concerns abound about its usage.

The EHR Incentive Program is what it is -an incentive for healthcare providers to digitize

The EHR Incentive Program is what it is -an incentive for healthcare providers to digitize

Key Takeaway:

The Centers for Medicare & Medicaid Services (CMS) are involved in a mammoth task of digitizing patient health records. They use the bait of incentives to accelerate the process while maintaining quality.

Digitizing health records is a mammoth task by any standards, considering the extent, size and nature of records that need to be made available in electronic format. To ensure that this becomes a national, pan-US activity; the federal government introduced a method by which to implement EHRs: by offering incentives to those professionals, eligible hospitals, and Critical Access Hospitals (CAHs) at various stages of adopting, implementation or upgrade, or if they have demonstrated meaningful use of certified EHR technology within set deadlines. Meeting deadlines is a very critical requirement of the EHR Incentive Program.

Criteria for being eligible for EHR incentive program

The Centers for Medicare & Medicaid Services (CMS), which oversees the EHR Incentive Program, has put forth many criteria for eligibility for EHR Incentive Programs

Thirdly, FDA 21 CFR Part 820 requires the manufacturer to establish and maintain procedures for the receipt, review, and evaluation of complaints.

What should records of investigation contain?

Records of investigation should contain the following:

• Identifiers related to the device and reported event
• If Medical Device Reporting is made, it should investigate the following:
• Whether there were any specifications the device failed to meet
• Whether it was for treatment or for diagnosis that the device was being used
• In what way the device was related to the reported event, if applicable

Effective Complaint Handling Guidelines serve as a basis for improvements in medical devices

Effective Complaint Handling Guidelines serve as a basis for improvements in medical devices

Key Takeaway:

Far from being frowned upon, complaints should serve as an opportunity for medical device manufacturers to understand the customer's expectations better and lead to improvements in the product quality.

The FDA describes a complaint as "any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution".

FDA's complaint handling guidelines are critical for ensuring that an organization maintains safety with regard to the medical devices they manufacture. Errors in medical devices can result in complaints, and improper handling of complaints can lead to problems for the patient, ranging from injury to fatality.

It is to prevent these problems that the FDA has issued complaint handling guidelines. FDA's thinking is based on the reasoning that a complaint may be an indicator of serious safety, but implementing effective complaint handling guidelines can greatly mollify the gravity of the issue. It is also the first step to initiating new product development, which in turn has the potential to greatly reduce risks associated with noncompliance.

Regulations in place

Provisions relating to effective complaint handling provisions are contained in FDA 21 CFR Part 820 and GxP regulations.

Firstly, these complaint handling guidelines require medical device manufacturers to maintain complaint files. Manufacturers have to make this the first step towards establishing a sustainable complaint management system.

Secondly, Section 198 of Part 820 warrants the following:

Thirdly, FDA 21 CFR Part 820 requires the manufacturer to establish and maintain procedures for the receipt, review, and evaluation of complaints.

What should records of investigation contain?

Records of investigation should contain the following:

• Identifiers related to the device and reported event
• If Medical Device Reporting is made, it should investigate the following:
• Whether there were any specifications the device failed to meet
• Whether it was for treatment or for diagnosis that the device was being used
• In what way the device was related to the reported event, if applicable

Digital Marketing for Pharmaceutical companies offers tremendous opportunities

Digital Marketing for Pharmaceutical companies offers tremendous opportunities

Key Takeaway:

There is enormous potential for digital marketing for pharmaceutical companies. Proper exploitation of the social media can take pharmaceutical companies to their market in a more pinpointed and accurate manner than traditional marketing.

Gone are the initial days of reluctance on the part of pharmaceutical companies to embrace social media as a powerful marketing medium. That was in the past, when the concept of social media was new, and regulations in the pharmaceutical industry had yet to catch up with explosive pace at which the social media grew.

More and more pharmaceutical companies are on the social media

Today, one is likely to see any pharmaceutical company worth its name being active on YouTube, Facebook and Twitter to interact with its customers. Changes brought about by digital marketing in the pharmaceutical industry have seen companies like Johnson and Johnson and Pfizer being among the several majors associated with YouTube lately for creating and promoting their image. This is a result of the realization that social media can, far from being unconducive to the industry, can be quite amiable to it.

• In a study in late 2014, the New England Journal of Medicine estimated that leading pharmaceutical companies spend up to a quarter of their marketing budgets on the social media
• The study pointed out that the social media were as powerful and effective as EHRs and mobile applications as marketing tools, signaling a new dynamic for digital marketing in the pharmaceutical industry.

