{"id":24160,"date":"2024-07-25T12:49:07","date_gmt":"2024-07-25T16:49:07","guid":{"rendered":"https:\/\/www.drugpatentwatch.com\/blog\/?p=24160"},"modified":"2026-10-06T21:02:22","modified_gmt":"2026-10-07T01:02:22","slug":"how-to-find-key-starting-materials-ksms-for-pharmaceutical-apis","status":"publish","type":"post","link":"https:\/\/www.drugpatentwatch.com\/blog\/how-to-find-key-starting-materials-ksms-for-pharmaceutical-apis\/","title":{"rendered":"How to Find Key Starting Materials (KSMs) for Pharmaceutical APIs: The ICH Q11 Sourcing Playbook"},"content":{"rendered":"\n
\"\"<\/figure>\n\n\n\n

FDA’s 2018 ICH Q11 Questions and Answers document says that a custom-synthesized chemical stays custom-synthesized for filing purposes, even after several suppliers begin to sell it [2]. A regulator will not treat a chemical as a commodity just because you can buy it from more than one vendor. This one rule changes how you search for a key starting material (KSM).<\/p>\n\n\n\n

Most guides on KSM sourcing start with supplier lists. That order is wrong. You must first decide where your API process begins in the regulatory file. Then you look for a manufacturer that can supply that exact material. This guide covers both jobs, with the regulatory text, the master-file mechanics, and the supply-chain data that apply to each.<\/p>\n\n\n\n

The Short Answer: How Do You Find a KSM for a Pharmaceutical API?<\/strong><\/h2>\n\n\n\n

You find a KSM in two stages. First, you select and justify the compound that your process will treat as the starting material, using the general principles in ICH Q11 [1][2]. Second, you locate, qualify, and contract a manufacturer of that compound, using regulator-published lists, master files, and direct supplier outreach.<\/p>\n\n\n\n

Four points summarize the method:<\/p>\n\n\n\n

    \n
  • The regulatory term is “starting material” (ICH Q11) or “API starting material” (ICH Q7). “KSM” is the industry term [1][2].<\/li>\n\n\n\n
  • You must test every candidate against all of the Q11 principles, not against a few of them [2].<\/li>\n\n\n\n
  • A supplier’s master file shows what the supplier told a regulator. It does not give you access to that information unless the holder authorizes it [3].<\/li>\n\n\n\n
  • You stay responsible for the quality of purchased materials, even when a supplier holds the master file [2].<\/li>\n<\/ul>\n\n\n\n

    What Is a Key Starting Material (KSM) in Pharmaceutical Manufacturing?<\/strong><\/h2>\n\n\n\n

    A KSM is the compound from which the regulated part of an API manufacturing process begins. The ICH Q11 text that we reviewed uses the term “starting material” and does not define “KSM” in its glossary [1]. Indian government documents use “KSM” for the same concept [7].<\/p>\n\n\n\n

    KSM vs. API Starting Material vs. Intermediate vs. Reagent<\/strong><\/h3>\n\n\n\n

    Four terms cause most of the confusion. The list below gives the working definition of each.<\/p>\n\n\n\n

      \n
    • Starting material (Q11) and API starting material (Q7): FDA states that these two terms refer to the same material [2]. ICH Q7 describes an API starting material as a raw material, an intermediate, or an API that is used to produce an API [2].<\/li>\n\n\n\n
    • Drug substance intermediate: a material produced during the processing of an API that undergoes further molecular change or purification before it becomes the API [3].<\/li>\n\n\n\n
    • Reagent: Q11 treats commonly available chemicals that are used to make salts, esters, or other simple derivatives as reagents [1].<\/li>\n\n\n\n
    • Significant structural fragment: a starting material must contribute such a fragment. This phrase separates starting materials from reagents, solvents, and other raw materials [1].<\/li>\n<\/ul>\n\n\n\n

      Why GMP Begins at the Starting Material<\/strong><\/h3>\n\n\n\n

      ICH Q7 GMP provisions apply to each branch of a drug substance process from the first use of a starting material [1]. Steps before that point are not under Q7. Because of this, the choice of starting material also sets the boundary of GMP inspection and of the change control that applies.<\/p>\n\n\n\n

      What Changes at the GMP Boundary<\/strong><\/h4>\n\n\n\n

      An EMA reflection paper from 2017 said that production of the API starting material was, at that time, outside the EU GMP Guide and had no regulatory framework for inspection [5]. That paper is now marked “no longer valid” [5]. Check the current EMA position before you rely on it. The practical point stays the same: upstream steps get less regulatory oversight, so the applicant must carry more of the risk control through the supplier relationship.<\/p>\n\n\n\n

      The Seven Findings That Matter<\/strong><\/h2>\n\n\n\n

      These findings are written to stand alone. Each has a source. Findings 6 and 7 include figures that we calculated, and we mark them as analysis.<\/p>\n\n\n\n

        \n
      1. Finding 1. The ICH Q11 “starting material” and the ICH Q7 “API starting material” are the same material, according to FDA’s 2018 Q&A guidance [2].<\/li>\n\n\n\n
      2. Finding 2. Availability from several suppliers is not enough to make a chemical “commercially available” under Q11. The Q&A says this holds even when a custom-synthesized chemical becomes available from multiple suppliers over time [2].<\/li>\n\n\n\n
      3. Finding 3. An applicant must consider all of the Q11 general principles for starting material selection. If a proposed material does not meet all of them, the applicant must give a rationale [2].<\/li>\n\n\n\n
      4. Finding 4. Adding purification steps before a proposed starting material, so that an earlier compound is not defined as the starting material, is not considered appropriate [2].<\/li>\n\n\n\n
      5. Finding 5. FDA does not independently review or approve a drug master file (DMF). It reviews the technical content only when an application references the DMF and the holder has submitted a letter of authorization [3].<\/li>\n\n\n\n
      6. Finding 6. India’s PLI scheme for KSMs, drug intermediates, and APIs covers 41 products with an outlay of Rs 6,940 crore for FY2020-21 to FY2029-30 [7]. Analysis: this is an average of about Rs 169 crore per product and about Rs 694 crore per fiscal year (calculation in the methodology section).<\/li>\n\n\n\n
      7. Finding 7. Of 3,804 DMFs registered in Japan at the time of one published analysis, 63.46% came from foreign manufacturers [10]. Analysis: that is about 2,414 foreign DMFs and about 1,390 domestic DMFs.<\/li>\n<\/ol>\n\n\n\n

