The regulatory criteria applied to BDP are very different from those for the manufacture of conventional vaccines, enzymes or other high molecular weight substances such as insulin, heparin and cellular blood components.
The essence of GMP when producing pharmaceuticals is commitment to quality; regardless of the status of the company, its corporate governance or the end product. What''s vital is, that at no time in the process-stream can operations NOT be under absolute control. Quintessentially, that''s what regulatory-compliance is all about.
When applied to biologics, cGMP is product-specific and the focus is to identify and correct non-conforming product quality by heuristic auto-audit regimens. That differentiates the in-process-audits required for conventional products where set procedures and personnel comportment are paramount.
Increasingly, BDP products are processed in closed-loops and are parametric up to the final aseptic sub-division stage. The manner and swiftness with which operational anomalies are detected and corrected, typically denotes the level of quality achievable.
MP mandates begin with the Master Cell Bank (MCB), which holds biologics thatexpress the protein product or monoclonal antibodies of interest. The cell seed lot system is used by manufacturers to assure identity and purity of that starting raw material. A cell seed lot consists of aliquots of a single culture. The MCB is derived from a single colony of bacteria or yeast, or a single eukaryotic cell, stored cryogenically to assure genetic stability and is composed of sufficient ampoules of culture to provide source material for the working cell bank (WCB). The WCB is defined as a quantity of cells derived from one or more ampoules of the MCB, stored cryogenically and used to initiate the production batch.
Because genetic stability of the cell bank during storage and propagation is a major concern, it is important to know the origin and number of passages of both the MCB, and WCB. An ampoule kept frozen or lyophilized can only be used once. Information about the construction of the expression vector, the fragment containing the genetic material that encodes the desired product, and the relevant genotype and phenotype of the host cells are submitted as part of a product application.
The major concerns of cGMP applied to biological systems are genetic stability of cell banks during production, and storage, contaminating microorganisms, and the presence of endogenous viruses in some mammalian cell lines.As part of the application document, manufacturers need to submit a description of all tests performed to characterize and qualify a cell bank. The tests required to characterize a cell bank [see Box] will depend on the intended use of the final product, the host expression system and the method of production including the techniques employed for purification of the product.As technology advances, GMP enjoins both the manufacturers and inspectorate to change the type and sensitivity of tests.
Tests must also show consistency in reproducible production of desired product and nutrient requirements.
Often for complex molecules, the physicochemical information may be extensive, but unable to confirm the higher order structure.However, that can be inferred from biological activity.In such cases, a biological assay with wider confidence limits may be acceptable when combined with a specific quantitative measure. Importantly, a biological assay to measure the biological activity of the product may be replaced by physicochemical tests. But only in those instances where:
- Sufficient physicochemical information about the drug, including higher order structure, can be thoroughly established by such physicochemical methods, and when relevant correlates to biological activity are demonstrated;
- A well-established manufacturing history exists.
Where physicochemical tests alone are used to quantitate the biological activity based on appropriate correlation, results should be expressed in mass.The manufacturer is required to justify the choice of relevant quantitative assay both biological and physicochemical, for the purpose of lot release.
When an antibody is the desired product, its immunological properties are also required to be fully characterized.Binding assays of the antibody to purified antigens and defined regions of antigens are usually performed to determine affinity, avidity, and immunoreactivity including cross-reactivity.In addition, the target molecule bearing the relevant epitope is biochemically defined and the epitope itself defined.
For some drug substances and drug products, the protein molecule may need to be examined using immunochemical procedures (e.g. ELISA, Western Blot) utilizing antibodies that recognize different epitopes of the protein molecule.Immunochemical properties of a protein may serve to establish its identity, homogeneity, or purity, or serve to quantify it.
When immunochemical properties constitute lot release criteria, all relevant information pertaining to the antibody is required to be made available.
The US Food and Drug Administration (FDA) has a draft guidance ''Q6B Specifications: Test procedures and Acceptance Criteria for Biotechnological / Biological Products, proposed under the auspices of the International Conference on Harmonisation (ICH) on Technical Requirements for Registration of Pharmaceuticals for Human Use.This outlines general principles for the selection of test procedures and the setting and justification of acceptance criteria for BDP and international specifications to support new marketing applications.
Those specifications are seen as the edifice for a total control strategy designed to ensure product quality and consistency.Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization.The GMP focus is on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product.
- GMP when applied to proteins and polypeptides, their derivates and products of which they are components (e.g. conjugates);and those that are produced from recombinant or non-recombinant cell-culture expression systems are highly purified and characterized. Standard analytical procedures include:
- Characterization of a biotechnological or biological product comprising the determination of physicochemical propertiesn Biological activityn Immunochemical propertiesn Purity and Impurities.Besides those, additional SOPs are necessary for physicochemical characterization that determines of the composition, physical properties, and primary structure of the desired product.
