Good Documentation Practices Relating to USP

Good Documentation Practices (GDP) is a quintessential part of regulated manufacturing and laboratory environments. GDP has to be adhered to in the regulated industries because it is the only truly authentic method of ensuring that documents are audited and accounted for. GDP is also essential to keep track of and maintain control at all stages of the process and the product. GDP is thus a core requirement of a thoroughly developed Quality System.

US Pharmacopeia (USP) has laid out a series of GDP’s. One of the major new updates is contained in the newly proposed USP-NF General Chapter <1029>.

Basis for GDP in USPGDP for USP is also formulated on the same principle and rationale on which any GDP is built: proper, accurate and comprehensive records are the backbone to proper documentation, which is the basis for all major and minor procedures and operation.

GDP for USP has guidelines in the General Chapter 1029. These guidelines are given with the intention of helping build a foundation for the Quality Systems, apart from also ensuring the integrity and control of documents.

These GDP’s are meant for use in the production and control of the following:

  • Active pharmaceutical ingredients (APIs)
  • Medical devices
  • Excipients
  • Pharmaceutical products
  • Dietary supplements
  • Food ingredients

The General Chapter explains the justification for putting in place Good Documentation Practices in USP and helps the user evaluate and construct GMP activities.

In what areas are GDP’s listed out in Chapter 1029?GDP’s for USP are mentioned in relation to electronic and paper records, which include reports, raw data, protocol, and procedures concerning analytical data and manufacturing controls, and has recommendations on the kind of information that should be recorded for different kinds of documents that require GMP. A prominent amendment brought into the new chapter 1029 is that there is no longer a distinction between instructions and records, and all records and instructions are broadly merged into “records”.

Some broad requirements of GDP as set out in Chapter 1029USP Good Documentation Practices spell out a number of principles. Some of these include:

  • There should be clarity, accuracy, conciseness and legality of records
  • Every time an action is performed, there should be a documentation
  • Anyone dealing with documents should not backdate or postdate any action
  • The initial of the person who carried out a change should attest her initials and offer an explanation whenever an amendment is made

Electronic or manual records should go by the following GDP’s:

  • Any data entry should be traced back to the person who did the entry
  • Shorthand notations are not allowed
  • Controls should be put in place to ensure integrity of the record
  • When a thermal paper is used, a verified copy of its accuracy should be retained, and the user should initial it with the date

FMEA in medical devices can work better when mated with ISO 14971

Failure Mode and Effects Analysis (FMEA) is a core aspect of risk management and risk analysis in medical devices. FMEA is essentially about analyzing the reasons for which a problem arises and the effects it has on the system. In the field of medical devices, it is absolutely critical to understand the failure mode and effects because the consequences of not doing this can be disastrous and many times, even fatal.

Required, but not clear about the steps

The FDA only broadly states that risk management has to be built into the manufacturing process. This leaves medical device manufacturers in a kind of quandary, because although the FDA is clear about the requirement for risk management; there is no clear-cut guideline on how this needs to be carried out. This leaves the implementation of FMEA in medical devices something that is at the discretion of the medical device company.

The FDA’s Final Rule on cGMP Quality System Regulation (QSR) is, to quote its own words, “less prescriptive and gives the manufacturer the flexibility to determine the controls that are necessary to be commensurate with risk” ( In other words, there is no specific guideline on risk management, using which medical device manufacturers can decide the ways and processes of implementing risk management. The guideline is all the more vague about risk analysis approaches and procedures like FMEA.

Complementarity with ISO 14971Since the guidelines on medical devices FMEA are rather general medical device companies that implement FMEA have to go by a buzzword: implementing FMEA at every level. In this regard, they can work complementarily with ISO 14971, whose guidelines relate to risk management.

FDA regulation on medical device packaging design

The FDA has regulations on medical device packaging design. This is quite natural, considering that the FDA has several regulations on all aspects of medical devices. However, it needs to be mentioned that the FDA regulation that covers medical device packaging design – Sec. 820.130 Device packaging under Subpart K–Labeling and Packaging Control -is a single liner, which only merely states that “each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.”