        Methodology: What We Reviewed and What We Calculated<\/strong><\/h2>\n\n\n\n

        We reviewed the documents below. We read the full text of the first four.<\/p>\n\n\n\n

          \n
        • FDA, ICH Q11 guidance (November 2012) [1].<\/li>\n\n\n\n
        • FDA, ICH Q11 Questions and Answers guidance (February 2018) [2].<\/li>\n\n\n\n
        • FDA, Drug Master Files guidance, draft Revision 1 (October 2019) [3].<\/li>\n\n\n\n
        • EMA, reflection paper on starting materials (Corr. 1, 3 July 2017) [5].<\/li>\n<\/ul>\n\n\n\n

          We also reviewed FDA and EDQM web pages [4][6], an Indian Department of Pharmaceuticals press note [7], two Indian rating-agency publications [8][9], a Japanese DMF analysis [10], and three commercial or industry pages [11][12][13].<\/p>\n\n\n\n

          Source selection: we used regulator and government documents first. We used rating-agency and trade sources only for market figures that no primary document gave us. We counted the principles in Q11 section 5.1.1 as the number of separate bullet points in the FDA text.<\/p>\n\n\n\n

          Calculations (all labeled as analysis where they appear):<\/p>\n\n\n\n

            \n
          • Average outlay per PLI product: Rs 6,940 crore divided by 41 products = Rs 169.3 crore.<\/li>\n\n\n\n
          • Average outlay per fiscal year: Rs 6,940 crore divided by 10 fiscal years (FY2020-21 through FY2029-30) = Rs 694 crore.<\/li>\n\n\n\n
          • Foreign DMFs in Japan: 3,804 multiplied by 0.6346 = 2,414 (rounded). Domestic: 3,804 minus 2,414 = 1,390.<\/li>\n\n\n\n
          • Share of shortage problems tied to API shortage: 21 divided by 46 = 45.7%.<\/li>\n\n\n\n
          • Value of bulk drug imports: 55% of USD 7.9 billion = about USD 4.3 billion.<\/li>\n\n\n\n
          • Value of API imports from China: two-thirds of Rs 35,000 crore = about Rs 23,300 crore.<\/li>\n<\/ul>\n\n\n\n

            Limits: DMF contents are confidential, so we did not see any supplier’s actual file. We did not analyze the route of any single drug. The FDA DMF guidance that we reviewed is marked as a draft. The market figures are for bulk drugs and intermediates as a group, not for KSMs alone. This article is not legal or regulatory advice. Information is current to October 6, 2026, to the extent that the sources allow.<\/p>\n\n\n\n

            How Does ICH Q11 Tell You to Select a Starting Material?<\/strong><\/h2>\n\n\n\n

            ICH Q11 section 5.1.1 lists six general principles for synthetic drug substances [1]. The guidance states that you must weigh them together and must not apply any one of them alone [1]. The Q&A repeats this and says that choosing just a few principles to justify a selection is not acceptable [2].<\/p>\n\n\n\n

            Principle (Q11 section 5.1.1)<\/th>Plain meaning<\/th>Source<\/th><\/tr><\/thead>
            Early changes carry less risk<\/td>Changes near the start of the process are less likely to affect drug substance quality than changes near the end.<\/td>[1]<\/td><\/tr>
            Enough process is described<\/td>The file must show how impurities form, how process changes affect them, and why the control strategy works. This normally means multiple chemical transformation steps.<\/td>[1]<\/td><\/tr>
            Steps that affect impurities are in the file<\/td>Steps that affect the impurity profile belong in the process description in CTD section 3.2.S.2.2.<\/td>[1]<\/td><\/tr>
            GMP from first use<\/td>Q7 GMP applies to each branch from the first use of a starting material.<\/td>[1]<\/td><\/tr>
            Defined structure<\/td>A starting material has defined chemical properties and structure. Non-isolated intermediates are usually not appropriate.<\/td>[1]<\/td><\/tr>
            Significant structural fragment<\/td>The material becomes a significant part of the drug substance structure. Simple salt or ester formers are reagents.<\/td>[1]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

            Principle 1: Does the Step Affect the Impurity Profile of the Drug Substance?<\/strong><\/h3>\n\n\n\n

            Q11 ties risk to the distance from the end of the process. The reason has two parts, and the next two subsections cover them.<\/p>\n\n\n\n

            Why Early Steps Carry Less Risk<\/strong><\/h4>\n\n\n\n

            The physical properties of a drug substance are set during the final crystallization and the operations after it, such as milling and micronizing [1]. Impurities that form early have more chances to leave the process in washes and crystallizations of isolated intermediates [1]. Late impurities have fewer chances to leave.<\/p>\n\n\n\n

            When the Distance Rule Bends<\/strong><\/h4>\n\n\n\n

            Q11 notes an exception for peptides and oligonucleotides that are made on a solid support. In those processes, the link between risk and the number of steps from the end is more limited [1].<\/p>\n\n\n\n

            Principle 2: Is Enough of the Manufacturing Process Described?<\/strong><\/h3>\n\n\n\n

            Regulators must see enough of the process to judge impurity control [1]. The Q&A gives a three-part method to decide what “enough” means [2].<\/p>\n\n\n\n

            The Three-Part Method in the Q&A<\/strong><\/h4>\n\n\n\n

            First, identify the chemical transformation steps that affect the impurity profile. These normally go into section 3.2.S.2.2 [2]. Second, check the steps just upstream. Include them if they need narrow control to prevent impurity formation, or if they contain a unit operation added to control specific impurities [2]. Third, if only a few steps remain, add one or more chemical transformation steps. This puts more steps under GMP and lowers the risk from contamination and from later route or supplier changes [2].<\/p>\n\n\n\n

            Why the Q&A Sets No Minimum Step Count<\/strong><\/h4>\n\n\n\n

            The Q&A says ICH Q11 does not specify how many steps must run under GMP [2]. Q11 Example 4 has three chemical transformation steps between the proposed starting material and the drug substance. The Q&A states that three is not a threshold and is not mandatory [2]. The ICH Q11 glossary defines a chemical transformation step as a step in the synthesis of the drug substance structure from precursor fragments, and it typically involves C-X or C-C bond formation or breaking [1].<\/p>\n\n\n\n

            Principle 3: Is the Material Defined and Isolated?<\/strong><\/h3>\n\n\n\n

            Q11 says that non-isolated intermediates are usually not appropriate starting materials [1]. The Q&A confirms that the principles also apply when several transformations run without isolation, and it adds that process design and unit operations must then control and purge impurities [2].<\/p>\n\n\n\n

