Introduction
An “animal-free” process does not contain any raw materials, starting materials, components or agents derived from animals. A “TSE-risk-free” process does not contain any raw materials, starting materials, components or agents derived from animals known to be susceptible to Transmissible Spongiform Encephalopathy (TSE) agents.
When an API process or processing work centre is converted to animal-free or TSE-risk-free status, the following process elements should be assessed and shown to be consistent with these definitions: master and working cell banks or biologic seeds, process materials and recycle streams, equipment cleaning, process aides (e.g resins), process seeding and solvent recovery.
Practice
For a process, process work center or process product to be considered “animal-free” or “TSE-risk-free” all elements of the process must be animal-free or TSE-risk-free according to the following definitions and requirements:
- Master and Working Cell Banks and Biologic Seeds – For master and working cell banks and biologic seeds to be animal-free or TSE-risk-free, those containing animal-derived materials should be recreated such that all animal-derived or all TSE-risk materials either are removed or are replaced with non-animal or non-TSE-risk counterparts.
Alternatively, the master and working cell banks and biologic seeds can be considered to have minimal TSE-risk if they are compliant with the European Medicine Agency’s “Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 Rev.2 – October 2003)” or its current equivalent. Compliant cell banks and seeds must have been created and described in a marketing authorization that was approved prior to 1 July 2000 for human health products or prior to 1 October 2000 for animal health products.
Alternatively, a marketing authorization holder can demonstrate compliance to the note for guidance by updating affected EU marketing authorizations individually with TSE-risk information or with an EP Certificate of Suitability for TSE compliance (TSE-CEP).
- Process Materials and Recycle Streams – All starting materials, raw materials, solvents, recycle streams, process aides, enzymes, cells or cell extracts, heels, tag ends, crystallization seeds, etc., must be defined to be of animal-free or TSE-risk free origin for an intermediate or API lot to be considered animal-free or TSE risk-free.
- Animal-free or TSE-risk-free process intermediate or API lots are considered different grades of material from their non-animal-free or non-TSE-risk-free counterparts and must be segregated and identified as animal-free or TSE-risk-free.
- Recycle streams such as mother liquors, filtrates, distillates, filter heels, or tag ends of lots must be animal-free to be added into an animal-free process. If an animal-containing material is added into an otherwise animal-free or TSE-risk-free process, the resulting lot must be considered animal-containing.
- Unless it is planned to retain a legacy animal-containing process in parallel with its animal-free or TSE-risk-free counterpart, legacy process recycle materials should be used up or destroyed upon conversion of a process to animal-free or TSE-risk-free status. If parallel manufacturing is planned, such legacy process materials must be clearly identified or segregated as not animal-free or not TSE-risk-free.
- Animal-free or TSE-risk-free lots may be reprocessed or reworked without jeopardizing their status so long as all elements of the reprocess or rework procedure meet the animal-free or TSE-risk-free criteria described in this bulletin. However, it is not possible to reprocess or rework a non-animal free lot or a non-TSE-risk-free lot to achieve animal-free or TSE-risk-free status.
- Equipment Cleaning – For an intermediate or API lot to be considered animal-free or TSE-risk-free, equipment product contact surfaces must be cleaned to prevent carryover of the previous product into the subsequent product. The equipment cleaning requirements and limits defined in the site guidelines should be followed.
- Cleaning procedures should be demonstrated to be effective.
- For multi-purpose equipment or work centers, the normal process changeover cleaning procedures define “clean.”
- For dedicated equipment or work centers, the normal cleaning requirements for cleaning between lots or between grades (e.g. Ag Grade to Rx Grade) define “clean.”
- Equipment, piping, tanks, etc. that are not product contact surfaces, but come in contact with animal-derived raw materials should be cleaned according to standard procedures prior to use in animal-free processing.
- A serial dilution approach may be used for bulk storage tanks, transfer lines and process systems that are difficult to clean and/or contain hazardous materials. The contents of such systems are considered to be animal-free or TSE-risk-free when the amount of remaining non-animal free or non-TSE-risk-free material is calculated to be NMT 25ppm. The next lot made after the bulk tank or system is animal-free is considered animal-free.
- When a change-out between the legacy animal-containing and the animal free or TSE-risk-free materials occurs, the product contact surfaces of the vessel, column, or apparatus that holds the aide or component must be cleaned to appropriate levels of residual product before introducing the animal-free or TSE-risk-free component or aide.
- Process Seeding – Crystal seed stocks used in animal-free or TSE-risk-free processes must be of animal-free or TSE-risk-free origin, respectively.
- For processes where seeding is optional, it should be omitted from use in the first lot of an animal-free or TSE-risk-free campaign. A portion of this first lot should be retained for future use as an animal-free or TSE-risk free seed.
- For processes requiring seeding, the first consideration should be to produce an animal-free or TSE-risk-free seed in a GLP laboratory or GMP pilot plant.
