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Overview of biological drug substance or API synthesis, from clinical development to small scale manufacturing, offered by CDMOs, CMOs, & CROs.

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01 Antibody Drug Conjugate

02 Antibody Drug Conjugate

03 Antibody Drug Conjugate

04 Antibody Drug Conjugate

05 Antibody Drug Conjugate

06 Antibody Drug Conjugate

07 Antibody Drug Conjugate

08 Biocatalysis

09 Biocatalysis

10 Biocatalysis

11 Biocatalysis

12 Clinical Supply

13 Clinical Supply

14 Clinical Supply

15 Clinical Supply

16 Clinical Supply

17 Clinical Supply

18 Clinical Supply

19 Clinical Supply

20 Complex APIs

21 Complex APIs

22 Complex APIs

23 Complex APIs

24 Complex APIs

25 Complex APIs

26 Complex APIs

27 Complex APIs

28 Controlled Substance

29 Controlled Substance

30 Controlled Substance

31 Controlled Substance

32 Controlled Substance

33 Crystallization Process

34 Custom Synthesis

35 Custom Synthesis

36 Custom Synthesis

37 Custom Synthesis

38 Custom Synthesis

39 Custom Synthesis

40 Custom Synthesis

41 Custom Synthesis

42 Custom Synthesis

43 Custom Synthesis

44 Custom Synthesis

45 Custom Synthesis

46 Custom Synthesis

47 Custom Synthesis

48 Custom Synthesis

49 Custom Synthesis

50 Custom Synthesis

51 Custom Synthesis

52 Fine Chemical / Intermediate

53 Fine Chemical / Intermediate

54 Fine Chemical / Intermediate

55 Fine Chemical / Intermediate

56 Fine Chemical / Intermediate

57 Fine Chemical / Intermediate

58 Fine Chemical / Intermediate

59 Fine Chemical / Intermediate

60 Fine Chemical / Intermediate

61 Fine Chemical / Intermediate

62 Fine Chemical / Intermediate

63 Fine Chemical / Intermediate

64 Fine Chemical / Intermediate

65 Fine Chemical / Intermediate

66 Fine Chemical / Intermediate

67 Fine Chemical / Intermediate

68 Fine Chemical / Intermediate

69 Halogenation

70 Halogenation

71 High Potency APIs (HPAPIs)

72 High Potency APIs (HPAPIs)

73 High Potency APIs (HPAPIs)

74 High Potency APIs (HPAPIs)

75 High Potency APIs (HPAPIs)

76 High Potency APIs (HPAPIs)

77 High Potency APIs (HPAPIs)

78 High Potency APIs (HPAPIs)

79 High Potency APIs (HPAPIs)

80 High Potency APIs (HPAPIs)

81 High Potency APIs (HPAPIs)

82 High Potency APIs (HPAPIs)

83 High Potency APIs (HPAPIs)

84 High Potency APIs (HPAPIs)

85 High Potency APIs (HPAPIs)

86 High Potency APIs (HPAPIs)

87 High Potency APIs (HPAPIs)

88 High Potency APIs (HPAPIs)

89 High Potency APIs (HPAPIs)

90 Hydrogenation

91 Low Temperature / Cryogenic Condition (-78 °C)

92 Low Temperature / Cryogenic Condition (-78 °C)

93 Micronization

94 Micronization

95 Oligonucleotide / Polynucleotide

96 Oligonucleotide / Polynucleotide

97 Oligonucleotide / Polynucleotide

98 Oligonucleotide / Polynucleotide

99 Oligosaccharides & Polysaccharides

100 Oligosaccharides & Polysaccharides

101 Oligosaccharides & Polysaccharides

102 Oligosaccharides & Polysaccharides

103 Oligosaccharides & Polysaccharides

104 Oligosaccharides & Polysaccharides

105 Ophthalmic

106 Organometallic Chemistry

107 Organometallic Chemistry

108 Overview

109 Overview

110 Overview

111 Overview

112 Overview

113 Overview

114 Overview

115 Overview

116 Overview

117 Overview

118 Overview

119 Overview

120 Overview

121 Overview

122 Overview

123 Overview

124 Overview

125 Overview

126 Overview

127 Process Development & Optimization

128 Process Development & Optimization

129 Process Development & Optimization

130 Process Development & Optimization

131 Process Development & Optimization

132 Process Development & Optimization

133 Process Development & Optimization

134 Process Development & Optimization

135 Protein / Peptide

136 Protein / Peptide

137 Protein / Peptide

138 Protein / Peptide

139 Protein / Peptide

140 Protein / Peptide

141 Protein / Peptide

142 Protein / Peptide

143 Protein / Peptide

144 Protein / Peptide

145 Protein / Peptide

146 Protein / Peptide

147 Route Evaluation & Development

148 Route Evaluation & Development

149 Route Evaluation & Development

150 Route Evaluation & Development

151 Route Evaluation & Development

152 Route Evaluation & Development

153 Route Scouting