            Principle 4: Is the Material a Significant Structural Fragment?<\/strong><\/h3>\n\n\n\n

            The Q&A says that people often read this principle as “the starting material should look like the drug substance.” That reading is wrong [2]. The principle only separates starting materials from reagents, catalysts, solvents, and other raw materials [2]. The Q&A also says that a justification that rests only on this principle will probably not be accepted [2].<\/p>\n\n\n\n

            Principle 5: Where Does GMP Start in a Convergent Synthesis?<\/strong><\/h3>\n\n\n\n

            A convergent process has more than one branch. The Q&A says you apply the Q11 principles to each branch independently, unless the branches converge upstream of an appropriate starting material [2]. Each branch needs its own starting material and its own justification.<\/p>\n\n\n\n

            How Do Impurity Thresholds Decide Which Steps Belong in the File?<\/strong><\/h3>\n\n\n\n

            The Q&A gives numeric tests for what “affects the impurity profile” means [2].<\/p>\n\n\n\n

            Related Substances and the ICH Q3A Identification Threshold<\/strong><\/h4>\n\n\n\n

            For non-mutagenic related substances, an acceptance criterion above the ICH Q3A identification threshold means the impurity affects the profile [2].<\/p>\n\n\n\n

            Mutagenic Impurities and the 30 Percent Rule<\/strong><\/h4>\n\n\n\n

            For mutagenic impurities, the level of 30 percent of the ICH M7 acceptable limit marks the point above which the impurity affects the profile [2]. The Q&A states exceptions for cases where ICH M7 and ICH S9 do not require this evaluation, such as genotoxic drug substances and advanced cancer indications [2].<\/p>\n\n\n\n

            Steps That Use Mutagenic Reagents Can Sit Upstream<\/strong><\/h4>\n\n\n\n

            Not every step with a mutagenic reagent must be in section 3.2.S.2.2. The Q&A says a mutagenic compound can be introduced before the starting material, or can be the starting material, if the Q11 principles are met [2]. The same logic applies to steps that set regio- or stereochemistry [2].<\/p>\n\n\n\n

            Commercially Available vs. Custom-Synthesized: Which Starting Materials Need Justification?<\/strong><\/h2>\n\n\n\n

            An applicant generally need not justify a commercially available chemical as a starting material. A custom-synthesized chemical must be justified against the general principles [1][2]. Q11 describes a commercially available chemical as one sold as a commodity in a pre-existing non-pharmaceutical market, in addition to its use as a starting material [1]. Chemicals made by custom synthesis are not commercially available [1].<\/p>\n\n\n\n

            What the Q&A Adds on Custom Synthesis<\/strong><\/h3>\n\n\n\n

            The Q&A defines a custom-synthesized chemical in general terms. It is made to a drug substance manufacturer’s requirements, in-house or by an outside party, or it is sold but has only a pharmaceutical use [2]. The reference to a non-pharmaceutical market is meant to stop applicants from calling purchased intermediates “commercially available” [2].<\/p>\n\n\n\n

            Three further points apply. A commercially available chemical made on a small scale can be suitable if the scale is enough for the drug substance and the chemical is also used in a non-pharmaceutical market [2]. A commercially available starting material can enter late in the synthesis, even at the last chemical transformation [2]. A chemical with no non-pharmaceutical use may still be accepted if it has a simple structure, with protected natural amino acids as the example, and if the applicant gives a rationale [2].<\/p>\n\n\n\n

            A Four-Tier Framework for KSM Candidates (Original Framework)<\/strong><\/h3>\n\n\n\n

            The table below is our own classification. It is not an ICH or FDA classification. We built it from the Q11 and Q&A text so that sourcing teams can sort candidates before they contact suppliers.<\/p>\n\n\n\n

            Tier<\/th>Description<\/th>What the regulatory text requires<\/th>Source<\/th><\/tr><\/thead>
            Tier 1<\/td>Commodity chemical sold into non-pharmaceutical markets at scale<\/td>Generally no justification. Give name, formula, molecular weight, impurity profile, and the link between the specification and the control strategy.<\/td>[1][2]<\/td><\/tr>
            Tier 2<\/td>Small-scale chemical that also has a non-pharmaceutical market<\/td>Can be suitable if the scale is enough for the drug substance.<\/td>[2]<\/td><\/tr>
            Tier 3<\/td>Simple custom-synthesized or pharma-only chemical (example in the Q&A: protected natural amino acids)<\/td>May be accepted with a rationale and an impurity control strategy.<\/td>[2]<\/td><\/tr>
            Tier 4<\/td>Complex custom-synthesized intermediate<\/td>Full justification against all general principles, plus the synthesis flow chart and impurity data for the material.<\/td>[1][2]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

            What If Several Suppliers Now Sell a Custom-Synthesized Chemical?<\/strong><\/h3>\n\n\n\n

            The chemical stays in the custom-synthesized group. The Q&A says that availability from multiple suppliers cannot be the only basis for calling a chemical commercially available [2]. You still justify it against the general principles. In a supplier search, a long vendor list is therefore a sourcing advantage but not a regulatory argument.<\/p>\n\n\n\n

            Step-by-Step: How to Find KSM Candidates for Your API<\/strong><\/h2>\n\n\n\n

            The steps below follow the logic of Q11 and the Q&A. The steps themselves are our practice recommendations. The regulatory points inside them carry citations.<\/p>\n\n\n\n

            Step 1: Map the Commercial Synthetic Route<\/strong><\/h3>\n\n\n\n

            Draw the full route, with every isolated intermediate, reagent, catalyst, and solvent. The Q&A says you should designate starting materials based on process knowledge of the intended commercial process [2]. If you plan to change the route later, map that route too.<\/p>\n\n\n\n

            Check the patent position of each route while you draw it. Process and intermediate patents can limit which routes and which suppliers you can use. Patent databases such as DrugPatentWatch give patent and expiry data for the marketed drug. They do not tell you whether a supplier’s route is free to operate. Supplier directories also warn that they do not verify the intellectual property rights of listed suppliers [13].<\/p>\n\n\n\n

            Step 2: Mark Every Chemical Transformation Step<\/strong><\/h3>\n\n\n\n

            Use the Q11 glossary definition: a step that builds the drug substance structure from precursor fragments, typically by C-X or C-C bond formation or breaking [1]. Do not count a simple recrystallization as a transformation step for this purpose.<\/p>\n\n\n\n

