INTRODUCTION

ACTIVE PHARMACEUTICAL INGREDIENT(API)

The active pharmaceutical ingredient (API) is the part of any drug that produces the intended

effects. Some drugs, such as combination therapies, have multiple active ingredients to treat

different symptoms or act in different ways.

Any drug formulation is composed of two components or aspects. The first is the actual API

or Active Pharmaceutical Ingredients, which is the central ingredient. The second is known as

an excipient which is the inactive ingredient. Excipient serves as a medium for conveying the

active ingredient. Active Pharmaceutical Ingredient: Any substance or mixture of substances

intended to be used in the manufacture of a drug (medicinal) product and that, when used in

the production of a drug, becomes an active ingredient of the drug product. Such substances

are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure,

mitigation, treatment, or prevention of disease or to affect the structure or function of the

body.

FDA Definitions of API: Any substance that is represented for use in a drug and that, when

used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient

or a finished dosage form of the drug. Such substances are intended to furnish

pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or

prevention of disease, or to affect the structure and function of the body of humans or other

animals.

APIs include substances manufactured by processes such as (1) chemical synthesis; (2)

fermentation; (3) recombinant DNA or other biotechnology methods; (4) isolation/recovery

from natural sources; or (5) any combination of these processes.

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Production of APIs has traditionally been done by the pharmaceutical companies themselves

in their home countries. But in recent years many corporations have opted to send

manufacturing overseas to cut costs. This has caused significant changes to how these drugs

are regulated, with more rigorous guidelines and inspections put into place. 

The quality of APIs has a significant effect on the efficacy (producing the result desired) and

the safety of medications. Poorly manufactured or compromised APIs have been connected to

serious issues, such as illnesses or death.

Even in the case of outsourcing, APIs are subject to stringent regulations and oversight from

the country they are shipped to. For example, API manufacturing plants overseas still go

through an inspection by the U.S. Food & Drug Administration.

As evidenced by the creation of APIs, the pharmaceutical industry is rapidly changing.

Companies no longer handle every step of the drug-making process. One company used to

create the API, build the capsule, and package the medicine—but no longer.

In response, governing bodies responsible for patient and public safety have instituted intense

screenings to ensure medication quality and prevent defects. Violating any of these

established standards can result in fines or very expensive recall for the pharmaceutical

companies behind these manufacturers.[1]

Active Pharmaceutical Ingredients (APIs) are integral components of both the quality and the

cost of pharmaceutical goods. Equality of access for developing country final formulators to

high quality essential medicine APIs should be pursued as a public health goal. This requires

looking at the API market from a sustainability and quality perspective as well as from a

price perspective.

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API Intermediate: A material produced during steps in the synthesis of an API that must

undergo further molecular change or processing before it becomes an API.

Drug Product: A finished dosage form, for example, a tablet, capsule or solution that

contains an active pharmaceutical ingredient, generally, but not necessarily, in association

with inactive ingredients (excipients).

Pharmaceutical Excipient: An excipient is pharmacologically inactive substance formulated

along with the active pharmaceutical ingredient of a medication or drug product. Examples of

excipients include fillers, extenders, diluents, wetting agents, solvents, emulsifiers,

preservatives, flavours, absorption enhancers, sustained-release matrices, and colouring

agents.

As every specific API market is diverse, each API market should be examined individually to

determine if it is competitive with affordable prices. If it is not, specific market’s problems

should be articulated so that corrective action that can be taken.

Pharmaceutical manufacturing occurs in two general steps. First, firms convert raw materials

into APIs. Then, firms create final formulations by mixing APIs and excipients (other non-

active ingredients), pressing the mixture into tablets, or filling capsules or preparing

solutions, and then packaging the product for the consumer market. For the purposes of this

paper, final formulations will refer to the second stage of pharmaceutical manufacturing and

not the entire process.