In some cases, information regarding higher-order structure, the fidelity of the final product is generally inferred by its biological activity that may be determined by appropriate methodologies.For instance, the manufacturer should define the pattern of heterogeneity of the desired product and demonstrate consistency with that of the lots used in preclinical and clinical studies.If a consistent pattern of product heterogeneity is demonstrated, an evaluation of the activity, efficacy, and safety or immunogenicity of individual forms may not be necessary.
Heterogeneity can also be produced during manufacture and during storage of the drug substance or drug product.Since the heterogeneity of these products defines their quality, the degree and profile of this heterogeneity should be characterized to ensure lot-to-lot consistency. When these variants of the desired product have properties comparable to those of the desired product with respect to activity, efficacy and safety, they are considered product-related substances.When process changes and degradation products result in heterogeneity patterns that differ from those observed in the material used during preclinical and clinical development, the significance of these alterations should be evaluated and definitive SOPs evolved and regularly tracked.
New analytical technology and modifications to existing technology are continually being developed. cGMP requires that such technologies be utilized when appropriate.
Although products regulated by FDA as biological products must also meet drug or device requirements, in the US, that agency does not require duplicate premarket approvals.For example, if FDA requires a Product License Agreement (PLA) to be submitted for the product as a biologic, the agency does not also require submission of a New Drug Application (NDA) or a device Premarket Approval Application (PMA).
Their statutory provisions governing biologics and drugs require interstate commerce nexus.That is created in various ways.For example, even if a biological drug product is manufactured entirely with materials that have not crossed State lines, transport of the product into another State by an individual patient creates the interstate commerce nexus.
Some products may contain a combination of biological products and drugs or devices. Under a provision of the Safe Medical Devices Act of 1990, US FDA determines the primary mode of action of the combination products (21 U.S.C. 353(g)).They then assign the primary jurisdiction for review of the product within the agency based on that determination. They have established procedures for designating the organisation, i.e. the Centre for Biologics Evaluation and Research (CBER), the Centre for Drug Evaluation and Research (CDER) or the Centre for Devices and Radiological Health (CDRH) to review combination products or any other products where the agency''s primary jurisdiction is unclear.
Considered as BDP, from a regulatory perspective, we must now touch upon:
- Somatic cell therapy
- Cellular products
- Gene therapy
Somatic cell therapy products are defined as autologous (i.e. self) , allogeneic (i.e. intra-species), or xerogeneic (i.e. inter-species). These are cells that have been propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics ex vivo to be administered to humans and applicable to the prevention, treatment, cure, diagnosis, or mitigation of disease or injuries. Cellular products intended for use as somatic cell therapy are biological products subject to regulation pursuant to the PHS Act (42 U.S.C. 262) and also fall within the definition of drugs in the act (21 U.S.C. 321 (g)). As biological products, somatic cell therapy products are subject to establishment and product licensure to ensure product safety, purity and potency.At the Investigational stage, these products must be in compliance with part 312.Clinical trials are, therefore, to be conducted under IND''s. As drugs, somatic cell therapy products are also subject to drug requirements such as conformity with cGMP regulations.
Gene therapy products contain genetic material administered to modify or manipulate the expression of genetic material or to alter the biological properties of living cells.Some gene therapy products e.g. those containing viral vectors, to be administered to humans fall within the definition of biological products and are subject to the licensing provisions of the PHS Act, as well as to the drug provisions of the act.Other gene therapy products, such as chemically synthesized products, meet the drug definition but not the biological product definition, and are regulated under the relevant provisions of the act only.
Biological products intended for use as source materials for further manufacture into licensed somatic cell therapy products or gene therapy products require premarketing approval as `biological products intended for further process'' when they are shipped from one legal entity to another.
Combination products, for which the primary mechanism of action is that of the somatic cell therapy component, are regulated as biological products.Many somatic cell products administered to patients will be combinations of a biological product, and a device or of a drug, some examples being 1) Encapsulated pancreatic islet cells secreting insulin, and 2) A device containing encapsulated cells secreting a neurotransmitter.
Ancillary products used during production also include:
- Bioreactors and cell culturing systems · Components of culture media
- Drug or biologic-like components used to activate or otherwise change thebiological characteristics of the cells · Certain antisense polynucleotidesand
- Agents used to purge, select, or stimulate specific cell populations.
A common characteristic of these products is that they are intended to act on the cells, rather than to have an independent effect on the patient.That is why, they are regulated by different arms of the FDA, e.g. CDRH oversees the approval of bioreactors ! !
- Source: Centre for Advancement of Pharmaceutics, Klenzaids Academy.