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It will be advisable to first prepare SOP for SOP. The following explanatory notes will be useful in preparing SOP for SOP

·                     Design a format for SOP. This will maintain uniformity in writing SOPs

·                     Device a system of assigning number to SOP. This may include a code for the department, activity to which it is related & version. For example, SOP for equipment cleaning in production department may be numbered as PR/EC/01/V1 or PR.EC01.V!

·                     Device a date format. Date format could be: DD/MM/YY or DD/MM/YYYY.
·                     Define elements of SOP, usually the following elements are included in a SOP:
-                      SOP number
-                      Title of SOP
-                      Department
-                      Prepared by, approved by, authorized or issued by:
-                      Purpose/object
-                      Scope
-                      Responsibility
-                      Procedure
-                      References
-                      Distribution

A blank format given on next page may be seen for guidance. It will be useful if a history page has record of revision to that SOP. This page may contain the following information:
-                      Version number
-                      Reasons for revision
-                      Nature of revision
-                       revised by
-                      Retrieval and distribution of obsolete copies (Sharma P.P)


Documentation System and Specifications
1.      All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved and distributed according to written procedures. Such documents can be in paper or electronic form.

2.      The issuance, revision, superseding and withdrawal of all documents should be controlled with maintenance of revision histories.

3.      A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

4.      All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.

5.      When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still readable.

6.      During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

7.      Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

8.      Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically impact on quality. Acceptance criteria should be established and documented for in-process controls.

9.      If electronic signatures are used on documents, they should be authenticated and secure.

Equipment Cleaning and Use Record
1.      Records of major equipment use, cleaning, sanitization and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance.

2.      If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.

Records of Raw Materials, Intermediates, API Labeling and Packaging Materials
1.      Records should be maintained including:
-          The name of the manufacturer, identity and quantity of each shipment of each batch of raw materials, intermediates or labeling and packaging materials for API's; the name of the supplier; the supplier's control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt;
-          The results of any test or examination performed and the conclusions derived from this;
-          Records tracing the use of materials;
-           Documentation of the examination and review of API labeling and packaging materials for conformity with established specifications; and
-          The final decision regarding rejected raw materials, intermediates or API labeling and packaging materials.

2.      Master (approved) labels should be maintained for comparison to issued labels.

Master Production Instructions (Master Production and Control Records)
1.      To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).

2.      Master production instructions should include:
-          The name of the intermediate or API being manufactured and an identifying document reference code, if applicable;
-          A complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics;
-          An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production should be included. Variations to quantities should be included where they are justified;
-          The production location and major production equipment to be used;
-          Detailed production instructions, including the:

(i)     sequences to be followed,

(ii)   ranges of process parameters to be used,

(iii) sampling instructions and in-process controls with their acceptance criteria, where appropriate,

(iv)time limits for completion of individual processing steps and/or the total process, where appropriate; and

(v)   expected yield ranges at appropriate phases of processing or time;
-          Where appropriate, special notations and precautions to be followed, or cross-references to these; and
-           The instructions for storage of the intermediate or API to assure its suitability for use, including the labeling and packaging materials and special storage conditions with time limits, where appropriate.

Batch Production Records (Batch Production and Control Records)
1.      Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to assure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

2.      These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the product code together with the date and time can serve as the unique identifier until the final number is allocated.

3.      Documentation of completion of each significant step in the batch production records (batch production and control records) should include:
-          Dates and, when appropriate, times;
-          Identity of major equipment (e.g., reactors, driers, mills, etc.) used;
-          Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing;
-          Actual results recorded for critical process parameters;
-           Any sampling performed;
-          Signatures of the persons performing and directly supervising or checking each critical step in the operation;
-          In-process and laboratory test results;
-          Actual yield at appropriate phases or times;
-          Description of packaging and label for intermediate or API;
-           Representative label of API or intermediate if made commercially available;
-           Any deviation noted, its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored separately; and
-          Results of release testing.

4.      Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

Laboratory Control Records
1.      Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:
-          A description of samples received for testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing;
-          A statement of or reference to each test method used;
-          A statement of the weight or measure of sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions;
-          A complete record of all raw data generated during each test, in addition to graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested;
-          A record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors;
-          A statement of the test results and how they compare with established acceptance criteria;
-          The signature of the person who performed each test and the date(s) the tests were performed; and
-          The date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

2.      Complete records should also be maintained for:
-          Any modifications to an established analytical method;
-          Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;
-          All stability testing performed on APIs; and
-          Out-of-specification (OOS) investigations.