Does this mean that the FDA regulation on medical device packaging design is simple, plain and broad, and can be bypassed? Not really. Compliance with the medical device packaging design has to be seen in relation to two factors:

Medical Device 3

Sits with device labeling requirements

FDA regulation on medical device packaging design has to be seen in conjunction with its twin regulation, namely Sec. 820.120 device labeling. This is the first of the two sections on medical device labeling and packaging. This section has elaborate details on how medical devices need to be packaged and labeled. The FDA has requirements in this section on the integrity, inspection, storage, operations, and control number of labeling. FDA regulation on medical device packaging design has to be complied with collectively with this section.

Scope for creativitySecondly, FDA regulation on medical device packaging design is only a set or regulations that require adherence to the device packaging design elements. Medical device packaging design manufacturers are free to use their creativity in designing device packaging. Adherence to FDA regulation on medical device packaging design does not mean that there should be no innovation; it only means that the medical device packaging design has to be complied with. As long as this is met, manufacturers are free to design imaginatively. Perhaps because there is enough scope for innovation, FDA has left this area general and nonspecific, with the only requirements being that the medical device packaging design adhere to guidelines aimed at protecting it.

Medical Device Process Validation is the Key Part of a Quality Process

Process validation is one of the essential functions of a quality system for medical devices. Medical device manufacturers who have to stay compliant with regulatory requirements have to obtain premarket approvals (PMA), as well as premarket notifications for both new and modified existing medical devices. The key to all these is medical device process validation.

The FDA standard for medical device process validation is CFR Part 820, Section 820.75(a), according to which, “where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures”.



The need for medical device process validation First of all, why should medical device process be validated? The rationale for this is spelt out by the FDA: “The organization shall validate any processes for production and service condition where the resulting output cannot be verified by subsequent monitoring or measurement. This includes any processes where deficiencies become apparent only after the product is in use or the service has been delivered”.

Further, medical device process validation helps in a number of ways:

  • It ensures safety of the device
  • Increases customer satisfaction and confidence in the device
  • Reduces wastage from production of medical devices, and
  • Leads to improvements in product quality, processes and design
  • Ensures adherence to product specifications
  • Most importantly, avoids a host of embarrassing and time-consuming activities such as Warning Letters, 483’s, inspections, penalties and the like.
In relation to which regulatory requirements should medical a device process be validated?A medical device process validation has to be conducted in relation to four important standards:

  • The FDA’s Quality System Regulation
  • ISO 9001:2008
  • ISO 13485:2003
  • Relevant and appropriate OSHA standards

What to validate and what not to?Although this question appears complex, the guidelines issued by the Global Harmonization Taskforce (GHTF) serve as a good indicator for this question. It states in simple and unequivocal ways that any process whose output is verifiable, and when this verification suffices and is cost effective, does not have to be validated. Every process that does not meet this criterion has to be revalidated. The Medical Device Quality Systems Manual provides more details on this matter.

When to validate a medical device process?Medical device process validation has to be done both during production and after release, depending on the product design and release. This means that medical device process validation is carried out both when a new product is being manufactured or when there is a need to revise the process, and when defects are discovered after the release into market, when the device has to be recalled and validated.

Advanced Process Control is Rooted in Regulatory Process Control

Organizations in any industry involving process control have to implement advanced process control mechanisms for maximizing return on investment (ROI). Maximization of ROI being a very important objective of any industry involving plant management; the key to realizing this is putting the right regulatory process control in place. No external activity, such as buying the most sophisticated control equipment or loading systems with the most advanced software is going to be of any use unless the organization gets its regulatory process control right.

An understanding of regulatory process control

Regulatory process control is the means of monitoring and controlling the process of metamorphosing raw materials and other inputs into final products. Since there is no clearly laid out, authoritative regulation concerning process control in the generalized sense; organizations have to rely on established best practices and principles to arrive at optimal regulatory process control. There is the existence of the proportional-integral-derivative controller (PID controller), but this is more a mechanism than a standard.


