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Overview of GMP contract manufacturing of APIs, from clinical production to commercial manufacturing, by contract manufacturing organizations (CMO).

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01 AbbVie Contract Manufacturing

02 Acharya Chemicals

03 Aesica Pharmaceuticals Limited

04 Almelo

05 Aragen Life Sciences

06 Ash Stevens, Inc.

07 Aurigene Pharmaceutical Services

08 Avara Pharmaceutical Services

09 Avra Laboratories

10 Axplora

11 BioSpectra

12 Biological E

13 Biophore India Pharmaceuticals Pvt Ltd

14 Biovian

15 CBL- Chemical and Biopharmaceutical Laboratories

16 CLEARSYNTH LABS LIMITED

17 CRMO Pharmmatecch

18 Cambrex Corporation

19 Century Pharmaceuticals

20 Cerbios-Pharma SA

21 ChemCon GmbH

22 Concord Biotech

23 Crenza Pharma

24 Curia

25 DPT Laboratories, Ltd

26 Dishman Carbogen Amcis

27 Diverchim S.A.

28 Dr Pradeep Reddy’s Laboratories Private Limited

29 DrugOn Pharma Switzerland

30 Egis Pharmaceuticals PLC

31 Evonik

32 Fermion Oy

33 Flamma SpA

34 Fujian South Pharmaceutical

35 Gensenta Pharmaceuticals

36 Gentec Pharmaceutical Group

37 Grunenthal

38 Huvepharma Italia S.r.l

39 Interquim SA

40 Jubilant HollisterStier

41 Kekule Pharma

42 Kimia Biosciences

43 LEBSA

44 Malladi Drugs & Pharmaceuticals Limited

45 Medichem S.A

46 Menadiona

47 Minakem

48 Nanjing Dorra Pharmaceutical Technology Co.,Ltd

49 Navin Fluorine International Limited

50 Norchim

51 Ocimum Labs

52 Olon S.p.A

53 Onyx Scientific

54 Orchid Pharma

55 Orofino Pharmaceuticals Group

56 PMC Isochem

57 Piramal Pharma Solutions

58 Polfa Tarchomin

59 Polpharma

60 Priyans Drugs

61 Quality Chemicals

62 Recipharm AB

63 Robinson Brothers

64 SIMS Srl

65 SPC Lifesciences Pvt. Ltd

66 ScinoPharm Taiwan, Ltd

67 Sekisui Diagnostics (UK) Limited

68 Seqens

69 Shanghai Chemspec Corporation

70 Solara Active Pharma Sciences

71 Suanfarma CDMO

72 USV Private Limited

73 Unique Biotech Limited

74 Valsynthese

75 ZACH System SA

76 ZCL Chemicals Limited

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Overview of GMP contract manufacturing of APIs, from clinical production to commercial manufacturing, by contract manufacturing organizations (CMO).

Q1. What is API contract manufacturing?

Contract manufacturing pertains to outsourcing a part or the entirety of the drug manufacturing process of a product, which was likely performed in house, to a third-party contract manufacturer. Nowadays, outsourcing activities like the design, production, assembly, and distribution of products to contract manufacturers has become commonplace in the pharmaceutical industry.

Contract manufacturing is beneficial for customers as it provides them a guaranteed supply of drug products from clinical production to commercial manufacturing under integrated cGMP and pre-GMP manufacturing operations. Furthermore, it enables companies to focus on selling and marketing products instead of focussing on the drug manufacturing process itself.

Pharmaceutical contract manufacturing organizations including CMOs and CDMOs can provide such contract manufacturing and analysis services. At times, pharmaceutical contract manufacturing organizations can be specialized in custom synthesis or API synthesis, chemical synthesis of small molecules, and custom API manufacturing services. 

- Custom Synthesis of Small Molecules: Small molecules are low molecular weight molecules that include lipids, monosaccharides, secondary messengers, other natural products and metabolites, as well as pharmaceutical drugs and other xenobiotics. Custom synthesis of small molecules refers to the production of such low weight molecules. 