Firms either sell APIs on the open market (“merchant market”) or use them to do their own

final formulations manufacturing. Firms that manufacture both APIs and final formulations

will usually still buy and sell APIs on the merchant market.[2]

Pharmaceutical manufacturing occurs in two general steps. First, firms convert raw materials

into Active Pharmaceutical Ingredients (APIs). API production is a highly sophisticated,

technically demanding chemical and biochemical fermentation and/or synthesis process. APIs

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constitute a significant portion of the total cost for a drug. For example, on average, 40-50%

of the cost of goods sold for generic oral solids comes from APIs.1 Commodity API

manufacturing tends to be a high-volume, low-margin business where economies of scale

play an important role. The average commodity API profit margin is less than 10%. In fact,

many large bulk API exporters from India work with a 3% margin on exported products.

The second step in pharmaceutical manufacturing is the final formulation of the drugs. Unlike

the chemical business of API production, final formulations belong to the manufacturing

sector. During this process, firms first mix APIs and excipients (other non-active ingredients),

then either press the mixture into pills and tablets or prepare powders for solutions or filling

of capsules, and finally, package the product for the public or private market. For the

purposes of this paper, final formulations will only refer to this second phase of

pharmaceutical manufacturing and not the entire process. Final formulations require different

skills and equipment than does API manufacturing.

Economies of scale matter, but less so than for API manufacturing as manufacturers can

produce fifty or more final formulations in a single plant with adaptable equipment.33 Profit

margins for final formulations average 20-30%.

Firms either sell APIs on the open market (“merchant market”) or use them to do their own

final formulations manufacturing. In 2005, the total world API market was $76B and growing

at an average annual rate of 8.2% (with generics growing at 10.9%). Forty one percent of

APIs were sold in the merchant market and generics comprised 43.5% of the total merchant

market. In 2005, final formulating firms in North America purchased 42% of APIs sold in the

merchant market (75% of which were branded), firms in Western Europe purchased 19%

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(62% of which were branded), and firms in Asia purchased 21% (35% of which were

branded).

Firms that manufacture both APIs and final formulations will still buy and sell APIs on the

merchant market - one firm cannot possibly manufacture every API it needs to manufacture

all its final formulations6 and a broad portfolio of APIs does not usually translate into

economies of scale. Furthermore, the API division of an integrated firm tends to be oriented

towards the external API market. For example,

Dr. Reddy’s, an Indian firm that manufactures both APIs and final formulations, charges

internal pricing on its APIs (e.g. if the final formulations division of Dr. Reddy’s wants to use

an API manufactured at a Dr. Reddy’s plant, it will have to pay the API division an internal

transfer price). The API team receives bonuses for profitability so, if they can get a higher

price by selling on the merchant market, the company incentives are structured for them to

consider this. Matrix Laboratories, (an Indian firm that is currently becoming a wholly-owned

subsidiary of Mylan Pharmaceuticals, a US firm) that manufactures both APIs and final

formulations for

HIV drugs provides another example. Matrix also sells some of the HIV APIs it manufactures

to Indian final formulation competitors.

Regulation of Active Pharmaceutical Ingredient industry

Several regulatory authorities can be involved in ensuring that firms manufacture APIs and

final formulations in a quality manner. Currently, the agency that regulates the final

formulation has the most power in keeping low quality APIs away from consumers. If the

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API and final formulation are locally manufactured and financed, the local regulatory

authority is the only regulatory body involved. If this scenario occurs in e.g., the United

States, then only the USFDA regulates. If this scenario occurs in e.g., Nigeria, then only the

National Agency for Food and Drug Administration and Control (NAFDAC) regulates the

drug. An international producer from e.g., China manufactures an API and sells it to a final

formulator in e.g., the United States. The API will be subject to the regulatory authorities in

China and the API manufacturer will have to produce it, at a minimum, with the quality

standards enforced by the Chinese authorities.