Social media as a key differentiator

The defining area in which the social media can be different and more effective than traditional marketing tactics for pharmaceutical companies is this: earlier methods such as trade conferences, promotions, gifting doctors for prescribing a company's brands were effective, but were carried out outside the healthcare setting and in isolation of the patient. The reach and intervention of the social media has made digital marketing for pharmaceutical companies so much more effective that they can get right into the arena of treatment and be of assistance with valuable inputs and suggestions.

Unravelling the DHF, Technical File and Design Dossier

Unravelling the DHF, Technical File and Design Dossier

Key Takeaway:

Design History File (DHF), Technical File and Design Dossier are important regulatory documents for a medical device. Design Control and Design History File are regulatory documents for medical devices in the FDA, while the Technical File and Design Dossier serve the same purpose for the EU's regulatory body, the MDD.

The Design History File

The history of the Design History File is an interesting one. It evolved out of the FDA's realization, over time and experience; that the major part of a device's problems was happening during the design stage and change phases, regardless of whether it was a new product or a changed one. This led to the birth of the concept of Design Control, aimed at tracking, monitoring and correcting the design elements at every stage from start to finish.

Outstanding characteristics of the Design History File

What should the Design History File contain?

The DHF should contain the following:

Now, the Technical File and Design Dossier...

In short and simple terms, one can understand the Technical File and the Design Dossier as the EU's version of the Design Control and the DHF. In other words, what Design Control and Design History File are for the FDA; the Technical File and Medical Device (MDD) are for the Medical Device Directive.

What should the TF and DD contain?

These files should have all the basic sections needed to support the requirements of the Medical Device Directive (MDD), Essential Requirements (for that product), and the company's "Declaration of Conformity" for that product:

• General Information/Product Description/EC Authorized Representative
• Classification Determination
• Essential Requirements
• Risk Analysis
• Labeling
• Product Specifications
• Design Control
• Clinical Evaluation
• System Test Reports
• Functional Bench Testing
• Lab Testing
• Sterilization validation (or AAMI TIR 28 Analysis)
• Packaging Qualifications
• Manufacturing
• Sterilization
• Conclusion
• Declaration of Conformity
• Appendix

Differences between the Technical File and Design Dossier

At a broad level, in general terms, while the Technical File is for MDD Class I and Class II a or II b; the Design Dossier is for MDD Class III devices

While Technical Files are retained in the premises of the manufacturer or the Authorized Representative for review of the Competent Authorities or/and Notified Body; Design Dossiers need to be submitted to the Notified Body for review before the product gets its CE-marking.

cGMP for Combination Products are pretty detailed and comprehensive

cGMP for Combination Products are pretty detailed and comprehensive

Key Takeaway:

The FDA has pretty detailed cGMPs for combination products. It seeks to clear common confusions inherent in the topic. A fresh Draft Guidance has been issued in January 2015.

Specifications on Current Good Manufacturing Practice (cGMP) for manufacturers of combination products are set out in the set of Part 4 regulations that the FDA promulgated in 2013.

What is a combination product?

The FDA has this description of a combination product as set out in 21 CFR Part 3: "a combination product is a product composed of any combination of a drug, device, or biological product. The drugs, devices, and biological products included in combination products are referred to as "constituent parts" of the combination product".

Overcoming confusion associated with classifying products

Each of the constituent parts of the combination product is governed by its own set of regulations on what cGMPs mean for these combination products. However, there was considerable confusion among manufacturers about cGMPs for combination products that were difficult to classify, such as when some products were both drugs and medical device. To help manufacturers overcome this, the FDA promulgated Part 4.

cGMPs prescribed in Part 4

Part 4 proceeds on the general consideration that compliance with its respective cGMP requirements should be the cornerstone for manufacturing a constituent part of a combination product. This seeks to clear the confusion regarding this issue.

Highlights of cGMPs for Combination Products:

A manufacturer of combination products has to demonstrate cGMPs by being compliant with the following:

• Part 4, which offers an exception to the general rule for combination products that are co-packaged (two or more separate products that are packaged together) or single-entity (comprised of parts that are physically, chemically, or otherwise combined into a single product) combination products.
• Accordingly, a manufacturing facility can fully comply with the cGMP requirements for any one of the constituent parts while supplementing the cGMP requirements for some specified provisions for the remaining constituent parts. Such facilities have these three options:

The Draft Guidance of 2015

The FDA issued a Draft Guidance on the subject in January 2015 making a few amendments to the above. cGMPs for combination products have been slightly revised.