            Step 3: Find the Steps That Affect the Impurity Profile<\/strong><\/h3>\n\n\n\n

            Apply the thresholds from the Q&A: the ICH Q3A identification threshold for related substances, and 30 percent of the ICH M7 limit for mutagenic impurities [2]. Record, for each impurity, how it forms, whether it reacts later, and where the process removes it. Q11 calls these formation, fate, and purge [1].<\/p>\n\n\n\n

            Step 4: Walk Back to Candidate Compounds<\/strong><\/h3>\n\n\n\n

            Start from the earliest step that affects the impurity profile. Then check the steps just upstream, using the Q&A method [2]. Mark each isolated, defined compound along the way as a candidate.<\/p>\n\n\n\n

            Step 5: Score Each Candidate Against All Principles<\/strong><\/h3>\n\n\n\n

            Use a scorecard. The scorecard below is our own tool. Each question comes from the Q11 text or the Q&A.<\/p>\n\n\n\n

            Scorecard question<\/th>Evidence you need<\/th>Source<\/th><\/tr><\/thead>
            Is the compound isolated and well defined?<\/td>Structure, characterization data, and an isolation step in the route<\/td>[1][2]<\/td><\/tr>
            Do steps upstream affect the final impurity profile?<\/td>Impurity fate and purge data against the Q3A and M7 thresholds<\/td>[2]<\/td><\/tr>
            Can analytical methods detect the impurities?<\/td>Validated methods in the starting material specification<\/td>[1][2]<\/td><\/tr>
            Are enough transformation steps under GMP?<\/td>A rationale for the number of steps, with the risk of supplier and route changes<\/td>[2]<\/td><\/tr>
            Was a purification step added only to move the boundary?<\/td>A process history that shows why each upstream unit operation exists<\/td>[2]<\/td><\/tr>
            Is the material commercially available or custom-synthesized?<\/td>Proof of a non-pharmaceutical market, or a full justification<\/td>[1][2]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

            Step 6: Write the Justification<\/strong><\/h3>\n\n\n\n

            Q11 says the applicant should explain how each starting material fits the general principles. The explanation can cover three items: the ability of analytical procedures to detect impurities in the material, the fate and purge of those impurities, and how the specification supports the control strategy [1]. The applicant also gives a flow diagram of the current synthetic route with the starting materials marked [1].<\/p>\n\n\n\n

            What to File for a Custom-Synthesized Material<\/strong><\/h4>\n\n\n\n

            Provide a flow chart of the starting material’s manufacturing process. It must show all reagents, catalysts, and solvents. Also provide information on actual and potential impurities in the material [2].<\/p>\n\n\n\n

            What to File for a Commercially Available Material<\/strong><\/h4>\n\n\n\n

            Provide the chemical name, formula, and molecular weight, plus the impurity profile and an explanation of how the drug substance control strategy supports the specification [2]. If the drug substance maker adds a purification step to get consistent quality, that step belongs in the process description. The file should then show specifications for both the incoming and the purified material [1][2].<\/p>\n\n\n\n

            Where Can You Find KSM Suppliers? Six Places to Look<\/strong><\/h2>\n\n\n\n

            Search several source types and rank them by how much a regulator or independent party has checked. The table lists each source and what it can and cannot show.<\/p>\n\n\n\n

            Source<\/th>What it can show<\/th>What it cannot prove<\/th>Source<\/th><\/tr><\/thead>
            FDA lists of DMFs<\/td>DMF holders, subjects, and types<\/td>That the DMF content is adequate for your use<\/td>[3][4]<\/td><\/tr>
            EDQM Certification Database<\/td>Granted CEPs: substance name, CEP number, issue date, validity status<\/td>Anything about a substance that has no Ph. Eur. monograph<\/td>[6]<\/td><\/tr>
            Regional master files (ASMF in the EU, DMF in Japan)<\/td>That a manufacturer has filed process data with a regulator<\/td>That you may read or use the file<\/td>[5][10]<\/td><\/tr>
            Commercial directories<\/td>Leads, with DMF numbers, status, and type, often copied from FDA data<\/td>Accuracy, completeness, or IP freedom<\/td>[12][13]<\/td><\/tr>
            DrugPatentWatch supplier and patent pages<\/td>Manufacturers, repackagers, relabelers, and private labelers for a product, and patent data<\/td>That a named company makes a given KSM<\/td>[11]<\/td><\/tr>
            Direct outreach to custom synthesis firms<\/td>Capability and capacity for a defined structure<\/td>Regulatory acceptability of the material as a starting material<\/td>[2]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

            FDA Drug Master File Lists<\/strong><\/h3>\n\n\n\n

            FDA publishes a list of DMFs. It also publishes a “List of Type II DMFs Available for Reference,” which holds DMFs that passed the completeness assessment and can be referenced by ANDAs under GDUFA [4]. FDA’s page describes the GDUFA fee and completeness provisions for Type II DMFs for APIs that support ANDAs. It does not mention intermediates in that passage [4].<\/p>\n\n\n\n

            Analysis: do not assume that the “available for reference” list covers KSM or intermediate DMFs. Ask FDA or the holder if you need confirmation.<\/p>\n\n\n\n

            Type II DMFs cover drug substances, drug substance intermediates, and materials used in their preparation, or drug products [3][4]. A Type II DMF should cover only one substance, and FDA asks for separate DMFs for drug substances that use different processes [3].<\/p>\n\n\n\n

            EDQM Certification Database for Ph. Eur. Substances<\/strong><\/h3>\n\n\n\n

            EDQM runs a Certification Database, updated daily, that you can search for granted CEPs [6]. A CEP applies to substances with a European Pharmacopoeia monograph. EDQM rejects applications for substances that are not in the Ph. Eur. [6]. If your candidate KSM has a Ph. Eur. monograph, the database can show who holds a CEP for it. For most custom-synthesized starting materials, the database will have no entry.<\/p>\n\n\n\n

            Regional Master Files: ASMF and Japanese DMFs<\/strong><\/h3>\n\n\n\n

            The EU uses the active substance master file (ASMF), and the 2017 EMA paper described ASMF holders as parties that must give enough data to justify starting materials [5]. In Japan, API makers file DMFs directly with the PMDA [10]. Master files protect a supplier’s confidential process. For you as a buyer, they show where a supplier has regulatory history. They do not replace your own supplier qualification.<\/p>\n\n\n\n