 

An API or an active pharmaceutical ingredient is any substance or mixture of substances intended to be used as active ingredients in medicinal drug products. Custom API manufacturing services refer to the production of desired quantities of pharma APIs, intermediates, fine chemicals, reference standards, impurities, and other drug substances under GMP (Good Manufacturing Practices) guidelines.

Active pharmaceutical ingredient (API) production is carried out exclusively according to a specified scale, which may include commercial scale APIs. Moreover, API manufacturing includes the chemical synthesis of niche APIs. Niche APIs are active ingredients for drug products that are needed in the world but are not produced on a large scale due to the small size of the market. Rapid change towards industry developing and manufacturing niche APIs is leading to smaller-scale facilities that offer higher containment and flexibility.

 

Custom API manufacturing services may also include physicochemical studies, route scouting, route optimization, purification, scale up, and process development, amongst other drug manufacturing capabilities. Recently, increased outsourcing to CMOs and CDMOs has been observed in small to large biotech and pharma companies, for early to late-stage API development and manufacturing projects.

While some companies are still hesitant to outsource their API production activities to contract manufacturers or active pharmaceutical ingredient (API) manufacturers, due to data security and quality concerns, the benefits of contract manufacturing outweigh the costs. In the coming years more firms are likely to join the trend of outsourcing drug manufacturing processes to contract manufacturers

Finally, as a significant part of the quality of a finished pharmaceutical product (FPP) is dependent on the quality of the active pharmaceutical ingredients (APIs), it is important for companies (in-house and contract manufacturers) to adopt outlined strategies and comply with regulations imposed on the development and manufacturing of APIs. 

Q2. What is an API and what are the differences between APIs, raw materials and intermediates?

An active pharmaceutical ingredient (API) is any substance or mixture of substances intended to be used as active ingredients in medicinal drug products. Active ingredients have direct effects in the diagnosis, cure, mitigation, treatment, and prevention of diseases. Pharma APIs and raw materials (API starting materials) are often confused due to the similar usage of the two terms, however, raw materials refer to the chemical compounds used as a base for API production.

The API production process is not completed in a single step, but rather via several chemical reactions between raw materials. The chemical compound which is in the process of becoming an API from a raw material is called an intermediate. Intermediates are the building blocks of active pharmaceutical ingredients (also known as API starting materials) and pharmaceutical intermediates are by-products of the chemical synthesis of APIs (API synthesis).

Furthermore, these pharmaceutical intermediates are produced during each and every reaction of custom synthesis or API synthesis. The intermediates are then used in API production for bulk drug substances and also for contract research and development (R&D) purposes by various pharma companies.

Q3. What is GMP contract manufacturing?

In the context of globalization, pharma APIs are sourced in a worldwide market and the risk of sourcing substandard or contaminated products is high. A proper system of regulation for contract manufacture and analysis service providers can promote the constant sourcing of active pharmaceutical ingredients (API) of appropriate quality, thereby safeguarding public health interests.

As mentioned above, contract GMP manufacturing service providers and GMP certified manufacturers take an integrated cGMP and pre-GMP manufacturing operations approach to fulfill their contractual assignments. Good Manufacturing Practices (GMP), is a system for ensuring that products are consistently produced and controlled according to quality standards, from clinical production to commercial manufacturing. It is designed to minimize the risks involved in pharmaceutical drug manufacturing that cannot be eliminated through testing the final product. 

GMP may also be referred to as cGMP in which the “c” stands for current, and roughly translates to current Good Manufacturing Practices. This is an important distinction as guidelines for cGMP contract manufacturing of active pharmaceutical ingredients are constantly evolving and only the most up-to-date system ensures the quality of the end product that reaches the consumers. GMP manufacturing guidelines are outlined and assessed by regulatory agencies like the FDA and ICH

A GMP certified active pharmaceutical ingredient (API) manufacturer is a production firm that demonstrates a strong regulatory commitment to cGMP contract manufacturing of active pharmaceutical ingredients, compliant with international GMP standards. The jump to cGMP manufacturing is never simple for GMP certified manufacturers, producing complex molecules within specification for the first time in cGMP is fraught with potential peril at every turn.

