HEALTH (PHARMACEUTICALS - MANUFACTURING)

Health (Pharmaceuticals – Manufacturing)

Negotiating and drafting of agreements, contracts, documents, forms and templates related to contract development and manufacturing organization (CDMO) practice, contract development organization (CDO) practice, contract manufacturing organization (CMO) practice and contract research organization (CRO) practice, such as: analytical services agreement (ASA); biologics contract development and manufacturing agreement (BCDMA); biotechnology commercialization agreement (BCA); confidentiality agreement (CA) – bilateral, unilateral, three-way; contract development agreement (CDA); contract development and manufacturing agreement (CDMA); contract manufacturing agreement (CMA); contract research agreement (CRA); definitive purchase agreement (DPA); development facility acquisition agreement (DFAA); environmental monitoring services agreement (EMSA); joint research agreement (JRA); letter of intent (LOI); logistics agreement (LA); non-compete agreement (NCA); non-disclosure agreement (NDA); non-interference agreement (NIA); non-solicitation agreement (NSA); manufacturing collaboration agreement (MCA); manufacturing facility acquisition agreement (MFAA); master services agreement (MSA); master supply chain services agreement (MSCSA); memorandum of understanding (MOU); partnership agreement (PA); quality agreement (QA); research facility acquisition agreement (RFAA); sterility assurance services agreement (SASA); strategic manufacturing services agreement (SMSA); strategic partnership agreement (SPA); strategic supply agreement (SSA); supply chain services agreement (SCSA); toll processing agreement (TPA).

Compliance with Federal agencies, codes, guidance documents, guidelines, international agreements, laws, regulations, rules, statutes and treaties for CDMO, CDO, CMO and CRO practice, such as the: 1935 National Labor Relations Act (NLRA); 1964 Civil Rights Act (CRA); 1986 and 1988 Anti-Drug Abuse Acts (ADAAs); 1992 Medical Device Amendments (MDA); 1992 Prescription Drug Amendments (PDA); 2007 Food and Drug Administration Amendments Act (FDAAA); 2017 FDA Reauthorization Act (FDARA); 21st Century Cures Act (TFCCA); Americans with Disabilities Act (ADA); Animal Drug Availability Act (ADAA); Animal Drug User Fee Act (ADUFA); Animal Medicinal Drug Use Clarification Act (AMDUCA); Best Pharmaceutical for Children Act (BPCA); Biologics Price Competition and Innovation Act (BPCI); Biomedical Advanced Research and Development Authority (BARDA); Bioterrorism Act (BA); Code of Federal Regulations (CFR) Section 21; Controlled Substances Act (CSA); Controlled Substances Import and Export Act (CSIEA); Dietary Supplement and Nonprescription Drug Consumer Protection Act (DSNDCPA); Dietary Supplement Health and Education Act (DSEA); Drug Price Competition and Patent Term Restoration Act (DPCPTRA); Drug Quality and Security Act (DQSA); Fair Packaging and Labeling Act (FPLA); Family and Medical Leave Act (FMLA); FDA Export Reform and Enhancement Act (FDAEREA); FDA Food Safety Modernization Act (FDAFSMA); Federal Advisory Committee Act (FACA); Federal Anti-Tampering Act (FATA); FDA Office of General Counsel (FDAOGC); Food, Drug, and Cosmetic Act (FD&CA); Federal Trade Commission Act (FTCA); Food and Drug Modernization Act (FDAMA); Food Quality Protection Act (FQPA); Generic Animal Drug and Patent Term Restoration Act (GADPTRA); Government in the Sunshine Act (GSA); Health Insurance Portability and Accountability Act (HIPAA); Medical Device User Fee and Modernization Act (MDUFMA); Minor Use and Minor Species Animal Health Act (MUMSAMA); Trademark Act (TA); National Environmental Policy Act (NEPA); National Institutes of Health (NIH); Nutrition Labeling and Education Act (NLEA); Occupational Safety and Health Act (OSHA); Orphan Drug Act (ODA); Over-the-Counter Monograph Safety, Innovation, and Reform Act (OTCMSIRA); Pediatric Research Equity Act (PREA); Prescription Drug Marketing Act (PDMA); Project Bioshield Act (PBA); Safe Medical Devices Act (SMDA).