Biotech and Pharmaceutical Courses are a gateway to a challenging and flourishing career

Biotech and Pharmaceutical Courses are a gateway to a challenging and flourishing career

Key Takeaway:

With over four million employed directly or in allied sectors and catering to the world's largest market and research area, biotech and pharma is a fast growing industry. Its courses are designed to prepare individuals for this giant industry.

Biotech and pharmaceutical courses are much sought after by aspiring professionals in the field of biotech and pharma. This is why:

• The US is the world's largest market for pharmaceuticals, as well as being the world leader in biopharmaceutical research
• Research by Pharmaceutical Research and Manufacturers Association (PhRMA) has revealed that the majority of the world's research and development (R & D) in pharmaceuticals is conducted by U.S. firms
• These firms hold the intellectual property (IP) rights on most new medicines.

Huge in every sense

Around 5,000 new medicines with approximately 3,400 compounds are currently being studied in the United States, the longest pipeline in any region in the world. The pharmaceutical industry employs nearly a million people and supports more than three times that number in related and supplementary industries. All these place a high demand on biotech and pharmaceutical courses.

What should those aspiring for courses look for?

Certification is the primary criterion to look out in those seeking a biotech and pharmaceutical courses. Whether it is classroom or online courses that are opted for; certification by a certifying authority should be the determining admission to biotech and pharmaceutical courses.

CFPIE or the Center for Professional Innovation and Education Inc., BioPharma Institute and Center for Professional Advancement (CFPA) are some of the better known providers of certified biotech and pharmaceutical courses. This is a partial list of the areas on which courses are offered by these institutes/centers:

The following tripod of software-related issues forms the IEC 62304:2006's foundation:

These three attributes form the backbone of the test of a medical device company's successful compliance with the regulatory requirements. For a medical device company to be successful in applying ISO 14971:2012 and IEC 62304:2006; it has to implement a cross-standard and resourceful way of integrating activities covering these requirements documents.

ISO 14971: 2012 and IEC 62304: 2006 mitigate risks in medical device software

Key Takeaway:

ISO 14971:2012 and IEC 62304:2006 are related but different global standards for risk management pertaining to software used in medical devices. Judicious application of these two standards is the way to go for medical device companies.

ISO 14971 and IEC 62304:2006 are global standards that govern risk management and lay out regulations and guidelines for software used in medical devices. The need for regulation of software in medical devices arises from the fact that software is the heart of a medical device. It is the medical device's software that ensures that the device performs its intended purposes. Hence regulation is of utmost importance to enable medical device and software organizations facilitate this in their products.

The ISO 14971: 2012 -a brief understanding

• The primary aim of ISO 14971, the global regulatory compliance standard is to ensure that a medical device carries medical safety into it
• This standard requires medical device manufacturers to undertake steps and measures by which they can foresee and eliminate risks in a medical device in the optimal manner
• Taking off from the above point, ISO 14971 requires medical devices to take steps to at least mitigate risks to the best extent. The ISO 14971standard prescribes the processes necessary for enabling this.

The ISO 14971's update in 2012

In 2012, the ISO carried out an update to the application of this standard within the European regulatory framework. This amendment to ISO 14971: 2012 is at the periphery and not at the core. Annex ZA is the main area in which this standard has been updated:

The use of the "As Low as Reasonably Practicable" (ALARP) approach is from now excluded in the risk acceptance process. This standard proscribes labelling as a risk control measure that can play a role in decreasing risk occurrence.

The IEC 62304:2006

The requirements for medical device software's life cycle are stated in IEC 62304:2006. This standard's group of activities, processes and tasks creates a common basis for the software life cycle processes in a medical device.

When it comes to the risk management aspect, IEC 62304:2006 supplements and strengthens ISO 14971. If ISO 14971 is the global standard for the development of medical software; IEC 62304:2006 standard is concerned with medical device software and their software lifecycle processes.

The following tripod of software-related issues forms the IEC 62304:2006's foundation:

These three attributes form the backbone of the test of a medical device company's successful compliance with the regulatory requirements. For a medical device company to be successful in applying ISO 14971:2012 and IEC 62304:2006; it has to implement a cross-standard and resourceful way of integrating activities covering these requirements documents.