            Commercial Supplier Directories<\/strong><\/h3>\n\n\n\n

            Directories such as PharmaCompass list suppliers by compound. One PharmaCompass page that we reviewed shows DMF number, submission date, status, type, and GDUFA fields, and it names FDA’s website as the original data source [12]. Pharmaoffer, another directory, states that it does not guarantee the accuracy or completeness of supplier data, and that it does not assess the intellectual property rights of listed suppliers [13]. Treat directory entries as leads. Verify each one against the regulator’s list and with the supplier.<\/p>\n\n\n\n

            DrugPatentWatch Supplier and Patent Data<\/strong><\/h3>\n\n\n\n

            DrugPatentWatch is a patent and drug-intelligence database. Its product-level supplier pages list manufacturers, repackagers, relabelers, and private labelers [11]. The same page type describes supplier categories that include API manufacturers and API intermediate suppliers where upstream process patents apply [11]. DrugPatentWatch is not a KSM registry. Use it for patent and market context around the drug, such as expiry dates that set your supply timeline, and use primary regulatory sources for supplier evidence. The site also states that its data is informational and carries no warranty [11].<\/p>\n\n\n\n

            How Strong Is Each Source? An Evidence Ladder (Original Framework)<\/strong><\/h3>\n\n\n\n

            This ladder is our own framework. It ranks supplier evidence by who has verified it.<\/p>\n\n\n\n

              \n
            • Level 1: Regulator-published records, such as FDA DMF lists and the EDQM Certification Database [4][6].<\/li>\n\n\n\n
            • Level 2: Supplier-provided documents that you review, such as a letter of authorization, a route flow chart, and a certificate of analysis [2][3].<\/li>\n\n\n\n
            • Level 3: Third-party directories that republish regulator data or supplier claims [12][13].<\/li>\n\n\n\n
            • Level 4: Unverified leads, such as trade-show contacts or unsolicited quotes.<\/li>\n<\/ul>\n\n\n\n

              Move every candidate supplier up the ladder to Level 2 before you select it.<\/p>\n\n\n\n

              How Do You Qualify a KSM Supplier?<\/strong><\/h2>\n\n\n\n

              You qualify a supplier by getting the documents that prove the material, the route, and the change-notice duty, and by placing the supplier under your quality system. The Q&A states that ICH Q10 section 2.7 makes the pharmaceutical company ultimately responsible for outsourced activities and the quality of purchased materials [2].<\/p>\n\n\n\n

              Which Documents Should You Request?<\/strong><\/h3>\n\n\n\n

              Ask for these items:<\/p>\n\n\n\n

                \n
              • The manufacturing flow chart for the starting material, with all reagents, catalysts, and solvents [2].<\/li>\n\n\n\n
              • The specification and validated analytical procedures [2].<\/li>\n\n\n\n
              • Information on actual and potential impurities, including mutagenic and elemental impurities [2].<\/li>\n\n\n\n
              • A written agreement that the supplier will tell you about changes to the process, site, or specification [2].<\/li>\n<\/ul>\n\n\n\n

                Which Quality System Rules Apply?<\/strong><\/h3>\n\n\n\n

                The Q&A points to ICH Q7 sections 7 (Materials Management) and 13 (Change Control), and to ICH Q10 section 2.7, as guidance for managing starting materials and their suppliers [2]. It also says ICH Q9 risk management applies to changes such as a new supplier, a new process, or a new specification [2].<\/p>\n\n\n\n

                What Does a DMF Give You, and What Does It Not?<\/strong><\/h3>\n\n\n\n

                If your supplier holds a DMF, three mechanics matter to you.<\/p>\n\n\n\n

                The Letter of Authorization<\/strong><\/h4>\n\n\n\n

                FDA will not review a DMF until the holder submits a letter of authorization (LOA) for a specific application or another DMF [3]. The LOA lets FDA review the DMF and lets you reference it. The LOA does not give you permission to view the DMF [3]. You must ask the supplier separately for the information you need.<\/p>\n\n\n\n

                One DMF per Process<\/strong><\/h4>\n\n\n\n

                FDA asks for separate DMFs for drug substances made by different processes [3]. If your supplier uses a second process, check that your LOA names the DMF that matches the process you use.<\/p>\n\n\n\n

                Holder and Manufacturer<\/strong><\/h4>\n\n\n\n

                FDA generally expects the DMF holder to be the manufacturer. If it is not, the DMF should state that the holder takes full responsibility for the manufacture of the material [3]. Read the administrative section to see who actually makes your material and where. FDA also requires a holder to list each authorized party in the DMF, and to notify authorized parties of changes [3].<\/p>\n\n\n\n

                Annual Reports and Closure<\/strong><\/h4>\n\n\n\n

                Holders must submit annual reports. If a holder does not respond when FDA cannot be sure the DMF is current, FDA can close it [3]. A closed DMF cannot support a new or amended application, so you would have to replace its content [3]. Check the status of a DMF at each audit and each renewal of your supplier approval.<\/p>\n\n\n\n

                What Should a KSM Specification Contain?<\/strong><\/h2>\n\n\n\n

                A starting material specification includes tests for identity and purity [2]. The Q&A says the tests and limits must rest on process knowledge and the drug substance control strategy, and that the justification must weigh the ability of later steps to control or purge impurities [2].<\/p>\n\n\n\n

                Specification element<\/th>When to include it<\/th>Source<\/th><\/tr><\/thead>
                Identity<\/td>Always<\/td>[2]<\/td><\/tr>
                Purity and impurity controls<\/td>Always<\/td>[2]<\/td><\/tr>
                Assay<\/td>Where applicable<\/td>[2]<\/td><\/tr>
                Specified, unspecified, and total impurities<\/td>Where applicable; include criteria for unspecified impurities if few steps remain after the material<\/td>[2]<\/td><\/tr>
                Residual solvents, reagents, elemental impurities<\/td>Where applicable<\/td>[2]<\/td><\/tr>
                Mutagenic impurities<\/td>Where applicable, tested at the acceptable limit when above the 30 percent threshold<\/td>[2]<\/td><\/tr>
                Validated analytical procedures<\/td>Always<\/td>[2]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

                Q11 Example 4 shows one use. In the Example 5 control strategy table, the enantiomeric purity of starting material D is controlled with an S-enantiomer limit of not more than 0.50 percent in the starting material specification [1]. The example is fictional and illustrates the approach only [1].<\/p>\n\n\n\n

                KSM Supply Chain Risk: What Do the Numbers Show?<\/strong><\/h2>\n\n\n\n

                The public numbers show high import concentration for bulk drugs and intermediates in India, and a high share of foreign DMF holders in Japan. They do not give a KSM-only picture. The table collects the figures.<\/p>\n\n\n\n