However, the US can require that for importation, it meets USFDA standards as well. The

USFDA uses Drug Master Files (DMFs) to regulate APIs by stipulating that a final

formulator manufacturing according to USFDA guidelines can only buy APIs from firms

with an approved US Drug Master File (US-DMF). An API manufacturer submits a US-DMF

to the USFDA with complete information on an API, including information on facilities,

processes, and articles used in manufacturing. The USFDA, however, will not review the

DMF until the final formulator files a New Drug Application (NDA), Abbreviated New Drug

Application (ANDA) or ANDA supplement with the USFDA which requests use of this API

in a finished formulation. Once a final formulator files, the USFDA schedules a Pre-Approval

Inspection of the API manufacturer and reviews the API manufacturer’s DMF. If a final

formulator does not file to use the API, the USFDA assigns the DMF a number when it

receives the DMF but does not review it. The USFDA does not approve DMFs, just

ANDAs/NDAs that contain a DMF.

API INDUSTRY AT A GLANCE

The Active Pharmaceutical Ingredient Industry is the organ by which active pharmaceutical

ingredients are manufactured from raw materials through both chemical and physical means.

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Depending on the complexity of the molecule required, synthesis of APIs might need multi-

step complex chemistry utilizing a range of processing technologies. Indian companies

manufacture 85% of the active pharmaceutical ingredients (API) required by the country and

account for 90% of the pharmaceutical exports. The Indian pharmaceutical sector has made

the country self-sufficient in almost all the 300 essential drugs through indigenous process

technology.

The Active Pharmaceutical Ingredient (API) forms the most vital part of every formulated

end product, and is an important part of the whole pharmaceutical industry. The overall API

market was valued at $ billion in 2010, and is expected to grow at a CAGR of 7.9% from

2011 to 2016.The API market is facing a period of unprecedented growth as market dynamics

have undergone a major change with the expiration of patents pertaining to global

blockbuster drugs in the U.S. The consequences of the economic crisis have hit the

Innovative drugs market hard, with less budgets allocated by the major players for the R&D

of Innovative drugs. This has led to drying up of pipelines for new drugs, and therefore the

market for generic drugs is quickly growing. Thus, the patent expiry factor is slated to drive

the API market for the coming years.

 API production is a highly sophisticated, technically demanding process and which is

accomplished by chemical synthesis or biochemical methods. APIs constitute a significant

portion of the total cost for a drug. Active pharmaceutical ingredients are first obtained in the

crude state. Subsequent production operations convert the crude material to the final API that

meets the pharmacopoeial and/or similar requirements. Pharmaceutical manufacturing occurs

in two general steps. First, raw materials are converted into Active Pharmaceutical

Ingredients (APIs). The second step in pharmaceutical manufacturing is the final formulation

of the drugs. Unlike the chemical business of API production, final formulations belong to

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the manufacturing sector. Basic production of API employs three major types of processes:

organic chemical synthesis, fermentation and biological and natural extraction.

Scale up in API manufacturing

Scale-up is generally defined as the process of increasing the batch size. Scale-up of a process

can also be viewed as a procedure for applying the same process to different output volumes.

In moving from R&D to production scale, it is essential to have an intermediate batch scale.

This is achieved at the so-called pilot scale, which is defined as the manufacturing of drug

product by a procedure fully representative of and simulating that used for full manufacturing

scale.

PHARMACOPOEIA

A pharmacopoeia is a book containing directions for the identification of

compound medicines, and published by the authority of a government or a medical

or pharmaceutical society.

A pharmacopoeia, pharmacopeia, or pharmacopoea, in its modern sense, is a legally binding

collection, prepared by a national or regional authority, of standards and quality

specifications for medicines used in that country or region. A quality specification is

composed of a set of appropriate tests that will confirm the identity and purity of the product,

ascertain the strength (or amount) of the active substance and, when needed, its performance

characteristics. Reference substances, i.e. highly-characterized, physical specimens, are used

in testing to help ensure the quality, such as identity, strength and purity, of medicines. The

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texts cover pharmaceutical starting materials, excipients, intermediates and finished

pharmaceutical products (FPPs). General requirements may also be given in the

pharmacopoeia on important subjects related to medicines quality, such as analytical

methods, microbiological purity, dissolution testing, stability, etc.

