| CAS No.: | 330936-69-1 |
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| Formula: | C119h204n34o32s2 |
| EINECS: | 330936-69-1 |
| Type: | Peptide API |
| Appearance: | Powder |
| Quality: | Pharma Grade |
| Samples: |
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| Customization: |
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Upstream peptide synthesis
Zhaobo Bio production plants are endowed with state-of-the-art equipment for solvent supply, peptide synthesis, purification and isolation of active ingredients and intermediates. All equipment and containment is GMP qualified and cleaning validated. Overlapping capacities and sizes of different equipment trains facilitate a smooth scale-up for increases in demand within the product life cycle.
Downstream purification and isolation of peptides
Zhaobo Bio is committed to the systematic expansion and modernization of its purification equipment in order to ensure the efficient production of ever-increasing amounts of bulk peptide pharmaceuticals.
It uses sophisticated methods for large scale purification campaigns such as preparative high performance liquid chromatography (HPLC), ion exchange (IEX), size-exclusion chromatography (SEC), and ultra-filtration (UF/TFF). The equipment in place permits highly efficient or even continuous manufacturing of extremely pure products up to multi-kg quantities per lot.
For preparative HPLC, dynamic axial compression (DAC) stainless steel columns of up to 60 cm diameter both in batch and continuous mode are packed with the appropriate high performance silica separation phase. For low-pressure chromatography columns up to 80 cm diameter are available. Solvent delivery is ensured from eluent tank farms and containers.
The control of microbiological contamination is a prerequisite for API manufacturing. Class D (ISO 8) and C (ISO 7) clean rooms are supplied via HEPA-filtered, temperature and humidity controlled air, down-flow booths are used for minimizing microbial contamination and protecting operators. Highly active pharmaceutical ingredients are handled in integrated safety workbenches or flexible isolators reaching OEB level 4 (1-10 µg/m3).
Predefined physicochemical properties of the API can only be achieved by a carefully controlled isolation process. Besides precipitation and crystallization, lyophilization of intermediates and final API is a standard unit operation. LaixingPharma have multiple lyophilizers in different sizes (up to 300 liters) located in clean rooms.
| Can you synthesize peptides with post-translational modifications? |
| Yes, we can synthesize peptides with a variety of modifications including post-translational modifications (PTMs). Some of the post-translational modifications that we can perform as a part of our peptide manufacturing services are: Acetylation Cyclizations (including disulfide bonding, stapling) Fatty Acylation Glycosylation Hydroxylation Incorporation of D-Amino Acids and Unnatural Amino Acids Methylation Pegylation Phosphorylation Questions? Feel free to contact us or request a quote for your upcoming peptide project today. LexinPharma has extensive experience in synthesizing peptides containing these modifications in scales up to late-clinical and commercial stages. |
| Do you make peptides as a starting material for radiolabeled peptides? |
| LexinPharma can manufacture chelator-modified peptides as a starting material for radiolabeled peptides or peptide radiotracers. Some examples include synthesis of DOTA/NODAGA-functionalized peptides. These peptides are then often later radiolabeled with 68Ga or 177Lu and used for tumor imaging for diagnosis and therapy or theranostics such as peptide receptor radionuclide therapy (PRRT). Other modifications include peptides modified with di-iodo-Tyr, dehydro-Leu, or dehydro-Pro for reductive tritiation, peptide resin for N-terminal capping with C14-acetic anhydride, and peptides modified for click chemistry introduction of radioactive fluorin-e isotopes. Contact us to learn more about our capabilities in peptide synthesis. |
| What synthesis approach should be taken for a toxicology (tox) and Phase I batch? |
| There are typically 2 approaches for a tox and Phase I batch. Here are a few guidelines: Two batch approach: A tox batch (nonGMP with batch records, additional release testing, and purposefully targets a lower purity) for a GLP tox study, followed by a cGMP clinical batch for a Phase 1 clinical trial (that has a higher purity than the tox batch & sets individual related substance limits based on the tox lot). One batch approach: A single cGMP batch to be used for both tox and Phase 1 that will have identical impurity profiles. There are advantages and disadvantages to be considered for each scenario. Have more questions? Our experienced staff would be happy to help you determine the type of strategy that your project needs. |
| When do I need cGMP peptides? |