In general, a CDMO is a type of development and manufacturing company (which may be a non-specialized full-service company, producing any product related to the pharmaceutical industry, from drugs to medical devices to transdermal patches, or it may be a highly-specialized company, which may produce only one type of drug or device) within the pharmaceutical industry, which provides complete drug development and manufacturing services, and usually the large sponsor pharmaceutical companies will partner with CDMOs (whether within the United States or in foreign jurisdictions) to outsource the complete development and manufacturing of any type of drug (whether a branded drug with a large commercial market, or down to a very specialized orphan drug with hardly any commercial market) or device.

A few CDMOs attempt to position themselves as partnership manufacturing and development organizations (PDMOs), by supposedly sharing funding costs, liabilities and risks with small-cap or mid-cap sponsor pharmaceutical companies.

Some CDMOs may have extremely-specialized chemistry, manufacturing and controls (CMC) teams to focus on biologics and small molecule pharmaceutical development and manufacturing services, with common technical document (CTD) support for regulatory filings.

A CDMO extends the limited functions performed by either a contract development organization (CDO) – which generally just performs development services for a proposed new drug or medical device to determine its efficacy and likelihood for approval – or a contract manufacturing organization (CMO) – which generally just manufactures copies of a final product that has already been tested and approved – in that the CDMO may theoretically attempt to engage in a long-term strategic relationship with the sponsor through the entire drug discovery and development cycle – a/k/a research and development, or R&D; preclinical research; clinical research; FDA review; FDA post-safety monitoring) and medical device development, through all regulatory approvals, and should then finally manufacture copies of the final product post-approval.

A sponsor may engage a contract research organization (CRO) to perform both drug discovery (first stage) and drug development (second stage) and clinical trials to determine the efficacy of a new device or drug, but some CDMOs may also be capable of performing such services for the sponsor, and there are also some specialized CDMOs which concentrate only on the development and manufacturing of active pharmaceutical ingredients (APIs) – those ingredients in a drug product that result in the anticipated performance of that particular drug product – for later production of an approved drug product by the sponsors or other CDMOs.

End-to-end CDMOs (a/k/a fully-integrated CDMOs – those which attempt to perform all phases of developing and manufacturing) may offer a wide range of services to the large sponsor pharmaceutical companies, to assure a turnkey experience when bringing a new device or drug to market, such as: analytical services (problem-solving and testing of various characteristics of the product, such as adhesion, component strengthor solubility); aseptic manufacturing; assembly; blending and mixing; bio analysis (such as for: biomarkers; clinical bioanalysis; discovery support; preclinical bioanalysis); assistance with the design and modeling of the device or formulation (through in-house laboratory services) of the drug; biologics development; biosimilars development; bulk manufacturing; cell therapy development; clinical logistics (such as for: coating; converting; documentary support (such as for: liaison support for regulatory audits, hearings and investigations; document submissions; writing scientific reports, quality verification and regulatory submissions); drug product and substance current good manufacturing practices (cGMPs) manufacturing; drug product and substance formulation development; drug product and substance analytical development; drug product labeling, packaging and supply; drug substance characterization (such as for molecular properties; molecular structure confirmation; powder properties; solid state properties); drug substance process development (such as for: crystallization process development; process scale up; route scouting); drug product and substance quality control; drug product and substance stability studies; early formulation development; gene therapy development; logistics; method development; monoclonal antibodies development; nanomedicine development (including the use of nanoscale and nanostructured materials); packaging; pre-formulation; registration batches; serialization (assigning unique markings to each out-going package for tracking purposes); shipment; solid form screening; solid form selection; solid state research (such as for: crystal structure by x-ray; intellectual property – IP – support for patent application filing and relevant IP portfolio management).