Descriptions of preparations are called monographs. In a broader sense it is a reference

work for pharmaceutical drug specifications.

The first United States Pharmacopeia (USP), which contained formulas for the preparation of

217 drugs considered to be the “most fully established and best understood” at the time. In

1888, the American Pharmaceutical Association created the National Formulary (NF), which

included formulations and unofficial preparations for widely sold products.

The USP–NF  contains more than 4,500 monographs for prescription and over-the-counter

products, dietary supplements, medical devices, and other healthcare products. In its present

form, somewhat different than Toshchanelli’s original black book, the USP–NF  is published

annually and is available as a USB flash drive, online, and in hardcover. USP also produces a

Spanish edition of the USP–NF, and is working on versions in other languages as well.

In addition to USP, there are three other large pharmacopeias’ in the world, the European

Pharmacopoeia (EP), the British Pharmacopoeia (BP), and the Japanese Pharmacopoeia (JP),

all of which share the goal of publishing and producing quality standards for pharmaceuticals.

Other countries have smaller national pharmacopoeias, and USP works collaboratively with

many of them as well as with their larger counterparts.

While its global counterparts are part of the ministries of health in their countries or

federations, USP has remained a practitioner based, nongovernmental standards-setting

organization. All pharmacopoeias, however, share the goal of advancing public health by

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helping to ensure the quality and consistency of medicines, thereby promoting the safe and

proper use of medications.

A pharmacopoeia is a legally binding collection of standards and quality specifications for

medicines used in a country or region. Within the pharmacopoeia, a quality specification is a

set of appropriate tests that will confirm the identity and purity of the product, ascertain the

strength (or amount) of the active substance and, when needed, the performance

characteristics. Reference substances are used in testing to help ensure the quality, such as

identity, strength and purity, of medicines. A pharmacopoeia also covers pharmaceutical

starting materials, excipients, intermediates and finished pharmaceutical products (FPPs).

General requirements may also be given on important subjects related to medicines quality,

such as analytical methods, microbiological purity, dissolution testing, or stability (1). The

role of a modern pharmacopoeia is to furnish quality specifications for active pharmaceutical

ingredients (APIs), FPPs and general requirements. The existence of such specifications and

requirements is necessary for the proper functioning or regulatory control of medicines

production. Pharmacopeial requirements form a basis for establishing quality requirements

for individual pharmaceutical preparations.

A large number of products are usually covered, reflecting the diligence and commitment of

pharmacopeial authorities and their appointed experts to develop a comprehensive working

tool with up-to-date scientific data. The complexity and diversity of most pharmacopoeias

results from mutual integration and interdependence with monographs for various types of

products such as active pharmaceutical ingredients (APIs), excipients, herbal products,

biologicals (vaccines, blood products), radiopharmaceuticals, dosage forms and homeopathic

preparations. It may be noted that there is a majority of finished dosage forms, which

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generally can be defined as the form of active ingredient which is or is intended to be

dispensed or administered to the patient and requires no further manufacturing or processing

other than packaging and labelling. This is in parallel to the decreasing tendency of specific

national monographs for APIs within some national pharmacopoeias due to replacement with

monographs from regional or international pharmacopoeias. As the pharmacopoeia itself has

emerged from experience gained throughout the centuries, the roots of this valuable

knowledge can still be seen in contemporary medicine as traditional medicine monographs,

represented mainly in the pharmacopoeias of China, France (overseas), Japan and Ph. Eur.