| A question we often get asked is when do I need cGMP peptides? Here is a guideline: Preclinical studies: research grade peptide (nonGMP) is sufficient for nearly all cases. Toxicology (tox) batch: If there are no plans for use of the batch in Phase I studies, research grade (nonGMP) material is acceptable, though batch records and additional release testing are recommended. If the tox batch will also be used in later clinical studies, cGMP grade is required. There are advantages and disadvantages to each scenario. While not a "requirement", it is recommended to use lower purity material for tox as the related substances from the tox batch will become the basis for related substance limits in subsequent cGMP batches (related substances limits that are set tight due to the constraints of an overly pure tox batch can reduce yield and drive up costs of the subsequent cGMP batches). Phase I and beyond: cGMP peptide is required. |
| Which salt form should I choose for my peptide? |
| When developing your peptide, you will need to select a salt form which is acceptable for your future clinical studies or desired application. Most peptides form salts if they contain a free amino group (found in a free N-terminus or on a side chain that has a free amine, for example, Arg, Lys, and His). In early research and development, many peptides are used as the trifluoroacetate (TFA) salt. This is because a TFA salt is typically formed due to exposure to a TFA/H2O buffer system in reverse phase high-performance liquid chromatography (HPLC) purification. In solid phase peptide synthesis (SPPS), the peptide may also be exposed to TFA during the cleavage of the peptide from the resin support. The TFA salt can be converted to another salt form (such as acetate or HCl) through ion exchange in subsequent step. Acetate salts are usually the most common counterion choice and preferred in later development over and HCl and TFA salts. They are also chosen because they usually result in a better lyophilizate cake, in contrast to some difficult to handle, "fluffy" peptides that may result from TFA salts. TFA salt may also induce undesirable immune responses during clinical trials, although two FDA-approved drugs are on the market as TFA salts, bivalirudin and corticoreli-n, with no issues. You might consider starting out with an acetate salt form to avoid having to make a change later in your product development. On the other hand, certain amino acid side chains may influence which counterion is better suited for the stability of your product. A sodium salt (Na+) is useful for peptides with acidic isoelectric points (pI) as with those containing several Asp and Glu, as well as a C-terminal acid. In many cases, peptides with free sulfhydryl groups as HCl salts have better stability against potential oxidation impurities. Similarly, salt form choice may impact peptide solubility. In addition, salt form can also play a role in secondary structure, with some anions inducing or suppressing helical structures and have also been seen to affect fibril formation and stability in peptides such as amyloid beta-protein (Aß). Careful peptide salt form consideration from the beginning may result in a cost savings later down the road. The team at LexinPharma is also here to help you as you choose a salt form most appropriate for your research and development needs. |
| What does cGMP mean? |
| cGMP refers to the current Good Manufacturing Practice regulations enforced by the U. S. Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. The regulations are in 21 CFR, parts 210 and 211. The purpose of these regulations is to assure the identity, strength, quality, and purity of drug products by requiring that peptide manufacturers adequately control manufacturing operations. This includes excellent quality management systems, robust peptide supply chain management and risk mitigation, obtaining high-quality raw materials, establishing and validating operating procedures (SOPs), detecting and investigating product quality deviations, and maintaining validated quality control testing laboratories. |
| What quality control data do you provide for non-GMP grade peptides? |
| Quality control (QC) data provided with every non-GMP grade peptide includes mass spectral (MS) and HPLC analyses determining composition and purity. Amino acid analysis (AAA) and peptide content are available upon request with an added cost for each test. We also provide storage and handling guidelines. Please see "What data is provided on the Certificate of Analysis (CoA)?" for a thorough description of all QC data which is available for both Non-GMP and cGMP peptides. |
| What is the advantage of capping the N and C termini of the peptide? |
| cGMP refers to the current Good Manufacturing Practice regulations enforced by the U. S. Food and Drug Administration (FDA) Acetylation or capping of the N-terminus will make a peptide appear more like native protein. It also helps to minimize amino peptidase degradation of the peptide. Amidation of the C terminus also helps to stabilize the peptide from carboxypeptidase degradation. |
| What does cGMP mean? |
| cGMP refers to the current Good Manufacturing Practice regulations enforced by the U. S. Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. The regulations are in 21 CFR, parts 210 and 214. The purpose of these regulations is to assure the identity, strength, quality, and purity of drug products by requiring that peptide manufacturers adequately control manufacturing operations. This includes excellent quality management systems, robust peptide supply chain management and risk mitigation, obtaining high-quality raw materials, establishing and validating operating procedures (SOPs), detecting and investigating product quality deviations, and maintaining validated quality control testing laboratories. |