- If it is impractical to produce an animal-free or TSE-risk-free seed outside of the commercial process environment, it is acceptable to use a serial dilution approach in which seed stocks of ever decreasing content of legacy animal-derived or TSE-risk materials are produced from successive lots of an otherwise animal-free or TSE-risk-free manufacturing campaign. At the point a manufacturing lot is calculated to have NMT 25ppm of the original animal-derived seed, an animal-free or TSE-risk-free seed can be generated. The next lot produced using the animal-free or TSE-risk-free seed may be identified as animal-free or TSE-risk-free.
- Recovered Solvents – Solvent recovery methods to produce solvents for process specific or general reuse must be robust to separate other solvent components and solids from the recovery stream (e.g. multiple plate or packed distillation columns). The recovered solvent should contain NMT 25ppm dissolved solids to be considered animal-free or TSE-risk-free. This requirement should also be applied to solvents recovered off-site or obtained from suppliers who use waste solvents as feed stocks.
Discussion and Recommendations
Animal-derived materials are used in the manufacture of many Site APIs intermediates, and drug products. Many of these animal-derived materials are of ruminant origin. Ruminants and several other species have been shown to be susceptible to a number of transmissible spongiform encephalopathies (TSE) agents that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in deer, elk and other cervids. Humans are also susceptible to certain TSE agents including sporadic Creuzfeldt-Jakob Disease (sCJD) and variant Creuzfeldt-Jakob Disease (vCJD). There is convincing evidence that vCJD in humans is caused by the same agent responsible for BSE in cattle. Cases of BSE in cattle have been documented in Europe, Asia, and North America, including a case in the US. Consequently, world health authorities have placed ever more stringent control on the sourcing of food and drugs produced from bovine tissues or bovine-derived materials.
Where possible animal-derived materials used in the production of APIs or drug products should be eliminated or replaced with equivalent materials of non-animal origin. For some APIs and products this will not be possible because they are derived from animal tissues (e.g. Heparin, ATGAM) or because no acceptable non-animal source or substitute exists. In the latter case, any bovine derived materials should be sourced from countries without documented cases of BSE.
Introduction of processes that are free of animal-derived materials or that are performed using animal-derived materials from selected sources poses logistics issues for tracking and segregation of inventories of intermediates and APIs. All aspects of API manufacturing must be taken into consideration. These include master and working cell banks and biologic seeds, operations, equipment cleaning, use of seed crystals, reuse of process aides and components (e.g., resins and membranes), and recycled or recovered materials.
During the transition to animal-free or TSE-risk-free processing, it is likely that the site will need to switch back and forth between animal-free or TSE-risk-free and legacy animal containing processes. The practices described here are intended to define how such switches should be done. These practices should only be applied to situations where there is no “documented risk of TSE contamination.” “Documented risk of TSE contamination” is communication from a supplier or other reputable source that a process material is understood or presumed to be produced or is contaminated with tissues or fluids from TSE-infected individuals (ovine, bovine, human, etc.). The fact that a process material is produced from tissues or fluids of TSE-susceptible species and originates from a country having confirmed cases of TSE is not considered to be a “documented risk of TSE contamination.”
Master and Working Cell Banks and Biologic Seeds
Changes to these elements of a process can have significant implications for the quality and quantity of the product produced. To a limited extent world health authorities realize this. Correspondingly, the European Medicines Agency (EMEA) considers certain master and working cell banks and biologic seeds reviewed and approved by a competent EU health authority to be in compliance with the EU “Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products –Revision 2.” The compliant cell banks and biologic seeds must have been created and described in a marketing authorization that was approved prior to 1 July 2000 for human health products or prior to 1 October 2000 for animal health products. Alternatively, a marketing authorization holder can demonstrate compliance to the note for guidance by updating affected EU marketing authorizations. One mechanism is to obtain an EP Certificate of Suitability for TSE compliance (TSE-CEP) for the API and file this as a variation to marketing authorizations. Many Site cell banks and biologic seeds are covered by TSE-CEPs for APIs or only utilize animal-derived materials that are exempted under the note for guidance. Nevertheless, it is recommended that when and where possible new cell banks and biologic seeds be created without the use of animal derived materials.
Process Materials and Recycle Streams
API manufacturing sites must have in place a materials control system that allows for the identification, tracking, and segregation of animal-free or TSE-risk-free materials from their legacy animal-derived counterparts. When a process or process work center is converted to animal-free or TSE-risk-free processing, only animal-free or TSE-risk-free starting materials, raw materials, solvents, recycle streams, process aides, enzymes, cells or cell extracts, heels, tag ends, crystallization seeds, etc. are to be used. Because many API processes recycle mother liquors, filtrates, distillates, filter-heels, or tag-ends of lots, upon conversion to animal free or TSE-risk-free processing, such legacy process materials must be strictly controlled and prevented from commingling with their counterparts in the animal-free or TSE-risk free process. If an animal-containing material is used in an otherwise animal-free lot, the resulting lot is considered to be animal-derived. Such legacy materials cannot be used into animal-free processes by applying a dilution strategy. To do so would be considered adulteration; the intent is clearly different than the applications of dilution strategies described elsewhere in this bulletin. It is recommended that legacy process recycle materials be tightly controlled to prevent unplanned commingling with otherwise animal free materials. Alternatively the legacy process materials should be destroyed unless it is planned to maintain both the legacy and the animal-free or TSE-risk-free processes.