                Metric<\/th>Value<\/th>Type<\/th>Source<\/th><\/tr><\/thead>
                Import dependence for some specific bulk drugs in India<\/td>80 to 100%<\/td>Reported (government)<\/td>[7]<\/td><\/tr>
                Share of API requirements that India imports<\/td>Almost one third<\/td>Reported (rating agency)<\/td>[8]<\/td><\/tr>
                API imports to India, FY2023<\/td>More than Rs 35,000 crore, two-thirds from China<\/td>Reported (rating agency)<\/td>[8]<\/td><\/tr>
                Chinese API imports in rupees<\/td>About Rs 23,300 crore<\/td>Analysis (two-thirds of Rs 35,000 crore)<\/td>[8]<\/td><\/tr>
                Bulk drugs as share of India’s pharma imports, FY23<\/td>About 55% of USD 7.9 billion<\/td>Reported (rating agency)<\/td>[9]<\/td><\/tr>
                Bulk drug imports, FY23, in dollars<\/td>About USD 4.3 billion<\/td>Analysis<\/td>[9]<\/td><\/tr>
                DMFs registered in Japan<\/td>3,804, of which 63.46% foreign<\/td>Reported<\/td>[10]<\/td><\/tr>
                Foreign DMFs in Japan<\/td>About 2,414<\/td>Analysis<\/td>[10]<\/td><\/tr>
                FY2013 drug shortage problems in Japan linked to API shortage<\/td>21 of 46 (45.7%)<\/td>Reported counts; share is analysis<\/td>[10]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

                What Does India’s Government Say About KSM Import Dependence?<\/strong><\/h3>\n\n\n\n

                India’s Department of Pharmaceuticals launched a PLI scheme to make critical KSMs, drug intermediates, and APIs inside India. Its December 2021 press note gives the reason in one sentence:<\/p>\n\n\n\n

                \n

                “In some specific bulk drugs, the import dependence is 80 to 100%.” (Government of India, Department of Pharmaceuticals, 2021) [7]<\/p>\n<\/blockquote>\n\n\n\n

                The scheme runs for FY2020-21 to FY2029-30 with an outlay of Rs 6,940 crore for 41 products. It sets minimum domestic value addition of at least 90 percent for the two fermentation-based segments and at least 70 percent for the two chemical-synthesis segments [7]. As of that note, the approved applications totaled 50 applicants with committed investment of Rs 4,498.38 crore [7].<\/p>\n\n\n\n

                What Rating Agencies Report<\/strong><\/h4>\n\n\n\n

                CRISIL reported that KSM and drug intermediate inventories are large, and that these materials are largely imported [8]. It also reported that new PLI capacity should reduce import dependence for bulk drugs by about one fifth [8]. CareEdge Ratings, quoted by BioSpectrum Asia, said that India still relies on China for more than 50 percent of some critical KSMs, and that the first two PLI rounds had not yet produced encouraging results at the time of its analysis [9].<\/p>\n\n\n\n

                What Does the Japanese DMF Data Show?<\/strong><\/h3>\n\n\n\n

                A published analysis of Japanese DMFs found 3,804 registered DMFs, with 63.46 percent held by foreign manufacturers [10]. The authors also reported that 21 of the 46 drug product shortage problems in FY2013 were associated with API shortage [10]. The data covers API DMFs registered with PMDA, so it is an API indicator. It is not a KSM indicator.<\/p>\n\n\n\n

                What the Numbers Do Not Say<\/strong><\/h3>\n\n\n\n

                Three limits apply. First, the Indian figures cover bulk drugs and intermediates, not each KSM. Second, import dependence for one compound can be far higher or lower than the average. Third, a share of DMFs held abroad says nothing about whether a given supplier is reliable. Use these figures to justify dual sourcing reviews. Do not use them as proof that a single supplier has a given risk.<\/p>\n\n\n\n

                What Happens If You Change a KSM Supplier or Route?<\/strong><\/h2>\n\n\n\n

                A change upstream of the starting material needs an impact assessment, and it may need a regulatory filing. The Q&A says that ICH Q11 does not explicitly cover post-approval changes upstream of the starting material, such as a new route, new reagents, new solvents, or a new supplier [2]. It says that you should apply the Q11 lifecycle concepts to these changes anyway [2].<\/p>\n\n\n\n

                What Must the Assessment Cover?<\/strong><\/h3>\n\n\n\n

                Evaluate the effect on the starting material first. This includes current and new impurities, including mutagenic and elemental impurities. Then evaluate the effect on the drug substance when appropriate. The assessment should include the adequacy of the specification and the ability of the analytical procedures to detect new impurities [2].<\/p>\n\n\n\n

                Who Must Tell Whom?<\/strong><\/h3>\n\n\n\n

                The Q&A cites ICH Q7 Q&A section 13.1: each party in the supply chain must pass quality and regulatory change information to the next customer, so that the drug product manufacturer gets it in time [2]. Changes made upstream of the starting material are managed under the applicant’s pharmaceutical quality system [2]. Changes to filed information on the starting material must be reported under regional rules [2].<\/p>\n\n\n\n

                Scenario Analysis: Three Supplier Changes<\/strong><\/h3>\n\n\n\n

                The scenarios below use assumptions that we state. They are analysis, not regulatory rulings.<\/p>\n\n\n\n

                Scenario<\/th>Assumption<\/th>Likely effect under Q11 and the Q&A<\/th>Source<\/th><\/tr><\/thead>
                A. Second supplier, same route and specification<\/td>The new supplier uses the same synthesis as the first<\/td>Assess impurity profile and specification fit. Regional supplier-change filing rules apply.<\/td>[1][2]<\/td><\/tr>
                B. Same supplier changes its upstream route<\/td>New reagents or solvents upstream of the starting material<\/td>Evaluate new impurities in the starting material. Supplier must notify you.<\/td>[2]<\/td><\/tr>
                C. You redefine the starting material to an earlier compound<\/td>You file a longer process<\/td>You describe more steps under GMP and justify the new material from the start.<\/td>[1][2]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

                One more rule applies to all three. The Q&A says that a starting material accepted for one manufacturer’s process may not be acceptable for another manufacturer’s process if the proposal does not comply with Q11 [2]. A competitor’s accepted KSM is evidence, not a precedent that binds a regulator in your case.<\/p>\n\n\n\n

                Case Study: Applying ICH Q11 Example 4 to a Starting Material Search<\/strong><\/h2>\n\n\n\n