| What purity percentage is required? |
| The required peptide purity percentage depends on your specific application. LexinPharma can synthesize peptides up to >98% purity. These are some general guidelines for peptide purity requirements: Purity Peptide Application or Use >80% Immunological applications and polyclonal antibody production >90%* Structure-Activity Relationships (SAR) studies, bioassays >95%* In vitro bioassays and in vivo biological activity tests, Ph I and early Ph II >98% Pharma-cGMP material with set impurity specifications (late PH II - Ph III and commercial) *For peptides utilized for Toxicology studies, it is recommended to have specifications for purity on the lower end, perhaps from 90 - 95%. |
| Do you provide cGMP-grade peptides? |
| cGMP peptide development and synthesis is the core of our business. LexinPharma provides large-scale cGMP peptide services with capacity up to 100 kilograms per project. Our comprehensive experience and capacity for cGMP-grade synthesis of new chemical entities (NCEs) or generic peptides (G-Rx) is unique in our industry. We partner from early preclinical studies through clinical evaluations and final commercial production. |
| What is the maximum peptide length you can synthesize? |
| We can synthesize peptides of lengths up to ~80 residues. Peptide lengths of 10 to 70 residues can usually be made by direct solid phase peptide synthesis (SPPS) chemical synthesis. Depending upon the scale and future requirements, combined strategies of using solution fragment condensation or even hybrid methods involving solid-phase couplings of protected peptide fragments may be developed specifically for each product. We also can utilize native chemical ligation (NCL) to make longer peptides and potentially mini-proteins using fully deprotected peptide fragments with an N-terminal Cys residue and another fragment containing a C-terminal thioester. While we have successfully manufactured peptides >80 residues, peptides greater than 80 amino acids are often more viably manufactured via a recombinant synthesis. On the other hand, peptides with 2-10 amino acids are often manufactured by solution or liquid phase peptide synthesis (LPPS). |
| What causes delays in peptide delivery? |
| Peptide production is unpredictable because every peptide sequence is unique. Each has specific characteristics depending upon the residues present and the difficulties which they may present. Unfortunately, this can result in delays in delivery as we must fine-tune a successful process and to prevent or circumvent these problems, in order to deliver a peptide with the quality that you expect. The scientists at AmbioPharm have experience in many types of peptides and many different peptide synthesis strategies, but sometimes a particular sequence can still require fine-tuning and additional process development. Sharing your prior experience with a specific peptide in advance can help us avoid synthesis difficulties or delays. In addition, unforeseen supply chain delays can affect delivery times. We try to procure reagents to avoid these types of delays. We provide weekly updates to all of our partners to keep them informed of our progress and any unanticipated delays which we may encounter. |
| What methods do you use to synthesize peptides? |
| We typically use Fmoc-tBu solid-phase peptide synthesis (SPPS), but we are also very skilled in the art of classical (solution phase or liquid phase peptide synthesis (LPPS)), and hybrid synthesis methods. Hybrid synthesis technology utilizes fully protected peptide fragments that are coupled onto resin-bound peptide fragments. For very long peptides, we may even consider native chemical ligation (NCL) approaches. |
| What is the best way to dissolve peptides? |
| The solubility of a given peptide varies depending on its amino acid sequence and modifications. LexinPharma purifies peptides by RP-HPLC using a water and acetonitril-e gradient. Here are some general tips for dissolving peptides: Sonication increases solubility. 10% acetic acid in the solvent will help dissolve basic peptides (Isoelectric Point, PI >7). 10% ammonium bicarbonate will help dissolve acidic peptides. (PI <7) For very hydrophobic peptides which are sparingly soluble in aqueous solutions, water-miscible organic solvents (such as dimethyl sulfoxide (DMSO), isopropano-l, methano-l, and acetonitril-e) should be used first. Once the peptides are completely dissolved, water may be gradually added until the desired concentration is obtained. |
| How should you store peptides? |
| We recommend that lyophilized peptides be stored long-term at -20°C. For peptides containing oxidation sensitive residues such as Cys, Met or Trp, we recommend storing under an inert atmosphere of N2 as well. |
| How is theoretical net peptide content calculated? |