154 Route Scouting

155 Route Scouting

156 Route Scouting

157 Route Scouting

158 Scale-Up Capabilities

159 Scale-Up Capabilities

160 Scale-Up Capabilities

161 Scale-Up Capabilities

162 Scale-Up Capabilities

163 Scale-Up Capabilities

164 Scale-Up Capabilities

165 Scale-Up Capabilities

166 Scale-Up Capabilities

167 Scale-Up Capabilities

168 Scale-Up Capabilities

169 Scale-Up Capabilities

170 Scale-Up Capabilities

171 Separation & Purification

172 Small Molecules

173 Small Molecules

174 Small Molecules

175 Small Molecules

176 Small Molecules

177 Small Molecules

178 Small Molecules

179 Small Molecules

180 Small Molecules

181 Small Molecules

182 Small Molecules

183 Small Molecules

184 Small Molecules

185 Small Molecules

186 Small Scale Batch

187 Small Scale Batch

188 Small Scale Batch

189 Spray Drying

190 Spray Drying

191 Steroid / Hormone

192 Steroid / Hormone

193 Steroid / Hormone

194 Steroid / Hormone

195 Steroid / Hormone

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01 Aarti Pharmalabs

02 Acharya Chemicals

03 Advinus Therapeutics Ltd

04 Ami Lifesciences Private Limited

05 Anhui Ribobay Pharmaceutical

06 Anthem Biosciences

07 Aspen API

08 Aurigene Pharmaceutical Services

09 Avra Laboratories

10 Axplora

11 Bachem AG

12 Bioindustria L.I.M. Spa

13 Biophore India Pharmaceuticals Pvt Ltd

14 Bioquim

15 CBL- Chemical and Biopharmaceutical Laboratories

16 CSBio

17 Cayman Chemical Company Inc

18 Century Pharmaceuticals

19 ChemCon GmbH

20 Crystec Pharma

21 EUROAPI

22 Egis Pharmaceuticals PLC

23 Evonik

24 Extrovis AG

25 FARMAK, a.s

26 Fareva

27 Farmhispania

28 Fermion Oy

29 Gentec Pharmaceutical Group

30 Hameln rds

31 ICE Pharma

32 Infinium Pharmachem

33 Inke S.A

34 JSC Olainfarm

35 LEBSA

36 Laboratorium Ofichem B.V

37 M2i Group

38 Malladi Drugs & Pharmaceuticals Limited

39 Microchem SRL

40 Minakem

41 Neuland Laboratories

42 PMC Isochem

43 Pfanstiehl

44 Pfizer CentreOne

45 Phyton Biotech LLC

46 Polpharma

47 Porton Pharma Solutions

48 Prague Scientific

49 Quotient Sciences

50 SEQUENT SCIENTIFIC LTD

51 SPC Lifesciences Pvt. Ltd

52 Seqens

53 Suanfarma CDMO

54 Tianjin Hankang Pharmaceutical Biotechnology

55 USV Private Limited

56 Valsynthese

57 Veranova

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01 Canada

02 China

03 China

04 China

05 Czech Republic

06 Czech Republic

07 Finland

08 France

09 France

10 France

11 France

12 France

13 Germany

14 Germany

15 Germany

16 Greece

17 Hungary

18 India

19 India

20 India

21 India

22 India

23 India

24 India

25 India

26 India

27 India

28 India

29 Italy

30 Italy

31 Latvia

32 Luxembourg

33 Netherlands

34 Netherlands

35 Poland

36 Slovakia

37 Spain

38 Spain

39 Spain

40 Spain

41 Spain

42 Spain

43 Switzerland

44 Switzerland

45 Switzerland

46 U.S.A

47 U.S.A

48 U.S.A

49 U.S.A

50 U.S.A

51 United Kingdom

52 United Kingdom

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Overview of biological drug substance or API synthesis, from clinical development to small scale manufacturing, offered by CDMOs, CMOs, & CROs.

Q1. What is API custom synthesis?

API Custom Synthesis:

Custom synthesis refers to the production of desired quantities of APIs and intermediates as well as fine chemicals, small molecules, reference standards, impurities, and other substances exclusively according to a specified scale. The amounts produced during custom synthesis of APIs tend to be small, ranging from a few milligrams to about 10 kg or so, and can be carried out in-house or by contract manufacturers.

Small molecule API manufacturing: 

- Small molecule APIs refer to APIs with lower molecular weights and small molecule API manufacturing refers to the drug substance development and manufacture of these molecules. Pharmaceutical product development service providers, with custom manufacturing expertise, can successfully undertake and deliver small molecule API manufacturing

An active pharmaceutical ingredient (API) is defined by the USFDA as: 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. Moreover, active ingredients can have a direct effect in restoring, correcting, or modifying physiological functions in human beings. 