Likewise, homeopathic approaches are represented in pharmacopoeias in Brazil, Germany

and Mexico, for example. The pharmacopoeias reviewed at the International Meeting of

World Pharmacopoeias contain standards for chemical and biological drug substances,

dosage forms, compounded preparations, excipients, medical devices and dietary

supplements. During the current meeting some countries, such as Brazil, France, Germany,

Mexico, Serbia and Switzerland, provided examples of incorporating a national formulary for

hospital and/or community pharmacy preparations into their pharmacopoeias. In Portugal,

there is a non-official national formulary which is published by the Portuguese Pharmacies

Association. During the meeting, examples were given of types of monographs with less

frequent occurrence than other types. For example, monographs for blood products were

presented by Argentina (12), Brazil (20) and India (21), while monographs for vaccines were

presented by Argentina (21), India (57), Kazakhstan (15) and Ukraine (26). Homeopathic

preparations described in monographs were presented mainly by France (320), Germany

(120) and Mexico (558) and finally monographs for traditional medicine were given as an

example by China (2165). A total of 92 herbal, traditional herbal and homeopathic

monographs are present in the British Pharmacopoeia 2012. Supplementary information is

included in some of the pharmacopoeias, for example general texts, reference tables, and

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texts on methods of analysis, reagents, materials/ containers, sutures, and reference

substances used in national monographs.

PHARMACOPOEIAL STANDARDS

Pharmacopeial standards help ensure the quality and safety of essential medicines by

providing analytical methods and appropriate limits for testing and assessing the active

pharmaceutical ingredients, excipients and finished products The International

Pharmacopoeia1 focuses on specifying the quality of essential medicines, i.e. those medicines

that satisfy the health care needs of the majority of the population in WHO Member States. It

underpins some of WHO’s most important activities, including those carried out by the WHO

Prequalification Team: medicines and the Department of Control of Neglected Tropical

Diseases, to assess and test the quality of medicines found in:

 the WHO Model List of Essential Medicines and the WHO Model List of Essential

Medicines for Children;

 invitations to manufacturers to submit an expression of interest for product evaluation

to the World Health Organization (WHO) Prequalification Team: medicines;

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PHARMACOEPIAL STANDARDS FOR ACTIVE PHARMACEUTICAL

INGREDIENTS

Priority is placed on monograph development for essential medicines that are not included or

not sufficiently described in other pharmacopoeias. Many of these medicines are needed

urgently, either because current production does not cover global treatment needs or because

available products are not quality-assured. Albendazole chewable tablets is one such

medicine.

In the past, the work on The International Pharmacopoeia used to be funded from WHO’s

regular budget. This funding source has decreased to virtually zero in recent years. The

activities are currently funded for the most part by UNITAID, whose financial contribution is

gratefully acknowledged. In addition, WHO Member States provide in-kind contributions and

support valued at a multiple of the programme’s operational budget. These contributions

include activities by national quality control laboratories, national support to WHO

collaborating centres, and – very importantly – time given by individual experts.

Three are the basic features of a medicine legally introduced on the market: efficacy, safety

and quality. With regarding to drugs listed in a national or international pharmacopoeia, the

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ratio between efficacy and safety, within the range of dosage established by the codex, must

be considered as official by the industry. As far as quality is concerned, the pharmacopoeia

plays a fundamental role in establishing methods of analysis and technical control intended as

official reference in case of controversy. The quality of drugs, pharmaceutical adjuvants or

preparations listed in a modern pharmacopoeia must be considered by the industry as the

minimum level of the acceptable standard for medical use, to ensure efficacy under proper

storage conditions. In fact, the specifications are largely based upon suggestions made by

manufacturers. Pharmaceutical specialties, being registered by Health Authorities following

suitable documentation, do not have to be subjected to the standards established by the

pharmacopoeia for new drugs or formulation adjuvants. The constant effort of the

manufacturers to minimize risks leads to optimum quality levels, considering that samples

used for control by the Health Authorities are usually picked from commercial packages

containing a small number of units. To ensure statistical compliance of every sample with

official pharmacopoeial standards, manufacturers are forced to exercise the highest care in