| Theoretical net peptide content (calculated assuming that counterions are the only non-peptide components present in your peptide sample) can be estimated by dividing molecular weight (MW) of the peptide by a sum of this molecular weight and a number of trifluoroacetate (TFA) or acetate (AcO-) counterions that are required to neutralize the peptide multiplied by the molecular weight of the TFA counterion (MW= 114) and the AcO- counterion is (MW= 59). For example, a synthetic peptide with a TFA salt and a MW= 1000 with a free N-terminal amino group and one Lys has theoretical net peptide content of 1000 / (1000 + (2 x 114)) = 1000/1228 =0.81 or 81%. This example peptide has 2 positions for the TFA salt to bind, hence the 2×114. Theoretical net peptide content formula: (peptide MW)/(peptide MW + (#bound salts x salt MW)) Counterions are not the only potential non-peptide components in the peptide sample. It can also contain residual water, adsorbed solvents and traces of other substances. As a result, the actual net peptide content is usually determined by either elemental analysis (N2 content) or quantitative amino acid analysis. |
| What is net peptide content? |
| It is important to understand the difference between net peptide content and total (gross) peptide content. The lyophilized peptide powder shipped to you usually contains not only peptide, but also some other substances such as water, adsorbed solvents, counterions and salts. The total peptide content refers to the weight of this mixture (Gross Weight). Net peptide weight indicates the actual weight of only the peptide component of your sample. In most peptides, net peptide content is usually 60-90% of the total peptide weight (also called gross peptide weight) and is usually determined by elemental analysis, amino acid analysis (AAA) or UV spectrophotometry. In the case of peptides purified by reverse-phase High Performance Liquid Chromatography (RP-HPLC), the buffer used (typically TFA/H2O) contributes a salt to any free amine groups within the peptide. Salt forms can be exchanged by ion-exchange. The vast majority of peptide APIs are produced as acetate salts. Net peptide content should not be confused with purity. Purity defines the percentage of the target peptide sequence in the peptide component of your sample. In concentration calculations, it is important to consider peptide content. |
| What peptide purification methods do you use? |
| Theoretical net peptide content (calculated assuming that counterions are the only non-peptide components present in your In most cases, we use preparative RP-HPLC for peptide purification. Occasionally, ion exchange chromatography (IEX) may be utilized as well. IEX is particularly useful in the case of pegylated peptides for removal of the free, unreacted PEG. Additionally, size exclusion (SEC) may be used to remove high-molecular-weight impurities and polymers such as with multi-disulfide peptides. |
| What is the typical purity percentage of custom peptides? |
| At LexinPharma, the purity percentage of custom peptides is set by our partner's specification. Typically, many researchers choose >95% by reverse-phase High Performance Liquid Chromatography (RP-HPLC or rHPLC). This means that 95% of the NET PEPTIDE content (but not the total peptide content, see "What is net peptide content?") of the lyophilized powder shipped to you is composed of your target peptide. The other 5% of the PEPTIDE material in your sample is usually composed of the deletion and/or addition sequences that sometimes co-elute with the target peptide. These deletion and addition sequences are generated during peptide synthesis due to the inefficiencies of coupling certain amino acids (typically β-branched residues (Ile, Val and Thr) or those with bulky protecting groups (Arg, Gln, Cys and Asn) are either missing or sometimes duplicated) in some of the synthesized molecules. Purity is usually determined by reverse-phase HPLC. We have the ability to meet any purity percentage which you may desire. |
| What data is provided on the Certificate of Analysis (CoA)? |
| For all non-GMP grade peptides, your CoA containing information such as amino acid sequence, modifications, purity, mass spectral data, and RP-HPLC (reversed-phase high-performance liquid chromatography) data will be provided. Additional data may be reported as well, such as amino acid analysis, peptide content, bioburden, endotoxin, water content, counter ion content, etc. if these have been requested in advance as quoted services in addition to our standard package. For GMP services, the CoA is much more comprehensive. A typical CoA for a cGMP peptide will contain the following data and customer-supplied specifications, including aspect or appearance, molecular weight by MS, purity by RP-HPLC or UPLC, specified impurities, unspecified impurities, total impurities, peptide content by elemental analysis, water content (Karl Fischer), counterion content by ion chromatography, amino acid analysis, mass balance, bioburden and endotoxin results. Other services can be requested, such as MS-MS sequencing, NMR, impurity synthesis and spiking studies, method development and validation, process development and optimization, etc. |
| What is the typical lead time for non-GMP custom peptide synthesis? |
| Our typical lead time for custom peptide synthesis is about three to four weeks. The lead time may vary depending on the peptide length and complexity of synthesis. For cGMP synthesis, the lead times are considerably longer due to the QA and QC activities associated with this work. |
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