Moreover, key elements of cGMP API manufacturing must be clearly defined, agreed to and controlled by GMP certified manufacturers in order to avoid misunderstandings which could result in unsatisfactory custom synthesis products. Some of the main aspects of cGMP contract manufacturing of active pharmaceutical ingredients or cGMP API manufacturing are enumerated below:

 

- Quality Management: Principles & Responsibility 

- Personnel: Qualifications & Hygiene

- Building & Facility: Design, Utility & Sanitation

- Process Equipment: Design, Calibration & Maintenance

- Documentation & Records

- Materials Management 

- Production & In-process Controls 

- Packaging and labeling of pharma APIs & Intermediates 

- Storage & Distribution

- Laboratory Controls 

- Validation

- Rejection & Re-use of Materials 

Q4. What is generic API manufacturing?

The FDA describes a generic drug as a medication that has exactly the same active pharmaceutical ingredient as the brand name drug and yields the same therapeutic effect. It is the same in dosing, safety, strength, quality, the way it works, the way it is taken, and the way it should be used. However, generic pharmaceutical drugs do not need to contain the same inactive ingredients as the brand name product. 

Generic drugs can only be manufactured once the patent protecting a brand name product expires, which could take upto 20 years. Following that, cost is the main difference between generic and brand name prescription drugs. Unlike branded companies, generic drug manufacturers engage in competitive pricing, resulting in lower prices for consumers.

There is a general misconception that brand name drugs are superior and more effective than their generic counterparts, however, this is just a myth. The only reason that generic drugs are less costly than branded pharmaceutical drugs is because the drug manufacturer doesn't need to conduct extensive and expensive clinical efficacy and safety tests, unlike its predecessor.

Generic API manufacturing is essentially equivalent to conventional API manufacturing, the only difference being that generic API manufacturing produces active pharmaceutical ingredients intended for generic finished dosage forms (FDFs) and not branded finished pharmaceutical products. 

Generic API manufacturing including commercial scale API manufacturing is undertaken by active pharmaceutical ingredient (API) manufacturers from preformulation studies to commercial manufacturing, bypassing the clinical testing phase of API synthesis. Generic API manufacturing companies often commence these production services prior to the expiration of patents, by using high quality, non-patent infringing processes of API development and manufacturing.

Q5. What are the key surprises and challenges involved in API manufacturing? How can they be handled by contract manufacturers?

The pharma API market is expected to grow 5% annually reaching approximately $219 billion by 2023 and as the API manufacturing industry evolves it will tackle various challenges. Some of these challenges and their corresponding solutions are explored below: 

Bad Raw Materials:

- Using contaminated raw materials or raw materials that fail to meet the requirements outlined in the Drug Master Files, produce subpar APIs. These are often discarded or returned and can result in delays in time to market. 

- CMOs or active pharmaceutical ingredient (API) manufacturers involved in API production can curb this activity by using trained and qualified personnel to source pharma APIs, perform site checks, and maintain relations with trusted raw material suppliers. 

 Low Yield:

- There are various impurities that may arise at different stages of API manufacturing. Purification by sedimentation, filtration, centrifugation, etc. may be performed to remove these impurities, however, if it is highly contaminated then purification will yield low quantities of API. 

- Using chemists with scientific expertise in handling such situations can reduce yield loss. Moreover, identifying impurity forming steps during API manufacturing and rectifying them can solve purification related low yield problems. 

Scale up/Tech Transfer Problems:

- Scale up and technology transfer are associated with risks that need to be managed in order for a mg procedure to become a multi-kg process. Sometimes new impurities and issues that dont arise during early phase small scale development can come up during late stage bulk drug substance manufacturing, which can be very costly.

- Proper training of personnel, using advanced technologies, and spending more time assessing production and related issues during early stage small scale development can eliminate such problems plaguing API production.

Regulatory Problems:

- Not meeting regulatory requirements results in short timelines given by the regulatory agencies to rectify said issues, which can be difficult to cope with. 

- Following the manufacturing guidelines in its entirety during the manufacturing process and ensuring compliance throughout the development process can result in speedier and less complicated regulatory approvals.