every process of production and packaging. There cannot possibly be a guarantee that every

single unit at the consumer's disposal will actually comply with the quality level established

by a modern pharmacopoeia. Optimum quality level in every package of medical products

can be achieved by following the "Good Manufacturing Practice" sponsored by the WHO;

this goal requires skilled people and sophisticated equipment. The practice of quality control

as an essential part of the manufacturing process in a wide range of pharmaceuticals, provides

an excellent experience that may be useful to the pharmacopoeial commissions. Therefore, a

closer co-operation between health officials and industry's experts must be considered the

best way to improve the specifications, to speed-up the revision of monographs and to collect

reports on stability tests. The part of a modern pharmacopoeia, devoted to tests and standards

appears today as the most important for the pharmaceutical industry because, when a

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controversy arises about drugs, the official methods established by the pharmacopoeia play a

fundamental role in the enforcement of law. The task of compiling each new edition of a

modern pharmacopoeia is becoming increasingly difficult; to speed revision any time a

problem arises, the revision committees may seek advice from the numerous experts of the

pharmaceutical industry thus achieving a most profitable collaboration.

Compliance with requirements published by pharmacopoeias around the world is a legal and

regulatory requirement in those countries and regions in which the pharmacopoeia is

applicable. This fundamental principle of pharmacopoeia compliance is an important

consideration for the bio/pharmaceutical industry, including innovator, generic, virtual, and

start-up companies who discover, develop, manufacture, and distribute small-molecule drug

products, biotherapeutic products, and vaccines, as well as the drug substances and excipients

used in these products. Across the entire industry and within any given company, it is crucial

that there is awareness and understanding of this need for pharmacopoeia compliance-from

the CEOs of multi-national innovator and generic-drug companies to the leadership at small

start-ups and contract manufacturers, to managers in their respective functional areas, to the

analytical bench chemists and microbiologists testing active ingredients and excipients for

use in drug products-so that global patients have uninterrupted access to the critical

medicines that extend and improve their lives.

There is often insufficient understanding, however, by stakeholders at all levels of the need to

comply with requirements in the pharmacopoeias. This situation can lead to a lack of

appropriate attention and resources allocated to ensure compliance. The compliance risk can

result in observations in FDA 483s, which may be summarized as follows: the company must

comply with applicable compendial standards in the United States Pharmacopeia–National

Formulary (USP–NF). A more nuanced observation is that the company must comply with

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“current” compendial requirements, which introduces the need to monitor and implement

updates published in USP–NF. The situation is not limited to the United States, as similar

expectations to comply with the applicable pharmacopoeia exist in Europe, Canada,

Australia, Japan, China, and in laws and regulations around the world.

The situation is made even more complex because a company must comply with the

compendial requirements that are applicable in a particular country, and also with their

product registrations as approved in countries around the world. This is true whether the

pharmacopoeia references are specifically listed in the registration, or because the

pharmacopoeias provide additional, well-recognized quality standards. The compliance

challenge is increased by the sheer number of pharmacopoeias that exist in important

markets, often with conflicting requirements due to lack of harmonization among the

pharmacopoeias. This lack of broad harmonization is the current reality, despite long-term

commitment and effort by pharmacopoeias to narrow the divide between their published

standards. Somewhat balancing this high-level view of the compliance challenge is the fact

that there is some flexibility in how a company ensures appropriate compliance to the

multitude of compendial requirements. But in this flexibility, there is also complexity, due to

the number of approaches that may be taken to demonstrate compliance, with the potential

for different situations to drive the approach in different directions. Click to view this article

as a PDF.

It is against this challenging backdrop that the authors have undertaken the preparation of a

series of articles to provide a common understanding of this far-reaching and complex

situation and to detail practical ways that pharmacopoeia compliance may be addressed. The

articles intend to give consistent language to, and awareness of, the tasks associated with the

effort and to give specific guidance to those groups and individuals within a company who

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are charged with ensuring ongoing compliance with pharmacopoeia requirements. While

focusing on the situation for innovator and generic companies, the information is also

potentially helpful in bringing greater awareness and understanding to regulatory and

pharmacopoeia authorities.