If a sponsor pharmaceutical company seeks to engage a CDMO, the sponsor pharmaceutical company must consider several factors, such as the: agility of the proposed CDMO to adapt rapidly to changing market or supply conditions, or to new instructions from the sponsor (for example, if the proposed CDMO and a very top-heavy management structure, it may take a lengthy period of time for the proposed CDMO to accept and approve new instructions from the sponsor regarding changes in the development and manufacturing process mandated to the sponsor by the FDA); alignment of the capabilities and size of the proposed CDMO manufacturing equipment and facilities, as well as the expertise of the CDMO personnel with the scale of the project proposed by the sponsor; availability of the CDMOs personnel and resources throughout the contract term, to complete all tasks on schedule and within budget; confidentiality track record of the CDMO personnel; cultural compatibility (whether the management and personnel of the sponsor and CDMO mesh efficiently); demonstrated competent scientific thought processes in all investigation and validation records; experience at all stages of the drug manufacturing process, including the biologics license application (BLA), investigational new drug application (IND) and new drug application (NDA) for achieving the orphan-drug designation from the Federal Food and Drug Administration (FDA) through the use of the Form FDA 4035, thus granting the drug sponsor a shortened regulatory process, but which the CDMO must guaranty will occur without any decrease in current good manufacturing practices (cGMP) whatsoever; location of the proposed CDMO facilities which will perform the development and manufacturing functions (for example, if such facilities are located in a foreign jurisdiction, the CDMO should provide the sponsor with guarantees that the highly-specialized process of developing and manufacturing the proposed orphan drug will be carried out pursuant to the most-stringent United States laws, and would thus be accepted by the FDA at the end of the process); the regulatory track record and reputation of the proposed CDMO with past projects, regarding approvals of the final product with all applicable regulators; and, the CDMO’s supply chain (whether such CDMO supply chain has: a business continuity plan – BCP – that anticipates foreseeable production disruptions; an experienced and proficient sourcing center of excellence – CoE; competitive bulk and unit pricing costs; excellent bargaining power; flexible transportation alternatives; global vendors for materials sourcing; a robust risk avoidance and mitigation plan; state-of-the-art inventory management processes and systems; timely support and transparency in providing any and all information in the CDMO’s possession regarding confidential information about the chemistry, manufacturing and controls (CMC) related to an API, if the sponsor voluntarily submits drug master files (DMFs) to the FDA in the required electronic common technical document (eCTD) format, which may then be used by the sponsor to support an abbreviated new drug application (ANDA), an investigational new drug (IND) application, a new drug application (NDA), or some other type of DMF (Type I is no longer accepted by the FDA for new filings, but old Type I’s that are still relevant are still kept on file at the FDA; Type II is the current most-common DMF, covering drug preparation materials, drug products, drug substance intermediates and drug substances; Type III includes everything involved with packaging materials and their manufacture; Type IV covers excipients – inert substances used as a diluent or vehicle for a drug, such as binders, cellulose, starch; Type V includes any technical information not covered in the other Types); and, well-established relationships with reputable air, land and sea transportation providers).

When considering whether to engage a CDMO that specializes in medical devices, a medical device original equipment manufacturer (OEM) should consider whether such CDMO has attributes similar to those required for a pharmaceutical CDMO, and also: a continuous quality assurance and quality control (QAQC) program; engineering expertise relevant to the specific type of device to be produced; expertise in procuring the specific type of materials and technology required to produce the medical device; expertise in the specific type of medical device to be produced; lean manufacturing practices (such as espoused by Six Sigma); a positive industry reputation and track-record; a robust risk avoidance and mitigation plan; a strong R&D capabilities for the specific type of medical device to be produced; and, turnkey manufacturing capabilities.

A sponsor pharmaceutical company may engage a specialized CDMO as a cost-effective method for developing and managing the production of orphan drugs (those aimed at the cure or treatment of extremely rare diseases, which cost large sums of money to produce but have little or no general commercial value to pharmaceutical companies because there are so few patients who may ever use such orphan drugs, although the Orphan Drug Act provides incentives for the pharmaceutical companies to produce such orphan drugs).

Some of the current challenges to the proliferation of CDMOs may be factors such as: decreasing branded drug prices due to pressure from generics; merging of large pharmaceutical companies (thus reducing duplicity in operations and providing expanded R&D facilities through consolidation of operations, resulting in a general decrease in outsourcing opportunities for CDMOs); price instability due to the pandemic; restrictions on global exports and imports (both regulatory and circumstantial – such as the current supply chain crisis); transportation disruptions due to the pandemic; working from home due to the pandemic.

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