Batch Production Record Review
1.      Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labeling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.
2.      Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of non-critical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).
3.      All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.
4.      The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company. (ICH Guideline)

Principle: -
Good documentation is an essential part of the quality assurance system and, as such, should exit for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and method of manufactured and control, to ensure that all personal concern with manufacture know what to do and when to do it, to ensure that authorized persons have all the information necessary to decide whether or not to realize a batch of a drug for sale, to ensure the existence of documented evidence, trace ability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of document depend upon the manufacturer

General information
·         Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant part of the manufacturing and marketing authorizations.

·         Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval.

·         Documents should have unambiguous contents: the title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

·         Documents should be regularly reviewed and kept up to date when a document has been revised, a system should exist to prevent inadvertent use of the superseded version superseded documents should be retained for a specific period of time.

·         Documents should not be hand written .Where documents require the entry should be clear, legible and indelible. Sufficient space should be provided for such entries.

·         Any alteration made to a document should be signed and dated: the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

·         Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product.

·         Data (and records for storage) may be recorded by electronic data processing systems or by photographic or other reliable means. Master formulae and detailed standard operating procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods. Only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions: access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by back-up transfer on magnetic tape, microfilm, paper print-outs or other means. It is particularly important that, during the period of retention, the data are readily available.

·         Each specification should be approved, signed and dated, and maintained by quality control, quality assurance unit or documentation center. Specifications for starting materials, intermediates, and bulk, finished products and packaging materials.

Standard operating procedures, specifications and master formulae
Descriptive documents give instructions on how to perform a procedure or a study, or give a description of specifications. The instruction type documents are: standard Operating procedures (SOP); protocols (for validation studies, stability studies, safety studies); and master formulae (manufacturing instructions). Each of these gives instruction on how to perform specific procedures. Specifications describe the required characteristics or composition of a product or material or test. These kinds of documents provide the specific details defining the quality of incoming materials, the quality of the production environment, the quality of the production and control process, and the quality of the final product.

Forms for recording data
Another type of documentation is the form used for recording data as it is taken during the performance of tasks, tests, or events. These are forms (datasheets, or data record forms), reports, batch processing records, and equipment log books. These documents provide the evidence that the raw materials, facility environment, the production process, and the final product consistently meet the established quality requirements.

Identification numbers
There are also the identification systems or codes devised to number and track both information and documents. These are SOP numbers, equipment numbers, form numbers, receiving codes, and batch/lot numbers. These numbering systems should be designed so that procedures, processes and materials can be traced throughout the data records.(Gillian Chaloner-Larsson)

Specification for starting & packaging material
Specifications for starting, primary and printed packaging materials should include, if applicable:
1.      A description of the materials. Including:
(a)    The designated name  and internal code reference:
(b)   The reference, if any, to a pharmacopoeial monograph.
(c)    Qualities and quantitative requirement with acceptance limit;

2.      Depending on the company’s practice other data may be added to the specification such as
(a)    The supplier and the original producer of the materials.
(b)   A specimen of printed materials
(c)    Direction for sampling and testing, or a reference to procedures.
(d)   Storage conditions and precautions.
(e)    The maximum period of storage before re-examination

Packaging material should conform to specifications, and should be compatible with the material and/or with the drug product it contains. The material should be examined for compliance with the specification, and for defects as well as for the correctness of identity markings.

Specification for intermediate & bulk product
Specifications for intermediate and bulk products should be available. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Specification for finished product
Specifications for finished products should include:
(a)    The designated name of the product and the code reference. Where applicable
(b)   The designated name (s) of the active ingredient (s) (if applicable, with the INN(s).
(c)    The formula or a reference to the formula.
(d)   A description of the dosage from and package details.
(e)    Direction for sampling and testing or a reference to producers.
(f)    The qualitative and quantitative requirement, with acceptance limits.
(g)   The storage conditions and precautions, where applicable.
(h)   The self-life

Master formulae and processing instructions
Formally authorized manufacturing formula and processing instructions should exist for each product and batch size to be manufactured. They are often combined in one document.

The Manufacturing formula should include:
(a)                The name of the product, with a product reference code relating to its Specifications.
(b)               A description of the pharmaceutical form, strength of the product and batch size.
(c)                A list of all starting materials to be used, with the amount of each, described using the designed name and a reference which is unique to that material, mention should be made of any substance that may disappear in the course of processing.
(d)               A statement of the expected final yield with the acceptable limits, and of relevant intermediate yield, where applicable.

The processing instructions should include:
(a)    A statement of the processing location and the principal equipment to be used.
(b)   The methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing).
(c)    Detailed stepwise processing instructions (e.g. checks on materials, pretreatment, sequence for adding materials, mixing time, temperatures).
(d)   The instruction for any in-process controls with their limits.
(e)    Where necessary, the requirement for bulk storage of the products. Including the container, labeling and special storage conditions where applicable.
(f)    Any special precautions to be observed.



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