                Q11 Example 4 is fictional, but it shows the decision logic that a sourcing team must follow [1]. The route is linear. A commercially available achiral precursor A reacts with a stereo-selective reagent in step 1 to give compound B. The reaction also forms a small amount of the opposite enantiomer [1].<\/p>\n\n\n\n

                Why Compound A Looks Like the Starting Material<\/strong><\/h3>\n\n\n\n

                Step 1 affects the impurity profile through the enantiomer. By the rule that steps with an impact belong in section 3.2.S.2.2, A would be the starting material [1].<\/p>\n\n\n\n

                Why Compound D Can Be Proposed Instead<\/strong><\/h3>\n\n\n\n

                The example then adds facts. All significant impurities other than the enantiomer arise in steps 4, 5, and 6. Steps 2 and 3 do not affect the impurity profile. The stereocenter is stable in all later steps, and a suitable method can measure the opposite enantiomer in compound D [1]. With these facts, D can be proposed as the starting material, and the enantiomer is controlled by a limit in the specification for D [1]. The Q&A calls this an impurity that “persists” and says it is acceptable to control such an impurity in the starting material specification [2]. The same logic can apply to impurities other than stereoisomers [2].<\/p>\n\n\n\n

                What This Means for Your Supplier Search<\/strong><\/h3>\n\n\n\n

                You would look for a manufacturer of D that can meet an enantiomer limit with a validated method, and that can show that its upstream steps (steps 2 and 3) add no other impurities that affect the drug substance [1][2]. The supplier search follows from the regulatory decision, not the reverse.<\/p>\n\n\n\n

                Timeline: The Documents That Shape KSM Selection<\/strong><\/h2>\n\n\n\n
                Date<\/th>Event<\/th>Source<\/th><\/tr><\/thead>
                April 2012<\/td>ICH Steering Committee endorses Q11 at Step 4<\/td>[1]<\/td><\/tr>
                November 2012<\/td>FDA publishes the Q11 guidance<\/td>[1]<\/td><\/tr>
                September 2014<\/td>CHMP adopts the first EMA reflection paper on starting materials<\/td>[5]<\/td><\/tr>
                December 2016<\/td>CHMP adopts the reviewed reflection paper<\/td>[5]<\/td><\/tr>
                3 July 2017<\/td>EMA issues Corr. 1 of the paper, now marked “no longer valid”<\/td>[5]<\/td><\/tr>
                August 2017<\/td>ICH Assembly endorses the Q11 Q&A at Step 4<\/td>[2]<\/td><\/tr>
                February 2018<\/td>FDA publishes the Q11 Q&A guidance<\/td>[2]<\/td><\/tr>
                October 2019<\/td>FDA issues draft Revision 1 of the DMF guidance<\/td>[3]<\/td><\/tr>
                9 December 2021<\/td>India’s Department of Pharmaceuticals issues a PLI approvals press note<\/td>[7]<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

                Analysis: the Q&A came about 64 months after the original Q11 (April 2012 to August 2017). The EMA paper’s problem statement said that disagreements between applicants and assessors on starting material suitability had become more frequent [5]. That is the gap the Q&A was written to narrow, and the Q&A states its goal as convergence and harmonization [2].<\/p>\n\n\n\n

                What This Means for Generic Developers, Brand Manufacturers, and API Makers<\/strong><\/h2>\n\n\n\n

                What This Means for Generic Developers<\/strong><\/h3>\n\n\n\n

                You must choose a starting material for your own process and justify it. An accepted starting material from the brand’s file does not carry over to your process by default [2]. Build the KSM search into your development plan early, and set the supplier timeline against the patent and exclusivity dates that decide when you can launch.<\/p>\n\n\n\n

                What This Means for Brand Manufacturers<\/strong><\/h3>\n\n\n\n

                Your own file needs the same justification, and your lifecycle plan must cover supplier and route changes upstream of the starting material [2]. Pharmaceutical quality system controls on purchased materials remain your duty even for outsourced steps [2].<\/p>\n\n\n\n

                What This Means for API Makers and Custom Synthesis Firms<\/strong><\/h3>\n\n\n\n

                Your customers need the route flow chart, impurity data, and change notices [2]. If you hold a DMF, you must keep it current, notify authorized parties of changes, and file annual reports [3]. A holder that does not keep the DMF current can have it closed [3].<\/p>\n\n\n\n

                Key Takeaways<\/strong><\/h2>\n\n\n\n
                  \n
                • “KSM” is an industry term. ICH Q11 says “starting material,” and FDA says this is the same material as the ICH Q7 “API starting material” [1][2].<\/li>\n\n\n\n
                • Test each candidate against all Q11 principles. A rationale is required where a principle is not met [2].<\/li>\n\n\n\n
                • Multiple suppliers do not make a custom-synthesized chemical “commercially available” [2].<\/li>\n\n\n\n
                • Q11 gives no minimum number of steps after the starting material. Three steps in Example 4 is not a threshold [2].<\/li>\n\n\n\n
                • FDA reviews a DMF only when an application references it with a letter of authorization, and the letter does not give you access to the file [3].<\/li>\n\n\n\n
                • FDA asks for separate DMFs per process and expects the holder to be the manufacturer, or to take full responsibility for it [3].<\/li>\n\n\n\n
                • Regulator-published lists rank above directories. Directories state that they do not guarantee accuracy or verify IP rights [4][6][13].<\/li>\n\n\n\n
                • India’s PLI scheme covers 41 products with an outlay of Rs 6,940 crore for FY2020-21 to FY2029-30 [7].<\/li>\n\n\n\n
                • The EMA reflection paper on starting materials is marked “no longer valid.” Check current EMA text before you cite it [5].<\/li>\n<\/ul>\n\n\n\n

                  FAQ: Key Starting Materials for Pharmaceutical APIs<\/strong><\/h2>\n\n\n\n

                  1. Can an API be a starting material for another API?<\/strong><\/h3>\n\n\n\n

                  Yes. A chemical that is also an API can be proposed as a starting material, but all of the Q11 general principles still apply to it [2].<\/p>\n\n\n\n

                  2. Does FDA approve a KSM supplier?<\/strong><\/h3>\n\n\n\n

                  No. FDA ordinarily neither independently reviews nor approves DMF submissions. It reviews the technical contents when an application references the DMF [3]. The applicant remains responsible for the quality of purchased materials [2].<\/p>\n\n\n\n

                  3. Does every KSM supplier need a DMF?<\/strong><\/h3>\n\n\n\n

                  No. DMFs are submitted at the holder’s discretion and are not required by statute or regulation. They are not typically submitted for nonproprietary materials [3].<\/p>\n\n\n\n

