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. 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. 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 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. 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.
Q2. What is an API and what are
the differences between APIs, raw materials and intermediates?
Q3. What is GMP contract
manufacturing?
Q4. What is generic API
manufacturing?
Q5. What are the key surprises
and challenges involved in API manufacturing? How can they be handled by
contract manufacturers?
All Suppliers
01
Evonik's CDMO solutions for APIs and HPAPIs: It specializes where the client needs it most!
Pharma Service : API Manufacturing
02
Seqens is an integrated global leader in pharmaceutical solutions & specialty ingredients & provides custom-made solutions.
Pharma Service : API Manufacturing
CONTRACT API MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
03
Axplora- The partner of choice for complex APIs.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
04
Interquim comes from an international group of 50 companies active in the pharma, hospital, diagnostics, fine chemicals & feed sectors.
Pharma Service : API Manufacturing
API CUSTOM SYNTHESIS & CONTRACT MANUFACT...
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
05
Minakem delivers API, HPAPI, steroids & CDMO services for generics with FDA/GMP certification, regulatory know-how & proven success.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
06
Polpharma is a Polish CDMO of APIs and a significant European API producer, delivering products to companies worldwide.
Pharma Service : API Manufacturing
07
AbbVie CDMO has been working with global companies to develop, manufacture & scale biopharmaceutical products.
Pharma Service : API Manufacturing
08
Biophore is a research-driven global pharmaceutical company focused on niche APIs for the generic industry.
Pharma Service : API Manufacturing
09
With Fermion, start the journey of your innovative API.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
10
LEBSA- Your strategic API source for niche molecules.
Pharma Service : API Manufacturing
CONTRACT MANUFACTURING FOR APIs
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
11
Suanfarma CDMO offers integrated end-to-end solutions for development & commercialization of intermediates & APIs for small molecules.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
12
Cohance Lifesciences, offers full range of CDMO services for small molecule APIs, intermediates, ADCs, Pellets and Formulations.
Pharma Service : API Manufacturing
13
Egis is a Hungarian generic pharma company with 110 years history. Our activities incorporate all areas of the pharma value chain.
Pharma Service : API Manufacturing
14
Gentec Pharmaceutical Group is focused on manufacturing & developing APIs/HPAPIs, Advanced Intermediates & Fine Chemicals.
Pharma Service : API Manufacturing
15
Malladi is a leader in Ephedrine, Pseudoephedrine Salts & Phenylephrine HCl // USFDA, EDQM, ANSM, KFDA, and TGA inspected.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
16
PMC Isochem is your partner for smart CDMOs of Intermediates, APIs, & excipients & a catalog of Intermediates & Generic APIs.
Pharma Service : API Manufacturing
17
Polfa Tarchomin is a leading Polish pharmaceutical company with 200 year tradition in manufacture and sale of pharmaceutical products.
Pharma Service : API Manufacturing
18
Valsynthese, part of the SSE Group, is a CDMO focused on highly energetic and highly hazardous chemistry.
Pharma Service : API Manufacturing
CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
19
Zach System is committed to providing Highly Customized Solutions for all your Development Programs.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
20
Aurigene is a global leader in accelerating drug innovation through discovery, development & manufacturing.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
21
Century has been an API manufacturer for over 30 years & is the partner of choice for multipurpose custom manufacturing projects.
Pharma Service : API Manufacturing
22
Gensenta is a trusted CDMO partner with robust history, commitment to quality, innovative mindset and commitment to sustainability.
Pharma Service : API Manufacturing
23
Medichem is a vertically integrated pharmaceutical company specializing in the development & manufacturing of APIs & FDFs.
Pharma Service : API Manufacturing
24
USV offers custom peptide synthesis ranging from gram to multi-gram to multi-kilogram quantities.
Pharma Service : API Manufacturing
PEPTIDE API CONTRACT MANUFACTURING
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
25
Farmhispania Group, a leading European CDMO in HPAPI Technologies & High Potency Fermentation.
Pharma Service : API Manufacturing
CONTRACT MANUFACTURING FOR APIs
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
26
Bioquim: An European GMP-certified company manufacturing bulk APIs, specializing in sterile lyophilization and chemical synthesis.
Pharma Service : API Manufacturing
API CONTRACT MANUFACTURING SERVICES
Category : Contract Manufacturing
Sub Category : Overview
Pharma Service : API Manufacturing
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