Intermediates are the building blocks of active pharmaceutical ingredients (APIs) and pharmaceutical intermediates are by-products of API synthesis. Furthermore, these pharmaceutical intermediates are produced during each and every reaction of API development. The intermediates are then used in the production of bulk drugs and also for contract research and development (R&D) purposes by various biopharma and pharma companies. 

If it is impossible or impractical for a company to make these molecules and compounds in-house, API & intermediate custom synthesis can be outsourced to contract manufacturers including CDMOs, CMOs, and CROs. CMOs and CDMOs offer contract manufacturing services to produce APIs & intermediates on a small or large scale. Whereas, fully integrated contract research organizations (CROs) offer custom synthesis services for clinical development

Fully integrated contract research organizations offer custom synthesis expertise and enable the outsourcing of a broad variety of contract research and development activities from small molecule API manufacturing to the full scale clinical development and manufacture of drug substances. Advantages of custom synthesis of APIs: API custom synthesis produces active pharmaceutical ingredients which impart therapeutic effects to treat ailments in patients. 

Furthermore, APIs can be mixed together during custom synthesis of APIs to achieve desired effects (if in when a single active ingredient cannot achieve the same).Custom synthesis is essential to the pharmaceutical industry since many of these active pharmaceutical ingredients (APIs) can sometimes be very difficult to find or hard to synthesize. Custom synthesis or drug substance development and manufacture ultimately provides the platform necessary for clients to accelerate time to market for finished dosage forms (FDF).

Q2. What are the steps involved in API / drug substance development?

Drug development begins with API synthesis itself, before undertaking API development, it is well worth considering the level of API and molecule development desired for the substance of interest and outlining the goals for the API synthesis project before going forward.

The API development process, also referred to as the drug substance development process, is a highly challenging task. Contradicting API synthesis goals must be balanced, including the consideration of quality, safety, robustness, costs and time constraints. Furthermore, there are several steps involved in API development and all of them have to be coordinated carefully, following which custom synthesis services can be carried out as planned. 

Steps Involved in API Custom Synthesis: 

Step 1: Physicochemical Studies

In this stage of API and molecule development, the physicochemical properties of a biological drug substance are characterized and established. Every biological drug substance has intrinsic chemical and physical properties which need to be considered before drug substance development can be conducted at a larger scale. 

Therefore, physicochemical studies provide relevant information for formulation selection for later stages of clinical development and commercial contract manufacturing. Physicochemical studies further anticipate the need for molecular modifications. 

Physicochemical studies include:

- Selection of suitable drug substance candidates

- Planning API and drug substance development and manufacturing processes

- Advancement of analytical development services

- Assignment of API retest periods

- Synthetic route scouting of APIs 

In the end, the goal is to select an appropriate process chemistry route and also to estimate the quantities of the chosen raw materials required to produce the desired quantity of APIs. 

Route Scouting & Route Optimization: 

Synthetic route scouting during early stages of process development offers significant benefits by decreasing processing times, reducing the steps involved in process chemistry, improving quality and safety profiles, reducing chemical waste production, and improving scalability. 

Route optimization can reduce costs, increase the efficiency of biological drug substance development processes, increase the safety of drug products, and accelerate the drug substance development and manufacturing process altogether. 

Custom synthesis and route scouting go hand in hand, lately there has been an increasing trend towards achieving route optimization and all the benefits that it imparts to the pharmaceutical product development process. Contract manufacturers provide such process chemistry, route scouting and route optimization - discovery and development services. 

Step 2: The raw materials, chosen during the early stages of drug substance development, are treated in a reactor to obtain the required intermediates. 

Step 3: Intermediates are purified to obtain individual drug products via sedimentation, filtration, centrifugation, etc. 

Step 4: Physicochemical studies, reactor treatments, and purification are followed by scale-up contract manufacturing services. Scale up is generally defined as the process of increasing batch sizes. In process scale up, a formula is transformed into a viable, robust product by the development of a reliable and practical method of manufacturing that affects the orderly transition from laboratory to routine processing in a full-scale production CDMO facility. This is explored in detail in the subsequent question. 

Steps 1 through 4, the development of drug substances via contract manufacturing services, are usually followed by packaging selection, discovery, and development services, and finally commercialization. 

Q3. How can drug substances be developed from milligram procedure to Kilogram process?

Custom synthesis services to go from preclinical to clinical development and then to commercial scale production can be challenging. The development process has to be carefully managed and clearly defined. This is achieved during the scale up phase of API & molecule development. 