Along with the understanding and assistance provided to those who perform this work, there

is the goal of ensuring continued availability of medicines with consistent quality, which

comply with compendial and regulatory expectations. Achieving compliance for these

medicines ensures meeting the needs of patients around the world, regardless of where the

patients live, where the medicines are manufactured, or which pharmacopoeias may apply.

The legal and regulatory basis for pharmacopoeia compliance

Pharmacopoeias are often referenced in the laws and regulations of countries around the

world to help ensure drug quality, safety, and efficacy. In the United States, the Federal Food,

Drug, and Cosmetic Act (FD&C Act) defines the term “official compendium” as the

official USP–NF  or any supplement to it and the term “drug” to include articles recognized in

the official USP–NF. FDA has responsibility to enforce compliance with USP–

NF requirements. In Europe, the European Union Directives on Medicines for Human and

Veterinary Use (2001/82/EC and 2001/83/EC) maintain the mandatory character

of European Pharmacopoeia (Ph. Eur.) monographs, which are applicable to all substances,

preparations, and pharmaceutical forms appearing in it when requesting marketing

authorization. In Japan, the Law on Securing Quality, Efficacy, and Safety of Products

including Pharmaceuticals and Medical Devices indicates the need for compliance with

the Japanese Pharmacopoeia (JP) in order to standardize and control the quality of drugs.

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The legal and regulatory framework for pharmacopoeia compliance in these and other

countries can be found in a useful summary prepared by the World Health Organization

(WHO) in conjunction with recent International Meetings of World Pharmacopoeias

(IMWP).

In an article published in 2004 on the bio/pharmaceutical industry’s pharmacopoeial

surveillance process (2), the need to remain compliant with “current” compendial

requirements was emphasized to ensure updated standards are incorporated into a company’s

testing procedures. If there is no process for surveillance, or if the process is ineffective in

identifying and addressing compendial changes, the resulting lack of compliance may be

listed in regulatory observations. Specific examples from FDA 483s are included in the

article, with observations such as: “… the firm did not follow the current USP specifications

… failed to implement changes to testing methodology as required by USP … and did not

address raw material monograph updates.” The common theme in all these observations is the

need to maintain alignment with applicable pharmacopoeia requirements, even as the

requirements change over time. Similar regulatory expectations to comply with current

pharmacopoeia requirements can be found in Europe, Japan, and other countries, because the

regulatory and compendial landscape is truly global. A review of data from inspections

conducted by the European Directorate for the Quality of Medicines and HealthCare

(EDQM) between 2006 and 2018 includes compliance issues with Ph. Eur. general methods

and general monographs among the deficiencies observed (3). The takeaway message is

clear; companies must comply with compendial requirements and must also remain up to date

with changes made to the requirements. This ongoing revision to the pharmacopoeias around

the world poses one of the main challenges for companies and will be further addressed in

later articles in this series.

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Pharmacopoeia impact throughout drug product lifecycle

Pharmacopoeias impact drugs and their ingredients throughout the entire product lifecycle.

Beginning with the development of a new drug substance or API, many of the pharmacopoeia

general chapters should be considered for potential quality and functionality testing. For

example, the compendial tests listed in general chapters for water content or loss on drying,

residual solvents, elemental impurities, and microbiological evaluation will likely be used for

quality release of the material later in the lifecycle. Similarly, information listed in the

chromatography chapter should be considered during analytical method development,

because many of the compendial requirements can be incorporated into the test procedures,

such as method repeatability and resolution for system suitability. Consideration should also

be given at the appropriate stage of product development to compendial requirements for

method validation, such as  “Validation of Compendial Procedures,” because this

information will ultimately be used to support the product registration.

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