                  4. Can one DMF cover two manufacturing processes?<\/strong><\/h3>\n\n\n\n

                  FDA asks for separate DMFs for drug substances made by different processes [3]. Match your LOA to the DMF for the process your supplier actually runs for you.<\/p>\n\n\n\n

                  5. How many steps must follow the starting material?<\/strong><\/h3>\n\n\n\n

                  The guidance sets no fixed number. The Q&A says you must describe enough of the process to cover impurity-affecting steps and to reduce risk from contamination and future changes. This often means adding steps when only a few remain [2].<\/p>\n\n\n\n

                  6. Can a CEP replace a starting material justification?<\/strong><\/h3>\n\n\n\n

                  A CEP exists only for substances with a European Pharmacopoeia monograph. EDQM rejects applications for substances that are not in the Ph. Eur. [6]. A starting material with no monograph cannot use this route.<\/p>\n\n\n\n

                  7. How can you tell whether a supplier’s DMF is current?<\/strong><\/h3>\n\n\n\n

                  Check the DMF status on FDA’s list and ask the supplier for its latest annual report and authorized-party list. FDA can close a DMF that is not kept current, and a closed DMF cannot support a new or amended application [3]. Directories show status fields drawn from FDA data, but you should confirm them at the source [12].<\/p>\n\n\n\n

                  8. Who is responsible for KSM quality: you or the supplier?<\/strong><\/h3>\n\n\n\n

                  Both, in different ways. The DMF holder is responsible for the content of the DMF [3]. The pharmaceutical company is ultimately responsible for the quality of purchased materials under ICH Q10 section 2.7 [2].<\/p>\n\n\n\n

                  9. Does a DMF for an intermediate get a GDUFA completeness assessment?<\/strong><\/h3>\n\n\n\n

                  FDA’s page ties the GDUFA fee and completeness provisions to Type II DMFs for APIs that support ANDAs, and it does not mention intermediates in that passage [4]. Ask FDA before you plan around it.<\/p>\n\n\n\n

                  10. Can you still rely on the EMA reflection paper on starting materials?<\/strong><\/h3>\n\n\n\n

                  The version we reviewed (Corr. 1, July 2017) is marked “no longer valid” [5]. Use the ICH Q11 text and the Q&A as the harmonized reference, and check EMA’s current position before you file in the EU [2][5].<\/p>\n\n\n\n

                  References<\/strong><\/h2>\n\n\n\n

                  [1] U.S. Food and Drug Administration. (2012, November). Q11 Development and manufacture of drug substances: Guidance for industry<\/em>. U.S. Department of Health and Human Services. https:\/\/www.fda.gov\/media\/80909\/download<\/p>\n\n\n\n

                  [2] U.S. Food and Drug Administration. (2018, February). Q11 Development and manufacture of drug substances (chemical entities and biotechnological\/biological entities): Questions and answers. Guidance for industry<\/em>. U.S. Department of Health and Human Services. https:\/\/www.fda.gov\/media\/103162\/download<\/p>\n\n\n\n

                  [3] U.S. Food and Drug Administration. (2019, October). Drug master files: Guidance for industry (Draft, Revision 1)<\/em>. U.S. Department of Health and Human Services. https:\/\/fda.gov\/media\/131861\/download<\/p>\n\n\n\n

                  [4] U.S. Food and Drug Administration. (n.d.). Types of drug master files (DMFs)<\/em>. https:\/\/www.fda.gov\/drugs\/drug-master-files-dmfs\/types-drug-master-files-dmfs<\/p>\n\n\n\n

                  [5] European Medicines Agency. (2017, July 3). Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances<\/em> (EMA\/CHMP\/CVMP\/QWP\/826771\/2016, Corr. 1) [Marked “No longer valid”]. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/reflection-paper-requirements-selection-and-justification-starting-materials-manufacture-chemical-active-substances_en.pdf<\/p>\n\n\n\n

                  [6] European Directorate for the Quality of Medicines and HealthCare. (n.d.). Submit a new application<\/em> [Certification of suitability]. https:\/\/edqm.eu\/submit-a-new-application<\/p>\n\n\n\n

                  [7] Government of India, Ministry of Chemicals and Fertilizers, Department of Pharmaceuticals. (2021, December 9). Press note: Approvals accorded under Production Linked Incentive (PLI) scheme for promotion of domestic manufacturing of critical key starting materials (KSMs)\/drug intermediates and active pharmaceutical ingredients (APIs) in the country<\/em>. https:\/\/pharma-dept.gov.in\/sites\/default\/files\/Press%20Note%20PLIBD_0_1.pdf<\/p>\n\n\n\n

                  [8] CRISIL Ratings. (2023, November). Rising volume to lift bulk drug maker revenue 6-8% this fiscal<\/em> [Press release]. https:\/\/www.crisil.com\/content\/crisilratings\/en\/home\/newsroom\/press-releases\/2023\/11\/rising-volume-to-lift-bulk-drug-maker-revenue-6-8percent-this-fiscal.html<\/p>\n\n\n\n

                  [9] BioSpectrum Asia. (2023, August 7). Bulk drug imports from China to stay at alarming 65% despite PLI schemes in India<\/em> [Reporting CareEdge Ratings analysis]. https:\/\/www.biospectrumasia.com\/news\/25\/22848\/bulk-drug-imports-from-china-to-stay-at-alarming-65-despite-pli-schemes-in-india.html<\/p>\n\n\n\n

                  [10] GaBI Journal. (2018, February 10). Analysis of drug master files registered in Japan: Aiming for a stable supply of active pharmaceutical ingredients<\/em>. https:\/\/gabi-journal.net\/?p=4150<\/p>\n\n\n\n

                  [11] DrugPatentWatch. (2026, July 26). Suppliers and packagers for MODEYSO<\/em> [Supplier page]. https:\/\/www.drugpatentwatch.com\/p\/supplier\/MODEYSO\/t<\/p>\n\n\n\n

                  [12] PharmaCompass. (n.d.). Prestwick2_001119: List of drug master files (DMF) submitted to the U.S. FDA<\/em>. https:\/\/pharmacompass.com\/us-drug-master-files-dmfs\/prestwick2-001119<\/p>\n\n\n\n

                  [13] Pharmaoffer. (n.d.). Ibandronate sodium monohydrate API manufacturers and suppliers: US-DMF-listed<\/em>. https:\/\/pharmaoffer.com\/api-excipient-supplier\/ibandronate-sodium-monohydrate\/usdmf<\/p>\n\n\n\n

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