Pharmaceutical process scale-up deals with a subject vitally important to the contract research & development industry—the procedures of transferring the results obtained via discovery and development services, explored above, from laboratory scale to the pharmaceutical pilot unit, and finally to production scale. Fully integrated contract manufacturers, for API and molecule development, have the custom synthesis expertise to provide scale up services at the laboratory and pilot scale of drug development

- Laboratory Scale: The early stage development phase, generally 100-1000 times lesser in quantity (milligrams) as compared to the production batch, takes place during the laboratory scale stage of formulation scale-up. 

- Pilot Plant: It is used to test the behavior of a product during small scale custom API development and manufacturing, before proceeding with large scale production. Pilot labs often use kilo lab units to achieve low volume, test batches of active pharmaceutical ingredients.It is also an important stage for hazard identification and toxicity testing of drug products in a quality controlled testing laboratory. The pilot plant stage is where a lab scale formula is transformed into a viable product by using practical custom synthesis services and manufacturing procedures. 

Production Scale: The last stage of scale-up (kilogram stage) is the production scale. Production batches are referred to as the 100X batch and this is the scale at which fully integrated contract research organizations, and more importantly contract development and manufacturing organizations, run during routine marketing of product.

Q4. What is the role of quality by design (QbD) approach in drug substance development and manufacturing?

Quality by design studies, which can be applied to a wide range of drugs, are usually implemented during the pilot plant stage of drug substance development. This discovery & development service can be used to validate analytical methodology, assess variability, perform method optimization of sample collection time intervals, and provide other information in a small number of subjects before proceeding with a full-scale bioequivalence study prior to commercialization.

The role of quality by design (QbD) in drug substance development and manufacturing

Quality by design processes permit derisked scale up during drug substance development and manufacture with process optimization. When we look at the quality by design (QbD) approach, quality signifies the suitability of a drug substance for its intended use and includes attributes such as the identity, strength, and purity of products.

Significance of QbD:

- Ensures predefined standards of quality.

- Enables custom synthesis expertise 

- Ensures product quality with effective control strategies.

Benefits of QbD:

- Eliminates batch failures during custom API development and manufacturing.

- Minimizes deviations and costly investigations.

- Enables regulatory intelligence monitoring.

- Enables better drug substance development and manufacturing decision making.

- Invests in future activities.

- Functions as small scale feasibility studies.

Q5. What is the difference between a chemical synthetic drug and a biologic drug substance?

Active pharmaceutical ingredients based on its sources can be divided into two major categories, including chemical synthetic drugs and natural chemical drugs.

Chemical Synthetic Drug:

A drug is typically manufactured through chemical synthesis, which means that it is made by combining specific chemical ingredients in an ordered process. The steps outlined in the custom synthesis of APIs, in question two, pertain to chemically synthesized APIs, whereas biologically sourced APIs are produced via fermentation

Non-biologic, conventional drugs, increasingly called "small-molecule drugs," have an easily identifiable structure that can be replicated with 100% confidence in scores of manufacturing sites, across the globe.

Biologic Drug Substance:

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules. Many biologics are produced using recombinant DNA technology

Biologics are medications targeted to specific genotypes or protein receptors and can cost thousands of dollars monthly and require special handling, as they are often less stable than chemically derived drugs and require controlled temperature and light, as well as protection from jostling when in liquid form.

Natural chemical drugs, based on its sources, can be divided into two categories including biochemical drugs and plant chemical drugs. Antibiotics are generally made by microbial fermentation, which is a biochemical process. 

Q6. What are the various considerations for biologic drug substance and drug product testing?

Ways to Ensure Regulated and Quality Controlled Development and Manufacture of Drug Substances:

In the context of globalization, APIs are sourced in a worldwide market and the risk of sourcing substandard or contaminated products is high. A proper system of regulation for drug substance development services can promote the constant sourcing of active ingredients of appropriate quality and thereby safeguard public health interests.

Biological drug development consists of two fundamental components: the drug substance (DS) development, which can include custom API manufacture, process development, and scale-up; and the drug product (DP) development, which includes the filling of the drug substance into the primary container. 

Biological drug substances and drug products are assessed on the basis of preset standards set by regulatory agencies like the FDA and ICH against the development and manufacture of drug substances. Furthermore, cGMP guidelines for custom API development and manufacturing as well as other drug substance development services, can be used to ensure the quality APIs or drug substances.

Another standard, set by the FDA, that is used to assert the quality of APIs is the process validation guideline, which covers early drug substance development services through to finished dosage form (FDF) assessments. 

As seen above, a significant part of the quality of a finished pharmaceutical product (FPP) is dependent on the quality of the active pharmaceutical ingredients (APIs). Therefore, it is important for companies (in-house manufacturers and contract manufacturers) to adopt the outlined strategies and comply with the regulations imposed on the development and manufacture of drug substances, to ensure not only the quality of the starting materials, but the overall quality of the end product that ultimately reaches consumers.

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