Animal-free or TSE-risk-free lots may be reprocessed or reworked without jeopardizing their status so long as all elements of the reprocess or rework procedure meet the animal free or TSE-risk-free criteria described in this bulletin. However, it is not possible to reprocess or rework a non-animal-free lot or a non-TSE-risk-free lot to achieve animal free or TSE-risk-free status
Equipment Cleaning
The equipment cleaning requirements and limits defined in the site procedure should be applied as long as there is no “documented risk of TSE contamination.” If a “documented risk of TSE contamination” situation were to occur, it should be addressed independently to define cleaning requirements. Normal or routine cleaning used for process changeovers of multi-process product contact equipment or work centres are adequate to support the next lot to be animal-free or TSE-risk-free.
For dedicated equipment or work centers, the normal cleaning requirements between lots or between grades (e.g. Ag Grade to Rx Grade) define “clean.” Equipment, piping, tanks etc. that are not product contact surfaces, but may be used to stage, transport or store animal-derived materials, need to be assessed for removal of the animal-derived materials before they can participate in animal-free or TSE-risk-free processing. In the absence of a “documented risk of TSE contamination” normal cleaning practices should be used.
For dedicated storage tanks or silos that are difficult to clean or contain hazardous materials, an assessment of the serial dilution of existing animal-containing materials with incoming animal-free or TSE-risk-free materials should be made. The storage tank or silo can be declared “animal-free” or “TSE-risk-free” when the legacy animal-derived component is below 25 ppm. If all other inputs into the process are animal-free, the first intermediate or API lot manufactured with this material may also be considered animal free or TSE-risk-free.
Processing Aides or Components
This grouping refers to ion-exchange and chromatography resins, carbon beds, filtration membranes or other elements that may be cleaned or regenerated for use in the next batch of intermediate or API. Generally, these types of materials are either dedicated to a particular process (e.g. ion-exchange and chromatography resins and filtration membranes) or are discarded as single use materials (e.g. carbon, celite, and other filtration and purification aids).
Because of the inherent difficulty to establish cleaning procedures and/or cleaning verification tests for such materials, it is recommended that where feasible such process components be discarded and replaced with virgin materials at the time of process changeover to animal-free or TSE-risk-free status. To the extent possible process changeover should be timed to the normal or routine replacement of these components. If there are situations during the transition to animal-free or TSE-risk free processing where both legacy animal-containing and animal-free or TSE-risk-free processes must be active, it is recommended that such components be dedicated to the alternate processes. If the resins, filtration membranes, etc. are changed out of common columns, vessels, or apparatus, then the common vessels, columns or apparatus and downstream equipment must be cleaned as per validation requirements.
If neither the discard nor process dedication of reusable aides and components is a desirable approach to the changeover to animal-free or TSE-risk-free processing, it is acceptable to develop cleaning procedures and verification tests. However, this approach should be taken case-by-case and the cleaning limit of 25ppm should be applied to these materials.
Process Seeding
Isolation or purification process steps may utilize seeds from previous batches to induce crystallization. Unless the use of seeds is absolutely required to induce crystallization or to induce the correct crystal form(s) of the product, it should not be practiced during the first lot of an animal-free or TSE-risk-free campaign. An animal free or TSE-risk-free seed can be generated with the first lot and used in subsequent lots or campaigns.
When the use of a seed is required, an animal-free or TSE-risk-free seed should be generated in a GLP laboratory or GMP pilot plant. If this is not feasible or practical, it is recommended that an animal-free or TSE-risk-free seed be prepared in a commercial work centre using a serial dilution approach. All other elements of the process through this point must be documented to be animal-free or TSE-risk-free.
The first lot of an otherwise animal-free or TSE-risk-free campaign is seeded with a legacy animal-containing seed and a new seed is generated from this first lot. This is repeated with successive lots until it is determined that the amount of the original animal-containing seed in a subsequent lot is NMT 25ppm. The NMT 25ppm animal-containing lot is acceptable to produce an animal-free or TSE-risk-free seed, but the lot cannot be declared animal-free or TSE-risk-free because the seed from the previous lot did not meet the NMT 25ppm carryover limit. The first lot made with the animal-free seed can be declared animal-free.
Recovered Solvents
If solvents are recovered on-site or off-site, the recovery process must be robust in separating other solvent components and solids from the recovery stream (e.g. multiple or packed distillation columns). It is expected that the recovered solvents have NMT 25ppm of dissolved solids to be considered to be animal-free or TSE risk-free. This requirement should be applied to solvents from any suppliers who use waste solvent as feedstock. If such suppliers are used, it is recommended that we understand if any of the waste solvent feedstock has had contact with animal and/or TSE risk materials.