So, meeting stringent quality standards involves the application of many highly scientific and precise steps and processes. It involves the use of tightly controlled techniques, into which a hierarchy of well-defined functions and responsibilities consisting of people, facilities and systems has to be instilled from management.

The basis to all this, as we have seen, has to be a regulatory process control system in which people and systems harmonize their functions.

General principles for regulatory process controlAn organization needs to put in a user-ready systems infrastructure which personnel having the requisite qualifications and experience should be able to start using straightway. A faulty or inaccurate regulatory process control mechanism or strategy will impede this, leading to suboptimal control.

The same principles of regulatory process control apply to control system testing as well. This is a process in which the organization uses established documentation techniques to record data relating to problems that could occur at any stage of the regulatory process control.

Types of regulatory process controlsTwo kinds of controls are often cited in regulatory process control: feedback and feedforward. These are usually implemented in tandem. In short, feedback control is the regulatory process control that is configured for control schemes such as the ratio, selective, cascade, and certain other kinds of control schemes, all of which are related to a common reference point called the setpoint. Any deviation from the setpoint should lead to remedial action by the person in charge of system control.

On the other hand, feedforward regulatory process control is a preventive step in which a load disturbance is measured and a corrective measure of dynamically compensating the disturbance is implemented beforehand.

Purpose of regulatory process controlThe essential role of regulatory process control is to bring down any unacceptable variability in the control system that is subject to changing and often, volatile conditions. In the absence of an effective regulatory control system; each succeeding operation unit has the potential to cause an amount of variation, however small or big, which can pile up throughout the process to eventually impact the quality and cost of the product. Regulatory process control aims to address this by introducing analytical and corrective measures at every stage of the control process.

What is the purpose of lyophilization & Where it will be applied?

Lyophilization is the clinical term for freeze-drying. In the simplest terms, it can be described as a technical process in which the moisture level of many materials is reduced, most times frozen, for the purpose of creating a new product or an ingredient.

When an injectable drug is freeze-dried -this is the process of lyophilization -its compounds are stabilized. This reconstitution process is helpful and necessary because substances in the drug get affected by outside or natural factors such as sunlight, oxygen, and pH values. These influences can bring down the effectiveness of these materials and molecules. It is to help them weather these countering factors that lyophilization is used. The aim of lyophilization is to make the best use of these compounds by preserving and protecting them in the form that can be used on patients.


Lyophilization not only shields the product from unwanted biological activity; it also extends shelf life, and can bring about greater precision in the dosage. This reconstitution is done just before administration.

Where is lyophilization technology applied?

Lyophilization technology is used in a number of applications. The most prominent ones that use lyophilization include biotech drugs, as well as a few complex or very sensitive molecules.

Many industries are in a state of flux, in that new technological keep coming up every now and then. Lyophilization should keep abreast of these technologies and help businesses in these industries to innovate their products to meet the market needs.

Is lyophilization a new process?

No. It may surprise many that its roots can be located to more than a millennium, to ninth-century Asia! However, it has regained some prominence of late, with the rise in the use of compounds, chemicals, molecules and other related substances in our daily lives. Today, nearly a third of products in the parenteral segment that come to the FDA for approvals are for lyophilized drugs. Market watchers speculate that in the very near future; this proportion to set to go up to 50 percent.


Characteristics of lyophilization

  • Products that are lyophilized can be expected to maintain their stability for 2 to 3 years in ideal conditions
  • Lyophilization calls for a high degree of expertise on the part of the manufacturer, since these drugs are derived out of formulations that are very complex
  • Labs form lyophilization cycles that help in optimizing its efficacy. They seek a reduction in the residual moisture, which is something that has to be done for every product. This process usually begins at a product’s clinical development stage and gets finessed at the time of commercial manufacture.

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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